Title of Invention

PROPANE-1,3-DIONE DERIVATIVE OR SALT THEREOF

Abstract Compounds useful as GnRH receptor antagonists are provided. The present inventors have further examined propane- 1,3-dione derivatives and confirmed as a result that a propane- 1,3-dione having 2-(1,3-dihydro-2H-benzimidazol-2-ylidene), or a compound which has benzene or thiophene ring substituted with a group derived from 1-hydroxymethyl, shows excellent availability, in addition to its excellent GnRH receptor antagonism, thereby accomplishing the invention. Since the compound of the invention shows excellent availability, in addition to its strong GnRH receptor antagonism, it can be expected that it exerts superior drug effect in the living body, and it is useful for the treatment of sex hormone dependent diseases such as prostate cancer, breast cancer, endometriosis, uterine leiomyoma, benign prostatic hypertrophy and the like. In addition, since the compound of the invention is excellent in metabolic stability in human and also is less in drug interaction, it has more desirable properties as a medicament to be used for the aforementioned diseases.
Full Text

Propane-1,3-dione Derivative or Salt Thereof
[Technical Field]
[0001]
The present invention relates to a novel propane-1,3-dione
derivative useful as a medicament, particularly a therapeutic
agent for sex hormone dependent diseases.
[Background of the Invention]
[0002]
It is known that a hypothalamic hormone or a pituitary
hormone is concerned in the secretion controlling mechanism of
peripheral hormones. In general, secretion of anterior
pituitary hormones is controlled by a secretion accelerating
hormone or a secretion inhibiting hormone secreted from its
upper central hypothalamus or by a peripheral hormone secreted
from a target organ of respective hormone.
Gonadotropin releasing hormone (to be referred to as GnRH
hereinafter, and GnRH is also called luteinizing hormone
releasing hormone; LHRH) is known as a hormone which controls
secretion of sex hormones at the highest position, and controls
secretion of anterior pituitary hormones luteinizing hormone (to
be referred to as LH hereinafter) and follicle-stimulating
hormone (to be referred to as FSH hereinafter) and sex hormones
in sex glands, via a receptor which is present in the anterior
pituitary (to be referred to as GnRH receptor hereinafter)
(Hormone To Rinsho (Hormone and Clinics), a special number for

spring, 46, 46 - 57 (1998)). Since antagonists specific and
selective for this GnRH receptor regulate the action of GnRH and
control secretion of subordinate LH and FSH and sex hormones,
they are expected as preventive or therapeutic agents for sex
hormone dependent diseases (aforementioned Hormone and Clinics,
a special number for spring (1998)).
To date, peptide compounds cetrorelix (Non-patent
Reference 1) and abarelix (Non-patent Reference 2) have been put
on the market as GnRH receptor antagonists.
On the other hand, as non-peptide compounds having GnRH
receptor antagonism, a thienopyrimidine derivative TAK-013 (Non-
patent Reference 3) and a uracil derivative NBI-42902 (Non-
patent Reference 4) are now under clinical tests.
In addition, Patent Reference 1 discloses that a propane-
1,3-dione derivative has the GnRH receptor antagonism.
[0003]

[0004]
(In the formula, A and B may be the same or different from each
other and each represents an aryl which may be substituted or a
heteroaryl which may be substituted. See the aforementioned
official gazette for details.)
In Patent Reference 1, and the group d is described

However the compound having a 1-hydroxyalkyl group as a
substituent group in the ring A or ring B is included in the
scope of the generic conceptive propane-1,3-dione derivative
having group d as a substituent group in the rings in Patent
Reference 1, there is no illustrative disclosure on the
compound.
[0005]
[Non-patent Reference 1] Proc. Natl. Acad. Sex., USA, 85,
1637 - 1641, 1988
[Non-patent Reference 2] J. Urol., 167, 1670 - 1674, 2002
[Non-patent Reference 3] J. Clin. Endocrinol. Metab., 88,
1697 - 1704, 2003
[Non-patent Reference 4] J. Med. Chem., 2005, 48, 1169 -
1178
[Patent Reference 1] International Publication WO
02/02533
[Disclosure of the Invention]
[Problems that the Invention is to Solve]
[0006]
The object of the invention is to provide a medicament
which exerts excellent GnRH receptor antagonism in the living
body, particularly a novel compound which is useful as a
therapeutic agent for prostate cancer, benign prostatic
hypertrophy and the like.

[Means for Solving the Problem]
[0007]
The present inventors have examined propane-1,3-dione
derivatives and confirmed as a result that a compound which has
benzene or thiophene ring substituted with a group derived from
1-hydroxyalkyl on a propane-1,3-dione having 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene) shows surprisingly excellent
availability by oral administration, in addition to its
excellent GnRH receptor antagonism, thereby accomplishing the
invention.
That is, the invention relates to a propane-1,3-dione
derivative represented by the general formula (I) or a salt
thereof. It also relates to a medicament, particularly a GnRH
receptor antagonist, which uses them as the active ingredient.
[0008]
I
[0009]
[Symbols in the formula mean as follows,
ring A: benzene which may be substituted, pyridine which may be
substituted or thiophene ring,
ring B: benzene or thiophene ring,
R1: H or -CO-lower alkyl,

R2: H, -O-R5, -N(R6)R7, -N3, -S(O)m-lower alkyl, -S (O) m-N(R6) R7,
halogen, pyridyl, or -imidazolyl which may be substituted,
R5: H, lower alkyl, -CO-lower alkyl which may be
substituted, or -CO-O-lower alkyl which may be substituted,
R6 and R7: may be the same or different from each other and
each is H, lower alkyl, or -CO-lower alkyl, with the proviso
that R1 and R2 may together form dioxolane which may be
substituted,
m: 0, 1 or 2,
R3: H or lower alkyl,
R401 and R402: may be the same or different from each other and
each is H, halogen, OH, -O-lower alkyl, or lower alkyl,
X: bond, lower alkylene which may be substituted, or
cycloalkanediyl,
R101, R102, R103 and R104: may be the same or different from one
another and each is H, halogen, OH, or -O-lower alkyl which may
be substituted with (aryl or heteroaryl). The same shall apply
hereinafter.]
Also this invention is a pharmaceutical composition
comprising as an active ingredient the propane—1,3—dione
compound represented by the aforementioned general formula (I)
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier, preferably the pharmaceutical
composition which is a GnRH receptor antagonist; and more preferably the
pharmaceutical composition wherein the GnRH receptor antagonist is an
agent for treating GnRH—related diseases, such as prostate cancer,

breast cancer, endometriosis, uterine leiomyoma, and benign prostatic
hypertrophy.
Moreover, the present invention provides a method for treating a patient
suffering from GnRH—related diseases, which comprises administering to
a patient an effective amount of the propane—1,3—dione compound
represented by the aforementioned general formula (I) or a
pharmaceutically acceptable salt thereof, preferably the method
for treating GnRH-related diseases, wherein the GnRH—related diseases
are prostate cancer, breast cancer, endometriosis, uterine leiomyoma,
and benign prostatic hypertrophy. Furthermore the present invention is
use of the propane—1, 3—dione compound for a manufacture of the GnRH
receptor antagonist comprising as an active ingredient the
propane—1,3—dione compound represented by the aforementioned
general formula (I) or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier.
[Advantage of the Invention]
[0010]
Since the compound of the invention shows excellent
availability by oral administration, in addition to it strong
GnRH receptor antagonism, it can be expected that it exerts
stronger drug effect in the living body, and it is useful for
the treatment of sex hormone dependent diseases, particularly
GnRH-related diseases, such as prostate cancer, breast cancer,
endometriosis and uterine leiomyoma (C. Huggins & C.V. Hodges,
Cancer Res., 1, 293 - 297 (1941), L. Bokser et al., Proc. Natl.
Acad. Sci. USA, 87, 7100 - 7104 (1990)), benign prostatic

hypertrophy (J. Clin. Endocrinol. Metab., 83, 3826 - 3931, 1998)
and the like. In addition, since the compound of the invention
is excellent in metabolic stability in human and has weak drug
interaction property, it has more desirable properties as a
medicament to be used for the aforementioned diseases.
[Best Mode for Carrying Out the Invention]
[0011]
Preferred embodiments of the invention are shown below.
(1) A propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof, wherein in the general formula (I),
ring A is benzene ring which may be substituted with halogen
atom or lower alkyl, ring B is benzene ring, R1 is H, R2 is OH,
R3 is H, and X is lower alkylene which may be substituted.
(2) The propane-1,3-dione derivative of the aforementioned
(1) or a pharmaceutically acceptable salt thereof, wherein X is
methylene which may be substituted.
(3) A propane-1,3-dione derivative represented by a
general formula (Ia) or a pharmaceutically acceptable salt
thereof


(symbols in the formula mean as follows,
R801, R802 and R803: may be the same or different from one another
and each is halogen or lower alkyl, and
R403 and R404: may be the same or different from each other and
each is H, halogen or lower alkyl; the same shall apply
hereinafter).
(4) A propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof according to claim 4, or a pharmaceutically
acceptable salt thereof, which is at least one compound selected from
the group consisting of:
2-(l,3-Dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-
dihydroxyethyl)phenyl]-3-(3,4,5-trifluorophenyl)propane-1,3-
dione; 1-{2-butyl-3-[(1R)-1,2-dihydroxyethyl]phenyl}-2- (1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)propane-
1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-[5-(1,2-dihydroxyethyl)-2-
fluorophenyl]propane-1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1R)-1,2-
dihydroxyethyl]-2-methylphenyl}propane-1,3-dione; 2- (1,3-
dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-1,2-
dihydroxyethyl]-2-methylphenyl}-3-(2-fluorophenyl)propane-1,3-
dione; 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-
dihydroxye thy1)phenyl]-3-(2,3,5-tri fluorophenyl)propane-1,3-
dione; 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3- [ (1R)-1,2-
dihydroxyethyl]-2-methylphenyl}-3-(3-methylphenyl)propane-1,3-
dione; 1-{2-chloro-3-[(1R)-1,2-dihydroxyethyl]phenyl}-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)propane-

1,3-dione; 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-
1,2-dihydroxyethyl]phenyl}-3-(3-fluorophenyl)propane-1,3-dione;
1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-[3-(1,2-dihydroxyethyl)-2-fluorophenyl]propane-1,3 -
dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-[3-(1,2-dihydroxyethyl)-4-fluorophenyl]propane-1,3-
dione; 1-{2-chloro-3-[(1R)-1,2-dihydroxyethyl]phenyl}-3-(3,5-
dif luorophenyl) -2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)propane-1,3-dione; 2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-1-{3-[(1R)-1,2-dihydroxyethyl]-2-fluorophenyl}-3-(3-
fluorophenyl)propane-1,3-dione; 1-{2-chloro-3-[(1R)-1,2-
dihydroxyethyl]phenyl}-3-(3-chlorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)propane-1,3-dione.
(5) A propane-1,3-dione derivative represented by a
general formula (lb) or a pharmaceutically acceptable salt
thereof
[0012]

[0013]
(symbols in the formula mean as follows,

R8 and R9: may be the same or different from each other and each
is H, lower alkyl, lower alkenyl or -O-lower alkyl; the same
shall apply hereinafter).
(6) The propane-1,3-dione derivative of general formula
(Ib) or a pharmaceutically acceptable salt thereof, wherein R801,
R802 and R803 may be the same or different from one another and
each represents H or a halogen atom.
(7) A propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof , which is at least one compound selected
from the group consisting of:
2-(1,3-Dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-
[3-(2-methoxy-l,3-dioxolan-4-yl)phenyl]propane-1,3-dione; 2-
(l,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-
(2-methoxy-2-methyl-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione
or a pharmaceutically acceptable salt thereof.
[0014]
The invention is described further in detail.
As the "halogen", fluorine, chlorine, bromine or iodine
can be exemplified.
The "lower alkyl" is a straight or branched saturated Ci_6
alkyl, preferably methyl, ethyl, isopropyl, hexyl or the like.
The "lower alkylene" is a straight or branched saturated
C1-6 alkylene, preferably methylene, ethylene, isopropylene or
the like.
The "benzene which may be substituted" and "pyridine which
may be substituted" are benzene ring or pyridine ring which may
be substituted with 1 to 3 substituent groups, wherein the

substituent group is halogen, CN, lower alkyl which may be
substituted with halogen, -O-lower alkyl, -CO-O-lower alkyl or
amino, preferably halogen or lower alkyl which may be
substituted with halogen.
The "imidazolyl which may be substituted" is imidazolyl
which may be substituted with 1 or 2 substituent groups, and
lower alkyl is desirable as the substituent group.
The "dioxolane which may be substituted" is dioxolane
which may be substituted with 1 or 2 substituent groups, and
lower alkyl, lower alkenyl, -O-lower alkyl or morpholino-lower
alkyl is desirable as the substituent group.
[0015]
The "lower alkyl which may be substituted" is lower alkyl
which may be substituted with 1 or 2 substituent groups, and
amino or mono- or di-lower alkylamino is desirable as the
substituent group.
The "lower alkylene which may be substituted" is lower
alkylene which may be substituted with 1 or 2 substituent
groups, and OH, COOH, -CO-O-lower alkyl, halogen, CN, phenyl, -
O-lower alkyl, -O-CO-lower alkyl, amino, mono- or di-lower
alkylamino, -CO-NH2, -CO-mono- or di-lower alkylamino and
cycloalkyl can be exemplified as preferred substituent groups.
The "cycloalkyl" means a C3-6 monocyclic saturated
hydrocarbon ring group, and is preferably cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
The "cycloalkanediyl" means divalent group of a C3-6
monocyclic saturated hydrocarbon ring, and is preferably

cyclopropanediyl, cyclobutanediyl, cyclopentanediyl,
cyclohexanediyl or the like, of which cyclopropanediyl is
particularly desirable.
The "availability" means a property in which an orally
administered agent is absorbed by digestive tract, exerts
initial liver passage effect and then enters into blood.
A compound in which a hydroxyl group is replaced by a
prodrug-forming group is also included in the compound of the
invention.
Examples of the prodrug-forming group include the groups
described in Prog. Med., 5, 2157 - 2161 (1985) and "Iyakuhin no
Kaihatsu (Development of Medicaments)" Vol. 7 (Hirokawa Shoten,
1990) Bunshi Sekkei (Molecular Design), pp. 163 - 198.
Tautomers are present in the compounds of the invention.
For example as described in the following.

[0016]

[0017]
Separated forms of these isomers or mixtures thereof are
also included in the invention. Also, the compounds of the
invention may have an asymmetric atom or axial asymmetry
depending on the kind of substituent group, so that isomers
based on an asymmetric atom or the like can be present.
Mixtures of these optical isomers and separated forms thereof
are included in the invention, too. In addition, compounds in
which the compounds of the invention are labeled with
radioactive isotopes are also included in the invention.
Also, a compound in which geometrical isomerism regarding
the 2-position double bond of propane as shown below can be
mutually converted via tautomerism as shown in the above is

present among the compounds of the invention. An example is
shown below.
[0018]

[0019]
In addition, the compound of the invention sometimes forms
acid addition salt or, depending on the kind of substituent
group, salt with base, and such the salt is included in the
invention, with the proviso that it is a pharmaceutically
acceptable salt. Its illustrative example includes an acid
addition salt with hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and
the like inorganic acid or with formic acid, acetic acid,
propionic acid, oxalic acid, malonic acid, succinic acid,
fumaric acid, maleic acid, lactic acid, malic acid, tartaric
acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-
toluenesulfonic acid, aspartic acid, glutamic acid and the like
organic acid, a salt with sodium, potassium, magnesium, calcium,
aluminum and the like inorganic base or with methylamine,
ethylamine, ethanolamine, lysine, ornithine and the like organic
base, ammonium salt and the like. Various hydrates and
solvates, and substances having polymorphism, of the compound of

the invention and a pharmaceutically acceptable salt thereof are
also included in the invention.
[0020]
(Production methods)
The compound of the invention and a pharmaceutically
acceptable salt thereof can be produced by employing various
conventionally known synthesis methods, making use of the
characteristics based on its basic nucleus or the kind of
substituent groups.
In some cases, depending on the kind of functional group,
it is effective in view of production techniques to replace said
functional group with an appropriate protecting group (a group
which is easily converted into said functional group) at a stage
of from the materials to intermediates. Examples of such a
functional group include amino group, hydroxyl group, carboxy
group and the like, and the protecting groups described in
"Protective Groups in Organic Synthesis (3rd Edition)" edited by
Greene and Wuts (JOHN WILEY & SONS, 1991) and the like can be
exemplified as their protecting groups which can be optionally
selected in response to the reaction conditions. By such a
method, a compound of interest can be obtained by carrying the
reaction after introduction of said protecting group, and then
removing the protecting group as occasion demands.
Typical production methods of the compound of the
invention is described in the following. In this connection,

the production methods of the invention are not limited to the
examples illustrated in the following.
Abbreviations in the following sentences are as follows.
DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; THF:
tetrahydrofuran; Tol: toluene; DCE: 1,2-dichloroethane; TEA:
triethylamine; Diglyme: diethylene glycol dimethyl ether; LiTMP:
lithium 2,2,6,6-tetramethylpiperidate; LDA: lithium
diisopropylamide; WSCHC1: 3-(3-dimethylaminopropyl)-1-ethyl
carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; CDI:
1,1'-carbonyldiimidazole

Production methods
First production method
[0021]

[0022]
(Symbols in the reaction scheme are as follows.
R: lower alkyl, R401, R402, R101, R102, R103 and R104 may be
optionally protected with a protecting group. The same shall
apply hereinafter.)

This production method is a method for obtaining the
compound (I) of the invention. By a method which is based on
the production method 4 described in the Patent Reference 1, a
2-methylimidazole compound (III) is obtained from a 1,2-
diaminobenzene compound (II), said compound (III) is allowed to
react with an acyl compound (IV), the thus obtained reaction
mixture is treated at room temperature to under heating in the
presence of morpholine or the like organic base in a reaction-
inert solvent, thereby obtaining an imidazole compound (VI).
This acyl compound (IV) can be obtained illustratively by
chlorinating a corresponding carboxylic acid compound with
thionyl chloride, oxalic acid chloride or the like chlorination
agent, in dichloromethane or the like solvent inert to the
reaction at room temperature or under heating in the presence or
absence of DMF or the like catalyst. Thionyl chloride or the
like may be directly used as the solvent. The thus obtained
reaction mixture can be purified by its azeotropic treatment
with Tol or the like, and further purification may be carried
out or not carried out. In addition, the intermediate (V) and
the like may be isolate or not isolated.
Next, an inter mediate (Villa) and the like are obtained
by allowing the imidazole compound (VI) and acyl compound (VII)
to undergo acylation reaction in Diglyme or the like reaction
inert solvent in the presence or absence of TEA or the like base
at room temperature to under heating, and then the compound (I)
of the invention is obtained by adding a carboxylic acid (Vila)
in a reaction corresponding amount with said compound (Villa) or

a reaction corresponding amount of water and heating the
mixture. The acyl compound (VII) can be obtained by the same
method for the preparation of compound (IV). In addition, the
intermediates (Villa) and the like may be isolated or not
isolated.
Second production method
[0023]

[0024]
This production method is a method particularly suitable
for obtaining the compounds (Ia) and (Ia-i) of the invention.
By this production method, optically active compounds of the
invention can be selectively produced by the use of optically
active compounds (VIId) and (VIIe) as the material compounds.

Step 1: This step is a conventionally known method regarding
protection of a 1,2- or 1,3-dihydroxy compound. The protecting
groups described in "Protective Groups in Organic Synthesis (3rd
Edition)" edited by Greene and Wuts (JOHN WILEY & SONS, 1991)
and the like may be optionally selected and used in response to
the reaction conditions.
In this connection, when optically active 1,2-dihydroxy
compounds (VIId) and (VIIe) are used as the starting materials
instead of the compound (VIIb), said compounds (VIId) and (VIIe)
can be produced by the method shown in the following [ ] .
(1): This step is a method conventionally known as a Stille
coupling reaction (e.g., J.K. Stille et al., J. Org. Chem.., 52,
422 - 424, 1987). More illustratively, this is carried out by
allowing a haloaryl compound or an aryl triflate compound,
preferably a bromoaryl compound (XI) or an iodoaryl compound, to
react with a reaction corresponding amount of tributyl(vinyl)tin
or the like organic tin reagent, in Tol or the like reaction
inert solvent at room temperature to under heating in the
presence of tris(dibenzylideneacetone)dipalladium or the like
palladium catalyst and tri-tert-butylphosphine or the like
phosphine compound, also preferably in an atmosphere of argon.
(2) This step is a conventionally known method for
asymmetrically dihydroxylating the olefin compound (XII). For
example, this is carried out by the method described in a
reference "Sharpless, K.B. et al., Chem. Rev., 94, 1994, 2483 -
2547", illustratively by carrying out oxidation of the olefin
compound with AD-mix (Aldrich, USA) in a tert-butanol-water

mixed solvent or the like reaction inert solvent. The reaction
is carried out at a temperature of from ice-cooling to heating,
preferably from 0°C to room temperature. The optically active
1,2-dihydroxy compounds (Vlld) and (Vile) having desired
absolute configuration can be respectively prepared by properly
using AD-mix-alpha and AD-mix-beta. See a scheme of a chemical
reaction below.
[0025]

[0026]
Step 2: This step is a conventionally known hydrolysis reaction,
which is effected by carrying out the reaction in THF, methanol
or the like reaction inert solvent in the presence of sodium
hydroxide or the like inorganic base, preferably at room
temperature.
Step 3: This step is carried out by a conventionally known
method (K.G. Akamanchi et al., Synlett, 1999, 11, 1763 - 1785).
Illustratively, an acid chloride forming reagent is prepared
from thionyl chloride and lH-benzotriazole in dichloromethane or
the like reaction inert solvent, and the acyl compound (X) is
obtained by allowing said reagent to react with a corresponding

carboxylic acid compound (IX) dissolved in dichloromethane or
the like reaction inert solvent under ice-cooling, at room
temperature or under heating. The thus obtained compound (X)
can be purified by its azeotropic treatment with Tol or the
like, and further purification may be carried out or not carried
out.
Step 4: This step is carried out in accordance with the first
production method.
Step 5: This step is a method for obtaining the dihydroxy
compound (Ia-i) by carrying out a conventionally known
deprotection reaction on an acetonide-protected compound (Ib-i)
of 1,2- or 1,3-dihydroxy compound. This method can be carried
out under the reaction conditions and the like described in
"Protective Groups in Organic Synthesis (3rd Edition)" edited by
Greene and Wuts (JOHN WILEY & SONS, 1991).
In addition, when vinyl group of the olefin compound (XII)
is positioned at the ortho position of fluorine atom like the
case of 3-vinyl-2-fluorobenzoic acid ethyl ester, or positioned
at the ortho position of a substituent group having chelation
ability, the vinyl group of said compound can also be introduced
via an aryl metal compound. In an example, it can also be
synthesized by preparing an aryl metal compound through the
treatment of 2-fluorobenzoic acid ethyl ester with LiTMP, LDA or
the like organic metal base in THF or the like reaction inert
solvent under a low temperature, preferably at -78°C,
subsequently obtaining 3-formyl-2-fluorobenzoic acid ethyl ester
by allowing said compound to react with a compound to be used as

a DMF or the like formyl group source under a low temperature,
preferably at -78°C, and then converting the formyl group into
vinyl group by the conventionally known Wittig reaction. More
illustratively, the Wittig reaction is carried out by allowing
an aldehyde compound and its reaction corresponding amount of a
phosphonium salt reagent to undergo the reaction in THF or the
like reaction inert solvent in the presence of sodium hydride,
alkyl lithium, potassium t-butoxide or the like base, preferably
at a temperature of from ice-cooling to room temperature and
also preferably in an atmosphere of argon.
Third production method
[0027]


[0028]
(In the reaction scheme, Ra and Rb may be the same or different
from each other and each represents H or lower alkyl, CH2NMe2,
CH2OMe, CN, Ph, C02Et, CF3 or cycloalkyl, or Ra and Rb may
together form cycloalkyl, and Re represents H or lower alkyl.
The same shall apply hereinafter.)
An imidazole compound (XIV) obtained from the compound
(VI) prepared in the first production method and an acyl
compound (XIII), in accordance with the first production method,
can be converted into a compound (Ia-ii) by a conventionally
known method for dihydroxylating an olefin compound (edited by
J. March, "ADVANCED ORGANIC CHEMISTRY" (JOHN WILEY & SONS,
1992). More preferably, this reaction is carried out by
oxidizing the an olefin compound with osmium tetroxide in THF-
water or the like reaction inert solvent in the presence of N-
methylmorpholine-N-oxide or the like co-oxidizing agent. The
reaction is carried out at a temperature of from ice-cooling to
heating, preferably at room temperature.
The compound (Ia-ii) as a 1,2-dihydroxy compound can be
converted into a ketal compound (Ib-ii) or an ortho ester
compound by a conventionally known method using a ketone
equivalent compound or an ortho ester compound. These can be
regarded as protecting reaction of the 1,2-dihydroxy compound,
and van be carried out using the reaction conditions and the
like described in the aforementioned "Protective Groups in
Organic Synthesis (3rd Edition)".

Fourth production method
[0029]

[0030]
(Symbols in the reaction scheme are as follows.
L1: halogen or the like leaving group,
Nu: nucleophilic reagent

Y: ketone or -C (R3) (OR1) - ,
Rd: substituent group on the lower alkylene corresponding to X
in the general formula (I), and
R201: -S(O)m-lower alkyl, -N3, N(R6)R7, -OCO-lower alkyl or
halogen. The same shall apply hereinafter.)
This production method is a method for producing a
compound having the aforementioned group represented by R201 as
the R2 among the compounds (I) of the invention.
This production method is carried out by allowing a
compound (XV) having a leaving group L1, converted from the
compound (VI) in accordance with the first production method,
and its reaction corresponding amount of a nucleophilic reagent
to undergo an SN2 type substitution reaction in THF, acetone,
DMF, acetonitrile, dichloromethane, methanol, DMSO or the like
reaction inert solvent, in the presence of potassium carbonate
or the like inorganic base or TEA or the like organic base as
occasion demands, and under cooling, from room temperature to
heating or under reflux. As the nucleophilic reagent, potassium
acetate, sodium azide, sodium thiomethoxide and the like anionic
compounds, or amine compounds and the like basic compounds,
chloride ions and the like can be exemplified.
When Y in the compound (XV) is ketone, a ketone compound
(XVII) converted from the compound (VI) in accordance with the
first production method is allowed to react with bromine or
hydrogen bromide in acetic acid or the like reaction inert
solvent to convert it into an α-bromoketone compound (XVIII),
and the aforementioned SN2 type substitution reaction can be

carried out on this compound (XVIII). The thus obtained
substituted compound can be converted into (I-i) by reducing the
ketone by the reduction reaction shown below.
When the nucleophilic reagent is an S-lower alkyl group,
thioalkyl group of the obtained compound can be oxidized into a
sulfoxide compound or sulfone compound using an oxidizing agent
in accordance with the 10th production method of Patent
Reference 1. As the oxidizing agent, m-chloroperbenzoic acid or
hydrogen peroxide is more preferably used.
Fifth production method
[0031]

[0032]
(In the reaction scheme, X2 represents halogen, and the ring D
means pyridine or imidazole which may be substituted.)
This production method is a method in which a hydroxy
compound (I-ii) is obtained by allowing a reaction corresponding

amount of an aldehyde compound (XIX) to react with an organic
lithium compound (XXI) prepared from a nitrogen-containing
haloaryl compound (XX) using n-butyl lithium or the like organic
base, in THF or the like reaction inert solvent at a temperature
of from -78°C to room temperature.
Sixth Production method
This production method is carried out by subjecting a
dithioacetal compound (XXII) and a diamine compound (XXIII) to a
condensation reaction in EtOH or the like reaction inert solvent
at room temperature to under heating, preferably heating under
reflux.
[0033]

[0034]
(In the reaction scheme, R111 and R112 represent lower
alkyl, or R111 and R112 may together form a ring, and the
substituent group on the ring B may be protected with an
appropriate protecting group.)

In addition, the compounds of the invention and
pharmaceutically acceptable salts thereof can be produced by
employing the following conventionally known substituent group
conversion methods making use of the characteristics based on
the kinds of the substituent group.
1. Reduction reaction
Reduction of ketone into hydroxyl group, reduction of
azido group into amino group, reduction of unsaturated alkyl
group into saturated alkyl group and the like reactions can be
carried out in accordance with the 4th production method of
Patent Reference 1. Examples of more desirable methods include
a method in which sodium borohydride, lithium borohydride,
diisobutylaluminum hydride, lithium aluminium hydride or the
like reducing agent is used, and a method in which catalytic
reduction is carried out using palladium (Pd), platinum (Pt),
nickel (Ni) or the like in an atmosphere of hydrogen or ammonium
formate or the like hydrogen donor.
2. Acylation reaction of hydroxyl group or amino group
Acylation reaction of hydroxyl group or amino group is
carried out by allowing a hydroxy compound or an amine compound
to react with a reaction corresponding amount of an acid
chloride compound or an acid anhydride in dichloromethane, DCE,
pyridine, THF, Tol or the like reaction inert solvent in the
presence or absence of dimethylaminopyridine or the like at room
temperature or under heating. Alternatively, it can also be

carried out by allowing a hydroxy compound and its reaction
corresponding amount of a carboxylic acid compound to undergo
the reaction in DMF or the like reaction inert solvent in the
presence or absence of WSCHC1, HOBt, CDI or the like condensing
agent, dimethylaminopyridine or the like reaction accelerator
and TEA or the like organic base, at room temperature or under
heating. When two or more hydroxyl groups are present, the
reaction can also be carried out selectively at a desired
position by optionally using a protecting group. Dihydroxy
compound can also be converted into a cyclic carbonic acid
compound (cyclic carbonate compound) by the use of CDI or the
like. In the case of a compound having two or more hydroxyl
groups and amino groups, all of them may be acylated or a part
thereof may be acylated.
3. Hydrolysis reaction
The reaction for hydrolyzing an ester compound into a
hydroxy compound and a carboxylic acid compound can be carried
out in accordance with the 8th production method of Patent
Reference 1. As a more preferred method, this is carried out in
THF using sodium hydroxide, potassium hydroxide or the like
base.
4. Conversion of a 1,2-dihydroxy compound into an aldehyde
compound
The reaction for converting a 1,2-dihydroxy compound into
an aldehyde compound is carried out by effecting oxidative

cleavage of 1,2-dihydroxyethy1 group in THF, water, methanol or
the like reaction inert solvent using periodic acid or a salt
thereof, lead tetracetate or the like oxidizing agent. The thus
obtained aldehyde compound can be converted into an amine
compound in dichloromethane or the like reaction inert solvent
in accordance with the 5th production method of Patent Reference
1.
[0035]
The compounds of the invention are isolated and purified
as free compounds, pharmaceutically acceptable salts thereof,
hydrates, solvates or polymorphic substances. The
pharmaceutically acceptable salt of the compound (I) of the
invention can also be produced by subjecting it to a usually
used salt formation reaction.
Isolation and purification are carried out by employing
usual chemical operations such as extraction, fractional
crystallization, various types of fractionation chromatography
and the like.
Various isomers can be separated by selecting appropriate
material compounds or making use of differences in
physicochemical properties among isomers. For example, an
optical isomer can be converted into a stereochemically pure
isomer by selecting an appropriate material or by a method for
separating racemic compounds (e.g., a method in which they are
converted into diastereomer salts with a general optically
active base or acid and then subjected to optical resolution, or

a method in which they are fractionated using a chiral column or
the like).
In addition to the compounds of the Examples which are
described later, compounds of the following tables can be
obtained in the same manner as in the production methods of the
invention.
In this connection, abbreviations in the specification are
as follows.
FA: FAB-MS (M + H)+; FN: FAB-MS (M - H)~; FAB-MS is a measured
value by fast atom bombardment ionization mass spectrometry; ES
+ is ESI +; ES - is ESI -; EI: EI-MS; EI-MS is a measured value
by atom bombardment ionization mass spectrometry; Nl:
characteristic peak 8 ppm of NMR (DMSO-d6, TMS internal
standard); N2: characteristic peak 8 ppm of NMR (CDC13, TMS
internal standard); brs: broad singlet; mp: melting point;
(round bracket) shows a solvent for recrystalization> EA-H is
ethyl acetate^ EA-ET-H is ethyl acetate-ether-hexane,. and EtOH is
ethanol for recrystalization; [a]D: angle of rotation at 25°C (c:
concentration (g solute/100 cm3) MeOH: measuring solvent); CN or
NC: cyano; vin: vinyl; Ph: phenyl; Me: methyl; diMe: dimethyl;
Et: ethyl; iPr: isopropyl; cPr: cyclopropyl; cBu: cyclobutyl;
nBu: butyl; cHex: cyclohexyl; Ac: acetyl; diCl: dichloro; diF:
difluoro; triF: trifluoro; diOH: dihydroxy; Py: pyridyl; Py3:
pyridin-3-yl; Py4: pyridin-4-yl; Py5: pyridin-5-yl; dixr4:
dioxolan-4-yl; Thiop: thiophene; Thiop2: thiophen-2-yl; Thiop3:
thiophen-3-yl; pheny: phenylene; yl:yl; diyl:diyl; oxal:
oxalate; Rex: Reference Example; Rex No.: Reference Example No.;

Ex: Example; Ex No.: Example No.; DATA: physicochemical
properties
[0036]








The active ingredient of the invention and the compound of
the invention or a pharmaceutically acceptable salt thereof can
be used alone as a medicament, but it can be generally prepared
from one or two or more of active ingredients using
pharmaceutical carriers, fillers and the like materials
generally used in said field by a generally used method. Its
administration may be in the form of either oral administration
by tablets, pills, capsules, granules, powders, solutions and
the like, or parenteral administration by intraarticular,
intravenous, intramuscular and the like injections,
suppositories, eye drops, eye ointments, percutaneous solutions,
ointments, percutaneous adhesive preparations, transmucosal
solutions, transmucosal adhesive preparations, inhalations and
the like.
The solid composition for use in the oral administration
according to the present invention is used in the form of
tablets, powders, granules and the like. In such a solid
composition, one or more active ingredients are mixed with at
least one inert diluent such as lactose, mannitol, glucose,
hydroxypropylcellulose, microcrystalline cellulose, starch,
polyvinyl pyrrolidone and/or aluminum magnesium silicate. In
the usual way, the composition may contain other additives than
the inert diluent, such as magnesium stearate or the like
lubricant, calcium cellulose glycolate or the like
disintegrating agent, a stabilizing agent and a solubilization
assisting agent. As occasion demands, tablets or pills may be
coated with a sugar coating or a film of a gastric or enteric

substance such as sucrose, gelatin, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate or the like.
The liquid composition for oral administration includes
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, elixirs and the like and contains a generally used inert
diluent such as purified water or ethanol. In addition to the
inert diluent, said composition may also contain a solubilizing
agent, a moistening agent, a suspending agent and the like
auxiliary agents, as well as sweeteners, flavors, aromatics and
antiseptics.
The injections for parenteral administration includes
aseptic aqueous or non-aqueous solutions, suspensions and
emulsions. Examples of the diluent for use in the aqueous
solutions and suspensions include distilled water for injection
and physiological saline. Examples of the diluent for use in
the non-aqueous solutions and suspensions include propylene
glycol, polyethylene glycol, olive oil or the like plant oil,
ethanol or the like alcohol, polysorbate 80 (trade name) and the
like. Such a composition may further contain a tonicity agent,
an antiseptic, a moistening agent, an emulsifying agent, a
dispersing agent, a stabilizing agent or a solubilization
assisting agent. These are sterilized for example by filtration
through a bacteria retaining filter, blending of a germicide or
irradiation. Alternatively, they may be used by firstly making
into sterile solid compositions and dissolving them in sterile
water or a sterile solvent for injection use prior to their use.

Transmucosal preparations such as transnasal preparations
are used in the form of solid, liquid or semi-solid state and
can be produced in accordance with a conventionally known
method. For example, conventionally known pH adjusting agents,
antiseptics, thickeners, and fillers are optionally added and
formed into a solid, liquid or semi-solid state. The transnasal
preparations are administered using a usual sprayer, nasal drop
container, tube, nasal cavity insertion tool or the like.
In the case of oral administration, proper dose per day is
generally from about 0.001 to 100 mg/kg, preferably from 0.1 to
30 mg/kg, more preferably from 0.1 to 10 mg/kg, and this is
administered in one portion or dividing into two to four doses.
In the case of intravenous administration, suitable dose per day
is approximately from 0.0001 to 10 mg/kg body weight, and this
is administered once a day or dividing it into two or more
doses. In addition, transmucosal preparations are administered
at a dose of approximately from 0.001 to 100 mg/kg body weight,
once a day or by dividing it into two or more doses. The dose
is optionally decided in response to each case by taking
symptoms, age, sex and the like into consideration.
[0040]
[Examples]
The following describes the invention further in detail
based on Examples. The compounds of the invention are not
limited to the compounds described in the following examples.

Also, production methods of the material compounds are shown in
Reference Examples.
The compound of Reference Example 1-1 is a known compound.
Reference Example 1-2
A 4.0 g portion of 2-methyl-lH-benzimidazole and 13.9 ml
of TEA were dissolved in 40 ml of Diglyme, and 17.5 g of 2-
chlorobenzoic acid chloride was added dropwise thereto. The
reaction mixture was stirred at 100°C for 3 hours. After
cooling to room temperature, the reaction mixture was mixed with
water, extracted with chloroform, dried with anhydrous sodium
sulfate and then concentrated, thereby obtaining an orange oily
substance. This was dissolved in 60 ml of methanol, mixed with
7.9 ml of morpholine and then heated under reflux for 3.5 hours.
The reaction mixture was cooled to room temperature, mixed with
water and then stirred for 1 hour. The thus formed precipitate
was collected by filtration, washed with cool water and then
dried to obtain 6.1 g (75%) of 1-(2-chlorophenyl)-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)ethanone (Reference Example 1-
2) as pale yellow powdery crystals. ES+: 271
The compounds shown in Table 5 and Table 6 were produced
in the same manner.




[0043]
Reference Example 2-1
A 3.8 g portion of oxalic acid chloride was gradually
added dropwise to 3 0 ml of methylene chloride solution
containing 1.54 g of 3-vinylbenzoic acid and a catalytically
effective amount of DMF and stirred at room temperature for
about 2 hours, and then an appropriate amount of Tol was poured
into the mixture and evaporation was carried out under a reduced
pressure, thereby preparing 3-vinylbenzoic acid chloride. This
was dissolved in a small amount of Diglyme and gradually added
dropwise to 5 ml of Diglyme solution containing 0.82 g of 1-
(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)ethanone which had been separately prepare in advance
and 1.4 ml of TEA, under heating at 70°C. After completion of
the dropwise addition, this was risen to 100°C and heated for
about 25 minutes, mixed with 0.1 ml of purified water, and
further risen to 175°C and heated for about 25 minutes. This

was mixed with sodium bicarbonate aqueous solution, extracted
several times with ethyl acetate, dried with anhydrous magnesium
sulfate and concentrated, and then the thus formed residue was
purified by a silica gel column chromatography to obtain 0-83 g
(Reference Example 2-1) (68%) of 1-(3,5-difluorophenyl)-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-(3-vinylphenyl)propane-1,3-
dione as a yellow foam compound from an ethyl acetate-hexane
(1:3) eluate. FA: 403
The compounds shown in Tables 7 to 9 were produced in the
same manner.






[0047]
Reference Example 3
A 4.96 g portion of ethyl orthoacetate dissolved in 10 ml
of ethanol was added to 50 ml of ethanol solution containing
4.68 g of 4-chloro-5-fluorobenzene-1,2-diamine and heated under

reflux for 4 hours. After concentration of the reaction liquid,
the thus formed residue was purified by a silica gel column
chromatography to obtain 2.10 g (39%) of 5-chloro-6-fluoro-2-
methyl-lH-benzimidazole from a chloroform-methanol (10:1)
eluate. ES+: 185
Reference Example 4-1
At -78°C, 17.62 ml of 1.59 M n-butyl lithium-THF solution
was added dropwise to 100 ml of THF solution containing 4.73 ml
of tetramethylpiperidine. This was stirred at -10°C for 10
minutes, cooled to -78°C, mixed with 5.00 g of tert-butyl 2,4-
difluorobenzoate dissolved in 20 ml of THF and then stirred for
1 hour. Subsequently, 7.23 ml of DMF was added dropwise
thereto, and the mixture was stirred for 1 hour, mixed with 5.34
ml of acetic acid and then risen to room temperature. This was
mixed with an appropriate amount of purified water, extracted
with ethyl acetate and dried with anhydrous magnesium sulfate.
After concentration, the thus formed residue was purified by a
silica gel column chromatography to obtain 5.65 g (100%) of
tert-butyl 2,4-difluoro-3-formylbenzoate (Reference Example 4-1)
from a hexane-ethyl acetate (20:1 - 10:1) eluate.
N2: 1.60 (9 H, s), 7.04 (1 H, m), 8.14 (1 H, m), 10.38 (1 H, s)
The compounds shown by Reference Examples 4-2 and 4-3 were
obtained in the same manner.
Reference Example 4-2 Tert-butyl 2-fluoro-3-formylbenzoate
FA: 225

N2: 1.62 (9 H, s) , 7.32 (1 H, t, J = 8 Hz), 8.08 (2 H, m) , 10.42
(1 H, s)
Reference Example 4-3 3-(2 , 2-Dimethyl-l,3-dioxolan-4-yl)-2-
fluorobenzaldehyde
FA: 225
[0048]
Reference Example 5-1
At -78°C, 9.50 ml of 1.59 M n-butyl lithium-THF solution
was added dropwise to 90 ml of THF solution containing 8.13 g of
methyltriphenylphosphonium iodide. This was stirred at 0°C for
10 minutes, cooled to -78°C and then mixed with 2.44 g of tert-
butyl 2,4-difluoro-3-formylbenzoate dissolved in 10 ml of THF.
After 4 0 minutes thereof, this was stirred at room temperature
for 1 hour, mixed with appropriate amounts of saturated ammonium
chloride aqueous solution and purified water, extracted with
ethyl acetate and then dried with anhydrous magnesium sulfate.
After concentration, the thus formed residue was purified by a
silica gel column chromatography to obtain 1.20 g (50%) of tert-
butyl 2,4-difluoro-3-vinylbenzoate (Reference Example 5-1) from
a hexane-ethyl acetate (50:1) eluate. ES-: 239
The compounds of the following Reference Examples 5-2 to
5-5 and those shown in Table 10 were obtained in the same
manner.
Reference Example 5-2 Tert-butyl 2-fluoro-3-prop-l-en-l-
ylbenzoate EI: 236,

Reference Example 5-3 Methyl 3-(cyclopropylidenemethyl)benzoate
FA: 189,
Reference Example 5-4 Methyl 2-methoxy-3-vinylbenzoate FA:
193,
Reference Example 5-5 l-Bromo-2-fluoro-3-vinylbenzene FA: 202
[0049]

[0050]
Reference Example 6-1
A 4.27 ml portion of trifluoroacetic acid was added to 30
ml of dichloromethane solution containing 1.33 g of tert-butyl
2,4-difluoro-3-vinylbenzoate and stirred for 5 hours. After

evaporation of the solvent, appropriate amounts of purified
water and saturated sodium bicarbonate aqueous solution were
added thereto and the water layer was washed with diethyl ether.
The water layer was adjusted to pH 1 with 1 M hydrochloric acid
aqueous solution, extracted with diethyl ether and then dried
with anhydrous magnesium sulfate. After concentration, 964 mg
(95%) of 2,4-difluoro-3-vinylbenzoic acid (Reference Example 6-
1) was obtained.
N2: 7.93 (m, 1 H), 6.98 (m, 1 H), 6.74 (dd, 1 H, J - 12 Hz, 18
Hz), 6.11 (dd, 1 H, J = 1 Hz, 18 Hz), 5.68 (dd, 1 H, J = 1 Hz,
12 Hz)
2-Fluoro-3-prop-l-en-l-ylbenzoic acid (Reference Example
6-2) was obtained in the same manner. FN: 179
Reference Example 7-1
At -78°C, 1.0 M sodium hexamethylenedisilazane-THF
solution was added dropwise to 10 ml of THF solution containing
300 mg of 3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-
fluorophenyl)-3-oxopropanoyl]benzaldehyde and 69 ul of acetone
and stirred for 15 minutes. This was mixed with appropriate
amounts of saturated ammonium chloride aqueous solution and
purified water, extracted with ethyl acetate and dried with
anhydrous magnesium sulfate. After concentration, the thus
formed residue was purified by a silica gel column
chromatography to obtain 184 mg (53%) of 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(1-hydroxy-3-

oxobutyl)phenyl]propane-1,3-dione (Reference Example 7-1) from a
hexane-ethyl acetate (2:1 - 1:2) eluate. ES+: 445
In the same manner, 1-{3-[2-(1,3-dihydro-2H-benzimidazol-
2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzoyl}-2-
hydroxypropyl acetate (Reference Example 7-2) was obtained.
ES+: 459
[0051]
Reference Example 8
A 0.57 ml portion of bromine was gradually added dropwise
to 80 ml of acetic acid solution containing 4.18 g of l-(3-
acetylphenyl)-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)propane-l,3-dione, and then 5 ml of 25%
hydrogen bromide-acetic acid solution was added thereto and
stirred as such at room temperature for about 1 hour. The
solvent was evaporated under a reduced pressure, the thus formed
residue was mixed with an appropriate amount of sodium
bicarbonate aqueous solution and extracted several times with
ethyl acetate, and the thus obtained organic layer was dried
with anhydrous magnesium sulfate and concentrated to obtain an
a-bromoketone intermediate. This intermediate was dissolved in
50 ml of DMSO without purification, mixed with 2.16 g of
potassium acetate and stirred at room temperature for about 4
hours. The reaction liquid was mixed with an appropriate amount
of saturated ammonium chloride aqueous solution, extracted
several times with ethyl acetate, dried with anhydrous magnesium
sulfate and concentrated, and then the thus formed residue was

purified by a silica gel column chromatography to obtain 2.62 g
(55%) of 2-{3-[3-(3,5-difluorophenyl)-2-(l,3-dihydro-2H-
benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}-2-oxoethyl
acetate as a greenish yellow foam from an ethyl acetate-hexane
(1:2) eluate. FA: 477
Reference Example 9
A 25 ml portion of THF solution containing 7.8 g of
tetrabutylammonium fluoride and 24 g of Molecular Sieve 4A was
stirred at room temperature for 12 hours in an atmosphere of
argon. After cooling to 0°C, 2 0 ml of THF solution containing
300 mg of 3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-
fluorophenyl)-3-oxopropanoyl]benzaldehyde and 1.7 g of
diphenyl(2,2,2-trifluoroethyl)phosphine oxide was added dropwise
thereto. This was stirred at room temperature for 5 hours. The
reaction mixture was filtered, the filtrate was washed with
water, dried with anhydrous sodium sulfate and concentrated, and
then the thus formed residue was purified by a silica gel column
chromatography to obtain 201 mg (57%) of 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-{3-[(lZ)-3,3,3-
trifluoroprop-l-en-l-yl]phenyl}propane-l,3-dione as a yellow
powder from an ethyl acetate-hexane (1:3) eluate. FA: 463
[0052]
Reference Example 10-1
A 13.55 g portion of manganese dioxide was added to 20 ml
of dichloromethane solution containing 2.11 g of l-(3,5-

difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-[3-
(hydroxymethyl)phenyl]propane-1,3-dione and stirred for 4.5
hours. After celite filtration and concentration, the thus
formed residue was crystallized from hexane-ethyl acetate to
obtain 1.09 g (52%) of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-
2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzaldehyde
(Reference Example 10-1). FA: 405
In the same manner, 1-[3-(2,2-dimethyl-l,3-dioxolan-4-yl)-
2-(fluorophenyl)-3-pyridin-3-ylpropane-l,3-dione (Reference
Example 10-2) was obtained. FA: 344
Reference Example 11-1
A 5.46 g portion of ethyl 3-(2,2-dimethyl-l,3-dioxolan-4-
yl)-2-fluorobenzoate was dissolved in 100 ml of THF and cooled
to 0°C, and then 40.8 ml of 1 N sodium hydroxide aqueous
solution was slowly added thereto. This was risen to room
temperature and further stirred for 17 hours. After evaporation
of THF, the residue was cooled to 0°C and acetic acid was slowly
added thereto until the pH value became 3 to 4. This was
extracted with diethyl ether, dried with sodium sulfate and
concentrated, and then subjected to azeotropic treatment three
times with Tol, thereby obtaining 4.66 g (95%) of 3-(2,2-
dimethyl-1,3-dioxolan-4-yl)-2-fluorobenzoic acid (Reference
Example 11-1). FN: 239
In the same manner, the compounds of Reference Example 11-
2 to Reference Example 11-13 shown in Table 11 were produced.
In this connection, the compounds of Reference Examples 11-6 to

11-12 were produced using corresponding optically active
materials.
Reference Example 12-1
After adding 35 mg of potassium acetate to 2 ml of DMSO
solution containing 100 mg of 1-[3-(chloromethyl)phenyl]-3-(3,5-
difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)propane-1,3-dione, the mixture was stirred at room
temperature for about 2 days. The reaction liquid was mixed
with an appropriate amount of saturated ammonium chloride
aqueous solution, extracted several times with ethyl acetate,
dried with anhydrous magnesium sulfate and concentrated, and
then the thus formed residue was purified by a silica gel column
chromatography to obtain 90 mg of a yellow oily substance from
an ethyl acetate-hexane (1:2) eluate. By crystallizing this
from a small amount of ethyl acetate-hexane (1:3) at 0°C, 68 mg
(64%) of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-oxopropanoyl]benzyl acetate (Reference
Example 12-1) was obtained as yellow crystals. FA: 449
In the same manner, 3-[2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzyl acetate
(Reference Example 12-2) was obtained. FA: 431
[0053]
Reference Example 13
A 25 ml portion of THF solution containing 1.2 g of ethyl
3- {3- [3- (3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-

ylidene)-3-oxopropanoyl]phenyl}acrylate was cooled to -78°C in a
stream of argon gas, 5.5 ml of 1.0 M diisobutylaluminum hydride-
Tol solution was gradually added dropwise thereto, and then the
mixture was stirred at 0°C for about 2 hours. This was again
cooled to -78°C the same amount of the reducing agent was added
dropwise thereto, and then the mixture was gradually risen to
room temperature and stirred for about 40 minutes. The reaction
liquid was cooled to -30°C or lower, small amount of methanol
and purified water were added thereto, and the thus formed
insoluble matter was removed by filtration through washing with
an appropriate amount of ethyl acetate. The organic layer
obtained by layer separation operation of the filtrate was
washed with water, dried with anhydrous magnesium sulfate and
concentrated, and then the thus obtained residue was purified by
a silica gel column chromatography to obtain 0.58 g (53%) of 1-
(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-
3-[3-(3-hydroxyprop-l-en-l-yl)phenyl]propane-l,3-dione as a
yellow foam from a ethyl acetate-hexane (1:1) eluate. FA: 433
Reference Example 14
A 104 mg portion of palladium acetate and 5 ml of TEA were
added one by one to 50 ml of acetonitrile solution containing
7.44 g of 3-iodobenzoic acid and 3.9 ml of ethyl acrylate, and
the mixture was sealed in a tube and heated at 100°C for about
12 hours. After spontaneous cooling, the catalyst was removed
by filtration while washing with appropriate amounts of methanol
and ethyl acetate, and the filtrate was evaporated under a

reduced pressure. The thus formed crude crystals were
recrystallized from a small amount of ethanol to obtain 5.82 g
(88%) of 3-(3-ethoxy-3-oxoprop-1-en-1-yl) benzoic acid as white
crystals. FA: 221
Reference Example 15-1
A 1 g portion of 4-(3-bromophenyl)-2,2-dimethyl-1,3-
dioxane was dissolved in 18 ml of THF solution and cooled to -
78°C, and then 2.35 ml of hexane solution containing 1.57 M n-
butyl lithium was added dropwise thereto spending 1 hour. After
completion of the dropwise addition, this was further stirred
for 3 0 minutes. After adding excess amount of carbon dioxide
thereto at -78°C, the mixture was risen to room temperature.
The reaction solution was mixed with ammonium chloride aqueous
solution and extracted 10 times with chloroform-methanol (5:1),
the organic layer was dried with sodium sulfate and
concentrated, and then the thus formed residue was purified by a
silica gel column chromatography (hexane:ethyl acetate =1:1) to
obtain 550 mg (63%) of 3 -(2,2-dimethyl-l,3-dioxan-4-yl)benzoic
acid (Reference Example 15-1). FA: 237
In the same manner, 2-butyl-3-(2,2-dimethyl-1,3-dioxan-4-
yl)benzoic acid (5%) (Reference Example 15-2) was obtained from
4-(3-bromo-2-fluorophenyl)-2,2-dimethyl-l,3-dioxane. FN: 277

[0054]
Reference Example 16-1
A 5.71 g portion of ethyl 3-[(1R) -1,2-dihydroxyethyl]-2-
fluorobenzoate was dissolved in 30 ml of 2,2-dimethoxypropane,
mixed with 4 76 mg of p-toluenesulfonic acid monohydrate and
stirred at room temperature for 3 0 minutes. This was mixed with
saturated sodium bicarbonate aqueous solution and extracted with
ethyl acetate, the organic layer was washed with saturated
brine, dried with sodium sulfate and concentrated, and then the
thus formed residue was purified by a silica gel column
chromatography (hexane:ethyl acetate = 10:1) to obtain 5.46 g
(81%) of ethyl 3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-
fluorobenzoate (Reference Example 16-1) . FA: 269
In the same manner, the compounds of the following
Reference Example 16-9 and the Reference Example 16-2 to the
Reference Example 16-8 shown in Table 11, were produced using
corresponding optically active materials.
Reference Example 16-9 (4R) -4-(3-Bromo-2-fluorophenyl)-2,2-
dimethyl-1,3-dioxolane FA: 276
Reference Example 17-1
A 12.76 g portion of ethyl 3-bromo-2-fluorobenzoate was
dissolved in 50 ml of Tol solution, 15.8 ml of
tributyl(vinyl)tin, 236 mg of
tris(dibenzylideneacetone)dipalladium and 1.25 ml of tri-tert-
butylphosphine 10 wt % hexane solution were added thereto in
order, and stirred at room temperature for 13 hours in an

atmosphere of argon. This was diluted with 300 ml of diethyl
ether, mixed with 25 g of potassium fluoride, and 5 ml of
purified water and stirred for 30 minutes, the insoluble matter
was filtered using a Kiriyama funnel, and then the mother liquid
was concentrated. The residue was purified by a silica gel
column chromatography (hexane:ethyl acetate = 40:1) to obtain
10.3 g (97%) of ethyl 2-fluoro-3-vinylbenzoate (Reference
Example 17-1).
In the same manner, the compounds of Reference Example 17-
2 to the Reference Example 17-5 shown in Table 11 were produced.
Reference Example 18-1
A 74.3 g portion of AD-mix β was added to a mixed solvent
of 265 ml tert-butanol and 265 ml purified water and dissolved
therein at room temperature spending 30 minutes. After cooling
to 0°C, this was mixed with 10.3 g of ethyl 2-fluoro-3-
vinylbenzoate and stirred for 3.5 hours. This was mixed with
79.6 g of sodium sulfite, stirred at room temperature for 30
minutes and then extracted with ethyl acetate. The organic
layer was washed with saturated brine, dried with sodium sulfate
and concentrated, and then the thus formed residue was purified
by a silica gel column chromatography (hexane:ethyl acetate *
1:2) to obtain 5.71 g (47%) of ethyl 3-[(lR)-l,2-
dihydroxyethyl]-2-fluorobenzoate (Reference Example 18-1) . FA:
229
In the same manner, the following optically active
compounds of Reference Example 18-8 and the Reference Example

18-2 to the Reference Example 18-7 shown in Table 11, were
produced.
Furthermore, (1S)-1-phenylethane-1,2-diol derivatives were
produced with AD-mix alpha in the same manner.
Reference Example 18-8 (1R) -1-(3-Bromo-2-fluorophenyl)ethane-
1,2-diol
FA: 236
[0055]
Reference Example 19
To a DMF solution (30 ml) containing 2.70 g of 3-bromo-2-
chlorobenzoic acid were added 1.10 ml of methyl iodide and 2.3 8
g of potassium carbonate in order at room temperature, followed
by 1 hour of stirring. The reaction liquid was mixed with water
and then diluted with ethyl acetate. After a layer separation
operation, the organic layer was washed with water and saturated
brine in that order, dried with anhydrous magnesium sulfate and
then concentrated under a reduced pressure. The thus obtained
residue was purified by a silica gel column chromatography using
ethyl acetate-n-hexane (100:3) as the elution solvent to obtain
2.26 g (79%) of methyl 3-bromo-2-chlorobenzoate. FA: 250
Reference Example 20
In a stream of argon, anhydrous THF solution containing
0.72 ml of N,N-diisopropylamine was cooled to about -70°C, 3.3
ml of 1.54 M n-butyl lithium-hexane solution was added dropwise
thereto, and then the reaction liquid was risen to about -15°C.

The reaction liquid was again cooled to about -70°C, mixed with
0.54 ml of 3-acetylpyridine and then stirred at the same
temperature for about 3 0 minutes, and subsequently, 5 ml of
anhydrous THF solution containing 1.1 g of 3-((4R)-2,2-dimethyl-
1,3-dioxolan-4-yl)-2-fluorobenzaldehyde was gradually added
dropwise thereto. After stirring at -70°C for about 20 minutes
and then at about -30°C for about 3 hours, this was mixed with
an appropriate amount of 0.2 M hydrochloric acid aqueous
solution and subjected to several times of extraction operation
with ethyl acetate. The organic layer was washed with saturated
brine and dried with anhydrous magnesium sulfate, and then the
solvent was evaporated and the thus formed residue was isolated
and purified by a silica gel column chromatography to obtain
0.77 g (45%) of 3-[3-((4R)-2,2-dimethyl-l,3-dioxolan-4-yl)-2-
fluorophenyl]-3-hydroxy-l-pyridin-3-yl-propan-1-one as a
colorless oil from an ethyl acetate-hexane (7:3) eluate. FA:
346
Reference Example 21
A 4 ml portion of DMF solution containing 0.38 g of l-[3-
((4R)-2,2-dimethyl-l,3-dioxolan-4-yl)-2-fluorophenyl]-3-pyridin-
3-yl-propan-l,3-dione and 1.3 g of potassium fluoride was mixed
with 0.1 g of carbon disulfide, stirred at room temperature for
about 2.5 hours under a closed condition, mixed with 0.16 ml of
methyl iodide and then further stirred for about 1 hour under
the same condition. The reaction liquid was mixed with an
appropriate amount of purified water and extracted several times

with ethyl acetate, and the thus obtained organic layer was
washed with saturated brine and dried with anhydrous magnesium
sulfate in that order. The solvent was evaporated and the thus
formed residue was isolated and purified by a silica gel column
chromatography to obtain 0.14 g (4 9%) of 2-
[bis(methylsulfanyl)methylene]-1-[3-((4R)-2,2-dimethyl-1,3 -
dioxolan-4-yl)-2-fluorophenyl]-3-pyridin-3-yl-propan-1,3-dione
as a yellow oil from an ethyl acetate-hexane (1:1) eluate. ES+:
448
[0056]



[0057]
Example 1-1
(1) An acid chloride forming reagent was prepared by
adding 5 ml of dichloromethane to a stirring solution of 0.80 ml
thionyl chloride and 1.31 g 1H-benzotriazole. Subsequently, the
reagent prepared in the above was added to 90 ml of
dichloromethane solution containing 1.96 g of (4R)-3-(2,2-
dimethyl-1,3-dioxolan-4-yl)benzoic acid and stirred at room
temperature for 10 minutes. After filtration of the formed
chloride, anhydrous magnesium sulfate was added to the filtrate.
After filtration and concentration, an acid chloride compound
was obtained.
(2) At 70°C, the acid chloride compound obtained in (1)
was dissolved in 10 ml of Diglyme and added dropwise to 10 ml of
Diglyme solution containing 933 mg of 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-1-(3-fluorophenyl)ethanone and 1.28 ml
of TEA. Next, this was risen to 100°C, mixed with 66 ul of
purified water and then heated under reflux for 4 0 minutes.
After cooling to room temperature, this was mixed with an
appropriate amount of purified water, extracted with ethyl
acetate and dried with anhydrous magnesium sulfate. After
concentration of the organic layer, the thus formed residue was
purified by a silica gel column chromatography to obtain 1.68 g
(100%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-[(4R)-
2,2-dimethyl-1,3-dioxolan-4-yl]phenyl}-3-(3-

fluorophenyl)propane-1,3-dione (Example 1-1) from a hexane-ethyl
acetate (6:1) eluate.
In the same manner, the compounds shown in Table 12 and
Table 13 were produced using corresponding optically active
materials.
[0058]




[0060]
Example 2-1
A THF (12 ml)-purified water (3 ml) solution containing 72
mg of N-methylmorpholine-N-oxide was mixed with 0.5 ml of 0.08 M
osmium tetroxide-t-butanol solution and 0.82 g of 1-(3,5-
difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-
vinylpheny1)propane-1,3-dione in that order, and then stirred at
room temperature for about 2 hours. The reaction liquid was
concentrated to about 1/4 volume, mixed with an appropriate
amount of sodium sulfite aqueous solution and extracted several
times with ethyl acetate. The thus obtained organic layer was
washed with water, dried with anhydrous magnesium sulfate and
concentrated, and then the resulting residue was purified by a
silica gel column chromatography to obtain 0.83 g (69%) of 1-
(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-
3-[3-(1,2-dihydroxyethyl)phenyl]propane-1,3-dione (Example 2-1)
as pale yellow crystals from a chloroform-methanol (80:1)
eluate.
In the same manner, the compounds shown in Table 14 to
Table 17 were produced.









[0065]
Example 3-1
A 6 ml portion of THF solution containing 0.21 g of 2-
(l,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-
dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione and
0.3 g of methyl orthoacetate was mixed with 63 mg of pyridinium
p-toluenesulfonate and then stirred at room temperature for
about 3 0 minutes. After evaporation of the solvent, the residue
was mixed with an appropriate amount of sodium bicarbonate
aqueous solution, extracted several times with ethyl acetate,
dried with anhydrous magnesium sulfate and concentrated. The
thus formed residue was purified by a silica gel column
chromatography to obtain 162 mg (68%) of 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(2-methoxy-2-
methyl-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione (Example 3-1)
as a pale yellow foam from an ethyl acetate-hexane (1:2) eluate.
In the same manner, the compounds shown in Table 18 were
produced.


[0067]
Example 4-1
A 20 ml portion of methanol solution containing 1.68 g of
2-(l,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(4R)-2,2-
dimethyl-1,3-dioxolan-4-yl]phenyl}-3-(3-fluorophenyl)propane-
1,3-dione was mixed with 560 mg of p-toluenesulfonic acid
monohydrate and stirred at room temperature for 18 hours. This
was mixed with appropriate amounts of purified water and
saturated sodium bicarbonate aqueous solution, extracted with
ethyl acetate and dried with anhydrous magnesium sulfate. After
concentration, the thus formed residue was purified by a silica
gel column chromatography to obtain 640 mg (42%) of 2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-1,2-

dihydroxye thy1]phenyl}-3 -(3 -fluoropheny1)propane-1,3-dione
(Example 4-1) from a hexane-ethyl acetate (3:1 - 1:3) eluate.
In this connection, the compound of Example 4-11 was
produced by the following method.
A 140 mg portion of 3 -(2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
fluorophenyl}-3-oxopropanoyl)benzonitrile was dissolved in 5 ml
of acetic acid-water (4:1) and stirred at 50°C for 3 hours. The
solvent was evaporated to carry out an azeotropic treatment
using Tol. The thus formed residue was purified by a silica gel
column chromatography, and the foamy substance obtained from a
chloroform-methanol (10:0 - 9:1) eluate was recrystallized from
ethyl acetate hexane to obtain 105 mg (82%) of 3-(2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1R)-1,2-
dihydroxyethyl]-2-fluorophenyl}-3-oxopropanoyl)benzonitrile
(Example 4-11) .
In the same manner, the compounds shown in Tables 19 to 21
were produced using corresponding optically active materials
derived from the dihydroxy compounds synthesized using AD-mix
beta.






[0071]
Example 5
A chloroform solution containing 0.11 g of l-(3,5-
difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-

[1-hydroxy-2-(methylsulfanyl)ethyl]phenyl}propane-1,3-dione was
mixed with 0.13 g of 77% 3-chloroperbenzoic acid and stirred at
room temperature for about 30 minutes. The reaction liquid was
mixed with an appropriate amount of sodium bicarbonate aqueous
solution, extracted several times with ethyl acetate, dried with
anhydrous magnesium sulfate and concentrated, and then the thus
formed residue was purified by a silica gel column
chromatography to obtain 85 mg (71%) of 1-(3,5-difluorophenyl)-
2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[l-hydroxy-2-
(methylsulfonyl)ethyl]phenyl}propane-1,3-dione as a yellow foam
from a chloroform-methanol (100:1) eluate. ES+: 499
[0072]
Example 6-1
At -10°C, 10 ml of ethanol solution containing 184 mg of
2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-
[3-(1-hydroxy-3-oxobutyl)phenyl]propane-1,3-dione was mixed with
sodium borohydride and stirred for 3 0 minutes. This was mixed
with an appropriate amount of saturated ammonium chloride
aqueous solution and purified water, extracted with ethyl
acetate and dried with anhydrous magnesium sulfate. After
concentration, the thus formed residue was purified by a silica
gel column chromatography to obtain 110 mg (60%) of 2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,3-
dihydroxybutyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione
(Example 6-1) from a hexane-ethyl acetate (1:1 - 1:3) eluate.

In the same manner, the compounds shown in Table 22 were
produced.

[0073]
Example 7-1
To 5 ml of DMF solution containing 200 mg of 2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-
dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione and
53 µl of 2-methylpropanoic acid were added 88 mg of 1-
hydroxybenzotriazole monohydrate, 110 mg of WSCHC1 and 70 mg of

dimethylaminopyridine in that order, and the mixture was stirred
at room temperature for 18 hours. This was mixed with an
appropriate amount of purified water, extracted with ethyl
acetate and dried with anhydrous magnesium sulfate. After
concentration, the thus formed residue was purified by a silica
gel column chromatography to obtain 90 mg (39%) of 2-{3-[2-(1,3 -
dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-
oxopropanoyl]phenyl}-2-hydroxyethyl-2-methyl propanoate (Example
7-5) from a hexane-ethyl acetate (2:1 - 0:1) eluate.
In the same manner, the compounds shown in Table 23 were
produced.
[0074]

[0075]
Example 8
A 0.35 g portion of 2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-1-[3-(1,2-dihydroxyethy1)phenyl]-3-(3-

fluorophenyl)propane-1,3-dione was added to 10 ml of DMF
solution containing 0.14 g of N,N-dimethylglycine hydrochloride,
0.14 g of HOBt, 0.19 g of WSCHC1 and 0.28 ml of TEA, and then
the mixture was stirred at room temperature for about 12 hours.
The reaction liquid was mixed with an appropriate amount of
ammonium chloride aqueous solution, extracted several times with
ethyl acetate, dried with anhydrous magnesium sulfate and
concentrated, and then the thus formed residue was purified by a
silica gel column chromatography to obtain 0.3 g of a yellow
foam from a chloroform-methanol (50:1) eluate. This was
dissolved in 15 ml of ethyl acetate, 0.5 ml of 4 N hydrochloric
acid-ethyl acetate solution was added dropwise thereto, the
mixture was stirred at room temperature for about 15 minutes,
and then the thus formed crystals were collected by filtration
and dried to obtain 0.2 g (44%) of 2-{3-[2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-
oxopropanoyl]phenyl}-2-hydroxyethyl (dimethylamino)acetate
hydrochloride as white crystals. FA: 504
Example 9-1
A 10 ml portion of THF solution containing 104 mg of 1-
t{3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3- (3-
fluorophenyl)-3-oxopropanoyl]phenyl}(hydroxy)methyl]-2-
hydroxypropyl acetate and 2 ml of methanol solution were mixed
with 0.62 ml of 1.0 M sodium hydroxide and stirred for 30
minutes. This was mixed with appropriate amounts of saturated
ammonium chloride aqueous solution and purified water, extracted

with ethyl acetate and dried with anhydrous magnesium sulfate.
After concentration, the thus formed residue was purified by a
silica gel column chromatography to obtain 35 mg (37%) of 2-
(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-
(1,2,3-trihydroxybutyl)phenyl]propane-1,3-dione (Example 9-1)
from a hexane-ethyl acetate (1:1 - 1:3) eluate.
In the same manner, the compounds shown in Table 24 and
Examples 9-5 and 9-6 were produced.
Example 9-5 2-(1, 3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-
fluorophenyl)-3-[3-(hydroxymethyl)phenyl]propane-1,3-dione
FA: 389
Example 9-6 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-[3-(hydroxymethyl)phenyl]propane-1,3 -
dione
FA: 407
[0076]


[0077]
Example 10
Under ice-cooling, 0.54 g of sodium periodate was added to
3 ml of THF-methanol aqueous solution (1:1:1) containing 0.25 g
of 2-(l,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[2-(1,2-
dihydroxyethyl)-1,3-dioxolan-4-yl]phenyl}-3-(3-
fluorophenyl)propane-1,3-dione and stirred at room temperature
for about 30 minutes. The reaction liquid was mixed with an
appropriate amount of saturated brine, extracted with ethyl
acetate, dried with anhydrous magnesium sulfate and then
concentrated to obtain a formyl inter mediate as yellow foam.
This was dissolved in 5 ml of methylene chloride, 60 µl of
morpholine and 0.3 ml of acetic acid were added thereto in that
order, and then 0.22 g of triacetoxy sodium borohydride was
added thereto under ice-cooling, and the mixture was stirred at
room temperature for about 30 minutes. After evaporation of the
solvent, the residue was mixed with an appropriate amount of
sodium bicarbonate, extracted several times with ethyl acetate,
dried with anhydrous magnesium sulfate and concentrated. The
thus formed residue was purified by a silica gel column
chromatography to obtain 0.16 g (60%) of 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-{3-[2-(morpholin-4-
ylmethyl)-1,3-dioxolan-4-yl]phenyl}propane-1,3-dione as a yellow
foam from an ethyl acetate eluate. FA: 530

Example 11-1
A 0.33 ml portion of 2-bromopyridine was dissolved in 3 ml
of THF, and the solution was cooled to -78°C, mixed with 2.2 ml
of n-butyl lithium and then stirred at the same temperature for
30 minutes. This solution was poured at -78°C into a solution
prepared by dissolving 3-[2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzaldehyde in 10 ml
of THF. This was slowly risen to room temperature and mixed
with 50 ml of saturated ammonium chloride aqueous solution.
This was extracted with ethyl acetate, dried with sodium sulfate
and then concentrated, and the thus formed residue was purified
by a silica gel column chromatography (chloroform:methanol =
from 100:0 to 90:10). By subjecting the thus obtained reddish
brown solid to salt formation with 4N HCl/EtOAC (0.2 ml), 151 mg
(42%) of 2-(l,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-
fluorophenyl)-3-{3-[hydroxy(pyridin-2-yl)methyl]phenyl}propane-
1,3-dione hydrochloride (Example 11-1) was obtained. FA: 466
In the same manner, 2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-1-(3-fluorophenyl)-3-{3-[hydroxy(1-methyl-lH-imidazol-
2-yl)methyl]phenyl}propane-1,3-dione hydrochloride (Example 11-
2) was obtained. FA: 469
Example 12
A 2 ml portion of DMSO solution containing 100 mg of l-[3-
(chloromethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)propane-l,3-dione was mixed with 35 mg of
potassium acetate and stirred at room temperature for about 2

days. The reaction liquid was mixed with an appropriate amount
of saturated ammonium chloride aqueous solution, extracted
several times with ethyl acetate, dried with anhydrous magnesium
sulfate and concentrated, and then the thus formed residue was
purified by a silica gel column chromatography to obtain 90 mg
of a yellow oily substance from an ethyl acetate-hexane (1:2)
eluate. By crystallizing this from a small amount of an ethyl
acetate-hexane (1:3) at a low temperature, 68 mg (64%) of 3-[3-
(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-
3-oxopropanoyl]benzylacetate was obtained as yellow crystals.
FA: 449
[0078]
Example 13-1
Resolution of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-[3-(1,2-dihydroxyethyl)phenyl]propane-
1,3-dione was carried out in the usual way using a chiral
column: CHIRALCEL OD-H (trade name, Daicel Chemical Industries)
and an eluent: hexane/ethanol 3:1. 1-(3,5-Difluorophenyl)-2-
(l,3-dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(IS)-1,2-
dihydroxyethy1]phenyl}propane-1,3-dione (Example 13-1) was
obtained as the isomer having shorter retention time.
Example 13-1 FA: 437, [α] D +21.3° (c 0.356 MeOH)
Also, 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-{3-[(1R)-1,2-dihydroxyethyl]phenyl)propane-1,3-dione
(Example 13-2) was obtained as the isomer having longer
retention time. FA: 437, N1: 3.27 (2 H, m), 4.42 (1 H, m), 4.71

(1 H, t, J - 6 Hz), 5.17 (1 H, d, J = 4 Hz), 6.91 (3 H, m), 7.14
(3 H, m), 7.30 (3 H, m), 7.74 (2 H, m) , 13.11 (2 H, s), mp: 189
- 190°C, [α]D -21.2° (c 0.367 MeOH)
Example 14-1
A 568 mg portion of 1-[3-(2-azido-1-hydroxyethyl)phenyl]-
3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)propane-1,3-dione and 120 mg of 10% palladium-carbon
were added to 50 ml of ethyl acetate and stirred at room
temperature for 8.5 hours under ordinary pressure and in an
atmosphere of hydrogen. This was filtered through celite,
concentrated, mixed with diethyl ether and then extracted with
water. By concentrating the water layer, 250 mg (47%) of l-[3-
(2-amino-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione (Example 14-
1) was obtained as a yellow solid. FA: 436
In the same manner, the following compounds were obtained.
Example 14-2 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(2-
ethyl-1,3-dioxolan-4-yl)phenyl]-3-(3-fluorophenyl)propane-1,3-
dione FA: 459
Example 14-3 1-(3 , 5-difluorophenyl)-3-{3-[(1R)-1,2-
dihydroxyethyl]-2-fluorophenyl}-2-(5-hydroxy-1,3-dihydro-2H-
benzimidazol-2-ylidene)propane-1,3-dine FA: 471
[0079]
Example 15-1

A 137 mg portion of 1-[3-(2-amino-1-hydroxyethyl)phenyl]-
3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)propane-1,3-dione was dissolved in 10 ml of pyridine,
and 35 mg of acetic anhydride was added thereto under ice-
cooling. After 2.5 hours of stirring at room temperature, the
reaction liquid was mixed with an appropriate amount of sodium
bicarbonate aqueous solution, extracted with ethyl acetate,
dried with anhydrous sodium sulfate and concentrated, and then
the thus formed residue was purified by a silica gel column
chromatography to obtain 120 mg (80%) of N-(2-{3-[3-(3 , 5-
difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-
oxopropanoyl]phenyl}-2-hydroxyethyl)acetamide (Example 15-1) as
a yellow foam from a chloroform-methanol (30:1) eluate. FA: 478
The following compounds were obtained in the same manner.
Example 15-2 2-{3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-
(3-fluorophenyl)-3-oxopropanoyl]phenyl}-2-hydroxyethyl
ethylcarbonate FA: 491
Example 15-3 1-{3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-
(3-fluorophenyl)-3-oxopropanoyl]phenyl}-2-hydroxyethyl acetate
FA: 461
Example 15-4 2-(acetyloxy)-2-{3-[2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-
oxopropanoyl]phenyl}ethyl(dimethylamino) acetate FA: 546
[0080]
Example 16

A 300 mg portion of 2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-1-[3-(1,2-dihydroxyethyl)phenyl]-3-(3-
fluorophenyl)propane-1,3-dione and 200 mg of CDI were dissolved
in 7 ml of Tol and stirred at 80°C for 12 hours. After
concentration of the reaction liquid, the thus formed residue
was purified by a silica gel column chromatography to obtain 30
mg (9%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-
fluorophenyl)-3-[3-(2-oxo-1,3-dioxolan-4-yl)phenyl]propane-1,3-
dione as a yellow solid from a chloroform-methanol (10:1)
eluate. ES+: 445
Example 17
In accordance with the aforementioned method of Example 1,
1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)phenyl]propane-
1,3-dione was obtained. ES+: 491
Example 18
A 0.12 g portion of 2-[bis(methylsulfanyl)methylene]-1-[3-
((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-pyridin-
3-yl-propan-1,3-dione and 3 6 mg of 1,2-phenylenediamine were
dissolved in 8 ml of ethanol and heated under reflux for 3
hours. After concentration of the reaction liquid, the thus
formed residue was purified by a silica gel column
chromatography to obtain 0.12 g (97%) of 2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-1-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-

yl]-2-fluorophenyl}-3-pyridin-3-yl-propane-1,3-dione as a yellow
solid from an ethyl acetate-hexane (3:1) eluate. FA: 460
[0081]
Test Example 1. Test on GnRH receptor antagonism
GnRH receptor antagonism of the compounds of the invention
was evaluated by calculating their concentration for inhibiting
50% of the binding of 125I-D-Trp6-LHRH to human GnRH receptor
(IC50 value), in accordance with the 1. GnRH receptor antagonism
test method described on p. 56 of the Patent Reference 1.
The results are shown in Table 25.
Test Example 2. Measurement of blood concentration of a
compound by ex vivo binding assay
Each compound to be tested was dissolved or suspended in
0.5% methyl cellulose (MC) solution and was orally administered
to Wistar male rat of 9 weeks of age (SLC Japan) at a dose of 10
mg/kg. Blood sample was collected after 2 hours of the
administration to obtain serum.
Each serum sample was mixed with the same volume of
methanol to remove protein and optionally diluted with an assay
buffer, and then the 125I-D-Trp6-LHRH binding inhibition ratio
was measured in the same manner as in Test Example 1. Using a
separately prepared calibration curve on the concentration-
binding inhibition of compounds to be tested, blood
concentration of each compound (µM) was calculated from the
binding inhibition ratio.



It is considered that strength of the action of a GnRH
receptor antagonist in the living body depends on both of the
receptor inhibitory activity and the blood drug concentration,
and that a compound having larger ratio of blood drug
concentration to in vitro receptor inhibitory activity has
stronger drug effect in the living body.
Since the compounds of the invention have GnRH receptor
antagonism which is similar to or larger than that of the
compounds disclosed in Patent Reference 1, and the value of
(B)/(A) as a ratio of blood concentration to receptor inhibitory
activity is further improved, it was confirmed that their effect
in the living body can be expected. For example, in Table 25,
when the blood concentration is higher, the value of IC50 on the
antagonism activity is smaller, and the value of the drug effect
became larger and stronger will be shown.
[0083]
Test Example 3. Test on antagonism for GnRH-induced blood
testosterone increasing reaction
In vivo GnRH receptor antagonism of the compounds of the
invention was evaluated in accordance with the method described
in "2. Test on antagonism for GnRH-induced blood testosterone
increasing reaction" on p. 57 of the Patent Reference 1. Each
compound to be tested was suspended in 0.5% methyl cellulose
(MC) aqueous solution and orally administered at a dose of 10
mg/kg, 2 or 4 hours before the administration of GnRH. The
compounds of the invention had good antagonism.

Test Example 4. Test on cytochrome P450 (CYP) 3A4 enzyme
inhibition (evaluation of drug interaction)
(1) Inhibition test I (calculation of inhibitory activity I)
Using a 96 well plate, a substrate (midazolam), a test
compound and human liver microsome (0.1 mg protein/ml) were
incubated at 37°C for 20 minutes in 100 mM phosphate buffer
containing 0.1 mM EDTA and 1 mM NADPH. Thereafter, the reaction
was stopped by adding an aqueous solution containing 80%
acetonitrile. Thereafter, each sample was analyzed by HPLC, and
the inhibitory activity I was calculated using the following
formula. The results are shown in Table 26.
On the basis of these results, it was considered that the
compounds of the invention had weak inhibitory effects on CYP3A4
and that these compounds showed low risk which occurred drug-
drug interaction with drugs of which CYP3A4 contributed to the
metabolism in the human liver in comparison with the compounds
of Ex40, Ex251 and Ex239 described in Patent Reference 1.
[0084]
Inhibitory activity I (%) = 100 - Vi.I/V0.I x 100
Vi.I: metabolic rate of substrate in the presence of a test
compound of known concentration in the inhibition test I
V0.I: metabolic rate of substrate in the absence of test compound
in the inhibition test I


(2) Inhibition test II (calculation of inhibitory activity II)
Using a 96 well plate, a test compound and human liver
microsome (0.1 mg protein/ml) were incubated at 37°C for 3 0
minutes in 145 µl in total volume of 100 mM phosphate buffer (pH
= 7.4) containing 0.1 mM EDTA and 1 mM NADPH. Thereafter,
midazolam as the substrate was added thereto and incubated at
37°C for 20 minutes. After the incubation, the reaction was
stopped by adding an aqueous solution containing 80%

acetonitrile. Thereafter, each sample was analyzed by HPLC, and
the inhibitory activity II was calculated.
[0085]
Inhibitory activity II (%) = 100 - Vi.II/V0.II/ (100 -
inhibitory activity I) x 100 x 100
Vi.II: metabolic rate of substrate in the presence of a test
compound of known concentration in the inhibition test II
V0.II: metabolic rate of substrate in the absence of test
compound in the inhibition test II
On the basis of these results, it was considered that the
compounds of Ex 2-4, Ex 4-1, Ex 4-4, Ex 4-5, Ex 4-21, Ex 4-22,
Ex 4-25, Ex 4-29 and Ex 4-30 had weak inhibitory effects on
CYP3A4 and that these compounds showed low risk which occurred
drug-drug interaction with drugs of which CYP3A4 contributed to
the netabolism in the human liver in comparison with the
compounds of Ex40, Ex251 and Ex239 described in Patent Reference
1.
Test Example 5. Test on metabolic stability in human liver
microsome
Using a test tube, a test compound and human liver microsome
(0.2 mg protein/ml) were incubated at 37°C for 15 minutes in 100
mM phosphate buffer (pH = 7.4) containing 0.1 mM EDTA and 1 mM
NADPH. After the incubation, the reaction was stopped by adding
an aqueous solution containing 80% acetonitrile. Thereafter,
each sample was analyzed by HPLC, and the in vitro clearance was
calculated with a integration plot.

As a result of this test, for example, the compounds of Ex 2-4,
Ex 4-1, Ex 4-4, Ex 4-5, Ex 4-21, Ex 4-22, Ex 4-25, Ex 4-29 and
Ex 4-30 showed superior metabolic stability in human liver and
it was considered that the compounds were less influenced by
first-pass effect in comparison with the compounds of Ex 40, Ex
251 and Ex 239 described in Patent reference 1.

What is claimed is:
1. A propane-1,3-dione derivative represented by the
general formula (I) or a pharmaceutically acceptable salt
thereof

[symbols in the formula mean as follows,
ring A: benzene which may be substituted, pyridine which may be
substituted or thiophene ring,
ring B: benzene or thiophene ring,
R1: H or -CO-lower alkyl,
R2: H, -O-R5, -N(R6)R7, -N3, -S(O)m-lower alkyl, -S (O) m-N (R6) R7,
halogen, pyridyl or imidazolyl which may be substituted,
R5: H, lower alkyl, -CO-lower alkyl which may be
substituted, or -CO-O-lower alkyl which may be substituted,
R6 and R7: may be the same or different from each other and
each is H, lower alkyl, or -CO-lower alkyl, with the proviso
that R1 and R2 may together form dioxolane which may be
substituted,
m: 0, 1 or 2,
R3: H or lower alkyl,

R401 and R 402: may be the same or different from each other and
each is H, halogen, OH, -O-lower alkyl, or lower alkyl,
X: bond, lower alkylene which may be substituted, or
cycloalkanediyl,
R101, R102, R103 and R 104: may be the same or different from one
another and each is H, halogen, OH, or -O-lower alkyl which may
be substituted with (aryl or heteroaryl)].
2. The propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof according to claim 1, wherein ring A is
benzene ring which may be substituted with halogen atom or lower
alkyl, ring B is benzene ring, R1 is H, R2 is OH, R3 is H, and X
is lower alkylene which may be substituted.
3. The propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof according to claim 2, wherein X is
methylene which may be substituted.
4. A propane-1,3-dione derivative represented by a general
formula (Ia) or a pharmaceutically acceptable salt thereof


(symbols in the formula mean as follows,
R801, R802 and R803: may be the same or different from one another
and each is halogen or lower alkyl,
R403 and R404: may be the same or different from each other and
each is H, halogen or lower alkyl, and,
R101, R102, R103 and R104: may be the same or different from one
another and each is H, halogen, OH, or -O-lower alkyl which may
be substituted with (aryl or heteroaryl).
5. The propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof according to claim 4, or a pharmaceutically
acceptable salt thereof, which is at least one compound selected from
the group consisting of:
2-(l,3-Dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-
dihydroxyethyl)phenyl]-3-(3,4,5-trifluorophenyl)propane-1,3 -
dione; 1-{2-butyl-3-[(1R)-1,2-dihydroxyethy1]phenyl}-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)propane-
1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)-3-[5-(1,2-dihydroxyethy1)-2-
fluorophenyl]propane-1,3-dione; 1-(3,5-difluorophenyl)-2-(1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-{3-[(1R)-1,2-
dihydroxyethyl]-2-methylphenyl}propane-1,3-dione; 2- (1,3-
dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-1,2-
dihydroxyethyl]-2-methylphenyl}-3-(2-fluorophenyl)propane-1,3-
dione; 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-
dihydroxyethy1)phenyl]-3 -(2,3,5-tri fluorophenyl)propane-1,3-
dione; 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-1,2-

dihydroxyethyl]-2-methylphenyl}-3-(3-methylphenyl)propane-1,3-
dione; 1-{2-chloro-3-[(1R)-1,2-dihydroxyethyl]phenyl}-2- (1,3-
dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)propane-
1,3-dione; 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(1R)-
1,2-dihydroxyethy1]phenyl}-3 -(3 -fluorophenyl)propane-1,3-dione;
1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-[3-(1,2-dihydroxyethyl)-2-fluorophenyl]propane-1,3-
dione; 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-3-[3-(1,2-dihydroxyethyl)-4-fluorophenyl]propane-1,3-
dione; 1-{2-chloro-3-[(1R)-1,2-dihydroxyethyl]phenyl}-3-(3,5-
difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)propane-1,3-dione; 2-(1,3-dihydro-2H-benzimidazol-2-
ylidene)-1-{3-[(1R)-1,2-dihydroxyethyl]-2-fluorophenyl}-3-(3-
fluorophenyl)propane-1,3-dione; 1-{2-chloro-3-[(1R)-1,2-
dihydroxyethyl]phenyl}-3-(3-chlorophenyl)-2-(1,3-dihydro-2H-
benzimidazol-2-ylidene)propane-1,3-dione.
6. A propane-1,3-dione derivative represented by a general
formula (lb) or a pharmaceutically acceptable salt thereof

(symbols in the formula mean as follows,
R8 and R9: may be the same or different from each other and each
is H, lower alkyl, lower alkenyl or -O-lower alkyl,

R801, R802 and R803: may be the same or different from one another
and each is halogen or lower alkyl,
R403 and R404: may be the same or different from each other and
each is H, halogen or lower alkyl, and,
R101, R102, R103 and R 104: may be the same or different from one
another and each is H, halogen, OH, or -O-lower alkyl which may
be substituted with (aryl or heteroaryl).
7. The propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof according to claim 6, wherein R801, R802 and
803
R may be the same or different from one another and each
represents H or a halogen atom.
8. The propane-1,3-dione derivative or a pharmaceutically
acceptable salt thereof according to claim 7, or a pharmaceutically
acceptable salt thereof, which is at least one compound selected from
the group consisting of:
2-(l,3-Dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-
[3-(2-methoxy-l,3-dioxolan-4-yl)phenyl]propane-1,3-dione; 2-
(l,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-
(2-methoxy-2-methyl-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising as an
active ingredient a propane—1,3—dione compound represented by
the general formula (I) or a pharmaceutically acceptable salt

thereof as claimed in claim 1, and a pharmaceutically acceptable
carrier.
10. The pharmaceutical composition as claimed in claim
9, which is a GnRH receptor antagonist.
11. The pharmaceutical composition as claimed in claim
10, which is the GnRH receptor antagonist for treating prostate
cancer, breast cancer, endometriosis, uterine leiomyoma, or
benign prostatic hypertrophy.


Compounds useful as GnRH receptor antagonists are
provided. The present inventors have further examined propane-
1,3-dione derivatives and confirmed as a result that a propane-
1,3-dione having 2-(1,3-dihydro-2H-benzimidazol-2-ylidene), or a
compound which has benzene or thiophene ring substituted with a
group derived from 1-hydroxymethyl, shows excellent
availability, in addition to its excellent GnRH receptor
antagonism, thereby accomplishing the invention. Since the
compound of the invention shows excellent availability, in
addition to its strong GnRH receptor antagonism, it can be
expected that it exerts superior drug effect in the living body,
and it is useful for the treatment of sex hormone dependent
diseases such as prostate cancer, breast cancer, endometriosis,
uterine leiomyoma, benign prostatic hypertrophy and the like.
In addition, since the compound of the invention is excellent in
metabolic stability in human and also is less in drug
interaction, it has more desirable properties as a medicament to
be used for the aforementioned diseases.

Documents:

03481-kolnp-2006 abstract.pdf

03481-kolnp-2006 claims.pdf

03481-kolnp-2006 correspondence others.pdf

03481-kolnp-2006 description(complete).pdf

03481-kolnp-2006 form-1.pdf

03481-kolnp-2006 form-2.pdf

03481-kolnp-2006 form-3.pdf

03481-kolnp-2006 form-5.pdf

03481-kolnp-2006 international publication.pdf

03481-kolnp-2006 international search authority report.pdf

03481-kolnp-2006 pct others document.pdf

03481-kolnp-2006 priority document.pdf

03481-kolnp-2006-correspondence others-1.1.pdf

03481-kolnp-2006-correspondence-1.2.pdf

03481-kolnp-2006-correspondence-1.3.pdf

03481-kolnp-2006-form-18.pdf

03481-kolnp-2006-international search authority report-1.1.pdf

03481-kolnp-2006-p.a.pdf

03481-kolnp-2006-pct others.pdf

3481-KOLNP-2006-(06-01-2012)-FORM-27.pdf

3481-KOLNP-2006-AMANDED CLAIMS.pdf

3481-KOLNP-2006-CORRESPONDENCE 1.1.pdf

3481-KOLNP-2006-CORRESPONDENCE 1.4.pdf

3481-KOLNP-2006-CORRESPONDENCE 1.5.pdf

3481-kolnp-2006-correspondence.pdf

3481-kolnp-2006-examination report.pdf

3481-kolnp-2006-form 13-1.1.pdf

3481-kolnp-2006-form 13.pdf

3481-kolnp-2006-form 18.pdf

3481-kolnp-2006-form 26.pdf

3481-KOLNP-2006-FORM 3.1.pdf

3481-kolnp-2006-form 3.pdf

3481-kolnp-2006-form 5.pdf

3481-kolnp-2006-granted-abstract.pdf

3481-kolnp-2006-granted-claims.pdf

3481-kolnp-2006-granted-description (complete).pdf

3481-kolnp-2006-granted-form 1.pdf

3481-kolnp-2006-granted-form 2.pdf

3481-kolnp-2006-granted-specification.pdf

3481-kolnp-2006-others-1.2.pdf

3481-KOLNP-2006-OTHERS.1.1.pdf

3481-KOLNP-2006-OTHERS.pdf

3481-kolnp-2006-reply to examination report-1.1.pdf

3481-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 247501
Indian Patent Application Number 3481/KOLNP/2006
PG Journal Number 15/2011
Publication Date 15-Apr-2011
Grant Date 12-Apr-2011
Date of Filing 22-Nov-2006
Name of Patentee ASTELLAS PHARMA INC.
Applicant Address 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 MASAAKI HIRANO C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
2 ISAO KINOYAMA C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
3 SHUNICCHIRO MATSUMOTO C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
4 KEI OHNUKI C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
5 KAZUYPSHI OBITSU C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
6 TOSHIYUKI KUSAYAMA C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
7 EIJI KAWAMINAMI C/O ASTELLAS PHARMA INC. 3-11, NIHONBASHI-HONCHO 2-CHOME, CHUO-KU, TOKYO 103-8411, JAPAN
PCT International Classification Number A61K 31/4184
PCT International Application Number PCT/JP2005/010184
PCT International Filing date 2005-06-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004-166486 2004-06-04 Japan
2 2005-099815 2005-03-30 Japan