Indian Patents
Title of Invention

SULFONAMIDE COMPOUND
Abstract A compound represented by the formula (1) [A represents a nitrogen-containing saturated ring; m represents an integer of O to 2; n represents an integer of 1 to 4; G1 represents hydrogen atom, chlorine atom, hydroxyl group, an alkoxy group, or amino group; G2 represents a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl group, an alkenyl group, and the like; G3 represents hydrogen atom, a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl group, an alkenyl group, and the like; G4 represents hydroxyl group, or -N(R1)(R2) (R1 and R2 represent hydrogen atom, an alkyl group, an aralkyl group, an alkenyl group, an alkynyl group, or a saturated heterocyclic group); G5 is a substituent on a ring-constituting carbon atom of A, and represents hydrogen atom, fluorine atom, or an alkyl group] or a salt thereof, or a derivative thereof that is a prodrug, which potently inhibits phosphorylation of the myosin regulatory light chain.
Full Text SPECIFICATION
Sulfonamide Compound
[0001]
Technical Field
The present invention relates to a novel sulfonamide compound or a salt
thereof, or a derivative thereof useful as a prodrug. The present invention also
relates to a medicament comprising said novel sulfonamide compound or a salt thereof,
or a derivative thereof which is a prodrug as an active ingredient.
Background Art
[0002]
Movements of cells include contraction, migration, release, aggregation and
the like, and phosphorylation of the myosin regulatory light chain is important for
these cell movements. The myosin regulatory light chain is a subunit having a
molecular weight of 20 kDa and constituting myosin, which exists in smooth muscle
cells and various non-muscle cells such as neutrophils, platelets and nerve cells of
warm-blooded animals (Barany, K., et al., Biochemistry of Smooth Muscle Contraction,
pp.21-35, 1996). Myosin existing in smooth muscle cells and various non-muscle cells
such as neutrophils, platelets and nerve cells of warm-blooded animals is constituted
by a myosin heavy chain subunit having a molecular weight of about 200 kDa, the
myosin regulatory light chain subunit having a molecular weight of about 20 kDa, and
a myosin constitutive light chain subunit having a molecular weight of about 17 kDa.
[0003]
The myosin regulatory light chain is mainly phosphorylated by the myosin
light chain kinase to increase the activity of myosin ATPase existing in the myosin
heavy chain subunit (Barany, M., et al., Biochemistry of Smooth Muscle Contraction,
pp.321-339, 1996). It is known that the activated myosin having the increased
ATPase activity becomes possible to interact with actin and activates movement
apparatuses of cytoskeleton to activate cell movements. That is, it is known that
activation of myosin relates to cell contraction (Kamm, K., et al., Annu. Rev. Physiol.,
51, pp.299-313, 1989). It is also known that activation of myosin relates to change of
cell morphology (Schmidt, J.T. et al., J, Neurobiol., 52 (3), pp.175-188, 2002). It is
known that activation of myosin relates to cell migration (Niggli, V., FEBS Lett., 445,
1

pp.69-72, 1999). Further, it is known that activation of myosin relates to cell release
(Kitani, S., et al., Biochem. Biophys. Res. Commun., 183, pp.48-54, 1992). It is
further known that activation of myosin relates to cell aggregation (Itoh, K., et al.,
Biochim. Biophys. Acta., 1136, pp.52-56, 1992). It is also known that activation of
myosin relates to cell apoptosis (Mills, J.C. et al., J. Cell Biol., Vol. 140, No. 3,
pp.627-636, 1998). Based on these findings, it is considered that an agent which
inhibits the phosphorylation of the myosin regulatory light chain suppresses cell
contraction, regulates change of cell morphology, suppresses cell migration, suppresses
cell release, suppresses cell aggregation and suppresses cell apoptosis.
[0004]
Cell contraction is deeply involved in diseases relating to contraction of
various smooth muscle layers. Examples of such diseases include, for example,
hypertension (Samlyo, A.P., et al., Rev. Physiol. Biochem. Pharmacol., Vol. 134,
pp.209"34, 1999), angina pectoris (Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4,
pp.1029-39, 1999; Satoh, H., et al., Jpn. J. Pharmacol, 79 (suppl.), p.211, 1999),
cerebral vascular spasm (M. Satoh et al., the 57th General Meeting of Japan
Neurosurgical Society, Collection of Abstracts, 153, 1998; N. Ono et al., Pharmacol.
Ther., Vol. 82, No. 2-3, pp.123-31, 1991; Shimokawa et al., Cardiovasc. Res., Vol. 43, No.
4, pp. 1029-39, 1999), erectile dysfunction (Andersson, KE. et al., World J. Vrol., 15,
pp. 14-20, 1997), bronchial asthma (K. Iidzuka, Allergy, 47, 943, 1998; K. Iidzuka et al.,
Jpn. J. Respirology Society, 37, 196, 1999) and the like.
[0005]
Change of cell morphology is deeply involved in diseases relating to
morphological change of various cells. Examples of the diseases relating to change of
cell morphology include, for example, as those relating to nerve cells of eyes, various
nerve dysfunctions such as diabetic retinopathy, and glaucoma (Arakawa, Y., et al.,
BIO Clinica, 17 (13), pp.26-28, 2002). Further, cell migration is deeply involved in
diseases relating to migration of various cells. Examples of such diseases include, for
example, cancer invasion and metastasis (Itoh, K. et al., Nat. Med., Vol. 5, No. 2,
pp.221-5, 1999; Keely, P. et al., Trends Cell Biol., Vol. 8, No. 3, pp. 101-6, 1998),
nephritis (Fujimoto, O. et al., Journal of Japanese Society of Internal Medicine, 88 (l),
pp. 148-58, 1998) and the like.
[0006]
2

Furthermore, it is considered that cell release is deeply involved in various
allergies and the like (Keane-Myers A. et al., Curr. Allergy Asthma Rep., l(6):550-557,
2001), and further, cell aggregation is considered to be deeply involved in thrombosis
and the like (Nakai, K. et al., Blood, Vol. 90, No. 10, pp.3736-42., 1997). Further, it is
known that cell apoptosis is involved in neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease and glaucoma, viral diseases, hepatic
diseases and the like (Thompson, C.B., Science, Vol. 267, pp. 1456-1462, 1995).
[0007]
Based on these findings, it is considered that a substance having an inhibitory
action on the phosphorylation of myosin regulatory light chain is useful as an active
ingredient of a medicament for prophylactic and/or therapeutic treatment of a disease
relating to cell contraction, disease relating to change of cell morphology, disease
relating to cell migration, disease relating to cell release, disease relating to cell
aggregation, and/or disease relating to cell apoptosis.
[0008]
As agents inhibiting the phosphorylation of myosin regulatory light chain,
isoquinoline derivatives are known. For example, it has been reported that
l-(5-isoquinolinesulfonyl)-2-methylpiperazine (H>7) inhibits the phosphorylation of
myosin regulatory light chain of mesenteric artery (Non-patent document l), and there
are also known drugs inhibiting the phosphorylation of myosin regulatory light chain
of iris smooth muscle (Non-patent document 2), and astrocyte (Non-patent document 3).
Further, 5-substituted isoquinoline derivatives are also known (Patent document 1).
However, the N atom of sulfonamide in these 5-substituted isoquinoline derivatives
does not form a ring, and thus they have a structure different from that of the
compounds of the present invention. Further, tricyclic compounds are also known
(Patent document 2). However, these compounds are tricyclic compounds and do not
have sulfonamide, and therefore they are structurally different from the compounds of
the present invention.
Patent document 1: International Patent Publication No. 2004/009555
Patent document 2: International Patent Publication No. 2004/108724
Non-patent document l: Suzuki, A. et al., Br. J. Pharmacol., 109, pp.703-712, 1993
Non-patent document 2: Howe, P.H. et al., Biochem J., 255, pp.423-429, 1988
Non-patent document 3: Mobley P.L., et al., Exp. Cell Res., 214, pp.55-66, 1994
3

Disclosure of the Invention
Object to be Achieved by the Invention
[0009]
An object of the present invention is to provide a novel substance having an
action of strongly inhibiting the phosphorylation of myosin regulatory light chain.
Another object of the present invention is to provide a medicament comprising a
substance having the aforementioned characteristic as an active ingredient and useful
for prophylactic and/or therapeutic treatment of diseases relating to cell contraction,
diseases relating to change of cell morphology, diseases relating to cell migration,
diseases relating to cell release, diseases relating to cell aggregation, and diseases
relating to cell apoptosis.
Means for Achieving the Object
[0010]
The inventors of the present invention conducted various researches to achieve
the aforementioned objects, namely, they synthesized various sulfonamide compounds
represented by the following formula (l) and studied pharmacological actions thereof.
As a result, they found that these sulfonamide compounds had an action of strongly
inhibiting the phosphorylation of myosin regulatory light chain, and were useful as an
active ingredient of a medicament for prophylactic and/or therapeutic treatment of
diseases in which the phosphorylation of myosin regulatory light chain is involved,
such as diseases relating to cell contraction, diseases relating to change of cell
morphology, diseases relating to cell migration, diseases relating to cell release, and
diseases relating to cell apoptosis. Further, in order to verify applicability of the
aforementioned sulfonamide compounds to specific diseases in which the
phosphorylation of myosin regulatory light chain is involved, they also examined
neutrophil migration inhibitory action and intraocular pressure reducing action of the
aforementioned sulfonamide compounds in animals. As a result, they also found that
the aforementioned sulfonamide compounds had a superior intraocular pressure
reducing action, and were useful also as therapeutic agents of ocular diseases such as
glaucoma. The present invention was accomplished on the basis of these findings.
[0011]
The present invention thus provides the followings.
A compound represented by the following general formula (l) or a salt thereof, or a
4


[in the general formula (l), A represents a nitrogen-containing saturated ring;
m represents an integer of 0, 1, or 2;
n represents an integer of 1, 2, 3, or 4,"
G1 represents hydrogen atom, chlorine atom, hydroxyl group, an alkoxy group, or
amino group!
G2 represents a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl
group which may be substituted, an alkenyl group which may be substituted, an
alkynyl group which may be substituted, an alkoxy group which may be substituted,
an alkylthio group which may be substituted, an amino group which may be
substituted, an alkylsulfinyl group which may be substituted, an alkylsulfonyl group
which may be substituted, or an aryl group which may be substituted;
G3 represents hydrogen atom, a halogen atom, hydroxyl group, cyano group, carboxy
group, an alkyl group which may be substituted, an alkenyl group which may be
substituted, an alkynyl group which may be substituted, an alkoxy group which may
be substituted, an alkylthio group which may be substituted, an amino group which
may be substituted, an alkoxycarbonyl group which may be substituted, an acyl group
which may be substituted, an acyloxy group which may be substituted, an alkylsulfinyl
group which may be substituted, an alkylsulfonyl group which may be substituted, or
an aryl group which may be substituted (provided that G3 substitutes at the 3", 6% 7",
5

or 8-position of the isoquinoline ring);
G4 represents hydroxyl group, or -NCROCR2) (R1 and R2 may be the same or different,
and independently represent hydrogen atom, an alkyl group which may be substituted,
an aralkyl group which may be substituted, an alkenyl group which may be substituted,
an alkynyl group which may be substituted, or a saturated heterocyclic group which
may be substituted); and
G5 represents a substituent on a ring-constituting carbon atom constituting the
nitrogen-containing saturated ring represented by A, and represents hydrogen atom,
fluorine atom, or an alkyl group];
[0012]
The compound or a salt, or a derivative thereof which is a prodrug according to
, wherein m is l;
The compound or a salt, or a derivative thereof which is a prodrug according to
, wherein n is 2 or 3;
The compound or a salt, or a derivative thereof which is a prodrug according to
, wherein G3 is hydrogen atom;
The compound or a salt, or a derivative thereof which is a prodrug according to
, wherein G5 is hydrogen atom! and
The compound or a salt, or a derivative thereof which is a prodrug according to
, wherein G4 is -N(R0(R2).
[0013]
From another aspect, the present invention provides a medicament comprising
a compound represented by the aforementioned formula (l) or a physiologically
acceptable salt thereof, or a derivative thereof which is a prodrug as an active
ingredient. This medicament can be used for prophylactic and/or therapeutic
treatment of a disease relating to cell contraction, disease relating to change of cell
morphology, disease relating to cell migration, disease relating to cell release, disease
relating to cell aggregation, and disease relating to cell apoptosis. The present
invention also provides an inhibitor of the phosphorylation of myosin regulatory light
chain containing a compound represented by the aforementioned formula (l) or a
physiologically acceptable salt thereof, or a derivative thereof which is a prodrug as an
active ingredient.
[0014]
6

From another aspect, the present invention provides use of a compound
represented by the aforementioned formula (l) or a physiologically acceptable salt
thereof, or a derivative thereof which is a prodrug for manufacture of the
aforementioned medicament, and a method for prophylactic and/or therapeutic
treatment of a disease relating to cell contraction, disease relating to change of cell
morphology, disease relating to cell migration, disease relating to cell release, disease
relating to cell aggregation, and disease relating to cell apoptosis, which comprises the
step of administrating a prophylactically and/or therapeutically effective amount of a
substance, for preparation of the aforementioned medicament, which is selected from
the group consisting a compound represented by the aforementioned formula (l), a
physiologically acceptable salt thereof, and a derivative thereof which is prodrug to a
mammal including human.
[0015]
The present invention further provides a medicament comprising a
combination of a substance selected from the group consisting of a compound
represented by the aforementioned formula (l), a physiologically acceptable salt
thereof, and a derivative thereof which is a prodrug, and a drug for combination use.
A medicament based on the aforementioned combination is useful for
prophylactic and/or therapeutic treatment of, for example, disease relating to cell
contraction, disease relating to change of cell morphology, disease relating to cell
migration, disease relating to cell release, disease relating to cell aggregation, and/or
disease relating to cell apoptosis, and it is provided by the present invention.
Best Mode for Carrying out the Invention
[0016]
This application is a patent application claiming the conventional priorities
based on the patent application filed in Japan: Japanese Patent Application No.
2005-248556 (filed on August 30, 2005). The entire disclosures of the specification
and claims of the aforementioned Japanese patent application are incorporated in this
specification as disclosure by reference.
In the specification, unless particularly indicated, examples of the halogen
atom include fluorine atom, chlorine atom, bromine atom, and iodine atom.
Examples of the alkyl group include, for example, a straight, branched, or
cyclic saturated hydrocarbon group, and a saturated hydrocarbon group consisting a
7

combination thereof, and a lower alkyl group is preferred. In the specification, the
term "lower" means that number of carbon atoms constituting a certain functional
group is, for example, 1 to 6. As the lower alkyl group, for example, an alkyl group
having 1 to 6 carbon atoms is preferred, and an alkyl group having 1 to 3 carbon atoms
is particularly preferred. The same shall apply to an alkyl moiety of other
substituents having the alkyl moiety (for example, an alkoxy group and the like).
[0017]
Preferred examples of the alkyl group having 1 to 3 carbon atoms include, for
example, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl
group and the like, and preferred examples of the alkyl group having 4 to 6 carbon
atoms include, for example, n-butyl group, isobutyl group, s-butyl group, t"butyl group,
cyclobutyl group, cyclopropylmethyl group, n-pentyl group, cyclopentyl group,
cyclopropylethyl group, cyclobutylmethyl group, n-hexyl group, cyclohexyl group,
cyclopropylpropyl group, cyclobutylethyl group, cyclopentylmethyl group and the like.
As the alkyl group, for example, methyl group, ethyl group, n-propyl group, and
isopropyl group are particularly preferred.
[0018]
Examples of the alkenyl group include, for example, a lower alkenyl group
containing one or more double bonds and the like, and a lower alkenyl group
containing one double bond is preferred. As the lower alkenyl group, for example, an
alkenyl group having 2 to 5 carbon atoms is preferred, and an alkenyl group having 2
to 4 carbon atoms is particularly preferred. Preferred examples of the alkenyl group
having 2 to 4 carbon atoms include, for example, vinyl group, allyl group, propenyl
group, butylidene group, but"l-enyl group, but"2-enyl group, but"3-enyl group, and the
like, and preferred examples of the alkenyl group having 5 carbon atoms include, for
example, pentylidene group, pent-1-enyl group, pent'2-enyl group, pent"3-enyl group,
pent-4-enyl group, and the like. As the alkenyl group, for example, vinyl group, allyl
group, and propenyl group are more preferred, vinyl group, and allyl group are still
more preferred, and allyl group is particularly preferred. There is also another
embodiment in which vinyl group is particularly preferred.
[0019]
Examples of the alkynyl group include, for example, a lower alkynyl group
containing one or more triple bonds, and the like, and a lower alkynyl group containing
8

one triple bond is preferred. As the lower alkynyl group, for example, an alkynyl
group having 2 to 5 carbon atoms is preferred. Specifically, preferred examples
include ethynyl group, prop-1-ynyl group, prop-2-ynyl group, but"l-ynyl group,
but-2-ynyl group, but"3-ynyl group, pent'1-ynyl group, pent-2-ynyl group, pent-3-ynyl
group, pent-4-ynyl group and the like. Ethynyl group, prop-2-ynyl group, and
but-3-ynyl group are more preferred, ethynyl group, and prop-1-ynyl group are still
more preferred, and ethynyl group is particularly preferred.
[0020]
Examples of the alkoxy group include, for example, a straight, branched, or
cyclic saturated alkyloxy group, and a saturated alkyloxy group consisting a
combination thereof, and a lower alkoxy group is preferred. Examples of the lower
alkoxy group include, for example, an alkoxy group having 1 to 6 carbon atoms, and an
alkoxy group having 1 to 4 carbon atoms is preferred. Preferred examples of the
alkoxy group having 1 to 4 carbon atoms include, for example, methoxy group, ethoxy
group, n-propoxy group, isopropoxy group, cyclopropoxy group, n-butoxy group,
isobutoxy group, s-butoxy group, t-butoxy group, cyclobutoxy group,
cyclopropylmethoxy group, and the like, and preferred examples of the alkoxy group
having 5 or 6 carbon atoms include, for example, n-pentyloxy group, cyclopentyloxy
group, cyclopropylethyloxy group, cyclobutylmethyloxy group, n-hexyloxy group,
cyclohexyloxy group, cyclopropylpropyloxy group, cyclobutylethyloxy group,
cyclopentylmethyloxy group, and the like.
[0021]
Examples of the alkylthio group include, for example, a straight, branched, or
cyclic saturated alkylthio group, and a saturated alkylthio group consisting a
combination thereof, and a lower alkylthio group is preferred. As the lower alkylthio
group, for example, an alkylthio group having 1 to 4 carbon atoms is preferred.
Specifically, preferred examples include methylthio group, ethylthio group,
n-propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group,
isobutylthio group, s-butylthio group, t-butylthio group, cyclobutylthio group,
cyclopropylmethylthio group, and the like.
Examples of the amino group include, for example, -NH2 group.
[0022]
Examples of the alkoxycarbonyl group include, for example, a group consisting
9

of the aforementioned alkoxy group to which carbonyl group is added at the end, and a
lower an alkoxycarbonyl group is preferred. Examples of the lower alkoxycarbonyl
group include, for example, a group consisting of an alkoxy group having 1 to 6 carbon
atoms to which carbonyl group is added at the end, and a group consisting of an alkoxy
group having 1 to 4 carbon atoms to which carbonyl group is added at the end is
preferred. Specifically, preferred examples include methoxycarbonyl group,
ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group,
cyclopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group,
S'butoxycarbonyl group, t-butoxycarbonyl group, cyclobutoxycarbonyl group,
cyclopropylmethoxycarbonyl group, and the like.
[0023]
Preferred examples of the acyl group include, for example, an alkanoyl group
and an arylcarbonyl group. An alkanoyl group is preferred, and a lower alkanoyl
group is more preferred. Examples of the alkanoyl group include, for example, a
straight, branched, or cyclic saturated alkylcarbonyl group, and a saturated
alkylcarbonyl group consisting a combination thereof, and the alkyl moiety may
contain one or more unsaturated bonds. As the lower alkanoyl group, for example, an
acyl group having 2 to 5 carbon atoms is preferred. Specifically, preferred examples
include acetyl group, propanoyl group, butanoyl group, 2-methylpropanoyl group,
cyclopropylcarbonyl group, pentanoyl group, 3-methylbutanoyl group,
2,2-dimethylpropanoyl group, cyclobutylcarbonyl group, and the like.
[0024]
Preferred examples of the acyloxy group include, for example, an alkanoyloxy
group (alkylcarbonyloxy group) and an arylcarbonyloxy group. An alkanoyloxy group
is preferred, and a lower alkanoyloxy group is more preferred. The alkyl moiety of the
alkanoyloxy group may contain one or more unsaturated bonds. As the lower
alkanoyloxy group, for example, an acyloxy group having 2 to 5 carbon atoms is
preferred. Specifically, preferred examples include acetoxy group, propanoyloxy
group, butanoyloxy group, 2-methylpropanoyloxy group, cyclopropylcarbonyloxy group,
pentanoyloxy group, 3-methylbutanoyloxy group, 2,2-dimethylpropanoyloxy group,
cyclobutylcarbonyloxy group, and the like.
[0025]
Preferred examples of the alkylsulfinyl group include, for example, a lower
10

alkylsulfinyl group. As the lower alkylsulfLnyl group, for example, an alkylsulfinyl
group having 1 to 4 carbon atoms is preferred. Specifically, preferred examples
include methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group,
isopropylsulfinyl group, cyclopropylsulfinyl group, n-butylsulfinyl group,
isobutylsulfinyl group, s-butylsulfinyl group, t-butylsulfinyl group, cyclobutylsulfinyl
group, cyclopropylmethylsulfinyl group, and the like.
[0026]
Preferred examples of the alkylsulfonyl group include, for example, a lower
alkylsulfonyl group. As the lower alkylsulfonyl group, for example, an alkylsulfonyl
group having 1 to 4 carbon atoms is preferred. Specifically, preferred examples
include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group,
isopropylsulfonyl group, cyclopropylsulfonyl group, n-butylsulfonyl group,
isobutylsulfonyl group, s-butylsulfonyl group, t-butylsulfonyl group, cyclobutylsulfonyl
group, cyclopropylmethylsulfonyl group, and the like.
[0027]
Examples of the aryl ring include, for example, a monocyclic aromatic ring, a
condensed polycyclic aromatic ring, and the like. Although the aryl ring may be a
hydrocarbon ring, it may contain one ore more, for example, 1 to 3, one or more kinds of
heteroatoms selected from the group consisting of nitrogen atom, sulfur atom, and
oxygen atom as ring-constituting atoms other than carbon atom.
Examples of the monocyclic aromatic ring include, for example, a monocyclic
aromatic hydrocarbon, a monocyclic aromatic heterocyclic ring containing one or more
heteroatoms, and the like. Examples include, for example, benzene ring, and a 5- or
6-membered aromatic heterocyclic ring containing one or more heteroatoms.
Specifically, preferred examples of the 5- or 6"membered aromatic heterocyclic ring
include thiophene, pyridine, furan, thiazole, oxazole, pyrazole, pyrazine, pyrimidine,
pyrrole, imidazole, pyridazine, isothiazole, isoxazole, 1,2,4-oxadiazole, 1,3,4'oxadiazole,
1,2,4-thiadiazole, l,3,4"thiadiazole, furazan, and the like.
[0028]
Examples of the condensed polycyclic aromatic ring include, for example, a
condensed polycyclic aromatic hydrocarbon, a condensed polycyclic aromatic
heterocyclic ring containing one or more heteroatoms, and the like. Examples of the
condensed polycyclic aromatic hydrocarbon include, for example, a condensed
11

polycyclic aromatic hydrocarbon having 9 to 14 carbon atoms, i.e., bi- or tricyclic
aromatic hydrocarbon, and specific preferred examples include, for example,
naphthalene, indene, fluorene, anthracene, and the like. Examples of the condensed
polycyclic aromatic heterocyclic ring include, for example, a 9- to 14-membered,
preferably 9- or lOmembered, condensed polycyclic aromatic heterocyclic ring
containing one or more, for example, 1 to 4, heteroatoms, and the like, and preferred
specific examples include, for example, benzofuran, benzothiophene, benzimidazole,
benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, quinoline,
isoquinoline, indole, quinoxaline, phenanthoridine, phenothiazine, phenoxazine,
phthalazine, naphthylidine, quinazoline, cinnoline, carbazole, j3 -carboline, acridine,
phenazine, phthalimide, thioxanthene, and the like.
[0029]
Examples of the aryl group include, for example, a monocyclic aromatic group,
a condensed polycyclic aromatic group, and the like, and a monovalent residue
obtained by removing arbitrary one hydrogen atom from the aryl ring explained above
can be exemplified.
Examples of the monocyclic aromatic group include, for example, a monovalent
residue obtained by removing arbitrary one hydrogen atom from a monocyclic aromatic
ring. Preferred specific examples of the monocyclic aromatic group include, phenyl
group, thienyl group (2- or 3-thienyl group), pyridyl group (2-, 3- or 4-pyridyl group),
furyl group (2- or 3-furyl group), thiazolyl group (2-, 4- or 5"thiazolyl group), oxazolyl
group (2-, 4- or 5-oxazolyl group), pyrazolyl group (l-, 3- or 4-pyrazolyl group),
2-pyrazinyl group, pyrimidinyl group (2-, 4- or 5-pyrimidinyl group), pyrrolyl group (l-,
2- or 3-pyrrolyl group), imidazolyl group (1-, 2- or 4-imidazolyl group), pyridazinyl
group (3- or 4-pyridazinyl group), 3-isothiazolyl group, 3"isoxazolyl group,
l,2,4-oxadiazol-5-yl group, l,2,4-oxadiazol-3-yl group, and the like.
[0030]
Examples of the condensed polycyclic aromatic group include, for example, a
monovalent residue obtained by removing arbitrary one hydrogen atom from a bi- to
tetracyclic, preferably, bi- or tricyclic, condensed polycyclic aromatic ring.
Preferred specific examples of the condensed polycyclic aromatic group include,
for example, 1-naphthyl group, 2-naphthyl group, 2-indenyl group, 2-anthryl group,
quinolyl group (2-, 3-, 4", 5", 6", 7- or 8-quinolyl group), isoquinolyl group (l-, 3-, 4-, 5",
12

6", 7- or 8-isoquinolyl group), indolyl group (1-, 2% 3-, 4-, 5", 6- or 7-indolyl group),
isoindolyl group (1-, 2-, 4- or 5"isoindolyl group), phthalazinyl group (1-, 5- or
6-phthalazinyl group), quinoxalinyl group (2% 3- or 5'quinoxalinyl group),
benzofuranyl group (2-, 3% 4-, 5- or 6'benzofuranyl group), benzothiazolyl group (2-, 4-,
5- or 6-benzothiazolyl group), benzimidazolyl group (1-, 2-, 4", 5- or 6-benzimidazolyl
group), fluorenyl group (1-, 2-, 3- or 4-fluorenyl group), thioxanthenyl group, and the
like.
[0031]
The aralkyl group represents, for example, an alkyl group substituted with an
aryl group (arylalkyl group). The alkyl moiety of the arylalkyl group is similar to the
aforementioned alkyl group, and the aryl moiety of the arylalkyl group is similar to the
aforementioned aryl. As the aryl moiety of the arylalkyl, a monocyclic aromatic group
is preferred, and examples of the arylalkyl group include, for example, benzyl group,
2-thienylmethyl group, 3-thienylmethyl group, 2-pyridylmethyl group,
3-pyridylmethyl group, 4-pyridylmethyl group, 2-furylmethyl group, 3-furylmethyl
group, 2-thiazolylmethyl group, 4-thiazolylmethyl group, 5-thiazolylmethyl group,
2-oxazolylmethyl group, 4-oxazolylmethyl group, 5-oxazolylmethyl group,
1-pyrazolylmethyl group, 3-pyrazolylmethyl group, 4-pyrazolylmethyl group,
2-pyrazinylmethyl group, 2-pyrimidinylmethyl group, 4-pyrimidinylmethyl group,
5-pyrimidinylmethyl group, 1-pyrrolylmethyl group, 2-pyrrolylmethyl group,
3-pyrrolylmethyl group, 1-imidazolylmethyl group, 2-imidazolylmethyl group,
4-imidazolylmethyl group, 3-pyridazinylmethyl group, 4-pyridazinylmethyl group,
3-isothiazolylmethyl group, 3-isoxazolylmethyl group, l,2,4-oxadiazol-5-ylmethyl
group, l,2,4-oxadiazol-3-ylmethyl group, and the like. Benzyl group, 2-thienylmethyl
group, 3-thienylmethyl group, 2-furylmethyl group, 3-furylmethyl group,
2-pyrrolylmethyl group, and 3-pyrrolylmethyl group are preferred, and 2-furylmethyl
group is particularly preferred.
[0032]
Examples of the arylalkyl group include, for example, 2-phenylethyl group,
2-(2-thienyl)ethyl group, 2'(3-thienyl)ethyl group, 2-(2-pyridyl)ethyl group,
2"(3-pyridyl)ethyl group, 2-(4-pyridyl)ethyl group, 2-(2-fui-yl)ethyl group,
2-(3-furyl)ethyl group, 2-(2"thiazolyl)ethyl group, 2-(4-thiazolyl)ethyl group,
2-(5"thiazolyl)ethyl group, 2-(2-oxazolyl)ethyl group, 2-(4-oxazolyl)ethyl group,
13

2-(5-oxazolyl)ethyl group, 2-(l-pyrazolyl)ethyl group, 2-(3"pyrazolyl)ethyl group,
2-(4-pyrazolyl)ethyl group, 2-(2-pyrazinyl)ethyl group, 2-(2-pyrimidinyl)ethyl group,
2-(4-pyrimidinyl)ethyl group, 2-(5-pyrimidinyl)ethyl group, 2-(l-pyrrolyl)ethyl group,
2-(2-pyrrolyl)ethyl group, 2-(3-pyrrolyl)ethyl group, 2"(l-imidazolyl)ethyl group,
2-(2-imidazolyl)ethyl group, 2-(4-imidazolyl)ethyl group, 2-(3-pyridazinyl)ethyl group,
2-(4-pyridazinyl)ethyl group, 2-(3-isothiazolyl)ethyl group, 2-(3-isoxazolyl)ethyl group,
2-(l,2,4-oxadiazol-5-yl)ethyl group, 2-(l,2,4-oxadiazol-3-yl)ethyl group, and the like.
2-Phenylethyl group, 2-(2-thienyl)ethyl group, 2-(3-thienyl)ethyl group,
2-(2-furyl)ethyl group, 2-(3-furyl)ethyl group, 2-(2-pyrrolyl)ethyl group, and
2-(3-pyrrolyl)ethyl group are preferred, and 2-(2-furyl)ethyl group is particularly
preferred.
[0033]
Examples of the arylalkyl group include, for example, 1-phenylethyl group,
l-(2'thienyl)ethyl group, l-(3"thienyl)ethyl group, l-(2-pyridyl)ethyl group,
l-(3-pyridyl)ethyl group, l-(4-pyridyl)ethyl group, l"(2-furyl)ethyl group,
l-(3-furyl)ethyl group, l-(2-thiazolyl)ethyl group, l-(4-thiazolyl)ethyl group,
l-(5-thiazolyl)ethyl group, l-(2-oxazolyl)ethyl group, l-(4-oxazolyl)ethyl group,
l-(5-oxazolyl)ethyl group, l-(l-pyrazolyl)ethyl group, l-(3-pyrazolyl)ethyl group,
l-(4-pyrazolyl)ethyl group, l-(2-pyrazinyl)ethyl group, l-(2-pyrimidinyl)ethyl group,
l-(4-pyrimidinyl)ethyl group, l-(5-pyrimidinyl)ethyl group, l-(l-pyrrolyl)ethyl group,
l-(2-pyrrolyl)ethyl group, l-(3-pyrrolyl)ethyl group, l-(l-imidazolyl)ethyl group,
l-(2-imidazolyl)ethyl group, l-(4-imidazolyl)ethyl group, l-(3-pyridazinyl)ethyl group,
l-(4-pyridazinyl)ethyl group, l-(34sothiazolyl)ethyl group, l-(3-isoxazolyl)ethyl group,
l-(l,2,4-oxadiazol-5-yl)ethyl group, l-(l,2,4-oxadiazol-3-yl)ethyl group, and the like.
1-Phenylethyl group, l-(2-thienyl)ethyl group, l-(3-thienyl)ethyl group,
l-(2-furyl)ethyl group, l'(3-furyl)ethyl group, l-(2-pyrrolyl)ethyl group, and
l-(3-pyrrolyl)ethyl group are preferred, and l-(2-furyl)ethyl group is particularly
preferred.
[0034]
Examples of the saturated heterocyclic group include, for example, a
monocyclic saturated heterocyclic group, and the ring thereof is, for example, a 3- to
7-membered, particularly preferably 5- or 6-membered ring containing one or two,
preferably one, heteroatom. Specifically, preferred examples include
14

tetrahydropyranyl group (3- or 4-tetrahydropyranyl group), 3-tetrahydrofuryl group,
piperidyl group (3- or 4-piperidyl group), 3-pyrrolidyl group, tetrahydrothiopyranyl
group (3- or 4-tetrahydrothiopyranyl group), 3-tetrahydrothiofuryl group, and the like.
Tetrahydropyranyl group can be mentioned as a particularly preferred example.
[0035]
Preferred examples of the substituent of the alkyl group which may be
substituted include, for example, hydroxyl group, a halogen atom, carboxy group,
cyano group, a saturated heterocyclic group, an acylamino group, an
alkylsulfonylamino group, aminocarbonylamino group, an alkylaminocarbonylamino
group, an arylaminocarbonylamino group, an alkylsulfonylamino group optionally
substituted with one or more halogen atoms, and the like. Hydroxyl group, and a
halogen atom are more preferred, hydroxyl group and fluorine atom are still more
preferred, and hydroxyl group is particularly preferred. There is also another
embodiment in which fluorine atom is particularly preferred.
As the alkyl group which may be substituted, a group selected from the group
consisting of the preferred examples mentioned above for the alkyl group,
trifluoromethyl group, difluoromethyl group, hydroxymethyl group, and
2-hydroxyethyl group is preferred. Methyl group, ethyl group, n-propyl group,
isopropyl group, cyclopropyl group, trifluoromethyl group, difluoromethyl group,
hydroxymethyl group, and 2-hydroxyethyl group are more preferred, and methyl group
is particularly preferred.
[0036]
The substituents of the alkenyl group which may be substituted and the
alkynyl group which may be substituted are similar to the substituent of the
aforementioned alkyl group which may be substituted.
As the alkenyl group which may be substituted, for example, the preferred
examples mentioned above for the alkenyl group are preferred, and as the alkynyl
group which may be substituted, for example, the preferred examples mentioned above
for the alkynyl group are preferred.
The substituent of the alkoxy group which may be substituted is similar to, for
example, the substituent of the aforementioned alkyl group which may be substituted,
and one or more halogen atoms are particularly preferred.
As the substituted alkoxy group, for example, an alkoxy group optionally
15

substituted with one or more halogen atoms is preferred, and an alkoxy group
optionally substituted with one or more halogen atoms and having 1 to 4 carbon atoms
is preferred. When the alkoxy group is substituted with two or more halogen atoms,
the halogen atoms may be the same or different.
As the alkoxy group which may be substituted, a group selected from the group
consisting of, for example, the preferred examples of the alkoxy group having 1 to 4
carbon atoms mentioned above, monofluoromethoxy group, difluoromethoxy group,
trifluoromethoxy group, and 2,2,2-trifluoroethoxy group is preferred, and a group
selected from the group consisting of the preferred examples of the alkoxy group
having 1 to 4 carbon atoms mentioned above, trifluoromethoxy group, and
2,2,2-trifluoroethoxy group is particularly preferred.
[0037]
Examples of the substituent of the alkylthio group which may be substituted
include, for example, a substituent similar to the substituent of the aforementioned
alkyl group which may be substituted.
As the alkylthio group which may be substituted, for example, the preferred
examples of the aforementioned alkylthio group are preferred.
Preferred examples of the alkoxycarbonyl group which may be substituted
include, for example, a group consisting of the aforementioned alkoxy group which may
be substituted to which carbonyl group is added at the end.
Examples of the amino group which may be substituted include, for example,
NH2 group, an alkylamino group, a dialkylamino group, an acylamino group, an
acyl(alkyl)amino group, an alkylsulfonylamino group, an alkylsulfonyl(alkyl)amino
group, an alkylamino group optionally substituted with one or more halogen atoms, an
alkylsulfonylamino group optionally substituted with one or more halogen atoms, an
alkylsulfonyl(alkyl)amino group optionally substituted with one or more halogen
atoms, and the like.
[0038]
Preferred examples of the alkylamino group include, for example, a lower
alkylamino group. As the lower alkylamino group, for example, an alkylamino group
having 1 to 4 carbon atoms is preferred. Specifically, preferred examples include
methylamino group, ethylamino group, n-propylamino group, isopropylamino group,
cyclopropylamino group, n-butylamino group, isobutylamino group, s-butylamino
16

group, t-butylamino group, cyclobutylamino group, cyclopropylmethylamino group,
and the like.
Examples of the dialkylamino group include, for example, an amino group
substituted with the same or different alkyl groups, and a lower dialkylamino group is
usually preferred. As the lower dialkylamino group, for example, an amino group
substituted with alkyl groups each having 1 to 4 carbon atoms is preferred.
Specifically, preferred examples include dimethylamino group, ethyl(methyl)amino
group, diethylamino group, methyl(n-propyl)amino group, isopropyl(methyl)amino
group, cyclopropyl(methyl)amino group, n-butyl(methyl)amino group,
isobutyl(methyl)amino group, s-butyl(methyl)amino group, t-butyl(methyl)amino
group, cyclobutyl(methyl)amino group, cyclopropylmethyl(methyl)amino group, and
the like.
[0039]
Examples of the acylamino group include, for example, an amino group
substituted with the aforementioned acyl group, and preferred examples of the acyl
group are similar to those mentioned above. Specifically, preferred examples include
acetylamino group, propanoylamino group, butanoylamino group,
2-methylpropanoylamino group, cyclopropylcarbonylamino group, pentanoylamino
group, 3-methylbutanoylamino group, 2,2-dimethylpropanoylamino group,
cyclobutylcarbonylamino group, and the like.
Examples of the acyl(alkyl)amino group include, for example, an amino group
simultaneously substituted with one acyl group and one alkyl group, and preferred
examples of the acyl group and the alkyl group are similar to those mentioned above.
Specifically, preferred examples include acetyl(methyl)amino group,
methyl(propanoyl)amino group, butanoyl(methyl)amino group,
methyl(2-methylpropanoyl)amino group, cyclopropylcarbonyl(methyl)amino group,
methyl(pentanoyl)amino group, methyl(3-methylbutanoyl)amino group,
2,2"dimethylpropanoyl(methyl)amino group, cyclobutylcarbonyl(methyl)amino group,
and the like.
[0040]
Examples of the alkylsulfonylamino group include, for example, an amino
group substituted with the aforementioned alkylsulfonyl group, and preferred
examples of the alkylsulfonyl group are similar to those mentioned above.
17

Specifically, preferred examples include methylsulfonylamino group,
ethylsulfonylamino group, n-propylsulfonylamino group, isopropylsulfonylamino group,
cyclopropylsulfonylamino group, n-butylsulfonylamino group, isobutylsulfonylamino
group, s-butylsulfonylamino group, t-butylsulfonylamino group,
cyclobutylsulfonylamino group, and cyclopropylmethylsulfonylamino group.
Examples of the alkylsulfonyl(alkyl)amino group include, for example, an
amino group simultaneously substituted with one alkylsulfonyl group and one alkyl
group, and preferred examples of the alkylsulfonyl group and the alkyl group are
similar to those mentioned above. Specifically, preferred examples include
methyl(methylsulfonyl)amino group, ethylsulfonyl(methyl)amino group,
methyl(n-propylsulfonyl)amino group, isopropylsulfonyl(methyl)amino group,
cyclopropylsulfonyl(methyl)amino group, n-butylsulfonyl(methyl)amino group,
isobutylsulfonyl(methyl)amino group, s-butylsulfonyl(methyl)amino group,
t-butylsulfonyl(methyl)amino group, cyclobutylsulfonyl(methyl)amino group, and
cyclopropylmethylsulfonyl(methyl)amino group.
[0041]
Examples of the aminocarbonylamino group include, for example, -NHCONH2
group.
Examples of the alkylaminocarbonylamino group include, for example, an
amino group substituted with an alkylaminocarbonyl group, and preferred examples of
the alkylamino moiety of the alkylaminocarbonyl group are similar to those of the
aforementioned alkylamino group. Specifically, preferred examples include
methylaminocarbonylamino group, ethylaminocarbonylamino group,
n-propylaminocarbonylamino group, isopropylaminocarbonylamino group,
cyclopropylaminocarbonylamino group, n-butylaminocarbonylamino group,
isobutylaminocarbonylamino group, s-butylaminocarbonylamino group,
t-butylaminocarbonylamino group, cyclobutylaminocarbonylamino group, and
cyclopropylmethylaminocarbonylamino group.
Examples of the arylaminocarbonylamino group include, for example, an
amino group substituted with an arylaminocarbonyl group, and preferred examples of
the aryl moiety of the arylaminocarbonyl group are similar to those of the
aforementioned aryl group. Specifically, preferred examples include
phenylaminocarbonylamino group, tolylaminocarbonylamino group,
18

xylylaminocarbonylamino group, mesitylaminocarbonylamino group,
(l-naphthyl)aminocarbonylamino group, and (2-naphthyl)aminocarbonylamino group.
[0042]
Examples of the alkylamino group optionally substituted with one or more
halogen atoms include, for example, an alkylamino group obtained by replacing one or
more of hydrogen atoms of the aforementioned alkylamino group with halogen atoms of
arbitrary type, and an alkylamino group optionally substituted with one or more
halogen atoms and having 1 to 4 carbon atoms is preferred. When the alkylamino
group is substituted with two or more halogen atoms, the halogen atoms may be the
same or different. Specifically, preferred examples include chloromethylamino group,
dichloromethylamino group, trichloromethylamino group, fluoromethylamino group,
difluoromethylamino group, trifluoromethylamino group, fluoroethylamino group,
2,2,2-trifluoroethylamino group, and the like.
Examples of the alkylsulfonylamino group optionally substituted with one or
more halogen atoms include, for example, an alkylsulfonylamino group obtained by
replacing one or more of hydrogen atoms of the aforementioned alkylsulfonylamino
group with halogen atoms of arbitrary type, and an alkylsulfonylamino group
optionally substituted with one or more halogen atoms and having 1 to 4 carbon atoms
is usually preferred. When the alkylsulfonylamino group is substituted with two or
more halogen atoms, the halogen atoms may be the same or different. Specifically,
examples include trifluoromethylsulfonylamino group, and the like.
[0043]
Examples of the alkylsulfonyl(alkyl)amino group optionally substituted with
one or more halogen atoms include, for example, an alkylsulfonyl(alkyl)amino group
obtained by replacing one or more of hydrogen atoms of the aforementioned
alkylsulfonyl(alkyl)amino group with halogen atoms of arbitrary type, and an
alkylsulfonyl(alkyl)amino group optionally substituted with one or more halogen
atoms and having 1 to 4 carbon atoms is usually preferred. When the
alkylsulfonyl(alkyl)amino group is substituted with two or more halogen atoms, the
halogen atoms may be the same or different. Specifically, examples include
methyl(trifluoromethylsulfonyl)amino group, and the like.
The substituent of the acyl group which may be substituted is similar to, for
example, the substituent of the aforementioned alkyl group which may be substituted,
19

and one ore more halogen atoms are particularly preferred.
[0044]
As the substituted acyl group, for example, an acyl group optionally
substituted with one or more halogen atoms is preferred, and an acyl group optionally
substituted with one or more halogen atoms and having 2 to 5 carbon atoms is
preferred. When the acyl group is substituted with two or more halogen atoms, the
halogen atoms may be the same or different. Preferred examples include
trifluoroacetyl group, and the like.
As the acyl group which may be substituted, for example, acetyl group,
propanoyl group, butanoyl group, 2-methylpropanoyl group, cyclopropylcarbonyl group,
pentanoyl group, 3-methylbutanoyl group, 2,2-dimethylpropanoyl group,
cyclobutylcarbonyl group, and the like are preferred. However, there is another
embodiment in which trifluoroacetyl group is preferred.
[0045]
As the aralkyl group which may be substituted, for example, the preferred
examples of the aforementioned aralkyl group are preferred. There is also another
embodiment in which examples in which a carbon atom among the constituent
elements forming the aryl ring of the aralkyl group is substituted with an alkyl group,
an alkoxy group, amino group, hydroxyl group, or a halogen atom are preferred.
Specifically, examples include 4-methylphenylmethyl group, 4-methoxyphenylmethyl
group, 4-aminophenylmethyl group, 4-hydroxyphenylmethyl group,
4-fluorophenylmethyl group, 5-methyl-2-furylmethyl group, 4-methyl-2-furylmethyl
group, 5-methyl-3-furylmethyl group, 5-methyl-2-pyrrolylmethyl group,
4-methyl-2-pyrrolylmethyl group, 5-methyl-3-pyrrolylmethyl group,
5-methyl-2-thienylmethyl group, 4-methyl-2-thienylmethyl group,
5-methyl-3-thienylmethyl group, and the like. Further, there is another embodiment
in which examples in which a nitrogen atom among the constituent elements forming
the aryl ring of the aralkyl group is substituted with an alkyl group, or an alkoxy group
are preferred. Specifically, examples include l-methyl-2-pyrrolylmethyl group,
l-ethyl-2-pyrrolylmethyl group, l-methyl-3-pyrrolylmethyl group, and the like.
As the saturated heterocyclic group which may be substituted, for example,
the preferred examples of the aforementioned saturated heterocyclic group are
preferred.
20

[0046]
In the aforementioned general formula (l), A represents a nitrogen-containing
saturated ring. Examples of the nitrogen-containing saturated ring include, for
example, a 3- to 8-membered, preferably 4- to 7-membered, monocyclic saturated
heterocyclic ring containing one nitrogen atom as a ring-constituting atom.
Specifically, azetidine, pyrrolidine, piperidine, homopiperidine, and the like are
preferred examples. Further, m represents an integer of 0, 1 or 2, preferably 1 or 2,
particularly preferably 1. Furthermore, when m is 1 or 2, n preferably represents an
integer of 1, 2 or 3, particularly preferably 2 or 3. Preferred examples of the structure
of the ring A include, for example, rings represented by the following formulas (l-a) to

[in the general formulas (l-a) to (l-c), G4 and G5 have the same meanings as those
defined above, and the ring-constituting nitrogen atom (N) binds to the SO2 moiety of
the compound represented by the general formula (l)], the structure of the formula
(l-b), or formula (l-c) is preferred, and the structure of the formula (l"b) is particularly
preferred. In the structures of the formula (l-b) and formula (l-c), the carbon atom to
which G4 binds becomes asymmetric carbon, and absolute configuration of the carbon
atom is preferably S"configuration. There is also another embodiment in which
R-configuration is preferred, and there is also another embodiment in which a mixture
thereof is preferred.
[0047]
G1 represents hydrogen atom, chlorine atom, hydroxyl group, an alkoxy group,
or amino group. Hydrogen atom, hydroxyl group, and amino group are preferred, and
hydrogen atom is particularly preferred. There is also another embodiment in which
hydroxyl group is particularly preferred.
G2 represents a halogen atom, hydroxyl group, cyano group, carboxy group, an
21

alkyl group which may be substituted, an alkenyl group which may be substituted, an
alkynyl group which may be substituted, an alkoxy group which may be substituted,
an alkylthio group which may be substituted, an amino group which may be
substituted, an alkylsulfinyl group which may be substituted, an alkylsulfonyl group
which may be substituted, or an aryl group which may be substituted.
[0048]
As G2, for example, a halogen atom, hydroxyl group, an alkyl group which may
be substituted, an alkenyl group which may be substituted, an alkynyl group which
may be substituted, and an amino group which may be substituted are preferred, and a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, and an alkynyl group which may be substituted are particularly
preferred.
When G2 is a halogen atom, fluorine atom, chlorine atom, and bromine atom
are preferred, and fluorine atom is particularly preferred. There is also another
embodiment in which chlorine atom is particularly preferred. There is further
another embodiment in which bromine atom is particularly preferred.
It is preferred that G2 is hydroxyl group.
When G2 is an alkyl group which may be substituted, a lower alkyl group
which may be substituted is preferred. Examples include methyl group, ethyl group,
n-propyl group, fluoromethyl group, difluoromethyl group, and trifluoromethyl group,
and methyl group is particularly preferred.
When G2 is an alkenyl group which may be substituted, a lower alkenyl group
which may be substituted is preferred, and vinyl group is particularly preferred.
When G2 is an alkynyl group which may be substituted, a lower alkynyl group
which may be substituted is preferred. Examples include ethynyl group,
methylethynyl group, trifluoroethynyl group, and 3-hydroxyprop-l-ynyl group, and
ethynyl group is particularly preferred. There is also another embodiment in which
3-hydroxyprop-l-ynyl group is preferred.
When G2 is an amino group which may be substituted, a lower amino group
which may be substituted is preferred. Examples include amino group (-NH2 group),
methylamino group, and dimethylamino group, and amino group is particularly
preferred.
[0049]
22

G3 represents hydrogen atom, a halogen atom, hydroxyl group, cyano group,
carboxy group, an alkyl group which may be substituted, an alkenyl group which may
be substituted, an alkynyl group which may be substituted, an alkoxy group which
may be substituted, an alkylthio group which may be substituted, an amino group
which may be substituted, an alkoxycarbonyl group which may be substituted, an acyl
group which may be substituted, an acyloxy group which may be substituted, an
alkylsulfinyl group which may be substituted, an alkylsulfonyl group which may be
substituted, or an aryl group which may be substituted, provided that G3 substitutes at
the 3% 6~, 7", or 8-position of the isoquinoline ring.
G3 preferably substitutes at the 3", 6", or 8-position of the isoquinoline ring,
particularly preferably at the 3- or 8-position of the isoquinoline ring.
As G3, for example, hydrogen atom, a halogen atom, hydroxyl group, carboxy
group, an alkyl group which may be substituted, an alkenyl group which may be
substituted, an alkynyl group which may be substituted, an alkoxy group which may
be substituted, an alkylthio group which may be substituted, and an amino group
which may be substituted are preferred, and hydrogen atom is particularly preferred.
[0050]
G4 represents hydroxyl group, or -NCROCR2) (R1 and R2 may be the same or
different, and independently represent hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, an alkenyl group which may
be substituted, an alkynyl group which may be substituted, or a saturated heterocyclic
group which may be substituted).
Preferred examples of G4 include, for example, hydroxyl group. There is also
another embodiment in which -NCROCR2) is preferred.
In -N(R0(R2) represented by G4, R1 and R2 may be the same or different, and
independently represent hydrogen atom, an alkyl group which may be substituted, an
aralkyl group which may be substituted, an alkenyl group which may be substituted,
an alkynyl group which may be substituted, or a saturated heterocyclic group which
may be substituted.
[0051]
It is preferred that one of R1 and R2 is hydrogen atom. It is particularly
preferred that one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an
alkyl group which may be substituted, an aralkyl group which may be substituted, or a
23

saturated heterocyclic group which may be substituted.
It is preferred that R1 and R2 are both hydrogen atoms. There is also another
embodiment in which it is preferred that one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted. Further, it is also preferred that
one of R1 and R2 is hydrogen atom, and the other is methyl group, or ethyl group, and it
is particularly preferred that one of R1 and R2 is hydrogen atom, and the other is
methyl group. There is also another embodiment in which it is preferred that one of
R1 and R2 is hydrogen atom, and the other is an aralkyl group which may be
substituted. Further, it is also preferred that one of R1 and R2 is hydrogen atom, and
the other is a furylalkyl group, and it is particularly preferred that one of R1 and R2 is
hydrogen atom, and the other is 2"furylmethyl group. There is also another
embodiment in which it is preferred that one of R1 and R2 is hydrogen atom, and the
other is a saturated heterocyclic group which may be substituted. It is also preferred
that one of R1 and R2 is hydrogen atom, and the other is tetrahydropyranyl group, and
it is particularly preferred that one of R1 and R2 is hydrogen atom, and the other is
4-tetrahydropyranyl group.
G5 is a substituent on a ring-constituting carbon atom constituting the
nitrogen-containing saturated ring represented by A, and represents hydrogen atom,
fluorine atom, or an alkyl group. G5 preferably substitutes on a carbon atom adjacent
to a nitrogen atom constituting the ring. G5 is preferably hydrogen atom, fluorine
atom, or a lower alkyl group, particularly preferably hydrogen atom.
[0052]
Although the combination of the substituents in the compounds represented by
the general formula (l) is not particularly limited, examples of the compounds and the
like include, for example,
(1) the compound wherein m is l;
(2) the compound wherein n is 2 or 3;
(3) the compound wherein the ring A has a structure of the formula (l-a), formula (l-b),
or formula (l-c);
(4) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c);
(5) the compound wherein the ring A has a structure of the formula (l"b);
(6) the compound wherein G3 is hydrogen atom!
24

(7) the compound wherein G5 is hydrogen atom!
(8) the compound wherein G4 is -NCROCR2);
(9) the compound wherein G1 is hydrogen atom, hydroxyl group, or amino group;

(10) the compound wherein G1 is hydrogen atom, or hydroxyl group,"
[0053]
(11) the compound wherein G2 is a halogen atom, hydroxyl group, an alkyl group which
may be substituted, an alkenyl group which may be substituted, an alkynyl group
which may be substituted, or an amino group which may be substituted;
(12) the compound wherein G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted;
(13) the compound wherein G2 is a halogen atom;
(14) the compound wherein G2 is an alkyl group which may be substituted;
(15) the compound wherein G2 is an alkenyl group which may be substituted;
(16) the compound wherein G2 is an alkynyl group which may be substituted;
(17) the compound wherein G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(18) the compound wherein G4 is N(R1)(R2), and R1 and R2 are both hydrogen atoms,'
(19) the compound wherein G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted;
(20) the compound wherein G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is an aralkyl group which may be substituted;
[0054]
(21) the compound wherein G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the
other is a saturated heterocyclic group which may be substituted;
(22) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), and G3 and G5 are both hydrogen atoms!
(23) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l"c), and Gl is hydrogen atom, or hydroxyl group!
(24) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), and G2 is a halogen atom, hydroxyl group, an alkyl group which may be
substituted, an alkenyl group which may be substituted, an alkynyl group which may
25

be substituted, or an amino group which may be substituted;
(25) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), and G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted;
(26) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), and G2 is a halogen atom;
(27) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), and G2 is an alkyl group which may be substituted;
(28) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), and G2 is an alkynyl group which may be substituted;
(29) the compound wherein the ring A has a structure of the formula (l-b), or formula
(1-c), and G4 is -N(Ri)(R2):
(30) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
[0055]
(31) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G4 is -N(R!)(R2), and R1 and R2 are both hydrogen atoms!
(32) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is an alkyl
group which may be substituted;
(33) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is an aralkyl
group which may be substituted;
(34) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is a saturated
heterocyclic group which may be substituted;
(35) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), G3 and G5 are both hydrogen atoms, and G4 is -N(R!)(R2);
(36) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G1 is hydrogen atom, or hydroxyl group, and G3 and G5 are both hydrogen atoms;
(37) the compound wherein the ring A has a structure of the formula (l"b), or formula
26

(l-c), G2 is a halogen atom, hydroxyl group, an alkyl group which may be substituted,
an alkenyl group which may be substituted, an alkynyl group which may be
substituted, or an amino group which may be substituted, and G3 and G5 are both
hydrogen atoms!
(38) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l'c), G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, and G3 and
G5 are both hydrogen atoms,'
(39) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G2 is a halogen atom, and G3 and G5 are both hydrogen atoms,'
(40) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G2 is an alkyl group which may be substituted, and G3 and G5 are both hydrogen
atoms,"
[0056]
(41) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G2 is an alkynyl group which may be substituted, and G3 and G5 are both
hydrogen atoms,'
(42) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G1 is hydrogen atom, or hydroxyl group, G2 is a halogen atom, hydroxyl group, an
alkyl group which may be substituted, an alkenyl group which may be substituted, an
alkynyl group which may be substituted, or an amino group which may be substituted,
and G3 and G5 are both hydrogen atoms;
(43) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), G1 is hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, and G3 and G5 are both hydrogen atoms;
(44) the compound wherein the ring A has a structure of the formula (l"b), or formula
(l-c), G1 is hydrogen atom, or hydroxyl group, G2 is a halogen atom, and G3 and G5 are
both hydrogen atoms,'
(45) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l"c), G1 is hydrogen atom, or hydroxyl group, G2 is an alkyl group which may be
substituted, and G3 and G5 are both hydrogen atoms,"
(46) the compound wherein the ring A has a structure of the formula (l-b), or formula
27

(l-c), G1 is hydrogen atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, and G3 and G5 are both hydrogen atoms;
(47) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l"c), G3 and G5 are both hydrogen atoms, G4 is 'NCROCR2), one of R1 and R2 is hydrogen
atom, and the other is hydrogen atom, an alkyl group which may be substituted, an
aralkyl group which may be substituted, or a saturated heterocyclic group which may
be substituted;
(48) the compound wherein the ring A has a structure of the formula (l"b), or formula
(1-c), G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), and Ri and R2 are both
hydrogen atoms;
(49) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen
atom, and the other is an alkyl group which may be substituted;
(50) the compound wherein the ring A has a structure of the formula (l-b), or formula
(1-c), G3 and G5 are both hydrogen atoms, G4 is -N(R!)(R2), one of R1 and R2 is hydrogen
atom, and the other is an aralkyl group which may be substituted;
[0057]
(51) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen
atom, and the other is a saturated heterocyclic group which may be substituted;
(52) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(53) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), and R1 and R2 are both hydrogen atoms!
(54) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l-c), G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
28

are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted;
(55) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l"c), G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the
other is an aralkyl group which may be substituted;
(56) the compound wherein the ring A has a structure of the formula (l-b), or formula
(l'c), G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the
other is a saturated heterocyclic group which may be substituted;
(57) the compound wherein the ring A has a structure of the formula (l-b), and G3 and
G5 are both hydrogen atoms,'
(58) the compound wherein the ring A has a structure of the formula (l-b), and G1 is
hydrogen atom, or hydroxyl group;
(59) the compound wherein the ring A has a structure of the formula (l-b), and G2 is a
halogen atom, hydroxyl group, an alkyl group which may be substituted, an alkenyl
group which may be substituted, an alkynyl group which may be substituted, or an
amino group which may be substituted;
(60) the compound wherein the ring A has a structure of the formula (l-b), and G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted;
[0058]
(61) the compound wherein the ring A has a structure of the formula (l-b), and G2 is a
halogen atom;
(62) the compound wherein the ring A has a structure of the formula (l"b), and G2 is an
alkyl group which may be substituted;
(63) the compound wherein the ring A has a structure of the formula (l-b), and G2 is an
alkynyl group which may be substituted;
(64) the compound wherein the ring A has a structure of the formula (l-b), and G4 is
N(Ri)(R2);
(65) the compound wherein the ring A has a structure of the formula (l-b), G4 is
29

-NCROCR2), one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl
group which may be substituted, an aralkyl group which may be substituted, or a
saturated heterocyclic group which may be substituted;
(66) the compound wherein the ring A has a structure of the formula (l-b), G4 is
-NCROCR2), and R1 and R2 are both hydrogen atoms;
(67) the compound wherein the ring A has a structure of the formula (l-b), G4 is
N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is an alkyl group which
may be substituted;
(68) the compound wherein the ring A has a structure of the formula (l-b), G4 is
-N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is an aralkyl group which
may be substituted;
(69) the compound wherein the ring A has a structure of the formula (l-b), G4 is
-N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is a saturated heterocyclic
group which may be substituted;
(70) the compound wherein the ring A has a structure of the formula (l-b), G3 and G5
are both hydrogen atoms, and G4 is -N(R!)(R2);
[0059]
(71) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, and G3 and G5 are both hydrogen atoms,'
(72) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, hydroxyl group, an alkyl group which may be substituted, an alkenyl
group which may be substituted, an alkynyl group which may be substituted, or an
amino group which may be substituted, and G3 and G5 are both hydrogen atoms,'
(73) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted, and G3 and G5 are both
hydrogen atoms;
(74) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, and G3 and G5 are both hydrogen atoms!
(75) the compound wherein the ring A has a structure of the formula (l-b), G2 is an
alkyl group which may be substituted, and G3 and G5 are both hydrogen atoms,"
(76) the compound wherein the ring A has a structure of the formula (l-b), G2 is an
alkynyl group which may be substituted, and G3 and G5 are both hydrogen atoms!
30

(77) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, hydroxyl group, an alkyl
group which may be substituted, an alkenyl group which may be substituted, an
alkynyl group which may be substituted, or an amino group which may be substituted,
and G3 and G5 are both hydrogen atoms!
(78) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, and G3 and G5 are both hydrogen atoms!
(79) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, and G3 and G5 are both
hydrogen atoms!
(80) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkyl group which may be substituted, and
G3 and G5 are both hydrogen atoms!
[0060]
(81) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkynyl group which may be substituted,
and G3 and G5 are both hydrogen atoms!
(82) the compound wherein the ring A has a structure of the formula (l-b), G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted!
(83) the compound wherein the ring A has a structure of the formula (l-b), G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), and R1 and R2 are both hydrogen atoms!
(84) the compound wherein the ring A has a structure of the formula (l-b), G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted!
(85) the compound wherein the ring A has a structure of the formula (l-b), G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is an aralkyl group which may be substituted;
(86) the compound wherein the ring A has a structure of the formula (l-b), G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
31

other is a saturated heterocyclic group which may be substituted;
[0061]
(87) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(88) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), and R1 and R2 are both hydrogen atoms;
(89) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
an alkyl group which may be substituted;
(90) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -N(R!)(R2), one of R1 and R2 is hydrogen atom, and the other is
an aralkyl group which may be substituted;
(91) the compound wherein the ring A has a structure of the formula (l-b), G2 is a
halogen atom, an alkyl group which may be substituted, an alkenyl group which may
be substituted, or an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is a
saturated heterocyclic group which may be substituted;
(92) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2),
one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group
which may be substituted, an aralkyl group which may be substituted, or a saturated
32

heterocyclic group which may be substituted;
(93) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, G3 and G5 are
both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(94) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is an alkyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R!)(R2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(95) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is an alkenyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(96) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(97) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2),
and R1 and R2 are both hydrogen atoms;
(98) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2),
33

one of R1 and R2 is hydrogen atom, and the other is an alkyl group which may be
substituted;
(99) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NdUXR2),
one of R1 and R2 is hydrogen atom, and the other is a lower alkyl group!
(100) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2),
one of R1 and R2 is hydrogen atom, and the other is methyl group, or ethyl group;
(101) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group
which may be substituted, an alkenyl group which may be substituted, or an alkynyl
group which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2),
one of R1 and R2 is hydrogen atom, and the other is methyl group;
(102) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is
hydrogen atom, and the other is an aralkyl group which may be substituted;
(103) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is
hydrogen atom, and the other is a saturated heterocyclic group which may be
substituted;
(104) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
34

(105) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, G3 and G5 are both hydrogen
atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(106) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkyl group which may be substituted, G3
and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(107) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkenyl group which may be substituted, G3
and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(108) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(109) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(Rl)(R2), and R1 and
R2 are both hydrogen atoms;
(110) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is an alkyl group which may be substituted;
35

(111) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and
R2 is hydrogen atom, and the other is a lower alkyl group!
(112) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is methyl group, or ethyl group!
(113) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is methyl group!
(114) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is an aralkyl group which may be substituted!
(115) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, or hydroxyl group, G2 is an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is a saturated heterocyclic group which may be substituted!
(116) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(117) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is
-N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl
36

group which may be substituted, an aralkyl group which may be substituted, or a
saturated heterocyclic group which may be substituted;
(118) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is an alkyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(119) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is an alkenyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(120) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(121) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), and R1 and R2 are both hydrogen
atoms!
(122) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is an alkyl group which may be substituted;
(123) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydrogen atom, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is a lower alkyl group,'
(124) the compound wherein the ring A has a structure of the formula (l"b), G1 is
37

hydrogen atom, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom,
and the other is methyl group, or ethyl group;
(125) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom,
and the other is methyl group;
(126) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
an aralkyl group which may be substituted;
(127) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydrogen atom, G2 is an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is a
saturated heterocyclic group which may be substituted;
(128) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(129) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is
N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl
group which may be substituted, an aralkyl group which may be substituted, or a
saturated heterocyclic group which may be substituted;
(130) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is an alkyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
38

be substituted, or a saturated heterocyclic group which may be substituted;
(131) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydroxyl group, G2 is an alkenyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(132) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(133) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(RX)(R2), and R1 and R2 are both hydrogen
atoms;
(134) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is an alkyl group which may be substituted;
(135) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydroxyl group, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is a lower alkyl group;
(136) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is a halogen atom, an alkyl group which may be substituted, an
alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is methyl group, or ethyl group!
(137) the compound wherein the ring A has a structure of the formula (l-b), G1 is
hydroxyl group, G2 is a halogen atom, an alkyl group which may be substituted, an
39

alkenyl group which may be substituted, or an alkynyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -NdtOdt2), one of R1 and R2 is hydrogen atom,
and the other is methyl group;
(138) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is -NdUXR2), one of R1 and R2 is hydrogen atom, and the other is
an aralkyl group which may be substituted;
(139) the compound wherein the ring A has a structure of the formula (l"b), G1 is
hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is a
saturated heterocyclic group which may be substituted;
(140) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), one of
R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may
be substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(141) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S"configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(142) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S^configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(143) the compound wherein the ring A has a structure of the formula (l-b), absolute
40

configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkenyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(144) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is "NCROCR2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(145) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), and R1
and R2 are both hydrogen atoms!
(146) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of
R1 and R2 is hydrogen atom, and the other is an alkyl group which may be substituted,
an aralkyl group which may be substituted, or a saturated heterocyclic group which
may be substituted;
(147) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), one of
R1 and R2 is hydrogen atom, and the other is an alkyl group which may be substituted!
41

(148) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of
R1 and R2 is hydrogen atom, and the other is a lower alkyl group!
(149) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of
R1 and R2 is hydrogen atom, and the other is methyl group, or ethyl group!
(150) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of
R1 and R2 is hydrogen atom, and the other is methyl group!
(151) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R!)(R2), one of R1 and R2 is
hydrogen atom, and the other is an aralkyl group which may be substituted!
(152) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is
hydrogen atom, and the other is a saturated heterocyclic group which may be
substituted;
(153) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
42

may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and
R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(154) the compound according to (153) which is the compound of Example 1-1, 1-3, 1-11,
1-14, 1-18, 1-30, 4-1, 7-1, 8-1, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-12, 8-13, 8-21, 8-26, 9-1, 10-1,
10-3, 10-7, 11-1, 18-1, 18-3, 18-7, 18-8, 18-31, 19-1, 19-3, 19-4, 19-8, 19-31, 19-40, 21-1,
23-1, 25-1, 29-1, 30-1, 35-1, 36-1, 37-1, or 38-15
(155) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S'configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4
is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an
alkyl group which may be substituted, an aralkyl group which may be substituted, or a
saturated heterocyclic group which may be substituted;
(156) the compound according to (155) which is the compound of Example 1-1, 1-3, 1-11,
1-14, 1-18, 1-30, 4-1, 7-1, 18-1, 18-3, 18-7, 18-8, 18-31, 19-1, 19-3, 19-4, 19-8, 19-31,
19-40, 21-1, 29-1, 30-1, 35-1, 36-1, 37-1, or 38-15
(157) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkyl group which may be substituted, G3 and G5 are
both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(158) the compound according to (157) which is the compound of Example 8"1, 8"3, 8-4,
8-5, 8-6, 8-7, 8-8, 8-12, 8-13, 8-21, 8-26, 11-1, 23-1, or 25-15
(159) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkenyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(160) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
43

atom, or hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(161) the compound according to (160) which is the compound of Example 10-1, 10-3, or
io-7;
(162) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), and R1 and
R2 are both hydrogen atoms;
(163) the compound according to (162) which is the compound of Example 1-1, 7-1, 8"1,
9-1, 10-1, 11-1, 18-1, 19-1, 23-1, 25-1, 29-1, or 30-1;
(164) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of
R1 and R2 is hydrogen atom, and the other is an alkyl group which may be substituted,
an aralkyl group which may be substituted, or a saturated heterocyclic group which
may be substituted;
(165) the compound according to (164) which is the compound of Example 1-3, I'll,
1-14, 1-18, 1-30, 4-1, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-12, 8-13, 8-21, 8-26, 10-3, 10-7, 18-3,
18-7, 18-8, 18-31, 19-3, 19-4, 19-8, 19"31, 19-40, 35-1, 36-1, or 38-15
(166) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is an alkyl group which may be substituted!
(167) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
44

atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is 'NCROCR2), one of R1 and
R2 is hydrogen atom, and the other is a lower alkyl group;
(168) the compound according to (166) or (167) which is the compound of Example 1-3,
8-3, 8-4, 8-5, 8-26, 10-3, 18-3, 19-3, 19-4, 35-1, 36-1, or 37"l;
(169) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), one of R1 and
R2 is hydrogen atom, and the other is methyl group, or ethyl group;
(170) the compound according to (169) which is the compound of Example 1"3, 8"3, 8-4,
10-3, 18-3, 19-3, 19-4, 35-1, 36-1, or 37-1;
(171) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is methyl group,"
(172) the compound according to (171) which is the compound of Example 1-3, 8*3, 18'3,
19-3, 35-1, 36-1, or 37-1;
(173) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is an aralkyl group which may be substituted;
(174) the compound according to (173) which is the compound of Example 10-7.'
(175) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the
other is a saturated heterocyclic group which may be substituted;
45

(176) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -NCROOl2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(177) the compound according to (176) which is the compound of Example 1-1, 1"3, 1-11,
1-14, 1-18, 1-30, 4-1, 8-1, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-12, 8-13, 8-21, 8-26, 9-1, 10-1,
10-3, 10-7, 11-1, 18-1, 18-3, 18-7, 18-8, 18-31, 19-1, 19"2, 19-3, 19-4, 19-8, 19-31, 19-40,
or 23-1;
(178) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of
R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may
be substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted!
(179) the compound according to (178) which is the compound of Example 1-1, 1"3, 1-11,
1-14, 1-18, 1-30, 4-1, 18-1, 18-3, 18-7, 18"8, 18-31, 19-1, 19"3, 19-4, 19-8, 19-31, or
19-40;
(180) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is an alkyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(181) the compound according to (180) which is the compound of Example 8-1, 8"3, 8"4,
8-5, 8-6, 8-7, 8-8, 8-12, 8-13, 8-21, 8-26, 111, or 23-1;
(182) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is an alkenyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
46

substituted, or a saturated heterocyclic group which may be substituted;
(183) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted!
(184) the compound according to (183) which is the compound of Example 10-1, 1O3, or
10-7J
(185) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), and R1 and R2 are both hydrogen atoms;
(186) the compound according to (185) which is the compound of Example 1-1, 8-1, 9-1,
10-1, 11-1, 18-1, 19-1, or 23-1;
(187) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(188) the compound according to (187) which is the compound of Example 1-3, 1-11,
1-14, 1-18, 1-30, 4-1, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-12, 8-13, 8-21, 8-26, 10-3, 10-7, 18-3,
18-7, 18-8, 18-31, 19-3, 19-4, 19-8, 19-31, or 19-40;
(189) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R!)(R2), one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted;
(190) the compound wherein the ring A has a structure of the formula (l-b), absolute
47

configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the
other is a lower alkyl group compound wherein
(191) the compound according to (190) which is the compound of Example 1-3, 8"3, 8-4,
8-5, 8-26, 18-3, 19-3, or 19-4;
(192) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the
other is methyl group, or ethyl group!
(193) the compound according to (192) which is the compound of Example 1"3, 8"3, 8-4,
10-3, 18-3, 19-3, or 19"4;
(194) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(RX)(R2), one of R1 and R2 is hydrogen atom, and the
other is methyl group!
(195) the compound according to (194) which is the compound of Example 1"3, 8"3, 10-3,
18-3, or 19-3;
(196) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and
the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(197) the compound according to (196) which is the compound of Example 7-1, 25-1,
29-1, 30-1, 35-1, 36-1, 37-1, or 38"l;
(198) the compound wherein the ring A has a structure of the formula (l-b), absolute
48

configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is -NG^XR2), one
of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which
may be substituted, an aralkyl group which may be substituted, or a saturated
heterocyclic group which may be substituted;
(199) the compound according to (198) which is the compound of Example 7-1, 29" 1,
30-1, 35-1, 36-1, 37-1, or 38-1;
(200) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is an alkyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(201) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is an alkenyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(202) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(203) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is N(R1)(R2), and R1 and R2 are both hydrogen atoms;
(204) the compound according to (203) which is the compound of Example 7"1, 25-1,
29-1, or 30-1;
(205) the compound wherein the ring A has a structure of the formula (l"b), absolute
49

configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and
the other is an alkyl group which may be substituted;
(206) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and
the other is a lower alkyl group;
(207) the compound wherein the ring A has a structure of the formula (l'b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and
the other is methyl group, or ethyl group;
(208) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and
the other is methyl group!
(209) the compound according to (208) which is the compound of Example 35-1, 36-1,
37-1, or 38-1;
(210) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is an aralkyl
group which may be substituted;
(211) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydroxyl
group, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
50

atoms, G4 is -NCROCR2), one of R1 and R2 is hydrogen atom, and the other is a saturated
heterocyclic group which may be substituted;
(212) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of
R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may
be substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(213) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, G3 and G5 are both
hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is
hydrogen atom, an alkyl group which may be substituted, an aralkyl group which may
be substituted, or a saturated heterocyclic group which may be substituted;
(214) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkyl group which may be substituted,
G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom,
and the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl
group which may be substituted, or a saturated heterocyclic group which may be
substituted;
(215) the compound wherein the ring A has a structure of the formula (l'b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkenyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted!
(216) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
51

substituted, G3 and G5 are both hydrogen atoms, G4 is -N(RX)(R2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(217) the compound wherein the ring A has a structure of the formula (l'b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), and R1
and R2 are both hydrogen atoms,'
(218) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of
R1 and R2 is hydrogen atom, and the other is an alkyl group which may be substituted;
(219) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), one of
R1 and R2 is hydrogen atom, and the other is a lower alkyl group,'
(220) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), one of
R1 and R2 is hydrogen atom, and the other is methyl group, or ethyl group,'
(221) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which
may be substituted, an alkenyl group which may be substituted, or an alkynyl group
which may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of
52

R1 and R2 is hydrogen atom, and the other is methyl group;
(222) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is
hydrogen atom, and the other is an aralkyl group which may be substituted!
(223) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, chlorine atom, or hydroxyl group, G2 is an alkynyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is
hydrogen atom, and the other is a saturated heterocyclic group which may be
substituted!
(224) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and
R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(225) the compound according to (224) which is the compound of Example 1"2, 4-2, 7-2,
8-2, 9-2, 10-2, 11-2, 18-2, 19-2, 23-2, 25-2, 27, 29-2, 30-2, 31"2, 32-2, 33-2, 34-2, 35-2,
36-2, 37-2, or 38-2;
(226) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4
is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an
alkyl group which may be substituted, an aralkyl group which may be substituted, or a
saturated heterocyclic group which may be substituted;
(227) the compound according to (226) which is the compound of Example 1-2, 4-2, 7-2,
18-2, 19-2, 29-2, 30-2, 31-2, 32-2, 33-2, 35-2, 36-2, 37-2, or 38-2;
(228) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
53

atom, or hydroxyl group, G2 is an alkyl group which may be substituted, G3 and G5 are
both hydrogen atoms, G4 is -NdlOdi2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(229) the compound according to (228) which is the compound of Example 8"2, 11-2,
23-2, 25-2, 27, or 34-2;
(230) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkenyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(231) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(232) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is N(R1)(R2), and R1 and
R2 are both hydrogen atoms;
(233) the compound according to (232) which is the compound of Example 1"2, 7"2, 8-2,
9-2, 10-2, 11-2, 18-2, 19-2, 23-2, 25-2, 29-2, or 30-2;
(234) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(RX)(R2), one of R1 and
R2 is hydrogen atom, and the other is an alkyl group which may be substituted!
(235) the compound wherein the ring A has a structure of the formula (l"b), absolute
54

configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and
R2 is hydrogen atom, and the other is a lower alkyl group,"
(236) the compound according to (235) which is the compound of Example 27, 31-2, 32-2,
33-2, 34-2, 35-2, 36-2, 37-2, or 38"2;
(237) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the
other is an aralkyl group which may be substituted;
(238) the compound according to (237) which is the compound of Example 4-2, or 38-2;
(239) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is a saturated heterocyclic group which may be substituted;
(240) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted,"
(241) the compound according to (240) which is the compound of Example 1-2, 4"2, 8'2,
9-2, 10-2, 11-2, 18-2, 19-2, 23-2, 31-2, 32-2, 33-2, or 34-2;
(242) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is -N(RX)(R2), one of
R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may
be substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
55

(243) the compound according to (242) which is the compound of Example 1-1,4-2, 8"2,
18-2, 19-2, 31-2, 32-2, or 33-2;
(244) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, G2 is an alkyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(245) the compound according to (244) which is the compound of Example 8-2, 11-2,
23-2, 27, or 34-2;
(246) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, G2 is an alkenyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(247) the compound wherein the ring A has a structure of the formula (l'b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
(248) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is -N(R1)(R2), and R1 and R2 are both hydrogen atoms!
(249) the compound according to (248) which is the compound of Example 1-2, 8-2, 9-2,
10-2, 11-2, 18-2, 19-2, or 23-2;
(250) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
56

are both hydrogen atoms, G4 is -NXROCR2), one of R1 and R2 is hydrogen atom, and the
other is an alkyl group which may be substituted;
(251) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydrogen
atom, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl group
which may be substituted, or an alkynyl group which may be substituted, G3 and G5
are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the
other is a lower alkyl group!
(252) the compound according to (251) which is the compound of Example 27, 31-2, 32-2,
33-2, or 34-2;
(253) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and
the other is hydrogen atom, an alkyl group which may be substituted, an aralkyl group
which may be substituted, or a saturated heterocyclic group which may be substituted;
(254) the compound according to (253) which is the compound of Example 7"2, 25-2,
29-2, 30-2, 35-2, 36-2, 37-2, or 38-2;
(255) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is Reconfiguration, G1 is hydroxyl
group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), one
of R1 and R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which
may be substituted, an aralkyl group which may be substituted, or a saturated
heterocyclic group which may be substituted;
(256) the compound according to (255) which is the compound of Example 7-2, 29-2,
30-2, 35-2, 36-2, 37-2, or 38-2;
(257) the compound wherein the ring A has a structure of the formula (l'b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydroxyl
group, G2 is an alkyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is hydrogen
atom, an alkyl group which may be substituted, an aralkyl group which may be
substituted, or a saturated heterocyclic group which may be substituted;
57

(258) the compound wherein the ring A has a structure of the formula (l'b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -NQlOCR2), and R1 and R2 are both hydrogen atoms!
(259) the compound according to (258) which is the compound of Example 7-2, 25-2,
29-2, or 30-2;
(260) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and
the other is an alkyl group which may be substituted;
(261) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydroxyl
group, G2 is a halogen atom, an alkyl group which may be substituted, an alkenyl
group which may be substituted, or an alkynyl group which may be substituted, G3 and
G5 are both hydrogen atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and
the other is a lower alkyl group,"
(262) the compound according to (263) which is the compound of Example 35-2, 36-2,
37-3, or 38-2;
(263) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydroxyl
group, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R0(R2), one of R1 and R2 is hydrogen atom, and the other is an aralkyl
group which may be substituted;
(264) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydroxyl
group, G2 is an alkynyl group which may be substituted, G3 and G5 are both hydrogen
atoms, G4 is -N(R1)(R2), one of R1 and R2 is hydrogen atom, and the other is a saturated
heterocyclic group which may be substituted;
(265) the compound wherein the ring A has a structure of the formula (l-c), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, an alkyl group which may be
58

substituted, an alkenyl group which may be substituted, or an alkynyl group which
may be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and
R2 is hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted;
(266) the compound wherein the ring A has a structure of the formula (l-c), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, or an alkyl group which may
be substituted, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one of R1 and R2 is
hydrogen atom, and the other is hydrogen atom, an alkyl group which may be
substituted, an aralkyl group which may be substituted, or a saturated heterocyclic
group which may be substituted!
(267) the compound wherein the ring A has a structure of the formula (l-c), G1 is
hydrogen atom, or hydroxyl group, G2 is a halogen atom, or an alkyl group which may
be substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R1)(R2), and R1 and R2 are
both hydrogen atoms!
(268) the compound according to (267) which is the compound of Example 2-1,2-2, 20-1,
20-2, 21-1, 21-2, 22-1, or 22"2!
(269) the compound wherein the ring A has a structure of the formula (l-c), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, or an alkyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R!)(R2), and R1 and R2 are
both hydrogen atoms!
(270) the compound according to (269) which is the compound of Example 2-1, 20-1,
21-1, or 22-1;
(271) the compound wherein the ring A has a structure of the formula (l-c), absolute
configuration of the carbon atom to which G4 binds is R-configuration, G1 is hydrogen
atom, or hydroxyl group, G2 is a halogen atom, or an alkyl group which may be
substituted, G3 and G5 are both hydrogen atoms, G4 is -N(R0(R2), and R1 and R2 are
both hydrogen atoms!
(272) the compound according to (271) which is the compound of Example 2-2, 20"2,
21-2, or 22-2!
(273) the compound wherein the ring A has a structure of the formula (l"b), absolute
configuration of the carbon atom to which G4 binds is S-configuration, G1 is amino
59

group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is -NCROCR2), one
of R1 and R2 is hydrogen atom, and the other is hydrogen atom, or an alkyl group;
(274) the compound wherein the ring A has a structure of the formula (l-b), absolute
configuration of the carbon atom to which G4 binds is S^configuration, G1 is amino
group, G2 is a halogen atom, G3 and G5 are both hydrogen atoms, G4 is -NCROGi2), one
of R1 and R2 is hydrogen atom, and the other is hydrogen atom, or methyl group;
(275) the compound according to (274) which is the compound of Example 39" 1, 40-1,
41-1, or 42-1;
(276) a salt of the compound according to any one of (l) to (275); and
(277) a derivative of the compound according to any one of (l) to (275), which is a
prodrug.
[0062]
The compounds of the present invention are novel compounds not described in
literatures. The compounds of the present invention represented by the general
formula (l) can be prepared by, for example, the following methods. However, the
preparation methods of the compounds of the present invention are not limited to the
following preparation methods.
In each reaction, reaction time is not particularly limited. Advance of the
reactions can be readily monitored by the analysis means described later, and
therefore the reactions may be terminated when yields of the objective substances
reach the maximum.
The compound represented by the general formula (l) can be decomposed into
a compound represented by the formula (4) and a compound represented by the
formula (5) according to the following reaction route. Therefore, the compounds of the
present invention can be prepared by the synthesis route reverse to the following
reaction route.
[0064]
(Preparation method l)
[Formula 3]
60


For example, the compounds represented by the general formula (l) can be
prepared by simultaneously or successively removing all the protective groups of a
compound represented by the general formula (2) [in the formula, A, m, and n have the
same meanings as those defined above, G2a, G3a, G4a and G5a have the same meanings
as those of G2, G3, G4 and G5 mentioned above, respectively, and one or more of these
groups may be protected], or a compound represented by the general formula (2"a)[in
the formula, A, m, n, G2a, G3a, G4a, and G5a have the same meanings as those defined
above, Gla is chlorine atom, hydroxyl group, an alkoxy group, or amino group, and
these groups may be protected] (Step 1-1).
The deprotection reactions can be carried out according to known methods, for
example, the methods described in "Protective Groups in Organic Synthesis",
published by John Wiley and Sons (1999), and the like. When Gla, G2a, G3a, G4a and
G5a are the same groups as G1, G2, G3, G4 and G5, respectively, the compounds of the
formula (2) and the formula (2-a) constitute a part of the compounds of the formula (l),
and thus Step 1-1 mentioned above is not required for the preparation.
[0065]
Further, the compounds of the formula (2) wherein G4a is -N(Rla)(R2a) [in the
formula, Rla and R2a have the same meanings as those of R1 and R2 mentioned above,
respectively, and one or more of these groups may be protected, provided that R2a is not
hydrogen atom] can be prepared from a compound of the formula (2) wherein G4a is
■NH(Rla) [Rla has the same meaning as that defined above].
61

Namely, such compounds can be prepared by subjecting a compound of the
formula (2) wherein G4a is -NH(Rla) to alkylation or reductive amination corresponding
to introduction of R2a. This method can be performed also for a compound of the
formula (2-a) wherein G4a is -NH(Rla).
[0066]
Examples of the method for the alkylation include, for example, a method of
using a halide of R2a (chloride, bromide, iodide, and the like). The reaction can
usually be performed in the presence of a base. As the base, for example, an inorganic
base is preferred, and examples include potassium carbonate, sodium carbonate,
cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium
hydroxide. Particularly preferred is potassium carbonate. The halide of R2a is
preferably used in an amount of 1 fold mole or more, particularly preferably 2 to 10 fold
moles, based on the compound of the formula (2) wherein G4a is -NH(Rla) [Rla has the
same meaning as that defined above]. Examples of the reaction solvent include, for
example, water, alcohol solvents such as methanol, and ethanol, inert solvents such as
N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, dimethyl
sulfoxide, and acetonitrile, and the like, which can be used independently or as a
mixed solvent thereof, and preferred are water, N,N-dimethylformamide, and acetone.
The reaction temperature is, for example, -10°C or higher, preferably 0 to 80°C. The
reaction time is, for example, usually 0.5 hour or longer, preferably 2 to 20 hours.
As for the reductive amination, the compounds can be prepared by, for example,
using an aldehyde or ketone corresponding to R2a according to the method of Step 1-7,
i) described later.
[0067]
Further, the compounds represented by the general formula (2~a) can be
prepared by, for example, any one of the following methods.
(i) The compounds of the formula (2-a) wherein Gla is chlorine atom can be prepared by
allowing a chlorinating reagent to act on a compound of the general formula (2"b) [in
the formula, A, m, n, G2a, G3a, G4a, and G5a have the same meanings as those defined
above] to clorinate it (Step 1-2). Examples of the chlorinating reagent include, for
example, phosphorous trichloride, phosphorous pentachloride, and phosphorus
oxychloride, and preferred examples include phosphorus oxychloride. The
chlorinating reagent is preferably used in an amount of 0.1 fold mole or more,
62

particularly preferably 1 to 10 fold moles, based on the compound of the formula (2-b).
As for the solvent, examples of the method include a method of performing the reaction
without solvent or in an inert solvent, and preferred examples include a method of
performing the reaction without solvent, or using dichloromethane, 1,2-dichloroethane,
chloroform, or toluene as the solvent. The reaction is preferably carried out at room
temperature or a higher temperature. The reaction time is preferably 0.1 to 48 hours.
[0068]
(ii) The compounds of the formula (2~a) wherein Gla is hydroxyl group can be prepared
by hydroxylating a compound of the formula (2-a) wherein Gla is chlorine atom
obtainable as described above. A hydrolysis reaction performed under an acidic
condition is preferred, and hydrolysis in a mineral acid is more preferred. Examples
of the mineral acid for use include, for example, hydrochloric acid, sulfuric acid, nitric
acid, and the like, and hydrochloric acid is particularly preferred. The acid is
preferably used in an amount of 0.1 fold mole or more, particularly preferably 1 to 100
fold moles, based on the compound of the formula (2-a) wherein Gla is chlorine atom.
As for the solvent, examples of the method include a method of performing the reaction
without solvent or in an inert solvent, and preferred examples include a method of
performing the reaction without solvent, or using water, or an ether solvent such as
tetrahydrofuran, and 1,4-dioxane. The reaction can be performed, for example, at
room temperature or a higher temperature. The reaction time is preferably 0.1 to 48
hours.
[0069]
(iii) The compounds of the formula (2-a) wherein Gla is an alkoxy group can be
prepared by alkoxylating a compound of the formula (2-a) wherein Gla is chlorine atom
obtainable as described above. An alkoxylation reaction under an acidic condition is
preferred, and a reaction with a corresponding alcohol in a mineral acid is more
preferred. Examples of the mineral acid for use include, for example, hydrochloric
acid, sulfuric acid, nitric acid and the like, and hydrochloric acid is particularly
preferred. The acid is preferably used in an amount of 0.1 fold mole or more,
particularly preferably 1 to 100 fold moles, based on the compound of the formula (2-a)
wherein Gla is chlorine atom. As for the solvent, examples of the method include a
method of performing the reaction without solvent or in an inert solvent, and preferred
examples include a method of performing the reaction without solvent or using an
63

ether solvent such as tetrahydrofuran and 1,4-dioxane. The alcohol is preferably used
in an amount of 0.1 fold mole or more, particularly preferably 1 to 100 fold moles,
based on the compound of the formula (2-a) wherein Gla is chlorine atom. The
reaction can be performed, for example, at room temperature or a higher temperature.
The reaction time is preferably 0.1 to 48 hours.
[0070]
Further, the compounds of the formula (2-a) wherein Gla is an alkoxy group
can be prepared directly from a compound of the aforementioned formula (2-b). For
example, a method of allowing a corresponding alcohol to act on a compound of the
formula (2"b) in an inert solvent in the presence of chloroformic acid ester and a base is
preferred. As for the solvent, examples of the method include a method of performing
the reaction without solvent or in an inert solvent, and the reaction can be preferably
performed without solvent. Examples of the chloroformic acid ester include, for
example, methyl chloroformate, ethyl chloroformate, and the like, and it is usually
preferable to use a respective corresponding chloroformic acid ester, for example,
methyl chloroformate for methoxylation, ethyl chloroformate for ethoxylation, and the
like. Examples of the base include, for example, organic bases such as trie thy lamine,
N,N-diisopropylethylamine, and pyridine, and inorganic bases such as potassium
carbonate, and sodium hydrogencarbonate. An organic base is preferred, and
triethylamine is particularly preferred. The base and the chloroformic acid ester are
usually used in an amount of 1 to 20 fold moles, preferably 1.1 to 5 fold moles, based on
the compound of the formula (2"b). The reaction temperature is about -10 to 40°C,
preferably about 0 to 30°C. The reaction time is preferably 0.1 to 48 hours.
[0071]
Further, the compounds of the formula (2-a) wherein Gla is hydroxyl group can
be prepared from a compound of the formula (2-a) wherein Gla is an alkoxy group. A
solvolysis reaction under an acidic condition is preferred, and solvolysis in a mineral
acid is more preferred. Examples of the mineral acid for use include, for example,
hydrochloric acid, sulfuric acid, nitric acid, and the like, and hydrochloric acid is
particularly preferred. The acid is preferably used in an amount of 0.1 fold mole or
more, particularly preferably 1 to 100 fold moles, based on the compound of the
formula (2-a) wherein Gla is an alkoxy group (for example, methoxy group, ethoxy
group, and the like). As for the solvent, examples include a method of using water, an
64

alcohol such as methanol and ethanol, an ether solvent such as tetrahydrofuran and
1,4-dioxane, and the like, and an alcohol is preferred. The reaction can be performed,
for example, at room temperature or a higher temperature. The reaction time is
preferably 0.1 to 48 hours.
[0072]
(iv) The compounds of the formula (2-a) wherein Gla is amino group can be prepared by
aminating a compound of the formula (2-a) wherein Gla is chlorine atom obtainable as
described above. For the amination, ammonia is preferably used, and aqueous
ammonia of a concentration of 5% or higher is more preferably used. As for the
amount of ammonia, it is preferably used in an amount of 0.1 fold mole or more,
particularly preferably 1 to 100 fold moles, in terms of the NH3 content. As for the
reaction solvent, examples of the method include a method of performing the reaction
without solvent or in an inert solvent, and preferred examples include a method of
performing the reaction without solvent or using an ether solvent such as
tetrahydrofuran and 1,4-dioxane. The reaction can be performed, for example, at
room temperature or a higher temperature. The reaction time is preferably 0.1 to 48
hours.
[0073]
The compounds represented by the general formula (2"b) can be prepared by
oxidizing a compound represented by the general formula (2) (Step 1"3). Examples of
the oxidizing agent include aqueous hydrogen peroxide, sodium periodate, sodium
perborate, 3-chloroperbenzoie acid, ruthenium trichloride, dimethyldioxirane, and the
like, and 3-chloroperbenzoic acid is preferred. The oxidizing agent is preferably used
in an amount of 0.1 fold mole or more, particularly preferably 1 to 20 fold moles, based
on the compound of the formula (2). Examples of the solvent include, for example,
acetic acid, trifluoroacetic acid, dichloromethane, 1,2-dichloroethane, chloroform,
acetonitrile, acetone, trichlorofluoromethane, benzene, 1,4-dioxane, tert-butanol,
water, and a mixed solvent thereof, and preferred examples include acetic acid. The
reaction is preferably carried out at room temperature or a higher temperature.
[0074]
The compounds represented by the general formula (2) can be prepared from a
compound represented by the general formula (3) [in the formula, A, m, n, G3a, G4a, and
G5a have the same meanings as those defined above, and X represents a halogen atom]
65

(Step 1-4). In the implementation of Step 1-4, X in the formula (3) represents a
halogen atom, and X is preferably chlorine atom, or bromine atom, particularly
preferably bromine atom. When G2a is the same group as X, the compounds of the
formula (3) constitute a part of the compounds of the formula (2), and therefore Step
1-4 mentioned above is not required for the preparation.
[0075]
Step 1-4 can be performed by any one of the following methods,
(i) The compounds of the formula (2) wherein G2a is an alkyl group which may be
substituted, an alkenyl group which may be substituted, an alkynyl group which may
be substituted, or an aryl group which may be substituted, and these groups may be
protected can be prepared from a compound of the formula (3). Namely, it is
preferable to alkylate, alkenylate, alkynylate, or arylate a compound of the formula (3)
in an inert solvent. Examples of the inert solvent include, for example, ether solvents
such as diethyl ether, tetrahydrofuran, and 1,2-dimethoxyethane, acetonitrile,
N,N-dimethylformamide, water, and mixed solvents thereof. The alkylation,
alkenylation, alkynylation, and arylation can be preferably performed, for example, by
reacting an alkylating reagent, an alkenylating reagent, an alkynylating reagent, or
an arylating reagent in the presence of a nickel catalyst or palladium catalyst.
[0076]
Examples of the nickel catalyst include, for example,
dichloro(l,l'-bis(diphenylphosphino)ferrocene)nickel(II),
dichloro(l,3-bis(diphenylphosphino)propane)nickel(II), and
bis(acetylacetonato)nickel(II), and examples of the palladium catalyst include, for
example, dichloro(l,l'-bis(diphenylphosphino)ferrocene)palladium(ll),
tetrakis(triphenylphosphine)palladium(0),
dichloro(bis(triphenylphosphine))palladium(II), and
dichloro(bis(benzonitrile))palladium(II). Examples of the alkylating reagent,
alkenylating reagent, alkynylating reagent, and arylating reagent include, for example,
Grignard reagents such as magnesium methyl iodide and magnesium methyl bromide,
organic zinc reagents such as (ethoxycarbonylethyl)zinc bromide and
(ethoxycarbonylmethyl)zinc bromide, organic tin reagents such as allyltributyltin and
vinyltributyltin, organic aluminum reagents such as vinyldiisobutylaluminum, organic
boron reagents such as an alkylboronic acid, an alkenylboronic acid, and an
66

arylboronic acid, organic lithium reagents such as methyllithium and vinyllithium,
organic copper reagents such as an alkylcopper and an alkenylcopper, organic silicon
reagents such as vinyltrimethylsilane and trimethylsylilacetylene, and the like. The
alkylating reagent, alkenylating reagent, alkynylating reagent, and arylating reagent
are preferably used in an amount of 1 to 20 fold moles, and the catalyst is preferably
used in an amount of 0.0001 to 1 fold mole, based on the compound of the formula (3).
[0077]
The reaction is performed, for example, at 0 to 150°C, preferably room
temperature to 120°C, and the reaction time is preferably 0.1 to 48 hours. For
example, by using tetramethyltin as the aforementioned alkylating reagent, the
compounds of the formula (2) wherein G2a is methyl group can be prepared. By using
allyltributyltin, the compounds wherein G2a is allyl group can be prepared. By using
(ethoxycarbonylethyl)zinc bromide, the compounds wherein G2a is ethoxycarbonylethyl
group can be prepared. By using (ethoxycarbonylmethyl)zinc bromide, the
compounds wherein G2a is ethoxycarbonylmethyl group can be prepared. By using
vinyltributyltin, the compounds wherein G2a is vinyl group can be prepared. Further,
by using an arylboronic acid, the compounds wherein G2a is a corresponding aryl group
can be prepared.
[0078]
Further, the objective compounds can also be prepared by reacting an alkenyl
compound or alkynyl compound including acrylic acid esters, acrylonitrile, propargyl
alcohol derivatives, end acetylene derivatives, and the like in the presence of a
palladium catalyst, base, copper(I) iodide, or the like. As for these reactions, Heck
R.F. et al., J. Org. Chem., 2947 (1978); Sonogashira, K. et al., Tetrahedron, 2303 (1984),
and the like can be referred to. Examples of the palladium catalyst include
tetrakis(triphenylphosphine)palladium(0))
dichlorobis(triphenylphosphine)palladium(Il), those of palladium(H)
acetate/triphenylphosphine type, tris(dibenzylideneacetone)"
dipalladium(0)/tri(tert-butyl)phosphine type, dichlorobis(benzonitrile)-
palladium(0)/tri(tert-butyl)phosphine type, and the like. Examples of the base
include triethylamine, diethylamine, diisopropylamine, sodium acetate, sodium
hydroxide, lithium hydroxide, potassium fluoride, potassium carbonate, cesium
carbonate, cesium fluoride, sodium tert-butoxide, and the like. When protection with
67

a protective group and following deprotection are required in the aforementioned
synthesis, the reaction can be properly carried out by utilizing the aforementioned
methods of Greene and Wuts, and Kocienski.
[0079]
(ii) The compounds of the formula (2) wherein G2a is an amino group which may be
substituted (and may contain a protective group) can be prepared from a compound of
the formula (3). Examples include, for example, a method of aminating a compound of
the formula (3) in an inert solvent. The animation referred to here include not only
conversion into unsubstituted -NH2, but also conversion into an amino group which
may have one or more substituents. Examples of the inert solvent include, for
example, ether solvents such as tetrahydrofuran, 1,4-dioxane, and
1,2-dimethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl
sulfoxide, sulfolane, alcohol solvents such as methanol and ethanol, water, and mixed
solvents thereof. Examples of the aminating reagent include, ammonia, primary
amines such as methylamine, and secondary amines such as dimethylamine. The
aminating reagent is preferably used in an amount of 1 fold mole or more to a large
excess amount based on the compound of the formula (3). The reaction is preferably
performed at room temperature or under a heating condition up to about 200°C, and
the reaction time is preferably 0.5 to 72 hours.
[0080]
As an alternative method, the coupling of a compound of the formula (3) and
an aminating agent can be performed in an inert solvent in the presence of a palladium
catalyst, phosphorus compound, and base (according to, for example, Buchwald, S.L., J.
Org. Chem., 1158 (2000); Buchwald, S.L., Organic Letters, 1101 (2000)). Examples of
the inert solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane and
1,2-dimethoxyethane, toluene, and N,N-dimethylformamide, and examples of the
palladium catalyst include, for example, tris(dibenzylideneacetone)dipalladium(0),
palladium(II) acetate, and the like. Examples of the phosphorus compound include,
for example, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,
2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, xanthophos, and tri(tert-butyl)phosphine.
Examples of the base include, for example, sodium tert-butoxide, cesium carbonate,
potassium phosphate, and the like. Examples of the aminating agent include, for
example, lithium hexamethyldisilazide, primary amines such as methylamine,
68

secondary amines such as dimethylamine, and the like. By using lithium
hexamethyldisilazide, the compounds of the formula (2) wherein amino group is
introduced as G2a can be prepared. Further, by using methylamine, methylamino
group can be introduced, and by using dimethylamine, dimethylamino group can be
introduced.
[0081]
(iii) The compounds of the formula (2) wherein G2a is an alkoxy group which may be
substituted (and may contain a protective group) can be prepared from a compound of
the formula (3). Preferred examples of the method include a method of etherifying a
compound of the formula (3) in an inert solvent. Examples of the inert solvent include,
for example, ether solvents such as tetrahydrofuran, 1,4-dioxane, and
1,2-dimethoxyethane, solvents such as N,N-dimethylformamide, N-methylpyrrolidone,
dimethyl sulfoxide, and sulfolane, water, and mixed solvents thereof. Examples of the
etherifying reagent include, for example, metal alcoholates such as those of lithium,
sodium, and potassium (including, for example, Ci-6 alkoxides such as methylate, and
ethylate, 2-hydroxyethylate, 2-methoxyethylate, 2-methanesulfonylethylate, and the
like). The reaction is preferably carried out in the presence of a copper catalyst, and
the reaction temperature is room temperature to about 180°C. The etherifying agent
is preferably used in an amount of 1 to 20 fold moles. For example, if a methylate is
used as the metal alcoholate, the compounds of the formula (2) wherein methoxy group
is introduced as G2a can be obtained. By using an ethylate, ethoxy group can be
introduced, by using 2-hydroxyethylate, 2-hydroxyethoxy group can be introduced, by
using 2-methoxyethylate, 2-methoxyethoxy group can be introduced, and by using
2-methanesulfonylethylate, 2-methanesulfonylethoxy group can be introduced. The
reaction time is preferably 0.1 to 72 hours.
[0082]
As an alternative method, the compounds of the formula (2) wherein G2a is an
alkoxy group which may be substituted (and may conatin a protective group) can be
prepared by reacting a compound of the formula (3) with an etherifying agent in an
inert solvent in the presence of a palladium catalyst, phosphorus compound, and base
(according to, for example, Buchwald, S.L., J. Org. Chem., 1158 (2000); Buchwald, S.L.,
Organic Letters, 1101 (2000)). Examples of the inert solvent include, for example,
ether solvents such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, and
69

toluene. Examples of the palladium catalyst include, for example, palladium(II)
acetate , tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate and the like.
Examples of the phosphorus compound include, for example,
2-(di-tert-butylphosphino)biphenyl, 2-(di"tert-butylphosphino)-l,l'-binaphthyl, and
2-(di-tert"butylphosphino)-2'-dimethylamino-l,r-binaphthyl. Examples of the base
include, for example, sodium tert'butoxide, potassium tert-butoxide, cesium carbonate,
potassium phosphate, and the like. Examples of the etherifying agent include, for
example, alcohols including methanol, ethanol, ethylene glycol,
methanesulfonylethanol, and the like. Depending on the type of the alcohol used, the
compounds of the formula (2) wherein G2a is converted into a corresponding alkoxy
group are obtained. Further, when the alkyl moiety of the alkoxy group is a protective
group, the compounds can be converted into the compounds wherein G2a is hydroxyl
group by performing a deprotection reaction. When protection with a protective
group and following deprotection are required, the reactions can be properly performed
by utilizing the methods described by Greene and Wuts, and Kocienski.
[0083]
(iv) The compounds of the formula (2) wherein G2a is an alkylthio group which may be
substituted (and may contain a protective group) can be prepared from a compound of
the formula (3). Preferred examples of the method include a method of
alkylthiolating a compound of the formula (3) in an inert solvent. Examples of the
inert solvent include, for example, solvents such as tetrahydrofuran, 1,4-dioxane,
l,2-dimethoxyethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl
sulfoxide, sulfolane, methanol, ethanol, and propanol, water, and mixed solvents
thereof. Examples of the alkylthiolating reagent include, for example, metal thiolates
such as those of lithium, sodium, and potassium (for example, Ci-6 alkylthiolates
including methylthiolate, ethylthiolate, and the like). The alkylthiolating reagent is
preferably used in an amount of 1 to 20 fold moles, and the reaction is preferably
carried out at room temperature to about 180°C. The reaction time is preferably 0.1
to 72 hours.
[0084]
The compounds of the formula (2) wherein G2a is an alkylsulfinyl group which
may be substituted (and may contain a protective group) can be prepared from a
compound of the formula (2) wherein G2a is an alkylthio group which may be
70

substituted (and may contain a protective group). Preferred examples of the method
include a method of oxidizing a compound of the formula (2) wherein G2a is an alkylthio
group which may be substituted (and may contain a protective group) in an inert
solvent. Examples of the inert solvent include, for example, dichloromethane,
chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, tert'butanol, acetic acid,
trifluoroacetic acid, water, and mixed solvents thereof. Examples of the oxidizing
agent include, for example, sodium metaperiodate, 3-chloroperbenzoic acid, and
hydrogen peroxide. The oxidizing agent is preferably used in an amount of 0.3 to 2
fold moles based on the starting compound, and the reaction time is preferably 0.1 to
48 hours.
[0085]
The compounds of the formula (2) wherein G2a is an alkylsulfonyl group which
may be substituted (and may contain a protective group) can be prepared from a
compound of the formula (2) wherein G2a is an alkylthio group which may be
substituted (and may contain a protective group). Preferred examples of the method
include a method of oxidizing a compound of the formula (2) wherein G2a is an alkylthio
group which may be substituted (and may contain a protective group) in an inert
solvent. The reaction can be performed by using an inert solvent and an oxidizing
agent similar to those used for the aforementioned oxidation step, and the oxidizing
agent is preferably used in an amount of 2 fold moles or more based on the starting
compound. As an alternative method, the compounds of the formula (2) wherein G2a
is an alkylsulfonyl group which may be substituted (and may contain a protective
group) can be prepared from a compound of the formula (3). Preferred examples of
the method include a method of sulfonylating a compound of the formula (3) in an inert
solvent. Examples of the inert solvent include, for example, solvents such as
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide,
N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, methanol, ethanol, and propanol,
water, and mixed solvents thereof. Examples of the sulfonylating reagent include, for
example, sodium or potassium alkylsulfinates, and they enables conversion into a
compounds of the formula (2) wherein G2a is a corresponding alkylsulfonyl group. The
reaction is preferably performed at room temperature to about 180°C. The reaction
time is preferably 0.1 to 48 hours. When protection with a protective group and
following deprotection are required, the reaction can be properly carried out by
71

utilizing the aforementioned methods described by Greene and Wuts, and Kocienski.
[0086]
(v) The compounds of the formula (2) wherein G2a is cyano group can be prepared from
a compound of the formula (3). Preferred examples of the method include a method of
cyanating a compound of the formula (3) in an inert solvent by using a suitable
cyanating agent (according to, for example, Newman, M.S. et al., J. Org. Chem., 2525
(1961)). Examples of the inert solvent include, for example, solvents such as
tetrahydrofuran, l,4"dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide,
N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, methanol, ethanol, and propanol,
water, and mixed solvents thereof. Examples of the cyanating agent include, for
example, copper(I) cyanide, sodium cyanide, potassium cyanide, zinc cyanide, silver
cyanide, potassium ferrocyanide, and the like. The cyanating agent is preferably used
in an amount of 1 to 20 fold moles, and the reaction is preferably carried out at room
temperature to about 180°C.
[0087]
As an alternative method, the coupling of a compound of the formula (2) and
the aforementioned cyanating agent can be performed in an inert solvent in the
presence of a catalyst and a phosphorus compound (according to, for example,
Weissman, S.A. et al., J. Org. Chem., 2005, 70, 1508). Examples of the catalyst
include dichloro(l,r-bis(diphenylphosphino)ferrocene)palladium(II),
tetrakis(triphenylphosphine)palladium(0),
dichloro(bis(triphenylphosphine))palladium(II),
dichloro(bis(benzonitrile))palladium(II), tris(dibenzylideneacetone)dipalladium(0),
palladium(II) acetate, dichloro(l,l'-bis(diphenylphosphino)ferrocene)nickel(II),
dichloro(l,3-bis(diphenylphosphino)propane)nickel(II),
dibromo(bis(triphenylphosphine))nickel(II), bis(acetylacetonato)nickel(II), and the like.
Examples of the phosphorus compound include, for example,
2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,
2,2'-bis(diphenylphosphino)-l,r-binaphthyl, l,l'-bis(diphenylphosphino)ferrocene,
xanthophos, and tri(tert"butyl)phosphine. When protection with a protective group
and following deprotection are required in the aforementioned synthesis, the reaction
can be properly carried out by utilizing the aforementioned methods described by
Greene and Wuts, and Kocienski. In addition, the compounds of the formula (2)
72

wherein G2a is carboxy group can be prepared from a compound of the formula (2)
wherein G2a is cyano group. Preferred examples of the method include a method of
hydrolyzing a compound of the formula (3) in an inert solvent under a known
appropriate acidic condition, or basic condition (according to, for example, Marvel, C.S.
et al., J. Am. Chem. Soc, 1945, 67, 2250).
[0088]
The compounds represented by the aforementioned formula (3) can be
prepared by coupling a compound represented by the general formula (4) [in the
general formula (4), X and G3a have the same meanings as those defined above] and a
compound represented by the general formula (5) [in the general formula (5), A, m, n,
G4a, and G5a have the same meanings as those defined above] in an inert solvent in the
presence of a base (Step 1-5). Examples of the inert solvent include, for example,
halogenated hydrocarbons such as dichloromethane, chloroform, and
1,2-dichloroethane, and acetonitrile. Examples of the base include, for example,
organic bases such as triethylamine, N,N-diisopropylethylamine, and pyridine, and
inorganic bases such as potassium carbonate, and sodium hydrogencarbonate. The
base and the compound of the formula (5) are usually used in an amount of 1 to 6 fold
moles, preferably 1.1 to 3.3 fold moles, based on the compound of the formula (4), and
the reaction temperature is about -10 to 40°C, preferably about 0 to 30°C. The
reaction time is preferably 0.1 to 48 hours.
[0089]
The compounds represented by the aforementioned formula (4) can be
prepared form a compound represented by the general formula (6) [in the formula, X
and G3a have the same meanings as those defined above] by a known method (Japanese
Patent No. 2763791), or a similar method (Step 1"6).
The compounds represented by the aforementioned formula (5) can be
prepared from a compound represented by the general formula (7) [in the formula, A,
m, n, and G5a have the same meanings as those defined above, G4b and G4c together
represent oxo group, or one of G4b or G4c represents hydrogen atom, and the other
represents hydroxyl group, or amino group, these hydroxyl group and amino group may
be protected with a protective group! and Z represents hydrogen atom, or an amino
protective group] by the following various methods (Step 1-7). As for the combination
of G4b and G5c, the compounds of the formula (7) except for the compounds wherein G4b
73

and G4c together form oxo group constitute a part of the compounds of the formula (5),
and therefore Step 1-7 mentioned above is not required in such a case.
[0090]
i) The compounds of the formula (5) wherein G4a is -NCROCR2) (which may contain a
protective group) can be prepared by coupling a compound of the formula (7) wherein
G4b and G4c together represent oxo group, and a compound represented by the following
formula (8):
H-N(Ri)(R2) (8)
[in the formula, R1 and R2 have the same meanings as those defined above, and one ore
more of these group may be protected]. A method of performing the coupling by
allowing a reducing agent to act on the compound in a solvent is preferred. Examples
of the reducing agent include, for example, metal hydride reducing agents such as
sodium borohydride, zinc borohydride, sodium triacetoxyborohydride, borane/dimethyl
sulfide complex, borane/pyridine complex, borane/triethylamine complex,
borane/tetrahydrofuran complex, lithium triethylboride, and the like, and preferred
examples include sodium borohydride and sodium triacetoxyborohydride. The
reducing agent is used in an amount of, for example, 0.1 fold mole or more, preferably 1
to 20 fold moles, based on the compound of the formula (7). Examples of the solvent
include, for example, alcohols such as methanol, ethanol, and isopropanol, ethers such
as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, halogenated hydrocarbons
such as dichloromethane, chloroform, and 1,2-dichloroethane, N,N-dimethylformamide
and the like, and preferred examples include methanol, tetrahydrofuran, and
1,2-dichloroethane. The reaction temperature is, for example 0°C or higher,
preferably 10°C to the reflux temperature of the solvent. The reaction time is, for
example, 0.1 hour or longer, preferably 0.5 to 30 hours.
[0091]
ii) The compounds of the formula (7) wherein G4b and G4c together represent oxo group
can be prepared by oxidizing a compound of the formula (7) wherein one of G4b and G4c
is hydrogen atom, and the other is hydroxyl group. As the method for the oxidization,
a usually used known method of converting a secondary alcohol into a ketone is widely
known, and the preparation can be easily attained by those skilled in the art
(according to, for example, Finney, N.S. et al., Org. Lett., 2002.4.3001).
Among the compounds of the formula (7) wherein one of G4b and G4c is
74

hydrogen atom, and the other is hydroxyl group or amino group, those compounds
wherein these hydroxyl group and amino group may be protected with a protective
group are known as cyclic amine compounds, and many commercial products are
provided. Therefore, those skilled in the art can easily perform the aforementioned
preparation method.
Further, the compounds of the formula (8) are known as primary or secondary
amines, and many commercial products are provided. Therefore, those skilled in the
art can easily perform the aforementioned preparation method.

For example, the compounds of the general formula (l) wherein G1 is chlorine
atom, hydroxyl group, an alkoxy group, or amino group, G2 is a halogen atom, or an
alkyl group which may be substituted, and G3 is hydrogen atom can be prepared by
simultaneously or successively removing all protective groups of a compound
represented by the general formula (2-a-l) when protective groups are present [in the
formula, Glb is chlorine atom, hydroxyl group, an alkoxy group, or amino group, G2b is
a halogen atom, or an alkyl group which may be substituted, and A, m, n, G4a, and G5a
have the same meanings as those defined above] according to the method of Step 1-1
mentioned above. When G4a and G5a are the same groups as G4 and G5, the
compounds of the formula (2-a-l) constitute a part of the compounds of the formula (l),
and therefore Step 1-1 is not required for the preparation.
Further, the compounds of the formula (2-a-l) wherein G4a is -N(Rla)(R2a) [in
75

the formula, Rla and R2a have the same meanings as those of R1 and R2 mentioned
above, respectively, and one or more of these groups may be protected, provided that
R2a is not hydrogen atom] can be prepared from a compound of the formula (2-a-l)
wherein G4a is -NH(Rla) [Rla has the same meanings as that defined above] in the same
manner as that of Preparation method 1.
The compounds of the general formula (2-a-l) can be prepared by using a
compound represented by the general formula (2-c) [in the formula, A, m, n, G2b, G4a,
and G5a have the same meanings as those defined above] in Step 2-2 described below.
When G1 in the general formula (2-a-l) is chlorine atom, the compounds of the formula
(2-c) constitute a part of the compounds of the formula (2-a-l), and therefore Step 2-2 is
not required for the preparation.
[Step 2-2]
(i) When Glb is hydroxyl group, the objective compounds can be prepared according to
the method of converting a compound of the formula (2-a) wherein Gla is chlorine atom
into a compound of the formula (2-a) wherein Gla is hydroxyl group mentioned in
Preparation method 1.
(ii) When Glb is an alkoxy group, the objective compounds can be prepared according to
the method of converting a compound of the formula (2-a) wherein Gla is chlorine atom
into a compound of the formula (2-a) wherein Gla is an alkoxy group mentioned in
Preparation method 1.
(iii) When Glb is amino group, the objective compounds can be prepared according to
the method of converting a compound of the formula (2-a) wherein Gla is chlorine atom
into a compound of the formula (2-a) wherein Gla is amino group mentioned in
Preparation method 1.
[Step 2-3]
The compounds represented by the general formula (2-c) can be prepared from
a compound represented by the general formula (3"c) [in the formula, X represents a
halogen atom, and A, m, n, G4a, and G5a have the same meanings as those defined
above]. Among the compounds of the formula (2-c), those wherein G2b is an alkyl
group which may be substituted can be prepared according to the method of
Preparation method 1, Step 1-4, (i) (in this case, X in the formula (3-c) is preferably
chlorine atom or bromine atom, particularly preferably bromine atom). When G2b is a
halogen atom, the compounds of the formula (3-c) constitute a part of the compounds of
76

the formula (2-c), and therefore Step 2-3 is not required for the preparation.
[Step 2-4]
The compounds represented by the general formula (3-c) can be prepared from
a compound represented by the general formula (4-c) [in the formula, X is a halogen
atom] and a compound of the aforementioned formula (5) according to the method of
Preparation method 1, Step 1-5.
[Step 2-5]
The compounds represented by the general formula (4-c) can be prepared from
a compound represented by the general formula (6-c) [in the formula, X is a halogen
atom] according to the method of Preparation method 1, Step 6.
[Step 2-6]
The compounds represented by the general formula (6-c) can be prepared by
reducing a compound represented by the general formula (7-c) (for the nitro group
moiety) [in the formula, X is a halogen atom]. This reduction is preferably carried out
in an acidic solvent. Examples of the acidic solvent include hydrochloric acid, and
acetic acid, and preferred examples include hydrochloric acid. Examples of the
method of the reduction include a method of using a tin (divalent) reagent as the
reducing agent. Preferred examples of the tin (divalent) reagent include stannous
chloride, and hydrates thereof. The reaction temperature is -20°C or higher,
preferably 80 to 150°C. The reaction time is, for example, 2 hours or longer,
preferably 4 to 15 hours.
As an alternative method, the compounds represented by the general formula
(6-c) can be prepared from a compound of the general formula (7-c) by hydrogenation in
an inert solvent in the presence of a platinum catalyst. Examples of the inert solvent
include, for example, alcohols such as methanol, ethanol, and isopropanol, ethers such
as tetrahydrofuran, and 1,2-dimethoxyethane, which can be used independently or as a
mixed solvent thereof, and a mixed solvent of ethanol and tetrahydrofuran is preferred.
Examples of the platinum catalyst include platinum/activated carbon, and
platinum-sulfur/activated carbon, and platinum-sulfur/activated carbon is preferred.
The reaction temperature is -20°C or higher, preferably 10 to 30°C. The reaction time
is, for example, 1 hour or longer, preferably 10 to 20 hours.
[Step 2-7]
The compounds represented by the general formula (7-c) can be prepared by
77

chlorinating a compound represented by the general formula (8-c) [in the formula, X is
a halogen atom]. The preparation of this step can be performed according to the
method of Preparation method 1, Step 1-2, (i).
[Step 2-8]
The compounds represented by the general formula (8-c) can be prepared by
oxidizing a compound represented by the general formula (9*c) [in the formula, X is a
halogen atom]. The preparation of this step can be performed according to the
method of Preparation method 1, Step 1-3.
The compounds represented by formula (9-c) [in the formula, X is a halogen
atom] can be prepared according to the method described in Reference Example 1,
Reference Example 5, or Example 1.
[0092]
The compounds of the invention obtainable as described above, respective
starting compounds and preparation intermediates can be isolated and purified by
conventional isolation and purification methods such as extraction, distillation and
chromatography. Products obtained in the reactions can also be used as starting
materials of the following steps without purification as the case may be.
[0093]
Salts can be prepared from the compounds represented by general formula (l).
While the method for preparing the salts are not particularly limited, an acid addition
salt of the compound represented by general formula (l) can be obtained by dissolving
the compound in an alcohol such as methanol and ethanol, and adding an acid
component to the solution in an equivalent amount or an amount of several times in
excess. The acid component for use may be an acid component corresponding to the
acid addition salts described later, and preferable examples include physiologically
acceptable inorganic or organic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, hydrogen sulfuric acid, phosphoric acid, dihydrogen phosphoric acid,
hydrogen phosphoric acid, citric acid, maleic acid, tartaric acid, fumaric acid,
glucuronic acid and methanesulfonic acid. As for the method of preparing a base
addition salt, a base addition salt can be prepared by, for example, dissolving the
compound in an alcohol such as methanol and ethanol, and adding a base component to
the solution in an equivalent amount or an amount of several times in excess. The
base component for use may be a base component corresponding to the base addition
78

salts described below, and preferred examples thereof include physiologically
acceptable inorganic and organic bases such as sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, ammonia, and methylamine.
[0094]
Type of the salt of the compound represented by general formula (1) is not
particularly limited in the present invention, and may be either an acid addition salt
or a base addition salt, or may be in the form of an intramolecular counter ion pair.
Examples of the acid addition salt include hydrochloride, hydrobromide, sulfate,
hydrogen sulfate, phosphate, dihydrogen phosphate, hydrogen phosphate, citrate,
maleate, tartrate, fumarate, gluconate and methanesulfonate, or acid addition salts
with optically active acids such as camphorsulfonic acid, mandelic acid, or a
substituted mandelic acid. Examples of the base addition salt include metal salts
such as sodium salt and potassium salt, and base addition salts of organic bases such
as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, 2-aminoethanol,
tris(hydroxymethyl)aminomethane, arginine and lysine. However, the type of the salt
is of course not limited to those described above, and it may be appropriately selected
by those skilled in the art. Among these salts, physiologically acceptable salts are
preferred. The compounds of the invention may exist as a hydrate or solvate, and
these substances also fall within the scope of the invention.
[0095]
Prodrugs can be prepared from the compounds represented by the
aforementioned general formula (l) or salts thereof. In the specification, "prodrug of
a compound represented by the general formula (l) or a salt thereof means a
compound or a salt thereof that is oxidized, hydrolyzed, or the like in living bodies,
preferably in blood, after oral or parenteral administration to mammals to produce a
compound of the aforementioned general formula (l) or a salt thereof. For example,
many means are known for making medicaments having carboxyl group, amino group,
hydroxyl group or the like into prodrugs, and an appropriate means can be chosen by
those skilled in the art. For example, a prodrug can be prepared by appropriately
binding a group constituting prodrug (for example, an acyl group, an alkoxycarbonyl
group, an alkyl group, and the like) to one or more arbitrary groups selected from
hydroxyl group and amino group in a compound represented by the general formula (l)
in a conventional manner using a corresponding prodrug forming reagent such as
79

halides, and performing isolation and purification as required.
[0096]
Although type of the prodrug of the compound of general formula (l) of the
present invention is not particularly limited, examples include a compound in which a
group constituting prodrug is introduced into at least one group selected from hydroxy
group, and amino group of the compound represented by general formula (l).
Examples of the group constituting prodrug include, for example, an acyl group and an
alkoxycarbonyl group. Preferred example includes acetyl group, propionyl group,
methoxycarbonyl group, and ethoxycarbonyl group, and ethoxycarbonyl group is
particularly preferred. There are other embodiments in which acetyl group is
preferred, propionyl group is preferred, or methoxycarbonyl group is preferred.
[0097]
The compounds of the present invention represented by the aforementioned
formula (l) and physiologically acceptable salts thereof have cell movement inhibitory
actions on the basis of inhibition against phosphorylation of the myosin regulatory
light chain in the cells, and are useful as active ingredients of medicaments.
Among the cell movement inhibitory actions of the compounds of the present
invention, the cell contraction inhibitory action can be confirmed by measuring
vasoconstriction inhibitory activity, bronchus relaxation activity, intraocular pressure
reducing activity, respiratory tract constriction inhibitory activity, or the like. The
action to regulate change of cell morphology can be confirmed by, for example,
measuring neurite outgrowth of retinal ganglion cells of eyes, or the like. The
inhibitory action on cell migration (the action will be abbreviated as "cell migration
inhibitory action") can be confirmed by measuring neutrophil migration inhibitory
activity, respiratory tract inflammation suppressing activity, or the like. The cell
release inhibitory action can be confirmed by measuring the chemical mediator
releasing amount from neutrophils. The cell aggregation inhibitory action can be
confirmed by measuring platelet aggregation inhibitory activity, or the like. Further,
the apoptosis inhibitory action can be confirmed by, for example, giving stimulation to
induce apoptosis to cells and then measuring cell viability or occurring frequencies of
morphological changes of cells characteristic to apoptosis such as nuclear condensation,
nuclear fragmentation, and blebbing of cells. However, since the cell movement
inhibitory actions on the basis of the inhibition of phosphorylation of the myosin
80

regulatory light chain in the cells are known to be associated with various biological
actions as described in the section of background art in the specification, the
aforementioned cell contraction inhibitory action, action to regulate change of cell
morphology, cell migration inhibitory action, cell release inhibitory action, cell
aggregation inhibitory action, and apoptosis inhibitory action should be construed to
constitute a part of the actions of the medicament of the present invention.
[0098]
More specifically, the compounds of the present invention represented by the
aforementioned formula (l) and physiologically acceptable salts thereof have an
inhibitory activity against phosphorylation of the myosin regulatory light chain (see,
Test Example 1 of the specification), vasoconstriction inhibitory activity, activity for
suppressing respiratory tract constriction induced by antigen stimulation, intraocular
pressure reducing activity (see, Test Example 2 in the specification), neutrophil
migration inhibitory activity (see, Test Example 3 in the specification), respiratory
tract inflammation suppressing activity, pulmonary inflammation suppressing activity,
trachea relaxation activity, and activity for suppressing respiratory tract constriction
induced by a constriction elicitor. Therefore, the compounds represented by the
aforementioned formula (l) and physiologically acceptable salts thereof as well as
derivatives thereof useful as prodrugs are useful as active ingredients of medicaments
for prophylactic and/or therapeutic treatment of diseases relating to contraction of
various cells, diseases relating to morphological change of various cells, diseases
relating to migration of various cells, diseases relating to release of various cells,
diseases relating to aggregation of various cells, diseases relating to apoptosis of
various cells, and the like.
[0099]
Although it is not intended to be bound by any specific theory, action
mechanism of the compounds of the present invention represented by the
aforementioned general formula (l) and salts thereof can be presumed as follows. It
is known that increase of the amount of phosphorylated myosin regulatory light chain
activates the actomyosin system, which is a movement apparatus of cytoskeleton, and
activates cell movements. Therefore, it is considered that the phosphorylation
reaction of myosin regulatory light chain is important for cell movements (Kamm, K.,
et al., Annu. Rev. Physiol., 51, pp.299-313, 1989; Niggli, V., FEBS Lett., 445, pp.69-72,
81

1999; Itoh, K., et al., Biochim. Biophys. Acta., 1136, pp.52-56, 1992; Kitani, S., et al.,
Biochem. Biophys. Res. Commun., 183, pp.48"54, 1992). Measurement of the amount
of phosphorylated myosin regulatory light chain in the cells revealed that the
compounds represented by the aforementioned formula (l) and salts thereof decrease
the amount of phosphorylated myosin regulatory light chain in the cells (refer to Test
Example 1 in the specification).
[0100]
It is known that the amount of phosphorylated myosin regulatory light chain
in the cells is determined by activated states of two reaction routes including Reaction
route 1 and Reaction route 2 described below (Fukata, Y., et al., Trends Pharmacol. Sci.,
22, pp.32-39, 2001).

Increase of intracellular calcium concentration —» Activation of myosin light chain
kinase —> Increase of amount of phosphorylated myosin regulatory light chain

Activation of low molecular weight G protein Rho —* Activation of Rho kinase —*
Phosphorylation (inactivation) of myosin phosphatase -* Increase of amount of
phosphorylated myosin regulatory light chain
It is considered that a compound that inhibits Reaction route 1 and/or
Reaction route 2 mentioned above has an activity for decreasing the amount of
phosphorylated myosin regulatory light chain. In order to estimate whether either or
both of Reaction route 1 and Reaction route 2 mentioned above are the target site for
the compounds of the present invention represented by the aforementioned formula (l)
and salts thereof, effects of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof on increase of intracellular calcium
concentration and activity of myosin light chain kinase were examined. As a result, it
was found that the compounds of the present invention and salts thereof gave no
influence on the increase of intracellular calcium concentration (see, Test Example 4),
and did not inhibit the myosin light chain kinase activity (see, Test Example 5).
Therefore, it is presumed that the compounds of the formula (l) according to the
present invention do not inhibit Reaction route 1 mentioned above, but inhibit
Reaction route 2 mentioned above to decrease the amount of phosphorylated myosin
regulatory light chain. Thus, the compounds of the present invention and salts
82

thereof can be used as inhibitors of the Rho/Rho kinase pathway. The inhibition of
Reaction route 2 mentioned above by the compounds of the present invention
represented by the aforementioned formula (l) and salts thereof may be confirmed by
measuring the inhibitory activity for the Rho kinase activity, or alternatively, by
measuring the inhibitory activity for the phosphorylation reaction of myosin
phosphatase.
[0101]
The activity of Rho kinase can be measured by, for example, the method
disclosed in WOO 1/56988. More specifically, ATP (y 32P-ATP) is added to a substrate
(Ribosomal S6 kinase substrate) together with a commercially available Rho kinase
(Upstate) to start the enzymatic reaction and phosphorylate the substrate. The
substrate is adsorbed on filter paper, and ATP is washed off with the phosphate buffer.
Then, the amount of the phosphorylated substrate is measured by using a liquid
scintillation counter. The inhibitory activity of the compounds of the present
invention represented by the aforementioned formula (l) for the Rho kinase activity
can be determined by adding the compounds before starting the enzymatic reaction,
and measuring suppression of the phosphorylation amount of the substrate. The
phosphorylation reaction of myosin phosphatase can be measured by, for example,
using an antibody specifically recognizing the phosphorylated myosin phosphatase
(Feng, J. et al., J. Biol. Chem., 274, pp.37385-37390, 1999). More specifically,
proteins including myosin phosphatase are extracted from a tissue, subjected to
electrophoresis on acrylamide gel, and transferred to a nitrocellulose membrane. The
proteins are reacted with antibodies specifically recognizing phosphorylated myosin
phosphatase to detect the amount of phosphorylated myosin phosphatase. The
inhibitory activity of the compounds of the present invention on the phosphorylation
reaction of myosin phosphatase can be determined by adding the compounds before
starting the extraction from the tissue, and measuring suppression of the
phosphorylation amount of the myosin phosphatase.
[0102]
It is considered that the compounds of the present invention represented by
the aforementioned formula (l) and salts thereof inhibit the Rho/Rho kinase pathway,
which is Reaction route 2 mentioned above, and exhibit potent cell contraction
inhibitory activity and cell migration inhibitory activity. It is known that the
83

Rho/Rho kinase route plays an important role for cell contraction and cell migration.
Other than the above, it has been reported that the Rho/Rho kinase pathway controls a
variety of cellular functions such as morphological change, aggregation, release,
production, division, apoptosis, and regulation of gene expression in various cell lines
(Fukata, Y., et al., Trends in Pharmacological Sciences, 22, pp.32-39, 2001; Murata T.,
et al., J. Hepatotol., 35, pp.474-481, 2001; Ohnaka, K., et al., Biochem. Biophys. Res.
Commun., 287, pp.337-342, 2001; Yuhong, S., et al., Exp. Cell Res., 278, pp.45'52,
2002 ; Arakawa, Y. et al., BIO Clinica, 17(13), pp.26-28, 2002; Inoue, M. et al., Nat.
Med., 10 pp.712-718, 2004). Therefore, the compounds of the present invention which
inhibit the Rho/Rho kinase pathway exhibit, based on that effect, potent cell
contraction inhibitory activity (for example, Test Example 2), cell morphology change
regulating activity, cell migration inhibitory activity (for example, Test Example 3),
cell release inhibitory activity, cell aggregation inhibitory activity, apoptosis inhibitory
activity, and activity of regulating gene expression, and are useful as active
ingredients of medicaments for prophylactic and/or therapeutic treatment of diseases
relating to contraction of various cells, diseases relating to morphological change of
various cells, diseases relating to migration of various cells, diseases relating to
release from various cells, diseases relating to aggregation of various cells, diseases
relating to apoptosis of various cells, and/or diseases relating to abnormal gene
expression in various cells (Jikken Igaku (Experimental Medicine) Vol. 17, 7, 1999).
[0103]
Examples of the diseases relating to contraction of various cells include, for
example, as those relating to vascular smooth muscles, hypertension, arteriosclerosis,
cerebral circulatory disturbance, brain function disorder with the aforementioned
disease (mental disorder, memory disorder, dementia, delirium, poriomania,
dyskinesia and the like), dizziness, auditory disorder, cardiac diseases, pokkuri-byou
(sudden death), disturbances of peripheral circulation, disturbances of retinal
circulation, renal failure and the like, as those relating to airway smooth muscles,
asthma, acute respiratory distress syndrome, pulmonary emphysema, peripheral
respiratory tract disease, chronic bronchitis, chronic obstructive pulmonary disease
(COPD), and the like (Ueki, J. et al., Gendai Iryo (Contemporary Medical Care), Vol.34,
No.9, pp.87-92, 2002), as those relating to digestive tract smooth muscles, vomiting,
chronic gastritis, reflux esophagitis, irritable bowel syndrome, and the like, as those
84

relating to smooth muscle cells existing in eyes, glaucoma, and the like, as those
relating to vitreum of eyes, vitreoretinal diseases, and the like (Hirayama, K., et al.,
Preliminary Published Abstracts of the 42nd Congress of the Vitreoretina Society of
Japan), as those relating to smooth muscles of bladder and urethra, dysuria,
pollakiuria, incontinence and the like, as those relating to smooth muscles of uterus,
gestational toxicosis, threatened premature delivery, abortion and the like, and as
those relating to smooth muscles of penis, erectile dysfunction. However, the diseases
are not limited to the aforementioned examples.
[0104]
More precisely, examples of hypertension include, for example, essential
hypertension, renal hypertension, renovascular hypertension, hypertension during
pregnancy, endocrine hypertension, cardiovascular hypertension, neurogenic
hypertension, iatrogenic hypertension, pulmonary hypertension and the like, and
examples of arteriosclerosis include those in which pathological change is observed in
major arteries in whole body such as coronary artery, aorta abdominalis, renal artery,
carotid artery, ophthalmic artery, and cerebral artery. Examples of cerebral
circulatory disturbance include cerebral thrombosis, cerebral infarction, cerebral
hemorrhage, transient brain ischemic attack, hypertensive encephalopathy, cerebral
arteriosclerosis, subdural hemorrhage, epidural hemorrhage, subarachnoid
hemorrhage, brain hypoxia, cerebral edema, encephalitis, brain abscess, head injury,
mental disorder, metabolic intoxication, drug intoxication, transient asphyxia, deep
anesthesia in operation and the like. The cardiac diseases include congestive heart
failure, acute myocardial infarction, previous myocardial infarction, subendocardial
infarction, right ventricular infarction, atypical myocardial infarction, ischemic
cardiomyopathy, variant angina pectoris, stable angina, effort angina, coronary
vasospasm, postinfarction angina, unstable angina pectoris, arrhythmia, acute cardiac
death, and the like.
[0105]
The peripheral circulatory disturbances include aortic diseases such as
Buerger's disease, arteriosclerotic obliteration, and Raynaud's syndrome, venous
diseases such as venous thrombosis and thrombophlebitis, hyperviscosity syndrome,
frostbite and chilblain, psychoesthesia and hypnagogic disturbance due to feeling of
cold, bedsore, cleft, capped skin, and alopecia. Examples of the retinal circulatory
85

disturbances include retinal vascular obstruction, arteriosclerotic retinopathy,
vasospastic retinopathy, hypertonic fundus, hypertensive retinopathy, renal
retinopathy, hypertensive neuroretinopathy, diabetic retinopathy and the like.
Glaucoma includes primary glaucoma, secondary glaucoma, developmental glaucoma,
childhood secondary glaucoma and the like. Primary glaucoma is classified into
primary open-angle glaucoma (broad sense), primary angle-closure glaucoma, and
mixed-type glaucoma, and primary open-angle glaucoma (broad sense) includes
primary open-angle glaucoma, normal ocular pressure glaucoma, and ocular
hypertension. Secondary glaucoma is classified into secondary open-angle glaucoma,
and secondary angle-closure glaucoma (Japanese Journal of Ophthalmology, vol. 107,
No. 3, 2003). Further, examples of the vitreoretinal diseases include retinal
detachment, retinoschisis, vitreoretinal interface syndrome, retinal pigment
epitheliosis, macular hole, phacomatosis, vitreous hemorrhage, retinal circulatory
disturbances, and the like (the vitreoretinal diseases mentioned herein include more
narrowly classified diseases belonging to each of the categories according to the
pathological typology described in Shin Zusetsu Rinsho Ganka Koza (Illustrative
Lecture of Clinical Ophthalmology, New Edition), Ed. By Tano, Y., Araie, M., et al, Vol.
5, Vitreoretinal Diseases, MEDICAL VIEW, 2003). The urinary disturbances include
dysuria, bladder neck contracture, bladder neck occlusion, urethral syndrome,
detrusor sphincter dyssynergia, unstable bladder, chronic prostatitis, chronic cystitis,
prostate pain, Hinman's syndrome, Fowler's syndrome, psychogenic dysuria,
drug-induced dysuria, dysuria with aging and the like. The erectile dysfunction
include organic erectile dysfunction accompanying diseases of diabetes mellitus,
arteriosclerosis, hypertension, multiple-sclerotic cardiac diseases, hyperlipidemia,
depression and the like, functional erectile dysfunction, erectile dysfunction with
aging, erectile dysfunction after radical prostatectomy, and the like.
[0106]
Examples of the diseases relating to morphological change of various cells
include, for example, as those relating to ocular nerve cells, neurodegenerative
diseases such as diabetic retinopathy, and glaucoma. Glaucoma refers to the same as
that mentioned above.
Examples of the diseases relating to migration of various cells include, for
example, as those relating to cancer cells, infiltration and metastasis of cancer.
86

Examples of those relating to vascular endothelial cells include angiogenesis,
neovascular maculopathy, macular edema, and the like (the macular diseases
mentioned herein include more narrowly classified diseases belonging to each of the
categories according to the pathological typology described in Shin Zusetsu Rinsho
Ganka Koza (Illustrative Lecture of Clinical Ophthalmology, New Edition), Ed. By
Tano, Y., Araie, M., et al, Vol. 5, Vitreoretinal Diseases, MEDICAL VIEW, 2003).
Examples of those relating to leukocytes include bacterial infection, allergic
hypersensitive diseases (e.g., bronchial asthma, atopic dermatitis, pollinosis,
anaphylactic shock and the like), collagen diseases (e.g., systemic lupus erythematodes,
multiple sclerosis, Sjogren's disease and the like), angiitis, inflammatory bowel
diseases (e.g., ulcerative colitis, Crohn's disease and the like), ischemic reperfusion
injury of visceral organs, pneumonia, hepatitis, nephritis, pancreatitis, otitis media,
sinusitis, fibrosis, AIDS, adult T-cell leukemia, rejection after organ transplantation
(graft versus host reaction), vascular restenosis, and endotoxin shock. Example of the
cancer include myelocytic leukemia, lymphatic leukemia, gastric cancer, carcinoma of
the colon and rectum, lung cancer, pancreatic carcinoma, hepatic carcinoma, carcinoma
of the esophagus, ovarian cancer, breast cancer, skin cancer, head and neck cancer,
cancer of the testicles, neuroblastoma, urinary tract epithelial cancer, multiple
myeloma, carcinoma uteri, melanoma, brain tumor and the like. Examples of
hepatitis include hepatitis by virus infection (e.g., hepatitis B, hepatitis C and the like),
and alcoholic hepatitis. Examples of the pneumonia include chronic obstructive
pulmonary disease (COPD) and interstitial pneumonia, which may shift to fibrosis.
Examples of nephritis include chronic nephritic syndrome, asymptomatic proteinuria,
acute nephritic syndrome, nephrotic syndrome, IgA nephropathy, pyelonephritis,
glomerulonephritis and the like. Fibrosis include chronic pathological changes
characterized by excess deposition of connective tissue proteins in lung, skin, heart,
liver, pancreas, kidney and the like. The major pathological conditions are pulmonary
fibrosis, hepatic fibrosis, and skin fibrosis. However, fibrosis is not limited to these
examples. In hepatic fibrosis, viral hepatitis progresses by infection of, in particular,
hepatitis B virus or hepatitis C virus, thus hepatic cells cause necrosis, and thereby
fibrosis progresses, which means macronodular hepatic cirrhosis. Further, hepatic
fibrosis also includes micronodular hepatic cirrhosis caused by progress of alcoholic
hepatitis.
87

[0107]
Examples of diseases relating to release of various cells include, as those
relating to leukocytes, for example, allergic diseases.
Examples of the allergic diseases include asthma, atopic dermatitis, allergic
conjunctivitis, allergic arthritis, allergic rhinitis, allergic pharyngitis and the like.
Examples of the diseases relating to aggregation of various cells include, as
those relating to platelets, for example, thrombosis.
Thrombosis include the aforementioned circulatory disturbances of major
arteries, major veins and peripheral arteries and veins in whole body, as well as shock
caused by hemorrhage, drug intoxication, or endotoxin, disseminated intravascular
coagulation (DIC) following it, and multiple organ failure (MOF).
Examples of the diseases relating to apoptosis of various cells include, as those
relating to nerves, for example, neurodegenerative diseases such as Alzheimer's
disease, Parkinson's disease, diabetic peripheral neuropathy, retinopathy, amyotrophic
lateral sclerosis due to cerebral ischemia, pigmented retinitis, and cerebellar
degeneration, and glaucoma. Examples of glaucoma are mentioned above. AIDS,
and fulminant hepatitis are examples of disease relating to viruses, chronic heart
failure due to myocardial ischemia is an example of diseases relating to smooth
muscles, and myelodysplasia, aplastic anemia, sideroblastic anemia, and
graft-versus-host disease (GVHD) after organ transplantation are examples of diseases
relating to blood.
Examples of the diseases relating to abnormal gene expression of various cells
include, for example, AIDS as one relating to virus, and cancers as those relating to
cancer cells.
Examples of AIDS include acquired immunodeficiency syndrome caused by
human immunodeficiency virus (HIV) infection. Examples of the cancers include
gastric cancer, carcinoma of the colon and rectum, hepatocellular carcinoma,
pancreatic carcinoma, lung cancer, leukemia, malignant lymphoma, carcinoma uteri,
ovarian cancer, breast cancer, skin cancer and the like.
[0108]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
88

treatment of hypertension can be confirmed by, for example, administering the
compound to various hypertension model animals or the like. Examples of
hypertension animal models include spontaneous hypertensive rat (SHR), renal
hypertensive rat, DOCA-salt hypertensive rat and the like (Uehata, M. et al., Nature,
389, 990-994, 1997). A compound is orally, intravenously or intraperitoneally
administered to a hypertension model animal at a dose of 0.1 to 1,000 mg/kg,
preferably 0.1 to 100 mg/kg, and the diastolic blood pressure is measured. The
usefulness as a medicament for hypertension can be confirmed based on an action of
reducing the diastolic blood pressure.
[0109]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of pulmonary hypertension can be confirmed by using, for example, a rat
model of pulmonary hypertension created by administering monocrotaline to a rat for 2
to 3 weeks (Ito, K.M. et al., Am. J. Physiol., 279, H1786-H1795, 2000). A compound is
orally, intravenously or intraperitoneally administered to a model animal of
pulmonary hypertension at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg,
and the intrapulmonary pressure is measured. The usefulness as a medicament for
pulmonary hypertension can be confirmed based on an action of decreasing the
intrapulmonary pressure.
[0110]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of arteriosclerosis can be confirmed by using, for example, a rat model of
L-NAME-induced arteriosclerosis (Cir. Res. 89(5):415"21, 2001), a rat model of
balloon-induced neointimal formation (Sawada N. et al., Circulation 101 (17)^2030-3,
2000) or the like. A compound is orally, intravenously or intraperitoneally
administered to a model animal of arteriosclerosis at a dose of 0.1 to 1,000 mg/kg,
preferably 0.1 to 100 mg/kg, and thickening of arteries is observed. The usefulness as
a medicament for arteriosclerosis can be confirmed based on an action of suppressing
neointimal formation in arteries.
89

[0111]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of cerebral circulatory dysfunction can be confirmed by using, for example, a
gerbil model of hippocampal neuronal death (Kirino et al., Brain Res., 239, 57-69,
1982) or the like. A compound is orally, intravenously or intraperitoneally
administered to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100
mg/kg, and the amount of energy-related substances and survival period of gerbil, or
inhibition of late-onset of neuronal death is measured. The usefulness as a
medicament for cerebral circulatory dysfunction can be confirmed based on actions for
maintaining, improving and activating cerebral metabolic ability, brain and nerve
protective action, and action for suppressing formation of cerebral infarction.
[0112]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of cardiac diseases can be confirmed by using, for example, a rat model of
myocardial infarction based on the ligation of artery (Xia Q.G. et al., Cardiovasc. Res.,
49(l): 110-7, 2001) or the like. Effectiveness as a medicament for cardiac diseases can
be confirmed by orally, intravenously or intraperitoneally administering a compound to
the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and
observing a cardiac tissue fixed by formalin perfusion after ischemic reperfusion.
[0113]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of disturbances of peripheral circulation can be confirmed by using, for
example, a rat model of bedsore (Pierce S.M. et al., Am. J. Physiol. Heart Circ. Physiol.,
28l(l):H67-74, 2001) or the like. Effectiveness as a medicament for bedsore
(peripheral circulatory disturbance) can be confirmed by orally, intravenously or
intraperitoneally administering a compound to the model animal at a dose of 0.1 to
1,000 mg/kg, preferably 0.1 to 100 mg/kg, compressing the hind leg skin at a pressure
90

of 50 mmHg, and then observing a tissue of necrotic area of the lesion or measuring
epithelial blood flow of the same.
[0114]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of disturbances of retinal circulation can be confirmed by using, for example,
rabbit model of rose bengal-mediated argon laser retinal vein photothrombosis (Jpn. J.
Ophthalmol., 45(4):359-62, 2001), or the like. Effectiveness as a medicament for
retinal circulatory disturbance can be confirmed by ocular instillation, orally,
intravenously, intraperitoneally or intraocularly (direct administration to vitreum,
retina and the like) administering a compound to the model animal at a dose of 0.1 to
1,000 mg/kg, preferably 0.1 to 100 mg/kg, comparing the degree of retinal circulatory
disturbance with that of a control based on count of laser spots.
[0115]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of renal failure can be confirmed by using, for example, a rat model of
one-kidney, one-clip renal hypertension (Kiso to Rinsho, 30, 511-524, 1996).
Effectiveness as a medicament for renal failure can be confirmed by orally,
intravenously or intraperitoneally administering a compound to the model animal at a
dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the diuretic
effect.
[0116]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of asthma such as bronchial asthma can be confirmed by using, for example,
suppression of constriction of a trachea isolated from an animal (Kunihiko Iizuka,
Allergy, 47:943, 1998; Kunihiko Iizuka, Akihiro Yoshii, Jpn. J. Respirol. Soc, 37:196,
1999.), antigen-stimulation induced respiratory tract constriction model,
antigen-stimulation induced chronic respiratory tract inflammation model (Henderson,
91

W. R., et al., Am. J. Respir. Cric. Care Med., 165(1), pp. 108-116, 2002), constriction
elicitor-induced respiratory tract constriction model (histamine, acetylcholine and the
like are generally used, Daniela, S. et al., J. Pharmacol. Exp. Ther., 297(1), pp. 280-290,
2001), LPS-induced acute respiratory tract inflammation model, inhibition of human
peripheral blood leucocyte migration and the like. The usefulness as a medicament
for bronchial asthma can be confirmed by orally, intravenously or intraperitoneally
administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg,
preferably 0.1 to 100 mg/kg, and measuring elevation of airway resistance caused by
tracheal constriction or relaxation, antigen stimulation, histamine inhalation, or
acetylcholine inhalation, migrating leucocyte count in bronchoalveolar lavage fluid
and the like, or performing analysis of histological inflammatory findings.
[0117]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of irritable bowel syndrome can be confirmed by administering the
compounds to a stress burden model animal, or the like. Examples of the stress
burden model animal include, for example, a rat model of arresting stress (Miyata, K.
et al., J. Pharmacol. Exp. Ther., 259, pp.815-819, 1991), a CRH-administered rat model
(Miyata, K. et al., Am. J. PhysioL, 274, G827-831, 1998), and the like. A compound is
orally, intravenously or intraperitoneally administered to a stress burden model
animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and counting the
number of fecal pellets. The usefulness as a medicament for curative medicine of
irritable bowel syndrome can be confirmed based on effect for reducing the number of
fecal pellets.
[0118]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of glaucoma can be confirmed by, for example, measuring intraocular
pressure of a rabbit, cat or monkey after administration of the medicaments by
instillation (Surv. Ophthalmol. 41^S9-S18, 1996). The usefulness as a medicament for
glaucoma can be confirmed by ocular instillation, or orally, intravenously,
92

intraperitoneally or intraocularly (direct administration to anterior chamber, vitreum
and the like) administering a compound to a locally anesthetized rabbit or monkey
model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and
measuring the intraocular pressure over time using a tonometer to evaluate degree of
intraocular pressure reducing activity, or sustained intraocular pressure reducing
activity.
[0119]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of vitreoretinal diseases can be confirmed by a known method, for example,
the methods described in Oshima, Y. et al., Gene Ther., 9(18), pp. 1214-20, 2002; and Ito,
S., et al., Graefes Arch. Clin. Exp. Ophthalmol., 237(8), pp.691-6., 1999. The
usefulness as a medicament for vitreoretinal diseases can be confirmed by ocular
instillation, orally, intravenously, intraperitoneally or intraocularly administering
(direct administration to vitreum or retina) a compound to a rabbit in which retinal
detachment is induced by cell transfer to the vitreoretinal interface, vitrectomy, or the
like at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and evaluating
amelioration of the pathological conditions on the basis of histological analysis.
[0120]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of dysuria can be confirmed by using, for example, a model of rhythmic
bladder contraction (Kaneko S. et al., Folia Pharmacol. Japon, Vol. 93(2), 55-60, 1989;
Nomura N. et al., Folia Pharmacol. Japon, Vol. 94(3), 173", 1989.) or the like. The
usefulness as a medicament for urinary disturbance can be confirmed by orally,
intravenously or intraperitoneally administering a compound to an anesthetized rat or
dog at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the
number of rhythmic contraction of filled bladder (micturition).
[0121]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
93

prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of erectile dysfunction can be confirmed by a known method, for example,
the method described in J. Uro., 151, 797-800, 1994. A compound is dissolved in a
hydrophilic ointment, 30 mg of the ointment was applied to a rat penis, and the rat is
held in an acrylic cylinder for 10 minutes so that the rat was not able to lick the penis.
The rat is moved to an acrylic cage of 30 cm x 30 cm, and videotaped for 60 minutes
from the side and the bottom of the cage. Then, the number of erection of the penis
per 30 minutes can be counted to confirm the usefulness as a medicament for erectile
dysfunction.
[0122]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for suppressing cancer metastasis and
invasion can be confirmed by, for example, the method described in Cancer Res.,
55:3551"3557 (1995). The usefulness as a medicament for cancer metastasis and
invasion can be confirmed by orally, intravenously or intraperitoneally administering a
compound at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, to a nude mouse
transplanted with human cancer cell suspension transplantable to immunodeficient
mice at the same site (spontaneous metastasis model), and measuring the
metastasized lesion.
[0123]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of collagen disease can be confirmed by using, for example, collagen-induced
arthritis model of a rat or mouse (Griffith, M.M. et al., Arthritis Rheumatism, 24:781,
1981; Wooley, P.H. et al., J. Exp. Med., 154:688, 1981). The usefulness as a
medicament for collagen disease can be confirmed by orally, intravenously or
intraperitoneally administering a compound to the model mouse or rat at a dose of 0.1
to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring footpad volume or
progression of bone destruction.
[0124]
Usefulness of the compounds of the present invention represented by the
94

aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of inflammatory bowel disease can be confirmed by using a rat model of
idiopathic ulcerative colitis induced by subserosal injection of acetic acid, a model of
sodium dextransulfate-induced colitis, a model of trinitrobenzenesulfonic acid-induced
colitis (Kojima et al., Folia. Pharmacol. Jpn., 118, 123-130, 2001), or the like. The
usefulness as a medicament for inflammatory bowel disease can be confirmed by, for
example, orally, intravenously or intraperitoneally administering a compound at a
dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, to a rat in which colitis is
induced by intraintestinal injection of acetic acid, dissecting the rat after several days
to two weeks, then observing and measuring the ulcer area of the intestinal epithelium,
and amount of leucotriene B4 in a colon homogenate.
[0125]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of pneumonia can be confirmed by using, for example, a mouse model of
OVA"induced chronic pneumonia (Henderson W.R. et al., Am. J. Respir. Crit. Care Med.,
165(l):lO8"16, 2002), a mouse model of LPS-induced acute pneumonia (Gonzales de
Moraes, VL., et al., Br. J. Pharmacol., 123, pp.631-6, 1998), or the like. Effectiveness
as a medicament for pneumonia can be confirmed by orally, intravenously or
intraperitoneally administering a compound to the model animal at a dose of 0.1 to
1,000 mg/kg, preferably 0.1 to 100 mg/kg, and evaluating change in number of
eosinophils or monocytes in the pulmonary cavity, and histological findings of
inflammation.
[0126]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of hepatitis can be confirmed by using a mouse model of endotoxin-induced
liver injury according to, for example, the method described in J. Immunol., 159,
3961-3967, 1997. The usefulness as a medicament for hepatitis can be confirmed by
orally, intravenously or intraperitoneally administering a compound to the mouse
95

model of endotoxinunduced liver injury at a dose of 0.1 to 1,000 mg/kg, preferably 0.1
to 100 mg/kg, and measuring the plasmic transaminase level or amount of
hydroxyproline in a hepatic tissue, which are indicators of liver function, or performing
histological analysis.
[0127]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of pancreatitis can be confirmed by using, for example, a mouse model of
cerulein-inducted acute pancreatitis (Niedirau, C. et'al., Gastroenterology 88 (5 Pt
1):1192-2O4, 1985) or the like. Effectiveness as a medicament for pancreatitis can be
confirmed by orally, intravenously or intraperitoneally administering a compound to
the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and
measuring the serum amylase activity, or weight of pancreas.
[0128]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of nephritis can be confirmed by using, for example, a nephritis rat model
prepared by administering anti-GBM antibodies obtained by immunizing a rabbit with
a GBM fraction derived from a rat to a rat (WOO 1/56988), or the like. A compound is
orally, intravenously or intraperitoneally administered to the nephritis rat model at a
dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and the urinary proteins are
measured. The usefulness as a medicament for nephritis can be confirmed based on
an action of reducing the urinary protein level.
[0129]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients for suppressing allograft rejection at the time of organ
transplantation can be confirmed by using, for example, a rat model of skin
transplantation, rat model of heart transplantation (Ochiai T. et al., Transplant. Proc,
19, 1284-1286, 1987), or the like. Effectiveness as a medicament for suppressing
rejection at the time of organ transplantation can be confirmed by orally, intravenously
96

or intraperitoneally administering a compound to a model animal at a dose of 0.1 to
1,000 mg/kg, preferably 0.1 to 100 mg/kg, and estimating the graft survival ratio.
[0130]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of chronic obstructive pulmonary disease (COPD) can be confirmed by using,
for example, suppression of constriction of a trachea isolated from an animal, an
antigen stimulation-induced respiratory tract constriction model, a constriction
elicitor-induced respiratory tract constriction model (histamine, acetylcholine and the
like are generally used), antigen stimulation-induced chronic respiratory tract
inflammation model, a mouse model of LPS-induced acute respiratory tract
inflammation, a tobacco smoke exposition model (Fuchigami J. et al., 73rd Meeting of
Japanese Pharmacological Society, Collection of Abstracts, 2000), inhibition of
chemotaxis of human peripheral leucocytes, or the like. The usefulness as a
medicament for COPD can be confirmed by orally, intravenously or intraperitoneally
administering a compound to any of the model animals mentioned above at a dose of 1
to 1,000 mg/kg, preferably 1 to 100 mg/kg, and measuring tracheal constriction or
relaxation, change in airway resistance, migrating leucocyte count in bronchoalveolar
lavage fluid, change in number of number of eosinophils or monocytes in the
pulmonary cavity, histological findings of inflammation, or the like.
[0131]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of hepatic fibrosis can be confirmed by using a carbon tetrachloride-induced
hepatic fibrosis model according to, for example, the method described in J. Hepatol.,
35(4), 474-81, 2001. The usefulness as a medicament for hepatic fibrosis can be
confirmed by orally, intravenously or intraperitoneally administering a compound to
the hepatic fibrosis model at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg,
and measuring the plasmic transaminase level, or amount of hydroxyproline in a
hepatic tissue, which are indicators of liver function, or performing histological
analysis.
97

[0132]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of pulmonary fibrosis can be confirmed by using an animal model of
Bleomycin-induced pulmonary fibrosis according to the method described in, for
example, Am. J. Respir. Crit. Care Med., 163(l), pp.210-217, 2001. The usefulness as
a medicament for pulmonary fibrosis can be confirmed by orally, intravenously or
intraperitoneally administering a compound to the pulmonary fibrosis mouse model at
a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring respiratory
function, or amount of hydroxyproline in a pulmonary tissue.
[0133]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of allergy can be confirmed by using an atopic dermatitis mouse model or
the like according to the method described in, for example, Allergy, 50 (12) 1152-1162,
2001. The usefulness as a medicament for allergy can be confirmed by orally,
intravenously or intraperitoneally administering a compound to an NC/Nga mouse
pretreated with a surfactant or an organic solvent at a dose of 0.1 to 1,000 mg/kg,
preferably 0.1 to 100 mg/kg, when eruption is induced in the mouse by using housedust
mite antigens, and measuring the plasmic IgE level, number of eosinophils and the
like.
[0134]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of thrombosis can be confirmed by using, for example, a rabbit model of
experimentally-induced venous thrombus (Maekawa, T. et al., Trombos. Diathes.
Haemorrh., 60, pp.363-370, 1974), or the like. Effectiveness as a medicament for
thrombosis can be confirmed by orally, intravenously or intraperitoneally
administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg,
preferably 0.1 to 100 mg/kg, and estimating the incidence of thrombus.
98

[0135]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of Alzheimer's disease can be confirmed by using, for example, an in vitro
culture system of nerve cells derived from rat embryos (Yankner, B.A. et al., Science,
250, pp.279-282, 1990), or the like. Effectiveness as a medicament for Alzheimer's
disease can be confirmed by adding 0.1 to 1 mM, preferably 0.1 to 100 /i M, of a
compound, and measuring suppression ratio for cell death induced by beta-amyloid
proteins.
[0136]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of AIDS can be confirmed by using, for example, a rhesus monkey model of
SIV-infection (Crub S. et al., Acta Neuropathol., 101(2), pp.85"91, 2001) or the like.
Effectiveness as a medicament for AIDS can be confirmed by orally, intravenously or
intraperitoneally administering a compound to the model animal at a dose of 0.1 to
1,000 mg/kg, preferably 0.1 to 100 mg/kg, and quantifying the SIV mRNA level in
blood.
[0137]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments for prophylactic and/or therapeutic
treatment of cancer can be confirmed by using, for example, a mouse model of
ultraviolet ray irradiation-induced skin cancer, a nude mouse model of tumor
xenograft (Orengo I.F. et al., Arch Dermatol., 138(6), pp.823-4, 2002; Ki D.W. et al.,
Anticancer Res., 22(2A), pp.777-88, 2002) or the like. Effectiveness as a medicament
for cancer can be confirmed by orally, intravenously or intraperitoneally administering
a compound to a model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100
mg/kg, and observing progression or reduction of the grafted cancer tissues on the body
surface.
[0138]
99

Further, when test compounds of the compounds of the present invention or
salts thereof were introduced into wells of a 96-well plate at a concentration three
times higher than the IC50 values obtained in Test Example 1, and the cell suspension
prepared in Test Example 1 was added at a density of 106/well, incubated for 30
minutes at room temperature and stained with trypan blue to determine the survival
rates of the cells, a viability as high as 90% or more was observed in all the wells.
Furthermore, when the compounds of the present invention or salts thereof were orally
administered to mice every day at a dose of 30 mg/kg for 5 days, death was not
observed. Furthermore, even when the compounds of the present invention or salts
thereof were continuously instilled to rabbit eyes in a volume of 50 i± 1 at 3 mM, severe
eye irritation was not observed. In a general genotoxicity test utilizing salmonella
and skin irritation test, they gave negative results. On the basis of the results of
these tests, the compounds the present invention or salts thereof have no particular
problem also in safety or toxicity. Furthermore, the compounds of the present
invention and salts thereof show superior solubility. Moreover, the compounds of the
present invention and salts thereof also have only weak inhibition to the P-450
enzymes.
[0139]
Furthermore, the compounds of the present invention and salts thereof as well
as derivatives thereof useful as prodrugs are excellent in safety (various toxicities and
safety pharmacology), pharmacokinetic performance, and the like, and thus usefulness
thereof as active ingredients of medicaments can be confirmed.
Examples of tests concerning safety include, for example, those listed below.
However, they are not limited to these examples. Examples include cytotoxic tests
(tests using HL60 cells, hepatocytes and the like), genotoxicity tests (Ames test, mouse
lymphoma TK test, chromosomal aberration test, micronucleus test and the like), skin
sensitization tests (Buehler method, GPMT method, APT method, LLNAtest and the
like), skin photosensitization tests (adjuvant and strip method and the like), eye
irritation tests (single instillation, short-term continuation instillation, repetitive
instillation and the like), safety pharmacology tests for the cardiovascular system
(telemetry method, APD method, hERG inhibition assay and the like), safety
pharmacology tests for the central nervous system (FOB method, modified version of
Irwin method and the like), safety pharmacology tests for the respiratory system
100

(measurement method utilizing a respiratory function measuring apparatus,
measurement method utilizing a blood gas analyzer and the like), general toxicity tests,
reproductive and developmental toxicity tests, and the like.
Examples tests concerning pharmacokinetic performance include, for example,
those listed below. However, they are not limited to these examples. Examples
include cytochrome P450 enzyme inhibition or induction tests, cell permeability tests
(tests using CaCO2 cells, MDCK cells and the like), drug transporter ATPase assay,
oral absorption tests, blood concentration transition measurement tests, metabolism
tests (stability test, metabolite molecular species test, reactivity test and the like),
solubility tests (solubility test based on turbidity method and the like), and the like.
[0140]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (1) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a cytotoxic test. Examples of the cytotoxic test include methods utilizing
various cultured cells, for example, HL-60 cells, which are human preleukemia cells,
primary isolated cultured cells of hepatocytes, a neutrophil fraction prepared from
human peripheral blood, and the like. Although the test can be carried out by the
method described below, the method is not limited only to the following description.
Cells are prepared as a suspension of 105 to 107 cells/ml, and the suspension is added to
microtubes or microplate in a volume of 0.01 to 1 mL. To the suspension, a solution
dissolving a compound is added in a volume of 1/100 to 1 fold volume of the cell
suspension, and the cells were cultured in a cell culture medium having a final
concentration of the compound of 0.001 to 1000 u M for 30 minutes to several days at
37°C under 5% CO2. After terminating the culture, survival rate of the cells is
evaluated by using the MTT method, WST-1 method (Ishiyama, M., et al., In Vitro
Toxicology, 8, p. 187, 1995), or the like. By measuring cytotoxicity of the compound to
cells, usefulness as active ingredients of medicaments can be confirmed.
[0141]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a genotoxicity test. Examples of the genotoxicity test include, the Ames test,
101

mouse lymphoma TK test, chromosomal aberration test, micronucleus test, and the
like. The Ames test is a method of determining reverse mutation by culturing
Salmonella or Escherichia bacteria of designated species on a culture dish or the like
added with a compound (refer to IYAKUSHIN (Notification by the chief of Evaluation
and Licensing Division, Pharmaceutical and Medical Safety Bureau, Ministry of
Health, Labor and Welfare, Japan), No. 1604, 1999, "Guideline for Genotoxicity Test",
II-1. Genotoxicity Test, and the like). The mouse lymphoma TK test is a genetic
mutation ability detection test targeting the thymidine kinase gene of the mouse
lymphoma L5178Y cell (refer to IYAKUSHIN No. 1604, 1999, "Guideline for
Genotoxicity Test", II-3. Mouse Lymphoma TK Test; Clive, D. et al., Mutat. Res., 31,
pp.17-29, 1975; Cole, J., et al., Mutat. Res., Ill, pp.371-386, 1983, and the like). The
chromosomal aberration test is a method for determining activity of causing
chromosomal aberration by culturing mammalian cultured cells in the presence of a
compound, then after fixation of the cells, staining and observing chromosomes of the
cells (refer to IYAKUSHIN No. 1604, 1999, "Guideline for Genotoxicity Test", II-2.
Chromosomal Aberration Test Utilizing Mammalian Cultured Cells, and the like).
The micronucleus test is a method of evaluating micronucleus forming ability caused
by chromosomal aberration, and a method of using a rodent (in vivo test) (IYAKUSHIN
No. 1604, 1999, "Guideline for Genotoxicity Test", II-4. Micronucleus Test Using
Rodent; Hayashi M. et al., Mutat. Res., 312, pp.293-304, 1994; Hayashi, M. et al.,
Environ. Mol. Mutagen., 35, pp.234-252, 2000), a method of using cultured cells (in
vitro test) (Fenech M., et al., Mutat. Res., 147, pp.29-36, 1985; Miller, B., et al., Mutat.
Res., 392, pp.45-59, 1997, and the like) are available. By elucidating genotoxicity of
the compounds based on one or more of these methods, usefulness of the compounds as
active ingredients of medicaments can be confirmed.
[0142]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (1) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a skin sensitization test. As the skin sensitization test using guinea pig, the
Buehler method (Buehler, E.V., Arch. Dermatol., 91, pp.171-177, 1965), GPMT method
(maximization method, Magnusson B., et al., J. Invest. Dermatol., 52, pp.268-276,
1969), APT method (adjuvant and patching method (Sato, Y. et al., Contact Dermatitis,
102

7, pp.225-237, 1981)) and the like are available. Further, as the skin sensitization
test using mouse, the LLNA (local lymph node assay) method (OECD Guideline for the
testing of chemicals 429, skin sensitization 2002>" Takeyoshi, M.et al., Toxicol. Lett.,
119 (3), pp.203-8, 2001; Takeyoshi, M. et al., J. Appl. Toxicol., 25 (2), pp.129-34, 2005)
and the like are available. By elucidating skin sensitization property of the
compounds based on one or more of these methods, usefulness of the compounds as
active ingredients of medicaments can be confirmed.
[0143]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a skin photosensitization test. Examples of the skin photosensitization test
include a skin photosensitization test using guinea pig (refer to "Drug Nonclinical Test
Guideline Commentary 2002", Yakuji Nippo, published on 2002, 1-9: Skin
Photosensitization Test, and the like), and the like, and examples of the method
include the adjuvant and strip method (Ichikawa, H.et al., J. Invest. DermatoL, 76,
pp.498-501, 1981), Harber method (Harber, L.C., Arch. DermatoL, 96, pp.646-653,
1967), Horio method (Horio, T., J. Invest. DermatoL, 67, pp.591-593, 1976), Jordan
method (Jordan, W.P., Contact Dermatitis, 8, pp. 109" 116, 1982), Kochever method
(Kochever, I.E. et al., J. Invest. DermatoL, 73, pp. 144-146, 1979), Maurer method
(Maurer, T. et al., Br. J. DermatoL, 63, pp.593-605, 1980), Morikawa method
(Morikawa, F. et al., "Sunlight and Man", Tokyo Univ. Press, Tokyo, pp.529-557, 1974),
Vinson method (Vinson, L.J., J. Soc. Cosm. Chem., 17, pp. 123-130, 1966), and the like.
By elucidating skin photosensitization property of the compounds based on one or more
of these methods, usefulness of the compounds as active ingredients of medicaments
can be confirmed.
[0144]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, an eye irritation test. Examples of the eye irritation test include the single
instillation test method using rabbit eyes, monkey eyes, and the like (instillation of
one time), short term continuous instillation test method (instillation of multiple times
103

in a short period of time with equal intervals), repetitive instillation test method
(repetitive intermittent instillation over several days to 10 days), and the like, and a
method of evaluating eye irritation symptoms during a certain period of time after
instillation according to the improved Draize scores (Fukui, N.et al., Gendai no Rinsho,
4 (7), pp.277-289, 1970) and the like are available. By elucidating eye irritation of the
compounds based on one or more of these methods, usefulness of the compounds as
active ingredients of medicaments can be confirmed.
[0145]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a safety pharmacology test for the cardiovascular system. Examples of the
safety pharmacology test for the cardiovascular system include the telemetry method
(method for measuring influence of administration of a compound under no
anesthetization on electrocardiogram, heart rate, blood pressure, blood stream, and
the like (Electrocardiographic, Echocardiographic, Blood Pressure and Pathological
Tests of Animals for Fundamental and Clinical Medicine, edited by Sugano S., Tsubone
H., Nakada Y., published on 2003, Maruzen), APD method (method for measuring
cardiac muscle cell action potential retention time (Muraki, K. et al., AM. J. Physiol.,
269, H524-532, 1995; Ducic, I. et al., J. Cardiovasc. Pharmacol., 30 (l), pp.42"54, 1997)),
hERG inhibition evaluation method (patch clamping method (Chachin, M. et al.,
Nippon Yakurigaku Zasshi, 119, pp.345-351, 2002), binding assay method (Gilbert, J.D.
et al., J. Pharm. Tox. Methods, 50, pp. 187-199, 2004), Rb+ efflex assay method (Cheng,
C.S. et al., Drug Develop. Indust. Pharm., 28, pp.177-191, 2002), Membrane potential
assay method (Dorn, A. et al., J. Biomol. Screen., 10, pp.339-347, 2005), and the like.
By elucidating influence on the cardiovascular system of the compounds based on one
or more of these methods, usefulness of the compounds as active ingredients of
medicaments can be confirmed.
[0146]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a safety pharmacology test for the central nervous system. Examples of the
104

safety pharmacology test for the central nervous system include the FOB method
(Functional Observational Battery, Mattson, J.L. et al., J. American College of
Technology, 15 (3), pp.239-254, 1996)), modified version of Irwin method (method for
evaluating observation of general symptoms and behavior (Irwin, S., Comprehensive
Observational Assessment (Berl.) 13, pp.222-257, 1968)), and the like. By elucidating
action on the central nervous system of the compounds based on one or more of these
methods, usefulness of the compounds as active ingredients of medicaments can be
confirmed.
[0147]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a safety pharmacology test for the respiratory system. Examples of the
safety pharmacology test for the respiratory system include the measurement method
using a respiratory function measuring apparatus (method of measuring respiration
rate, single ventilation volume, minute ventilation and the like, Drorbaugh, J.E. et al.,
Pediatrics, 16, pp.81-87, 1955," Epstein, M.A. et al., Respir. Physiol., 32, pp.105-120,
1978), measurement method of using a blood gas analyzer (method of measuring blood
gas, hemoglobin oxygen saturation and the like, Matsuo, S., Medicina, 40, pp. 188",
2003), and the like. By elucidating action on the respiratory system of the compounds
based on one or more of these methods, usefulness of the compounds as active
ingredients of medicaments can be confirmed.
[0148]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a general toxicity test. The general toxicity test is a method of orally or
intravenously administering a compound dissolved or suspended in an appropriate
solvent once or repetitively (over several days) to a rodent such as rat and mouse or
non-rodent such as monkey and dog, and evaluating observation of general conditions,
clinicochemical changes, pathohistological changes, and the like of the administered
animal. By elucidating general toxicity of a compound based on these methods,
usefulness of the compound as an active ingredient of medicament can be confirmed.
105

[0149]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a reproductive and developmental toxicity test. The reproductive and
developmental toxicity test is a test for examining induction of harmful effect by a
compound on the reproductive and developmental processes by using a rodent such as
rat and mouse or non-rodent such as monkey and dog (refer to "Drug Nonclinical Test
Guideline Commentary 2002", Yakuji Nippo, published on 2002, 1"6: Reproductive and
Developmental Toxicity Test and the like). Examples of the reproductive and
developmental toxicity test include tests concerning fertility and early embryogenesis
up to nidation, tests concerning development and maternal functions before and after
birth, tests concerning embryogenesis and fetal development (refer to IYAKUSHIN No.
1834, 2000, Appendix, "Guideline for Drug Toxicity Test", [3] Reproductive and
Developmental Toxicity Test and the like), and the like. By elucidating reproductive
and developmental toxicity of a compound based on these methods, usefulness of the
compound as an active ingredient of medicament can be confirmed.
[0150]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a cytochrome P450 enzyme inhibition or induction test (Gomez-Lechon, M.J.
et al., Curr. Drug Metab., 5 (5), pp.443-462, 2004). Examples of the cytochrome P450
enzyme inhibition or induction test include, for example, the method of determining in
vitro whether a compound inhibits activity of a cytochrome P450 enzyme by using a
cytochrome P450 enzyme of each molecular species purified from cells or prepared by
using a genetic recombinant, or a human P450 expression system microsome (Miller,
V.P. et al., Ann. N.Y. Acad. Sci., 919, pp.26-32, 2000), method of measuring changes of
expression of cytochrome P450 enzyme of each molecular species and enzyme activity
by using human liver microsomes or disrupted cell suspension (Hengstler, J.G. et al.,
Drug Metab. Rev., 32, pp.81-118, 2000), method of extracting RNA from human
hepatocytes exposed to a compound, and comparing mRNA expression amount with
that of a control to investigate enzyme induction ability of the compound (Kato, M. et
106

al., Drug Metab. Pharmacokinet., 20 (4), pp.236-243, 2005), and the like. By
elucidating action of the compounds on inhibition or induction of cytochrome P450
enzyme based on one or more of these methods, usefulness of the compounds as active
ingredients of medicaments can be confirmed.
[0151]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a cell permeability test. Examples of the cell permeability test include, for
example, the method of measuring cell membrane permeability of a compound in an in
vitro cell culture system using CaCO2 cells (Delie, F. et al., Crit. Rev. Ther. Drug
Carrier Syst., 14, pp.221-286, 1997; Yamashita, S. et al., Eur. J. Pham. Sci., 10,
pp.195-204, 2000; Ingels, F.M. et al., J. Pham. Sci., 92, pp.1545-1558, 2003), method of
measuring cell membrane permeability of a compound in an in vitro cell culture system
using MDCK cells (Irvine, J.D. et al., J. Pham. Sci., 88, pp.28-33, 1999), and the like.
By elucidating cell permeability of the compounds based on one or more of these
methods, usefulness of the compounds as active ingredients of medicaments can be
confirmed.
[0152]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a drug transporter ATPase assay. Examples of the drug transporter ATPase
assay include the method of examining whether a compound is a substrate of
P-glycoprotein (P-gp) by using a P'gp baculovirus expression system (Germann, U.A.,
Methods Enzymol., 292, pp.427-41, 1998), and the like. By elucidating action of the
compounds on Pgp based on these methods, usefulness of the compounds as active
ingredients of medicaments can be confirmed.
[0153]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, an oral absorption test. Examples of the oral absorption test include a
107

method of orally administering a compound of a certain amount dissolved or suspended
in an appropriate solvent to a rodent, monkey, dog or the like, and measuring blood
level of the compound after the oral administration over time to evaluate blood
transition of the compound by oral administration using the LOMS/MS method
("Newest Mass Spectrometry for Life Science", Kodansha Scientific, 2002, edited by
Harada K. et al, and the like), and the like. By elucidating oral absorption of the
compounds based on these methods, usefulness of the compounds as active ingredients
of medicaments can be confirmed.
[0154]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a blood concentration transition measurement test. Examples of the blood
concentration transition measurement test include a method of orally or parenterally
(e.g., intravenously, intramuscularly, intraperitoneally, subcutaneously, transdermally,
by instillation, transnasally, and the like) administering a compound to a rodent,
monkey, dog or the like, and measuring change of the blood level of the compound over
time after the administration using the LOMS/MS method ("Newest Mass
Spectrometry for Life Science", Kodansha Scientific, 2002, edited by Harada K. et al,
and the like), and the like. By elucidating blood concentration transition of the
compounds based on these methods, usefulness of the compounds as active ingredients
of medicaments can be confirmed.
[0155]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a metabolic test. Examples of the metabolic test include the blood stability
test method (method of predicting metabolic clearance in vivo based on metabolic rate
of a compound in hepatic microsomes of human or other animal species (refer to Shou,
W.Z. et al., J. Mass Spectrom., 40 (10) pp. 1347" 1356, 2005; Li, C. et al., Drug Metab.
Dispos., 34 (6), 901-905, 2006, and the like), metabolite molecular species test method,
reactive metabolite test method, and the like. By elucidating metabolic profile of the
compounds based on one or more of these methods, usefulness of the compounds as
108

active ingredients of medicaments can be confirmed.
[0156]
Usefulness of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs as active ingredients of medicaments can be confirmed by performing, for
example, a solubility test. Examples of the solubility test include the solubility test
based on the turbidity method (Lipinski, C.A. et al., Adv. Drug Deliv. Rev., 23, pp.3-26,
1997; Bevan, CD. et al., Anal. Chem., 72, pp.1781-1787, 2000), and the like. By
elucidating solubility of the compounds based on these methods, usefulness of the
compounds as active ingredients of medicaments can be confirmed.
[0157]
As the active ingredients of the medicaments of the present invention, the
compounds represented by the aforementioned formula (l), physiologically acceptable
salts thereof, and derivatives thereof useful as prodrugs are preferred.
The aforementioned substance, per se, may be administrated as the
medicament of the present invention. A pharmaceutical composition containing one
or more kinds of the aforementioned substances as the active ingredients and one or
more kinds of pharmaceutical additives can be generally prepared and administrated
orally or parenterally (e.g., intravenous administration, intramuscular administration,
subcutaneous administration, transdermal administration, intrapulmonary
administration, intranasal administration, instillation, intraurethral administration,
intravaginal administration, sublingual administration, intrarectal administration,
and the like) to human or an animal other than human. The aforementioned
pharmaceutical composition can be prepared in a dosage form suitable for an intended
administration route. More specifically, examples of the pharmaceutical composition
suitable for oral administration include oral drug products (tablets, filnvcoated tablets,
intraoral collapsing tablets, hard capsules, soft capsules, powders, fine granules,
granules, dry syrups, syrups, pills, troches and the like), and examples of the
pharmaceutical composition suitable for parenteral administration include injections
(liquid dosage forms, lyophilized dosage forms, suspensions and the like), inhalants,
suppositories, transdermally absorbed agents (e.g., tapes), ointments, ophthalmic
solutions, ophthalmic ointments, ophthalmic membrane adherent agents and the like.
For glaucoma, preferred examples of the dosage form include oral drug products,
109

ophthalmic solutions, ophthalmic ointments, and ophthalmic membrane adherent
agents. Further, preferred dosage forms for bronchial asthma or chronic obstructive
pulmonary disease include oral drug products, inhalants (for example, a method of
inhaling powder of the pharmaceutical composition or a liquid dosage form prepared by
dissolving or suspending the pharmaceutical composition in a solvent as it is, or
inhaling mist thereof by using a sprayer called atomizer or nebulizer), and
transdermal preparations.
[0158]
These pharmaceutical compositions can be prepared in a conventional manner
by using pharmaceutical additives usually used in this field (e.g., excipients,
disintegrants, binders, lubricants, colorants, buffering agents, coating agents, flavors,
fragrances, emulsifying agents, isotonic agents, solubilizing agents, preservatives,
viscosity improvers, pH adjusters and the like). Examples of the excipients include
saccharides such as lactose, sucrose, and trehalose, sugar alcohols such as D-mannitol,
erythritol, xylitol, and sorbitol, starches such as maize starch, crystalline cellulose,
calcium hydrogenphosphate and the like, examples of the disintegrants include
starches, partially pregelatinized starch, carmellose and metal salts thereof,
croscarmellose sodium, sodium carboxymethyl starch, agar powder, crospovidone, low
substituted hydroxypropylcellulose and the like, examples of the binders include
hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol,
methylcellulose, ethylcellulose, popidone, acacia powder, pullulan, pregelatinized
starch and the like, and examples of the lubricants include stearic acid and metal salts
thereof, talc, silicic acid and metal salts thereof, salt-hardened oil, sucrose fatty acid
esters, sodium laurylsulfate, sodium stearyl fumarate and the like
[0159]
When solid pharmaceutical compositions are prepared, there are used
pharmaceutical additives including, for example, sucrose, lactose, glucose, fructose,
trehalose, D-mannitol, sorbitol, erythritol, xylitol, maltitol, maize starch, potato starch,
wheat starch, rice starch, crystalline cellulose, carmellose, carmellose calcium, low
substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, dextrin,
cyclodextrin, dextran, agar, xanthane gum, guar gum, rosin, acacia,
hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose,
polyvinyl alcohol, povidone, pregelatinized starch, partly pregelatinized starch,
110

pullulan, pectin, polysorbate, polyethylene glycol, propylene glycol, glycerol,
magnesium stearate, talc, light anhydrous silicic acid, hydrated silicon dioxide, kaolin,
sucrose fatty acid esters, sodium laurylsulfate, silicic acid, aluminum silicate,
magnesium aluminometasilicate, calcium carbonate, sodium hydrogencarbonate,
sodium chloride, sodium citrate, citric acid, succinic acid, tartaric acid, hydrogenated
castor oil, hydrogenated tallow, stearic acid, cetanol, olive oil, orange oil, soybean oil,
cacao butter, carnauba wax, paraffin, vaseline, triacetin, triethyl citrate, iron oxide,
caramel, tartrazine, vanillin, carmellose sodium, cellulose derivatives such as
hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate
succinate, carboxymethylethylcellulose, carboxyvinyl polymer, cellulose acetate
phthalate, cellulose acetate trimellitate, ethylcellulose, and cellulose acetate,
polyethylene glycol, gelatin, shellac, methacrylic acid and derivatives thereof as well
as copolymers thereof, ethylcellulose aqueous dispersion (Aquacoat), silicone oil,
triacetin and the like. The tablets can be tablets having usual surfaces of the tablets
as required, and examples include sugar-coated tablets, enteric coating tablets,
film-coated tablets, bilayer tablets, and multilayer tablets.
[0160]
When semi-solid pharmaceutical compositions are prepared, there are used
pharmaceutical additives including, for example, animal fats and oils (olive oil, maize
oil, castor oil and the like), mineral fats and oils (vaseline, white petrolatum, solid
paraffin and the like), waxes (jojoba oil, carnauba wax, beeswax and the like), partially
or totally synthesized glycerol fatty acid esters. Examples of commercial products
include Witepsol (Dynamit Nobel), Pharmasol (Nippon Oil & Fats) and the like.
When liquid pharmaceutical compositions are prepared, pharmaceutical additives
including, for example, sodium chloride, glucose, sorbitol, glycerol, olive oil, propylene
glycol, ethyl alcohol and the like can be used. When injections are prepared, sterile
liquid media, for example, physiological saline, isotonic solutions, oily liquids such as
sesame oil and soybean oil are used. Further, if necessary, suitable suspending
agents such as carboxymethylcellulose sodium, nonionic surfactants, solubilizing
agents such as benzyl benzoate and benzyl alcohol and the like may be used together.
When eye drops are prepared, they can be prepared as aqueous liquids or aqueous
solutions. For example, aqueous solutions can be prepared by using a sterile aqueous
solution for injections. To these liquids for instillation, various additives such as
111

buffers (borate buffers, acetate buffers, carbonate buffers and the like are preferred in
view of reduction of stimulus), isotonic agents (for example, sodium chloride,
potassium chloride and the like can be mentioned), preservatives (for example, methyl
paraoxybenzoate, ethyl paraoxybenzoate, benzyl alcohol, chlorobutanol and the like
can be mentioned), viscosity improvers (for example, methylcellulose, sodium
carboxymethylcellulose and the like can be mentioned) and the like may be optionally
added. As for preparation of inhalants, when the composition is inhaled as powder,
for example, preparation of the aforementioned solid pharmaceutical composition can
be referred to, and the obtained powder is preferably further pulverized. Further,
when the composition is inhaled as a liquid, preferable methods include a method of
preparing the pharmaceutical composition by referring to the aforementioned
preparation of solid pharmaceutical composition to prepare a solid composition and
dissolving the solid in distilled water or a suitable solvent to obtain a medicament
solution upon use, or a method of preparing the pharmaceutical composition by
referring to the aforementioned preparation of liquid pharmaceutical composition to
obtain a medicament solution. The size of particles in the aforementioned powder or
medicament solution to be inhaled is preferably a particle size suitable for inhalation,
and the upper limit of the size is, for example, preferably 100 M m or less, more
preferably 50 n m or less, particularly preferably 10 /imor less. The lower limit of
the particle size is not particularly limited, and a smaller particle size is more
preferred.
[0161]
A content of the active ingredient in the aforementioned pharmaceutical
composition can be suitably chosen depending on a dosage form. Although the lower
limit of the content of the active ingredient is not particularly limited so long as the
desired pharmacological efficacy of the medicament of the present invention can be
exhibited, the content is, for example, 0.00001% by weight or more, preferably 0.0001%
by weight or more, more preferably 0.001% by weight or more, based on the total
weight of the pharmaceutical composition. Further, the content may be 0.01% by
weight or more, 0.1% by weight or more, or 1% by weight or more, based on the total
weight of the composition. Although the upper limit of the content of the active
ingredient is not also particularly limited so long as the desired pharmacological
efficacy of the medicament of the present invention can be exhibited, the content is, for
112

example, 100% by weight or less, preferably 80% by weight or less, more preferably
50% by weight or less, still more preferably 10% by weight or less, based on the total
weight of the pharmaceutical composition. Further, it may also be 5% by weight or
less, 1% by weight or less, or 0.1% by weight or less.
Dose of the medicament of the present invention can be suitably determined
for each case in consideration of age, body weight, sexuality of patients, type of disease,
severity of pathological condition, and the like. The lower limit is, for example, 0.001
mg or more, preferably 0.01 mg or more, more preferably 0.1 mg or more, still more
preferably 1 mg or more, per day for adults. The upper limit may be 1000 mg or less,
preferably 500 mg or less, more preferably 100 mg or less, still more preferably 30 mg
or less, per day for adults. These doses can be administered once in a day or several
times a day as divided portions.
[0162]
A drug used for the combination with the compounds of the present invention
represented by the aforementioned formula (l) and salts thereof as well as derivatives
thereof useful as prodrugs is hereinafter referred to as a drug for combination use. As
the drug for combination use, for example, drugs in various molecular forms such as
low molecular weight compounds, low molecular peptides, polypeptides, nucleic acid
oligomers, peptide-nucleic acid (PNA) oligomers, and antibodies can be used, and the
drug can be chosen depending on administration object, administration route, objective
disease and the like from various drugs of which objective diseases are diseases
relating to contraction of various cells, diseases relating to morphological change of
various cells, diseases relating to migration of various cells, diseases relating to
release of various cells, diseases relating to aggregation of various cells, diseases
relating to apoptosis of various cells, and/or diseases relating to abnormal gene
expression in various cells, and the like.
A medicament characterized by comprising, in combination, the compound of
the present invention represented by the aforementioned formula (l), a salt thereof, or
a derivative thereof useful as a prodrug and a drug for combination use may sometimes
be more preferred compared with a pharmaceutical composition comprising the
compound of the present invention represented by the aforementioned formula (l), a
salt thereof, or a derivative thereof useful as a prodrug alone as an active ingredient.
Such characteristic feature can be understood by any kind of more preferred result
113

provided by a medicament comprising, in combination, the compound of the present
invention represented by the aforementioned formula (l), a salt thereof, or a derivative
thereof useful as a prodrug and a drug for combination use compared with a
pharmaceutical composition comprising solely the compound of the present invention
represented by the aforementioned formula (l), a salt thereof, or a derivative thereof
useful as a prodrug, for example, in any of the test methods described below.
The following test methods are examples for indicating that usefulness of
medicaments based on the aforementioned combination can be demonstrated on the
basis of the prophylactic and/or therapeutic effect on, for example, glaucoma, and the
methods are not intended to indicate that the usefulness of the medicaments based on
the combination is limited to the application. Glaucoma referred to in the present
invention is as exemplified and explained above in detail in relation to the diseases
relating to contraction of various cells.
[0163]
For example, it can be concluded that a medicament based on the
aforementioned combination is useful as a medicament for prophylactic and/or
therapeutic treatment of glaucoma as follows. First, usefulness of the compounds of
the present invention represented by the aforementioned formula (l) and salts thereof
as well as derivatives thereof useful as prodrugs can be confirmed by a result obtained
by evaluation of the compounds of the present invention represented by the
aforementioned formula (l) and salts thereof as well as derivatives thereof useful as
prodrugs in the aforementioned test methods. Further, usefulness of a medicament
based on the combination, such as enhancement of an intraocular pressure reducing
action, and extension of duration of an intraocular pressure reducing action, can be
confirmed by a result obtained by evaluating each compound combined with each drug
for combination use, for example, a prostaglandin-relating agent such as
isopropylunoprostone and latanoprost, a carbonic anhydrase inhibitor such as
dorzolamide hydrochloride, brinzolamide hydrochloride, and acetazolamide
hydrochloride, an adrenergic receptor blocker such as bunazosin hydrochloride, timolol
maleate, carteolol hydrochloride, befunolol hydrochloride, betaxolol hydrochloride and
nipradilol hydrochloride.
[0164]
The aforementioned medicament based on the combination include, for
114

example, a medicament for simultaneous administration of the compound of the
present invention represented by the aforementioned formula (l), a salt thereof, or a
derivative thereof useful as a prodrug, and a drug for combination use, a medicament
for administering the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug,
and a drug for combination use with an interval within which efficacy of each
substance can be expected, and the like. Further, a medicament prepared in a single
form in which the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug
and a drug for combination use are mixed, and a medicament comprising the compound
of the present invention represented by the aforementioned formula (l), a salt thereof,
or a derivative thereof useful as a prodrug and a drug for combination use, which are
prepared in separate forms are also included. Furthermore, a medicament for
administering the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug
and a drug for combination use via the same route, a medicament for administering the
compound of the present invention represented by the aforementioned formula (l), a
salt thereof, or a derivative thereof useful as a prodrug and a drug for combination use
via different routes, and the like are also included.
[0165]
In the aforementioned medicament based on the combination, a mixing ratio of
the compound of the present invention represented by the aforementioned formula (l),
a salt thereof, or a derivative thereof useful as a prodrug and a drug for combination
use, a form of the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug
and a drug for combination use after mixing when the compound of the present
invention represented by the aforementioned formula (l), a salt thereof, or a derivative
thereof useful as a prodrug and the drug for combination use are prepared in a single
form, and the like can be suitably determined depending on object of administration,
administration route, disease to be treated, symptoms, physicochemical properties of
the medicament, ease of administration, and the like, and the dose thereof can be
suitably chosen on the basis of, for example, clinically used doses of the compound of
the present invention represented by the aforementioned formula (l), a salt thereof, or
115

a derivative thereof useful as a prodrug and the drug for combination use.
[0166]
When the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug
and a drug for combination use are prepared in a single form, the aforementioned
pharmaceutical additives may be used in addition to the compound of the present
invention represented by the aforementioned formula (l), a salt thereof, or a derivative
thereof useful as a prodrug and the drug for combination use to prepare a
pharmaceutical composition, and a preferred form such as oral agents, injections
(solution, suspension and the like), fusion drips, inhalants, suppositories,
transdermally absorbed agents (e.g., tapes), ointments, ophthalmic solutions,
ophthalmic ointments, ophthalmic membrane adherent agents and the like can be
prepared and used.
When the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug
and a drug for combination use are prepared in separate forms, each of the compound
of the present invention represented by the aforementioned formula (l), a salt thereof,
or a derivative thereof useful as a prodrug and the drug for combination use can be
prepared in a preferred from in the same manner as mentioned above and used.
[0167]
The medicament characterized by comprising, in combination, the compound
of the present invention represented by the aforementioned formula (l), a salt thereof,
or a derivative thereof useful as a prodrug and a drug for combination use can be used
as an agent for prophylactic and/or therapeutic treatment of various diseases. The
diseases are preferably those relating to contraction of various cells, and among the
diseases relating to contraction of various cells, glaucoma is preferred.
[0168]
The following [l] to [10] are encompassed within the scope of the present
invention.
[l] A medicament comprising the compound of the present invention represented by
the aforementioned formula (l), a salt thereof, or a derivative thereof useful as a
prodrug and a drug having an intraocular pressure reducing action and/or a drug
having an optic nerve protective action in combination.
116

[2] A medicament comprising the compound of the present invention represented by
the aforementioned formula (l), a salt thereof, or a derivative thereof useful as a
prodrug and any one or more of an adrenergic receptor stimulant, a
prostaglandin-related agent, a carbonic anhydrase inhibitor, an adrenergic receptor
blocker, a cholinesterase inhibitor, a calcium antagonist, a Rho kinase inhibitor, an
angiotensin II receptor antagonist, and an NMDA receptor blocker in combination.
[3] A medicament comprising the compound of the present invention represented by
the aforementioned formula (l), a salt thereof, or a derivative thereof useful as a
prodrug and a drug having an intraocular pressure reducing action in combination.
[4] A medicament comprising the compound of the present invention represented by
the aforementioned formula (l), a salt thereof, or a derivative thereof useful as a
prodrug and any one or more of a prostaglandin-related agent, a carbonic anhydrase
inhibitor, and an adrenergic receptor blocker.
[5] The medicament according to [4], which is an agent for prophylactic and/or
therapeutic treatment of glaucoma.
[6] A medicament comprising the compound of the present invention represented by
the aforementioned formula (l), a salt thereof, or a derivative thereof useful as a
prodrug and a drug having an optic nerve protective action in combination.
[7] The medicament according to [4] wherein the prostaglandin-related agent
mentioned in [4] is any one of latanoprost, bimatoprost, travoprost,
isopropylunoprostone, and tafluprost.
[0169]
[8] The medicament according to [4] wherein the carbonic anhydrase inhibitor
mentioned in [4] is any one of dorzolamide hydrochloride, brinzolamide hydrochloride,
and acetazolamide hydrochloride.
[9] The medicament according to [4] wherein the adrenergic receptor blocker
mentioned in [4] is any one of bunazosin hydrochloride, timolol maleate, carteolol
hydrochloride, levobunolol hydrochloride, betaxolol hydrochloride, nipradilol
hydrochloride, and befunolol hydrochloride.
[10] A method for therapeutic and/or prophylactic treatment of glaucoma, which uses
the medicament according to any one of [l] to [9].
[0170]
The compounds of the present invention represented by the aforementioned
117

formula (l), and salt thereof, as well as derivatives thereof useful as prodrugs have an
intraocular pressure reducing action as demonstrated in Test Example 2, and it was
confirmed that the medicaments of [l], [2], and [3] mentioned above exhibited
enhancement of the intraocular pressure reducing action, extension of duration of the
intraocular pressure reducing action and the like compared with a pharmaceutical
composition containing the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug
alone as an active ingredient as demonstrated in Test Examples 6 and 7. Thus, they
are preferred as agents for therapeutic and/or prophylactic treatment of glaucoma.
Further, a medicament comprising the compound of the present invention
represented by the aforementioned formula (l), a salt thereof, or a derivative thereof
useful as a prodrug and an agent for therapeutic and/or prophylactic treatment of
glaucoma in combination is also preferred. As the agent for therapeutic and/or
prophylactic treatment of glaucoma, for example, drugs having an intraocular pressure
reducing action, drugs having an optic nerve protective action, drugs having an
intraocular pressure reducing action, and/or an optic nerve protective action and the
like are also known.
Among the drugs for combination use used for the present invention, the drug
having an intraocular pressure reducing action is not particularly limited so long as
the drug has an intraocular pressure reducing action. Examples include adrenergic
receptor stimulants, prostaglandin-related agents, carbonic anhydrase inhibitors (also
abbreviated as CAI), adrenergic receptor blockers, cholinesterase inhibitors, Rho
kinase inhibitors (Honjo, M. et al., Invest. Ophthalmol. Vis. Sci., 42 (l), pp. 137-44
(2001); Honjo, M. et al., Arch. Ophthalmol. 119 (8), pp. 1171-8 (2001)), angiotensin II
receptor antagonists (Inoue, T. et al., Current Eye Res., 23 (2), pp. 133-8 (2001)) and
the like, and any one or more of these drugs can be used. When two or more kinds of
drugs for combination use are selected, two or more kinds of the drugs may be selected
from drugs belonging to the same classification, or one or more kind of the drugs may
be selected from drugs belonging to each of different classifications. The drugs are
preferably selected from those belonging to different classifications. Further, as the
drug having an intraocular pressure reducing action, one or more kinds of drugs
among a prostaglandin-related agent, a carbonic anhydrase inhibitor, and an
adrenergic receptor blocker are preferred. This medicament is preferred as an agent
118

for therapeutic and/or prophylactic treatment of glaucoma.
[0171]
Among the drugs for combination use used in the present invention, the drug
having an optic nerve cell protective action means a drug having an action of
protecting optic nerves, and examples include drugs having an action of protecting
optic nerve cells based on an action of suppressing cell death as well as an action of
improving eyeground vascular flow. The action of suppressing cell death of optic
nerve cells can be confirmed as, for example, an action of suppressing cell death
induced via a glutamate receptor in an exo vivo culture system using retinal nerve
cells extracted from a rat or the like by adding NMDA (Hahn et al., Proc. Natl. Acad.
Sci. USA, 85, 6556. (1998)), and the action of improving the eyeground vascular flow
can be confirmed by, for example, quantitatively analyzing change of the eyeground
vascular flow in human, rabbit, monkey, or the like administered with the drug using
the laser speckle method (Tamaki, Y. et al., Surv. OphthalmoL, 42 (Suppl. l), S52-S63.
(1997)).
Examples of the drug having an optic nerve protective action include
adrenergic receptor stimulants (Wheeler, LA. et al., Eur. J. OphthalmoL, 11 (Suppl. 2)
403-11. (2001)), adrenergic receptor blockers (Wood, J P., et al., Exp. Eye Res. 76 (4),
505-16. (2003) and the like), calcium antagonists (Toriu, N. et al., Exp. Eye Res., 70 (4)),
475-84. (2000)), NMDA receptor blockers (Kim, T W. et al., Korean J. OphthalmoL, 16
(l), 1-7. (2002)), prostaglandin-related agents (Tamaki, Y. et al., and J. Ocul.
Pharmacol. Ther., 17 (5), 403-11. (2001) and the like), carbonic anhydrase inhibitors
(Harris, A. et al., J. Ocul. Pharmacol. Ther., 15,189-197. (1999)), angiotensin II
receptor antagonists (Inoue, T. et al., Ophthalmic Res., 35, pp. 351-4. (2003)) and the
like, and any one or more of these drugs can be used.
[0172]
Moreover, besides drugs having either of the intraocular pressure reducing
action and the optic nerve protective action, drugs having both the intraocular
pressure reducing action and the optic nerve protective action as a single agent are
also known. Examples of such drugs include, for example, adrenergic receptor
stimulants, prostaglandin-related agents, carbonic anhydrase inhibitors, adrenergic
receptor blockers, calcium antagonists and the like, and any one or more these drugs
may be used.
119

Specifically, among the drugs for combination use used for the present
invention, the drugs having an intraocular pressure reducing action and/or drugs
having an optic nerve protective action can be divided into the aforementioned drugs
having an intraocular pressure reducing action, drugs having an optic nerve protective
action, and drugs having both of an intraocular pressure reducing action and an optic
nerve protective action as a single agent. Examples of the drugs having an
intraocular pressure reducing action and/or drugs having an optic nerve protective
action include, for example, one or more of adrenergic receptor stimulants,
prostaglandin-related agents, carbonic anhydrase inhibitors, adrenergic receptor
blockers, cholinesterase inhibitors, calcium antagonists, Rho kinase inhibitors,
angiotensin II receptor antagonists, NMDA receptor blockers and the like.
Furthermore, preferred examples include one or more of prostaglandin-related agents,
carbonic anhydrase inhibitors, adrenergic receptor blockers, and the like.
[0173]
In this specification, the adrenergic receptors include, for example, those of a
lA-subtype, a IB-subtype, a ID-subtype, a 2A-subtype, a 2B-subtype, a
2Osubtype, i3 1-subtype, j3 2"subtype, and j3 3-subtype, which considered to be
involved in control of constriction and relaxation of various smooth muscles. (Kurose et
al., Protein Nucleic Acid Enzyme, Vol. 42, No. 3, pp. 316-26. (1997)).
In this specification, the adrenergic receptor stimulants means a medicament
that acts as an agonist against at least one of the aforementioned adrenergic receptors
and has an regulatory action on various smooth muscles. Examples of the regulatory
action on various smooth muscles include, for example, an intraocular pressure
reducing action, and a tracheal dilational action. The medicaments herein referred to
mean those exhibiting an intraocular pressure reducing action. Depending on the
degree of selectivity for the adrenergic receptors, for example, those selectively acting
on a -receptors may be described as a -stimulants, and those selectively acting on a
2-receptors may be described as a 2-stimulants.
In the present invention, examples of the adrenergic receptor stimulants
include, for example, non-selective sympathetic nerve stimulants, a 1-stimulants, and
a 2-stimulants. Epinephrine, dipivefrin (U.S. Patent No. 3,809,714), apraclonidine
(U.S. Patent No. 4,517,199), brimonidine (U.S. Patent No. 4,517,199), and
physiologically acceptable salts thereof are preferred, and epinephrine hydrochloride,
120

dipivefrin hydrochloride, apraclonidine, and brimonidine tartrate are preferred. Any
one of these drug is preferred, and any two or more of them are also preferred.
[0174]
The prostaglandin-related agents are roughly classified into prostaglandin
receptor (FP receptor) binding prostaglandins (Richard, M B. et al., Annu. Rev.
Pharmacol. Toxicol., 41, pp. 661-90. (2001)), and metabolic type prostaglandins. In
addition, isopropylunoprostone and the like as derivatives thereof can also be
exemplified. The prostaglandin receptor (FP receptor) binding prostaglandins are
prostaglandins having an ability to bind to an FP receptor, and they are generally
naturally occurring prostaglandins or compounds having similar structures in many
cases. The prostaglandin-related agents preferably further exhibit an intraocular
pressure reducing action, and preferably have a curative effect for glaucoma.
Examples of the naturally occurring prostaglandins include, for example,
prostaglandin F2 a and the like. Examples of the FP receptor binding
prostaglandins having a structure similar to that of naturally occurring
prostaglandins include, for example, latanoprost, travoprost, bimatoprost, tafluprost
and the like.
The metabolic type prostaglandins mean compounds produced by metabolism
of the FP receptor binding prostaglandins in the living bodies.
Therefore, in the present invention, as the prostaglandurrelated agents,
isopropylunoprostone (U.S. Patent No. 5,627,209), latanoprost (U.S. Patent No.
5,296,504), travoprost (U.S. Patent No. 5,510,383), bimatoprost (U.S. Patent No.
6,403,649), tafluprost (Japanese Patent Unexamined Publication (Kokai) No.
2003-321442), and physiologically acceptable salts thereof are preferred, and
isopropylunoprostone, latanoprost, travoprost, bimatoprost, and tafluprost are
preferred. Any one of these is preferred, and any two or more of them are also
preferred.
[0175]
In this specification, the carbonic anhydrase inhibitors mean isozymes of
carbonic anhydrase having at least type II and/or type IV enzyme inhibitory action.
Examples of the carbonic anhydrase inhibitors include, for example, dorzolamide
(European Patent Publication No. 296879), brinzolamide (U.S. Patent No. 5,378,703),
acetazolamide (U.S. Patent No. 2,554,816), and physiologically acceptable salts thereof,
121

and dorzolamide hydrochloride, brinzolamide hydrochloride, and acetazolamide
hydrochloride are preferred. Any one of these is preferred, or any two or more of them
are also preferred.
In this specification, the adrenergic receptors are the same as those mentioned
above. The adrenergic receptor blockers means drugs that act as an antagonist
against at least one type of adrenergic receptor, and have an action of regulating
various smooth muscles. The action of regulating various smooth muscles preferably
means an action exhibiting an intraocular pressure reducing action. Depending on
the degree of selectivity for adrenergic receptors, they may be described as a -blockers,
# -blockers, or a j3 -blockers. Examples of the adrenergic receptor blockers include,
for example, a -blockers, # -blockers, and a /3 -blockers. Bunazosin (British Patent
Application Publication No. 1398455), timolol (U.S. Patent No. 5,354,860), carteolol
(U.S. Patent No. 3,953,456), befunolol (U.S. Patent No. 4,515,977), betaxolol (U.S.
Patent No. 4,252,984), nipradilol (Japanese Patent Publication (Kokoku) No. 60-54317),
levobunolol (U.S. Patent No. 5,426,227), and physiologically acceptable salts thereof
are preferred, and bunazosin hydrochloride, timolol maleate, carteolol hydrochloride,
befunolol hydrochloride, betaxolol hydrochloride, and nipradilol hydrochloride are also
preferred. Any one of these is preferred, and any two or more of them are also
preferred.
[0176]
Examples of the cholinesterase inhibitors include, for example, demecarium,
physostigmine (U.S. Patent No. 4,791,107), echothiophate, and physiologically
acceptable salts thereof, and physostigmine sulfate and the like are preferred. Any
one of these is preferred, and any two or more of them are also preferred.
Examples of the calcium antagonists include, iganidipine (U.S. Patent No.
2,554,816), lomerizine (Japanese Patent Unexamined Publication No. 60-222472), and
physiologically acceptable salts thereof, and iganidipine hydrochloride, and lomerizine
hydrochloride are also preferred. Any one of these is preferred, and any two or more
of them are also preferred.
Examples of the Rho kinase inhibitors include, for example,
(+)-trans-4-(l-aminoethyl)-l-(4-pyridylcarbamoyl)cyclohexane,
(+)-trans-N-(pyrrolo[lH[2,3-b]pyridin-4-yl)-4-(l-aminoethyl)cyclohexanecarboxamide,
(R)-(+)-N"(4-pyridyl)-4-(l-aminoethyl)benzamide,
122

(R)'(+)'N-(lH-pyrrolo[2,3-b]pyridin-4-yl)-4-(l-aminoethyl)benzamide (International
Patent Publication WO02/083175), HA-1077 (Nagumo, H. et al., Am. J. Physiol. Cell
Physiol., 278 (l) pp. C57-65. (2000)), physiologically acceptable salts thereof, and
pharmaceutical compositions comprising these compounds. Any one of these is
preferred, and any two or more of them are also preferred.
[0177]
In this specification, the angiotensin II receptors include those of ATIA, ATIB,
AT2, AT3, and AT4 subtypes, which bind to angiotensin II to be involved in blood
pressure regulating action, and the like, and the angiotensin II receptor antagonists
mean drugs having a binding activity at least to an ATi receptor for antagonizing
against angiotensin II, and attenuating the action of angiotensin II. Examples of the
angiotensin II receptor antagonists include, for example, olmesartan (CS-088) (U.S.
Patent No. 5,616,599), and physiologically acceptable salts thereof, and olmesartan is
preferred. Any one of these is preferred, and any two or more of them are also
preferred.
Examples of the NMD A receptor antagonists include, for example, memantine
(U.S. Patent No. 4,122,193), and physiologically acceptable salts thereof, and
memantine hydrochloride is preferred. Any one of these is preferred, and any two or
more are also preferred.
Moreover, a method for therapeutic and/or prophylactic treatment of glaucoma,
which uses any of the medicaments mentioned above is also preferred.
[0178]
When the aforementioned medicaments are used as an eye drop, for example,
one to ten drops, preferably one or two drops (volume of one drop is about 50 M L), as a
single dose for administration, can be preferably administered about 1 to 6 times a day.
When the object of the administration is human, for example, the drug for
combination use is generally preferably used in an amount of 0.001 to 1000 parts by
weight with 1 weight part of the compound of the present invention represented by the
aforementioned formula (l), a salt thereof, or a derivative thereof useful as a prodrug.
More specifically, although the lower limit of the amount of the drug for combination
use is not particularly limited so long as the effect of the present invention is exhibited,
the drug for combination use is used in an amount of, for example, 0.00001 part by
weight or more, preferably 0.0001 part by weight or more, more preferably 0.001 part
123

by weight or more, further preferably 0.01 part by weight or more, with 1 weight part
of the compound of the present invention represented by the aforementioned formula
(l), a salt thereof, or a derivative thereof useful as a prodrug. Although the upper
limit of the amount of the drug for combination use is not also particularly limited, for
example, the drug for combination use is generally used in an amount of 1000 parts by
weight or less, preferably 500 parts by weight or less, more preferably 250 parts by
weight or less, or 100 parts by weight or less.
Examples
[0179]
The present invention will be further specifically explained with reference to
the following examples. However, the present invention is not limited to these
examples.
For thin layer chromatography (TLC), Precoated Silica Gel 60 F254 (produced
by Merck) was used. After development with chloroform-methanol (100-1 to 4^1), or
n-hexane:ethyl acetate (100-1 to 1-10), spots were observed by UV irradiation (254 nm)
or coloration with ninhydrine or phosphomolybdic acid. For drying organic solvent,
anhydrous magnesium sulfate or anhydrous sodium sulfate was used. For flash
column chromatography, Silica gel 60N (spherical shape, neutral, 40 to 100 i± m,
produced by Kanto Chemicals) was used. For preparative thin layer chromatography
(PTLC), Precoated Silica Gel 60 F254 (20 x 20 cm, thickness'- 2 mm, produced by
Merck) was used. For the measurement of nuclear magnetic resonance (NMR)
spectra, the measurement was performed by using Gemini-300 (FT-NMR, produced by
Varian), or AL-300 (FT-NMR, produced by JOEL). As a solvent, deuterated
chloroform was used, unless otherwise indicated. Chemical shifts were measured by
using tetramethylsilane (TMS) as an internal standard, and indicated with 8 (ppm),
and binding constant was indicated with J (Hz). Mass spectrum (MS) was measured
by liquid chromatographymass spectrometry (LC-MS). PlatfornvLC type mass
spectrometry apparatus (produced by Micromass) was used as the mass spectrometer,
and the measurement was performed by the electrospray ionization (ESI) method. As
the liquid chromatography apparatus, an apparatus produced by GILSON was used.
As the separation column, Mightysil RP'18 GP 50-4.6 (produced by Kanto Chemicals)
was used. Elution was generally performed at a flow rate of 2 ml/minute using a
linear gradient of 5 to 100% (v/v) Solution B [acetonitrile containing 0.1% (v/v) acetic
124

acid] in Solution A [water containing 0.1% (v/v) acetic acid] from 0 minute to 5 minutes
as the solvent.
[0180]
Reference Example l: 4-Fluoroisoquinoline
A solution of n-butyllithium in n-hexane (1.58 M, 60.1 ml, Kanto Chemicals)
was added with tetrahydrofuran (345 ml), and the mixture was sufficiently cooled on a
dry ice-acetone bath. The mixture was added dropwise with a solution of
4-bromoisoquinoline (9.0 g, Tokyo Kasei Kogyo) in tetrahydrofuran (65 ml) over 1 hour
so that the temperature of the reaction mixture should not exceed -65°C. The mixture
was stirred at the same temperature for 30 minutes, and then added dropwise with a
solution of N-fluorobenzenesulfonimide (30 g, Tokyo Kasei Kogyo) in tetrahydrofuran
(100 ml) over 1 hour so that the temperature of the reaction mixture should not exceed
■65°C. Subsequently, the mixture was stirred at the same temperature for 1 hour,
then the cooling bath was removed, and the mixture was gradually warmed to room
temperature. The reaction mixture was added with saturated aqueous sodium
hydrogencarbonate (300 ml) and ethyl acetate (300 ml), and stirred at room
temperature for 12 hours. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate 3 times (200 ml for each time). The combined
organic layer was washed with saturated brine (500 ml), and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced pressure, the residue
was added with chloroform (250 ml), and the insoluble matters were removed by
filtration. The solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography (n-hexane^ethyl acetate = 5^1) to obtain the title
compound (3.6 g).
MS (m/z): 148 (MH+)
iH-NMR (CDCls) 5 (ppm): 7.26-7.71 (1H, m), 7.75-7.82 (1H, m), 8.03 (1H, dd, J=1.2Hz,
J=8.4Hz), 8.10 (1H, d, J=8.4Hz), 8.38 (1H, s), 9.08 (1H, s)
[0181]
Reference Example 2- 4"Fluoro-5-nitroisoquinoline
4-Fluoroisoquinoline (3.6 g) obtained in Reference Example 1 was dissolved in
concentrated sulfuric acid (20 ml), and the solution was added dropwise with a solution
of potassium nitrate (3.25 g, Wako Pure Chemical Industries) in concentrated sulfuric
acid (28 ml) under cooling at -5°C so that the temperature of the reaction mixture
125

should not exceed 5°C. The reaction mixture was stirred at 0°C for 1 hour, poured
into ice water, neutralized with 28% aqueous ammonia (pH 8), and extracted 3 times
with ethyl acetate (150 ml for each time). The combined organic layer was washed
with saturated aqueous sodium hydrogencarbonate (300 ml), and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced pressure, and the
residue was purified by silica gel chromatography (n-hexane^ethyl acetate = 3:1) to
obtain the title compound (2.2 g).
[0182]
Reference Example 3- 5-Amino-4-fluoroisoquinoline
4"Fluoro-5-nitroisoquinoline (2.2 g) obtained in Reference Example 2 was
added with concentrated hydrochloric acid (40 ml), and added with stannous chloride
dihydrate (13 g, Wako Pure Chemical Industries) at 0°C, and the mixture was refluxed
for 12 hours by heating. The reaction mixture was cooled to room temperature, and
the solvent was evaporated under reduced pressure. The residue was neutralized
with 5 N aqueous sodium hydroxide, and extracted 4 times with chloroform (50 ml for
each time). The combined organic layer was washed with saturated brine (200 ml),
and dried over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel chromatography
(chloroform: acetone = 15-1) to obtain the title compound (1.45 g).
MS (m/z): 163 (MH+)
iH-NMR (CDCls) 5 (ppm): 6.85 (1H, dd, J=1.2Hz, J=7.5Hz), 7.31-7.35 (lH, m), 7.42
(1H, t, J=7.8Hz), 8.19 (1H, d, J=5.lHz), 8.91 (lH, s)
[0183]
Reference Example 4- 4"Fluoro-54soquinolinesulfonyl chloride
The title compound was obtained from 5-amino-4-fluoroisoquinoline obtained
in Reference Example 3 according to a known method (Japanese Patent No. 2763791).
Reference Example 5: 4-Chloro-5-nitroisoquinoline
According to the method described in Reference Example 2, the title compound
was obtained from 4-chloroisoquinoline obtained according to the method described in
a known literature (Vaughan et al., J. Org. Chem., 1961, 26, 468).
MS (m/z): 209 (MH+)
iH-NMR (CDCls) 5 (ppm): 7.75 (lH, t, J=7.8Hz), 7.94 (lH, dd, J=1.2Hz, J=7.8Hz),
8.22 (1H, dd, J=1.2Hz, J=7.8Hz), 8.71 (lH, s), 9.26 (lH, s)
126

Reference Example 6: 5-Amincr4-chloroisoquinoline
The title compound was obtained from 4-chloro-5-nitroisoquinoline obtained in
Reference Example 5 according to the method described in Reference Example 2.
MS (m/z): 179 (MH+)
iH-NMR (CDCls) 5 (ppm): 6.89 (1H, dd, J=1.3Hz, J=7.4Hz), 7.25-7.44 (2H, m), 8.32
(1H, s), 8.96 (1H, s)
Reference Example !'■ 4-Chloro"5"isoquinolinesulfonyl chloride
The title compound was obtained from 5-amino-4-chloroisoquinoline obtained
in Reference Example 6 according to the method described in Japanese Patent No.
2763791.
[0184]
Example l: (R/S)-3'Amino-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate l)
A solution of 4-bromo-5-isoquinolinesulfonyl chloride (0.50 g) prepared
according to a known method (described in Japanese Patent No. 2763791), and
3-(tert-butoxycarbonylamino)pyrrolidine (0.33 g, Tokyo Kasei Kogyo) in methylene
chloride (5 ml) was added with triethylamine (0.68 ml, Wako Pure Chemical
Industries) at 0°C, and the mixture was stirred at the same temperature for 30
minutes, and then further stirred at room temperature for 5 hours. The reaction
mixture was washed with saturated brine (10 ml), and then dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced pressure, and then
the residue was purified by silica gel chromatography (n-hexane^ethyl acetate = 1:1) to
obtain the title compound (0.62 g).
MS (m/z): 456 (MH+)
iH-NMR (CDCls) 8 (ppm): 1.44 (9H, s), 1.96-2.06 (1H, m), 2.26-2.37 (1H, m),
3.36-3.41 (1H, m), 3.52-3.56 (1H, m), 3.62-3.71 (2H, m), 4.36 (1H, m), 4.82 (1H, m), 7.70
(1H, t, J=7.8Hz), 8.20 (1H, dd, J=1.3, 7.8Hz), 8.41 (1H, dd, J=1.3, 7.8Hz), 9.01 (1H, s),
9.22 (1H, s)
[0185]
Step B
3-Amino-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
127

Intermediate 1 (120 mg) prepared in Step A mentioned above was added with
10% hydrogen chloride/methanol (2 ml, Tokyo Kasei Kogyo), and the mixture was
stirred at room temperature for 12 hours. The solvent was concentrated under
reduced pressure, and the obtained solid was collected by filtration to obtain the title
compound as hydrochloride (84 mg).
MS (m/z): 356 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.15-2.25 (1H, m), 2.37-2.48 (1H, m), 3.49-3.58 (2H, m),
3.66-3.80 (2H, m), 4.00-4.08 (1H, m), 7.90 (1H, t, J=7.8Hz), 8.42 (1H, d, J=7.8Hz), 8.52
(1H, d, J=8.1Hz), 8.96 (1H, s), 9.45 (1H, s)
[0186]
Example 1"1: (S)-3-Amino-l'(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
(S)-3-(tert-Butoxycarbonylamino)-l-(4-bromo-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate la) was prepared by using (S)"3-(tert"butoxycarbonyl-
amino)pyrrolidine (Tokyo Kasei Kogyo) in the method of Example 1, Step A instead of
3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of Step B in a
similar manner to obtain the title compound as hydrochloride.
MS (m/z): 356 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.15-2.25 (lH, m), 2.37-2.48 (1H, m), 3.49-3.58 (2H, m),
3.66-3.80 (2H, m), 4.00-4.08 (lH, m), 7.90 (lH, t, J=7.8Hz), 8.42 (1H, d, J=7.8Hz), 8.52
(1H, d, J=8.1Hz), 8.96 (1H, s), 9.45 (lH, s)
[0187]
Example 1-2: (R)-3-Amino-l'(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
(R)-3-(tert-Butoxycarbonylamino)"l-(4-bromo-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate lb) was prepared by using
(R)-3-(tert-butoxycarbonylamino)pyrrolidine (Tokyo Kasei Kogyo) in the method of
Example 1, Step A instead of 3-(tert-butoxycarbonylamino)pyrrolidine, and then used
in the method of Step B in a similar manner to obtain the title compound as
hydrochloride.
MS (m/z): 356 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.15-2.25 (lH, m), 2.37-2.48 (lH, m), 3.49-3.58 (2H, m),
3.66-3.80 (2H, m), 4.00-4.08 (lH, m), 7.90 (lH, t, J=7.8Hz), 8.42 (lH, d, J=7.8Hz), 8.52
(1H, d, J=8.1Hz), 8.96 (lH, s), 9.45 (lH, s)
[0188]
128

Example 2' (R/S)-3-Amino-l-(4-bromo-5-isoquinolinesulfonyl)piperidine
(R/S) - 3- (tert-Butoxycarbonylamino) ■ 1 - (4-bromo-5-isoquinolinesulfonyl) ■
piperidine (Intermediate 2) was prepared from 4-bromcr5-isoquinolinesulfonyl chloride
and 3-(tert-butoxycarbonylamino)piperidine (AstaTech) according to the method
described in Example 1, Step A, and then used in the method of Example 1, Step B in a
similar manner to obtain the title compound as hydrochloride.
MS (m/z): 370 (MH+)
[0189]
Example 2-1" (S)-3"Amino-l"(4-bromo'5-isoquinolinesulfonyl)piperidine
(S)-3-(tert-Butoxycarbonylamino)-l-(4-bromo-5-isoquinolinesulfonyl)-
piperidine (Intermediate 2a) was prepared by using (S)^3-(tert-butoxycarbonyl-
amino)piperidine (AstaTech) in the method of Example 1, Step A instead of
3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of Example 1,
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 370 (MH+)
[0190]
Example 2-2: (R)-3-Amino-l"(4-bromo-5-isoquinolinesulfonyl)piperidine
(R) • 3 - (tert"B utoxycarbony lamino) ■ 1 - (4-bromo- 5 -isoquinolinesulfonyl) ■
piperidine (Intermediate 2b) was prepared by using
(R)-3-(tert-butoxycarbonylamino)piperidine (AstaTech) in the method of Example 1,
Step A instead of 3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the
method of Example 1, Step B in a similar manner to obtain the title compound as
hydrochloride.
MS (m/z): 370 (MH+)
[0191]
Example 3: 3-Amino-l-(4-bromo-5-isoquinolinesulfonyl)azetidine
The title compound was obtained as hydrochloride from
4-bromo-5'isoquinolinesulfonyl chloride and 3-(tert-butoxycarbonylamino)azetidine
(AstaTech) according to the method described in Example 1, Step A and Step B.
MS (m/z): 342 (MH+)
[0192]
Example 4:
(R/S)-3-(2-Furylmethyl)amino'l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
129

A suspension of 3-amino- l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
hydrochloride (172 mg) obtained in Example 1 in 1,2-dichloroethane (10 ml) was added
with triethylamine (0.28 ml, Wako Pure Chemical Industries), and then with furfural
(42 mg, Aldrich), and the mixture was stirred at room temperature for 30 minutes,
then added with sodium triacetoxyborohydride (170 mg, Aldrich), and further stirred
at room temperature for 30 hours. The reaction mixture was added with saturated
aqueous sodium hydrogencarbonate (15 ml), and the organic layer was separated.
The aqueous layer was extracted 3 times with chloroform (10 ml for each time), and the
combined organic layer was washed with saturated brine (30 ml). The organic layer
was dried over anhydrous magnesium sulfate, and then the solvent was evaporated
under reduced pressure. The residue was purified by silica gel chromatography
(chlorofornvmethanol = 30:1) to obtain the title compound (52 mg).
MS (m/z): 436 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.29-2.55 (2H, m), 3.47-3.73 (3H, m), 3.79-3.85 (1H, m),
3.98-4.08 (1H, m), 4.32 (2H, m), 6.55 (1H, dd, J=1.8, J=3.3Hz), 6.70 (1H, d, J=3.3Hz),
7.81 (1H, d, J=1.8Hz), 7.90 (1H, t, J=7.8Hz), 8.42 (1H, d, J=7.8Hz), 8.53 (1H, d,
J=7.8Hz), 8.95 (1H, s), 9.46 (1H, s)
[0193]
Example 4"l:
(S)-3-(2-Furylmethyl)amino-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
The compound of Example 1"1 was used in the method of Example 4 instead of
the compound of Example 1 to obtain the title compound as hydrochloride.
MS (m/z): 436 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.29-2.55 (2H, m), 3.47-3.73 (3H, m), 3.79-3.85 (1H, m),
3.98-4.08 (1H, m), 4.32 (2H, m), 6.55 (1H, dd, J=1.8, J=3.3Hz), 6.70 (1H, d, J=3.3Hz),
7.81 (1H, d, J=1.8Hz), 7.90 (1H, t, J=7.8Hz), 8.42 (1H, d, J=7.8Hz), 8.53 (1H, d,
J=7.8Hz), 8.95 (1H, s), 9.46 (1H, s)
[0194]
Example 4-2:
(R)-3-(2-Furylmethyl)amino-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
The compound of Example 1-2 was used in the method of Example 4 instead of
the compound of Example 1 to obtain the title compound as hydrochloride.
MS (m/z): 436 (MH+)
130

iH-NMR (DMSO) 8 (ppm): 2.29-2.55 (2H, m), 3.47-3.73 (3H, m), 3.79-3.85 (1H, m),
3.98-4.08 (1H, m), 4.32 (2H, m), 6.55 (1H, dd, J=1.8, J=3.3Hz), 6.70 (1H, d, J=3.3Hz),
7.81 (1H, d, J=1.8Hz), 7.90 (1H, t, J=7.8Hz), 8.42 (lH, d, J=7.8Hz), 8.53 (1H, d,
J=7.8Hz), 8.95 (1H, s), 9.46 (1H, s)
[0195]
Example 5: (R/S)-3-(Allylamino)-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
A suspension of 3-amino- l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
hydrochloride (65 mg) obtained in Example 1 and potassium carbonate (148 mg, Wako
Pure Chemical Industries) in N,N-dimethylformamide (5 ml) was added with allyl
bromide (0.453 ml, Tokyo Kasei Kogyo), and the mixture was stirred at 50°C for 12
hours. The reaction mixture was cooled to room temperature, and then added with
saturated brine (10 ml) and chloroform (10 ml), and the organic layer was separated.
The aqueous layer was extracted 3 times with chloroform (10 ml for each time), and the
combined organic layer was washed twice with saturated brine (20 ml for each time).
The organic layer was dried over anhydrous magnesium sulfate, and then the solvent
was evaporated under reduced pressure. The residue was purified by silica gel
chromatography (chlorofornvmethanol = 30-1) to obtain the title compound (30 mg).
MS (m/z): 396 (MH+)
[0196]
Example 5-1: (S)-3-(Allylamino)-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
The compound of Example 1-1 was used in the method of Example 5 instead of
the compound of Example 1 to obtain the title compound as hydrochloride.
MS (m/z): 396 (MH+)
Example 5-2: (R)-3-(Allylamino)-l-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine
The compound of Example 1-2 was used in the method of Example 5 instead of
the compound of Example 1 to obtain the title compound as hydrochloride.
MS (m/z): 396 (MH+)
[0197]
Example 6: (R/S)-3"Amino-l-(4-bromo-l-methoxy-5-isoquinolinesulfonyl)pyrrolidine
Step A
3-(tert-Butoxycarbonylamino)-l-(2-oxy-4-bromo-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 3)
A suspension of Intermediate 1 (455 mg) obtained in Example 1, Step A and
131

sodium acetate (164 mg) in methylene chloride (20 ml) was cooled on an ice bath, and
added with 3-chloroperbenzoic acid (70%, 493 mg, Tokyo Kasei Kogyo) as several
portions, and the mixture was stirred at the same temperature for 30 minutes. The
mixture was further stirred at room temperature for 15 hours, and then added with
saturated aqueous sodium hydrogencarbonate (25 ml), and the organic layer was
separated. The organic layer was washed with saturated brine (20 ml), and dried
over anhydrous magnesium sulfate, and then the solvent was evaporated under
reduced pressure. The residue was purified by silica gel chromatography (ethyl
acetate: methanol = 10: l) to obtain the title compound (312 mg).
MS (m/z): 472 (MH+)
[0198]
Step B
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-bromo-l-methoxy-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate 4)
A solution of Intermediate 3 (236 mg) obtained in Step A mentioned above in
methanol (3.5 ml) was cooled on an ice bath, and added dropwise with methyl
chloroformate (0.08 ml, Tokyo Kasei Kogyo), and then triethylamine (0.18 ml, Wako
Pure Chemical Industries). The reaction mixture was stirred at room temperature for
3 hours, then cooled again on an ice bath, added with triethylamine (0.18 ml), and then
methyl chloroformate (0.08 ml), and stirred at room temperature for 12 hours. The
solvent was evaporated under reduced pressure, and the residue was added with
saturated aqueous sodium hydrogencarbonate (10 ml) and methylene chloride (10 ml).
The organic layer was separated, washed with saturated brine, and then dried over
anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure,
and the residue was purified by silica gel chromatography (ethyl acetate: methanol =
20:l) to obtain the title compound (120 mg).
MS (m/z): 486 (MH+)
Step C
(R/S)-3-Amino-l-(l-methoxy4-bromo-5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 4 obtained in Step B mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 386 (MH+)
132

[0199]
Example 6-l- (S)-3-Amino-l-(4"bromo-l-methoxy-5-isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 6 instead of Intermediate
1 to obtain the title compound as hydrochloride.
MS (m/z): 386 (MH+)
Example 6"2: (R)-3-Amino-l-(4-bromo-l-methoxy-5-isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 6 instead of Intermediate
1 to obtain the title compound as hydrochloride.
MS (m/z): 386 (MH+)
[0200]
Example T- (R/S)-3"Amino-l"(l-hydroxy4-bromo-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 4 (25 mg) obtained in Example 6, Step B was added with 10%
hydrogen chloride/methanol (10 ml), and the mixture was stirred at 50°C for 50 hours.
The solvent was evaporated under reduced pressure to obtain the title compound as
hydrochloride (13 mg).
MS (m/z): 372 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.05-2.17 (1H, m), 2.33-2.45 (1H, m), 3.37-3.51 (2H, m),
3.59-3.70 (2H, m), 3.95-4.03 (lH, m), 7.68 (1H, s), 7.69 (1H, t, J=7.9Hz), 8.18 (1H, dd,
J=l.l, 7.9Hz), 8.56 (1H, dd, J=l.l, 7.9Hz)
[0201]
Example 7"l: (S)-3"Amino-l-(l-hydroxy-4-bromo-5-isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Example 6, Step B in a
similar manner, and then the title compound was obtained as hydrochloride according
to the method of Example 7.
MS (m/z): 372 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.05-2.17 (lH, m), 2.33-2.45 (lH, m), 3.37-3.51 (2H, m),
3.59-3.70 (2H, m), 3.95-4.03 (lH, m), 7.68 (1H, s), 7.69 (lH, t, J=7.9Hz), 8.18 (1H, dd,
J=l.l, 7.9Hz), 8.56 (1H, dd, J=l.l, 7.9Hz)
[0202]
Example 7-2: (R)-3-Amino-l-(l-hydroxy-4-bromo"5-isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Example 6, Step B in a
133

similar manner, and then the title compound was obtained as hydrochloride according
to the method of Example 7.
MS (m/z): 372 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.05-2.17 (1H, m), 2.33-2.45 (1H, m), 3.37-3.51 (2H, m),
3.59-3.70 (2H, m), 3.95-4.03 (1H, m), 7.68 (1H, s), 7.69 (1H, t, J=7.9Hz), 8.18 (1H, dd,
J=l.l, 7.9Hz), 8.56 (1H, dd, J=l.l, 7.9Hz)
[0203]
Example 8: (R/S)-3-Amino-l-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 5)
A solution of Intermediate 1 (228 mg) obtained in Example 1, Step A and
tetramethyltin (0.69 ml, Tokyo Kasei Kogyo) in N,N"dimethylformamide (4 ml) was
added with tetrakis(triphenylphosphine)palladium(0) (29 mg, Kanto Chemicals), and
the mixture was stirred at 120°C with heating for 12 hours. The reaction mixture
was cooled to room temperature, then added with saturated brine (5 ml), and extracted
3 times with ethyl acetate (5 ml for each time). The combined organic layer was
washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, and then the residue was purified
by silica gel chromatography (n-hexane^ethyl acetate = l:i) to obtain the title
compound (176 mg).
MS (m/z): 392 (MH+)
[0204]
Step B
(R/S)-3-Amino-l-(4"methyl-5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 5 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 292 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.17-2.28 (1H, m), 2.44-2.55 (1H, m), 3.03 (3H, s),
3.56-3.64 (2H, m), 3.72-3.87 (2H, m), 4.04-4.12 (1H, m), 7.97 (1H, t, J=7.8Hz), 8.45 (lH,
d, J=7.8Hz), 8.64 (1H, d, J=7.8Hz), 8.67 (lH, s), 9.64 (lH, s)
[0205]
134

Example 8"1' (S)-3\Amino-l-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 5a was prepared by using Intermediate la in the method of
Example 8 instead of Intermediate 1, and then used in the method of Step B in a
similar manner to obtain the title compound as hydrochloride.
MS (m/z): 392 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.17-2.28 (1H, m), 2.44-2.55 (1H, m), 3.03 (3H, s),
3.56-3.64 (2H, m), 3.72-3.87 (2H, m), 4.04-4.12 (1H, m), 7.97 (1H, t, J=7.8Hz), 8.45 (1H,
d, J=7.8Hz), 8.64 (1H, d, J=7.8Hz), 8.67 (1H, s), 9.64 (1H, s)
[0206]
Example 8-2: (R)-3-Amino-l-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 5b was prepared by using Intermediate lb in the method of
Example 8 instead of Intermediate 1, and then used in the method of Step B in a
similar manner to obtain the title compound as hydrochloride.
MS (m/z): 392 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.17-2.28 (1H, m), 2.44-2.55 (lH, m), 3.03 (3H, s),
3.56-3.64 (2H, m), 3.72-3.87 (2H, m), 4.04-4.12 (1H, m), 7.97 (1H, t, J=7.8Hz), 8.45 (1H,
d, J=7.8Hz), 8.64 (lH, d, J=7.8Hz), 8.67 (1H, s), 9.64 (lH, s)
[0207]
Example 9: (R/S)"3-Amino-l-(4-vinyl-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-vinyl-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 6)
A solution of Intermediate 1 (250 mg) obtained in Example 1, Step A,
2,6-di(tert-butyl)-4-methylphenol (0.5 mg, Tokyo Kasei Kogyo), and tri(n-butyl)vinyltin
(0.25 ml, Tokyo Kasei Kogyo) in toluene (8 ml) was added with
tetrakis(triphenylphosphine)palladium(0) (13 mg, Kanto Chemicals) under a nitrogen
gas atmosphere, and the mixture was refluxed by heating for 12 hours. The reaction
mixture was cooled to room temperature, and then the solvent was evaporated under
reduced pressure. The residue was purified by silica gel chromatography
(n-hexane:ethyl acetate = 2:l) to obtain the title compound (195 mg).
MS (m/z): 404 (MH+)
[0208]
Step B
135

(R/S) ■ 3-Amincr 1 ■ (4-vinyl- 5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 6 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 304 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.09-2.20 (1H, m), 2.34-2.45 (1H, m), 3.41-3.53 (2H, m),
3.62-3.75 (2H, m), 3.95-4.03 (1H, m), 5.43 (1H, ABq, J=1.2, 10.8Hz), 5.69 (1H, AB,,
J=1.2, 17.0Hz), 7.84 (1H, ABq, J=10.8, 17.0Hz), 7.89 (1H, t, J=7.8Hz), 8.55 (1H, d,
J=7.8Hz), 8.71 (1H, s), 9.51 (1H, s)
[0209]
Example 9"i: (S)-3-Amino-l-(4-vinyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 6a was prepared by using Intermediate la in the method of
Example 9, Step A instead of Intermediate 1, and then used in the method of Step B in
a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 304 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.09-2.20 (1H, m), 2.34-2.45 (1H, m), 3.41-3.53 (2H, m),
3.62-3.75 (2H, m), 3.95-4.03 (1H, m), 5.43 (1H, ABq, J=1.2, 10.8Hz), 5.69 (1H.AB,,
J=1.2, 17.0Hz), 7.84 (lH, ABq, J=10.8, 17.0Hz), 7.89 (1H, t, J=7.8Hz), 8.55 (1H, d,
J=7.8Hz), 8.71 (1H, s), 9.51 (1H, s)
[0210]
Example 9"2: (R)-3-Amino-l-(4-vinyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 6b was prepared by using Intermediate lb in the method of
Example 9, Step A instead of Intermediate 1, and then used in the method of Step B in
a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 304 (MH+)
!H-NMR (DMSO) 3.62-3.75 (2H, m), 3.95-4.03 (1H, m), 5.43 (lH, ABq, J=1.2, 10.8Hz), 5.69 (lH, ABq,
J=1.2, 17.0Hz), 7.84 (1H, ABq, J=10.8, 17.0Hz), 7.89 (lH, t, J=7.8Hz), 8.55 (lH, d,
J=7.8Hz), 8.71 (1H, s), 9.51 (lH, s)
[0211]
Example 10: (R/S)-3-Amino-l-(4-ethynyl-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S) "3" (tert-Butoxycarbonylamino) -1 - [4- (2"trimethylsilyl)ethynyl- 5-
136

isoquinolinesulfonyl]pyrrolidine (Intermediate 7)
A suspension of Intermediate 1 (160 mg) obtained in Example 1, Step A,
dichlorobis(benzonitrile)palladium(II) (31 mg, Tokyo Kasei Kogyo),
tri(tert-butyl)phosphonium tetrafluoroborate (49 mg, Aldrich), and copper iodide (9 mg,
Wako Pure Chemical Industries) in 1,4-dioxane (2 ml) was added with
trimethylsilylacetylene (0.146 ml, Tokyo Kasei Kogyo) and diisopropylamine (0.148 ml,
Wako Pure Chemical Industries) under a nitrogen gas atmosphere, and the mixture
was stirred at room temperature for 18 hours. The reaction mixture was added with
ethyl acetate (20 ml), and filtered through silica gel. The solvent was evaporated
under reduced pressure, and then the residue was purified by silica gel
chromatography (n-hexane^ethyl acetate = 2:i) to obtain the title compound (98 mg).
MS (m/z): 474 (MH+)
[0212]
Step B
(R/S)-3-(tert-Butoxycarbonylamino)-l-[4-ethynyl-5-isoquinolinesulfonyl]pyrrolidine
(Intermediate 8)
A solution of Intermediate 7 (92 mg) obtained in Step A mentioned above in
methanol (2 ml) was added with potassium carbonate (2.7 mg), and the mixture was
stirred at room temperature for 3 hours. The solvent was evaporated under reduced
pressure, and then the residue was added with methylene chloride (2 ml) and water(2
ml). The organic layer was separated, and dried over anhydrous magnesium sulfate,
and then the solvent was evaporated under reduced pressure. The residue was
purified by silica gel chromatography (n-hexane^ethyl acetate = l:l) to obtain the title
compound (74 mg).
MS (m/z): 402 (MH+)
[0213]
Step C
(R/S)-3-Amino-l-(4-ethynyl-5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 8 obtained in Step B mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride (50 mg).
MS (m/z): 302 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.11-2.22 (lH, m), 2.35-2.45 (1H, m), 3.46-3.56 (2H, m),
137

3.63-3.79 (2H, m), 3.93-4.10 (1H, m), 4.59 (1H, s), 7.89 (1H, t, J=7.8Hz), 8.40 (1H, d,
J=7.8Hz), 8.51 (1H, d, J=7.8Hz), 8.87 (1H, s), 9.50 (lH, s)
[0214]
Example 10-l: (S)-3-Amino-l-(4-ethynyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 10 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 302 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.11-2.22 (1H, m), 2.35-2.45 (lH, m), 3.46-3.56 (2H, m),
3.63-3.79 (2H, m), 3.93-4.10 (lH, m), 4.59 (lH, s), 7.89 (lH, t, J=7.8Hz), 8.40 (lH, d,
J=7.8Hz), 8.51 (1H, d, J=7.8Hz), 8.87 (lH, s), 9.50 (1H, s)
[0215]
Example 10-2: (R)-3"Amino-l-(4-ethynyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 10 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 302 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.11-2.22 (1H, m), 2.35-2.45 (lH, m), 3.46-3.56 (2H, m),
3.63-3.79 (2H, m), 3.93-4.10 (lH, m), 4.59 (lH, s), 7.89 (1H, t, J=7.8Hz), 8.40 (1H, d,
J=7.8Hz), 8.51 (1H, d, J=7.8Hz), 8.87 (lH, s), 9.50 (lH, s)
[0216]
Example 11: (R/S)-3"Amino-l-(4-cyclopropyl-5"isoquinolinesulfonyl)pyrrolidine
Step A
(R/S) - 3- (tert-Butoxycarbonylamino) -1 - (4-cyclopropyl-5-isoquinolinesulfonyl) -
pyrrolidine (Intermediate 9)
A suspension of Intermediate 1 (200 mg) obtained in Example 1, Step A,
cyclopropylboronic acid (57 mg, Aldrich), anhydrous potassium phosphate (372 mg,
Aldrich), and tricyclohexylphosphonium tetrafluoroborate (33 mg, Aldrich) in toluene
(2 ml) was added with palladium acetate (10 mg, Wako Pure Chemical Industries), and
the mixture was stirred at 80°C with heating for 14 hours under a nitrogen gas
atmosphere. The reaction mixture was cooled to room temperature, and then added
with ethyl acetate (5 ml), and the insoluble matters were removed by filtration through
Celite. The solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography Grhexane:ethyl acetate = 1:1) to obtain the title
compound (53 mg).
138

MS (m/z): 418 (MH+)
[0217]
Step B
(R/S)-3-Amino-l-(4-cyclopropyl-5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 9 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride (38 mg).
MS (m/z): 318 (MH+)
iH-NMR (DMSO) 8 (ppm): 0.86-0.92 (2H, m), 1.07-1.16 (2H, m), 2.13-2.24 (1H, m),
2.41-2.51 (1H, m), 3.07-3.16 (1H, m), 3.37-3.60 (2H, m), 3.68-3.80 (2H, m), 4.02-4.08
(1H, m), 7.91 (1H, t, J=7.8Hz), 8.39 (1H, d, J=7.8Hz), 8.49 (1H, s), 8.56 (lH, d, J=7.8Hz),
9.50 (1H, s)
[0218]
Example 11-1: (S)-3-Amino-l-(4-cyclopropyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 11 instead of Intermediate
1 to obtain the title compound as hydrochloride.
MS (m/z): 318 (MH+)
iH-NMR (DMSO) 5 (ppm): 0.86-0.92 (2H, m), 1.07-1.16 (2H, m), 2.13-2.24 (lH, m),
2.41-2.51 (1H, m), 3.07-3.16 (lH, m), 3.37-3.60 (2H, m), 3.68-3.80 (2H, m), 4.02-4.08
(1H, m), 7.91 (1H, t, J=7.8Hz), 8.39 (lH, d, J=7.8Hz), 8.49 (lH, s), 8.56 (lH, d, J=7.8Hz),
9.50 (1H, s)
[0219]
Example 11"2: (R)-3-Amino-l-(4-cyclopropyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 11 instead of Intermediate
1 to obtain the title compound as hydrochloride.
MS (m/z): 318 (MH+)
iH-NMR (DMSO) 8 (ppm): 0.86-0.92 (2H, m), 1.07-1.16 (2H, m), 2.13-2.24 (lH, m),
2.41-2.51 (1H, m), 3.07-3.16 (1H, m), 3.37-3.60 (2H, m), 3.68-3.80 (2H, m), 4.02-4.08
(1H, m), 7.91 (1H, t, J=7.8Hz), 8.39 (lH, d, J=7.8Hz), 8.49 (lH, s), 8.56 (lH, d, J=7.8Hz),
9.50 (1H, s)
[0220]
Example 12: (R/S)-3-Amino-l-(4-amino-5-isoquinolinesulfonyl)pyrrolidine
Step A
139

(R/S) - 3-(tert'Butoxycarbonylamino) ■ 1 ■ [4- (tert-butoxycarbonylamino) • 5-
isoquinolinesulfonyl]pyrrolidine (Intermediate 10)
A suspension of Intermediate 1 (137 mg) obtained in Example 1, Step A,
tris(dibenzylideneacetone)dipalladium(0) (55 mg, Aldrich),
(±)-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (37 mg, Aldrich), tert-butyl carbamate
(70 mg, Aldrich), and cesium carbonate (196 mg, Aldrich) in toluene (5 ml) was stirred
at 100°C for 15 hours. The reaction mixture was cooled to room temperature, and
then added with ethyl acetate (5 ml), and the insoluble matters were removed by
filtration through Celite. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel chromatography (n-hexane^ethyl acetate = l:l) to
obtain the title compound (48 mg).
[0221]
Step B
(R/S)-3-Amino-l-(4-amino"5"isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 10 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride (36 mg).
MS (m/z): 293 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.06-2.17 (1H, m), 2.31-2.43 (1H, m), 3.45-3.76 (6H, m),
3.94-4.02 (1H, m), 7.90 (1H, t, J=7.8Hz), 8.16 (1H, s), 8.40 (1H, d, J=7.8Hz), 8.49 (1H, d,
J=7.8Hz), 8.93 (1H, s)
[0222]
Example 12-1: (S)-3-Amino-l-(4-amino-5-isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 12 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 293 (MH+)
!H-NMR (DMSO) 8 (ppm): 2.06-2.17 (1H, m), 2.31-2.43 (1H, m), 3.45-3.76 (6H, m),
3.94-4.02 (1H, m), 7.90 (1H, t, J=7.8Hz), 8.16 (lH, s), 8.40 (1H, d, J=7.8Hz), 8.49 (1H, d,
J=7.8Hz), 8.93 (1H, s)
[0223]
Example 12~2: (R)-3"Amino-l-(4-amino-5'isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 12 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
140

MS (m/z): 293 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.06-2.17 (1H, m), 2.31-2.43 (1H, m), 3.45-3.76 (6H, m),
3.94-4.02 (1H, m), 7.90 (lH, t, J=7.8Hz), 8.16 (1H, s), 8.40 (1H, d, J=7.8Hz), 8.49 (1H, d,
J=7.8Hz), 8.93 (1H, s)
[0224]
Example 13: (R/S)"3-Amino-l-(4-cyano-5-isoquinolinesulfonyl)pyrrolidine
Step A
3-(tert-Butoxycarbonylamino)-l-(4-cyano-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 11)
The title compound was obtained from Intermediate 1 obtained in Example 1,
Step A according to the method described in a known literature (Weissman S.A. et al.,
J. Org. Chem., 2005, 70, 1508).
[0225]
Step B
The protective group of Intermediate 11 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 303 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.01-2.12 (lH, m), 2.31-2.42 (lH, m), 3.40-3.78 (4H, m),
3.92-3.98 (1H, m), 8.04 (lH, t, J=7.8Hz), 8.60 (lH, dd, J=1.3, 7.8Hz), 8.68 (1H, dd,
J=1.3, 7.8Hz), 9.23 (1H, s), 9.80 (1H, s)
[0226]
Example 13-1: (S)-3"Amino-l-(4-cyano-5-isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 13 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 303 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.01-2.12 (lH, m), 2.31-2.42 (lH, m), 3.40-3.78 (4H, m),
3.92-3.98 (1H, m), 8.04 (lH, t, J=7.8Hz), 8.60 (lH, dd, J=1.3, 7.8Hz), 8.68 (lH, dd,
J=1.3, 7.8Hz), 9.23 (lH, s), 9.80 (lH, s)
[0227]
Example 13-2: (R)-3-Amino-l"(4-cyano"5-isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 13 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
141

MS (m/z): 303 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.01-2.12 (1H, m), 2.31-2.42 (1H, m), 3.40-3.78 (4H, m),
3.92-3.98 (1H, m), 8.04 (1H, t, J=7.8Hz), 8.60 (1H, dd, J=1.3, 7.8Hz), 8.68 (1H, dd,
J=1.3, 7.8Hz), 9.23 (1H, s), 9.80 (1H, s)
[0228]
Example 14: (R/S)-3-Amino-l-(4-phenyl-5'isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-[4-phenyl-5-isoquinolinesulfonyl]pyrrolidine
(Intermediate 12)
Intermediate 1 (228 mg) obtained in Example 1, Step A was added with
phenylboronic acid (122 mg, Aldrich), tetrakis(triphenylphosphine)palladium(0) (116
mg), 1,2-dimethoxyethane (5 ml) and 2 N aqueous sodium carbonate (2 ml), and the
mixture was refluxed by heating for 5 hours under a nitrogen gas atmosphere. The
reaction mixture was cooled to room temperature, then added with water(25 ml), and
extracted 3 times with ethyl acetate (20 ml for each time), and the combined organic
layer was washed with saturated brine (30 ml), and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography (n-hexane^ethyl acetate = 2:l) to obtain the title
compound (158 mg).
MS (m/z): 454 (MH+)
[0229]
Step B
(R/S)-3-Amino-l-(4-phenyl-5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 12 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 354 (MH+)
[0230]
Example 14-1: (S)-3-Amino-l-(4-phenyl-5"isoquinolinesulfonyl)pyrrolidine
Intermediate la was used in the method of Example 14 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 354 (MH+)
Example 14-2: (R)-3-Amino-l-(4-phenyl-5-isoquinolinesulfonyl)pyrrolidine
142

Intermediate lb was used in the method of Example 14 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 354 (MH+)
[0231]
Example 15: (R/S)"3\A.mino-l-(4-methoxy5"isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3'(tert-Butoxycarbonylamino)-l-(4-methoxy5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 13)
A solution of Intermediate 1 (337 mg) obtained in Example 1, Step A in
methanol (2.7 ml) and pyridine (2.7 ml) was added with a solution of 28% sodium
methylate (847 mg) in methanol, and then with copper iodide (70 mg), and the mixture
was stirred at 65°C for 30 hours. The reaction mixture was cooled to room
temperature, and added with water(30 ml) and ethyl acetate (30 ml), and the insoluble
matters were removed by filtration through Celite. The organic layer of the filtrate
was separated, and the aqueous layer was extracted 3 times with ethyl acetate (20 ml
for each time). The combined organic layer was washed 3 times with saturated brine
(30 ml for each time), and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and the residue was purified by silica gel
chromatography (chloroform^methanol = 30:1) to obtain the title compound (98 mg).
MS (m/z): 408 (MH+)
Step B
(R/S)"3"Amino"l-(4-methoxy-5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 13 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 308 (MH+)
[0232]
Example 15" 1: (S)-3-Amino-l-(4"methoxy5"isoquinolinesulfonyl)pyrrolidine
Intermediate 13a was prepared by using Intermediate la in the method of
Example 15, Step A instead of Intermediate 1, and then used in the method of Example
15, Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 308 (MH+)
iH-NMR(DMSO) 5 (ppm):
143

Example 15-2: (R)-3-Amino-l-(4-methoxy5-isoquinolinesulfonyl)pyrrolidine
Intermediate 13b was prepared by using Intermediate lb in the method of
Example 15, Step A instead of Intermediate 1, and then used in the method of Example
15, Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 308 (MH+)
iH-NMR(DMSO) S (ppm):
[0233]
Example 16: (R/S)-3"Amino-l-(4"hydroxy5-isoquinolinesulfonyl)pyrrolidine
30% Hydrogen bromide/acetic acid (1.5 ml, Tokyo Kasei Kogyo) was gradually
added with Intermediate 13 (45 mg) obtained in Example 15, Step A at 0"C, and the
mixture was stirred at the same temperature for 30 minutes. The solvent was
concentrated under reduced pressure, and the obtained solid was collected by filtration
to obtain the title compound as hydrobromide (13 mg).
MS (m/z): 294 (MH+)
Example 16-1: (S)-3"Amino-l-(4-hydroxy5-isoquinolinesulfonyl)pyrrolidine
Intermediate 13a was used in the method of Example 16 instead of
Intermediate 13 to obtain the title compound as hydrochloride.
MS (m/z): 294 (MH+)
Example 16"2: (R)-3"Amino-l-(4-hydroxy5-isoquinolinesulfonyl)pyrrolidine
Intermediate 13b was used in the method of Example 16 instead of
Intermediate 13 to obtain the title compound as hydrochloride.
MS (m/z): 294 (MH+)
[0234]
Example 17: (R/S)-3-Amino-l-[4-(l-butylthio)-5-isoquinolinesulfonyl]pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-[4-(l-butylthio)-5-isoquinolinesulfonyl]-
pyrrolidine (Intermediate 14)
The title compound was obtained from Intermediate 1 obtained in Example 1,
Step A according to the method described in a known literature (Itoh et al., Org. Lett.,
2004, 6, 4587).
Step B
The protective group of Intermediate 14 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
144

compound as hydrochloride.
MS (m/z): 366 (MH+)
[0235]
Example 17-1: (S)-3-Amino-l-[4-(l-butylthio)-5-isoquinolinesulfonyl]pyrrolidine
Intermediate la was used in the method of Example 17 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 366 (MH+)
Example 17-2: (R)-3"Amino-l-[4-(l-butylthio)-5-isoquinolinesulfonyl]pyrrolidine
Intermediate lb was used in the method of Example 17 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 366 (MH+)
[0236]
Example 18: (R/S)-3"Amino-l-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 15)
4-Fluoro"5-isoquinolinesulfonyl chloride (147 mg) obtained in Reference
Example 4 was used in the method of Example 1, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride, and reacted with
3-(tert-butoxycarbonylamino)pyrrolidine (134 mg) to obtain the title compound (190
mg).
MS (m/z): 396 (MH+)
iH-NMR (CDCls) 5 (ppm): 1.42 (9H, s), 1.88-1.99 (1H, m), 2.19-2.30 (1H, m),
3.34-3.39 (1H, m), 3.46-3.70 (3H, m), 4.22-4.32 (1H, m), 7.73 (1H, t, J=7.8Hz), 8.25 (1H,
ddd, J=1.2, 1.9, 7.8Hz), 8.54 (1H, dd, J=1.2, 7.8Hz), 8.57 (1H, d, J=4.5Hz), 9.16 (1H, s)
[0237]
Step B
(R/S) - 3-Amino-1 - (4-fluoro- 5-isoquinolinesulfonyl)pyrrolidine
The title compound was obtained as hydrochloride (106 mg) from Intermediate
15 (158 mg) according to the method of Example 1, Step B.
MS (m/z): 296 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.12-2.23 (1H, m), 2.34-2.45 (1H, m), 3.49-3.58 (2H, m),
3.64-3.72 (1H, m), 3.77-3.83 (1H, m), 3.95-4.03 (1H, m), 7.93 (1H, t, J=7.8Hz), 8.46 (1H,
145

d, J=7.8Hz), 8.58 (1H, d, J=7.8Hz), 8.72 (1H, d, J=4.8Hz), 9.41 (1H, s)
[0238]
Example 18-1: (S)-3-Amino-l-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine
(S)"3-(tert-Butoxycarbonylamino)-l-(4-fluoro-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate 15a) was prepared by using
(S)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 18, Step A
instead of 3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 296 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.12-2.23 (1H, m), 2.34-2.45 (lH, m), 3.49-3.58 (2H, m),
3.64-3.72 (1H, m), 3.77-3.83 (lH, m), 3.95-4.03 (lH, m), 7.93 (lH, t, J=7.8Hz), 8.46 (lH,
d, J=7.8Hz), 8.58 (lH, d, J=7.8Hz), 8.72 (1H, d, J=4.8Hz), 9.41 (lH, s)
[0239]
Example 18"2: (R)-3-Amino-l-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine
(R)-3"(tert-Butoxycarbonylamino)-l-(4-fluoro-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate 15b) was prepared by using
(R)-3-(tert-Butoxycarbonylamino)pyrrolidine in the method of Example 18, Step A
instead of 3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 296 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.12-2.23 (lH, m), 2.34-2.45 (lH, m), 3.49-3.58 (2H, m),
3.64-3.72 (1H, m), 3.77-3.83 (lH, m), 3.95-4.03 (lH, m), 7.93 (lH, t, J=7.8Hz), 8.46 (lH,
d, J=7.8Hz), 8.58 (lH, d, J=7.8Hz), 8.72 (lH, d, J=4.8Hz), 9.41 (lH, s)
[0240]
Example 19: (R/S)-3"Amino-l-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 16)
4-Chloro-5-isoquinolinesulfonyl chloride (157 mg) obtained in Reference
Example 7 was used in the method of Example 1, Step A instead of
4-bromo-5'isoquinolinesulfonyl chloride, and reacted with
3-(tert-butoxycarbonylamino)pyrrolidine (134 mg) to obtain the title compound (198
mg).
146

MS (m/z): 412 (MH+)
iH-NMR (CDCh) 5 (ppm): 1.44 (9H, s), 1.97-2.05 (1H, m), 2.25-2.36 (1H, m),
3.36-3.41 (1H, m), 3.48-3.56 (lH, m), 3.63-3.67 (2H, m), 4.35 (1H, m), 4.78 (1H, m), 7.71
(1H, t, J=7.8Hz), 8.22 (lH, dd, J=1.3, 7.8Hz); 8.45 (1H, dd, J=1.3, 7.8Hz), 8.78 (lH, s),
9.19 (1H, s)
[0241]
Step B
(R/S)-3-Amino-l-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine
The title compound was obtained as hydrochloride (148 mg) from Intermediate
16 (165 mg) in the same manner as Example 1, Step B.
MS (m/z): 312 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.13-2.21 (lH, m), 2.39-2.50 (lH, m), 3.47-3.56 (2H, m),
3.65-3.80 (2H, m), 4.00-4.08 (lH, m), 7.90 (lH, t, J=7.8Hz), 8.37 (lH, d, J=7.8Hz), 8.54
(1H, d, J=7.8Hz), 8.78 (lH, s), 9.44 (1H, s)
[0242]
Example 19-1: (S)-3-Amino-l-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine
(S) - 3- (tert-Butoxycarbonylamino) ■ 1 -(4-chloro- 5-isoquinolinesulfonyl) -
pyrrolidine (Intermediate 16a) was prepared by using
(S)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 19, Step A
instead of 3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 312 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.13-2.21 (lH, m), 2.39-2.50 (1H, m), 3.47-3.56 (2H, m),
3.65-3.80 (2H, m), 4.00-4.08 (lH, m), 7.90 (lH, t, J=7.8Hz), 8.37 (lH, d, J=7.8Hz), 8.54
(1H, d, J=7.8Hz), 8.78 (lH, s), 9.44 (lH, s)
[0243]
Example 19"2: (R)-3-Amino-l-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine
(R)-3" (tert-Butoxycarbonylamino)-1-(4-chloro-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate 16b) was prepared by using
(R)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 19, Step A
instead of 3-(tert-butoxycarbonylamino)pyrrolidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 312 (MH+)
147

iH-NMR (DMSO) 5 (ppm): 2.13-2.21 (1H, m), 2.39-2.50 (1H, m), 3.47-3.56 (2H, m),
3.65-3.80 (2H, m), 4.00-4.08 (lH, m), 7.90 (1H, t, J=7.8Hz), 8.37 (lH, d, J=7.8Hz), 8.54
(1H, d, J=7.8Hz), 8.78 (1H, s), 9.44 (lH, s)
[0244]
Example 20: (R/S)-3-Amino-l-(4-£luoro-5-isoquinolinesulfonyl)piperidine
(R/S) "3- (tert-Butoxycarbonylamino) -1 - (4-fluoro- 5-isoquinolinesulfonyl) -
piperidine (Intermediate 17) was prepared from 4-fluoro-5-isoquinolinesulfonyl
chloride (172 mg) and 3-(tert"butoxycarbonylamino)piperidine (168 mg) according to
the method of Example 1, Step A, and then used in the method of Example 1, Step B in
a similar manner to obtain the title compound as hydrochloride (156 mg).
MS (m/z): 310 (MH+)
[0245]
Example 20-l: (S)-3-Amino-l-(4-fluoro-5-isoquinolinesulfonyl)piperidine
(S)-3-(tert-Butoxycarbonylamino)-1-(4-fluoro-5-isoquinolinesulfonyl) ■
piperidine (Intermediate 17a) was prepared by using
(S)-3-(tert-butoxycarbonylamino)piperidine in the method of Example 20, Step A
instead of 3-(tert-butoxycarbonylamino)piperidine, and used in the method of Step B in
a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 310 (MH+)
[0246]
Example 20"2: (R)-3-Amino-l-(4-fluoro-5'isoquinolinesulfonyl)piperidine
(R)-3-(tert-Butoxycarbonylamino)-l-(4-fluoro-5-isoquinolinesulfonyl)-
piperidine (Intermediate 17b) was prepared by using
(R)-3-(tert-butoxycarbonylamino)piperidine in the method of Example 20, Step A
instead of 3-(tert-butoxycarbonylamino)piperidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 296 (MH+)
[0247]
Example 21: (R/S)-3-Amino-l-(4-chloro-5-isoquinolinesulfonyl)piperidine
(R/S) ■ 3" (tert-Butoxycarbonylamino)-1 - (4-chloro- 5-isoquinolinesulfonyl) -
piperidine (Intermediate 18) was prepared from 4-chloro-5-isoquinolinesulfonyl
chloride (183 mg) and 3-(tert-butoxycarbonylamino)piperidine (168 mg) according to
the method described in Example 1, Step A, and then used in the method of Example 1,
148

Step B in a similar manner to obtain the title compound as hydrochloride (164 mg).
MS (m/z): 326 (MH+)
[0248]
Example 21-1- (S)-3-Amino-l-(4-chloro-5-isoquinolinesulfonyl)piperidine
(S)-3-(tert"Butoxycarbonylamino)-l-(4-chloro-5-isoquinolinesulfonyl)-
piperidine (Intermediate 18a) was prepared by using
(S)-3-(tert-butoxycarbonylamino)piperidine in the method of Example 21, Step A
instead of 3-(tert-butoxycarbonylamino)piperidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 326 (MH+)
[0249]
Example 21-2: (R)-3-Amino-l-(4-chloro-5-isoquinolinesulfonyl)piperidine
(R)-3-(tert-Butoxycarbonylamino)-l-(4-chloro-5-isoquinolinesulfonyl)-
piperidine (Intermediate 18b) was prepared by using
(R)-3-(tert-butoxycarbonylamino)piperidine in the method of Example 21, Step A
instead of 3-(tert"butoxycarbonylamino)piperidine, and then used in the method of
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 326 (MH+)
[0250]
Example 22: (R/S)-3-Amino-l-(4-methyl-5-isoquinolinesulfonyl)piperidine
Intermediate 2 was used in the method of Example 8, Step A instead of
Intermediate 1, and then the protective group of the resultant was removed according
to the method described in Example 1, Step B to obtain the title compound as
hydrochloride.
MS (m/z): 306 (MH+)
iH-NMR (DMSO) 8 (ppm): 1.55-2.20 (4H, m), 3.04 (3H, s), 3.16-3.36 (3H, m),
3.65-3.71 (1H, m), 3.93-3.99 (lH, m), 7.97 (1H, dd, J=6.6Hz, J=8.1Hz), 8.38 (1H, d,
J=6.6Hz), 8.51 (3H, br.s), 8.65 (1H, d, J=8.1Hz), 8.69 (1H, s), 9.67 (lH, s)
[0251]
Example 22-1: (S)-3"Amino-l-(4-methyl-5-isoquinolinesulfonyl)piperidine
Intermediate 2a was used in the method of Example 22instead of Intermediate
2, and then the protective group of the resultant was removed in a similar manner to
obtain the title compound as hydrochloride.
149

MS (m/z): 306 (MH+)
iH-NMR (DMSO) 6 (ppm): 1.55-2.20 (4H, m), 3.04 (3H, s), 3.16-3.36 (3H, m),
3.65-3.71 (1H, m), 3.93-3.99 (1H, m), 7.97 (1H, dd, J=6.6Hz, J=8.1Hz), 8.38 (1H, d,
J=6.6Hz), 8.51 (3H, br.s), 8.65 (1H, d, J=8.1Hz), 8.69 (1H, s), 9.67 (1H, s)
[0252]
Example 22-2: (R)-3-Amincr l-(4-methyl-5-isoquinolinesulfonyl)piperidine
Intermediate 2b was used in the method of Example 22 instead of
Intermediate 2, and then the protective group of the resultant was removed in a
similar manner to obtain the title compound as hydrochloride.
MS (m/z): 306 (MH+)
iH-NMR (DMSO) 8 (ppm): 1.55-2.20 (4H, m), 3.04 (3H, s), 3.16-3.36 (3H, m),
3.65-3.71 (1H, m), 3.93-3.99 (1H, m), 7.97 (1H, dd, J=6.6Hz, J=8.1Hz), 8.38 (1H, d,
J=6.6Hz), 8.51 (3H, br.s), 8.65 (1H, d, J=8.1Hz), 8.69 (1H, s), 9.67 (1H, s)
[0253]
Example 23: (R/S)-3-Amino-l-(4-ethyl-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(4-ethyl-5-isoquinolinesulfonyl)pyrrolidine
(Intermediate 19)
A solution of Intermediate 6 (120 mg) obtained in Example 9, Step A in ethanol
(2 ml) was added with 10% palladium/activated carbon (90 mg, Wako Pure Chemical
Industries), and the mixture was stirred at room temperature for 72 hours under a
hydrogen gas atmosphere. The atmosphere was replaced with nitrogen gas, and then
the insoluble matters were removed by filtration through Celite. The solvent was
evaporated under reduced pressure, and the residue was purified by silica gel
chromatography (n-hexane:ethyl acetate = 2:1) to obtain the title compound (195 mg).
MS (m/z): 406 (MH+)
Step B
(R/S) ■ 3-Amino-1 - (4-ethyl- 5-isoquinolinesulfonyl)pyrrolidine
The protective group of Intermediate 19 obtained in Step A mentioned above
was removed according to the method described in Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 406 (MH+)
[0254]
150

Example 23-l: (S)-3-Amino-l-(4-ethyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 6a was used in the method of Example 23 instead of
Intermediate 6 to obtain the title compound as hydrochloride.
MS (m/z): 406 (MH+)
Example 23'2: (R)-3-Amino-l-(4-ethyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 6b was used in the method of Example 23 instead of
Intermediate 6 to obtain the title compound as hydrochloride.
MS (m/z): 406 (MH+)
[0255]
Example 24: (R/S)-3"Amino-l-[4-(4-isoxazolyl)-5-isoquinolinesulfonyl]pyrrolidine
The title compound was obtained from Intermediate 1 as hydrochloride by
using 4-isoxazoleboronic acid pinacol ester in the method of Example 14 instead of
phenylboronic acid.
MS (m/z): 345 (MH+)
Example 24-1: (S)-3-Amino-l-[4-(4-isoxazolyl)-5-isoquinolinesulfonyl]pyrrolidine
Intermediate la was used in the method of Example 24 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 345 (MH+)
Example 24-2: (R)-3-Amino-l"[4-(4-isoxazolyl)-5-isoquinolinesulfonyl]pyrrolidine
Intermediate lb was used in the method of Example 24 instead of
Intermediate 1 to obtain the title compound as hydrochloride.
MS (m/z): 345 (MH+)
[0256]
Example 25: (R/S)-3-Amino-l-(l-hydroxy-4-methyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 5 was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 308 (MH+)
iH-NMR (DMSO) 3.46-3.57 (2H, m), 3.65-3.79 (2H, m), 4.00-4.07 (1H, m), 7.18 (1H, d, J=5.1Hz)7.62 (1H,
t, J=7.8Hz), 8.13 (1H, dd, J=1.5, 7.8Hz), 8.60 (1H, dd, J=1.5, 7.8Hz)
[0257]
151

Example 25"l: (S)-3-Amino-l-(l-hydroxy-4-methyl-5'isoquinolinesulfonyl)pyrrolidine
Intermediate 5a was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 308 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.13-2.24 (1H, m), 2.37-2.49 (1H, m), 2.56 (3H, s),
3.46-3.57 (2H, m), 3.65-3.79 (2H, m), 4.00-4.07 (1H, m), 7.18 (1H, d, J=5.1Hz)7.62 (1H,
t, J=7.8Hz), 8.13 (1H, dd, J=1.5, 7.8Hz), 8.60 (1H, dd, J=1.5, 7.8Hz)
[0258]
Example 25-2- (R)-3-Amino-l-(l-hydroxy-4-methyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 5b was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 308 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.13-2.24 (1H, m), 2.37-2.49 (1H, m), 2.56 (3H, s),
3.46-3.57 (2H, m), 3.65-3.79 (2H, m), 4.00-4.07 (1H, m), 7.18 (1H, d, J=5.1Hz)7.62 (lH,
t, J=7.8Hz), 8.13 (1H, dd, J=1.5, 7.8Hz), 8.60 (1H, dd, J=1.5, 7.8Hz)
[0259]
Example 26: 3-Amino-l-(4-methyl-5-isoquinolinesulfonyl)azetidine
The title compound was obtained as hydrochloride from
4-bromo-5-isoquinolinesulfonyl chloride and 3-(tert-butoxycarbonylamino)azetidine
according to the methods of Example 1, Step A, Example 8, Step A, and Example 1,
Step B used in this order.
MS (m/z): 278 (MH+)
iH-NMR (DMSO) 5 (ppm): 3.02 (1H, s), 4.10-4.80 (5H, m), 7.93 (lH, t, J=7.8Hz), 8.61
(1H, dd, J=0.9Hz, J=7.8Hz), 8.65 (lH, s), 8.80 (3H, br.s), 8.97 (lH, dd, J=0.9Hz,
J=7.8Hz), 9.55 (1H, s)
[0260]
Example 27: (R)-3-(Methylamino)-l-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine
Intermediate lb was used in the method of Example 8, Step A instead of
Intermediate 1, then the protective group of the resultant was removed according to
152

the method described in Example 1, Step B, and then the resultant was used in the
method of the method of Example 5 using methyl iodide (Tokyo Kasei Kogyo) instead of
allyl bromide to obtain the title compound as hydrochloride.
MS (m/z): 306 (MH+)
[0261]
Example 28:
(R/S)-3-Amino-l-[4-(2-hydroxymethyl)ethynyl"5-isoquinolinesulfonyl]pyrrolidine
2-Propyn-l-ol (Tokyo Kasei Kogyo) was used in the method of Example 10,
Step A instead of trimethylsilylacetylene, and then the resultant was used in the
method of Example 1, Step B to obtain the title compound as hydrochloride.
MS (m/z): 332 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.11-2.22 (1H, m), 2.38-2.49 (1H, m), 3.45-3.57 (2H, m),
3.65-3.81 (2H, m), 3.95-4.06 (1H, m), 4.39 (2H, s), 7.84-7.89 (lH, m), 8.31-8.33 (1H, m),
8.48-8.51 (1H, m), 8.78 (lH, s), 9.45 (lH, s)
[0262]
Example 28-1:
(S)-3-Amino-l-[4-(2-hydroxymethyl)ethynyl-5-isoquinolinesulfonyl]pyrrolidine
Intermediate la and 2-propyn-l-ol were used in the method of Example 10,
Step A instead of Intermediate 1 and trimethylsilylacetylene, respectively, and then
the resultant was used in the method of Example 1, Step B to obtain the title
compound as hydrochloride.
MS (m/z): 332 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.11-2.22 (1H, m), 2.38-2.49 (lH, m), 3.45-3.57 (2H, m),
3.65-3.81 (2H, m), 3.95-4.06 (lH, m), 4.39 (2H, s), 7.84-7.89 (lH, m), 8.31-8.33 (lH, m),
8.48-8.51 (1H, m), 8.78 (lH, s), 9.45 (lH, s)
[0263]
Example 28-2:
(R)"3-Amino-l-[4-(2-hydroxymethyl)ethynyl-5-isoquinolinesulfonyl]pyrrolidine
Intermediate lb and 2-propyn-l-ol were used in the method of Example 10,
Step A instead of Intermediate 1 and trimethylsilylacetylene, respectively, and then
the resultant was used in the method of Example 1, Step B, to obtain the title
compound as hydrochloride.
MS (m/z): 332 (MH+)
153

iH-NMR (DMSO) 5 (ppm): 2.11-2.22 (1H, m), 2.38-2.49 (1H, m), 3.45-3.57 (2H, m),
3.65-3.81 (2H, m), 3.95-4.06 (lH, m), 4.39 (2H, s), 7.84-7.89 (lH, m), 8.31-8.33 (1H, m),
8.48-8.51 (1H, m), 8.78 (lH, s), 9.45 (lH, s)
Example 29- (R/S)-3-Amino-l-(l-hydroxy4-£luoro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 15 was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 312 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.02-2.12 (1H, m), 2.31-2.42 (lH, m), 3.37-3.51 (2H, m),
3.58-3.74 (2H, m), 3.92-4.00 (lH, m), 7.58 (lH, d, J=8.1Hz), 7.72 (1H, t, J=7.8Hz), 8.25
(1H, dd, J=1.2, 7.8Hz), 8.54 (lH, ddd, J=1.2, 2.3, 7.8Hz)
Example 29-1: (S)-3"Amino-l-(l-hydroxy4-fluoro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 15a was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 312 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.02-2.12 (lH, m), 2.31-2.42 (lH, m), 3.37-3.51 (2H, m),
3.58-3.74 (2H, m), 3.92-4.00 (1H, m), 7.58 (lH, d, J=8.1Hz), 7.72 (lH, t, J=7.8Hz), 8.25
(1H, dd, J=1.2, 7.8Hz), 8.54 (1H, ddd, J=1.2, 2.3, 7.8Hz)
Example 29-2: (R)-3"Amino-I"(l-hydroxy4-fluoro-5"isoquinolinesulfonyl)pyrrolidine
Intermediate 15b was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 312 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.02-2.12 (lH, m), 2.31-2.42 (lH, m), 3.37-3.51 (2H, m),
3.58-3.74 (2H, m), 3.92-4.00 (lH, m), 7.58 (lH, d, J=8.1Hz), 7.72 (lH, t, J=7.8Hz), 8.25
(1H, dd, J=1.2, 7.8Hz), 8.54 (lH, ddd, J=1.2, 2.3, 7.8Hz)
Example 30: (R/S)-3"Amino-l-(l-hydroxy4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 16 was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
154

manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 328 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.09-2.19 (1H, m), 2.35-2.46 (1H, m), 3.42-3.53 (2H, m),
3.61-3.74 (2H, m), 3.96-4.04 (1H, m), 7.58 (1H, s), 7.71 (1H, t, J=7.9Hz), 8.20 (1H, dt,
J=1.2, 7.9Hz), 8.57 (1H, dd, J=1.2, 7.9Hz)
Example 30-l: (S)-3-Amino-l-(l-hydroxy-4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 16a was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 328 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.09-2.19 (1H, m), 2.35-2.46 (1H, m), 3.42-3.53 (2H, m),
3.61-3.74 (2H, m), 3.96-4.04 (1H, m), 7.58 (1H, s), 7.71 (1H, t, J=7.9Hz), 8.20 (lH, dt,
J=1.2, 7.9Hz), 8.57 (lH, dd, J=1.2, 7.9Hz)
Example 30-2: (R)-3"Amino-l-(l-hydroxy-4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 16b was used in the method of Example 6, Step A instead of
Intermediate 1, then the resultant was used in the method of Step B in a similar
manner, and then the title compound was obtained as hydrochloride according to the
method described in Example 7.
MS (m/z): 328 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.09-2.19 (lH, m), 2.35-2.46 (lH, m), 3.42-3.53 (2H, m),
3.61-3.74 (2H, m), 3.96-4.04 (lH, m), 7.58 (lH, s), 7.71 (lH, t, J=7.9Hz), 8.20 (lH, dt,
J=1.2, 7.9Hz), 8.57 (lH, dd, J=1.2, 7.9Hz)
[0264]
Examples 1-3 to 1-38, 2-3 to 2-40, 8-3 to 8-78, 9"3 to 9-78, 10-3 to 10-78, 18-3 to 18-40
and 20-3 to 20-40, 19-3 to 19-40 and 21-3 to 21-40
Synthesis of the compounds of Examples 1-3 to 1-38, 2-3 to 2-40, 8-3 to 8-78,
9-3 to 9-78, 10-3 to 10-78, 18-3 to 18-40 and 20"3 to 20-40, 19-3 to 19-40 and 21-3 to
21-40 was performed according to the method of Examples 4 or 5.
The details of the compounds of Examples 1-3 to 1-38, 2-3 to 2-40, 8-3 to 8-78,
9-3 to 9-78, 10-3 to 10-78, 18-3 to 18-40 and 20-3 to 20-40, or 19-3 to 19-40 and 21-3 to
21-40 are shown in Table 1.
155

Meanings of the symbols used in Table 1 are as follows.
CH2=CH: Vinyl group
HCC:Ethynyl group,
Exp.: Example number,
Str.: Structure represented by either one of the following general formulas
[0265]

Q1: Group Q1 in the structural formulas mentioned for Str.
Q2: Group Q2 in the structural formulas mentioned for Str., which may be indicated
with the numbers of the groups mentioned in Fig. 1 mentioned below
SM: Example number or intermediate number of starting substance (example numbers
are shown only with numbers, and intermediate numbers are shown as
"IM-Intermediate number" (for example, "IM"2a" means Intermediate 2a))
MS: Mass spectrum data obtained in LCMS
Ref.: Corresponding preparation method of intermediate. The symbols used in the
columns of "Ref." mean preparation methods of intermediates as follows, and two or
more symbols mean that the preparation methods were performed from the left. EA:
preparation method shown in Example 4, EB: preparation method shown in Example 5,
EC: preparation method shown in Example 8, ED'- preparation method shown in
Example 9, and EE: preparation method shown in Example 10.
MS: Mass spectrum data obtained in LCMS
[0266]
[Formula 6]
156



[Table l]

Exp. Str. Q1 Q2 SM Mass
(MH+) Ref.
1-3 Qa Br CHs 1-1 370 EB
1-4 Qa Br CH2CH3 1-1 384 EB
1-5 Qa Br CH2CH2CH3 1-1 398 EA
1-6 Qa Br q-1 1-1 446 EA
1-7 Qa Br q-2 1-1 476 EA
1-8 Qa Br q-3 11 490 EA
1-9 Qa Br q-4 1-1 491 EA
1-10 Qa Br q-5 1-1 461 EA
1-11 Qa Br q-6 11 462 EA
1-12 Qa Br q-7 1-1 460 EA
1-13 Qa Br q-8 1-1 460 EA
1-14 Qa Br q-10 1-1 436 EA
1-15 Qa Br q-11 1-1 450 EA
1-16 Qa Br q-12 1-1 452 EA
1-17 Qa Br q-13 1-1 466 EA
1-18 Qa Br q-14 1-1 435 EA
1-19 Qa Br q-15 1-1 450 EA
1-20 Qa Br q-16 1-1 449 EA
1-21 Qa Br q-17 1-1 460 EA
1-22 Qa Br q-18 1-1 450 EA
1-23 Qa Br q-19 1-1 466 EA
1-24 Qa Br q-20 11 449 EA
1-25 Qa Br q-21 1-1 410 EA
1-26 Qa Br q-22 1-1 398 EA
1-27 Qa Br q-23 1-1 410 EA
1-28 Qa Br q-24 1-1 424 EA
1-29 Qa Br q-25 1-1 438 EA
1-30 Qa Br q-26 1-1 440 EA
1-31 Qa Br q-27 1-1 399 EA
158



2-29 Qb Br q-24 2-1 438 EA
2-30 Qb Br q-25 2-1 452 EA
2-31 Qb Br q-26 2-1 454 EA
2-32 Qb Br q-27 2-1 413 EA
2-33 Qb Br q-28 2-1 455 EA
2-34 Qb Br q-29 2-1 410 EB
2-35 Qb Br q-30 2-1 468 EA
2-36 Qb Br q-31 2-1 453 EA
2-37 Qb Br q-32 2-1 474 EA
2-38 Qb Br q-33 2-1 409 EB
2-39 Qb Br q-34 2-1 423 EB
2-40 Qb Br q-35 2-1 518 EA
8-3 Qa CHs CHs 8-1 306 EB
8-4 Qa CHs CH2CH3 8-1 320 EB
8-5 Qa CH3 CH2CH2CH3 8-1 334 EA
8-6 Qa CH3 q-1 8-1 382 EA
8-7 Qa CH3 q-2 8-1 412 EA
8-8 Qa CHs q-3 8-1 426 EA
8-9 Qa CH3 q-4 8-1 427 EA
8-10 Qa CHs q-5 8-1 397 EA
8-11 Qa CHs q-6 8-1 398 EA
8-12 Qa CHs q-7 8-1 396 EA
8-13 Qa CHs q-8 8-1 396 EA
8-14 Qa CHs q-9 8-1 372 EA
8-15 Qa CHs q-10 8-1 372 EA
8-16 Qa CHs q-11 8-1 386 EA
8-17 Qa CHs q-12 8-1 388 EA
8-18 Qa CHs q-13 8-1 402 EA
8-19 Qa CHs q-14 8-1 371 EA
8-20 Qa CHs q-15 8-1 386 EA
8-21 Qa CHs q-16 8-1 385 EA
8-22 Qa CHs q-17 8-1 396 EA
8-23 Qa CH3 q-18 8-1 386 EA
160

8-24 Qa CH3 q-19 8-1 402 EA
8-25 Qa CH3 q-20 8-1 385 EA
8-26 Qa CHs q-21 8-1 346 EA
8-27 Qa CH3 q-22 8-1 334 EA
8-28 Qa CH3 q-23 8-1 346 EA
8-29 Qa CHs q-24 8-1 360 EA
8-30 Qa CHs q-25 8-1 374 EA
8-31 Qa CHs q-26 8-1 376 EA
8-32 Qa CHs q-27 8-1 335 EA
8-33 Qa CHs q-28 8-1 377 EA
8-34 Qa CHs q-29 8-1 332 EB
8-35 Qa CHs q-30 8-1 390 EA
8-36 Qa CHs q-31 8-1 375 EA
8-37 Qa CHs q-32 8-1 396 EA
8-38 Qb CHs CHs IM-2a 320 EC,EB
8-39 Qb CHs CH2CH3 IM-2a 334 EC,EB
8-40 Qb CHs CH2CH2CH3 IM-2a 348 EC,EA
8-41 Qb CHs q-1 IM-2a 396 EC,EA
8-42 Qb CHs q-2 IM-2a 426 EC,EA
8-43 Qb CHs q-3 IM-2a 440 EC.EA
8-44 Qb CHs q-4 IM-2a 441 EC,EA
8-45 Qb CHs q-5 IM-2a 411 EC,EA
8-46 Qb CHs q-6 IM-2a 412 EC.EA
8-47 Qb CHs q-7 IM-2a 410 EC,EA
8-48 Qb CHs q-8 IM-2a 410 EC,EA
8-49 Qb CHs q-9 IM-2a 386 EC.EA
8-50 Qb CHs q-10 IM-2a 386 EC,EA
8-51 Qb CHs q-11 IM-2a 400 EC,EA
8-52 Qb CHs q-12 IM-2a 402 EC,EA
8-53 Qb CHs q-13 IM-2a 416 EC,EA
8-54 Qb CHs q-14 IM-2a 385 EC,EA
8-55 Qb CHs q-15 IM-2a 400 EC,EA
8-56 Qb CHs q-16 IM-2a 399 EC.EA
161

8-57 Qb CH3 q-17 IM-2a 410 EC,EA
8-58 Qb CHs q-18 IM-2a 400 EC,EA
8-59 Qb CHs q-19 IM-2a 416 EC,EA
8-60 Qb CHs q-20 IM-2a 399 EC,EA
8-61 Qb CH3 q-21 IM-2a 360 EC,EA
8-62 Qb CH3 q-22 IM-2a 348 EC,EA
8-63 Qb CHs q-23 IM-2a 360 EC,EA
8-64 Qb CHs q-24 IM-2a 374 EC,EA
8-65 Qb CHs q-25 IM-2a 388 EC,EA
8-66 Qb CHs q-26 IM-2a 390 EC,EA
8-67 Qb CHs q-27 IM-2a 349 EC,EA
8-68 Qb CH3 q-28 IM-2a 391 EC,EA
8-69 Qb CH3 q-29 IM-2a 346 EC,EB
8-70 Qb CHs q-30 IM-2a 404 EC,EA
8-71 Qb CHs q-31 IM-2a 389 EC,EA
8-72 Qb CHs q-32 IM-2a 410 EC,EA
8-73 Qa CHs q-33 8-1 331 EB
8-74 Qa CHs q-34 8-1 345 EB
8-75 Qa CHs q-35 8-1 454 EA
8-76 Qb CHs q-33 IM-2a 345 EC,EB
8-77 Qb CHs q-34 IM-2a 359 EC,EB
8-78 Qb CHs q-35 IM-2a 468 EC,EA
9-3 Qa CH2=CH CHs 9-1 318 EB
9-4 Qa CH2=CH CH2CHs 91 332 EB
9-5 Qa CH2=CH CH2CH2CHs 91 346 EA
9-6 Qa CH2=CH q-1 9-1 394 EA
9-7 Qa CH2=CH q-2 91 424 EA
9-8 Qa CH2=CH q-3 9-1 438 EA
9-9 Qa CH2=CH q-4 9-1 439 EA
9-10 Qa CH2=CH q-5 9-1 409 EA
9-11 Qa CH2=CH q-6 91 410 EA
9-12 Qa CH2=CH q-7 9-1 408 EA
9-13 Qa CH2=CH q-8 91 408 EA
162

9-14 Qa CH2=CH q-9 9-1 384 EA
9-15 Qa CH2=CH q-10 9-1 384 EA
9-16 Qa CH2=CH q-11 9-1 398 EA
9-17 Qa CH2=CH q-12 9-1 400 EA
9-18 Qa CH2=CH q-13 9-1 414 EA
9-19 Qa CH2=CH q-14 91 383 EA
9-20 Qa CH2=CH q-15 91 398 EA
9-21 Qa CH2=CH q-16 91 397 EA
9-22 Qa CH2=CH q-17 9-1 408 EA
9-23 Qa CH2=CH q-18 9-1 398 EA
9-24 Qa CH2=CH q-19 91 414 EA
9-25 Qa CH2=CH q-20 9-1 397 EA
9-26 Qa CH2=CH q-21 9-1 358 EA
9-27 Qa CH2=CH q-22 91 346 EA
9-28 Qa CH2=CH q-23 91 358 EA
9-29 Qa CH2=CH q-24 9-1 372 EA
9-30 Qa CH2=CH q-25 9-1 386 EA
9-31 Qa CH2=CH q-26 9-1 388 EA
9-32 Qa CH2=CH q-27 91 347 EA
9-33 Qa CH2=CH q-28 91 389 EA
9-34 Qa CH2=CH q-29 9-1 344 EB
9-35 Qa CH2=CH q-30 9-1 402 EA
9-36 Qb CH2=CH CHs IM-2a 332 ED,EB
9-37 Qb CH2=CH CH2CH3 IM-2a 346 ED,EB
9-38 Qb CH2=CH CH2CH2CH3 IM-2a 360 ED,EA
9-39 Qb CH2=CH ql IM-2a 408 ED.EA
9-40 Qb CH2=CH q-2 IM-2a 438 ED,EA
941 Qb CH2=CH q-3 IM-2a 452 ED,EA
9-42 Qb CH2=CH q-4 IM-2a 453 ED.EA
9-43 Qb CH2=CH q-5 IM-2a 423 ED,EA
9-44 Qb CH2=CH q-6 IM-2a 424 ED,EA
9-45 Qb CH2=CH q-7 IM-2a 422 ED.EA
9-46 Qb CH2=CH q-8 IM-2a 422 ED,EA
163

9-47 Qb CH2=CH q-9 IM-2a 398 ED,EA
9-48 Qb CH2=CH q-10 IM-2a 398 ED,EA
9-49 Qb CH2=CH q-11 IM-2a 412 ED,EA
9-50 Qb CH2=CH q-12 IM-2a 414 ED,EA
9-51 Qb CH2=CH q-13 IM-2a 428 ED,EA
9-52 Qb CH2=CH q-14 IM-2a 397 ED,EA
9-53 Qb CH2=CH q-15 IM-2a 412 ED,EA
9-54 Qb CH2=CH q-16 IM-2a 411 ED,EA
9-55 Qb CH2=CH q-17 IM-2a 422 ED,EA
9-56 Qb CH2=CH q-18 IM-2a 412 ED,EA
9-57 Qb CH2=CH q-19 IM-2a 428 ED,EA
9-58 Qb CH2=CH q-20 IM-2a 411 ED,EA
9-59 Qb CH2=CH q-21 IM-2a 372 ED,EA
9-60 Qb CH2=CH q-22 IM-2a 360 ED,EA
9-61 Qb CH2=CH q-23 IM-2a 372 ED,EA
9-62 Qb CH2=CH q-24 IM-2a 386 ED,EA
9-63 Qb CH2=CH q-25 IM-2a 400 ED,EA
9-64 Qb CH2=CH q-26 IM-2a 402 ED,EA
9-65 Qb CH2=CH q-27 IM-2a 361 ED,EA
9-66 Qb CH2=CH q-28 IM-2a 403 ED,EA
9-67 Qb CH2=CH q-29 IM-2a 358 ED.EB
9-68 Qb CH2=CH q-30 IM-2a 416 ED,EA
9-69 Qa CH2=CH q-31 9-1 387 EA
9-70 Qa CH2=CH q-32 91 408 EA
9-71 Qa CH2=CH q-33 9-1 343 EB
9-72 Qa CH2=CH q-34 91 357 EB
9-73 Qa CH2=CH q-35 9-1 466 EA
9-74 Qb CH2=CH q-31 IM-2a 401 ED,EA
9-75 Qb CH2=CH q-32 IM-2a 422 ED.EA
9-76 Qb CH2=CH q-33 IM-2a 357 ED,EB
9-77 Qb CH2=CH q-34 IM-2a 371 ED.EB
9-78 Qb CH2=CH q-35 IM-2a 480 ED.EA
10-3 Qa HCC CHs 10-1 316 EB
164

10-4 Qa HCC CH2CH3 10-1 330 EB
10-5 Qa HCC CH2CH2CH3 10-1 344 EA
10-6 Qa HCC q-1 10-1 392 EA
10-7 Qa HCC q-2 10-1 422 EA
10-8 Qa HCC q-3 10-1 436 EA
10-9 Qa HCC q-4 10-1 437 EA
10-10 Qa HCC q-5 10-1 407 EA
10-11 Qa HCC q-6 10-1 408 EA
10-12 Qa HCC q-7 10-1 406 EA
10-13 Qa HCC q-8 10-1 406 EA
10-14 Qa HCC q-9 10-1 382 EA
10-15 Qa HCC q-10 10-1 382 EA
10-16 Qa HCC q-11 10-1 396 EA
10-17 Qa HCC q-12 10-1 398 EA
10-18 Qa HCC q-13 10-1 412 EA
10-19 Qa HCC q-14 10-1 381 EA
10-20 Qa HCC q-15 10-1 396 EA
10-21 Qa HCC q-16 10-1 395 EA
10-22 Qa HCC q-17 10-1 406 EA
10-23 Qa HCC q-18 10-1 396 EA
10-24 Qa HCC q-19 10-1 412 EA
10-25 Qa HCC q-20 10-1 395 EA
10-26 Qa HCC q-21 10-1 356 EA
10-27 Qa HCC q-22 10-1 344 EA
10-28 Qa HCC q-23 10-1 356 EA
10-29 Qa HCC q-24 10-1 370 EA
10-30 Qa HCC q-25 10-1 384 EA
10-31 Qa HCC q-26 10-1 386 EA
10-32 Qa HCC q-27 10-1 345 EA
10-33 Qa HCC q-28 10-1 387 EA
10-34 Qa HCC q-29 10-1 342 EB
10-35 Qa HCC q-30 10-1 400 EA
10-36 Qb HCC CH3 IM-2a 330 EE.EB
165

10-37 Qb HCC CH2CH3 IM-2a 344 EE,EB
10-38 Qb HCC CH2CH2CH3 IM-2a 358 EE.EA
10-39 Qb HCC q-1 IM-2a 406 EE,EA
10-40 Qb HCC q-2 IM-2a 436 EE,EA
10-41 Qb HCC q-3 IM-2a 450 EE.EA
10-42 Qb HCC q-4 IM-2a 451 EE,EA
10-43 Qb HCC q-5 IM-2a 421 EE,EA
10-44 Qb HCC q-6 IM-2a 422 EE,EA
10-45 Qb HCC q-7 IM-2a 420 EE,EA
10-46 Qb HCC q-8 IM-2a 420 EE,EA
10-47 Qb HCC q-9 IM-2a 396 EE,EA
10-48 Qb HCC q-10 IM-2a 396 EE,EA
10-49 Qb HCC q-11 IM-2a 410 EE,EA
10-50 Qb HCC q-12 IM-2a 412 EE,EA
10-51 Qb HCC q-13 IM-2a 426 EE,EA
10-52 Qb HCC q-14 IM-2a 395 EE.EA
10-53 Qb HCC q-15 IM-2a 410 EE,EA
10-54 Qb HCC q-16 IM-2a 409 EE,EA
10-55 Qb HCC q-17 IM-2a 420 EE,EA
10-56 Qb HCC q-18 IM-2a 410 EE,EA
10-57 Qb HCC q-19 IM-2a 426 EE,EA
10-58 Qb HCC q-20 IM-2a 409 EE,EA
10-59 Qb HCC q-21 IM-2a 370 EE,EA
10-60 Qb HCC q-22 IM-2a 358 EE,EA
10-61 Qb HCC q-23 IM-2a 370 EE,EA
10-62 Qb HCC q-24 IM-2a 384 EE,EA
10-63 Qb HCC q-25 IM-2a 398 EE,EA
10-64 Qb HCC q-26 IM-2a 400 EE.EA
10-65 Qb HCC q-27 IM-2a 359 EE.EA
10-66 Qb HCC q-28 IM-2a 401 EE,EA
10-67 Qb HCC q-29 IM-2a 356 EE,EB
10-68 Qb HCC q-30 IM-2a 414 EE,EA
10-69 Qa HCC q-31 10-1 385 EA
166

10-70 Qa HCC q-32 10-1 406 EA
10-71 Qa HCC q-33 10-1 341 EB
10-72 Qa HCC q-34 10-1 355 EB
10-73 Qa HCC q-35 10-1 464 EA
10-74 Qb HCC q-31 IM-2a 399 ED,EA
10-75 Qb HCC q-32 IM-2a 420 ED,EA
10-76 Qb HCC q-33 IM-2a 355 ED,EB
10-77 Qb HCC q-34 IM-2a 369 ED,EB
10-78 Qb HCC q-35 IM-2a 478 ED,EA
18-3 Qa F CH3 18-1 310 EB
18-4 Qa F CH2CH3 18-1 324 EB
18-5 Qa F CH2CH2CH3 18-1 338 EA
18-6 Qa F q-1 18-1 386 EA
18-7 Qa F q-2 18-1 416 EA
18-8 Qa F q-3 18-1 430 EA
18-9 Qa F q-4 18-1 431 EA
18-10 Qa F q-5 18-1 401 EA
18-11 Qa F q-6 18-1 402 EA
18-12 Qa F q-7 18-1 400 EA
18-13 Qa F q-8 18-1 400 EA
18-14 Qa F q-9 18-1 376 EA
18-15 Qa F q-10 18-1 376 EA
18-16 Qa F q-11 18-1 390 EA
18-17 Qa F q-12 18-1 392 EA
18-18 Qa F q-13 18-1 406 EA
18-19 Qa F q-14 18-1 375 EA
18-20 Qa F q-15 18-1 390 EA
18-21 Qa F q-16 18-1 389 EA
18-22 Qa F q-17 18-1 400 EA
18-23 Qa F q-18 18-1 390 EA
18-24 Qa F q-19 18-1 406 EA
18-25 Qa F q-20 18-1 389 EA
18-26 Qa F q-21 18-1 350 EA
167

18-27 Qa F q-22 18-1 338 EA
18-28 Qa F q-23 18-1 350 EA
18-29 Qa F q-24 18-1 364 EA
18-30 Qa F q-25 18-1 378 EA
18-31 Qa F q-26 18-1 380 EA
18-32 Qa F q-27 18-1 339 EA
18-33 Qa F q-28 18-1 381 EA
18-34 Qa F q-29 18-1 336 EB
18-35 Qa F q-30 18-1 394 EA
18-36 Qa F q-31 18-1 379 EA
18-37 Qa F q-32 18-1 400 EA
18-38 Qa F q-33 18-1 335 EB
18-39 Qa F q-34 18-1 349 EB
18-40 Qa F q-35 18-1 444 EA
19-3 Qa Cl CHs 191 326 EB
19-4 Qa Cl CH2CH3 191 340 EB
19-5 Qa Cl CH2CH2CH3 19-1 354 EA
19-6 Qa Cl q-1 191 402 EA
19-7 Qa Cl q-2 19-1 432 EA
19-8 Qa Cl q-3 191 446 EA
19-9 Qa Cl q-4 19-1 447 EA
19-10 Qa Cl q-5 19-1 417 EA
19-11 Qa Cl q-6 19-1 418 EA
19-12 Qa Cl q-7 19-1 416 EA
19-13 Qa Cl q-8 19-1 416 EA
19-14 Qa Cl q-9 191 392 EA
19-15 Qa Cl q-10 19-1 392 EA
19-16 Qa Cl qll 191 406 EA
19-17 Qa Cl q-12 191 408 EA
19-18 Qa Cl q-13 19-1 422 EA
19-19 Qa Cl q-14 191 391 EA
19-20 Qa Cl q-15 191 406 EA
19-21 Qa Cl q-16 191 405 EA
168

19-22 Qa Cl q-17 19-1 416 EA
19-23 Qa Cl q-18 19-1 406 EA
19-24 Qa Cl q-19 19-1 422 EA
19-25 Qa Cl q-20 191 405 EA
19-26 Qa Cl q-21 19-1 366 EA
19-27 Qa Cl q-22 19-1 354 EA
19-28 Qa Cl q-23 19-1 366 EA
19-29 Qa Cl q-24 191 380 EA
19-30 Qa Cl q-25 19-1 394 EA
19-31 Qa Cl q-26 19-1 396 EA
19-32 Qa Cl q-27 191 355 EA
19-33 Qa Cl q-28 191 397 EA
19-34 Qa Cl q-29 191 352 EB
19-35 Qa Cl q-30 19-1 410 EA
19-36 Qa Cl q-31 19-1 395 EA
19-37 Qa Cl q-32 19-1 416 EA
19-38 Qa Cl q-33 19-1 351 EB
19-39 Qa Cl q-34 191 365 EB
19-40 Qa Cl q-35 19-1 460 EA
20-3 Qb F CHs 20-1 324 EB
20-4 Qb F CH2CH3 20-1 338 EB
20-5 Qb F CH2CH2CH3 20-1 352 EA
20-6 Qb F q-1 20-1 400 EA
20-7 Qb F q-2 20-1 430 EA
20-8 Qb F q-3 20-1 444 EA
20-9 Qb F q-4 20-1 445 EA
20-10 Qb F q-5 20-1 415 EA
20-11 Qb F q-6 20-1 416 EA
20-12 Qb F q-7 20-1 414 EA
20-13 Qb F q-8 20-1 414 EA
20-14 Qb F q-9 20-1 390 EA
20-15 Qb F q-10 20-1 390 EA
20-16 Qb F q-11 20-1 404 EA
169

20-17 Qb F q-12 20-1 406 EA
20-18 Qb F q-13 20-1 420 EA
20-19 Qb F q-14 20-1 389 EA
20-20 Qb F q-15 20-1 404 EA
20-21 Qb F q-16 20-1 403 EA
20-22 Qb F q-17 20-1 414 EA
20-23 Qb F q-18 20-1 404 EA
20-24 Qb F q-19 20-1 420 EA
20-25 Qb F q-20 20-1 403 EA
20-26 Qb F q-21 20-1 364 EA
20-27 Qb F q-22 20-1 352 EA
20-28 Qb F q-23 20-1 364 EA
20-29 Qb F q-24 20-1 378 EA
20-30 Qb F q-25 20-1 392 EA
20-31 Qb F q-26 20-1 394 EA
20-32 Qb F q-27 20-1 353 EA
20-33 Qb F q-28 20-1 395 EA
20-34 Qb F q-29 20-1 350 EB
20-35 Qb F q-30 20-1 408 EA
20-36 Qb F q-31 20-1 393 EA
20-37 Qb F q-32 20-1 414 EA
20-38 Qb F q-33 20-1 349 EB
20-39 Qb F q-34 20-1 363 EB
20-40 Qb F q-35 20-1 458 EA
21-3 Qb Cl CH3 21-1 340 EB
21-4 Qb Cl CH2CH3 211 354 EB
21-5 Qb Cl CH2CH2CH3 21-1 368 EA
21-6 Qb Cl q-1 21-1 416 EA
21-7 Qb Cl q-2 21-1 446 EA
21-8 Qb Cl q-3 21-1 460 EA
21-9 Qb Cl q-4 21-1 461 EA
21-10 Qb Cl q-5 21-1 431 EA
2111 Qb Cl q-6 21-1 432 EA
170

21-12 Qb Cl q-7 21-1 430 EA
21-13 Qb Cl q-8 21-1 430 EA
21-14 Qb Cl q-9 21-1 406 EA
21-15 Qb Cl q-10 21-1 406 EA
21-16 Qb Cl q-11 21-1 420 EA
21-17 Qb Cl q-12 21-1 422 EA
21-18 Qb Cl q-13 21-1 436 EA
21-19 Qb Cl q-14 21-1 405 EA
21-20 Qb Cl q-15 21-1 420 EA
21-21 Qb Cl q-16 21-1 419 EA
21-22 Qb Cl q-17 21-1 430 EA
21-23 Qb Cl q-18 21-1 420 EA
21-24 Qb Cl q-19 21-1 436 EA
21-25 Qb Cl q-20 21-1 419 EA
21-26 Qb Cl q-21 21-1 380 EA
21-27 Qb Cl q-22 21-1 368 EA
21-28 Qb Cl q-23 21-1 380 EA
21-29 Qb Cl q-24 21-1 394 EA
21-30 Qb Cl q-25 21-1 408 EA
21-31 Qb Cl q-26 21-1 410 EA
21-32 Qb Cl q-27 21-1 369 EA
21-33 Qb Cl q-28 21-1 411 EA
21-34 Qb Cl q-29 211 366 EB
21-35 Qb Cl q-30 21-1 424 EA
21-36 Qb Cl q-31 21-1 409 EA
21-37 Qb Cl q-32 21-1 430 EA
21-38 Qb Cl q-33 21-1 365 EB
21-39 Qb Cl q-34 21-1 379 EB
21-40 Qb Cl q-35 211 474 EA
[0268]
Reference Example 8" 5-Amino-l-chloro-4-bromoisoquinoline
A solution of 4-bromo-l-chloro-5-nitroisoquinoline (14.0 g) prepared according
to the method described in a known literature (Nair et al., Indian J. Chem., 1967, 5,
171

403) in ethanol (75 ml) and tetrahydrofuran (75 ml) was added with 3%
platinum-sulfur/activated carbon (3% Pt"S/C, NE Chemcat, CM101, 14.0 g), and the
mixture was stirred at room temperature for 15 hours under a hydrogen gas
atmosphere. The atmosphere was replaced with nitrogen gas, and then the insoluble
matters were removed by filtration through Celite, and the solvent was evaporated
under reduced pressure to obtain the title compound (12.8 g).
MS (m/z): 257 (MH+)
iH-NMR (CDCls) 5 (ppm): 6.95 (1H, dd, J=1.2, 8.1Hz), 7.46 (1H, t, J=8.1Hz), 7.75 (lH,
dd, J=1.2, 8.1Hz), 8.25 (1H, s)
[0269]
Reference Example 9: l-Chloro-4-bromo-54soquinolinesulfonyl chloride
(Solution A)
A suspension of 5-amino-l-chloro-4-bromoisoquinoline (4.83 g) obtained in
Reference Example 8 in concentrated hydrochloric acid (40 ml) was slowly added with
an aqueous solution (8 ml) of sodium nitrite (1.82 g, Wako Pure Chemical Industries)
so that the temperature of the solution should be maintained around -15°C, and the
mixture was stirred at the same temperature for 1 hour.
(Solution B)
A suspension of cupric chloride dihydrate (960 mg, Wako Pure Chemical
Industries) in water (8 ml) and glacial acetic acid (50 ml) was bubbled with sulfur
dioxide gas at 0°C for 1.5 hours with stirring.
Solution B was cooled to 0°C, and slowly added with Solution A mentioned
above so that the temperature of the mixture should be maintained to be 5°C or lower,
and the mixture was stirred at room temperature for 2 hours. The reaction mixture
was poured into ice water, and the mixture was extracted 3 times with methylene
chloride (100 ml for each time). The combined organic layer was washed twice with
water (200 ml for each time), and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure to obtain the title compound (5.0 g).
MS (m/z): 374 (MH+)
[0270]
Reference Example 10: 2-Oxy4-chloro-5-nitroisoquinoline
A solution of 4-chloro-5-nitroisoquinoline (35.2 g) obtained in Reference
Example 5 in chloroform(500 ml) was cooled on an ice bath, and added with
172

3-chloroperbenzoic acid (70% , 67.0 g, Tokyo Kasei Kogyo) as several portions, and the
mixture was stirred at the same temperature for 30 minutes. The mixture was
further stirred at room temperature for 24 hours, and then added with saturated
aqueous sodium hydrogencarbonate (l, 000 ml), and the organic layer was separated.
The aqueous layer was extracted 3 times with chloroform (300 ml for each time), and
the combined organic layer was washed with saturated brine (1,000 ml). The organic
layer was dried over anhydrous magnesium sulfate, and then the solvent was
evaporated under reduced pressure to obtain the title compound (31.2 g).
MS (m/z): 225 (MH+)
[0271]
Reference Example 11: l,4-Dichloro-5-nitroisoquinoline
A suspension of 2-oxy4-chloro-5-nitroisoquinoline (37.9 g) obtained in
Reference Example 10 in chloroform (735 ml) was added with phosphorus oxychloride
(77.8 g, Wako Pure Chemical Industries) under ice cooling, and the mixture was stirred
at 60°C with heating for 24 hours. The reaction mixture was cooled to room
temperature, and poured into ice water (500 ml), and the mixture was extracted 3
times with chloroform (for each time 400 ml). The combined organic layer was
washed twice with saturated aqueous sodium hydrogencarbonate (800 ml for each
time), and dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and the obtained solid was recrystallized (n-hexane/ethyl
acetate) to obtain the title compound (15.5 g).
MS (m/z): 243 (MH+)
iH-NMR (CDCls) 5 (ppm): 7.83 (1H, t, J=8.0Hz), 7.97 (1H, dd, J=0.9, 8.0Hz), 8.46 (1H,
s), 8.62 (1H, dd, J=0.9, 8.0Hz)
[0272]
Reference Example 12: 5-Amino-l,4"dichloroisoquinoline
l,4-Dichloro-5-nitroisoquinoline (11.2 g) obtained in Reference Example 11
was used in the method of Reference Example 8 instead of
4-bromo-l-chloro-5-nitroisoquinoline to obtain the title compound (7.5 g).
MS (m/z): 213 (MH+)
iH-NMR (CDCI3) 5 (ppm): 6.93 (1H, dd, J=l.l, 8.1Hz), 7.47 (1H, t, J=8.1Hz), 7.73 (lH,
dd, J=l.l, 8.lHz), 8.09 (1H, s)
[0273]
173

Reference Example 13:i,4-Dichloro-5-isoquinolinesulfonyl chloride
5-Amino-l,4-dichloroisoquinoline (4.0 g) obtained in Reference Example 12
was used in the method of Reference Example 9 instead of
5-amino-l-chloro-4-bromoisoquinoline to obtain the title compound (4.34 g).
MS (m/z): 329 (MH+)
[0274]
Reference Example 14: 2-Oxy4-fluoro'5-nitroisoquinoline
4-Fluoro-5-nitroisoquinoline (12.8 g) obtained in Reference Example 2 was
used in the method of Reference Example 10 instead of 4"chloro"5-nitroisoquinoline to
obtain the title compound (13.5 g).
MS (m/z): 209 (MH+)
[0275]
Reference Example 15:l-Chloro-4-fluoro-5-nitroisoquinoline
2-Oxy-4-fluoro-5-nitroisoquinoline (10.5 g) obtained in Reference Example 14
was used in the method of Reference Example 11 instead of
2-oxy4-chloro-5-nitroisoquinoline to obtain the title compound (4.2 g).
MS (m/z): 227 (MH+)
[0276]
Reference Example 16: 5-Amino-l'chloro-4-fluoroisoquinoline
l-Chloro"4-fluoro-5-nitroisoquinoline (3.8 g) obtained in Reference Example 15
was used in the method of Reference Example 8 instead of
4-bromo-l-chloro-5-nitroisoquinoline to obtain the title compound (3.1 g).
MS (m/z): 197 (MH+)
[0277]
Reference Example 17: l-Chloro-4-fluoro"5-isoquinolinesulfonyl chloride
5-Amino-l-chloro-4-fluoroisoquinoline (3.69 g) obtained in Reference Example
15 was used in the method of Reference Example 9 instead of
5-amino-l-chloro-4-bromoisoquinoline to obtain the title compound (2.89 g).
MS (m/z): 313 (MH+)
Example 31: (R/S)-l-(4-Bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Step A
(R/S)-3-[N-(tert-Butoxycarbonyl)-N"methylamino]-l-(4-bromo-5-isoquinolinesulfonyl)p
yrrolidine (Intermediate 20)
174

A solution of 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine (0.110 g)
obtained from 4-bromo'5-isoquinolinesulfonyl chloride (0.153 g) and
l-benzyl-3-(methylamino)pyrrolidine (Tokyo Kasei Kogyo) according to the method
described in a known literature (Barlocco et al., Tetrahedron, 1995, 51, 11547) in
methylene chloride (3 ml) was added with triethylamine (0.140 ml) at 0°C, and the
mixture was stirred at the same temperature for 30 minutes, and then further stirred
at room temperature for 5 hours. The reaction mixture was washed with saturated
brine (6 ml), and then dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure, and then the residue was purified by silica gel
chromatography (n-hexane-ethyl acetate = 2:1) to obtain the title compound (0.200 g).
MS (m/z): 470 (MH+)
iH-NMR (CDCls) 5 (ppm): 1.35 (9H, s), 2.00-2.14 (2H, m), 2.72 (3H, s), 3.22-3.26 (lH,
m), 3.31-3.38 (lH, m), 3.51-3.55 (1H, m), 3.59-3.64 (1H, m), 4.76 (lH, m), 7.57 (1H, t,
J=7.6Hz), 8.06 (1H, dd, J=1.2, 7.6Hz), 8.21 (lH, dd, J=1.2, 7.6Hz), 8.83 (1H, s), 9.06
(1H, s)
Step B
(R/S)-l-(4-Bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 20 (0.157 g) prepared in Step A mentioned above was added with
10% hydrogen chloride/methanol (2 ml), and the mixture was stirred at room
temperature for 12 hours. The solvent was evaporated under reduced pressure to
obtain the title compound as hydrochloride (125 mg).
MS (m/z): 370 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.26-2.35 (1H, m)2.39-2.51 (lH, m), 2.60 (3H, s), 3.48-3.73
(3H, m), 3.80-3.86 (1H, m), 3.94-4.00 (lH, m), 7.90 (lH, t, J=7.5Hz), 8.42 (lH, dd, J=0.9,
7.5Hz), 8.51 (1H, dd, J=0.9, 7.5Hz), 8.96 (lH, s), 9.46 (lH, s)
[0278]
Although the compound of Example 1-3 can be prepared by the aforementioned
method, it can also be prepared by the following method as an alternative method.
That is, (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]-l-(4-bromo-
5-isoquinolinesulfonyl)pyrrolidine (Intermediate 20a) was prepared by using
(S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine obtained from
(S)-l-benzyl-3-(methylamino)pyrrolidine (Tokyo Kasei Kogyo) instead of
3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine according to the method
175

described in a known literature (Barlocco et al., Tetrahedron, 1995, 51, 11547) in
Example 31, Step A, and used in the method of Example 31, Step B in a similar manner
to obtain the title compound as hydrochloride.
MS (m/z): 370 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.26-2.35 (1H, m)2.39-2.51 (1H, m), 2.60 (3H, s), 3.48-3.73
(3H, m), 3.80-3.86 (1H, m), 3.94-4.00 (1H, m), 7.90 (1H, t, J=7.5Hz), 8.42 (1H, dd, J=0.9,
7.5Hz), 8.51 (1H, dd, J=0.9, 7.5Hz), 8.96 (1H, s), 9.46 (1H, s)
Example 31-2: (R)■ 1 -(4-Bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(4-bromo-5-isoquinolinesulf
onyl)pyrrolidine (Intermediate 20b) was prepared by using (R)-3-[N-(tert'butoxy
carbonyl)-N-methylamino]pyrrolidine obtained from (R)"l-benzyl-3-(methylamino)-
pyrrolidine (Tokyo Kasei Kogyo) instead of 3-(tert-butoxycarbonylamino)pyrrolidine
according to the method described in a known literature (Barlocco et al., Tetrahedron,
1995, 51, 11547) in Example 31, Step A, and used in the method of Example 31, Step B
in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 370 (MH+)
!H-NMR (DMSO) (3H, m), 3.80-3.86 (1H, m), 3.94-4.00 (lH, m), 7.90 (lH, t, J=7.5Hz), 8.42 (lH, dd, J=0.9,
7.5Hz), 8.51 (1H, dd, J=0.9, 7.5Hz), 8.96 (lH, s), 9.46 (lH, s)
[0279]
Example 32: (R/S)-l-(4-Chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(4-chloro-5-isoquinoline-
sulfonyl)pyrrolidine (Intermediate 21) was prepared by using 4-chloro-5-isoquinoline-
sulfonyl chloride in the method of Example 31, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride, and then used in the method of Example 31,
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 326 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.25-2.37 (lH, m), 2.40-2.50 (1H, m), 2.60 (3H, s),
3.51-3.75 (3H, m), 3.82-3.88 (lH, m), 3.94-4.03 (1H, m), 7.91 (1H, t, J=7.8Hz), 8.43 (lH,
dd, J=0.9, 7.8Hz), 8.53 (lH, dd, J=0.9, 7.8Hz), 8.78 (lH, s), 9.44 (lH, s)
[0280]
Although the compound of Example 19"3 can be prepared by the
aforementioned method, it can also be prepared by the following method as an
176

alternative method.
That is, (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]-l-(4-chlorcr
5-isoquinolinesulfonyl)pyrrolidine (Intermediate 21a) was prepared by using
4-chloro-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methyl-
amino]pyrrolidine in the method of Example 31, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methyl-
amino]pyrrolidine, respectively, and then used in the method of Example 31, Step B in
a similar manner to obtain the compound of Example 19-3 as hydrochloride.
MS (m/z): 326 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.25-2.37 (1H, m), 2.40-2.50 (1H, m), 2.60 (3H, s),
3.51-3.75 (3H, m), 3.82-3.88 (1H, m), 3.94-4.03 (1H, m), 7.91 (1H, t, J=7.8Hz), 8.43 (1H,
dd, J=0.9, 7.8Hz), 8.53 (1H, dd, J=0.9, 7.8Hz), 8.78 (1H, s), 9.44 (1H, s)
[0281]
Example 32-2: (R)-1 -(4-Chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]"l-(4-chloro-5-isoquinolinesulf
onyOpyrrolidine (Intermediate 21b) was prepared by using
4-chloro-5-isoquinolinesulfonyl chloride and (R)-3-[N-(tert-butoxycarbonyl)-N-methyl-
aminolpyrrolidine in the method of Example 31, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride and 3-(tert-butoxyearbonylamino)pyrrolidine,
respectively, and then used in the method of Example 31, Step B in a similar manner to
obtain the title compound as hydrochloride.
MS (m/z): 326 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.25-2.37 (1H, m), 2.40-2.50 (1H, m), 2.60 (3H, s),
3.51-3.75 (3H, m), 3.82-3.88 (1H, m), 3.94-4.03 (1H, m), 7.91 (1H, t, J=7.8Hz), 8.43 (1H,
dd, J=0.9, 7.8Hz), 8.53 (1H, dd, J=0.9, 7.8Hz), 8.78 (1H, s), 9.44 (1H, s)
[0282]
Example 33: (R/S)-l-(4-Fluoro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(4-fluoro-5-isoquinoline-
sulfonyl)pyrrolidine (Intermediate 22) was prepared by using
4-fluoro-5-isoquinolinesulfonyl chloride in the method of Example 31, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride, and then used in the method of Example 31,
Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 310 (MH+)
177

iH-NMR (DMSO) 8 (ppm): 2.21-2.32 (1H, m), 2.35-2.46 (1H, m), 2.57 (3H, s),
3.48-3.71 (3H, m), 3.81-3.98 (2H, m), 7.92 (1H, t, J=7.8Hz), 8.45 (1H, dd, J=0.9, 7.8Hz),
8.56 (1H, dd, J=0.9, 7.8Hz), 8.70 (1H, d, J=4.8Hz), 9.39 (1H, s)
[0283]
Although the compound of Example 18-3 can be prepared by the
aforementioned method, it can also be prepared by the following method as an
alternative method.
That is, (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]-r(4-fluoro-5-
isoquinolinesulfonyOpyrrolidine (Intermediate 22a) was prepared by using
4-fluoro-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methyl-
amino]pyrrolidine in the method of Example 31, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methyl-
aminolpyrrolidine, respectively, and then used in the method of Example 31, Step B in
a similar manner to obtain the compound of Example 18"3 as hydrochloride.
MS (m/z): 310 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.21-2.32 (1H, m), 2.35-2.46 (1H, m), 2.57 (3H, s),
3.48-3.71 (3H, m), 3.81-3.98 (2H, m), 7.92 (1H, t, J=7.8Hz), 8.45 (1H, dd, J=0.9, 7.8Hz),
8.56 (1H, dd, J=0.9, 7.8Hz), 8.70 (1H, d, J=4.8Hz), 9.39 (1H, s)
[0284]
Example 33-2: (R)-l-(4-Fluoro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(4-fluoro-5-isoquinolinesulf
onyl)pyrrolidine (Intermediate 22b) was prepared by using
4-fluoro-5-isoquinolinesulfonyl chloride and (R)-3-[N-(tert-butoxycarbonyl)-N-methyl-
amino]pyrrolidine in the method of Example 31, Step A instead of
4-bromo-5-isoquinolinesulfonyl chloride and 3-(tert-butoxycarbonylamino)pyrrolidine,
respectively, and then used in the method of Example 31, Step B in a similar manner to
obtain the title compound as hydrochloride.
MS (m/z): 310 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.21-2.32 (lH, m), 2.35-2.46 (1H, m), 2.57 (3H, s),
3.48-3.71 (3H, m), 3.81-3.98 (2H, m), 7.92 (lH, t, J=7.8Hz), 8.45 (lH, dd, J=0.9, 7.8Hz),
8.56 (1H, dd, J=0.9, 7.8Hz), 8.70 (1H, d, J=4.8Hz), 9.39 (lH, s)
[0285]
Example 34: (R/S)-l-(4-Methyl-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
178

3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(4-methyl-5-isoquinoline-
sulfonyl)pyrrolidine (Intermediate 23) was prepared by using Intermediate 20
obtained in Example 31, Step A in the method of Example 8, Step A instead of
Intermediate 1, and then used in the method of Example 31, Step B in a similar
manner to obtain the title compound as hydrochloride.
MS (m/z): 306 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.30-2.43 (1H, m), 2.46-2.51 (lH, m), 2.62 (lH, s), 3.01 (1H,
s), 3.55-3.97 (5H, m), 7.92 (lH, t, J=7.8Hz), 8.45 (lH, d, J=7.8Hz), 8.57 (lH, d, J=7.8Hz),
8.64 (1H, s), 8.64 (lH, s)
[0286]
Although the compound of Example 8"3 can be prepared by the aforementioned
method, it can also be prepared by the following method as an alternative method.
That is, 3-[N-(tert-butoxycarbonyl)-N-methylamino]-l-(4-methyl-5-
isoquinolinesulfonyOpyrrolidine (Intermediate 23a) was prepared by using
Intermediate 20 obtained in Example 31, Step A in the method of Example 8, Step A
instead of Intermediate 1, and then used in the method of Example 31, Step B in a
similar manner to obtain the compound of Example 8"3 as hydrochloride.
MS (m/z): 306 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.30-2.43 (lH, m), 2.46-2.51 (lH, m), 2.62 (lH, s), 3.01 (lH,
s), 3.55-3.97 (5H, m), 7.92 (1H, t, J=7.8Hz), 8.45 (lH, d, J=7.8Hz), 8.57 (lH, d, J=7.8Hz),
8.64 (1H, s), 8.64 (lH, s)
[0287]
Example 34-2: (R)-l-(4-Methyl-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(4-methyl-5-isoquinoline-
sulfonyOpyrrolidine (Intermediate 23b) was prepared by using Intermediate 20
obtained in Example 31, Step A in the method of Example 8, Step A instead of
Intermediate 1, and then used in the method of Example 31, Step B in a similar
manner to obtain the title compound as hydrochloride.
MS (m/z): 306 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.30-2.43 (1H, m), 2.46-2.51 (lH, m), 2.62 (lH, s), 3.01 (lH,
s), 3.55-3.97 (5H, m), 7.92 (lH, t, J=7.8Hz), 8.45 (1H, d, J=7.8Hz), 8.57 (lH, d, J=7.8Hz),
8.64 (1H, s), 8.64 (1H, s)
[0288]
179

Example 35:
(R/S)-l-(l-Hydroxy4-bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Step A
(R/S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l-chloro-4-bromo-5-isoquinoline-
sulfonyOpyrrolidine (Intermediate 24)
A solution of l-chloro-4-bromo-5"isoquinolinesulfonyl chloride (6.49 g)
obtained in Reference Example 9 in tetrahydrofuran (50 ml) was slowly added with a
solution of 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine (2.93 g) in
tetrahydrofuran (20 ml), so that the temperature of the mixture should be kept at -5°C
or lower. Then, the mixture was slowly added with triethylamine (2.66 ml) at the
same temperature, and the mixture was stirred at -5°C for 1 hour. The reaction
mixture was poured into cooled saturated brine (70 ml), and extracted 3 times with
ethyl acetate (50 ml for each time). The combined organic layer was washed twice
with saturated brine (for each time 100 ml), and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography Grhexane^ethyl acetate=3:l) to obtain the title
compound (4.43 g).
MS (m/z): 504 (MH+)
•H-NMR (CDCh) 5 (ppm): 1.48 (9H, s), 2.14-2.31 (2H, m), 2.85 (3H, s), 3.34-3.52 (2H,
m), 3.61-3.79 (2H, m), 4.85-4.91 (1H, m), 7.79 (lH, t, J=8.1Hz), 8.34 (1H, dd, J=0.8,
8.1Hz), 8.67 (1H, dd, J=0.8, 8.1Hz), 8.71 (lH, s)
Step B
(R/S)-l-(l-Hydroxy-4-bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 24 (168 mg) obtained in Step A mentioned above was added with
10% hydrogen chloride/methanol (4 ml), and the mixture was stirred at 60°C for 30
hours. The solvent was evaporated under reduced pressure to obtain the title
compound as hydrochloride (123 mg).
MS (m/z): 386 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.17-2.23 (lH, m), 2.39-2.45 (lH, m), 2.62 (1H, s),
3.46-3.53 (2H, m), 3.59-3.67 (1H, m), 3.73-3.79 (1H, m), 3.92-3.96 (1H, m), 7.58 (lH, s),
7.71 (1H, t, J=7.9Hz), 8.18 (1H, dd, J=1.2, 7.9Hz), 8.57 (1H, dd, J=1.2, 7.9Hz)
[0289]
Example 35-1:
180

(S)-l-(l-Hydroxy-4-bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l-chloro-4-bromo-5-
isoquinolinesulfonyl)pyrrolidine (Intermediate 24a) was prepared by using
(S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example
35, Step A mentioned above instead of 3-[N-(tert-butoxycarbonyl)-N-methyl-
aminolpyrrolidine, and then used in the method of Example 35, Step B in a similar
manner to obtain the title compound as hydrochloride.
MS (m/z): 386 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.17-2.23 (1H, m), 2.39-2.45 (1H, m), 2.62 (1H, s),
3.46-3.53 (2H, m), 3.59-3.67 (1H, m), 3.73-3.79 (lH, m), 3.92-3.96 (1H, m), 7.58 (lH, s),
7.71 (1H, t, J=7.9Hz), 8.18 (lH, dd, J=1.2, 7.9Hz), 8.57 (lH, dd, J=1.2, 7.9Hz)
[0290]
Example 35-2:
(R)-l-(l-Hydroxy-4-bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R)-3-[N-(tert"Butoxycarbonyl)-N-methylamino]-l-(l-chloro-4-bromo-5-
isoquinolinesulfonyl)pyrrolidine (Intermediate 24b) was prepared by using
(R)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example
35, Step A mentioned above instead of 3-[N-(tert-butoxycarbonyl)-N-methyl-
amino]pyrrolidine, and then used in the method of Example 35, Step B in a similar
manner to obtain the title compound as hydrochloride.
MS (m/z): 386 (MH+)
iH-NMR (DMSO) S (ppm): 2.17-2.23 (lH, m), 2.39-2.45 (lH, m), 2.62 (lH, s),
3.46-3.53 (2H, m), 3.59-3.67 (lH, m), 3.73-3.79 (lH, m), 3.92-3.96 (lH, m), 7.58 (lH, s),
7.71 (1H, t, J=7.9Hz), 8.18 (1H, dd, J=1.2, 7.9Hz), 8.57 (lH, dd, J=1.2, 7.9Hz)
[0291]
Example 36:
(R/S)-l-(l-Hydroxy-4-chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R/S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l,4-dichloro-5-
isoquinolinesulfonyl)pyrrolidine (Intermediate 25) was prepared by using
l,4-dichloro-5-isoquinolinesulfonyl chloride obtained in Reference Example 13 in the
method of Example 35, Step A instead of l-chloro-4-bromo"5-isoquinolinesulfonyl
chloride, and then used in the method of Step B in a similar manner to obtain the title
compound as hydrochloride.
181

MS (m/z): 342 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.21-2.32 (1H, m), 2.36-2.48 (lH, m), 2.60 (3H, s),
3.44-3.58 (2H, m), 3.61-3.69 (1H, m), 3.76-3.82 (lH, m), 3.91-4.00 (lH, m), 7.58 (1H, s),
7.71 (1H, t, J=7.8Hz), 8.25 (lH, dd, J=l.l, 7.8Hz), 8.57 (1H, dd, J=l.l, 7.8Hz)
[0292]
Example 36-1:
(S)-l-(l-Hydroxy-4-chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l,4-dichloro-5-
isoquinolinesulfonyDpyrrolidine (Intermediate 25a) was prepared by using
l,4-dichloro-5-isoquinolinesulfonyl chloride and
(S)-3'[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example
35, Step A instead of l-chloro-4-bromo-5'isoquinolinesulfonyl chloride and
3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in
the method of Example 35, Step B in a similar manner to obtain the title compound as
hydrochloride.
MS (m/z): 342 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.21-2.32 (lH, m), 2.36-2.48 (1H, m), 2.60 (3H, s),
3.44-3.58 (2H, m), 3.61-3.69 (lH, m), 3.76-3.82 (lH, m), 3.91-4.00 (1H, m), 7.58 (1H, s),
7.71 (1H, t, J=7.8Hz), 8.25 (lH, dd, J=l.l, 7.8Hz), 8.57 (lH, dd, J=l.l, 7.8Hz)
[0293]
Example 36"2:
(R)-l-(l-Hydroxy-4-chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l,4-dichloro-5-isoquinoline
sulfonyl)pyrrolidine (Intermediate 25b) was prepared by using
l,4-dichloro-5-isoquinolinesulfonyl chloride and
(R)-3-[N-(tert"butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example
35, Step A instead of l-chloro-4-bromo-5-isoquinolinesulfonyl chloride and
3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in
the method of Example 35, Step B in a similar manner to obtain the title compound as
hydrochloride.
MS (m/z): 342 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.21-2.32 (lH, m), 2.36-2.48 (1H, m), 2.60 (3H, s),
3.44-3.58 (2H, m), 3.61-3.69 (lH, m), 3.76-3.82 (1H, m), 3.91-4.00 (1H, m), 7.58 (lH, s),
182

7.71 (1H, t, J=7.8Hz), 8.25 (1H, dd, J=l.l, 7.8Hz), 8.57 (1H, dd, J=l.l, 7.8Hz)
[0294]
Although the compound of Example 30 can be prepared by the aforementioned
method, it can also be prepared by the following method as an alternative method.
That is, (R/S)-3-(tert-butoxycarbonyl)amino-l-(l,4-dichloro-5-
isoquinolinesulfonyl)pyrrolidine (Intermediate 26) was obtained by using
l,4"dichloro-5-isoquinolinesulfonyl chloride and 3-(tert-butoxycarbonylamino)-
pyrrolidine in the method of Example 35, Step A instead of
l-chloro-4-bromo-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxy
carbonyl)-N-methylamino]pyrrolidine, respectively. Then, the resultant was used in
the method of Step B in a similar manner to obtain the compound of Example 30 as
hydrochloride.
[0295]
Although the compound of Example 30-1 can be prepared by the
aforementioned method, it can also be prepared by the following method as an
alternative method.
That is, (S)-3-(tert-butoxycarbonyl)amino-l-(l,4-dichloro-5-
isoquinolinesulfonyl)pyrrolidine (Intermediate 26a) was obtained by using
l,4-dichloro-5-isoquinolinesulfonyl chloride and (S)-3-(tert-butoxycarbonyl-
amino)pyrrolidine in the method of Example 35, Step A instead of
l-chlonr4-bromo-5-isoquinolinesulfonyl chloride and
3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively. Then, the
resultant was used in the method of Step B in a similar manner to obtain the
compound of Example 30-1 as hydrochloride.
[0296]
Although the compound of Example 30*2 can be prepared by the
aforementioned method, it can also be prepared by the following method as an
alternative method.
That is, (R)-3-(tert-butoxycarbonyl)amino-l-(l,4-dichloro-5-
isoquinolinesulfonyOpyrrolidine (Intermediate 26b) was obtained by using
l,4-dichloro-5-isoquinolinesulfonyl chloride and (R)-3-(tert"butoxycarbonyl-
amino)pyrrolidine in the method of Example 35, Step A instead of
l-chloro-4-bronur5-isoquinolinesulfonyl chloride and
183

3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively. Then, the
resultant was used in the method of Step B in a similar manner to obtain the
compound of Example 30-2 as hydrochloride.
[0297]
Example 37:
(R/S)-l-(l-Hydroxy4-fluoro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R/S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l-chlonr4-fluonr5-isoqui
nolinesulfonyOpyrrolidine (Intermediate 27) was prepared by using
l-chloro-4-fluoro-5-isoquinolinesulfonyl chloride in the method of Example 35, Step A
instead of l-chloro-4-bromo-5-isoquinolinesulfonyl chloride, and then used in the
method of Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 326 (MH+)
[0298]
Example 37-1:
(S)-l-(l-Hydroxy4-fluoro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(S)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l-chloro-4-fluoro-5-isoquin
olinesulfonyl)pyrrolidine (Intermediate 27a) was prepared by using
l-chloro-4-fluoro-5-isoquinolinesulfonyl chloride obtained in Reference Example 17
and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of
Example 35, Step A instead of l-chloro"4-bromo-5-isoquinolinesulfonyl chloride and
3-[N-(tert"butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in
the method of Example 35, Step B in a similar manner to obtain the title compound as
hydrochloride.
MS (m/z): 326 (MH+)
[0299]
Example 37"2:
(R)-l"(l"Hydroxy4-fluoro"5"isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-l-(l-chloro-4-fluoro-5-isoquin
olinesulfonyl)pyrrolidine (Intermediate 27b) was prepared by using
l-chloro-4-fluoro-5-isoquinolinesulfonyl chloride and (R)-3-[N-(tert"butoxy
carbonyl)-N-methylamino]pyrrolidine in the method of Example 35, Step A instead of
l-chloro-4-bromo-5"isoquinolinesulfonyl chloride and 3-[N-(tert"butoxycarbonyl)-N-
methylamino]pyrrolidine, respectively, and then used in the method of Example 35,
184

Step B in a similar manner to obtain the title compound as hydrochloride.
MS (m/z): 326 (MH+)
[0300]
Example 38:
(R/S)-l-(l-Hydroxy4-bromo-5-isoquinolinesulfonyl)-3-(2-furylmethylamino)-
pyrrolidine
A suspension of hydrochloride of the compound of Example 7 (186 mg),
triethylamine (209 ii 1), furfural (124 ix 1), and powdery molecular sieves 3A (220 mg,
Aldrich) in methanol (7 ml) was stirred at room temperature for 20 hours. The
reaction mixture was cooled to 0°C, and added with sodium borohydride (95 mg), and
the mixture was stirred at the same temperature for 1 hour, and then poured into
cooled saturated brine (10 ml). The reaction mixture was filtered through Celite, and
then extracted 3 times with chloroform (10 ml for each time), and the combined organic
layer was washed twice with water (20 ml for each time), and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced pressure, and the
residue was purified by silica gel chromatography (chloroform^acetonitrile = 2:i) to
obtain the title compound (195 mg).
MS (m/z): 452 (MH+)
iH-NMR (hydrochloride, DMSO) 5 (ppm): 2.22-2.34 (1H, m), 2.38-2.47 (1H, m),
3.35-3.55 (2H, m), 3.59-3.66 (1H, m), 3.74 (1H, dd, J=7.2, 10.5Hz), 3.98 (1H, m), 4.31
(2H, s), 6.53-6.55 (lH, m), 6.85 (1H, d, J=3.0Hz), 7.68 (1H, s), 7.70 (1H, t, J=7.8Hz),
7.80 (1H, m), 8.22 (1H, dd, J=l.l, 7.8Hz), 8.56 (1H, dd, J=l.l, 7.8Hz)
[0301]
Example 38-1:
(S)-l-(l-Hydroxy4-bromo-5-isoquinolinesulfonyl)-3-(2-furylmethylamino)pyrrolidine
The compound of Example 7-1 was used in the method of Example 38 instead
of the compound of Example 7 to obtain the title compound.
MS (m/z): 452 (MH+)
!H-NMR (hydrochloride, DMSO) 5 (ppm): 2.22-2.34 (1H, m), 2.38-2.47 (lH, m),
3.35-3.55 (2H, m), 3.59-3.66 (lH, m), 3.74 (lH, dd, J=7.2, 10.5Hz), 3.98 (lH, m), 4.31
(2H, s), 6.53-6.55 (lH, m), 6.85 (lH, d, J=3.0Hz), 7.68 (lH, s), 7.70 (lH, t, J=7.8Hz),
7.80 (1H, m), 8.22 (1H, dd, J=l.l, 7.8Hz), 8.56 (lH, dd, J=l.l, 7.8Hz)
[0302]
185

Example 38"2:
(R)-l-(l-Hydroxy4-bromo-5-isoquinolinesulfonyl)-3-(2-furylmethylamino)pyrrolidine
The compound of Example 7-2 was used in the method of Example 38 instead
of the compound of Example 7 to obtain the title compound.
MS (m/z): 452 (MH+)
!H-NMR (hydrochloride, DMSO) 5 (ppm): 2.22-2.34 (1H, m), 2.38-2.47 (1H, m),
3.35-3.55 (2H, m), 3.59-3.66 (1H, m), 3.74 (1H, dd, J=7.2, 10.5Hz), 3.98 (lH, m), 4.31
(2H, s), 6.53-6.55 (lH, m), 6.85 (1H, d, J=3.0Hz), 7.68 (lH, s), 7.70 (lH, t, J=7.8Hz),
7.80 (1H, m), 8.22 (lH, dd, J=l.l, 7.8Hz), 8.56 (1H, dd, J=l.l, 7.8Hz)
Example 39: (R/S)-3"Amino-l-(l-amino-4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonyl)amino-l-(l-amino-4-chloro-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate 28)
A suspension of Intermediate 26 (0.20 g), and potassium carbonate (0.31 g) in
l,3-dimethyl-2-imidazolidinone (3 ml, Tokyo Kasei Kogyo) was added with 25%
aqueous ammonia (2 ml), and the mixture was stirred at 80°C for 24 hours in a sealed
tube. The reaction mixture was added with saturated brine (30 ml), and extracted 3
times with chloroform (30 ml for each time). The combined organic layer was washed
twice with saturated brine (50 ml for each time), and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure, and the residue was
purified by silica gel chromatography (chloroform^methanol = 9:l) to obtain the title
compound (64.4 mg).
MS (m/z): 427 (MH+)
iH-NMR (CDCls) 5 (ppm): 1.44 (9H, s), 1.96-2.00 (lH, m), 2.24-2.31 (lH, m),
3.32-3.36 (1H, m), 3.48-3.52 (lH, m), 3.60-3.63 (2H, m), 4.96 (lH, m), 7.50 (lH, t,
J=8.1Hz), 8.04 (1H, d, J=8.1Hz), 8.13 (1H, s), 8.32 (lH, d, J=8.1Hz)
Step B
(R/S)-3-Amino-l-(l-amino-4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 28 (30 mg) obtained in Step A mentioned above was added with
10% hydrogen chloride/methanol (4 ml), and the mixture was stirred at room
temperature for 20 hours. The solvent was evaporated under reduced pressure to
obtain the title compound as hydrochloride (25 mg).
MS (m/z): 327 (MH+)
186

iH-NMR (DMSO) 5 (ppm): 2.14-2.23 (1H, m), 2.38-2.45 (1H, m), 3.45-3.55 (2H, m),
3.64-3.76 (2H, m), 4.01 (1H, m), 7.84 (1H, t, J=7.8Hz), 8.07 (1H, s), 8.36 (1H, d,
J=7.8Hz), 8.77 (1H, d, J=7.8Hz)
[0303]
Example 39-1: (S)-3-Amino-l-(l-amino-4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 26a was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 327 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.14-2.23 (1H, m), 2.38-2.45 (1H, m), 3.45-3.55 (2H, m),
3.64-3.76 (2H, m), 4.01 (1H, m), 7.84 (1H, t, J=7.8Hz), 8.07 (1H, s), 8.36 (1H, d,
J=7.8Hz), 8.77 (1H, d, J=7.8Hz)
Example 39-2: (R)-3\Amincr l'(l-amino-4-chloro-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 26b was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 327 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.14-2.23 (1H, m), 2.38-2.45 (1H, m), 3.45-3.55 (2H, m),
3.64-3.76 (2H, m), 4.01 (1H, m), 7.84 (1H, t, J=7.8Hz), 8.07 (1H, s), 8.36 (1H, d,
J=7.8Hz), 8.77 (1H, d, J=7.8Hz)
[0304]
Example 40:
(R/S)-l-(l-Amino'4-chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 25 was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 341 (MH+)
!H-NMR (DMSO) 5 (ppm): 2.23-2.30 (1H, m), 2.40-2.46 (1H, m), 2.60 (3H, s),
3.61-3.69 (2H, m), 3.77-3.83 (2H, m), 3.93-3.95 (1H, m), 7.78 (1H, t, J=7.9Hz), 8.04 (lH,
s), 8.35 (1H, d, J=7.9Hz), 8.68 (1H, d, J=7.9Hz)
[0305]
Example 40"i:
(S)-l-(l-Amino-4-chloro-5-isoquinolinesulfonyl)'3-(methylamino)pyrrolidine
Intermediate 25a was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 341 (MH+)
187

iH-NMR (DMSO) 3.61-3.69 (2H, m), 3.77-3.83 (2H, m), 3.93-3.95 (1H, m), 7.78 (1H, t, J=7.9Hz), 8.04 (lH,
s), 8.35 (1H, d, J=7.9Hz), 8.68 (lH, d, J=7.9Hz)
[0306]
Example 40"2:
(R)-l-(l-Amino-4-chloro-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 25b was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 341 (MH+)
!H-NMR (DMSO) 8 (ppm): 2.23-2.30 (lH, m), 2.40-2.46 (1H, m), 2.60 (3H, s),
3.61-3.69 (2H, m), 3.77-3.83 (2H, m), 3.93-3.95 (lH, m), 7.78 (lH, t, J=7.9Hz), 8.04 (lH,
s), 8.35 (1H, d, J=7.9Hz), 8.68 (lH, d, J=7.9Hz)
[0307]
Example 41: (R/S)-3"Amino-l-(l-amino-4-bromo-5-isoquinolinesulfonyl)pyrrolidine
Step A
(R/S)-3-(tert-Butoxycarbonylamino)-l-(l-chloro-4-bromo-5-isoquinolinesulfonyl)-
pyrrolidine (Intermediate 29)
3-(tert-Butoxycarbonylamino)pyrrolidine was used in the method of Example
35, Step A instead of 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine to obtain
the title compound.
MS (m/z): 471 (MH+)
iH-NMR (CDCls) 8 (ppm): 1.44 (9H, s), 1.92-2.03 (1H, m), 2.22-2.33 (lH, m),
3.27-3.35 (1H, m), 3.41-3.51 (lH, m), 3.58-3.65 (2H, m), 5.03 (1H, m), 7.47 (lH, t,
J=8.1Hz), 8.04 (1H, d, J=8.1Hz), 8.25 (1H, d, J=8.lHz), 8.30 (lH, s)
Step B
(R/S)-3-Amino-l-(l-amino-4-bromo-5-isoquinolinesulfonyl)pyrrolidine
Intermediate 29 was used in the method of Example 39, Step B instead of
Intermediate 28 to obtain the title compound as hydrochloride.
MS (m/z): 371 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.15-2.20 (lH, m), 2.33-2.45 (lH, m), 3.42-3.52 (2H, m),
3.61-3.73 (2H, m), 3.98-4.00 (lH, m), 7.81 (lH, t, J=7.8Hz), 8.17 (lH, s), 8.39 (lH, d,
J=7.8Hz), 8.74 (1H, d, J=7.8Hz)
[0308]
188

Example 41-1: (S)-3-Amino-l-(l-amino-4-bromo-5-isoquinolinesulfonyl)pyrrolidine
(S)-3-(tert-Butoxycarbonylamino)-l-(l-chloro-4'bromo-5-isoquinoline-
sulfonyOpyrrolidine was prepared by using (S)-3-(tert-butoxycarbonylamino)-
pyrrolidine in the method of Example 35, Step A instead of
3"[N-(tert-butoxycarbonyl)-N"methylamino]pyrrolidine, and then the protective group
of the obtained compound was removed according to the method described in Example
39, Step B to obtain the title compound as hydrochloride.
MS (m/z): 371 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.15-2.20 (1H, m), 2.33-2.45 (1H, m), 3.42-3.52 (2H, m),
3.61-3.73 (2H, m), 3.98-4.00 (1H, m), 7.81 (1H, t, J=7.8Hz), 8.17 (1H, s), 8.39 (lH, d,
J=7.8Hz), 8.74 (1H, d, J=7.8Hz)
[0309]
Example 41"2: (R)-3-Amino-l-(l-amino-4-bromo-5-isoquinolinesulfonyl)pyrrolidine
(R)-3-(tert-Butoxycarbonylamino)-l-(l-chloro-4-bromo-5-isoquinoline-
sulfonyDpyrrolidine was prepared by using (R)-3-(tert"butoxycarbonylamino)-
pyrrolidine in the method of Example 35, Step A instead of
3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, and then the protective group
of the obtained compound was removed according to the method described in Example
39, Step B to obtain the title compound as hydrochloride.
MS (m/z): 371 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.15-2.20 (lH, m), 2.33-2.45 (lH, m), 3.42-3.52 (2H, m),
3.61-3.73 (2H, m), 3.98-4.00 (lH, m), 7.81 (lH, t, J=7.8Hz), 8.17 (lH, s), 8.39 (lH, d,
J=7.8Hz), 8.74 (1H, d, J=7.8Hz)
[0310]
Example 42:
(R/S)-l-(l-Amino-4-bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 24 was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 385 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.20-2.32 (1H, m), 2.36-2.45 (lH, m), 2.60 (3H, s),
3.60-3.68 (2H, m), 3.74-3.80 (2H, m), 3.93-3.97 (lH, m), 7.83 (lH, t, J=7.9Hz), 8.17 (lH,
s), 8.38 (1H, d, J=7.9Hz), 8.73 (lH, d, J=7.9Hz)
[0311]
189

Example 42-1:
(S)-l-(l-Amino-4-bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 24a was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 385 (MH+)
iH-NMR (DMSO) 5 (ppm): 2.20-2.32 (1H, m), 2.36-2.45 (1H, m), 2.60 (3H, s),
3.60-3.68 (2H, m), 3.74-3.80 (2H, m), 3.93-3.97 (1H, m), 7.83 (1H, t, J=7.9Hz), 8.17 (1H,
s), 8.38 (1H, d, J=7.9Hz), 8.73 (1H, d, J=7.9Hz)
[0312]
Example 42-2:
(R)-l-(l-Amino-4'bromo-5-isoquinolinesulfonyl)-3-(methylamino)pyrrolidine
Intermediate 24b was used in the method of Example 39 instead of
Intermediate 26 to obtain the title compound as hydrochloride.
MS (m/z): 385 (MH+)
iH-NMR (DMSO) 8 (ppm): 2.20-2.32 (1H, m), 2.36-2.45 (1H, m), 2.60 (3H, s),
3.60-3.68 (2H, m), 3.74-3.80 (2H, m), 3.93-3.97 (1H, m), 7.83 (1H, t, J=7.9Hz), 8.17 (1H,
s), 8.38 (1H, d, J=7.9Hz), 8.73 (1H, d, J=7.9Hz)
[0313]
Test Example l: Inhibitory action on phosphorylation of myosin regulatory light chain
A volume of 50 to 100 ml of peripheral blood collected from healthy volunteers
was centrifuged by using Mono-Poly separator solution (Dainippon Pharmaceutical) to
prepare a neutrophil containing fraction. The neutrophils were washed with PBS(-)
and resuspended in Hanks' Balanced Salt Solution (HBSS+, Gibco) to prepare a cell
suspension (8 x 106/ml). The cell suspension was diluted to 5 x 106/ml, introduced into
Eppendorf tubes in a volume of 0.4 ml each, then 0.1 ml each of solutions of a test
compound at various concentrations were added to the suspension and allowed to react
at 25°C for 5 minutes. After the reaction, 0.1 ml of trichloroacetic acid solution was
added to each reaction mixture, the reaction mixture was gently shaken and
centrifuged at 12,000 rpm (4°C, 5 minutes), and the supernatant was removed.
Subsequently, 3 M 1 of 1 M Tris solution was added to the residue, the mixture was
further mixed with 50 n 1 of extraction buffer (8 M urea, 0.02% 2-mercaptoethanol,
0.002% bromophenol blue) and left stand at room temperature for 1 hour. Then, the
reaction mixture was loaded on a spin column (0.45 n m, Millipore) to remove the
190

insoluble solids and a sample buffer for SDS polyacrylamide gel electrophoresis (25
mM, Tris-HCl pH 6.8, 2.5% 2-mercaptoethanol, 2% sodium dodecylsulfate, 5% sucrose,
0.002% bromophenol blue as final concentrations) was added, and 10 n 1 of each
sample was subjected to electrophoresis.
The gel after the electrophoresis was blotted on a nitrocellulose membrane
(BioRad), blocked with 5% skim milk, and reacted successively with antibodies pLCl
(Sakurada K. et al, Am. J. PhysioL, 274, C1563-C1572 (1998)), which specifically
recognize the phosphorylated myosin regulatory light chain, and donkey anti-mouse
IgG (Chemicon) conjugated with horseradish peroxidase. The band of the
phosphorylated myosin regulatory light chain was detected on a film by using ECL
Plus Kit (Amersham Pharmacia Biotech). This band was subjected to quantification
using a densitometer. By using this value, the inhibitory ratio (%) for
phosphorylation of the myosin regulatory light chain was calculated by using the
following equation.
Phosphorylation inhibition ratio (%) = 1 - (Band intensity of phosphorylated myosin
regulatory light chain with addition of the test compound/Band intensity of
phosphorylated myosin regulatory light chain without addition of the test compound) x
100
[0314]
Further, the phosphorylation inhibition ratio was calculated with changing the
concentrations of the test compound, and a compound concentration providing an
inhibition ratio of 50% was obtained as IC50. The results for the compounds are
shown below.
Compounds which gave an IC50 not lower than 10 n M and not higher than 40
fj. M were the compounds of the example numbers of 1-19, l'30, 1"33, 8"9, 8-16, 8-18,
8-27, 8-29, 8-30, 8-31, 8-73, 10-14, 10-31, 12"1, 18-1, 18-16, 19-14, 19-17, 19-21, and
19-31, and compounds which gave an IC50 lower than 10 u M (IC50 compounds of the example numbers of 1-3, I'll, 1-14, 1-18, 2-1,2-2, 4-1, 7-1, 8-1, 8-2,
8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-12, 8-21, 8-26, 8-28, 8-32, 8-34, 8-37, 9-1, 10-1, 11-1, 18-7,
18-8, 19-1, 19-3, 19-8, 19-40, 22-1, 22-2, 23-1, 25-1, 26, 27, 29-1 and 30-1. Further
compounds which gave an IC50 not lower than 10 \i M and not higher than 40 jt M (10
At M ^ IC50 ^ 40 /i M) were the compounds of the example numbers of 15-1, 19-4,
21-1, 21-2, 36"2, 38-1 and 40-1, and further compounds which gave an IC50 lower than
191

10 ii M (IC50 1-13, 1-20, 1-31, 1-38, 10-3, 10-7, 19"2, 32-2, 35-1, 36-1, 39-1, 41-1 and 42-1.
Thus, it was revealed that the aforementioned compounds of the present
invention inhibited the phosphorylation of the myosin regulatory light chain.
[0315]
Test Example 2- Intraocular pressure reducing action
A Japanese white rabbit having a body weight of about 2 kg was placed in a
positioner and naturalized for one week before the experiment. An ophthalmologic
local anesthesant (Benoxil) was administered to both eyes, and then intraocular
pressure was measured by using a tonometer (Classic 30, Solan). A 3 mM aqueous
solution of a test compound was administered in a volume of 50 ul to the left eye, and
the right eye was not treated (control eye). The intraocular pressure values were
measured for the left and right eyes immediately before, and 2, 4 and 6 hours after the
administration of the aqueous solution of the test compound, and the difference of the
measured values for the left and right eyes was considered an intraocular pressure
reduction value of the test medicament at each measurement time. The largest
difference of the values for the left and right eyes among the measured values at the
measurement times (after 2, 4 and 6 hours) was considered the maximum intraocular
pressure reduction value (max ZlIOP) of each test medicament. The intraocular
pressure reducing degree representing the intraocular pressure reducing action of each
test medicament was calculated according to the following formula. Since rabbits
show significant daily variation of intraocular pressure, daily variation is added when
change of intraocular pressure is measured over time, and the intraocular pressure
reducing action may be overestimated. Therefore, we used this calculation method of
intraocular pressure reduction value in order to minimize the influence of the
variation.
Intraocular pressure reducing degree (%) = (max ZllOP/Intraocular pressure value
immediately before administration) x 100
Compounds which gave an intraocular pressure reducing degree not lower
than 5% and lower than 10% are the compounds of the example numbers of 1-14, 1-19,
8-26, 8-28, 8-29, 8-30, 8-32, 8-33, 8-34, 8-36, 8-37, 10-14, 11-1, 13-1, 18-7, 18-14, 19-14,
19-17, 19-40, 24-1, 26, and 27, and compounds which gave an intraocular pressure
reducing degree not lower than 10% and lower than 20% are the compounds of the
192

example numbers of 1-18, 8-4, 8-21, 8-27, 8-31, 8-74, 12-1, 18-21, 22-1, 22-2, 23-1, 25-1
and 29-1. Further, compounds which gave an intraocular pressure reducing degree
not lower than 20% are the compounds of the example numbers of 1-3, 1-30, 2-1, 2-2,
4-1, 7-1, 8-1, 8-2, 8-3, 8-12, 9-1, 10-1, 10-31, 18-1, 18-31, 19-1, 19-3, 19-21, 19-31, 28-1
and 30-1. Further compounds which gave an intraocular pressure reducing degree
not lower than 5% and lower than 10% are the compounds of the example numbers of
1-7, 15-1, 35-1, 38-1, 40-1 and 42-1, and further compounds which gave an intraocular
pressure reducing degree not lower than 10% and lower than 20% are the compounds of
the example numbers of 1-20, 1-31, 10-7, 10-29, 21-2, 32-2, 36-1, 36-2 and 39-1.
Further compounds which gave an intraocular pressure reducing degree not lower
than 20% are the compounds of the example numbers of 10"3, 18"3, 19-2, 19-4 and 21-1.
Further, when the same test as that of Test Example 2 was performed with a test
compound of 1 mM, compounds which gave an intraocular pressure reducing degree
not lower than 20% were the compounds of the example numbers of 1-3, 2-1, 4-1, 8-1,
8-3, 10-1, 10-3, 18-1, 19-1 and 19-3.
It was demonstrated that the aforementioned compounds of the present
invention reduced the rabbit normal intraocular pressure. In addition, even 6 hours
after the administration of these compounds, the intraocular pressure reducing action
did not disappear, and thus they had a sustained intraocular pressure reducing action.
Thus, it was confirmed that the compounds of the present invention were
useful as medicaments for prophylactic and/or therapeutic treatment of glaucoma.
The compounds, per se, metabolite thereof after administration, or both may exhibit
the intraocular pressure reducing action.
[0316]
Test Example 3^ Neutrophil migration inhibitory action
Neutrophils were isolated from 50 to 100 ml of peripheral blood collected from
healthy human donors by the method described in Test Example 1 to obtain a cell
suspension (8 x 106/ml). Subsequently, solutions of a test compound at various
concentrations were introduced into wells of a 96-well plate in a volume of 125 fi 1 per
well, the cell suspension of an equivalent volume was added to it and the plate was
preincubated at room temperature for 5 minutes. During the preincubation, FMLP (l
li M, Sigma) solution was added to the lower chamber to set Boyden Chamber, the
preincubated cell suspension was added to the upper chamber in a volume of 200/x 1
193

per well, and the cells were allowed to migrate at 37°C under 5% carbon dioxide for 30
minutes. The filter after the migration was collected, and the non-migrated cells
adhered to the surface that faced the upper chamber were carefully wiped off. Then,
the migrated cells on the back surface were stained with DifQuick dye solution
(International Reagents), washed with water and dried, and then absorbance was
measured at 595 nm. The inhibition ratio against migration (%) of a test compound
was calculated by using the following equation^
Migration inhibition ratio (%) = (1 -Absorbance of the group with addition of test
compound /Absorbance of the group without addition of test compound) x 100
• Further, the migration inhibitory ratio was calculated with changing the test
compound concentration, and a compound concentration providing an inhibition ratio
of 50% was obtained as IC50. The results for the compounds are shown below.
Compounds which gave an IC50 not lower than 10 A M and not higher than 40
fi M (10 /iM ^ IC50 Sa 40 p M) are the compounds of the example numbers of 1-3,
1-11, 1-14, 2-1, 2-2, 8-3, 8-4, 8-5, 8-6, 8-12, 8-21, 8-26, 8-28, 8-32, 8-34, 8-37, 9-1, 10-1,
11-1, 18-7, 18-8, 19-1, 19-3, 22"1, 22-2, 23-1, 26, and 27. Further compounds which
gave an IC50 not lower than 10 p M and not higher than 40 p M (10 fiM ^ IC50 2a
40 p M) are the compounds of the example numbers of 1-6, 1"12, 1-20, 1-31, 1-38, 10-3,
10-7, 19-2, 32-2, 39-1, 41-1 and 42-1. Compounds which gave an IC50 lower than 10
p M (IC50 8-2, 8-7, 8-8, 19-8, 19-40, 25-1, 29-1 and 30-1. Further compounds which gave an IC50
lower than 10 p M (ICso 35"1 and 36-1. The aforementioned compounds of the present invention inhibited
migration of neutrophils.
Thus, it was confirmed that the compounds of the present invention were
useful for prophylactic and/or therapeutic treatment of diseases relating to cell
migration.
[0317]
Test Example 4: Action on increase of intracellular calcium concentration
According to the method described in Test Example 1, a neutrophil containing
fraction was prepared. Fura2-AM (Sigma) at a final concentration of 3 pM. was
added to the human neutrophil fraction and the mixture was incubated at 37°C for 1
hour. After centrifugation (250 g for 5 minutes), the supernatant was discarded, and
194

the neutrophils were resuspended in Hanks' Balanced Salt Solution (HBSS', Gibco) to
prepare a cell suspension (8 x 106/ml) for measurement of intracellular calcium
concentration. The cell suspension for measurement of intracellular calcium
concentration was left stand at room temperature for 30 minutes. Then, 490 n 1 of
the cell suspension for measurement of intracellular calcium concentration was placed
in a cuvette, 10 n 1 of calcium chloride solution at a final concentration of 1 /JM was
added to it and the cuvette was set in an intracellular calcium concentration analyzer
(CAF110, Nippon Bunko). fMLP (Sigma) solution at a final concentration of 1 uM
was added to the cell suspension, and F340 and F380, which are fluorescence intensity
at 340 nm and 380 nm, respectively, were measured to obtain an R value (F340/F380)
as an index of the intracellular calcium concentration. A test compound (l n M) was
added 3 minutes before the addition of fMLP, and the action on the intracellular
calcium concentration was observed. The ratios of the maximum R value obtained
with addition of each test compound relative to the maximum R value obtained without
addition of test compound and taken as 100% were obtained.
It was revealed that the compounds of the present invention had almost no
effect on the increase of the intracellular calcium concentration caused by the fMLP
stimulation.
[0318]
Test Example 5- Action on myosin light chain kinase (MLCK) activity
A myosin light chain kinase (MLCK) was purified from chicken gizzard smooth
muscle by a conventional method (Yoshida, M., et al., J. Biochem., 99, 1027-1036
(1986)). The myosin regulatory light chain as a substrate was purified from the
chicken gizzard smooth muscle by a conventional method (Grand, R. J., et al., Biochem.
J., 211, 267-272 (1983)). The MLCK activity was measured by ELISA (Sakurada, K.,
et al., J. Biochem., 115, 18-21 (1994)) using anti-phosphorylated myosin regulatory
light chain-recognizing antibodies (Sakurada, K., et al., Am. J. Physiol., 274,
C1563-C1572, 1998). The myosin regulatory light chain was diluted in
phosphate-buffered saline (PBS, Sigma) to a concentration of 5.0 g/ml, added to 96-well
Immunoplate (Nunc) in a volume of 100 ix 1 per well and left stand overnight at 4°C.
Each well was washed with PBS, and 25 mM Tris/HCl buffer containing 100 n M ATP,
3 mM MgCb, 1 mM CaCl2, 100 ng/ml of calmodulin (Sigma) and 100 ng/ml of MLCK
(pH 7.4, Buffer A) was added to each well and incubated at 30°C for 10 minutes. In a
195

volume of 100 p. 1 each of 20% aqueous phosphoric acid solution was added to each well
to terminate the enzymatic reaction. Each well was washed with 25 mM Tris/HCl
buffer (TTBS) containing 0.1% Tween 20, and then 100 n 1 of antibodies specifically
recognizing phosphorylated myosin regulatory light chain (Sakurada, K., et al., Am. J.
Physiol., 274, C1563-C1572, 1998) was added to each well and incubated at room
temperature for 90 minutes.
Each well was washed with TTBS, and then 100 » 1 of the HRP-labeled
anti-mouse IgG antibodies (BkrRad) were added to each well and incubated at room
temperature for 90 minutes. Each well was washed with TTBS, and then 25 mM
citrate buffer (pH 5.0) containing orthophenylenediamine (Sigma) as a substrate of
HRP and aqueous hydrogen peroxide (0.03%) was added in a volume of 100 n 1 per well
and incubated at room temperature for 5 minutes. 50 /x 1 of 4 N sulfuric acid was
added to each well to terminate the reaction, and then absorbance was measured by
using an immunoplate reader (Bio-Rad). The MLCK activity inhibition ratio was
calculated by adding the test compound to Buffer A at various concentrations to obtain
a compound concentration providing an inhibition ratio of 50% as IC50.
It was revealed that the compounds of the present invention had almost no
inhibitory effect on MLCK.
[0319]
Test Example 6^ Rabbit intraocular pressure reduction enhancing action
For evaluation of intraocular pressure reduction enhancing action of a
combination of the compound of the present invention and a drug for combination use,
Japanese white rabbits are used as experimental animals, and the action is
demonstrated as follows.
As for a test example, the compound of the example number 19-1 (henceforth
referred to as 19" 1 compound) was used as a test compound to demonstrate the effect of
combination use. However, the effect is not limited to the 19-1 compound, and the
ophthalmic solution concentration of the 19-1 compound is not limited to those used in
this test example. Moreover, as for the test compound used for combination use,
similar effect can be obtained also with the compounds of the present invention
represented with the example numbers mentioned in Test Example 2.
Test Example 6-1
As a test compound, the 19" 1 compound was dissolved in physiological saline,
196

and the solution was neutralized by addition of sodium hydroxide (pH 7.0 to 8.0) to
prepare a 0.01 weight % aqueous solution (19-1 compound aqueous solution). As the
drugs for combination use, isopropyl unoprostone (trade name: Rescula, Santen
Pharmaceutical) was used as a prostaglandin-related drug, and brinzolamide
hydrochloride (trade name: Azopt, Alcon Japan) was used as a carbonic anhydrase, as
the marketed formulations as they were.
A Japanese white rabbit having a body weight of about 2 kg was placed in a
positioner and naturalized for one week before the experiment. An ophthalmologic
local anesthesant (Benoxil) was administered to both eyes, and then intraocular
pressure before instillation was measured by using a tonometer (Classic 30, Solan). A
test aqueous solution or the drug for combination use was administered to the left eye,
and the right eye was not treated (control eye). The test groups consisted of (l)
control group, (2) group instilled only with the 19" 1 compound aqueous solution (single
drug group l), (3) group instilled only with the drug for combination use (single drug
group 2), and (4) group instilled with the drug for combination use and the 19' 1
compound aqueous solution (combination use group), and six rabbits were used for
each group. As for the rabbits of these groups, 50 n L of physiological saline was first
instilled to the control group, single drug group 1, and single drug group 2, and the
drug for combination use was first instilled in the same volume to the combination use
group. Then, 5 minutes after the instillation of physiological saline or the drug for
combination use, 50 ix L of physiological saline was instilled to the control group, the
same volume of the 19-1 compound aqueous solution was instilled to the single drug
group 1, and the combination use group, and 50 p. L of the drug for combination use
was instilled to the single drug group 2. The intraocular pressure thereafter was
measured for each group 2, 4 and 6 hours after the second administration of the test
compound, and the difference of the measured values for the left and right eyes at each
measurement time was considered an intraocular pressure reduction value of each
group. The largest difference of the intraocular pressure values for the left and right
eyes among those of the measured values of the measurement times was considered
the maximum intraocular pressure reduction value (max ZlIOP) of each drug group.
The results are shown in Tables 2 and 3.
197

[Table 2]

Max Z1IOP (mmHg)
(l) Control group 0.2
(2) Single drug group 1 (19-1 compound) 4.3
(3) Single drug group 2 (brinzolamide hydrochloride) 2.3
(4) Combination use group (19-1 compound + brinzolamide
hydrochloride) 6.3
[Table 3]

Max ziIOP (mmHg)
(l) Control group 0.2
(2) Single drug group 1 (19-1 compound) 4.3
(3) Single drug group 2 (isopropyl unoprostone) 4.4
(4) Combination use group (19-1 compound + isopropyl
unoprostone) 6.1
Test Example 6-2
As a test compound, the 19-1 compound was dissolved in physiological saline,
and the solution was neutralized by addition of sodium hydroxide (pH 7.0 to 8.0) to
prepare a 0.01 weight % aqueous solution (19-1 compound aqueous solution). As a
drug for combination use, timolol maleate (trade name: Timoptol, Santen
Pharmaceutical) was used as an adrenergic receptor # blocker, as the marketed
formulation as it was.
A Japanese white rabbit having a body weight of about 2 kg was placed in a
positioner and naturalized for one week before the experiment. An ophthalmologic
local anesthesant (Benoxil) was administered to both eyes, and then intraocular
pressure before instillation was measured by using a tonometer (Classic 30, Solan). A
test aqueous solution or the drug for combination use was administered to the left eye,
and the right eye was not treated (control eye). The test groups consisted of (l)
control group, (2) group instilled only with the 19-1 compound aqueous solution (single
drug group l), (3) group instilled only with the drug for combination use (single drug
group 2), and (4) group instilled with the drug for combination use and the 19-1
198

compound aqueous solution (combination use group), and 12 rabbits were used for each
group. As for the rabbits of these groups, 50 [i L of physiological saline was first
instilled to the control group, single drug group 1, and single drug group 2, and the
drug for combination use was first instilled in the same volume to the combination use
group. Then, 5 minutes after the instillation of physiological saline or the drug for
combination use, 50 v L of physiological saline was instilled to the control group, the
same volume of the 19-1 compound aqueous solution was instilled to the single drug
group 1, and the combination use group, and 50 M L of the drug for combination use
was instilled to the single drug group 2. The intraocular pressure thereafter was
measured for each group 1, 2 and 4 hours after the second administration of the test
compound, and the difference of the measured values at each measurement time for
the each group and the control group was considered an intraocular pressure reduction
value of each group. The largest difference of the intraocular pressure values relative
to the control group among those of the measured values of the measurement times
was considered the maximum intraocular pressure reduction value (max ziIOP) of
each drug group. The results are shown in Table 4.
[Table 4]

Max ZlIOP (mmHg)
(l) Control group ...
(2) Single drug group 1 (19" 1 compound) 4.1
(3) Single drug group 2 (timolol maleate) 1.9
(4) Combination use group (19-1 compound + timolol
maleate) 6.4
In Test Examples 6-1 and 6-2, the compound of the present invention
exemplified with the 19-1 compound exhibited the intraocular pressure reducing action
in the single drug group 1 in a degree exceeding that of the control group, and the
intraocular pressure reducing action in the combination use group in a degree
exceeding those of both the single drug group 1 and single drug group 2 (Tables 2, 3,
and 4).
From these results, it was confirmed that intraocular pressure reducing action
was enhanced in rabbits by combination of the compound of the present invention
199

exemplified with the 19-1 compound and a carbonic anhydrase inhibitor, a
prostaglandin-related drug, or an adrenergic receptor j3 blocker. Moreover, the
compounds of the example numbers 1-3, 4-1, 1O3, and 19"3 can also be evaluated by
the same methods as those of Test Examples 6*1 and 6-2 to confirm the effectiveness
thereof.
Moreover, it is also possible to confirm the effectiveness of the compounds of
the present invention indicated with the example numbers mentioned in Test
Examples 2 other than the 19-1 compound by performing the test using the compounds
in combination with a carbonic anhydrase inhibitor, a prostaglandin-related drug, or
an adrenergic receptor j3 blocker.
Furthermore, when the compositions A to C described in Preparation Example
1, the compositions E to G described in Preparation Example 2, and compositions
comprising, in combination, the aforementioned example compounds and a drug for
combination use were administered as the combination use group instead of
successively instilling a solution of the compound of the present invention and a drug
for combination use, the intraocular pressure reducing action was exhibited in the
combination use group in a degree exceeding those of both the single drug group 1 and
single drug group 2.
Therefore, it was revealed that medicaments consisting of the compounds of
the present invention and drugs for combination use were useful as medicaments for
prophylactic and/or therapeutic treatment of glaucoma.
[0320]
Test Example !'• Intraocular pressure reduction enhancing action in monkey
For evaluating the intraocular pressure reduction enhancing action of a
combination of the compound of the present invention and latanoprost (trade name-
Xalatan, Pfizer) as a prostaglandin related drug, the action can be demonstrated by
using a monkey (cynomolgus monkey).
Although the effect of the combination use is demonstrated by using the 19" 1
compound for the test example, the effect is not limited to the 19-1 compound, and the
ophthalmic solution concentration of the 19-1 compound is not limited to those used in
this test example. Moreover, as for the test compound used for combination use,
similar effect can be obtained also with the compounds of the present invention
represented with the example numbers mentioned in Test Example 2. The test is
200

performed by using cynomolgus monkeys sufficiently naturalized for the operation of
fixation on a monkey chair and ophathalmotonometry.
As the test compound, Compound A is dissolved in physiological saline, and the
solution is neutralized by addition of sodium hydroxide (pH 7.0 to 8.0) to prepare a
0.01 weight % aqueous solution (19-1 compound aqueous solution). As a drug for
combination use, latanoprost (trade name- Xalatan, Pfizer) is used as the marketed
formulation per se. The test aqueous solution or the drug for combination use is
instilled to the left eye, and the right eye is not treated (control eye). The test groups
consist of (l) control group, (2) group instilled only with the 19-1 compound aqueous
solution (single drug group 1), (3) group instilled only with the drug for combination
use (single drug group 2), and (4) group instilled with the drug for combination use and
the 19-1 compound aqueous solution (combination use group). After initial
intraocular pressure values of the monkeys are measured for each group, 30 ii L of
physiological saline is instilled to the control group, single drug group 1, and single
drug group 2, and latanoprost is instilled in the same volume to the combination use
group. Then, 5 minutes after the instillation of physiological saline or latanoprost, 30
li L of physiological saline is instilled to the control group, the same volume of the 191
compound aqueous solution is instilled to the single drug group 1, and the combination
use group, and 30 v L of the drug for combination use is instilled to the single drug
group 2. Then, the intraocular pressure is measured over time for each group.
In Test Example 7, the 19-1 compound exhibits the intraocular pressure
reducing action in the single drug group 1 in a degree exceeding that of the control
group, and the intraocular pressure reducing action in the combination use group in a
degree exceeding those of both the single drug group 1 and single drug group 2. It is
thereby confirmed that the intraocular pressure reducing action is enhanced in
monkeys by combining the compound of the present invention and a
prostaglandin-related drug. Moreover, the compounds of the example numbers 1-3,
4-1, 10-3, and 19-3 can also be evaluated by the same method as that of Test Example 7
to confirm the effectiveness thereof.
Moreover, it is also possible to confirm the effectiveness of the compounds of
the present invention indicated with the example numbers mentioned in Test
Examples 2 other than the 19-1 compound by performing the test using the compounds
in combination with a prostaglandin-related drug.
201

Furthermore, when the composition D described in Preparation Example 1,
the composition H described in Preparation Example 2, and compositions comprising
the aforementioned example compounds and latanoprost in combination are
administered as the combination use group instead of successively instilling a solution
of the compound of the present invention and latanoprost, the intraocular pressure
reducing action is exhibited in the combination use group in a degree exceeding those
of both the single drug group 1 and single drug group 2.
Therefore, it is revealed that medicaments consisting of the compounds of the
present invention and latanoprost are useful as medicaments for prophylactic and/or
therapeutic treatment of glaucoma.
[0321]
Preparation Example 1
Examples of the preparation of a composition for instillation in which the 19-1
compound and a drug for combination use are combined by dissolving them in
physiological saline are mentioned below. However, the present invention is not
limited to these examples, and compositions in which a drug for combination use is
combined can be prepared with the compounds other than the 19-1 compound.
Furthermore, eye drops comprising a desired combination and having desired
concentrations can be prepared by appropriately changing type and amount of the drug
for combination use, types and amounts of additives, and the like.
A physiological saline solution containing 0.01% by weight of the 19-1
compound, 0.12% by weight of isopropyl unoprostone (Funakoshi), and 0.005% by
weight of benzalkonium chloride is designated Composition A.
A physiological saline solution containing 0.01% by weight of the 19-1
compound, 1.0% by weight of brinzolamide hydrochloride (Hydrus Chemical), and
0.005% by weight of benzalkonium chloride is designated Composition B.
A physiological saline solution containing 0.01% by weight of the 19-1
compound, 0.5% by weight of timolol maleate (Sigma Aldrich), and 0.005% by weight of
benzalkonium chloride is designated Composition C.
A physiological saline solution containing 0.01% by weight of the 19-1
compound, 0.005% by weight of latanoprost (Funakoshi), and 0.005% by weight of
benzalkonium chloride is designated Composition D.
[0322]
202

Preparation Example 2
Examples of the preparation of a composition for instillation in which the 19-1
compound and a drug for combination use are combined by dissolving the 19-1
compound in a commercially available eye drop for therapeutic treatment of glaucoma
are mentioned below. However, the present invention is not limited to these examples,
and compositions in which a drug for combination use is combined can be prepared
with the compounds other than the 19-1 compound. Furthermore, eye drops
comprising a desired combination and having desired concentrations can be prepared
by appropriately changing type and amount of the drug for combination use, types and
amounts of additives, and the like.
A solution obtained by dissolving the 19-1 compound at a concentration of
0.01 % by weight in the eye drop, Rescula (active ingredient: isopropyl unoprostone,
Fujisawa Pharmaceutical), is designated Composition E.
A solution obtained by dissolving the 19-1 compound at a concentration of
0.01 % by weight in the eye drop, Azopt (active ingredient: brinzolamide hydrochloride,
Alcon Japan), is designated Composition F.
A solution obtained by dissolving the 19-1 compound at a concentration of
0.01 % by weight in the eye drop, Timoptol (active ingredient: timolol maleate, Santen
Pharmaceutical), is designated Composition G.
A solution obtained by dissolving the 19-1 compound at a concentration of
0.01 % by weight in the eye drop, Xalatan (active ingredient: latanoprost, Pfizer), is
designated Composition H.
Industrial Applicability
[0323]
The compounds of the present invention represented by the formula (l), salts
thereof and derivatives thereof useful as prodrugs have an action of potently inhibiting
phosphorylation of myosin regulatory light chain. Medicaments comprising a
substance selected from the group consisting of the compounds of the present invention
represented by the formula (l), salts thereof and derivatives thereof useful as prodrugs
as active ingredients are useful as medicaments for prophylactic and/or therapeutic
treatment of diseases relating to contraction of cells, diseases relating to
morphological change of cells, diseases relating to migration of cells, diseases relating
to release of cells, diseases relating to aggregation of cells, and diseases relating to
203

apoptosis of cells, based on the myosin regulatory light chain phosphorylation
inhibitory action.
204

What is claimed is:
[l] A compound represented by the following general formula (l) or a salt thereof, or
a derivative thereof which is a prodrug:

[in the formula, A represents a nitrogen-containing saturated ring!
m represents an integer of 0, 1, or 2!
n represents an integer of 1, 2, 3, or 4;
G1 represents hydrogen atom, chlorine atom, hydroxyl group, an alkoxy group, or
amino group!
G2 represents a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl
group which may be substituted, an alkenyl group which may be substituted, an
alkynyl group which may be substituted, an alkoxy group which may be substituted,
an alkylthio group which may be substituted, an amino group which may be
substituted, an alkylsulfinyl group which may be substituted, an alkylsulfonyl group
which may be substituted, or an aryl group which may be substituted!
G3 represents hydrogen atom, a halogen atom, hydroxyl group, cyano group, carboxy
group, an alkyl group which may be substituted, an alkenyl group which may be
substituted, an alkynyl group which may be substituted, an alkoxy group which may
be substituted, an alkylthio group which may be substituted, an amino group which
may be substituted, an alkoxycarbonyl group which may be substituted, an acyl group
205

which may be substituted, an acyloxy group which may be substituted, an alkylsulfinyl
group which may be substituted, an alkylsulfonyl group which may be substituted, or
an aryl group which may be substituted (provided that G3 substitutes at the 3-, 6-, 7-,
or 8-position of the isoquinoline ring);
G4 represents hydroxyl group, or -NCR^R2) (R1 and R2 may be the same or different,
and independently represent hydrogen atom, an alkyl group which may be substituted,
an aralkyl group which may be substituted, an alkenyl group which may be substituted,
an alkynyl group which may be substituted, or a saturated heterocyclic group which
may be substituted); and
G5 represents a substituent on a ring-constituting carbon atom constituting the
nitrogen-containing saturated ring represented by A, and represents hydrogen atom,
fluorine atom, or an alkyl group].
[2] The compound or a salt, or a derivative thereof which is a prodrug according to
claim 1, wherein m is 1.
[3] The compound or a salt, or a derivative thereof which is a prodrug according to
claim 1 or 2, wherein n is 2 or 3.
[4] The compound or a salt, or a derivative thereof which is a prodrug according to
any one of claim 1 to claim 3, wherein G3 is hydrogen atom.
[5] The compound or a salt, or a derivative thereof which is a prodrug according to
any one of claim 1 to claim 4, wherein G5 is hydrogen atom.
[6] The compound or a salt, or a derivative thereof which is a prodrug according to
any one of claim 1 to claim 5, wherein G4 is -NXROCR2).
[7] A medicament comprising the compound, a salt thereof, or a derivative thereof
which is a prodrug according to any one of claim 1 to claim 6 as an active ingredient.
[8] The medicament according to claim 7, which inhibits phosphorylation of the
myosin regulatory light chain.
[9] The medicament according to claim 7, which inhibits the Rho/Rho kinase
pathway.
[10] The medicament according to claim 7, which is used for therapeutic and/or
prophylactic treatment of glaucoma.
[11] A myosin regulatory light chain phosphorylation inhibitor comprising the
compound, a salt thereof, or a derivative thereof which is a prodrug according to any
one of claim 1 to claim 6.
206

[12] A Rho/Rho kinase pathway inhibitor comprising the compound, a salt thereof, or
a derivative thereof which is a prodrug according to any one of claim 1 to claim 6.
[13] A medicament comprising the compound, a salt thereof, or a derivative thereof
which is a prodrug according to claim 1, and a drug having an intraocular pressure
reducing action and/or a drug having an optic nerve protective action in combination.
[14] A medicament comprising the compound, a salt thereof, or a derivative thereof
which is a prodrug according to claim 1 and any one or more of an adrenergic receptor
stimulant, a prostaglandin-related agent, a carbonic anhydrase inhibitor, an
adrenergic receptor blocker, a cholinesterase inhibitor, a calcium antagonist, a Rho
kinase inhibitor, an angiotensin II receptor antagonist, and an NMDA receptor blocker
in combination.
[15] A medicament comprising the compound, a salt thereof, or a derivative thereof
which is a prodrug according to claim 1 and a drug having an intraocular pressure
reducing action in combination.
[16] A medicament comprising the compound, a salt thereof, or a derivative thereof
which is a prodrug according to claim 1 and any one or more of a prostaglandin-related
agent, a carbonic anhydrase inhibitor, and an adrenergic receptor blocker.
[17] The medicament according to claim 16, which is an agent for prophylactic and/or
therapeutic treatment of glaucoma.
[18] A medicament comprising the compound, a salt thereof, or a derivative thereof
which is a prodrug according to claim 1 and a drug having an optic nerve protective
action in combination.
[19] The medicament according to claim 16, wherein the prostaglandin-related agent
mentioned in claim 16 is any one of latanoprost, bimatoprost, travoprost,
isopropylunoprostone, and tafluprost.
[20] The medicament according to claim 16, wherein the carbonic anhydrase inhibitor
mentioned in claim 16 is any one of dorzolamide hydrochloride, brinzolamide
hydrochloride, and acetazolamide hydrochloride.
[21] The medicament according to claim 16, wherein the adrenergic receptor blocker
mentioned in claim 16 is any one of bunazosin hydrochloride, timolol maleate, carteolol
hydrochloride, levobunolol hydrochloride, betaxolol hydrochloride, nipradilol
hydrochloride, and befunolol hydrochloride.
[22] A method for therapeutic and/or prophylactic treatment of glaucoma, which uses
207

208
the medicament according to any one of claim 13 to claim 21.

A compound represented by the formula (1) [A represents a
nitrogen-containing saturated ring; m represents an integer of O to 2; n represents an
integer of 1 to 4; G1 represents hydrogen atom, chlorine atom, hydroxyl group, an
alkoxy group, or amino group; G2 represents a halogen atom, hydroxyl group, cyano
group, carboxy group, an alkyl group, an alkenyl group, and the like; G3 represents
hydrogen atom, a halogen atom, hydroxyl group, cyano group, carboxy group, an alkyl
group, an alkenyl group, and the like; G4 represents hydroxyl group, or -N(R1)(R2) (R1
and R2 represent hydrogen atom, an alkyl group, an aralkyl group, an alkenyl group,
an alkynyl group, or a saturated heterocyclic group); G5 is a substituent on a
ring-constituting carbon atom of A, and represents hydrogen atom, fluorine atom, or an
alkyl group] or a salt thereof, or a derivative thereof that is a prodrug, which potently
inhibits phosphorylation of the myosin regulatory light chain.

Documents:

01251-kolnp-2008-abstract.pdf

01251-kolnp-2008-claims.pdf

01251-kolnp-2008-correspondence others.pdf

01251-kolnp-2008-form 1.pdf

01251-kolnp-2008-form 2.pdf

01251-kolnp-2008-form 3.pdf

01251-kolnp-2008-form 5.pdf

01251-kolnp-2008-gpa.pdf

01251-kolnp-2008-international search report.pdf

01251-kolnp-2008-others pct form.pdf

01251-kolnp-2008-pct priority document notification.pdf

01251-kolnp-2008-pct request form.pdf

1251-KOLNP-2008-(02-02-2012)-CORRESPONDENCE.pdf

1251-KOLNP-2008-(13-03-2009)-FORM-13.pdf

1251-KOLNP-2008-(13-05-2013)-ANNEXURE TO FORM 3.pdf

1251-KOLNP-2008-(13-05-2013)-CORRESPONDENCE.pdf

1251-KOLNP-2008-(13-05-2013)-OTHERS.pdf

1251-KOLNP-2008-(29-08-2011)-ABSTRACT.pdf

1251-KOLNP-2008-(29-08-2011)-AMANDED CLAIMS.pdf

1251-KOLNP-2008-(29-08-2011)-CORRESPONDENCE.pdf

1251-KOLNP-2008-(29-08-2011)-FORM 1.pdf

1251-KOLNP-2008-(29-08-2011)-FORM 2.pdf

1251-KOLNP-2008-(29-08-2011)-OTHERS.pdf

1251-KOLNP-2008-(29-08-2011)-PCT SEARCH REPORT.pdf

1251-KOLNP-2008-ABSTRACT 1.1.pdf

1251-KOLNP-2008-AMANDED CLAIMS 1.1.pdf

1251-KOLNP-2008-AMANDED CLAIMS 1.2.pdf

1251-KOLNP-2008-AMENDED CLAIMS.pdf

1251-KOLNP-2008-CORRESPONDENCE 1.3.pdf

1251-KOLNP-2008-CORRESPONDENCE OTHERS 1.1.pdf

1251-KOLNP-2008-CORRESPONDENCE-1.1.pdf

1251-KOLNP-2008-CORRESPONDENCE-1.2.pdf

1251-KOLNP-2008-DESCRIPTION (COMPLETE) 1.1.pdf

1251-KOLNP-2008-EXAMINATION REPORT REPLY RECIEVED.pdf

1251-KOLNP-2008-FORM 1-1.1.pdf

1251-KOLNP-2008-FORM 13-1.1.pdf

1251-KOLNP-2008-FORM 13-1.2.pdf

1251-KOLNP-2008-FORM 13.pdf

1251-KOLNP-2008-FORM 18-1.1.pdf

1251-kolnp-2008-form 18.pdf

1251-KOLNP-2008-FORM 2-1.1.pdf

1251-KOLNP-2008-FORM 3-1.1.pdf

1251-KOLNP-2008-INTERNATIONAL EXM REPORT.pdf

1251-KOLNP-2008-INTERNATIONAL SEARCH REPORT.pdf

1251-KOLNP-2008-IPRB.pdf

1251-KOLNP-2008-OTHERS 1.1.pdf

1251-KOLNP-2008-OTHERS.pdf

1251-KOLNP-2008-PETITION UNDER RULE 137.pdf

abstract-01251-kolnp-2008.jpg


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Patent Number 258563
Indian Patent Application Number 1251/KOLNP/2008
PG Journal Number 04/2014
Publication Date 24-Jan-2014
Grant Date 21-Jan-2014
Date of Filing 27-Mar-2008
Name of Patentee ASAHI KASEI PHARMA CORPORATION
Applicant Address 9-1, KANDA MITOSHIRO-CHO, CHIYODA-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 RINTARO YAMADA 1-2, YURAKU-CHO 1-CHOME, CHIYODA-KU, TOKYO 100-8440
2 MINORU SETO 1-2, YURAKU-CHO 1-CHOME, CHIYODA-KU, TOKYO 100-8440
PCT International Classification Number C07D 401/12
PCT International Application Number PCT/JP2006/316913
PCT International Filing date 2006-08-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2005-248556 2005-08-30 Japan