Title of Invention

THIENOPYRIMIDINE COMPOUNDS AND USE THEREOF .

Abstract The present invention provides a compound represented by the formula: wherein R1 is a C1- 4 alkyl; R2 is (l) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1') a halogen, (2') a hydroxy group, (3') a C1- 4 alkyl and (4') a C1- 4 alkoxy, (2) a phenyl which may have a substituent selected from the group consisting of (1') a halogen, (2') a C1- 4 alkoxy-C1- 4 alkyl, (3') a mono-C1- 4 alkyl-carbamoyl-C1- 4 alkyl, (4') a C1- 4 alkoxy and (5') a mono-C1- 4 alkylcarbamoyl-C1- 4 alkoxy, or the like; R3 is a C1- 4 alkyl; R4 is a C1- 4 alkoxy, or the like; n is an integer of 1 to 4; or a salt thereof, as a thienopyrimidine compound having gonadotropin-releasing hormone antagonistic activity.
Full Text Specification
Thienopyrimidine Compounds And Use Thereof
Technical field
The present invention relates to thieno[2,3-d]pyrimidine
compounds exhibiting gonadotropin releasing hormone (GnRH)
antagonizing activity, their production and use.
Background art
Secretion of anterior pituitary hormones undergoes feedback
control by peripheral hormones secreted from target organs of the
respective hormones and by secretion-regulating hormones from the
hypothalamus, which is the upper central organ of the anterior lobe of
the pituitary (hereinafter, these hormones are collectively called
"hypothalamic hormones" in this specification). Presently, as
hypothalamic hormones, the existence of nine kinds of hormones
including, for example, thyrotropin releasing hormone (TRH), and
gonadotropin releasing hormone [GnRH, sometimes called as LH-RH
(luteinizing hormone releasing hormone)] has been confirmed. These
hypothalamic hormones are believed to show their actions via the
receptors which are considered to exist in the anterior lobe of the
pituitary, and efforts to find the receptor-gene expression specific to these
hormones, including cases of human, have been made. Accordingly,
antagonists or agonists specifically and selectively acting on these
receptors should control the action of the hypothalamic hormone and the
secretion of anterior pituitary hormone. As a result, such antagonists or
agonists are expected to prevent or treat anterior pituitary hormone
dependent diseases.
Known compounds possessing GnRH-antagonizing activity include
GnRH-derived linear peptides (USP 5,140,009 and USP 5,171,835), a
cyclic hexapeptide derivative (JP-A-61-191698), a bicyclic peptide
derivative (Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273
(1993)), and so forth. Non-peptide compounds possessing GnRH-
antagonizing activity include compounds described in JP-A-8-295693
(WO 95/28405), JP-A-9-169768 (WO 96/24597), JPA-9-169735 (WO
97/14682), JP-A-9-169767 (WO 97/14697), JP-A-11-315079 (WO
99/33831), JP-A-2000-219691 (WO 00/00493), JP-A-2001-278884 (WO
00/56739) and JP-A-2002-30087.
Peptide compounds pose a large number of problems to be resolved
with respect to oral absorbability, dosage form, dose volume, drug
stability, sustained action, metabolic stability etc. There is strong
demand for an oral GnRH antagonist, especially one based on a non-
peptide compound, that has excellent therapeutic effect on hormone-
dependent cancers, e.g., prostatic cancer, endometriosis, precocious
puberty etc., that does not show transient hypophysial-gonadotropic
action (acute action) and that has excellent oral absorbability.
Disclosure of Invention
We, the present inventors, have conducted various investigations,
and as a result, have synthesized the following novel compound
represented by the formula [hereinafter sometimes referred to briefly as
Compound d)J:

wherein
R1 is a C1-4 alkyl; R2 is (1) a C1-6 alkyl which may have a substituent
selected from the group consisting of (1') a hydroxy group, (2') a C1-4
alkoxy, (3') a C1-4 alkoxy-carbonyl, (4') a di-C1-4alkyl-carbamoyl, (5') a 5- to
7-membered nitrogen-containing heterocyclic group, (6') a C1-4 alkyl-
carbonyl and (7') a halogen,
(2) a C3- 8 cycloalkyl which may have (1') a hydroxy group or (2') a mono-
C1-4 alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containing
heterocyclic group which may have a substituent selected from the group
consisting of (1') a halogen, (2') a hydroxy group, (3') a C1-4 alkyl and (4') a
C1-4 alkoxy, (4) a phenyl which may have a substituent selected from the
group consisting of (l') a halogen, (2') a C1-4 alkoxy-C1-4 alkyl, (3') a mono-
C1-4alkyl-carbamoyl-C1-4alkyl, (4') a C1-4alkoxy and (5') a mono-C1-4
alkylcarbamoyl-C1-4 alkoxy or (5) a C1-4 alkoxy; R3 is a C1-4 alkyl," R4 is (1) a
hydrogen atom, (2) a C1-4 alkoxy, (3) a C6-10aryl, (4) a N-C1-4alkyl-N-C1-4
alkylsulfonylamino, (5) a hydroxy group or (6) a 5- to 7-membered
nitrogen-containing heterocyclic group which may have a substituent
selected from the group consisting of (1') oxo, (2') a C1-4 alkyl, (3') a
hydroxy-C1-4 alkyl, (4') a C1-4alkoxy-carbonyl, (5') a mono-C1-4 alkyl -
carbamoyl and (6') a C1-4 alkylsulfonyl; n is an integer of 1 to 4; provided
that when R2 is a phenyl which may have a substituent, R4 is a 5- to 7-
membered nitrogen-containing heterocyclic group which may have a
substituent selected from the group consisting of (l) oxo, (2) a hydroxy-
C1-4alkyl, (3) a C1-4 alkoxy-carbonyl, (4) a mono-C1-4 alkyl-carbamoyl and
(5) a C1-4 alkylsulfonyl; or a salt thereof; which is characterized by having
3-C1-4 alkoxyureido on the para-position of its phenyl group at the six
position of the thieno[2,3-d]pyrimidine skeleton. And we also have
found that Compound (I) has an unexpected, excellent GnRH-
antagonizing activity, especially strong antagonistic activity, based upon
the above specific chemical structure, and extremely low toxicity and is
therefore satisfactory as a medicine having GnRH-antagonizing activity,
and developed the present invention based on these findings.
Accordingly, the present invention relates to-
[ 1] A compound of the formula-
wherein
R1 is a C1-4 alkyl;
R2is
(1) a C1-6 alkyl which may have a substituent selected from the group
consisting of (l') a hydroxy group, (2') a C1-4 alkoxy, (3') a C1-4 alkoxy-
carbonyl, (4') a di-C1-4 alkyl-carbamoyl, (5') a 5- to 7-membered nitrogen-
containing heterocyclic group, (6') a C1-4 alkyl-carbonyl and (7') a halogen,
(2) a C3- 8 cycloalkyl which may have (1') a hydroxy group or (2') a mono-
C1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (1') a halogen,
(20 a hydroxy group, (3') a C1-4 alkyl and (4') a C1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group
consisting of (l') a halogen, (2') a C1-4alkoxy-C1-4alkyl, (3') a mono-C1-4
alkyl-carbamoyl-C1-4 alkyl, (4') a C1-4 alkoxy and (5') a mono-C1-4
alkylcarbamoyl-C1-4 alkoxy, or
(5) a C1-4 alkoxy;
R3 is a C1-4 alkyl;
R4is
(1) a hydrogen atom,
(2) a C1-4 alkoxy,
(3) a C6-10aryl,
(4) a N-C1-4 alkyl-N-C1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (l') oxo, (2') a C1-4
alkyl, (3') a hydroxy-C1-4 alkyl, (4') a C1-4 alkoxy-carbonyl, (5') a mono-Ci4
alkyl-carbamoyl and (6') a C1-4 alkylsulfonyl"
n is an integer of 1 to 4;
provided that when R2 is a phenyl which may have a substituent, R4 is a
5- to 7-membered nitrogen-containing heterocyclic group which may have
a substituent selected from the group consisting of (l) oxo, (2) a hydroxy-
C1-4 alkyl, (3) a C1-4 alkoxy-carbonyl, (4) a mono-C1-4 alkyl-carbamoyl and
(5) a C1-4 alkylsulfonyl; or a salt thereof;
[2] A compound as defined in [1] above, wherein
R2is
(1) a C1-4 alkyl which may have a substituent selected from the group
consisting of (1') a hydroxy group, (2') a C1-4 alkoxy, (3') a C1-4 alkoxy-
carbonyl, (4') a di-C1-4 alkyl-carbamoyl and (5') a 5 to 7-membered
nitrogen-containing heterocyclic group,
(2) a C3-8 cycloalkyl which may have (l') a hydroxy group or (2') a mono-
C1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (1') a halogen,
(2') a hydroxy group, (3') a C1-4 alkyl and (4') a C1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group
consisting of (1') a halogen, (2') a C1-4 alkoxyC1-4 alkyl, (3') a mono-C1-4
alkyl-carbamoyl-C1-4 alkyl and (4') a mono-C1-4 alkylcarbamoyl-C1-4 alkoxy,
or
(5) a C1-4 alkoxy;
R4is
(1) a C1-4 alkoxy,
(2) a C6-10aryl,
(3) a N-C1-4 alkyl-N-C1-4 alkylsulfonylamino or
(4) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (l') oxo, (2') a
hydroxy-C1-4 alkyl, (3') a C1-4 alkoxy-carbonyl, (4') a mono-C1-4 alkyl -
carbamoyl and (5') a C1-4 alkylsulfonyl'
[3] A compound as defined in [l] above, wherein R1 is methyl;
[4] A compound as defined in [l] above, wherein R2 is a 5- to 7-
membered nitrogen-containing heterocyclic group which may have a
substituent selected from the group consisting of (l) a halogen, (2) a
hydroxy group, (3) a C1-4 alkyl and (4) a C1-4 alkoxy;
[5] A compound as defined in [l] above, wherein R3 is methyl;
[6] A compound as defined in [l] above, wherein R4 is a C1-4 alkoxy;
[7] A compound as defined in [l] above, wherein n is 2;
[8] A compound as defined in [l] above, wherein R3 is methyl, R4 is a
hydrogen atom and n is 1,'
[9] N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-l,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, N-(4-(l-
(2,6-difluorobenzyl)-5-(((2-ethoxyethyl)(methyl)amino)methyl)-2,4-dioxo-
3-(2-pyridmyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea, N-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-
(6-methoxy-3-pyridazinyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or
N-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyD-3-(6-
methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahy drothieno[2,3 - dlpyrimidin-
6-yl)phenyl)-N'-methoxyurea, or a salt thereof;
[10] N-(4-(5-((2-methoxyethyl)methylamino)methy1)-1-(2,6-
difluorobenzyl)-l,2,3,4-tetrahydro-2,4-dioxo-3-(4-
methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or
N-(4-(l-(2,6difluorobenzyl)-5-((dimethylamino)methyl)-3-(4-
methoxyphenyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-
yl)phenyl)-N'-methoxyurea, or a salt thereof;
[11] A prodrug of the compound as defined in [ l] above;
[12] A pharmaceutical which comprises the compound as defined in [l]
above or a prodrug thereof:
[13] A pharmaceutical as defined in [12] above, which is a
gonadotropin-releasing hormone antagonist;
[14] A pharmaceutical as defined in [12] above, which is for preventing
or treating a sex hormone dependent disease;
[15] A pharmaceutical as defined in [12] above, which is for preventing
or treating sex hormone-dependent cancer, bone metastasis of sex
hormone-dependent cancer, prostatic hypertrophy, hysteromyoma,
endometriosis, metrofibroma, precocious puberty, amenorrhea,
premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome,
polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility,
irritable bowel syndrome, benign or malignant tumor which is hormone
independent and LH-RH sensitive or hot flash; reproduction regulator;
contraceptive agent; ovulation inducer; or for prevention of postoperative
recurrence of sex hormone-dependent cancer;
[16] A method for antagonizing gonadotropin-releasing hormone, which
comprises administering an effective amount of the compound as defined
in [l] above to a mammal;
[17] Use of the compound as defined in [l] above for manufacturing a
pharmaceutical composition for antagonizing gonadotropin-releasing
hormone;
[ 18] A compound of the formula:

wherein
Ra is (l) a hydrogen atom, (2) an aryl group which may have 1 to 5
substituents selected from the group consisting of (0 a halogen, (ii) nitro,
(iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or
amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an
alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl
group which may have a substituent or (4) a heterocyclic group which
may have a substituent; Rb is a nitrogen-containing heterocyclic group
which may have a substituent; Rc is an amino group which may have a
substituent; Rd is an aryl group which may have a substituent; p is an
integer of 0 to 3; q is an integer of 0 to 3; or a salt thereof; and so forth.
The definition of each term is described in the following
paragraphs.
Examples of the "C1-4 alkyl" include a linear C1-4 alkyl (e.g. methyl,
ethyl, propyl, butyl, and the like), a branched C3-4 alkyl (e.g., isopropyl,
isobutyl, sec-butyl, tert-butyl, and the like), and the like.
Examples of the "C1-6 alkyl" include a linear C1-6 alkyl (e.g. methyl,
ethyl, propyl, butyl, pentyl, hexyl and the like), a branched C3- 6 alkyl (e.g.,
isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like), and the
like.
Examples of the "C1-4 alkoxy" include a linear C1-4 alkoxy (e.g.
methoxy, ethoxy, propoxy, butoxy, and the like), a branched Cs 4 alkoxy
(e.g., isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like), and the
like.
Examples of the "C1-4 alkoxy-carbonyl" include methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and the like.
Examples of the "di-C1-4alkyl-carbamoyl" include
dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,
diisopropylcarbamoyl, N-ethyl-N-methylcarbamoyl, and the like.
Examples of the "5- to 7-membered nitrogen-containing
heterocyclic group" include pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-
yl, oxazolidin-3-yl, thiazolidin-3-yl, isoxazolidin-2-yl, isothiazolidin-2-yl,
imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-1-yl,
pyrazolidin-3-yl, pyrazolidin-4-yl, pyrrol- 1-yl, pyrrol-2-yl, pyrrol-3-yl,
imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-1-yl, pyrazol-3-yl,
pyrazol-4-yl, 1,2,3-triazoM-yl, 1,2,5-triazol-1-yl, tetrazo1-1-yl, tetrazol-2-
yl, tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol'3-yl,
isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, tbiazol-4-yl, thiazol-5-yl,
isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, piperidin-1-yl, piperidin-2-
yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl,
morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, pyridin-2-yl, pyridin-3-yl,
pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,
pyridazin-3-yl, pyridadin-4-yl, and the like. Among them, preferable
examples are pyrrolidin-1-yl, pyrrolidin-2-yl, imidazol-1-yl, imidazol-2-yl,
1,2,3-triazol-l-yl, 1,2,5-triazoM-yl. tetrazol-1-yl, tetrazol-2-yl, pyridin-2-
yl, pyridin-4-yl, and the like.
Examples of the "C1-4 alkyl-carbonyl" include methyl-carbonyl,
ethyl-carbonyl, propyl-carbonyl, isopropyl-carbonyl, butyl-carbonyl,
isobutyl-carbonyl, sec-butyl-carbonyl, tert-butyl-carbonyl, and the like.
The "halogen" include fluorine, chlorine, bromine and iodine.
Examples of the "mono-C1-4 alkyl-carbonylamino" include
methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino,
isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino,
sec-butylcarbonylamino, tert-butylcarbonylamino, and the like.
Examples of the "C3-8 cycloalkyl" include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The "C1-4 alkoxy-C1-4 alkyl" include methoxymethyl, 1-
methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-
methoxypropyl, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-
methoxybutyl, 1-methoxy-l-methylethyl, 2-methoxy-l-methylethyl, 1-
methoxy-1-methylpropyl, 2-methoxy-l-methylpropyl, 3-methoxyl-
methylpropyl, l-(methoxymethyl)propyl, l-methoxy-2-methylpropyl, 2-
methoxy-2-methylpropyl, 3-methoxy-2-methylpropyl, 2-methoxy-1,1-
dimethylethyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-
ethoxybutyl, and the like.
Examples of the "mono-C1-4 alkyl-carbamoyl-C1-4 alkyl" include
methylaminocarbonylmethyl, ethylaminocarbonylmethyl, 2-
methylaminocarbonylethyl, 2-ethylaminocarbonylethyl, and the like.
Examples of the "mono-C1-4 alkyl-carbamoyl-C1-4 alkoxy" include
methylaminocarbonylmethoxy, ethylaminocarbonylmethoxy, 2-
methylaminocarbonylethoxy, 2-ethylaminocarbonylethoxy, and the like.
Examples of the "C6-10 aryl" include phenyl, lnaphthyl, 2-
naphthyl, and the like.
Examples of the "N-C1-4 alkyl-N-C1-4 alkylsulfonylamino" include N-
methyl-N-methylsulfonylamino, N-ethyl-N-methylsulfonylamino, N-
ethylsulfonyl-N-methylamino, N-ethyl-N-ethylsulfonylamino, and the
like.
Examples of the "hydroxy-C1-4 alkyl" include hydroxymethyl, 1-
hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-
hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-
hydroxybutyl, 1-hydroxy 1-methylethyl, 2-hydroxy-1-methylethyl, 1-
hydroxy-1-methylpropyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-l-
methylpropyl, l-(hydroxymethyl)propyl, l-hydroxy-2-methylpropyl, 2-
hydroxy-2-methylpropyl, 3-hydroxy-2-methylpropyl, 2-hydroxy-1,1-
dimethylethyl, and the like.
Examples of the "mono-C1-4 alkyl-carbamoyl" include
methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,
butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-
butylcarbamoyl, and the like.
Examples of the "C1-4 alkylsulfony1" include methylsulfonyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, and the like.
As R1, methyl and ethyl are preferable, and especially methyl is
preferable.
As R2, 5- to 7-membered nitrogen-containing heterocyclic group
which may have a substituent selected from the group consisting of (l) a
halogen, (2) a hydroxy group, (3) a C1-4 alkyl and (4) a C1-4 alkoxy is
preferable. Among them, pyridyl (pyridin-2-yl, pyridin-3-yl, pyridin-4-
yl), which may have a substituent selected from the group consisting of
(l) a halogen, (2) a hydroxy group, (3) a C1-4 alkyl and (4) a C1-4 alkoxy is
more preferable. Especially, unsubstituted pyridin-2-yl is preferable.
As R3, methyl and ethyl are preferable. Especially, methyl is
preferable.
As R4, a C1-4 alkoxy is preferable. Especially, methoxy and ethoxyare preferable.
As n, 1 or 2 is preferable. Especially, 2 is preferable.
Preferable examples of the combination of R3, R4 and n, includes
the case that R3 is methyl, R4 is a hydrogen atom and n is 1.
Preferable examples of Compound (I) include N-(4-(l-(2,6-
difluorobenzyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-
(2-pyridmyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea, N-(4-(l-(2,6-difluorobenzyD-5-(((2-
ethoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-l,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, N-(4-(l-
(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-
pyridazinyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-
yDphenyl)-N'-methoxyurea or N-(4-(l-(2,6-difluorobenzyD-5-
((dimethylamino)methyl) - 3 - (6-methoxypyridin - 3-yl) - 2,4-dioxo-1,2,3,4-
tetrahy drothieno[2,3 - dlpyrimidin -6 -yl)phenyl) -N' -methoxyurea.
Salts of Compound (I) are preferably physiologically acceptable
acid addition salts. Such salts include, for example, salts with inorganic
acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
phosphoric acid, etc.), salts with organic acids (e.g., formic acid, acetic
acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic
acid, citric acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the like. When
Compound (I) has an acidic group, it may be formed into a physiologically
acceptable salt with an inorganic base (e.g., alkali metals and alkaline
earth metals such as sodium, potassium, calcium, magnesium, etc.!
ammonia, and the like) or an organic base (e.g., trimethylamine,
triethylamine, pyridine, picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and
the like).
For example, Compound (I) can be produced according to the
following production methods. Compounds illustrated in the following
reaction schemes include their salts. Examples of the salts include the
same salts as the salts of Compound (I), etc. Compounds G)-(TV)
illustrated in the following reaction schemes may be formed into the
acceptable salts depending on the reaction conditions.
(Production Method l)

In the above formula, L is a leaving group, and other symbols are
the same as defined above.
Examples of 'leaving group" represented by L are a halogen atom,
C1-4 alkylsulfonyloxy which may have a halogen atom, and the like.
Examples of "C1-4 alkylsulfonyloxy which may have a halogen atom" are
methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy,
and the like.
Compound (II) can be produced in any per se known manner, for
example, according to the methods disclosed in JP-A-2001-278884, WO
00/56739 or analogous methods thereto.
For example, Compound (I) can be produced by reacting Compound
(II) and a compound represented by the formula: R4-(CH2)n-L. This
reaction is preferably carried out in the presence of a base.
Examples of "base" are inorganic bases such as sodium carbonate,
sodium hydrogen carbonate, potassium carbonate, potassium hydrogen
carbonate, sodium hydroxide, potassium hydroxide, thallium hydroxide,
and the like; and organic bases such as triethylamine,
diisopropylethylamine, pyridine, and the like.
The amount of the compound represented by the formula: R4-
(CH2)n'L in the reaction of Compound &I) and the compound represented
by the formula: R4-(CH2)n-L is about 1 to about 3 moles per 1 mole of
Compound (II). The amount of a base is about 1 to about 3 moles per 1
mole of Compound (II).
This reaction is usually carried out in a solvent inert to the
reaction. Examples of "solvent" are an ether (e.g., diethyl ether, dioxane,
dimethoxyethane, tetrahydrofuran, and the like), an aromatic
hydrocarbon (e.g., benzene, toluene, and the like), an amide (e.g.,
dimethylformamide, dimethylacetamide, and the like), a halogenated
hydrocarbon (e.g., chloroform, dichloromethane, and the like), and the
like.
The reaction temperature is usually about 0 to about 150 °C,
preferably about 50 to about 80 °C. The reaction time is usually about 1
to about 24 hours.
(Production method 2)

In the above formula, R' is a hydrogen atom or a C1-4 alkyL' R" is a
C1-4 alkyl; and the other symbols are as defined above.
Examples of the C1-4 alkyl represented by R' and R" are a linear C1-4
alkyl (e.g., methyl, ethyl, propyl, butyl, and the like), a branched C1-4
alkyl (e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, and the like), and the
like.
Compound (HI) can be produced in any perse known manner, for
example, by reacting p-nitrophenylacetone with a cyanoacetic ester
compound and sulphur [e.g., Chem. Ber., 9_9_, 94-100(1966)] followed by
subjecting the obtained 2-amino-4-methyl-5-(4-nitrophenyl)thiophene to
the methods disclosed in JP-A9-169768, WO 96/24597 or analogous
methods thereto.
l) When R' is hydrogen atom, Compound (I) can be produced by
reacting Compound (III) with a compound represented by the formula-
R2-NH2 or a salt thereof in the presence of a condensing agent, to obtain
Compound (TV), following by subjecting to cyclization.
Examples of "condensing agent" are WSC (l-ethyl-3-(3-
dimethylaminopropyOcarbodiimide hydrochloride), DCC
(dicyclohexylcarbodiimide), diethyl cyanophosphate, benzotriazol-1-
yloxytripyrrolidinophosphonium hexafluorophosphate: PyBOP), and the
like.
The amount of "condensing agent" is about 1 to about 3 moles per 1
mole of Compound (III).
This reaction is advantageously carried out in a solvent inert to the
reaction.
Examples of the solvent are an alcohol (e.g., ethanol, methanol,
and the like), an aromatic hydrocarbon (e.g., benzene, toluene, and the
like), an amide (e.g., dimethylformamide, dimethylacetamide, and the
like), a halogenated hydrocarbon (e.g., chloroform, dichloromethane, and
the like), and so the like.
The reaction temperature is usually about 0 to about 150 °C,
preferably about 0 to 25 °C. The reaction time is usually about 1 to
about 36 hours.
The product as produced in the manner mentioned above may be
applied to the next reaction while it is still crude in the reaction mixture,
or may be isolated from the reaction mixture in any ordinary manner.
Compound (TV) is subjected to cyclization in the presence of a base.
Examples of "base" are inorganic bases such as sodium methoxide,
sodium carbonate, sodium hydrogen carbonate, potassium carbonate,
potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide,
thallium hydroxide; and organic bases such as triethylamine, pyridine,
and the like; and the like.
The amount of "base" is about 2 to about 20 moles, preferably
about 5 to about 12 mole per 1 mole of Compound (TV).
This reaction is usually carried out in a solvent inert to the
reaction.
Examples of the solvent are an alcohol (e.g., ethanol, methanol,
and the like), an aromatic hydrocarbon (e.g., benzene, toluene, and the
like), an amide (e.g., dimethylformamide, dimethylacetamide, and the
like), a halogenated hydrocarbon (e.g., chloroform, dichloromethane, and
the like), and the like.
The reaction temperature is usually about 0 to 150 °C, preferably
room temperature (about 15 to 25 °C). The reaction time is usually
about 1 to 36 hours.
2) When R' is an alkyl group, Compound (I) can be produced by
reacting Compound (III) with an activated R2-NH2.
The activated R2-NH2 can be produced in any per se known
manner, for example, by reacting an organo-aluminum reagent with R2-
NH2 in a solvent inert to the reaction.
Examples of "organo-aluminum reagent" are trimethyl aluminum,
dimethyl aluminum chloride, and the like; and a solution including them,
and the like.
The amount of "organo-aluminum reagent" is about 1 to about 5
moles, preferably about 1 mole per 1 mole of R2-NH2.
Examples of the solvent are a halogenated hydrocarbon (e.g.,
chloroform, dichloromethane, and the like).
The reaction temperature is usually about 0 to about 150 °C,
preferably about 0 to 25 °C. The reaction time is usually about 1 to
about 6 hours.
The cyclization can be carried out by reacting Compound (III) with
an activated R2-NH2 to obtain Compound (I).
The amount of "Compound (III)" is about 1/5 volume of a mixture of
R2-NH2 and the organo-aluminum reagent.
This reaction is usually carried out in a solvent inert to the
reaction.
Such solvent is the same as those used in the reaction to obtain an
activated R2-NH2.
The reaction temperature is usually about 0 to about 150 °C,
preferably about 0 to 25 °C. The reaction time is usually about 1 to
about 48 hours.
Compound (I) can also be produced by a known hydrolysis reaction,
deprotection reaction, acylation reaction, alkylation reaction, oxidation
reaction, cyclization reaction, carbon bond expanding reaction,
substituent exchanging reaction, or a combination thereof.
Compound (I) may be isolated and purified by per se known means
of separation such as recrystallization, distillation and chromatography,
and the like.
When Compound (I) is obtained in free form, it can be converted to
a salt by per se known methods or methods analogous thereto. When
Compound (I) is obtained in salt form, it can be converted to the free form
or another salt by perse known methods or methods analogous thereto.
Compound (I) may be a hydrate or a non-hydrate. The hydrate is
exemplified by monohydrate, sesquihydrate and dihydrate.
When Compound (I) is obtained as a mixture of optically active
configurations, it can be resolved into the (R)- and (S)-forms by the
conventional optical resolution techniques.
Compound (I) can be used as a prodrug. The prodrug of
Compound (I) or a salt thereof means a compound which is converted to
Compound (I) of the present invention under physiological conditions or
with a reaction due to an enzyme, an gastric acid, and the like in the
living body, that is, a compound which is converted to Compound CD of
the present invention with oxidation, reduction, hydrolysis, and the like
according to an enzyme; a compound which is converted to Compound (I)
of the present invention with gastric acid, etc. The prodrug for
Compound (I) may for example be a compound obtained by subjecting an
amino group in Compound (I) to an acylation, alkylation or
phosphorylation (e.g., a compound obtained by subjecting an amino group
in Compound CD or to an eicosanoylation, alanylation,
pentylaminocarbonylation, (5-methyl-2-oxo-l,3-dioxolen-4-
yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation and tert-butylation, etc.); a compound obtained
by subjecting a hydroxy group in Compound (I) to an acylation,
alkylation, phosphorylation or boration (e.g., a compound obtained by
subjecting an hydroxy in Compound (I) to an acetylation, palmitoylation,
propanoylation, pivaloylation, succinylation, fumarylation, alanylation,
dimethylaminomethylcarbonylation, etc.). Any of these compounds can
be produced from Compound (I) by a method known per se.
A prodrug of Compound (I) may also be one which is converted into
Compound (I) under a physiological condition, such as those described in
'TYAKUHIN no KAIHATSU (Development of Pharmaceuticals)", Vol.7,
Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN
(1990).
Compound (I) may be labeled with an isotope (e.g., 3H, 14C, 35S) and
the like.
In the reaction described above, a starting compound having an
amino group, a carboxy group or a hydroxy group as its substituent may
be present as a compound in which a protective group employed
ordinarily in a peptide chemistry has been introduced into such a
substituent, and an intended compound can be obtained by deprotection
if necessary after the reaction.
A protective group for an amino group may for example be an
optionally substituted C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, and the
like), formyl, phenylcarbonyl, a C1-6 alkyloxycarbonyl (e.g.,
methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like),
phenyloxycarbonyl, a C7-14 aralkyloxycarbonyl (e.g., benzyloxycarbonyl,
9-fluorenylmethoxycarbonyl, and the like), trityl, phthaloyl and the like.
Its substituent may for example be a halogen atom (e.g., fluorine,
chlorine, bromine and iodine), a C1-6 alkylcarbonyl (e.g., acetyl, propionyl,
butyryl, and the like), nitro and the like, and the number of the
substituents may be 1 to 3.
A protective group for a carboxy may for example be an optionally
substituted C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-
butyl, and the like), phenyl, trityl, silyl and the like. Its substituent
may for example be a halogen atom (e.g., fluorine, chlorine, bromine and
iodine), a C1- 6 alkylcarbonyl (e.g., acetyl, propionyl, butyryl, and the like),
formyl, nitro, and the number of the substituents may be 1 to 3.
A protective group for a hydroxy group may for example be an
optionally substituted C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl,
butyl, tert-butyl, and the like), phenyl, a C7-10 aralkyl (e.g., benzyl, and
the like), a C1-6 alkylcarbonyl (e.g., acetyl, propionyl, and the like), formyl,
phenyloxycarbonyl, a C7-10 aralkyloxycarbonyl (e.g., benzyloxycarbonyl,
and the like), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like.
Its substituent may for example be a halogen atom (e.g., fluorine,
chlorine, bromine and iodine), a C1-6 alkyl, phenyl, a C7-11 aralkyl, nitro,
and the like, and the number of the substituents may be 1 to 4.
The method for introducing and removing the protective group is
demonstrated in accordance with a known method or analogous method
thereof (e.g., the method described in Protective Groups in Organic
Chemistry (J.F.W.McOmie et al, Plenum Press). A deprotection method
may be a treatment with an acid, base, reduction, UV, hydrazine,
phenylhydrazine, sodium N-methyldithiocarbamate,
tetrabutylammonium fluoride, palladium acetate and the like.
Compound (I) of the present invention or a salt thereof (hereinafter
also refe.rred to as "the compound of the present invention") possesses
excellent GnRH-antagonizing activity and low toxicity (for example, acute
toxicity, chronic toxicity, genetic toxicity, reproduction toxicity,
cardiotoxicity, drug interaction, carcinogenicity). In addition, it is
excellent in oral absorbability, action sustainability, stability and
pharmacokinetics. Also, it is scarcely influenced by plasma ingredients.
The compound of the present invention can therefore be safely used in a
mammal (e.g., human, monkey, bovine, horse, dog, cat, rabbit, rat,
mouse, etc.) for the preventing and/or treating diseases depending on
male or female hormones, diseases due to excess of these hormones, etc.,
by suppressing gonadotropin secretion with its GnRH receptor-
antagonizing action to control plasma sex hormone concentrations.
For example, the compound of the present invention is useful for
preventing and/or treating sex hormone-dependent cancers (e.g., prostatic
cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone
metastasis of sex hormone-dependent cancer, prostatic hypertrophy,
hysteromyoma, endometriosis, metrofibroma, precocious puberty,
amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary
syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease
(Alzheimer's disease, senile dementia of Alzheimer type and a mixed type
thereof), and the like. The compound of the present invention is also
useful for the regulation of reproduction in males and females (e.g.,
pregnancy regulators, menstruation cycle regulators, etc.). The
compound of the present invention can be also used as a male or female
contraceptive, or as a female ovulation inducer. Based on its rebound
effect after withdrawal, the compound of the present invention can be
used to treat infertility. And the compound of this invention can be used
as an agent for preventing and/or treating benign or malignant tumor
which is hormone independent and LH-RH sensitive. And the
compound of the present invention can be used as an agent for
preventing and/or treating irritable bowel syndrome and for preventing
postoperative recurrence of sex hormone-dependent cancer (an agent for
preventing postoperative recurrence of prostatic cancer; an agent for
preventing postoperative recurrence of breast cancer or ovarian cancer in
the condition before or after menopause! especially, an agent for
preventing postoperative recurrence of breast cancer or ovarian cancer in
the condition before menopause).
In addition, the compound of the present invention is useful for
regulation of animal estrus, improvement of meat quality and promotion
of animal growth in the field of animal husbandry. The compound of the
present invention is also useful as a fish spawning promoter.
The compound of the present invention can be also used to
suppress the transient rise in plasma testosterone concentration (flare
phenomenon) observed in administration of a GnRH super-agonist such
as leuprorelin acetate. The compound of the present invention can be
used in combination with a GnRH super-agonist such as leuprorelin
acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin,
deslorelin, meterelin, lecirelin, and the like. Among others, preferred is
leuprorelin acetate.
It is also beneficial to use the compound of the present invention in conjunction with at least one member selected from the steroidal or
nonsteroidal antiandrogen agent or antiestrogen agent, chemotherapeutic
agent, GnRH antagonistic peptide, orreductase inhibitor, a-receptor
inhibitor, aromatase inhibitor, 17ß-hydroxysteroid dehydrogenase
inhibitor, adrenal androgen production inhibitor, kinase inhibitor, drug
for hormone therapy, and drug inhibiting cell growth factor or its
receptor, among others.
The "chemotherapeutic agent" mentioned above includes
ifosfamide, adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU,
UFT, methotrexate, mitomycin C, mitoxantrone, etc.
The "GnRH antagonistic peptide" mentioned above includes non-
oral GnRH antagonistic peptides such as cetrorelix, ganirelix, abarelix,
etc.
The "adrenal androgen production inhibitor" mentioned above
includes lyase (C17,20-lyase) inhibitors, etc.
The "kinase inhibitor" mentioned above includes tyrosine kinase
inhibitor, etc.
The "drugs for hormone therapy" includes antiestrogens,
progesterons (e.g., MP A, etc.), androgens, estrogens and androgen
antagonists, among others.
The "cell growth factor" may be any substance that promotes
proliferation of cells and generally includes peptides with molecular
weights not over 20,000 which express the action at low concentrations
through binding to receptors. Specifically, there can be mentioned (l)
EGF (epidermal growth factor) or substances having the substantially the
same activity (e.g., EGF, heregulin (HER2 ligand), etc.), (2) insulin or
substances having substantially the same activity (e.g., insulin, IGF
(insulin-like growth factor)-1, IGF-2, etc.), (3) FGF (fibroblast growth
factor) or substances having substantially the same activity (aFGF,
bFGF, KGF (keratinocyte growth factor), HGF (hepatocyte growth factor),
FGF-10, etc.), and (4) other growth factors (e.g., CSF (colony stimulating
factor), EPO (erythropoietin), IL-2 dnterleukin-2), NGF (nerve growth
factor), PDGF (platelet-derived growth factor) and TGF0 (transforming
growth factor p), etc.), among others.
The "cell growth factor receptor" may be any receptor capable of
binding said cell growth factor, including EGF receptor, heregulin
receptor (HER2), insulin receptor-1, insulin receptor-2, IGF receptor,
FGF receptor-1, FGF receptor-2, etc.
The drug inhibiting the cell growth factor mentioned above
includes herceptin (anti-HER2 receptor antibody), among others.
The drug inhibiting the growth factor mentioned above or its
receptor includes herbimycin, PD153035 [e.g., Science, 265 (5175) p 1093,
(1994)], etc.
As a further class of drugs inhibiting the cell growth factor or its
receptor includes HER2 inhibitors. The HER2 inhibitor may be any
substance that inhibits the activity of HER2 (e.g., phosphorylating
activity), thus including an antibody, a low-molecular weight compound
(synthetic or natural product), an antisense, an HER2 ligand, heregulin,
and any of them as partially modified or mutated in structure.
Moreover, it may be a substance which inhibits HER2 activity by
inhibiting HER2 receptor (e.g. HER2 receptor antibody). The low
molecular weight compound having HER2 inhibiting activity includes, for
example, the compounds described in WO 98/03505, namely l-[3-[4-[2-
((E)-2-phenylethenyl)-4-oxazolylmethoxy]phenyl]propyl]-l,2,4-triazole
and the like.
For prostatic hypertrophy, examples of such combination includes
the compound of the present invention in combination with the GnRH
super-agonist, androgen antagonist, antiestrogen, GnRH antagonistic
peptide, crreductase inhibitor, a-receptor inhibitor, aromatase inhibitor,
17p-hydroxysteroid dehydrogenase inhibitor, adrenal androgen
production inhibitor, kinase inhibitor, or the like.
For prostatic cancer, examples of such combination includes the
compound of the present invention in combination with the GnRH super-
agonist, androgen antagonist, antiestrogen, chemotherapeutic agent (e.g.,
ifosfamide, UFT, adriamycin, peplomycin, cisplatin, etc.), GnRH
antagonistic peptide, aromatase inhibitor, 17ß-hydroxysteroid
dehydrogenase inhibitor, adrenal androgen production inhibitor, kinase
inhibitor, drug for hormone therapy such as estrogenes (e.g., DSB, EMP,
etc.), androgen antagonist (e.g., CMA. etc.), drug antagonizing growth
factor or its receptor, and so forth.
For breast cancer, examples of such combination includes the
compound of the present invention in combination with the GnRH super-
agonist, antiestrogen, chemotherapeutic agent (e.g., cyclophosphamide, 5-
FU, UFT, methotrexate, adriamycin, mitomycin C, mitoxantrone, etc.),
GnRH antagonistic peptide, aromatase inhibitor, adrenal androgen
production inhibitor, kinase inhibitor, drug for hormone therapy such as
antiestrogen (e.g., tamoxifen, etc.), progesterons (e.g., MPA, etc.),
androgens, estrogens, etc., drug antagonizing growth factor or its
receptor, or the like.
The administration mode of the compound of the present invention
and a concomitant medicament are not particularly limited, provided that
the compound of the present invention and the concomitant medicament
are combined upon administration. Such an administration mode may
for example be (l) an administration of a single formulation obtained by
formulating the compound of the present invention and a concomitant
medicament simultaneously, (2) a simultaneous administration via an
identical route of two formulations obtained by formulating the
compound of the present invention and a concomitant medicament
separately, (3) a sequential and intermittent administration via an
identical route of two formulations obtained by formulating the
compound of the present invention and a concomitant medicament
separately, (4) a simultaneous administration via different routes of two
formulations obtained by formulating the compound of the present
invention and a concomitant medicament separately, (5) a sequential and
intermittent administration via different routes of two formulations
obtained by formulating the compound of the present invention and a
concomitant medicament separately (for example, the compound of the
present invention followed by concomitant medicament, or inverse
order) and the like.
When the compound of the present invention is used as a
preventing and/or treating agent for the above-mentioned diseases or
used in the field of animal husbandry or fishery, it can be administered
orally or non-orally, as formulated with a pharmaceutically acceptable
carrier, normally in the form of solid preparations such as tablets,
capsules, granules and powders for oral administration, or in the form of
intravenous, subcutaneous, intramuscular or other injections,
suppositories or sublingual tablets for non-oral administration. It may
also be sublingually, subcutaneously, intramuscularly or otherwise
administered in the form of sustained-release preparations of sublingual
tablets, microcapsules, etc. Depending on symptom severity; subject
age, sex, weight and sensitivity," duration and intervals of administration;
property, dispensing and kind of pharmaceutical preparation; kind of
active ingredient etc., daily dose is not subject to limitation. For use in
the treatment of the above-described sex hormone-dependent cancers
(e.g., prostatic cancer, uterine cancer, breast cancer, pituitary tumor,
etc.), prostatic hypertrophy, hysteromyoma, endometriosis, precocious
puberty etc., daily dose is normally about 0.01 to 30 mg, preferably about
0.02 to 10 mg, and more preferably 0.1 to 10 mg, especially preferably 0.1
to 5 mg per kg weight of mammal, normally in 1 to 4 divided dosages.
The above doses of the active ingredient (the compound of the
present invention) for oral administration are applicable to the use of the
compound of the present invention in the field of animal husbandry or
fishery. Daily dose is about 0.01 to 30 mg, preferably about 0.1 to 10 mg,
per kg weight of subject organism, normally in 1 to 3 divided dosages.
In the pharmaceutical composition of the present invention, the
amount of Compound (I) is 0.01 to 100 % by weight or so of the total
weight of the composition.
The above pharmaceutically acceptable carriers are various
organic or inorganic carrier substances in common use as pharmaceutical
materials, including excipients, lubricants, binders and disintegrants for
solid preparations; solvents, dissolution aids, suspending agents,
isotonizing agents, buffers and soothing agents for liquid preparations,"
and the like. Other pharmaceutical additives such as preservatives,
antioxidants, coloring agents and sweetening agents may be used as
necessary.
Preferable examples of excipients include, for example, lactose,
sucrose, D-mannitol, starch, crystalline cellulose, light silicic anhydride,
and the like. Preferable examples of lubricants include, for example,
magnesium stearate, calcium stearate, talc, colloidal silica, and the like.
Preferable examples of binders include, for example, crystalline cellulose,
sucrose, D-mannitol, dextrin, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and the like.
Preferable examples of disintegrants include, for example, starch,
carboxymethyl cellulose, carboxymethyl cellulose calcium, crosslinked
carmellose sodium, carboxymethyl starch sodium, and the like.
Preferable examples of solvents include, for example, water for injection,
alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like.
Preferable examples of dissolution aids examples of include, for example,
polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,
ethanol, trisaminomethane, cholesterol, triethanolamine, sodium
carbonate, sodium citrate, and the like. Preferable examples of
suspending agents include, for example, surfactants such as
stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,
lecithin, benzalkonium chloride, benzethonium chloride, monostearic
glycerol, and the like" and hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose,
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
and the like. Preferable examples of isotonizing agents include, for
example, sodium chloride, glycerol, D-mannitol, and the like. Preferable
examples of buffers include, for example, buffer solutions of phosphates,
acetates, carbonates, citrates, and the like. Preferable examples of
soothing agents include, for example, benzyl alcohol, and the like.
Preferable examples of preservatives include, for example,
paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl
alcohol, dehydroacetic acid, sorbic acid, and the like. Preferable
examples of antioxidants include, for example, sulfites, ascorbic acid, and
the like.
By adding suspending agents, dissolution aids, stabilizers,
isotonizing agents, preservatives, and the like, the compound of the
present invention can be prepared as an intravenous, subcutaneous or
intramuscular injection by a commonly known method. In such cases,
the compound of the present invention can be freeze-dried as necessary
by a commonly known method. In administration to humans, for
example, the compound of the present invention can be safely
administered orally or non-orally as such or as a pharmaceutical
composition prepared by mixing it with a pharmacologically acceptable
carrier, excipient and diluent selected as appropriate.
Such pharmaceutical compositions include oral preparations (e.g.,
powders, granules, capsules, tablets), parenteral preparations [e.g.,
injections, drip infusions, external preparations (e.g., nasal preparations,
transdermal preparations, and the like), suppositories (e.g., rectal
suppositories, vaginal suppositories, and the like), and the like].
These preparations can be produced by commonly known methods
in common use for pharmaceutical making processes.
An injection can be produced by, for example, preparing the
compound of the present invention as an aqueous injection along with a
dispersing agent (e.g., Tween 80 (produced by Atlas Powder Company,
USA), HCO 60 (produced by Nikko Chemicals Co., Ltd.), polyethylene
glycol, carboxymethyl cellulose, sodium alginate, and the like), a
preservative (e.g., methyl paraben, propyl paraben, benzyl alcohol, and
the like), an isotonizing agent (e.g., sodium chloride, mannitol, sorbitol,
glucose, and the like), and the like, or as an oily injection in solution,
suspension or emulsion in a vegetable oil such as olive oil, sesame oil,
cottonseed oil or corn oil; propylene glycol and the like.
An oral preparation can be produced by formulating the
compound of the present invention by a compression molding after
addition of an excipient (e.g., lactose, sucrose, starch, and the like), a
disintegrant (e.g., starch, calcium carbonate, and the like), a binder (e.g.,
starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone,
hydroxypropyl cellulose, and the like), a lubricant (e.g., talc, magnesium
stearate, polyethylene glycol 6000, and the like) and other additives, and,
where necessary, coating the formulated product for the purpose of taste
masking, enteric dissolution or sustained release by a commonly known
method. Coating agents for this purpose include, for example,
hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,
hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Prulonic F68,
cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,
hydroxymethyl cellulose acetate succinate, Eudragit (produced by Rohm
Company, Germany,' methacrylic acid/acrylic acid copolymer), dyes (e.g.,
iron oxide, titanium dioxide), and the like. For an enteric preparation,
an intermediate phase may be provided between the enteric phase and
the drug-containing phase for the purpose of separation of the two phases
by a commonly known method.
An external preparation can be produced by converting the
compound of the present invention as a solid, semi-solid or liquid
composition by a commonly known method. Such a solid composition is
produced by, for example, powdering the compound of the present
invention as such or in mixture with an excipient (e.g., glycol, mannitol,
starch, microcrystalline cellulose, and the like), a thickening agent (e.g.,
natural rubber, cellulose derivative, acrylic acid polymer, and the like)
and other additives. Such a liquid composition is produced by preparing
the compound of the present invention as an oily or aqueous suspension
in almost the same manner as the injection. The semi-solid composition
is preferably an aqueous or oily gel, or an ointment. All these
compositions may contain pH regulators (e.g., carbonic acid, phosphoric
acid, citric acid, hydrochloric acid, sodium hydroxide, and the like),
preservatives (e.g., paraoxybenzoic acid esters, chlorobutanol,
benzalkonium chloride, and the like) and other additives.
A suppository is produced by preparing the compound of the
present invention as an oily or aqueous solid, semi-solid or liquid
composition by a commonly known method. Useful oily bases for such
compositions include glycerides of higher fatty acids (e.g., cacao fat,
witepsols (produced by Dynamite Nobel Company, Germany) and the
like,' medium fatty acids (e.g., MIGLIOL, produced by Dynamite Nobel
Company, Germany); and vegetable oils (e.g., sesame oil, soybean oil,
cottonseed oil, and the like). Aqueous bases include, for example,
polyethylene glycols and propylene glycol. Bases for aqueous gels
include, for example, natural rubbers, cellulose derivatives, vinyl
polymers and acrylic acid polymers.
A compound of the formula:

wherein R11 and R13 each is a C1-4 alkyl, R14 is a hydrogen atom or a C1-4
alkoxy and m is an integer of 1 to 4 (hereinafter briefly referred to as
Compound (V)) or a salt thereof also has an excellent GnRH antagonizing
activity, especially a strong antagonistic activity though the compound
falls outside the scope of Compound (I).
Examples of the "C1-4 alkyl" represented by R11 or R13 include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
Examples of the "C1-4 alkoxy" represented by R14 include methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
etc.
As R11, methyl is preferable.
As R13, methyl is preferable.
As R14, a hydrogen atom and methoxy are preferable.
Preferable examples of m are 1 and 2.
Preferable examples of Compound (V) are N-(4-(5-((2-
methoxy ethyl)methylamino)methyl) -1 - (2,6 - difluorobenzyl) -1,2,3,4-
tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-
yl)phenyl)-N'-methoxyurea or N-(4-(l-(2,6-difluorobenzyl)-5-
((dimethylamino)methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea and a salt
thereof.
Salts of Compound (V) are preferably physiologically acceptable
acid addition salts. Such salts include, for example, salts with inorganic
acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
phosphoric acid), salts with organic acids (e.g., formic acid, acetic acid,
trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
citric acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the like. When
Compound (V) has an acidic group, it may form a physiologically
acceptable salt with an inorganic base (e.g., alkali metals and alkaline
earth metals such as sodium, potassium, calcium and magnesium,
ammonia, and the like) or an organic base (e.g., trimethylamine,
triethylamine, pyridine, picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and
the like).
Compound (V) can be produced by the method described in JP-A-9-
169768 (WO 96/24597) and JP-A-2001-278884 (WO 00/56739) and its
analogous method.
Compound (V) may be a hydrate or a non-hydrate. The hydrate is
exemplified by monohydrate, sesquihydrate and dihydrate.
Compound (V) can be used as a prodrug. The prodrug means a
compound which is converted to Compound (V) by a reaction due to an
enzyme, an gastric acid, or the like under physiological conditions in the
living body, that is, a compound which is converted to Compound (V) with
oxidation, reduction, hydrolysis, or the like according to an enzyme, or a
compound which is converted to Compound (V) with gastric acid, etc.
The prodrug for Compound (V) may for example be a compound obtained
by subjecting an amino group in Compound (V) to an acylation,
alkylation or phosphorylation (e.g., a compound obtained by subjecting an
amino group in Compound (V) to an eicosanoylation, alanylation,
pentylaminocarbonylation, (5-methyl-2-oxo-l,3-dioxolen-4-
yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation and tert-butylation, etc.). These compounds can
be produced from the compound of the present invention.
A prodrug of Compound (V) may also be one which is converted
into Compound (V) under a physiological condition, such as those
described in TYAKUHIN no KAIHATSU (Development of
Pharmaceuticals)", Vol.7, Design of Molecules, p.163-198, Published by
HIROKAWASHOTEN (1990).
Compound (V) may be labeled with an isotope (e.g., 3H, 14C,35S)
and the like.
And the compound represented by the formula-

wherein Ra is (l) a hydrogen atom, (2) an aryl group which may have 1 to
5 substituent(s) selected from the group consisting of (i) a halogen, (ii) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3)
a cycloalkyl group which may have a substituent or (4) a heterocyclic
group which may have a substituent; Rb is a nitrogen-containing
heterocyclic group which may have a substituent; Rc is an amino group
which may have a substituent; Rd is an aryl group which may have a
substituent; p is an integer of 0 to 3; and q is an integer of 0 to 3
(hereinafter as abbreviated as Compound (A)) or a salt thereof, which
contains a part of the Compound (I) of the present invention, has an
excellent GnRH antagonizing activity, especially strong antagonistic
activity similar to Compound (I).
The definitions of the substituents of Compound (A) are shown
below.
Examples of "aryl" of "aryl group which may have 1 to 5
substituentOs) selected from the group consisting of (0 a halogen, Gi) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xO an alkylsulfonyl"
represented by Ra are Ce-u aryl such as phenyl, 1-naphthyl, 2-naphthyl,
anthryl, phenanthryl, acenaphthylenyl, and the like.
Examples of "halogen" of "aryl group which may have 1 to 5
substituent(s) selected from the group consisting of (0 a halogen, (h) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xO an alkylsulfonyr
represented by R" are fluorine, chlorine, bromine and iodine.
Examples of "carboxyl group which may be esterified or amidated"
of "aryl group which may have 1 to 5 substituent(s) selected from the
group consisting of (0 a halogen, (ii) a nitro, (iii) a cyano, (iv) an amino,
(v) a carboxyl group which may be esterified or amidated, (vi) an
alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an
alkylsulfinyl and (xi) an alkylsulfonyl" represented by Ra are carboxyl, a
Ci 6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,
hexyloxycarbonyl, and the like), a C3 6 cycloalkyloxycarbonyl (e.g.,
cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl,
cyclohexyloxycarbonyl, and the like), a Ce-u aryloxycarbonyl (e.g.,
phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl,
anthryloxycarbonyl, phenanthryloxycarbonyl,
acenaphthylenyloxycarbonyl, and the like), a C710 aralkyloxycarbonyl
(e.g., benzyloxycarbonyl, and the like), carbamoyl, a N-mono-Ci 6 alkyl-
carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,
isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-
butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl,
and the like), a N-mono-Ca-e cycloalkyl-carbamoyl (e.g.,
cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl,
cyclohexylcarbamoyl, and the like), a N-mono-C6 u aryl-carbamoyl (e.g.,
phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl,
anthrylcarbamoyl, phenanthryloxycarbamoyl,
acenaphthylenyloxycarbamoyl, and the like), N-mono-C710 aralkyl-
carbamoyl (e.g., benzylcarbamoyl, and the like), and the like.
Examples of "alkylenedioxy" of "aryl group which may have 1 to 5
substituentCs) selected from the group consisting of G) a halogen, Gi) a
nitro, Gii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, Gx) an alkylthio, (x) an alkylsulfinyl and Go) an alkylsulfonyl"
represented by Ra are a Ci-6 alkylenedioxy (e.g., -OCH2O, -(XCH^O-, -
(XCHsDaO-, -0(CH2)40-, -CKCH^sO-, -CKCH^sO-).
Examples of "alkyl" of "aryl group which may have 1 to 5
substituentCs) selected from the group consisting of (0 a halogen, (ii) a
nitro, Gii) a cyano, Gv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, Gx) an alkylthio, (x) an alkylsulfinyl and (xO an alkylsulfonyl"
represented by R" are a Ci-e alkyl (e.g., methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like), and the
like.
Examples of "alkoxy" of "aryl group which may have 1 to 5
substituent(s) selected from the group consisting of G) a halogen, Gi) a
nitro, Gii) a cyano, Gv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, Gx) an alkylthio, (x) an alkylsulfinyl and (xO an alkylsulfonyl"
represented by Ra are a Ci e alkoxy (e.g., methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,
hexyloxy, and the like), and the like.
Examples of "alkylthio" of "aryl group which may have 1 to 5
substituent(s) selected from the group consisting of G) a halogen, Gi) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and Od) an alkylsulfonyl"
represented by R» are a Cie alkylthio (e.g., methylthio, ethylthio,
propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-
butylthio, pentylthio, hexylthio, and the like), and the like.
Examples of "alkylsulfinyl" of "aryl group which may have 1 to 5
substituent(s) selected from the group consisting of 6) a halogen, (ii) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xO an alkylsulfonyl"
represented by Ra are a Ci-e alkylsulfinyl (e.g., methylsulfinyl,
ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,
isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl,
hexylsulfinyl, and the like), and the like.
Examples of "alkylsulfonyl" of "aryl group which may have 1 to 5
substituent(s) selected from the group consisting of (0 a halogen, (ii) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xO an alkylsulfonyl"
represented by R« are a Ci-6 alkylsulfonyl (e.g., methylsulfonyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,
hexylsulfonyl, and the like), and the like.
Examples of "cycloalkyl group" of "cycloalkyl group which may
have a substituent" represented by R« are a Ca 6 cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like), and the
like.
Examples of "heterocyclic group" of "heterocyclic group which may
have a substituent" represented by Ra are (l) a 5-membered cyclic group
which contains 1 to 4 heteroatom(s) selected from an oxygen atom, a
sulfur atom, a nitrogen atom and the like in addition to a carbon atom
(e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-
oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-
pyrazolyl, 4-pyrazolyi, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-
imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-
isothiazolyl, 5-isothiazolyl, 3-(l,2,4-oxadiazolyl), 5-(l,2,4-oxadiazolyl),
1,3,4-oxadiazolyl, 3-(l,2,4-thiadiazolyl), 5-(l,2,4-thiadiazolyl), 1,3,4-
thiadiazolyl, 4-(l,2,3-thiadiazolyl), 5-(l,2,3-thiadiazolyl), 1,2,5-
thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetrazolyl, 2H-tetrazolyl,
oxoimidazinyl, dioxotziazinyl, pyrrolidinyl, and the like), (2) a 6-
membered cyclic group which contains 1 to 4 heteroatomCs) selected from
an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition
to a carbon atom (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-pyridyl,
N-oxido-3-pyridyl, N-oxido-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-
pyrimidinyl, N-oxido-2-pyrimidinyl, N-oxido-4-pyrimidinyl, N-oxido-5-
pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-
morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-
thiazinyl, 1,3-thiazinyl, 2-piperazinyl, 3-piperazinyl, triazinyl,
oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl, pyrazinyl, N-oxido-3-
pyridazinyl, N-oxido-4-pyridazinyl, and the like), and (3) a bicyclic or
tricyclic condensed cyclic group which contains 1 to 4 heteroatom(s)
selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like
in addition to a carbon atom (e.g., benzofuryl, benzothiazolyl,
benzoxazolyl, tetrazolo[l,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl,
benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylidinyl,
purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl,
phenanthrydinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, and the like).
Examples of "substituent" of "cycloalkyl group which may have a
substituent" and "heterocydic group which may have a substituent"
represented by Ra are G) a Ci e alkyl (e.g., methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like), Gi) a C2 s
alkenyl (e.g., vinyl, allyl, 1-butenyl, 2-butenyl, and the like), (iii) a C2 e
alkynyl (e.g., ethynyl, propargyl, 2-butynyl, 5-hexynyl, and the like), dv)
a C36cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, and
the like), (v) a Ce-u aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, and the
like), (vi) a C7-14 aralkyl (e.g., benzyl, phenethyl, and the like), (vii) a
nitro, (viii) a hydroxy, (ix) a mercapto, (x) a cyano, (xO a carbamoyl, (xii) a
carboxyl, Cxiii) a Ci 6 alkoxy-carbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl, hexyloxycarbonyl, and the like), (xiv) a sulfo, (xv) a
halogen (e.g., fluorine, chlorine, bromine and iodine), (xvi) a C1-6 alkoxy
(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
tert-butoxy, pentyloxy, hexyloxy, and the like), which may have a Ci-e
alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-
butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like), (xvii) a Cs-io
aryloxy (e.g., phenoxy, 1-naphthyloxy, 2-naphthyloxy, and the like),
(xviii) a C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,
pentylthio, hexylthio, and the like), (xix) a Cs-io arylthio (e.g., phenylthio,
1-naphthylthio, 2-naphthylthio, and the like), (xx) a Ci e alkylsulfinyl
(e.g., methylsulfinyl, ethylsulfinyl, prppylsulfinyl, isopropylsulfinyl,
butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl,
pentylsulfinyl, hexylsulfinyl, and the like), (xxi) a Ce 10 arylsulfinyl (e.g.,
phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like),
(xxii) a Ci 6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-
butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the
like), (xxiii) a Ce 10 arylsulfinyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,
2-naphthylsulfonyl, and the like), (xxiv) an amino, (xxv) a Ci-e acylamino,
(e.g., formylamino, acetylamino, propionylamino, butyrylamino,
isobutyrylamino, valerylamino, and the like), (xxvi) a mono-Ci 6
alkylamino (e.g., methylamino, ethylamino, propylamino,
isopropylamino, butylamino, and the like), (xxvii) a drCi e alkylamino
(e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino,
dibutylamino, and the like), (xxviii) a C3 -e cycloalkylamino (e.g.,
cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,
and the like), Gorix) a Cs-io arylamino (e.g., anilino, 1-naphthylamino, 2-
naphthylamino, and the like), (xxx) a Ci e acyl (e.g., formyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, and the like), (xxxO a Ce 10
arylcarbonyl (e.g., benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl, and
the like), (xxxii) a Ci-4 alkylenedioxy (e.g., -OCH2O-, -0(CH2)20-, -
OiCHsdsO- and -OiCH^O-), (xxxiii) a 5- or 6-membered heterocyclic
group which contains 1 to 4 heteroatom(s) selected from an oxygen atom,
a sulfur atom, a nitrogen atom and the like in addition to a carbon atom
(e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3*pyrrolyl, 2-
oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-
pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-
imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-
isothiazolyl, 5-isothiazolyl, 3*(l,2,4-oxadiazolyl), 5-(l,2,4-oxadiazolyl),
1,3,4-oxadiazolyl, 3-(l,2,4-thiadiazolyl), 5-(l,2,4-thiadiazolyl), 1,3,4-
thiadiazolyl, 4-(l,2,3-thiadiazolyl), 5-(l,2,3-thiadiazolyl), 1,2,5-
thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetrazolyl, 2H-tetrazolyl,
oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-thiomorpholinyl, 3-
thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl,
thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl, 3-
piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl,
pyrazinyl, and the like), (xxxiv) oxo, (xxxv) thioxo, and the like. The
number of substituent is 1 to 6, preferably 1 to 3, and the substitution
position may be any place on which the substitution is possible.
Examples of "nitrogen-containing heterocyclic group" of "nitrogen-
containing heterocyclic group which may have a substituent" represented
by Rb are a 5- to 7-membered nitrogen-containing heterocyclic group (e.g.,
pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazolidin-3-yl,
thiazolidin-3-yl, isoxazolidin-2-yl, isothiazolidin-2-yl, imidazolidin-1-yl,
imidazolidiri-2-yl, iniidazolidin-4-yl, pyrazoIidin-2-yI, pyrazolidin-3-yl,
pyrazoKdin-4-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazoM-yl,
imidazol-2-yl, imidazol-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,2,3-
triazoM-yl, 1,2,5-triazoM-yl, tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl,
oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-
5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,
isothiazol-5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-
yi, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, morpholin-3-yl,
morpholin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl,
pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-
4-yl, l,2,3-triazin-4-yl, l,2,3-triazin-5-yl, l,2,4-triazin-3-yl, 1,2,4-triazin-
5-yl, l,2,4-triazin-6-yl, l,3,5-triazin-2-yl, l,2,3,4-tetrazin-5-yl, 1,2,3,5-
tetrazin-4-yl, azepan-1-yl, azepan-2-yI, l,2-diazepan-3-yl, l,2-diazepan-4i
yl, l,2-diazepan-5-yl, l,3-diazepan-2-yl, l,3-diazepan-4-yl, 1,3-diazepan-
5-yl, l,4-diazepan-2-yl, l,4-diazepan-3-yl, l,4-diazepan-5-yl, 1,2,3-
triazepan-4-yl, l,2,3-triazepan-5*yl, l,2,4-txiazepan-3-yl, 1,2,4-triazepan-
5-yl, and the like), and the like.
Examples of "substituent" of "nitrogen-containing heterocyclic
group which may have a substituent" represented by Rb are same number
and same kind as "substituent" of "cycloalkyl group which may have a
substituent" and "heterocyclic group which may have a substituent"
represented by RExample of "amino group which may have a substituent"
represented by Rc is a group of the formula" -NReRf wherein R° is (l) a
hydrogen atom, (2) a Ci 6 alkyl which may have a substituent, (3) a C3-6
cycloalkyl which may have a substituent, (4) a Cg-u aryl which may have
a substituent, (5) a C7-20 aralkyl which may have a substituent, (6) a
carbamoyl which may have a substituent or (7) a heterocyclic group; and
Rf is a hydrogen atom or a C1-6 alkyl whish may have a substituent.
Examples of "Ci -e alkyl" of "Ci-e alkyl which may have a
substituent" represented by Re and Rf are methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, peutyl, hexyl, and the like.
Examples of the substituent of "Cm alkyl which may have a
substituent" represented by Re and Rf are (l) a Ci-e alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
hexyl, and the like), (2) a C2-ealkenyl (e.g., vinyl, 1-methylvinyl, 1-
propenyl, allyl, and the like), (3) a C2-6alkynyl (e.g., ethynyl, 1-propynyl,
propargyl and the like), (4) a Ca-e cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and the like), (5) a Ce-7 cycloalkenyl (e.g.,
cyclopentenyl, cyclohexenyl, and the like), (6) a C711 aralkyl (e.g., benzyl,
a-methylbenzyl, phenethyl, and the like), (7) a C6-uaryl (e.g., phenyl,
naphthyl, and the like), (8) a &-6 alkoxy (e.g., methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like), (9) a
Ce 14 aryloxy (e.g., phenoxy, 1-naphthoxy, 2-naphthoxy, and the like), (10)
a Ci-6 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, and the
like), (ll) a C614 aryl-carbonyl (e.g., benzoyl, 1-naphthylcarbonyl, 2-
naphthylcarbonyl, and the like)* (12) a Ci-e alkanoyloxy (e.g., formyloxy,
acetoxy, propionyloxy, butyryloxy, isobutyryloxy, and the like), (13) a Ce 14
aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthylcarbonyloxy, 2-
naphthylcarbonyloxy, and the like), (14) a carboxy, (15) a C1-6 alkoxy-
carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-
butoxycarbonyl, and the like), (16) a carbamoyl, (17) a N-mono-Ci-4
alkylcarbamoyl (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N-
propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, and the like),
(18) a N,N-di-Ci 4 alkylcarbamoyl (e.g., N,N-dimethylcarbamoyl, N,N-
diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, and
the like), (19) a cyclic aminocarbonyl (e.g., 1-aziridinylcarbonyl, 1-
azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-
methylpiperazinylcarbonyl, morpholinocarbonyl, and the like), (20) a
halogen (e.g., fluorine, chlorine, bromine, iodine), (21) a Ci 4 alkyl
substituted by 1 to 3 halogen(s) (e.g., chloromethyl, dichloromethyl,
trifluoromethyl, trifluoroethyl, and the like), (22) an oxo, (23) an amidino,
(24) an imino, (25) an amino, (26) a mono- or di-Ci 4 alkylamino (e.g.,
methylamino, ethylamino, propylamino, isopropylamino, butylamino,
isobutylamino, secbutylamino, tert-butylamino, pentylamino,
hexylamino, dimethylamino, diethylamino, dipropylamino, and the like),
(27) a 3- to 6-membered cyclic amino which may contain 1 to 3
heteroatom(s) selected from an oxygen atom, a sulfur atom, a nitrogen
atom, and the like in addition to carbon atom (e.g., aziridinyl, azetidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl,
piperidino, morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-
ethylpiperazinyl, and the like), (28) a Ci 6 alkanoylamino (e.g.,
formylamino, acetylamino, triQuoroacetylamino, propionylamino,
butyrylamino, isobutyrylamino, and the like), (29) a benzamido, (30)
carbamoylamino, (31) a (N-Ci-4 alkylcarbamoyl)amino (e.g., (N-
methylcarbamoyl)amino, (N-ethylcarbamoyl)amino, (N-
propylcarbamoyDamino, (N-isopropylcarbamoyDamino, (N-
butylcarbamoyDamino, and the like), (32) a (N,N-di-Ci 4
alkylcarbamoyDamino (e.g., (N,N-dimethylcarbamoyl)amino, (N,N-
diethylcarbamoyDamino, CN,N-dipropylcarbamoyl)amino, (N,N-
dibutylcarbamoyDamino, and the like), (33) a Ci e alkylenedioxy (e.g., -
OCH2O-, -0(CH2)20-, -0(CH2)sO-, -CXCH^O, -CKCHskO-, -0(CHd*0-(34) a dihydroboryl, (35) a hydroxy, (36) an epoxy, (37) a nitro, (38) a
cyano, (39) a mercapto, (40) a sulfo, (41) a sulfino, (42) a phosphono, (43)
a sulfamoyl, (44) a N-Ci-e alkylsulfamoyl (e.g., N-methylsulfamoyl, N-
ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-
butylsulfamoyl, and the like), (45) a N,N-di-Ci s alkylsulfamoyl (e.g., N,N-
dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-
dibutylsulfamoyl, and the like), (46) a Ci-e alkylthio (e.g., methylthio,
ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-
butylthio, and the like), (47) a phenylthio, (48) a Ci* alkylsulfinyl (e.g.,
methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like),
(49) a phenylsulfinyl, (50) a Ci s alkylsulfonyl (e.g., methylsulfonyl,
ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like), (51) a
phenylsulfonyl, and the like. The number of substituent is 1 to 6,
preferably 1 to 3, and the substitution position may be any place on
which the substitution is possible.
Examples of "Cs-6 cycloalkyl" of "Ca e cycloalkyl which may have a
substituent" represented by Re are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and the like.
Examples of the substituent of "Cs-e cycloalkyl which may have a
substituent" represented by R« are the same as the substituent of "Ci-e
alkyl which may have a substituent" represented by Re and Rf above.
The number of substituents is 1 to 6, preferably 1 to 3, and the
substitution position may be any place on which the substitution is
possible.
Examples of Ce-u aryl of "Ce-u aryl which may have a substituent"
represented by Re are phenyl, naphthyl, anthracenyl, and the like.
Examples of the substituent of "Ce-u aryl which may have a
substituent" are the same as the substituent of "Ci-6 alkyl which may
have a substituent" represented by Re and Rf above except for oxo and
epoxy. The number of substituents is 1 to 6, preferably 1 to 3, and the
substitution position may be any place on which the substitution is
possible.
Examples of C720aralkyl of "C720aralkyl which may have a
substituent" represented by Re are benzyl, phenethyl, phenylpropyl,
benzhydoryl, trityl and the like.
Examples of the substituent of "C7-20 aralkyl which may have a
substituent" are the same as the substituent of "Ci e alkyl which may
have a substituent" represented by R° and Rf above. The number of
substituent is 1 to 6, preferably 1 to 3, and the substitution position may
be any place on which the substitution is possible.
Examples of the substituent of "carbamoyl which may have a
substituent" represented by Re are (l) a Ci-e alkyl which may have a
substituent, (2) a Cse cycloalkyl which may have a substituent, (3) a Ce-u
aryl which may have a substituent, (4) a C7-20 aralkyl which may have a
substituent, (5) a hydroxy, (6) a Ci-e alkoxy which may have a substituent,
(7) a Ci-6 alkoxy-carbonyl which may have a substituent, and the like.
The number of the substituent may be 1 or 2.
Examples of "Ci-e alkyl which may have a substituent" as a
substituent of "carbamoyl which may have a substituent" represented by
Re are the same as "Ci-6 alkyl which may have a substituent" represented
by Re and Rf above.
Examples of "Cs-6 cycloalkyl which may have a substituent", "Ce u
aryl which may have a substituent" and "C7-20 aralkyl which may have a
substituent" as a substituent of "carbamoyl which may have a
substituent" represented by Re are the same as "C3 e cycloalkyl which may
have a substituent", "Cei4 aryl which may have a substituent" and "C7 -20
aralkyl which may have a substituent" represented by R" above.
Examples of the Ci e alkoxy of "Cie alkoxy which may have a
substituent" as a substituent of "carbamoyl which may have a
substituent" represented by R9 are methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the
like. Examples of the substituent of "Ci 6 alkoxy which may have a
substituent" are the same as the substituent of "Ci-e alkyl which may
have a substituent" represented by Re above. The number of
substituents is 1 to 6, preferably 1 to 3, and the substitution position may
be any place on which the substitution is possible.
Example of "Ci e alkoxy-carbonyl which may have a substituent" as
a substituent of "carbamoyl which may have a substituent" represented
by Reis a group comprising combining "Ci-6 alkoxy which may have a
substituent" as a substituent of "carbamoyl which may have a
substituent" represented by Re above with carbonyl.
Examples of "heterocyclic group" represented by Re are (l) a 5-
membered cyclic group containing 1 to 4 heteroatom(s) selected from an
oxygen atom, a sulfur atom, a nitrogen atom, and the like in addition to
carbon atom (e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-
pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-
thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-
isothiazolyl, 5-isothiazolyl, 3-(l,2,4-oxadiazolyl), 5-(l,2,4-oxadiazolyl),
1,3,4-oxadiazolyl, 3-(l,2,4-thiadiazolyl), 5-(l,2,4-thiadiazolyl), 1,3,4-
thiadiazolyl, 4-(l,2,3-thiadiazolyl), 5-(l,2,3-thiadiazolyl), 1,2,5-
thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, lH-tetrazolyl, 2H-tetrazolyl,
oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, and the like), (2) a 6-
membered cyclic group containing 1 to 4 heteroatomCs) selected from, an
oxygen atom, a sulfur atom, a nitrogen atom, and the like in addition to
carbon atom (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-pyridyl, N-
oxido-3-pyridyl, N-oxLdo-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-
pyrimidinyl, N-oxido-2-pyrimidinyl, N-oxido-4-pyrimidinyl, N-oxido-5-
pyrimidinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-
morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-
thiazinyl, 1,3-thiazinyl, 2-piperazinyl, 3-piperazinyl, triazinyl,
oxotriazinyl, 3*pyridazinyl, 4-pyridazinyl, pyrazinyl, N-oxido-3-
pyridazinyl, N-oxido-4-pyridazinyl, and the like), and (3) a bicyclic or
tricyclic condensed cyclic group which contains 1 to 4 heteroatomCs)
selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like
in addition to a carbon atom (e.g., benzofuryl, benzothiazolyl,
benzoxazolyl, tetrazolo[l,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl,
benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylidinyl,
purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl,
phenanthrydinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, and the like).
Examples of the aryl of "aryl which may have a substituent"
represented by Rd are phenyl, naphthyl, anthracenyl, and the like.
Examples of the substituent of "aryl which may have a
substituent" represented by Rd are (l) a C6 u aryl (e.g., phenyl, naphthyl,
and the like) which may have 1 to 4 substituent(s) selected from the
group consisting of (i) a hydroxy, (ii) an amino, (iii) a mono- or di-Ci 6
alkylamino (e.g., methylamino, ethylamino, propylamine, dimethylamino,
diethylamino, and the like), (iv) a Ci e alkoxy (e.g., methoxy, ethoxy,
propoxy, butoxy, pentyloxy, hexyloxy, and the like), and (v) a halogen
(e.g., fluorine, chlorine, bromine and iodine), (2) a hydroxy, (3) a carboxy,
(4) a nitro, (5) a Ci-e alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, pentyloxy, hexyloxy, and the like), (6) a Ci-e alkyl-carbonyloxy
(e.g., acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,
isovaleryloxy, pivaloyloxy, pentylcarbonyloxy, hexylcarbonyloxy, and the
like), (7) a Ci-e alkylthio (e.g., methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,
pentylthio, hexylthio, and the like), (8) a Ci-6 alkylsulfinyl (e.g.,
methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,
butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl,
pentylsulfinyl, hexylsulfinyl, and the like), (9) a Ci 6 alkylsulfonyl (e.g.,
methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,
butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,
pentylsulfonyl, hexylsulfonyl, and the like), (10) a halogen (e.g., fluorine,
chlorine, bromine and iodine), (ll) a group of the formula: -NR*Rh
wherein Re is (a) a hydrogen atom, (b) a Ci-e alkyl which may have a
substituent, (c) a Ca 6 cycloalkyl which may have a substituent, (d) a Ce u
aryl which may have a substituent, (e) a C7-20 aralkyl which may have a
substituent, (f) a carbamoyl which may have 1 or 2 substituentCs) selected
from the group consisting of (0 a Ca-6 cycloalkyl which may have a
substituent, (u) a Ca-w aryl which may have a substituent, (iii) a C7-20
aralkyl which may have a substituent, (iv) hydroxy, (v) a Ci-e alkoxy
which may have a substituent and (vi) aCi-e alkoxy-carbonyl which may
have a substituent, (g) a heterocyclic group; and Rh is a hydrogen atom or
a Ci e alkyl which may have a substituent, (12) a 5-membered cyclic group
containing 1 to 4 heteroatom(s) selected from an oxygen atom, a sulfur
atom, a nitrogen atom, and the like in addition to carbon atom (e.g., 2-
thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-
oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-
pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-
isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-
isothiazolyl, 3-(l,2,4-oxadiazolyl), 5-(l,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,
3-(l,2,4-thiadiazolyl), 5-(l,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-(l,2,3-
thiadiazolyl), 5-(l,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, lH-tetrazolyl, 2H-tetrazolyl, oxoimidazinyl, dioxotriazinyl,
pyrrolidinyl, and the like), (13) a 6-membered cyclic group containing 1 to
4 heteroatom(s) selected from an oxygen atom, a sulfur atom, a nitrogen
atom, and the like in addition to carbon atom (e.g., 2-pyridyl, 3-pyridyl, 4-
pyridyl, N-oxido-2-pyridyl, N-oxido-3-pyridyl, N-oxido-4-pyridyl, 2-
pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, N-oxido-2-pyrimidinyl, N-
oxido-4-pyrimidinyl, N-oxido-5-pyrimidinyl, 2-thiomorpholinyl, 3-
thiomorpholinyl, 2-morpholinyl, 3-morpholinyl, piperidinyl, pyranyl,
thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2-piperazinyl, 3-
piperazinyl, triazinyl, oxotriazinyl, 3-pyridazinyl, 4-pyridazinyl,
pyrazinyl, N-oxido-3-pyridazinyl, N-oxido-4-pyridazinyl, and the like),
(14) a bicyclic or tricyclic condensed cyclic group which contains 1 to 4
heteroatom(s) selected from an oxygen atom, a sulfur atom, a nitrogen
atom and the like in addition to a carbon atom (e.g., benzofuryl,
benzothiazolyl, benzoxazolyl, tetrazolo[l,5-b]pyridazinyl, triazolo[4,5-
blpyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8*
naphthylidinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl,
phenanthrydinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, and the like), (15) a Ci6alkoxycarbonyl (e.g.,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-
butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like), (16)
a carbamoyl, (17) a N-mono-Ci 6 alkylcarbamoyl (e.g., N-
methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-
isopropylcarbamoyl, and the like), (18) a N,N-di-Ci 6 alkylcarbamoyl (e.g.,
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,
and the like), and the like. The number of substituent is 1 to 6,
preferably 1 to 3, and the substitution position may be any place on
which the substitution is possible.
The definitions of Re and Rf utilized in the group of the formula-
-NR*Rh wherein Re and Rh have the same meanings defined above as a
substituent of "aryl which may have a substituent" represented by Rd are
shown below.
Examples of "Ci 6 alkyl which may have a substituent" represented
by Re and Rh are the same as "Ci-6 alkyl which may have a substituent"
represented by Re and Rf described above.
Examples of "C3 6 cycloalkyl which may have a substituent", "C6 -m
aryl which may have a substituent", "C7-20 aralkyl which may have a
substituent" and "heterocyclic group" represented by Re are the same as
"C3 -6 cycloalkyl which may have a substituent", "Ceu aryl which may have
a substituent", "C7 20 aralkyl which may have a substituent" and
"heterocyclic group" represented by Re described above.
Examples of "C3-6 cycloalkyl which may have a substituent", "Ceu
aryl which may have a substituent" and "C7-20 aralkyl which may have a
substituent" of "carbamoyl which may have 1 or 2 substituent(s) selected
from the group consisting of (0 a C3 s cycloalkyl which may have a
substituent, (ii) a Ce-u aryl which may have a substituent, (iii) a C7-20
aralkyl which may have a substituent, (iv) a hydroxy, (v) a Ci-e alkoxy
which may have a substituent and (vi) a Ci 6 alkoxy-carbonyl which may
have a substituent" represented by Re are the same as "C3 e cycloalkyl
which may have a substituent", "C6-14 aryl which may have a substituent"
and "C7 20 aralkyl which may have a substituent" represented by Re
described above.
Examples of "Cie alkoxy which may have a substituent" of
"carbamoyl which may have 1 or 2 substituent(s) selected from the group
consisting of (0 a Cs 6 cycloalkyl which may have a substituent, Gi) a C6-u
aryl which may have a substituent, (iii) a C7 20 aralkyl which may have a
substituent, (iv) a hydroxy, (v) a C1-6 alkoxy which may have a substituent
and (vi) a Ci-6 alkoxy-carbonyl which may have a substituent" represented
by R* are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-
butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Examples of the
substituent of said "Ci-6 alkoxy which may have a substituent" are the
same as the substituent of "Ci-6 alkyl which may have a substituent"
represented by Re described above. The number of substituents is 1 to 6,
preferably 1 to 3, and the substitution position may be any place on
which the substitution is possible.
Example of "Ci e alkoxy-carbonyl which may have a substituent" of
"carbamoyl which may have 1 or 2 substituent(s) selected from the group
consisting of (0 a Cs6cycloalkyl which may have a substituent, Gi) a C6 u
aryl which may have a substituent, (iii) a C720 aralkyl which may have a
substituent, (iv) a hydroxy, (v) a Ci-6 alkoxy which may have a substituent
and (vi) a Ci-6 alkoxy-carbonyl which may have a substituent" represented
by Re is a group comprising combining "Ci 6 alkoxy which may have a
substituent" as a substituent of "carbamoyl which may have a
substituent" represented by R* above with carbonyl.
Preferable examples of Ra are an aryl group which may have 1 to 5
substituent(s) selected from the group consisting of (0 a halogen, (ii) a
nitro, (iii) a cyano, (iv) an amino, (v) a carboxyl group which may be
esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an
alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl.
Among them, a phenyl which is mono* or di- substituted by a halogen,
especially 2,6-difluorophenyl, are preferable.
Preferable examples of Rb are pyrrolidin-1-yl, pyrrolidin-2-yl,
imidazol-1-yl, imidazol-2-yl, 1,2,3-triazol-l-yl, 1,2,5-triazol-l-yl, tetrazol-
1-yl, tetrazol-2-yl, pyridin-2-yl, pyridin-4-yl. Among them, pyridin-2-yl
is preferable.
Preferable example of Rc is a group represented by the formula- -
NRe'Rf wherein Re is (l) a Ci 6 alkyl which may have a substituent or (2) a
C7 20 aralkyl; Rf is a Ci-6 alkyl. Among them, a group of the formula- -
N(Me)Re" wherein Re" is a Ci 6 alkyl which is substituted by a Ci-e alkoxy;
or benzyl is preferable.
Preferable example of Rd is phenyl which may have a substituent.
Among them, phenyl group which is substituted at its 4-position by a
group represented by the formula -NReRh: wherein each Re and Rh has
the meaning defined above, is preferable, and especially, phenyl group
which is substituted at its 4-position by a group represented by the
formula -NHRc" wherein R* is carbamoyl which may have 1 or 2
substituent(s) selected from the group consisting of (0 a C3-6 cycloalkyl
which may have a substituent, (ii) a C6 u aryl which may have a
substituent, Gii) a C7 20 aralkyl which may have a substituent, (iv)
hydroxy, (v) a Ci 6 alkoxy which may have a substituent and (vO a Ci 6
alkoxy-carbonylamino is preferable. Especially, a phenyl group
substituted at its 4-position by a Ci 6 alkoxyamino-carbonylamino (e.g. 4-
methoxyaminocarbonylaminophenyl, 4-
ethoxyaminocarbonylaminophenyl, and the like) is more preferable,
p is preferably 1. And q is preferably 1.
Salts of Compound (A) are preferably physiologically acceptable
acid addition salts. Such salts include, for example, salts with inorganic
acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
phosphoric acid), salts with organic acids (e.g., formic acid, acetic acid,
trichloroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
citric acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the like. When
Compound (A) has an acidic group, it may form a physiologically
acceptable salt with an inorganic base (e.g., alkali metals and alkaline
earth metals such as sodium, potassium, calcium and magnesium,
ammonia, and the like) or an organic base (e.g., trimethylamine,
triethylamine, pyridine, picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and
the like).
Compound (A) can be produced by the method described in JP-A-9-
169768 (WO 96/24597) and JP-A-2001278884 (WO 00/56739) and its
analogous method.
Compound (A) may be a hydrate or a non-hydrate. The hydrate is
exemplified by monohydrate, sesquihydrate and dihydrate.
When Compound (A) is obtained as a mixture of optically active
configurations, it can be resolved into the (R)- and (S)forms by the
conventional optical resolution techniques.
Compound (A) can be used as a prodrug. The prodrug of
Compound (A) or a salt thereof means a compound which is converted to
Compound (A) of the present invention under physiological conditions or
with a reaction due to an enzyme, an gastric acid, and the like in the
living body, that is, a compound which is converted to Compound (A) of
the present invention with oxidation, reduction, hydrolysis, and the like
with an enzyme; a compound which is converted to Compound (A) of the
present invention with gastric acid, etc. The prodrug for Compound (A)
may for example be a compound obtained by subjecting an amino group
in Compound (A) to an acylation, alkylation or phosphorylation (e.g., a
compound obtained by subjecting an amino group in Compound (A) or to
an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-
oxo-l,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation,
pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.);
a compound obtained by subjecting a hydroxy group in Compound (A) to
an acylation, alkylation, phosphorylation or boration (e.g., a compound
obtained by subjecting an hydroxy in Compound (A) to an acetylation,
palmitoylation, propanoylation, pivaloylation, succinylation,
fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); a
compound obtained by subjecting a carboxy group in Compound (A) to an
esterification or amidation (e.g., a compound obtained by subjecting a
carboxyl group in compound (A) to an ethylesterification,
phenylesterification, carboxymethylesterification,
dimethylaminomethylesterification, pivaloyloxymethylesterification,
ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-
2-oxo-l,3-dioxolen-4-yl)methylesterification,
cyclohexyloxycarbonylethylesterification and methylamidation, etc.) and
the like. Any of these compounds can be produced from the compound of
the present invention by a method known per se.
A prodrug of Compound (A) may also be one which is converted
into Compound (A) under a physiological condition, such as those
described in TYAKUHIN no KAIHATSU (Development of
Pharmaceuticals)", Vol.7, Design of Molecules, p. 163-198, Published by
HIROKAWA SHOTEN (1990).
Compound (A) may be labeled with an isotope (e.g., 3H, 14C, 35S)
and the like.
The present invention is hereinafter described in more detail by
means of, but is not limited to, the following Reference Examples,
Examples, Preparation Examples and Experimental Examples.
^-NMR spectra are determined with tetramethylsilane as the
internal standard, using the Varian GEMINI 200 (200 MHz)
spectrometer, the JEOL LAMBDA 300 (300 MHz) spectrometer or the
Bruker AM500 (500 MHz) spectrometer,' all 5 values are shown in ppm.
Unless otherwise specifically indicated, "%" is by weight. Yield indicates
mol/mol%. The other symbols used herein have the following
definitions:

Et : ethyl
Ph : phenyl
TBS : tertbutyl dimethyl silyl
Ms •" methanesulfonyl
The term "room temperature" indicates the range from about 15 to
25°C, but is not to be construed as strictly limitative. Each of lactose, corn
starch, D-mannitol, low substituted hydroxypropylcellulose, talc,
hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, titanium
oxide and light silicic acid anhydride used in the following Preparation is
suited for standard of Pharmacopoeia, Fourteenth Edition.
Examples
Reference Example 1
Production of ethyl 2-[(2,6-difluorobenzyl)(ethoxycarbonyl)amino]-5-(4-
{[(methoxyamino)carbonyl]amino}phenyl)-4-
[(methylamino)methyl]thiophene-3-carboxylate

To a solution of ethyl 4-(N-benzyl-N-methylaminomethyl)-2-[N-
(2,6 - difluorobenzyl)-N-ethoxycarbonyllamino^ 5 - [4-(3-
methoxyureido)phenyl]thiophene-3-carboxylate (3.64 g, 5.47 mmol) in
ethanol (100 ml) were added IN hydrochloric acid (8 ml) and 10 %
palladium-carbon (50 % wet, 1.82 g). The mixture was stirred vigorously
under hydrogen atmosphere for 6 hours. The catalyst was removed, and
the filtrate was neutralized with IN sodium hydroxide solution. The
solvent was distilled off, and the residue was distributed between ethyl
acetate and water. The organic layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure. The residue was subjected to an NH-silica
gel (Fuji Silysia Chemical) chromatography to give the title compound
(2.43 g, 77 %) as yellow powders.
iH-NMR(CDCl3) 5: 1.18 (3H, t, J = 7.0 Hz), 1.33 (3H, t, J = 7.2 Hz), 2.33
(3H, s), 3.65 (2H, s), 3.82 (5H, s), 4.16 (2H, q, J = 7.0 Hz), 4.24(2H, q, J =
7.2 Hz), 4.96 (2H, s), 6.84 (2H, t, J = 7.8 Hz), 7.1-7.35 (3H, m), 7.44 (2H,
d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.63 (lH, s).
Reference Example 2
Production of ethyl 2-[(2,6-difluorobenzyl)(ethoxycarbonyDamino]-5-(4-
{[(methoxyamino)carbonyl]ammo}phenyl)-4-{[methyl^yridin-2-
ylmethyl)amino]methyl}thiophene-3-carboxylate

The compound obtained in Reference Example 1 (2.43 g, 4.21
mmol) was dissolved in DMF (20 ml), and N,N-diisopropylethylamine
(2.93 ml, 16.84 mmol) and 2-chloromethylpyridine hydrochloride (1.04 g,
6.32 mmol) were added thereto. The mixture was stirred at room
temperature for 24 hours, combined with saturated an aqueous solution
of sodium hydrogen carbonate and extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent: ethyl acetate) to
give the title compound (2.34 g, 83 %) as yellow powders.
Reference Example 3
Production of 2-[(2,6-difluorobenzyD(ethoxycarbonyl)amino]-5-(4-
{[(methoxyamino)carbonyl]amino}phenyl)-4-{[methyl(pyridin-2-
ylmethyl)amino]methyl}thiophene-3-carboxylicacid

To a solution of the compound obtained in Reference Example 2
(2.34 g, 3.5 mmol) in ethanol (40 ml) was added 2N sodium hydroxide
solution (8.75 ml), and the mixture was stirred at 50-60 °C for 14 hours.
The reaction mixture was cooled to room temperature and neutralized
with IN hydrochloric acid. The solvent was distilled off and the
obtained residue was distributed between ethyl acetate and water. The
organic layer was washed with saturated brine and dried over
magnesium sulfate. The solvent was distilled off under reduced
pressure to give the title compound (2.06 g, 92 %) as pale yellow powders.
iH-NMR(CDCl3) 5: 1.1-1.3 (3H, m), 2.28 (3H, s), 3.7-3.9 (2H, brm), 3.84
(3H, s), 3.91 (3H, s), 4.1-4.3 (2H, m), 5.07 (2H, s), 6.7-6.85 (2H, m), 7.15-
7.8 (10H, m), 8.5-8.6 (1H, m).
Reference Example 4
Production of methyl 6-(bromomethyl)nicotinate
Methyl 6-methylnicotinate (1.05 g, 10 mmoD was dissolved in ethyl
acetate (50 ml), and NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol)
were added thereto. The reaction mixture was stirred at 80 °C for 3
hours, combined with an aqueous solution of sodium hydrogen carbonate
and extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (eluent: ethyl acetate/hexane = 1/4) to give the title
compound (682 mg, 28 %) as an orange amorphous compound.
iH-NMR(CDCls) 8: 3.96 (3H, s), 4.58 (2H, s), 7.53 (1H, d, J = 8.2 Hz), 8.30
(2H, dd, J = 1.8,8.2 Hz), 9.17 (lH, d, J = 1.8 Hz).
Reference Example 5
Production of ethyl 2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonyl]amino-4-
[N*(2-methoxyethy0-N-methylaminomethyl]-5-(4-
aminophenyl)thiophene-3-carboxylate

A solution of 2N hydrochloride in diethyl ether (21 ml) and 10 %
palladium-carbon (50 % wet, 3.73 g) were added to a solution of ethyl 2-
[N-(2,6-difluorobenzyl)-N-ethoxycarbonyl|amino}4-[N-(2-methoxyethyl)*
N-methylaminomethyl]-5-(4-nitrophenyl)thiophene-3*carboxylate (12.43
g) (JP-A-2001-278884, WO 00/56739) in ethanol (315 ml). The mixture
was stirred vigorously under hydrogen atmosphere for 1 hour. The
catalyst was removed, and the nitrate was neutralized with sodium
hydrogen carbonate solution. The solvent was distilled off, and the
residue was distributed between ethyl acetate and water. The organic
layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure. The residue was subjected to an NH-silica gel (Fuji Silysia
Chemical) chromatography to give the title compound (11.44 g) as an oil.
iH-NMR (CDCls) 8: 1.12-1.30 (3H, br), 2.05 (3H, s), 2.39 (2H, t, J = 6.3
Hz), 3.27 (3H, s), 3.32 (3H, t, J = 6.3 Hz), 3.59 (2H, s), 3.78 (2H, s), 4.20
(2H, q, J = 7.1 Hz), 4.10-4.23 (2H, br), 5.00 (2H, s), 6.66 (2H, d, J = 8.6
Hz), 6.84 (2H, t, J = 8.2 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.15-7.30 (1H, in).
IR (KBr): 1717, 1626, 1609, 1472, 1406, 1300, 1246 cm*.
Reference Example 6
Production of ethyl 2-[(2,6-difluorobenzyD(ethoxycarbonyDamino]-5-(4-
{[0tnethoxyamino)carbonyl]amino}phenyl)-4-{[(2-
methoxyethyl)(methyDammo]methyl}-3-tluophenecarboxylate

N-ethyldiisopropylamine (3.06 ml) was added to a solution of the
compound obtained in Reference Example 5 (4.89 g) in dichloromethane
(l 13 ml) under ice cooling, and the mixture was stirred. N,N'-
carbonyldiimidazole (2.82 g) was added to the mixture under ice cooling.
The reaction mixture was warmed to room temperature and stirred for 67
hours. The reaction mixture was cooled under ice cooling, and O
methylhydroxyamine hydrochloride J[7.26g) and N-ethyldiisopropylamine
(15.6 ml) were added thereto. The reaction mixture was warmed to room
temperature and stirred at room temperature for 19 hours. The reaction
mixture was distributed between chloroform and saturated aqueous
solution of sodium hydrogen carbonate, and extracted with chloroform.
The combined extract was washed with brine and dried over magnesium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel column chromatography to give the title
compound (4.89 g) as a pale yellow caramelized product.
iH-NMR (CDCb) 5: 1.19 (3H, brs), 1.30 (3H, t, J = 6.9 Hz), 2.04 (3H, s),
2.40 (2H, t, J = 6.0 Hz), 3.27 (3H, s), 3.33 (2H, t, J = 6.0 Hz), 3.60 (2H, s),
3.81 (3H, s), 4.13-4.24 (4H, m), 5.00 (2H, s), 6.84 (2H, t, J = 7.8 Hz), 7.19-
7.29 (2H, m), 7.36 (2H, d, J = 8.7 Hz), 7.50 (2H, d, J = 8.7 Hz), 7.60 (1H,
s).
IR (KBr): 1717, 1590, 1528, 1472, 1408, 1304cm'.
Reference Example 7
Production of 2-[(2,6"difluorobenzyD(ethoxycarbonyl)amino]-5-(4-
{[(methoxyamino)carbonyl]amino}phenyD-4-{[(2-
methoxyethy0(methy0amino]methyl}-3-thiophenecarboxylicacid

An aqueous solution of 2N sodium hydroxide (18.9 ml) was added
to a solution of the compound obtained in Reference Example 6 (4.81 g) in
ethanol (114 ml), and the mixture was stirred at 60 °C for 5 hours. The
reaction mixture was warmed to room temperature and combined with
IN hydrochloric acid (37.8 ml). The solvent was distilled off. The
residue was dissolved in ethanol and toluene, and the solvent was
distilled off. The residue was combined with anhydrous ethanol (30 ml),
and the inorganic products were filtered off. The filtrate was
concentrated to dryness. The obtained residue was fined by anhydrous
ether, collected by filtration and dried to give the title compound (4.43 g).
iH-NMR (CDCla) S' 1.17 (3H, brs), 2.45 (3H, s), 2.81 (2H, brs), 3.28 (3H,
s), 3.55 (2H, t, J = 4.8 Hz), 3.82 (3H, s), 3.92 (2H, s), 4.10-4.35 (2H, m),
5.06 (2H, s), 6.82 (2H, t, J = 7.8 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.22-7.35
(1H, m), 7.60 (2H, d, J = 8.4 Hz), 8.00-8.50 (2H, br).
IR (KBr): 1713, 1605, 1528, 1472, 1408 cm1.
Reference Example 8
Production of 4-(l-hydroxy-l-methylethyl)aniline (l) and 4-(l-methoxy-l-
methylethyDaniline (2)

To a solution of 2-methyl-2-(4-nitrophenyl)-2-propanol (2.0 g) in
methanol (55 ml) was added 5 % platinum-carbon (0.3 g), and the
mixture was stirred under hydrogen atmosphere for 4 hours. The
catalyst was filtered off, and the filtrate was concentrated to dryness.
The obtained residue was purified by aminopropylsilica gel column
chromatography (Fuji Silysia Chemical) (120 g; eluent hexane/ethyl
acetate 9/1 to 1/4) to give 4-(l-hydroxy 1-methylethyDaniline (l) (l.O g)
and 4-(l-methoxy-1-methylethyDaniline (2) (0.35 g).
4-(l-hydroxy-l-methylethyl)aniline (l)
m-NMR (CDCla) 5:1.45 (1H, s), 1.55 (6H, s), 3.64 (2H, brs), 6.66 (2H, d, J
= 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz).
IR (KBr): 3335, 2975, 1613, 1516, 1256 cm K
4-(l-methoxy-l-methylethyl)aniline (2)
iH-NMR (CDCla) 5: 1.49 (6H, s), 3.03 (3H, s), 3.64 (2H, brs), 6.67 (2H, d, J
= 8.7 Hz), 7.20 (2H, d, J = 8.7 Hz).
IR (KBr): 2978, 1630, 1613, 1518, 1358, 1264 cm1.
Reference Example 9
Production of 3-methoxy-6-methyl-2-nitropyridine

Potassium carbonate (4.15 g) and methyl iodide (2.80 ml) were
added to a solution of 6-methyl-2-nitro-3-hydroxypyridine (4.63 g) in
DMF (120 ml), and the mixture was stirred at room temperature for 14
hours. The reaction mixture was distributed between ethylacetate and
water. The organic layer was washed with saturated brine and dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue was recrystallized from ethyl
acetate/hexane to give the title compound (3.94 g) as needle crystals.
iH-NMR (CDCls) 5: 2.54 (3H, s), 3.95 (3H, s), 7.37 (lH, d, J = 8.8 Hz), 7.44
(1H, d, J = 8.8 Hz).
IR (KBr): 1541, 1489, 1381, 1308, 1289 cm1.
Reference Example 10
Production of 2-amino-3-methoxy-6-methylpyridine

To a solution of 3-methoxy-6-methyl-2-nitropyridine (3.85 g) in
ethanol (91.6 ml) was added 10 % palladium-carbon (50 % wet, 0.96 g),
and the mixture was stirred under hydrogen atmosphere for 2 hours.
The catalyst was filtered off, and the filtrate was concentrated to dryness.
The residue was recrystallized from ethyl acetate/hexane to give the title
compound (2.89 g).
iH-NMR (CDCla) 8: 2.32 (3H, s), 3.81 (3H, s), 4.61 (2H, s), 6.44 (lH, d, J =
8.4 Hz), 6.81 (1H, d, J = 8.4 Hz).
IR (KBr): 1624, 1576, 1480, 1439, 1258 cm 1.
Reference Example 11
Production of 2-amino-3-hydroxy-6-methylpyridine

The similar reaction as described in Reference Example 10 by
using 6-methyl-2-nitro-3-hydroxypyridine (4.63 g) gave the title
compound (2.81 g) as crystalline powders.
iH-NMR (DMSO-de) 5: 2.14 (3H, s), 5.29 (2H, s), 6.20 (lH, d, J = 7.5 Hz),
6.70 (1H, d, J = 7.5 Hz), 9.09 (lH, s).
Reference Example 12
Production of 3-methoxy-2-nitropyridine

The similar reaction as described in Reference Example 9 by using
2-nitro-3-hydroxypyridine (7.0 g), potassium carbonate (6.91 g) and
methyl iodide (4.67 ml) gave the title compound (7.5 g) as crystalline
powders.
iH-NMR (CDCls) 8: 3.99 (3H, s), 7.54-7.56 (2H, m), 8.09-8.12 (1H, m).
IR (KBr): 1601, 1537, 1530, 1422, 1364, 1275 cm-1.
Reference Example 13
Production of 2-amino-3-methoxvpyridine

The similar reaction as described in Reference Example 10 by
using 3-methoxy-2-nitropyridine (7.5 g) gave the title compound (5.42 g)
as crystalline powders.
iH-NMR (CDCls) 5: 3.84 (3H, s), 4.65 (2H, brs), 6.62 (lH, d, J = 5.0 Hz,
7.6 Hz), 6.90 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.66 (lH, dd, J = 1.4 Hz, 5.0
Hz).
IR (KBr): 3443, 3142, 1634, 1601, 1570, 1483, 1460, 1441 cm 1.
Example 1
Production of N-(4-(5-((benzyl(methyl)amino)methyD-1-(2,6-
difluorobenzy0-2,4-dioxo-3-(2-pyridinyD-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6 -yl)phenyl)-N'-methoxyurea

Ethyldiisopropylamine (1.05 ml, 6.02 mmol) and diethyl
cyanophosphate (0.86 ml, 5.64 mmol) were added to a solution of 4-(N-
benzyl-N-methylaminometiiyl)-2-[N-(2,6-difluorobenzyl)-N-
ethoxycarbonylJaminol-5-[4-(3-methoxyureido)phenyl]thiophene-3-
carboxylic acid (2.40 g, 3.76 mmoD and 2-aminopyridine (1.06 g, 11.28
mmol) in DMF (20 ml), and the mixture was stirred at room temperature
for 3 days. The reaction mixture was combined with sodium hydrogen
carbonate solution and extracted with ethyl acetate. The organic layer
was washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (eluent: ethyl acetate) to give an amide compound. The
obtained amide compound was dissolved in methanol (40 ml), and sodium
methoxide (2.03 mg, 37.6 mmol) was added thereto. The reaction
mixture was stirred at room temperature for 5 hours, concentrated,
neutralized with IN hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was purified by
NH-silica gel column chromatography (Fuji Silysia Chemical) (eluent:
ethyl acetate) to give the title compound (1.59 g, 63 %) as a pale yellow
amorphous compound.
iH-NMRteDCls) 5: 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.89 (2H, s),
5.34 (2H, brs), 6.91 (2H, t, J = 8.0 Hz), 7.1-7.45 (9H, m), 7.56 (2H, d, J =
8.8 Hz), 7.65 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.91 (lH, dt, J = 2.0, 7.7
Hz), 8.7-8.75 (1H, m).
Elemental analysis for C35H30F2N6O4S2
Calcd.: C, 62.86; H, 4.52; N, 12.57.
Found : C, 62.72; H, 4.31; N, 12.40.
mp 179-182 °C
Reference Example 14
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methylamino)methyO-2,4-
dioxo-3-(2-pyridinyD-l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-
yl)phenyl)-N'-methoxyurea
To a solution of the compound obtained in Example 1 (1.59 g, 2.38
mmol) in ethanol (40 ml) were added IN hydrochloric acid (7 ml) and
10 % palladium-carbon (50 % wet, 0.63 g), and the mixture was stirred
vigorously under hydrogen atmosphere for 20 hours. The catalyst was
removed, and the filtrate was neutralized with IN sodium hydroxide
solution. The solvent was distilled off. The residue was distributed
between ethyl acetate and water, and the organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was distilled off, and the obtained powders were washed with
diethyl ether to give the title compound (980 mg, 71 %) as pale yellow
powders.
iH-NMrKCDCla) 5: 2.34 (3H, s), 3.78 (2H, s), 3.82 (2H, s), 5.38 (2H, brs),
6.92 (2H, t, J = 8.2 Hz), 7.2-7.8 (9H, m), 7.92 (1H, dt, J = 1.8 Hz, 7.6 Hz),
8.72 (1H, d, J = 4.8 Hz).
Example 2
Production of N-{2-[{[l-(2,6-difluorobenzyD-6-(4-
{[(methoxyamino)carbonyl]amino}pheny0-2,4-dioxo-3-(2-pyridinyl)-
1,2,3,4-tetr ahydrothieno[2,3 - djpyrimidin - 5-
yllmethyl} (methyl) amino]ethyl}-N-methylsulfonamide
2-(Methylamino)ethanol (0.14 g, 1.903 mmol) was dissolved in
THF(10 ml), and triethylamine (0.58 ml, 4.15 mmol) and
methanesulfonyl chloride (0.27 ml, 3.46 mmol) were added thereto. The
reaction mixture was stirred at room temperature for 1 hour. The
reaction mixture was combined with an aqueous solution of sodium
hydrogen carbonate and extracted with ethyl acetate. The water layer
was salted out and extracted with ethyl acetate. The combined organic
layer was dried over magnesium sulfate and concentrated under reduced
pressure to give a mesylate. A solution of the obtained mesylate, the
compound obtained in Reference Example 14 (200 mg, 0.346 mmol), N,N-
diisopropylethylamine (0.12 ml, 0.692 mmol) and potassium iodide (230
mg, 1.38 mmol) in DMF (8 ml) was stirred at 50"60 °C for 16 hours. The
reaction mixture was combined with an aqueous solution of sodium
hydrogen carbonate and extracted with ethyl acetate. The organic layer
was washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (eluent- ethyl acetate/methanol = 80/1) and
recrystallized from dichloromethane/methanol/diethyl ether to give the
title compound (115 mg, 47 %) as pale yellow crystals.
iH-NMEtfCDCla) 8: 2.11 (3H, s), 2.45-2.6 (2H, m), 2.70 (3H, s), 2.75 (3H,
s), 3.1-3.25 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J
= 8.2 Hz), 7.14 (1H, s), 7.2-7.6 (7H, m), 7.65 (lH, s), 7.85-7.95 (1H, m),
8.65-8.75 (1H, m).
IR (KBr): 1715, 1669, 1530, 1462, 1333, 1146, 1032, 781 cm i.
Elemental analysis for C32H33F2N7O6S2 O.3H2O
Calcd.: C, 53.44; H, 4.711 N, 13.63.
Found : C, 53.76; H, 4.75; N, 13.21.
mp 185-187 °C
Example 3
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-(2-oxo-l-
pyrroUdinyl)ethy0amino)methyD-2,4-dioxo-3-te-pyridinyl)-l,2,3,4-
tetrahydrotMeno^.S-dlpyrimidin-e-yOphenyD-N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 14 (200 mg, 0.346 mmol) and
l-(2-hydroxyethyl)-2-pyrrolidone (0.25 g, 1.903 mmol) gave the title
compound (97 mg, 41 %) as colorless crystals.
iH-NMR(CDCl3) 8- 1.7-1.85 (2H, m), 2.17 (3H, s), 2.15-2.3 (2H, m), 2.5-2.6
(2H, m), 3.15 (2H, t, J = 7.0 Hz), 3.2-3.4 (2H, m), 3.76 (2H, s), 3.83 (3H, s),
5.36 (2H, brs), 6.93 (2H, t, J = 8.4 Hz), 7.16 (lH, s), 7.2-7.7 (8H, m), 7.85-
7.95 (1H, m), 8.65-8.75 (lH, m).
IR (KBr): 1715, 1672, 1526, 1464, 1329, 1032, 783 cm1.
Elemental analysis for C34H33F2N7O5S O.5H2O
Calcd.: C, 58.44; H, 4.90; N, 14.03.
Found : C, 58.75; H, 4.98; N, 13.71.
mp 199-201 °C.
Example 4
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-
pjrridinylmethyDamino)methyD-2,4-dioxo-3-(2-pyridinyI)-l,2,3,4-
tetrahydrotMeno[2,3-6Upyrimidin-6-yl)phenyl)-N,-methoxyurea

The compound obtained in Reference Example 14 (150 mg, 0.259
mmol) was dissolved in DMF (4 ml), and N,N-diisopropylethylamine (0.20
ml, 1.14 mmol) and 2-cMoromethylpyridine hydrochloride (85 mg, 0.518
mmol) were added thereto. The reaction mixture was stirred at room
temperature for 1 hour, combined with an aqueous solution of sodium
hydrogen carbonate and extracted with ethyl acetate. The organic layer
was washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (eluent: ethyl acetate/methanol = 40/l), and
recrystallized from dichloromethane/methanol/diethyl ether to give the
title compound (70 mg, 40 %) as pale yellow crystals.
iH-NMR(CDCl3) 5: 2.10 (3H, s), 3.70 (2H, s), 3.82 (3H, s), 3.96 (3H, s),
5.34 (2H, brs), 6.85-7.7 (14H, m), 7.85-7.95 (lH, m), 8.4-8.5 (lH, m), 8.65-
8.75 (1H, m).
IR (KBr): 1717, 1672, 1526, 1464, 1331, 1236, 1036, 772 cm>.
Elemental analysis for C34H29F2N7O4S 0.3H2O •
Calcd.: C, 62.36; H, 4.58; N, 12.47.
Found : C; 62.22; H, 4.32; N, 12.57.
mp 165-167 °C.
Example 5
Production of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-
difluorobenzyD-3-(2-hydroxyethyD-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

Ethyldiisopropylamine (0.56 ml, 3.2 mmol) and
diethylcyanophosphate (0.46 ml, 3 mmol) were added to a solution of 4-
(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-
ethoxycarbonyltamin carboxylic acid (1.28 g, 2 mmol) and 2-aminoethanol (183 mg, 3 mmol) in
DMF (12 ml), and the mixture was stirred at room temperature for 3
days. The reaction mixture was combined with an aqueous solution of
sodium hydrogen carbonate, extracted with ethyl acetate, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by NH-silica gel column chromatography (Fuji
Silysia Chemical) (eluent: ethyl acetate/methanol = 80/1) to give an
amide. The obtained amide was dissolved in methanol (20 ml), and
sodium methoxide (589 mg, 10.9 mmol) was added thereto. The reaction
mixture was stirred at 50-60 °C for 3 hours, concentrated under reduced
pressure, neutralized with IN hydrochloric acid and extracted with ethyl
acetate. The extract was washed with brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent: ethyl acetate) and
recrystallized from dichloromethane/methanol/diethyl ether to give the
title compound (511 mg, 74 %) as colorless crystals.
iH-NMRCCDCla) 5: 2.04 (3H, s), 2.5-2.65 (lH, m), 3.58 (2H, s), 3.83 (3H,
s), 3.91 (2H, s), 3.9-4.0 (2H, m), 4.37 (2H, t, J = 5.0 Hz), 5.34 (2H, s), 6.92
(2H, t, J = 8.2 Hz), 7.1-7.4 (7H, m), 7.54 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J
= 8.6 Hz), 7.6-7.7(1H, m).
IR (KBr): 1711, 1649, 1535, 1470, 1323, 1236, 1028, 785 cm *.
Elemental analysis for C32H31F2N6O5S O.5H2O
Calcd.: C, 59.62; H, 5.00; N, 10.86.
Found : C, 59.75; H, 4.81; N, 10.93.
Example 6
Production of N-(4-(5-(0benzyl(methyDamino)methyl)-1-(2,6-
difluorobenzyl)-2,4-dioxo-3-(2-(2H-l,2,3-triazol-2-yDethyl)-1,2,3,4-
tetrahydrotMeno[2,3-dJpyrimidin-6-yDphenyD-N'-methoxyurea (l)

Production of N-(4-(5-((benzyl(methyl)amino)methyl)-l-(2,6-
difluorobenzyl)-2,4-dioxo-3-(2-(lH-1,2,3-triazol-l-yl)ethyD-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyD-N'-methoxyurea(2)

The similar reaction as described in Example 2 by using the
compound obtained in Example 5 (450 mg, 0.708 mmol) gave a mesylate.
A solution of the obtained mesylate, 1,2,3-triazole (148 mg, 2.12 mmol
and potassium carbonate (294 mg, 2.12 mmol) in DMF (8 ml) was stirred
at room temperature for 18 hours, and at 50-60 °C for 3 hours. The
reaction mixture was combined with an aqueous solution of sodium
hydrogen carbonate and extracted with ethyl acetate. The organic layer
was washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (eluent: ethyl acetate) to give the title compound 2-yl
form (243 mg, 50 %) as a white amorphous compound. On the other
hand, the residue was recrystallized from
dichloromethane/methanoiydiethyl ether to give the title compound 1-yl
form (177 mg, 36 %) as colorless crystals.
2-yl form (l)
iH-NMR (CDCL) 5: 2.04 (3H, s), 3.51 (2H, s), 3.82 (3H, s), 3.86 (2H, s),
4.57 (2H, t, J = 6.2 Hz), 4.81 (2H, t, J = 6.2 Hz), 5.28 (2H, s), 6.91 (2H, t, J
= 8.4 Hz), 7.15-7.35 (6H, m), 7.46 (2H, s), 7.53 (2H, d, J = 8.6 Hz), 7.62
(1H, s), 7.70 (2H, t, J = 8.6 Hz), 7.75 (lH, s).
IR (KBr): 1705, 1663, 1530, 1472, 1323, 1034, 786 cm *.
1-yl form (2)
iH-NMR (CDCla) 5: 2.02 (3H, s), 3.52 (2H, s), 3.82 (3H, s), 3.85 (2H, s),
4.58 (2H, t, J = 6.4 Hz), 4.78 (2H, t, J = 6.4 Hz), 5.30 (2H, s), 6.92 (2H, t, J
= 8.2 Hz), 7.12 (1H, s), 7.15-7.4(7H, m), 7.54 (2H, d, J = 8.8 Hz), 7.55-7.65
(2H, m), 7.67 (2H, d, J = 8.8 Hz).
IR (KBr): 1709, 1659, 1526, 1472, 1319, 1028, 799 cm'.
Elemental analysis for CsJiaaFzNsC^S O.8H2O
Calcd.: C, 58.24; H, 4.83; N, 15.98.
Found : C, 58.48; H, 4.89; N, 15.65.
Example 7
Production of N-(4-(5-((benzyl(methyl)amino)methyl)-l-(2,6-
difluorobenzyD-2,4-dioxo-3-(2-(2H-tetrazol-2-yl)ethyD-l,2,3,4-
tetrazolotMeno[2,3-dJpyrimidin-6-yl)phenyl)-N'-methoxyurea (l)

Production of N-(4-(5-((benzyl(methyl)amino)methyD-l-(2,6-
diQuorobenzyD-2,4-dioxo-3-(2-(lH-tetrazol- 1-yOethyl)-1,2,3,4-
teteahydrotMeno[2,3-d]pyrimidin-6-yl)pb.enyl)-N'-methoxyurea (2)

The similar reaction as described in Example 6 by using the
compound obtained in Reference Example 5 (636 mg, 1 mmol) and
tetrazole (210 mg, 3 mmol) gave the title compound 2-yl form (234 mg,
34 %) as a white amorphous compound. On the other hand, the residue
was powdered by diethylether to give the title compound, 1-yl form, (34
mg, 5 %) as pale yellow crystals.
2-yl form (l)
iH-NMR(CDCl3) 5: 2.02 (3H, s), 3.51 (2H, s), 3.83 (5H, s), 4.6-4.7 (2H, m),
5.0-5.1 (2H, m), 5.28 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (lH, s), 7.2-7.75
(HH,m), 8.38 (lH,s).
IR (KBr): 1705, 1663, 1530, 1472, 1323, 1236, 1032, 777 cm 1.
1-yl form (2)
iH-NMR(CDCls) 5: 2.01 (3H, s), 3.51 (2H, s), 3.83 (3H, s), 3.8-4.0 (2H, m),
4.6-4.7 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.65-6.75 (lH, m), 6.85-7.0
(2H, m), 7.1-7.7 (11H, m), 8.68 (lH, s).
Example 8
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(2-hydroxyethyl)-5-(((2-
methoxyethyl)(methyl)amino)methyD-2,4-dioxo-l,2,3,4-
tetrahydrothieno^.S-dlpyrimidin-e-yl^phenyO-N'-methoxyurea

The similar reaction as described in Example 5 by using 4*(N-
benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-
ethoxycarbonyQaminoF5-[4-(3-methoxyureido)phenyl]thiophen-3-
carboxylic acid (1.21 g, 2 mmol) and 2-aminoethanol (0.18 ml, 3 mmol) to
give the title compound (302 mg, 25 %) as a pale yellow amorphous
compound.
iH-NMRCCDCIa) 8: 2.11 (3H, s), 2.65 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.46
(2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.9-4.0 (2H, m), 4.35 (2H, t, J = 5.2 Hz),
5.34 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.14 (1H, s), 7.2-7.35 (1H, m), 7.5-
7.65 (5H, m).
Example 9
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyD(methy])amino)methyl)-2,4-dioxo-3-(2 -(2H-tetrazol-2 -
y0ethyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea (l)

Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-
methoxyethyl)(methyDamino)methyD-2,4-dioxo-3-(2 -(lH-tetrazol-1 -
yDethyl)-l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea (2)

The similar reaction as described in Example 6 by using the
compound obtained in Example 8 (250 mg, 0.414 mmol) and tetrazole
(145 mg, 2.07 mmol) gave the title compound 2-yl form (66 mg, 24 %) and
1-yl form (27 mg, 10 %) as white amorphous compounds.
2-yl form (l)
iH-NMR(CDCls) 5: 2.10 (3H, brs), 2.55-2.65 (2H, m), 3.31 (3H, s), 3.4-3.5
(2H, m), 3.76 (2H, s), 3.82 (3H, s), 4.62 (2H, t, J = 5.8 Hz), 5.02 (2H, t, J =
5.8 Hz), 5.27 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (lH, s), 7.25-7.4 (1H,
m), 7.5-7.65 (5H, m), 8.43 (lH, s).
1-yl form (2)
*H-NMR(CDCl3) 5: 2.07 (3H, s), 2.55-2.65 (2H, m), 3.30 (3H, s), 3.4-3.5
(2H, m), 3.74 (2H, s), 3.82 (3H, s), 4.55-4.65 (2H, m), 4.8-4.9 (2H, m), 5.30
(2H, s), 6.93 (2H, t, J = 7.8 Hz), 7.10 (lH, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H,
m), 8.69 (1H, s).
Example 10
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyD(methyl)amino)methyl)-2,4-dioxo-3-(2-(2H-l,2,3-triazol-2-
yl)ethy0-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyD-N'-
methoxyurea

The similar reaction as described in Reference Example 14 by
using the compound obtained in Example 6 (l-yl form) (200 mg, 0.291
mmol) gave de-benzyl-form (0.11 g, 63 %) as colorless powders. The
similar reaction as described in Example 4 by using the de-benzyl-form
(0.11 g, 0.184 mmol) and 2-(chloromethyl)methylether (0.10 ml, 1.104
mmol) gave the title compound (35 mg, 29 %) as colorless crystals.
iH-NMR(CDCl3) 5-* 2.11 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.31 (3H, s), 3.44
(2H, t, J = 5.8 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.55 (2H, t, J = 5.6 Hz), 4.79
(2H, t, J = 5.6 Hz), 5.27 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.10 (1H, s), 7.2-
7.4 (2H, m), 7.51 (2H, s), 7.45-7.65 (4H, m).
Elemental analysis for C30H32F2N8O5S
Calcd.: C, 55.04; H, 4.93; N, 17.12.
Found : C, 55.02; H, 4.85; N, 16.83.
Reference Example 15
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((metliylamino)methyl)-2,4-
dioxo-3-phenyl-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea

The similar reaction as described in Reference Example 14 by
using 5-(N-benzyl-N-methylaminomethyl)-l*(2,6-difluorobenzyl)-6-[4-(3-
methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidin-2,4(lH, 3H)-
dione (6.68 g, 10 mmol) gave the title compound (5.52 g, 96 %) as white
powders.
iH-NMR(CDCl3) S: 2.35 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H, s),
6.92 (2H, t, J = 8.2 Hz), 7.25-7.7 (12H, m).
Example 11
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-(2H-1,2,3-triazol-
2-yDethy0amino)methyl)-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yDphenyl)-N'-methoxyurea (l)

Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-(lH- 1,2,3-triazol-
l-yl)ethy0amino)methyl)-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (2)

Potassium carbonate (1.33 g, 10 mmol) was added to a solution of
1,2,3-triazole (0.46 g, 6.67 mmol) and l-bromo-2-chloroethane (0.83 ml,
10 mmol) in DMF (5 ml), and the mixture was stirred at room
temperature for 1 hour, and 50-60 °C for 3 hours. The reaction mixture
was combined with saturated brine and extracted twice with ethyl
acetate. The combined organic layer was dried over magnesium sulfate
and concentrated to give a halide.
The compound obtained in Reference Example 15 (700 mg, 1.21
mmol) was dissolved in DMF (12 ml), and N,N-diisopropylethylamine
(1.16 ml, 6.67 mmol) and the halide obtained above were added thereto.
The mixture was stirred at 50-60 °C for 16 hours, combined with an
aqueous solution of sodium hydrogen carbonate and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by NH-silica gel column chromatography (eluent-"
ethyl acetate) and recrystallized from dichloromethane/methanol/diethyl
ether to give the title compound 2-yl form (140 mg, 17 %) and 1-yl form
(332 mg, 41 %) as colorless crystals.
2-yl form (l)
iH-NMR(CDCl3) 8: 2.23 (3H, s), 3.00 (2H, t, J = 6.3 Hz), 3.78 (2H, s), 3.82
(3H, s), 4.45 (2H, t, J = 6.3 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-
6.95 (1H, m), 7.11 (1H, s), 7.2-7.6 (12H, m).
IR (KBr): 1715, 1671, 1530, 1470, 1331, 1236, 1032, 822, 735 cm'.
Elemental analysis for C33H30F2N8O4S 0.3H2O
Calcd.: C, 58.45; H, 4.55; N, 16.52.
Found : C, 58.75; H, 4.27; N, 16.20.
mp 166-168 °C.
1-yl form (2)
iH-NMR(CDCl3) 6: 2.14 (3H, s), 2.82 (2H, t, J = 6.0 Hz), 3.80 (2H, s), 3.82
(3H, s), 4.39 (2H, t, J = 6.0 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-
6.95 (1H, m), 7.14 (1H, s), 7.2-7.55 (llH, m), 7.63 (lH, s).
IR (KBr): 1719, 1672, 1526, 1470, 1236, 1231, 1028, 824, 733 cm'.
Elemental analysis for C33H30F2N8O4S O.4H2O
Calcd.: C, 58.30; H, 4.57; N, 16.48.
Found : C, 58.53; H, 4.50; N, 16.29.
mp 194-196 °C.
Example 12
Production of N-(4(l-(2,6-difluorobenzyl)-5-((methyl(2-(2-
pyridinyl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahy drothieno [2,3- djpyrimidin -6 -yDphenyl) -N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (350 mg, 0.606 mmol) and
2-(2-hydroxyethyl)pyridine (0.45 g, 3.64 mmol) gave the title compound
(233 mg, 56 %) as colorless crystals.
iH-NMEtfCDCla) 5: 2.20 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.37 (2H, s),
6.93 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 (lH, s), 7.2-7.55 (11H, m),
7.60 (1H, s), 8.43 (lH, d, J = 4.0 Hz).
IR(KBr): 1717, 1667, 1530, 1470, 1331, 1236, 1030, 735 cm h
Elemental analysis for C36H32F2N6O4S
Calcd.: C, 63.33; H, 4.72; N, 12.31.
Found : C, 63.17; H, 4.56; N, 12.31.
mp 159-160 °C.
Example 13
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-(4-
pyridinyl)ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydrothieno[2,3-dJpyriniidin-6-yl)phenyl)-N,-methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (350 mg, 0.606 mmol) and
4-(2-hydroxyethyDpyridine hydrochloride (0.58 g, 3.64 mmol) gave the
title compound (166 mg, 40 %) as colorless crystals.
iH-NMR(CDCl3) 5: 2.18 (3H, s), 2.68 (4H, s), 3.83 (5H, s), 5.37 (2H, s),
6.85-7.0 (5H, m), 7.16 (lH, s), 7.2-7.65 (10H, m), 8.35-8.4 (2H, m).
ffi (KBr): 1715, 1667, 1532, 1470, 735 cm1.
Elemental analysis for C36H32F2N6O4S O.IH2O
Calcd.: C, 63.16; H, 4.74; N, 12.28.
Found : C, 62.91; H, 4.68; N, 12.26.
mp 194-196 °C.
Example 14
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-
pyridinylmethyl)amino)methyD-2,4-dioxo-3-phenyl-l,2,3,4-
tetrahydrotlaieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 4 by using the
compound obtained in Reference Example 15 (350 mg, 0.606 mmol) and
2-cMoromethylpyridine hydrochloride (149 mg, 0.908 mmol) gave the title
compound (297 mg, 73 %) as colorless crystals.
iH-NMEtCDCla) 6: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.99 (2H, s),
5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.0-7.1 (lH, m), 7.15 (1H, s), 7.2-7.35
(4H, m), 7.4-7.65 (9H, m), 8.4-8.5 (1H, m).
Ht (KBr): 1715, 1667, 1532, 1472, 735 cm1.
Elemental analysis for CssHaoFssNeC^S 0.5H2O
Calcd.: C, 62.03; H, 4.61; N, 12.40.
Found : C, 62.13; H, 4.59; N, 12.47.
mp 181-182 °C.
Reference Example 16
Production of N-(4-(5-((benzyl(methyDamino)methyl)-l-(2,6-
diQuorobenzyD-2,4-dioxo-3-(4-fluorophenyD-l,2,3,4-tetrahydrothieno[2,3-
d1pyrimidin-6-yDphenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using 4-(N-
benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyD-N-
ethoxycarbonyl|amin$5-[4-(3-methoxyureido)phenyl]thiophene-3-
carboxylic acid (2.87 g, 4.49 mmol) and 4-fluoroaniline (0.64 ml, 6.735
mmol) gave the title compound (2.71 g, 88 %) as pale yellow powders.
iH-NMR(CDCl3) 8- 2.05 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.89 (2H, s),
5.36 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.1-7.35 (llH, m), 7.56 (2H, d, J =
8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J = 8.4 Hz).
Elemental analysis for C36H30F3N6O4S O.5H2O
Calcd.: C, 62.24; H, 4.50; N, 10.08.
Found : C, 62.43; H, 4.21; N, 9.84.
Reference Example 17
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-
((methylamino)methyl)-2,4-dioxo-l,2,3,4-tetrahydrotbieno[2,3-
d]pyrimidin-6-yDphenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 14 by
using the compound obtained in Reference Example 16 (2.50 g, 3.65
mmol) gave the title compound (1.85 g, 85 %) as white powder.
iH-NlVQKCDCls) 6: 2.37 (3H, s), 3.76 (2H, s), 3.82 (3H, s), 5.37 (2H, s),
6.92 (2H, t, J = 8.2 Hz), 6.85-7.0 (lH, brs), 7.15-7.35 (6H, m), 7.42 (2H, d,
J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.63 (lH, s).
Example 15
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-
((methyl(2-pyridinylmethyDamino)methyl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]p3rrimidin-6-y])phenyl)-N'-methox5mrea

The similar reaction as described in Example 4 by using the
compound obtained in Reference Example 17 (150 mg, 0.25 mmol) and 2-
chloromethylpyridine hydrochloride (85 mg, 0.52 mmol) gave the title
compound (105 mg, 61 %) as colorless crystals.
iH-NMR(CDCl3) 8: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.97 (2H, s),
5.35 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.0-7.7 (14H, m), 8.4-8.5 (lH, m).
IR (KBr): 1723, 1665, 1532, 1510, 1474, 1236, 1032, 761 cm i.
Elemental analysis for C36H29F3N6O4S €.7H20
Calcd.: C, 60.11; H, 4.38; N, 12.02.
Found : C, 59.76; H, 4.03; N, 11.71.
mpl83-185°C.
Example 16
Production of N-(4-(l-(2,6-difluorobenzyD-3-(4-fluorophenyl)-5-
((methyl(2-(2-pyridinyl)ethyDamino)methyl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 17 (150 mg, 0.25 mmol) and 2-
(2-hydroxyethyDpyridine (0.19 g, 1.512 mmol) gave the title compound
(100 mg, 57 %) as colorless crystals.
iH-NMR(CDCl3) 5: 2.19 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.36 (2H, s), 6.9-
7.55 (13H, m), 7.60 (lH, s), 8.4-8.45 (1H, m).
IR (KBr): 1723, 1665, 1534, 1510, 1474, 1464, 1238, 1034, 762 cm1.
Elemental analysis for CaeHaiFsNeC^S 0.5H20
Calcd.: C, 60.92; H, 4.54; N, 11.84.
Found : C, 61.12; H, 4.63; N, 11.78.
mp 185-187 °C.
Example 17
Production of N-(4-(l-(2,6-difluorobenzyD-5-((methyl(2-(2-
pyridinyDethyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-
tetrahydrotmeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea
The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 14 (150 mg, 0.259 mmoD and
2-(2-hydroxyethyDpyridine (0.18 g, 1.425 mmoD gave the title compound
(83 mg, 47 %) as pale yellow crystals.
iH-NMR(eDCIs) 5: 2.21 (3H, s), 2.8-2.9 (4H, m), 3.82 (5H, s), 5.34 (2H,
brs), 6.85-7.75 (13H, m), 7.60 (1H, s), 7.85-7.95 (1H, m), 8.4-8.5 (lH, m),
8.65-8.75 (1H, m).
IR (KBr): 1715, 1671, 1530, 1458, 1329, 1032, 781 cm'.
mp 194-196 °C.
Example 18
Production of N-(4-(l-(2,6-difiuorobenzyl)-5-((methyl(3-
pyridinylmethyDamino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahyd^otMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea
The similar reaction as described in Example 4 by using the
compound obtained in Reference Example 15 (150 mg, 0.26 mmol) and 3-
cMoromethylpyridine hydrochloride (85 mg, 0.52 mmol) gave the title
compound (117 mg, 67 %) as colorless crystals.
iH-NMR(CDCl3) 5: 2.04 (3H, s), 3.58 (2H, s), 3.83 (3H, s), 3.92 (2H, s),
5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.05-7.7 (14H, m), 8.35-8.45 (2H, m).
IR (KBr): 1713, 1669, 1532, 1464, 1329, 1238, 1032, 787 cm1.
Elemental analysis for C36H30F2N6O4S O.3H2O
Calcd.: C, 62.36; H, 4.58; N, 12.47.
Found : C, 62.22; H, 4.32; N, 12.57.
mp 184-185 °C.
Example 19
Production of N-(4-(l-(2,6-diQuorobenzyl)-5-((((6-(hydroxymethyl)-2-
pyridinyl)methyl)(methyDamino)methyl)-2,4-dioxo-3-phenyl-l,2,3,4-
tetrahydbrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea
The similar reaction as described in Example 4 by using the
compound obtained in Reference Example 15 (150 mg, 0.26 mmol) and 6-
bromomethyl-2-pyridinemethanol (105 mg, 0.52 mmol) gave the title
compound (115 mg, 63 %) as colorless crystals.
ra-NMtUCDCla) 5: 2.13 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s),
4.05-4.1 (1H, m), 4.65-4.75 (2H, m), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz),
6.9-7.05 (1H, m), 7.1-7.2 (2H, m), 7.2-7.7 (12H, m).
IR (KBr): 1713, 1669, 1534, 1472, 1032, 789, 735 cm'.
Elemental analysis for C36H32F2N6OBS I.IH2O
Calcd.: C, 60.17; H, 4.80; N, 11.70.
Found : C, 60.02; H, 4.70; N, 11.53.
Example 20
Production of methyl 6-((((l-(2,6-difluorobenzyD-6-(4-
(((methoxyamino)carbony0amino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-5-
yI)methyl)(methyOamino)methyl)nicotinate
The similar reaction as described in Example 4 by using the
compound obtained in Reference Example 15 (280 mg, 0.485 mmol) and
methyl 6-(bromomethyl)nicotinate (0.19 g, 0.825 mmol) gave the title
compound (267 mg, 76 %) as colorless crystals.
iH-NMR(CDCl3) 5: 2.09 (3H, s), 3.76 (2H, s), 3.83 (3H, s), 3.93 (3H, s),
3.99 (2H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.26 (lH, s), 7.2-7.6
(11H, m), 7.64 (1H, s), 8.05-8.15 (lH, m), 9.0-9.05 (lH, s).
IR (KBr): 1732, 1715, 1669, 1526, 1470, 1296, 1032, 789, 735 cm1.
Elemental analysis for C37H32F2N6O6S
Calcd.: C, 61.15; H, 4.44; N, 11.56.
Found : C, 60.96; H, 4.47; N, 11.52.
Example 21
Production of 6-((((l-(2,6-difluorobenzyl)-6-(4-
(((methoxyammo)carbony0amino)phenyl)-2,4-dioxo-3-phenyl-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-5-yl)methyD(methyl)amino)methyl)-N-
methylnicotin amide
Ethyldiisopropylamine (0.48 ml, 2.76 mmol) and a solution of
dimethylaluminium chloride in hexane (0.98 M, 1.69 ml, 1.656 mmol)
were added dropwise to a solution of methylamine (2M in THF) (1.38 ml,
2.76 mmol) in dichloromethane (4 ml) under ice cooling, and the mixture
was stirred at room temperature for 30 minutes. A solution of the
compound obtained in Example 20 (200 mg, 0.275 mmol) in
dichloromethane (14 ml) was added to the mixture, and the mixture was
stirred at room temperature for 2 days. The reaction mixture was
combined with an aqueous solution of sodium hydrogen carbonate and
extracted with chloroform. The organic layer was washed with brine,
dried over magnesium sulfate and concentrated under reduced pressure.
The residue was purified by NH-silica gel column chromatography (Fuji
Silysia Chemical) (eluent: ethyl acetate/methanol = 40/1) and
recrystallized from dichloromethane/methanol/diethyl ether to give the
title compound (68 mg, 34 %) as colorless crystals.
iH-NMR(CDCl3) 8: 2.2l(3H, s), 3.00 (3H, d, J = 4.6 Hz), 3.74 (2H, s), 3.84
(3H, s), 3.92 (2H, s), 5.36 (2H, s), 6.5-6.65 (lH, m), 6.92 (2H, t, J = 8.0
Hz), 7.15-7.6 (12H, m), 7.71 (lH, s), 7.9-8.0 (lH, m), 8.80-8.85 (lH, m).
IR (KBr): 1713, 1665, 1534, 1470, 1327, 1032, 735 cm'.
Elemental analysis for C37H33F2N7O5S -I.6H2O
Calcd.: C, 58.89; H, 4.84; N, 12.99.
Found : C, 59.12; H, 5.06; N, 12.66.
Example 22
Production of ethyl 6-((((l-(2,6-difluorobenzyl)-6-(4-
( tetrahydrothieno[2,3-d]pyrimio^-5T0methyl)(methy0amino)methyl)-2-
pyridinecarboxylate

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (578 mg, 1 mmol) and ethyl
6-hydroxymethyl-2-pyridinecarboxylate (797 mg, 4.4 mmol) gave the title
compound (590 mg, 80 %) as colorless crystals.
iH-NMR(CDCl3) 5: 1.40 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.79 (2H, s), 3.83
(3H, s), 4.01(2H, s), 4.43 (2H, q, J = 7.2 Hz), 5.35 (2H, s), 6.92 (2H, t, J =
8.2 Hz), 7.15 (1H, s), 7.2-7.7 (13H, m), 7.88 (lH, d, J = 7.4 Hz).
IR(KBr): 1717, 1667, 1530, 1464, 1310, 1236, 1032, 747 cm1.
Elemental analysis for C38H34F2N6O6S
Calcd.: C, 61.61; H, 4.63; N, 11.34.
Found : C, 61.39; H, 4.65; N, 11.17.
Example 23
Production of 6-((((l-(2,6-difluorobenzyl)-6-(4-
(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-3-phenyl-l,2,3,4-
tetiahydrothieno[2,3-d]pyrimidin-5-yl)methyO(methyl)amino)methyO-N-
methyl-2-pyridinecarboxamide
The similar reaction as described in Example 21 by using the
compound obtained in Example 22 (300 mg, 0.413 mmol) and a solution
of methylamine in THF (2 M, 2.07 ml, 4.13 mmoD gave the title
compound (158 mg, 53 %) as colorless crystals.
iH-NMR(CDCl3) 5: 2.13 (3H, s), 2.95 (3H, d, J = 5.2 Hz), 3.74 (2H, s), 3.84
(3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.15-7.7 (13H,
m), 7.9-8.1 (3H,m).
IR (KBr): 1719, 1663, 1534, 1472, 1331, 1032, 737 cm 1.
Elemental analysis for C37H33F2N7O5S -1.0H2O
Calcd.: C, 59.75; H, 4.74; N, 13.18.
Found : C, 59.60; H, 4.77; N, 13.12.
Example 24
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-(lH-imidazol-1-
yl)ethyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yDphenyD-N'-methoxyurea
The compound obtained in Reference Example 15 (289 mg, 0.5
mmol) was dissolved in DMF (30 ml), and ethyldiisopropylamine (0.44
ml, 2.5 mmol) and l-bromo-2-chloroethane (0.17 ml, 2.5 mmol) were
added thereto. The reaction mixture was stirred at 50-60 °C for 1 hour,
combined with an aqueous solution of sodium hydrogen carbonate and
extracted with ethyl acetate. The combined organic layer was dried over
magnesium sulfate and concentrated under reduced pressure to give a
halide. A solution of the obtained halide, imidazole (177 mg, 2.6 mmol)
and potassium carbonate (72 mg, 0.52 mmol) in DMF (4 ml) was stirred
at room temperature for 18 hours and at 50-60 °C for 1 hour, combined
with water and extracted with ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by NH-silica gel
column chromatography (Fuji Silysia Chemical) (eluent-' ethyl
acetate/methanol = 80/1 to 20/1) and recrystallized from
dichloromethane/methanol/diethyl ether to give the title compound (40
mg, 23 %) as colorless crystals.
iH-NMR(CDCl3) 6: 2.17 (3H, s), 2.6-2.8 (2H, m), 3.80 (2H, s), 3.83 (3H, s),
3.9-4.0 (2H, m), 5.38 (2H, s), 6.78 (lH, s), 6.85-7.0 (3H, m), 7.2-7.6 (12H,
m), 7.71 (1H, s).
Example 25
Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-(2-(2-hydroxyethyl)- 1H-
imidazol- l-yl)ethyl)(methyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydrothie^o[2,3-d]pyrimidin-6-yl)phenyl)-N,-methoxyurea

The similar reaction as described in Example 24 by using the
compound obtained in Reference Example 15 (289 mg, 0.5 mmol) and 2-
(2-hydroxyethyl)imidazole (292 mg, 2.6 mmol) gave the title compound
(19 mg, 10 %) as colorless crystals.
iH-NMR(CDCl3) 5: 1.9-2.1 (2H, m), 2.16 (3H, s), 2.6-2.8 (4H, m), 3.78 (2H,
s), 3.83 (2H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.70 (lH, s), 6.80 (lH, s),
6.94 (2H, t, J = 8.0 Hz), 7.2-7.6 (llH, m), 7.73 (lH, s).
Example 26
Production of 2-(4-(l-(2,6-difluorobenzyD-6-t4-
(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-
pyridinylmethyDamino)methyD-2,4-dioxo-l,4-dihydrothieno[2,3-
dJpyrimidin-3(2H)-yl)phenoxy)-N-methylacetamide
The similar reaction as described in Example 5 by using the
compound obtained in Reference Example 3 (320 mg, 0.5 mmol) and 4-
aminophenoxy-N-methylacetamide (135 mg, 0.75 mmol) gave the title
compound (192 mg, 51 %) as colorless crystals.
iH-NMItfCDCls) 5: 2.09 (3H, s), 2.93 (3H, d, J = 4.8 Hz), 3.72 (2H, s), 3.83
(3H, s), 3.97 (2H, s), 4.55 (2H, s), 5.35 (2H, s), 6.55-6.65 (1H, m), 6.92 (2H,
t, J = 8.0 Hz), 7.0-7.65 (14H, m), 8.44 (lH, d, J = 6.0 Hz).
IR(KBr): 1721, 1669, 1532, 1472, 1236, 1032, 764 cm 1.
Elemental analysis for CaaHadFsiNiOeS O.5H2O
Calcd.: C, 59.68; H, 4.74; N, 12.82.
Found : C, 59.51; H, 4.66; N, 12.68.
Example 27
Production of 2-(4-(l-(2,6-difluorobenzyl)-6-(4-
((Onethoxyamino)carbonyl)amino)phenyl) - 5 - ((methyl(2 -
pyridinymiethy0amino)methyl)-2,4-dioxo-l,4-dihydrothieno[2,3-
d]pyrimidin-3(2H)-yl)-N-ethylacetamide
The similar reaction as described in Example 5 by using the
compound obtained in Reference Example 3 (320 mg, 0.5 mmol) and 4-
aminophenyl-N-ethylacetamide (134 mg, 0.75 mmol) gave the title
compound (145 mg, 38 %) as pale yellow crystals.
iH-NMR(CDCl3) 5: 1.10 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.2-3.4 (2H, m),
3.64 (2H, s), 3.72 (2H, s), 3.83 (3H, s), 3.98 (2H, s), 5.36 (2H, s), 5.45-5.55
(1H, m), 6.93 (2H, t, J = 8.0 Hz), 7.0-7.1 (1H, m), 7.16 (lH, s), 7.25-7.7
(12H, m), 8.44 (lH, d, J = 4.0 Hz).
IR (KBr): 1721, 1672, 1534, 1470, 1032, 762 cm 1.
Elemental analysis for C39H37F2N7O5S O.5H2O
Calcd.: C, 61.41; H, 5.02; N, 12.85.
Found : C, 61.44; H, 4.90; N, 12.75.
Example 28
Production of methyl 3-(l-(2,6-difluorobenzyl)-6-(4-
(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-
pyridinylmethyl)amino)methyl)-2,4-dioxo-1,4-dihy drothieno[2,3 -
d]pyrimidin-3(2H)-yDpropanate
The similar reaction as described in Example 5 by using the
compound obtained in Reference Example 3 (320 mg, 0.5 mmol) and 6-
alanine methyl ester (115 mg, 0.75 mmoD gave the title compound (255
mg, 75 %) as a pale yellow amorphous compound.
iH-NMR(CDCl3) 5: 2.10 (3H, s), 2.65-2.8 (2H, m), 3.68 (3H, s), 3.72 (2H,
s),3.83 (3H, s), 3.98 (2H, s), 4.3-4.5 (2H, m), 5.31 (2H, s), 6.91 (2H, t, J =
7.6 Hz), 7.0-7.4 (5H, m), 7.45-7.65 (5H, m), 8.4-8.5 (lH, m).
Example 29
Production of 3-(l-(2,6-difluorobenzyl)-6-(4-
(((methoxyamino)carbonyl)amino)phenyl)-5-((methyl(2-
pyridlnylmethyl)amino)methyl)-2,4-dioxo-l,4-dihydrothieno[2,3-
d]pyrimidin-3(2H)-yl)-N,N-dimethylpropanamide
The similar reaction as described in Example 21 by using the
compound obtained in Example 28 (300 mg, 0.413 mmol) and a solution
of dimethylamine in THF (2M) (1.63 ml, 3.26 mmol) gave the title
compound (73 mg, 33 %) as pale yellow powders.
iH-NMR(CDCls) 8: 2.09 (3H, s), 2.75 (3H, d, J = 7.8 Hz), 2.94 (3H, s), 3.02
(3H, s), 3.73 (2H, s), 3.83 (3H, s), 4.07 (2H, s), 4.40 (2H, t, J = 7.8 Hz),
5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.35 (5H, m), 7.5-7.65 (5H, m),
8.45 (1H, d, J = 4.0 Hz).
IR (KBr): 1703, 1659, 1530, 1472, 1321, 1034, 779 cm'.
Elemental analysis for C34H35F2N7O5S I.OH2O
Calcd.: C, 57.54; H, 5.25; N, 13.81.
Found : C, 57.56; H, 5.05; N, 13.59.
Example 30
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(4-liydroxycyclohexyl)-5-
((methyl(2-pyridinylmeUiy0amino)methyl)-2,4-dioxo-l,2,3,4-
tetrahydrottaeno[2,3-d]pyrimidin-6-yDphenyD-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound obtained in Example 28 (320 mg, 0.5 mmol) and 4-
aminohexanol (86 mg, 0.75 mmol) gave the title compound (154 mg, 45 %)
as colorless crystals.
iH-NMR(CDCl3) 5: 1.4-1.8 (4H, m), 2.0-2.1 (2H, m), 2.12 (3H, s), 2.55-2.75
(2H, m), 3.73 (2H, s), 3.7-3.8 (lH, m), 3.82 (3H, s), 3.98 (2H, s), 4.9-5.1
(1H, brm), 5.29 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.4 (7H, m), 7.457.65
(5H, m), 8.45 (lH, d, J = 4.8 Hz).
IR(KBr): 1705, 1659, 1530, 1470, 1312, 1236, 1069, 1034, 783 cmElemental analysis for CssHaeFisNeOisS I.5H2O
Calcd.: C, 58.57; H, 5.48; N, 11.71.
Found : C, 58.65; H, 5.35; N, 11.64.
Example 31
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-(2H-tetrazol-2-
yDethyDaminomethyl))-2,4-dioxo-3-phenyl-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea (l)

Production of N-(4-(l-(2,6-difluorobenzyD-5-(6nethyl(2-(lH-tetrazol-1-
yl)ethyl)annno)methyD*2,4-dioxo-3-phenyl-l,2,3,4-tetraliydrothieno[2,3-
d]pyrimidin-6-yl)pheiiyl)-N'-methoxyurea (2)

Potassium carbonate (2.075 g, 15 mmol) was added to a solution of
tetrazole (0.70 g, 10 mmol) and l-bromo-2-chloroethane (1.25 ml, 15
mmol) in DMF (5 ml), and the mixture was stirred at room temperature
for 16 hours. The reaction mixture was combined with saturated brine
and extracted twice with ethyl acetate. The combined extract was dried
over magnesium sulfate and concentrated under reduced pressure to give
a halide (4.23 g including DMF).
N,N-diisopropylethylamine (1.16 ml, 6.67 mmol) and the halide
obtained above were added to a solution of the compound obtained in
Reference Example 15 (578 mg, 1 mmol) in DMF (10 ml), and the mixture
was stirred at 60-70 °C for 16 hours. The reaction mixture was combined
with an aqueous solution of sodium hydrogen carbonate and extracted
with ethyl acetate. The organic layer was washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent- ethyl
acetate/hexane = 9/1) and recrystallized from
dichloromethane/methanol/diethyl ether to give the title compound 2-yl
form (80 mg, 12 %) and 1-yl form (38 mg, 57 %) as colorless crystals.
2-yl form (l)
iH-NMR(CDCl3) 5: 2.25 (3H, s), 3.04 (2H, t, J = 6.2 Hz), 3.78 (2H, s), 3.83
(3H, s), 4.66 (2H, t, J = 6.2 Hz), 5.38 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.16
(1H, s), 7.2-7.6 (10H, m), 7.64 (lH, s), 8.30 (lH, s).
IR (KBr): 1713, 1669, 1530, 1470, 1325, 1032, 735 cm'.
Elemental analysis for C32H29F2N9O4S 0.5H2O
Calcd.: C, 56.30; H, 4.43; N, 18.46.
Found : C, 56.18; H, 4.42; N, 18.19.
1-yl form (2)
iH-NMR(CDCl3) 5: 2.02 (3H, s), 2.7-2.8 (2H, m), 3.78 (2H, s), 3.83 (3H, s),
4.4-4.5 (2H, m), 5.38 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.17 (lH, s), 7.25-
7.65 (10H, m), 7.66 (lH, s).
IR (KBr): 1713, 1669, 1530, 1470, 1327, 1236, 1032, 735 cm'.
Elemental analysis for C32H29F2N9O4S O.5H2O
Calcd.: C, 56.30; H, 4.43; N, 18.46.
Example 32
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(2-hydroxyethyl)-5-
(0nethyl(2-pyridinylmethy])amino)methyD-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrinudin-6-yl)phenyl)-N'-methoxyurea
-N^ o
MeO O F
The similar reaction as described in Example 5 by using the
compound obtained in Reference Example 3 (410 mg, 0.64 mmol) and 2*
aminoethanol (0.06 ml, 0.96 mmol) gave the title compound (76 mg, 19 %)
as colorless crystals.
iH-NMR(CDCl3) 6: 2.22 (3H, s), 3.3-3.5 (lH, br), 3.78 (2H, s), 3.83 (3H, s),
3.9-4.05 (2H, m), 3.99 (2H, s), 4.35-4.4 (2H, m), 5.27 (2H, s), 6.91 (2H, t, J
= 8.0 Hz), 6.9-7.1 (1H, m), 7.15 (lH, s), 7.2-7.65 (8H, m), 8.35-8.4 (lH, m).
IR (KBr): 1709, 1649, 1470, 1323, 1030, 787 cm1.
Elemental analysis for C31H30F2N6O6S O.5H2O
Calcd.: C, 57.67; H, 4.84; N, 13.02.
Found : C, 57.77; H, 4.90; N, 12.82.
Example 33
Production of N-(4-(l-(2,6-difluorobenzyD-5-((methyl(3-(2-oxo-1-
pyrroUdinyl)propyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyO-N'-methoxyurea
-N^ O
MeO O F
p6

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (404 mg, 0.7 mmol) and 1-
(3-hydroxypropyl)-2-pyrrolidone (0.55 g, 3.85 mmol) gave the title
compound (322 mg, 66 %) as colorless crystals.
^H-NMRteDCla) 5:1.5-1.7 (2H, m), 1.8-2.0 (2H, m), 2.05 (3H, s), 2.25-2.45
(4H, m), 3.15 (2H, t, J = 7.8 Hz), 3.23 (2H, t, J = 7.2 Hz), 3.76 (2H, s), 3.83
(3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.15 (lH, s), 7.2-7.6 (10H,
m), 7.67 (1H, s).
IR (KBr): 1715, 1671, 1532, 1470, 1327, 1032, 735 cm1.
Elemental analysis for CasHaeF^sOsS I.OH2O
Calcd.: C, 59.99; H, 5.3K N, 11.66.
Found : C, 60.21; H, 5.18; N, 11.74.
mp 128-129 °C
Example 34
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((methyl(2-(2-oxo-1-
pyiroUdiny0ethyl)amino)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyD-N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (404 mg, 0.7 mmol) and 1-
(3-hydroxyethyD-2-pyrrolidone (0.50 g, 3.85 mmol) gave the title
compound (290 mg, 60 %) as colorless crystals.
iH-NMRtCDCla) 5: 1.7-1.85 (2H, m), 2.14 (3H, s), 2.21 (2H, t, J = 8.1 Hz),
2.54 (2H, t, J = 6.2 Hz), 3.19 (2H, t, J = 7.0 Hz), 3.29 (2H, t, J = 6.2 Hz),
3.77 (2H, s), 3.83 (3H, s), 5.38 (2H, s), 6.93 (2H, t, J = 8.1 Hz), 7.18 (1H,
s), 7.25-7.7 (11H, m).
IR (KBr): 1715, 1672, 1530, 1470, 1323, 1238, 1032, 735 cm 1.
Elemental analysis for C35HS4F2N6O6S O.5H2O
Calcd.: C, 60.25; H, 5.06; N, 12.04.
Found : C, 60.29; H, 5.04; N, 12.13.
mp 134-136 °C
Example 35
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(4-fluorophenyl)-5-((methyl-
(2-(2-oxo- l-pyrroHdinyl)ethyl)amino)methyl)-2,4-dioxo-1,2,3,4-
tetrahy drothieno[2,3- d]pyrimidin-6 -yDphenyl) -N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 17 (350 mg, 0.588 mmol) and
l-(3-hydroxyethyl)-2-pyrrolidone (0.50 g, 3.85 mmol) gave the title
compound (283 mg, 68 %) as pale yellow crystals.
iH-NMR(CDCl3) 8: 1.7-1.9 (2H, m), 2.15 (3H, s), 2.15-2.3 (2H, m), 2.52
(2H, t, J = 6.2 Hz), 3.20 (2H, t, J = 6.8 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77
(2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.35 (6H,
m), 7.5-7.65 (4H, m), 7.64 (lH, s).
IR (KBr): 1723, 1667, 1532, 1472, 1236, 1034, 837, 762 cm1.
Elemental analysis for CssHsaFaNeOsS O.5H2O
Calcd.: C, 58.73; H, 4.79; N, 11.74.
Found : C, 58.99; H, 4.98; N, 11.92.
mp 198-200 °C
Example 36
Production of N-(2-(((l-(2,6-difluorobenzyD-3-(4-fluorophenyl)-6-(4-
(((methoxyamino)carbonyl)amino)phenyl)-2,4-dioxo-l,2,3,4-
tetrahyd^othieno[2,3-d]pyrimidin-5-yl)methyO(methy])amino)ethyD-N-
methylmethanesulfonamide

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 17 (350 mg, 0.588 mmol) and
2-methylaminoethanol (0.29 g, 3.85 mmol) gave the title compound (263
mg, 61 %) as pale yellow crystals.
iH-NME(CDCl3) 5: 2.13 (3H, s), 2.55 (2H, t, J = 6.4 Hz), 2.70 (3H, s), 2.71
(3H, s), 3.15 (2H, t, J = 6.4 Hz), 3.81 (2H, s), 3.83 (3H, s), 5.37 (2H, s),
6.93 (2H, t, J = 8.2 Hz), 7.1-7.7 (11H, m).
IR (KBr): 1725, 1663, 1534, 1474, 1331, 1236, 1142, 1034, 793 cm'.
Elemental analysis for C33H33F3N6O6S2
Calcd.: C, 54.24; H, 4.55; N, 11.50.
Found : C, 54.10; H, 4.45; N, 11.36.
mp 218-220 °C
Example 37
Production of N-(4-(l-(2,6-difluorobenzyD-5-((methyl(((2S)-1-
(methylsulfony0-2-pyrroHdiny0methyl)amino)methyl)-2,4-dioxo-3-
phenyl-l,2,3,4-tetrahydrothieno[2,3-dJpyrimidin-6-yDphenyl)-N'-
methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (404 mg, 0.7 mmol) and (L)-
2-hydroxymethylpyrrolidine (0.39 g, 3.85 mmoD gave the title compound
(262 mg, 51 %) as colorless crystals.
iH-NMR (CDCb) 5: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (lH, m), 2.5-
2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83 (3H, s),
5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (lH, s), 7.2-7.7 (11H, m).
IR (KBr): 1713, 1667, 1528, 1470, 1333, 1148, 1030, 785 cm1.
Elemental analysis for CasHsdfoNeOeSa
Calcd.: C, 56.90; H, 4.91; N, 11.37.
Found : C, 56.55; H, 4.87; N, 11.23.
mpl95-197°C
Example 38
Production of N-(4-(l-(2,6-difluorobenzyD-3-(4-fluorophenyl)-5-
((methyl(((2S)-l-(methylsulfonyD-2-pyrroHdinyl)methyl)amino)methyl)-
2,4-dioxo-l,2,3,4-tetrahydrotMeno[2,3-Qlpyrimidin-6-yl)phenyD-N'-
methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 17 (400 mg, 0.672 mmol) and
(L)-2-hydroxymethylpyrrolidine (0.39 g, 3.85 mmol) gave the title
compound (222 mg, 44 %) as colorless crystals.
iH-NMR(CDCl3) 5: 1.7-1.85 (4H, m), 2.09 (3H, s), 2.25-2.35 (lH, m), 2.55-
2.65 (1H, m), 2.71 (3H, s), 3.15-3.3 (2H, m), 3.65-3.7 (2H, m), 3.74 (lH, d,
J = 12.0 Hz), 3.83 (3H, s), 3.87 (lH, d, J = 12.0 Hz), 5.36 (2H, s), 6.92 (2H,
t, J = 8.2 Hz), 6.85-6.95 (lH, m), 7.1-7.35 (5H, m), 7.49 (2H, d, J = 8.4 Hz),
7.55 (2H, d, J = 8.4 Hz), 7.62 (lH, s).
HI CKBr): 1715, 1667, 1530, 1470, 1333, 1236, 1152, 1032, 795 cm 1.
Elemental analysis for C36H36F3N6O6S2
Calcd.: C, 55.55; H, 4.66; N, 11.10.
Found: C, 55.42; H, 4.45; N, 11.01.
mp 202-204 °C
Example 39
Production of N-(4-(l-(2,6-difluorobenzyD-5-((methyl(((2R)-1-
(methylsulfony0-2-pyrrohdinyl)methyl)amino)methyl)-2,4-dioxo-3-
phenyl-l,2,3,4-tetrahydrotMeno[2,3-6Upyrimidin-6-yl)phenyl)-N'-
methoxyurea

The similar reaction as described in Example 2 by using the
compound obtained in Reference Example 15 (188 mg, 0.325 mmol) and
(R)-2-hydroxymethylpyrrolidine (0.14 g, 1.38 mmol) gave the title
compound (136 mg, 57 %) as colorless crystals.
iH-NMR(CDCla) 5: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65
(1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7-3.9 (3H, m), 3.83 (3H, s), 5.37
(2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.7 (11H, m).
IR (KBr): 1713, 1665, 1530, 1470, 1333, 1148, 1030, 785 cm1.
Elemental analysis for C35H36F2N6O6S2 {L5H2O
Calcd.: C, 56.21; H, 4.99; N, 11.24.
Found : C, 56.29; H, 4.79; N, 11.11.
mp 208-210 °C
Example 40
Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-
methoxyethyl)(methy0amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-
tetrahy drothieno[2,3 -d]pyrimidin-6 -yDphenyl) -N'-methoxyurea

Diethyl cyanophosphate (245 mg) and N-ethyldiisopropylamine
(284 pi) were added to a solution of the compound obtained in Reference
Example 7 (607 mg) and 2-aminopyridine (142 mg) in DMF (10 ml) under
ice cooling, and the reaction mixture was warmed gradually to room
temperature and stirred for 13 hours. The reaction mixture was
distributed between ethyl acetate and water. The organic layer was
successively washed with water and saturated brine, dried over
magnesium sulfate, and concentrated under reduced pressure. The
obtained residue was roughly purified by aminopropyl silica gel column
chromatography (Fuji Silysia Chemical). The obtained a crude amide
(350 mg) was dissolved in ethanol (25.5 ml), and a solution of 28 %
sodium methoxide in methanol (196 mg) was added thereto. The
mixture was stirred at room temperature for 15 hours. The reaction
mixture was neutralized with IN hydrochloric acid (l ml), and the
solvent was distilled off. The residue was distributed between ethyl
acetate and water. The organic layer was successively washed with
water and saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The obtained
residue was purified by aminopropyl silica gel column chromatography
(45 g, eluent: ethyl acetate/hexane 7/3 to ethyl acetate) and recrystallized
from THF-ethanol to give the title compound (210 mg) as colorless
crystals.
Elemental analysis for CaiHaoNeOsSFz
Calcd.:C, 58.48; H, 4.75; N, 13.20.
Found :C, 58.46; H, 4.68; N, 12.93.
iH-NMR (CDCk) 6: 2.15 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41
(2H, t, J = 5.9 Hz), 3.80 (3H, s), 3.81 (2H, brs), 5.34 (2H, brs), 6.91 (2H, t,
J = 8.1 Hz), 7.24-7.40 (4H, m), 7.53 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J =
8.4 Hz), 7.65 (1H, s), 7.88 (lH, dt, J = 1.5 Hz, 7.8 Hz), 8.67-8.69 (lH, m).
IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm *.
Example 41
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
ethoxyethyl)(methy0amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-l,2,3,4-
tetrahydrotMeno[2,3-d]p5rrimidin-6-yl)phenyl)-N,-methoxyurea

To a solution of the compound obtained in Reference Example 14
(251 mg) in DMF (4.3 ml) were added 2-ethoxyethyl chloride (141 mg), N-
ethyldiisopropylamine (245 pi) and potassium iodide (107 mg), and the
mixture was stirred at 60 °C for 24 hours. The reaction mixture was
distributed between ethyl acetate and water. The organic layer was
washed with saturated brine and dried over magnesium sulfate. The
solvent was distilled off, and the residue was purified by aminopropyl
silica gel column chromatography (Fuji Silysia Chemical) (45 g, eluent:
ethyl acetate/hexane = 3/2 to 4/1) and recrystallized from ethyl acetate to
give the title compound (62 mg) as colorless crystals.
Elemental analysis for C32H32N6O5SF2 O.lAcOEt
Calcd.:C, 59.01; H, 5.01; N, 12.74.
Found :C, 59.11; H, 5.13; N, 12.55.
iH-NMR (CDCla) 6: 1.13 (3H, t, J = 6.9 Hz), 2.15 (3H, s), 2.63 (2H, t, J =
6.2 Hz), 3.39 (2H, q, J = 6.9 Hz), 3.44 (2H, t, J = 6.2 Hz), 3.80 (2H, brs),
3.81 (3H, s), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.19 (lH, s), 7.27-7.32
(1H, m), 7.35-7.41 (2H, m), 7.53 (2H, d, J = 8.4 Hz), 7.63 (lH, s), 7.64 (2H,
d, J = 8.4 Hz), 7.88 (lH, dt, J = 1.2 Hz, 7.5 Hz), 8.68 (lH, dt, J = 0.9 Hz,
4.8 Hz).
IR (KBr): 1717, 1674, 1591, 1530, 1460, 1329 cm 1.
Example 42
Production of N-(4-(l-(2,6-d1fluorobenzyl)-3-(5-fluoro-2-pyridinyD-5-(((2-
methoxyethyl)(methyDamino)methyl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

By a similar manner to Example 40, a crude amide (270 mg) was
obtained from the compound obtained in Reference Example 7 (304 mg),
diethyl cyanophosphate (153 ul), 2-amino*5-fluoropyridine (113 mg) and
N-ethyldiisopropylamine (190 pJ), and the title compound (113 mg) was
obtained from the crude amide by using methanol (19 ml) and a solution
of 28 % sodium methoxide in methanol (146 mg).
Elemental analysis for C31H29N6O5SF3
Calcd.:C, 56.87; H, 4.46; N, 12.84.
Found :C, 56.69; H, 4.57; N, 12.83.
iH-NMR (CDCI3) 5: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41
(2H, t, J = 5.9 Hz), 3.80 (2H, brs), 3.82 (3H, s), 5.33 (2H, brs), 6.92 (2H, t,
J = 8.3 Hz), 7.19 (1H, s), 7.28-7.38 (2H, m), 7.52-7.63 (6H, m), 8.51 (1H, d,
J = 3.0 Hz).
IR (KBr): 1715, 1674, 1586, 1530, 1462 cm 1.
Example 43
Production of N-(4-(3-(5-bromo-2-pyridinyl)-l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyl)(methyDamino)methyl)-2,4-dioxo-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyO-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (304 mg), diethyl
cyanophosphate (153 pJ), 2-amino-5-bromopyridine (173 mg) and N-
ethyldiisopropylamine (190 pJ) gave a crude amide (228 mg).
Furthermore, the similar reaction by using methanol (14.5 ml) and a
solution of 28 % sodium methoxide in methanol (112 mg) gave the title
compound (113 mg).
Elemental analysis for CaiHiajNeOsSB^ 0.5H20
CalccUC, 51.39; H, 4.17; N, 11.60.
Found :C, 51.68; H, 4.25; N, 11.53.
iH-NMR (CDCls) 5: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41
(2H, t, J = 5.9 Hz), 3.78 (2H, brs), 3.80 (3H, s), 5.32 (2H, brs), 6.92 (2H, t,
J = 8.1 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.27-7.33 (lH, m), 7.37 (lH, s), 7.54
(2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.64 (lH, s), 7.98 (lH, dd, J =
2.7 Hz, 8.4 Hz), 8.72 (lH, d, J = 2.7 Hz).
IR (KBr): 2938, 1717, 1674, 1590, 1456 cm1.
Example 44
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyO(methyDamino)methyD-3-(5-methyl-2-pyridinyl)-2,4-dioxo-
l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-yl)pheny0-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (304 mg), diethyl
cyanophosphate (153 pJ), 2-amino-5-methylpyridine (109 mg) and N-
ethyldiisopropylamine (190 pi) gave a crude amide (188 mg).
Furthermore, the similar reaction by using methanol (13.5 ml), a solution
of 28 % sodium methoxide in methanol (103 mg) gave the title compound
(122 mg).
Elemental analysis for C32H32N6OBSF2 O.5H2O
Calcd.:C, 58.26; H, 5.04; N, 12.74.
Found :C, 58.55; H, 5.14; N, 12.67.
iH-NMR (CDCls) 5: 2.14 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26
(3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.77 (2H, brs), 3.80 (3H, s), 5.26 (1H, brs),
5.38 (lH, brs), 6.91 (2H, t, J = 8.3 Hz), 7.23-7.34 (2H, m), 7.42 (1H, s),
7.53 (2H, d, J = 8.7 Hz), 7.62 (2H, d, J = 8.7 Hz), 7.66 (1H, s), 7.66-7.69
(1H, m), 8.48 (1H, d, J = 2.4 Hz).
IR (KBr): 2938, 1717, 1675, 1586, 1530, 1462 cm¦».
Example 45
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyO(methyDammo)methyO-3-(6-methyl-2-pyridinyl)-2,4-dioxo-
l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-yDphenyD-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (423 mg), diethyl
cyanophosphate (212 pJ), 2-ammo-6-methylpyridine (151 mg) and N-
ethyldiisopropylamine (265 pJ) gave a crude amide (242 mg).
Furthermore, the similar reaction by using methanol (17 ml), a solution
of 28 % sodium methoxide in methanol (131 mg) gave the title compound
(145 mg).
Elemental analysis for C32H32N6O6SF2 O.5H2O
Calcd.:C, 58.26; H, 5.04; N, 12.74.
Found :C, 58.39; H, 4.86; N, 12.79.
iH-NMR (CDCls) 8: 2.15 (3H, s), 2.60 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.27
(3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.66-3.94 (2H, m), 3.81 (3H, s), 5.15 (1H,
d, J = 15.3 Hz), 5.48 (1H, d, J = 15.3 Hz), 6.91 (2H, t, J = 8.1 Hz), 7.16
(1H, d, J = 7.8 Hz), 7.21 (lH, d, J = 7.8 Hz), 7.25 (1H, s), 7.26-7.35 (1H,
m), 7.53 (2H, d, J = 8.7 Hz), 7.63 (lH, s), 7.53 (2H, d, J = 8.7 Hz), 7.64
(2H, d, J = 8.7 Hz), 7.76 (lH, t, J = 7.8 Hz).
IR (KBr): 2936, 1715, 1672, 1603, 1530, 1472 cm1.
Example 46
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyO(methyDamino)methyl)-3-(3-methoxy-6-methyl-2-
pyridiny0-2,4-dioxo-l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-
yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 nig), diethyl
cyanophosphate (227 pi), 2-amino-3-methoxy-6-methylpyridine (208 mg)
and N-ethyldiisopropylamine (310 pJ) gave a crude amide (130 mg).
Furthermore, the similar reaction by using methanol (8.5 ml), a solution
of 28 % sodium methoxide in methanol (666 mg) gave the title compound
(107 mg).
Elemental analysis for C33H34N6O6SF2 O.5H2O
Calcd.:C, 57.47; H, 5.11; N, 12.18.
Found :C, 57.54; H, 5.03; N, 12.26.
iH-NMR (CDCI3) 8: 2.13 (3H, s), 2.51 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26
(3H, s), 3.40 (2H, t, J = 5.9 Hz), 3.77 (lH, d, J = 12.3 Hz), 3.77 (3H, s),
3.79 (3H, s), 3.86 (lH, d, J = 12.3 Hz), 5.24 (lH, d, J = 15.6 Hz), 5.40 (lH,
d, J = 15.6 Hz), 6.90 (2H, t, J = 8.1 Hz), 7.19 (lH, d, J = 8.4 Hz), 7.23-7.34
(1H, m), 7.27 (1H, d, J = 8.4 Hz), 7.51 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J =
8.7 Hz), 7.65 (1H, s), 7.69 (lH, s).
IR (KBr): 2938, 1715, 1674, 1589, 1532, 1470 cm1.
Example 47
Production of N-(4-(l-(2,6-diQuorobenzyl)-3-(3-hydroxy-6-methyl-2-
pyridinyD-5-(((2-methoxyetfiyD(jnethyDamiiio)methyl)"2,4-dioxo-1,2,3,4-
tetrahydrotlueno[2,3-6Upyrimidiii-6-y])phenyl)-N'-methoxyurea

A crude amide (163 mg) was produced by reacting the compound
obtained in Reference Example 7 (455 mg) with l-ethyl-3-(3-
dimethylaininopropyl)-carbodiiniide hydrochloride (306 mg), 1-
hydroxybenzotriazole (288 mg), 2-amino-3-hydroxy-6-methylpyridine
(187 mg) and N-ethyldiisopropylamine (517 ul). Furthermore, the title
compound (127 mg) was obtained from the crude amide by using
methanol (l 1 ml) and a solution of 28 % sodium methoxide in methanol
(85 mg).
Elemental analysis for C33H34N6O6SF2 H2O
Calcd.:C, 56.13; H, 5.015 N.12.27.
Found :C, 56.03; H, 5.2K N.12.05.
iH-NMR (CDCI3) 6: 2.11 (3H, s), 2.48 (3H, s), 2.51-2.59 (2H, m), 3.20 (3H,
s), 3.30-3.46 (4H, m), 3.60 (1H, d, J = 12.3 Hz), 3.79 (3H, s), 4.05 (lH, d, J
= 12.3 Hz), 5.21 (1H, d, J = 15.6 Hz), 5.31 (lH, d, J = 15.6 Hz), 6.88 (2H, t,
J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.21-7.31 (2H, m), 7.43-7.51 (4H, m),
7.69 (1H, s).
IR (KBr): 2936, 1715, 1669, 1591, 1530, 1472 cm1.
Example 48
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyD(me1^y0amino)methyD-3-(3-methoxy-2-p5nridinyl)-2,4-
6Uoxo-l,2,3,4•tetrahydl»tMeno[2,3-dJpyrilnidin-6-yDphenyl)-N,-
methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
#
cyanophosphate (285 pi), 2-amino-3-methoxypyridine (233 mg) and N-
ethyldiisopropylamine (388 pJ) gave a crude amide (226 mg).
Furthermore, the similar reaction by using methanol (15.5 ml), a solution
of 28 % sodium methoxide in methanol (120 mg) gave the title compound
(115 mg).
Elemental analysis for C32H32N6O6SF2 O.5H2O
Calcd.:C, 56.88; H, 4.92; N, 12.44.
Found :C, 56.88; H, 4.96; N, 12.31.
iH-NMR (CDCb) 5: 2.20 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.28 (3H, s), 3.41
(2H, t, J = 6.2 Hz), 3.78 (lH, d, J = 12.3 Hz), 3.82 (3H, s), 3.84 (3H, s),
3.88 (1H, d, J = 12.3 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.1 Hz), 7.17 (lH,
s), 7.23-7.39 (3H, m), 7.54 (2H, d, J = 8.8 Hz), 7.57 (lH, s), 7.69 (2H, d, J
= 8.8 Hz), 8.23-8.27 (lH, m).
IR (KBr): 1717, 1674, 1590, 1530, 1470 cm K
Example 49
Production of N-(4-(l-(2,6-difluorobenzyD-3-(4-(l-hydroxy-1-
methylethyl)phenyl)-5-(((2-methoxyethyl)(methyDamino)methyl)-2,4-
dloxo-l,2,3,4-tetrahy6^othieno[2,3-d]pyrimidin-6-yDphenyl)-N'-
methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (1.22 g), diethyl
cyanophosphate (456 pJ), 4-(l-hydroxy-l-methylethyl)aniline (454 mg)
and N-ethyldiisopropylamine (569 pJ) gave a crude amide (1.12 g).
Furthermore, the similar reaction by using ethanol (60 ml), a solution of
28 % sodium methoxide in methanol (579 mg) gave the title compound
(849 mg).
Elemental analysis for C36H37N5O6SF2 O.5H2O
Calcd.:C, 59.82; H, 5.45; N, 9.97.
Found :C, 60.09; H, 5.40; N, 10.06.
iH-NMR (CDCla) 5: 1.60 (6H, s), 1.79 (1H, s), 2.14 (3H, s), 2.63 (2H, t, J =
5.9 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.82 (2H, s),
5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20-7.34 (4H, m), 7.53 (2H, d, J =
8.7 Hz), 7.60-7.63 (5H, m).
IR (KBr): 1713, 1669, 1590, 1532, 1470 cm 1.
Example 50
Production of N-(4-(5-((benzyl(methyl)amino)methyl)-1"(2,6-
difluorobenzyD-3-(4-(l-hydroxy- l-methylethyl)phenyl)-2,4-dioxo-1,2,3,4-
tetr ahy drothieno[2,3 - d]pyrimidin-6 -yDphenyl) -N'-methoxyurea

The similar reaction as described in Example 40 by using 4-(N-
benzyl-N-methylaminomethyD-2-[N-(2,6-difluorobenzyl)-N-
ethoxycarbonyHaminqf5-[4-(3-methoxyureido)phenyl]thiophene-3-
carboxylic acid (470 mg), diethyl cyanophosphate (167 pJ), 4-(l-hydroxy-
1-methylethyD aniline (166 mg) and N-ethyldiisopropylamine (209 pi)
gave a crude amide (422 mg). Furthermore, the similar reaction by
using ethanol (25.5 ml) and sodium ethoxide (70 mg) gave the title
compound (113 mg).
Elemental analysis for C39H37N5O6SF2
Calcd.:C, 64.54; H, 5.14; N, 9.65.
Found :C, 64.46; H, 5.05; N, 9.70.
iH-NMR (CDCls) 5: 1.62 (6H, s), 1.77 (1H, s), 2.05 (3H, s), 3.56 (2H, s),
3.82 (3H, s), 3.90 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.14-7.38
(9H, m), 7.55 (2H, d, J = 9.0 Hz), 7.62 (lH, s), 7.64 (2H, d, J = 8.7 Hz),
7.72 (2H, d, J = 8.4 Hz).
IR (KBr): 1713, 1669, 1590, 1530, 1470 cm'.
Example 51
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyl) (methyl) amino)methyl)"3-(4-(l-methoxy-l-
methylethyl)pheny0-2,4-dioxo-l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-
6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (364 mg), diethyl
cyanophosphate (136 pJ), 4-(l-methoxy-l-methylethyl)aniline (149 mg)
and N-ethyldiisopropylamine (171 pi) gave a crude amide (292 mg).
Furthermore, the similar reaction by using ethanol (19 ml), a solution of
28 % sodium methoxide in methanol (146 mg) gave the title compound
(146 mg).
Elemental analysis for C36H39N5O6SF2
CalccUC, 61.09; H, 5.55; N, 9.89.
Found :C, 60.97; H, 5.54; N, 9.92.
iH-NMR (CDCla) 6: 1.55 (6H, s), 2.15 (3H, s), 2.64 (2H, t, J = 5.9 Hz), 3.11
(3H, s), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.83 (2H, s),
5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.16 (lH, s), 7.24-7.36 (4H, m), 7.51-
7.63 (6H, m).
IR(KBr): 1715, 1674, 1590, 1532, 1464, 1327 cm 1.
Example 52
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyO(methyl)amino)methyl)-3-(l-methyl-lH-imidazol-2-yD-2,4-
dioxo- l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
cyanophosphate (228 pi), 2 - amino-1 -methyl- 1H -imidazole hydrochloride
(214 mg) and N-ethyldiisopropylamine (586 pJ) gave a crude amide (48
mg). Furthermore, the similar reaction by using methanol (3.3 ml), a
solution of 28 % sodium methoxide in methanol (25 mg) gave the title
compound (17 mg).
iH-NMR (CDCk) 5: 2.15 (3H, s), 2.61 (2H, dt, J = 1.8 Hz, 6.90 Hz), 3.27
(3H, s), 3.40 (2H, dt, J = 1.8 Hz, 6.0 Hz), 3.53 (3H, s), 3.75 (lH, d, J = 12.3
Hz), 3.80 (3H, s), 3.81 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 15.9 Hz), 5.57
(1H, d, J = 15.9 Hz), 6.91 (2H, t, J = 8.1 Hz), 6.99 (1H, d, J = 1.5 Hz), 7.14
(1H, d, J = 1.5 Hz), 7.28 (lH, s), 7.25-7.34 (1H, m), 7.53 (2H, d, J = 9.0
Hz), 7.60 (2H, d, J = 9.0 Hz), 7.70 (lH, s).
IR (KBr): 1725, 1682, 1590, 1530, 1470 cm i.
Example 53
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethy0Gnethy0amino)methyD'3-(3-methylbutyl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
cyanophosphate (228 pJ), isoamylamine (139 mg) and N-
ethyldiisopropylamine (310 pJ) gave a crude amide (102 mg).
Furthermore, the stirring with methanol (7 ml), a solution of 28 %
sodium methoxide in methanol (55 mg) at 55 °C for 20 hours and the
similar treatment gave the title compound (80 mg).
Elemental analysis for C31H37N5O5SF2
Calcd.:C, 59.13; H, 5.92; N, 11.12.
Found :C, 58.97; H, 5.99; N, 10.90.
iH-NMR (CDCI3) 5: 0.98 (6H, d, J = 6.3 Hz), 1.52-1.58 (2H, m), 1.64-1.71
(1H, m), 2.14 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.45 (2H, t, J =
5.9 Hz), 3.81 (3H, s), 3.85 (2H, s), 4.04-4.09 (2H, m), 5.33 (2H, s), 6.90
(2H, t, J = 8.3 Hz), 7.17 (lH, s), 7.24-7.35 (lH, m), 7.51 (2H, d, J = 8.7
Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (lH, s).
IR (KBr): 2959, 1705, 1659, 1590, 1531, 1472 cm 1.
Example 54
Production of N-(4-(l-(2,6-difluorobenzyD-3-(2-methoxyethyD-5-(((2-
methoxyethy0(methy0amino)methyl)-2,4-dioxo-1,2,3,4-
tetiahydrothieno[2,3-d]pyrimidin-6-yl)plieny])-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
cyanophosphate (228 pi), 2-methoxyethylamine (120 mg) and N-
ethyldiisopropylamine (310 pi) gave a crude amide (266 mg).
Furthermore, the similar reaction by using methanol (19.6 ml), a solution
of 28 % sodium methoxide in methanol (152 mg) gave the title compound
(140 mg).
Elemental analysis for C29H33N5O6SF2
Calcd.:C, 56.39; H, 5.39; N, 11.34.
Found :C, 56.40; H, 5.35; N, 11.15.
iH-NMR (CDCls) 5: 2.14 (3H, s), 2.65 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.36
(3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.66 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.84
(2H, s), 4.30 (2H, t, J = 5.9 Hz), 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.15
(1H, s), 7.24-7.34 (lH, m), 7.51 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0
Hz), 7.60 (1H, m).
IR (KBr): 2936, 1705, 1663, 1590, 1532, 1472 cm 1.
Example 55
Production of N-(4(l-(2,6-difluorobenzyD-3-(2-ethoxyethyl)-5-(((2-
methoxyethyD(methyDamino)methyD-2,4-dioxo-1,2,3,4-
tetrahydrothieno[2,3-dJpyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
cyanophosphate (228 pJ), 2-ethoxyethylamine (143 mg) and N-
ethyldiisopropylamine (310 pi) gave a crude amide (259 mg).
Furthermore, the similar reaction by using methanol (18.7 ml), a solution
of 28 % sodium methoxide in methanol (144 mg) gave the title compound
(193 mg).
Elemental analysis for C30H35N5O6SF2
Calcd..C, 57.04; H, 5.58; N, 11.09.
Found :G, 57.01; H, 5.66; N, 10.93.
iH-NMR (CDCls) 8: 1.15 (3H, t, J = 6.9 Hz), 2.14 (3H, s), 2.66 (2H, t, J =
6.0 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 6.0 Hz), 3.54 (2H, q, J = 6.9 Hz), 3.69
(2H, t, J = 6.0 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.29 (2H, t, J = 6.0 Hz), 5.32
(2H, s), 6.89 (2H, t, J = 8.1 Hz), 7.17 (lH, s), 7.23-7.34 (1H, m), 7.52 (2H,
d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (lH, m).
IR (KBr): 2975, 1705, 1663, 1590, 1532, 1472 cm1.
Example 56
Production of N-(4-(l-(2,6-difluorobenzyl)-3-isopropyl-5-(((2-
methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-l,2,3,4-
tetrahydrotteeno[2,3-d]pyrimidin-6-yDphenyD-N'-methoxyurea
The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
cyanophosphate (228 ul), isopropylamine (95 mg) and N-
ethyldiisopropylamine (310 ul) gave a crude amide (306 mg).
Furthermore, the stirring with methanol (23.2 ml) and a solution of 28 %
sodium methoxide in methanol (179 mg) at 60 °C for 17 hours and the
similar treatment gave the title compound (192 mg).
Elemental analysis for C29H33N5O5SF2
Calcd.:C, 57.89; H, 5.53; N, 11.64.
Found :C, 57.98; H, 5.49; N, 11.72.
iH-NMR (CDCla) 5: 1.52 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.66 (2H, t, J =
5.9 Hz), 3.31 (3H, s), 3.46 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s),
5.31 (2H, s), 5.34 (lH, m), 6.90 (2H, t, J = 8.1 Hz), 7.16 (lH, s), 7.24-7.35
(1H, m), 7.52 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.60 (lH, m).
IR (KBr): 2973, 1703, 1659, 1590, 1534, 1472 cm'.
Example 57
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyO(methyDamino)methyl)-3-(6-methoxy-3-pyridazinyD-2,4-
dioxo-l,2,3,4-tetrahydrothieno[2,3*dlpyrimidin-6-yl)phenyD-N'-
methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (455 mg), diethyl
cyanophosphate (285 pJ), 3-amino-6-chloropyridine (243 mg) and N-
ethyldiisopropylamine (388 pJ) gave a crude amide (207 mg).
Furthermore, the similar reaction by using methanol (14.2 ml), a solution
of 28 % sodium methoxide in methanol (109 mg) gave the title compound
(132 mg).
iH-NMR (CDCls) 5: 2.13 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41
(2H, t, J = 5.7 Hz), 3.74 (2H, brs), 3.82 (3H, s), 4.18 (3H, s), 5.32 (2H, brs),
6.92 (2H, t, J = 8.3 Hz), 7.12 (lH, d, J = 9.3 Hz), 7.24 (1H, s), 7.29-7.35
(1H, m), 7.41 (2H, d, J = 9.3 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J =
8.7 Hz), 7.66 (1H, s).
IR (KBr): 2936, 1717, 1674, 1591, 1530, 1460 cm1.
Example 58
Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-
methoxyethy0(methyDamino)methyl)-2,4-dioxo-3-(3-pyridaziny0-l,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyD-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (364 mg), diethyl
cyanophosphate (182 pD, 3-aminopyridazine hydrochloride (158 mg) and
N-ethyldiisopropylamine (414 pJ) gave a crude amide (55 mg).
Furthermore, the similar reaction by using methanol (4 ml), a solution of
28 % sodium methoxide in methanol (30 mg) gave the title compound (15
mg).
iH-NMR (CDCla) 8: 2.12 (3H, s), 2.61 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.39
(2H, t, J = 5.7 Hz), 3.78 (2H, brs), 3.82 (3H, s), 5.34 (2H, brs), 6.93 (2H, t,
J = 8.1 Hz), 7.26 (1H, s), 7.29-7.37 (lH, m), 7.53-7.61 (5H, m), 7.67 (lH,
s), 7.69 (1H, dd, J = 4.8 Hz, 8.4 Hz), 9.28 (lH, dd, J = 1.8 Hz, 4.8 Hz).
IR (KBr): 2936, 1717, 1674, 1590, 1530, 1470 cm1.
Example 59
Production of N-(4-(l-(2>6-difluorobenzyl)-5-(((2-
methoxyethyl)(methyDamino)methyl)-3-methoxy-2,4-dioxo-l,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (607 mg), diethyl
cyanophosphate (304 pJ), o-methylhydroxylamine hydrochloride (334 mg)
and N-ethyldiisopropylamine (1.04 ml) gave a crude product, which was
purified by aminopropyl silica gel column chromatography (Fuji Silysia
Chemical) to give the title compound (283 mg).
!H-NMR (CDCk) 5: 2.14 (3H, s), 2.68 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.47
(2H, t, J = 6.0 Hz), 3.82 (3H, s), 3.83 (2H, s), 4.06 (3H, s), 5.35 (2H, s),
6.92 (2H, t, J = 8.3 Hz), 7.20 (lH, s), 7.29-7.35 (lH, m), 7.55 (4H, s), 7.63
(1H, s).
IR (KBr): 1725, 1684, 1590, 1530, 1472 cm 1.
Example 60
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethy0(methyl)amino)methyD-3-methyl-2,4-dioxo-l,2,3,4-
tetrahydrothif>nof2,3-d]pyrimiHin-fi-y1)pliftny1)-N>-Tnftthnxyurftfl

The similar reaction as described in Example 40 by using the
compound obtained in Reference Example 7 (607 mg), diethyl
cyanophosphate (304 pJ), methylamine hydrochloride (270 mg) and N-
ethyldiisopropylamine (1.04 ml) gave a crude amide (133 mg).
Furthermore, the stirring with methanol (9.1 ml) and a solution of 28 %
sodium methoxide in methanol (70 mg) at 60 °C for 17 hours and the
similar treatment gave the title compound (83 mg).
iH-NMR (CDCla) 5: 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.45
(3H, s), 3.48 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.33 (2H, s),
6.91 (2H, t, J = 8.3 Hz), 7.17 (lH, s), 7.25-7.35 (1H, m), 7.55 (4H, s), 7.62
(1H, s).
IR (KBr): 1705, 1661, 1590, 1532, 1472 cm 1.
Reference Example 18
production of N-(4-(5-chloromethyl-l-(2,6*difluorobenzyD-1,2,3,4-
tetrahydro-2,4-dioxo-3-phenyltMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea

Into a solution of N-(4-(5-((benzylGnethyl)amino)methyl)-l-(2,6-
difluorobenzyO-l^.S^-tetrahydro^^-dioxo-S-phenylthieno^.S-
d]pyrimidm-6-yl)phenyl)-N'-methoxyurea (7.7 g, 11.53 mmol) in THF
(200 ml) which was cooled with a dry ice-acetone bath was added cr
choloroethyl chloroformate (1.7 ml, 11.64 mmol). The temperature of the
mixture was elevated up to room temperature, and the mixture was
stirred for 2.5 hours. The reaction mixture was diluted with saturated
aqueous solution of sodium bicabonate and extracted with chloroform.
The organic layer was washed with saturated aqueous solution of sodium
chloride, dried over magnesium sulfate and concentrated under reduced
pressure.
The residue was purified with silica gel chromatography (eluent,"
ethyl acetate/chloroform; from 1/4 to 1/3) and recrystallized from
chloroform/diethylether, whereby the title compound (5.66 g, 84 %) was
obtained as white crystals.
iH NMR (CDCls) 6 3.83 (3H, s), 4.84 (2H, s), 5.27 (2H, s), 5.37 (2H, s),
6.92 (2H, t, J= 7.8 Hz), 7.23-7.35 (4H, m), 7.41-7.66 (8H, m).
Reference Example 19
Production of N-(4-(5-chloromethyl- l-(2,6-difluorobenzyD-1,2,3,4-
tetrahydro-2,4-dioxo-3-(4-methoxyphenyDthieno[2,3-d]pyrimidin-6-
yl)phenyl) -N'-methoxyurea

The similar reaction as described in Example 5 by using 4-(N-
benzyl-N-methylaminomethyl)-2-(N-(2,6-diQuorobenzyl)-N-
ethoxycarbonyBlaminQf5-(4-(3-methoxyiireido)plienyDthiophene-3-
carboxylic acid (5.0 g, 7.83 mmol) and p-anisidine (1.93 g, 15.65 mmol)
gave N-(4-(5-((benzyl(methyl)amino)methyD- l"(2,6-difluorobenzyD-3-(4-
methoxypheny0"2,4-dioxo-l,2,3,4-tetrahydrotlu^no[2,3-d]pyrimidin-6-
yDphenyl-N'-methoxyurea (3.39 g, 62 %) as white solids. The similar
reaction as described in Reference Example 18 by using the compound
(80 mg, 0.11 mmol) gave the title compound (50 mg, 74 %) as white
crystals.
*H NMR (CDCla) 5 3.81 (3H, s), 3.83 (3H, s), 4.83 (2H, s), 5.35 (2H, s),
6.92 (2H, t, J= 8.1 Hz), 7.00 (2H, d, J= 10.2 Hz), 7.18-7.35 (3H, m), 7.48-
7.65 (5H, m).
Reference Example 20
Production of N-(4-(5-chloromethyl-l-(2,6-difiuorobenzyl)-1,2,3,4-
tetrahydro-2,4-dioxo-3-(4-hydroxycyclohexyDthieno[2,3-d]pyrimidin-6-
yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using 4-(N-
benzyl-N-methylaminomethyl) -2 - (N- (2,6 - difluorobenzyD -N-
ethoxycarbonyUamino} 5 - (4- (3 -methoxyureido)pheny])thiophene- 3 -
carboxylic acid (10.0 g, 15.65 mmol) and 4-aminocyclohexanol(3.61 g,
31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-l-(2,6-
difluorobenzyD-3-(4-hydroxycydohexyl)-2,4-dioxo-l,2,3,4-
tetrahydrothieno[2,3• dlpyrimidin-6-yDphenyl-N'-methoxyurea (5.20 g,
48 %) as white crystals. The similar reaction as described in Reference
Example 18 by using the compound (500 mg, 0.72 mmol) gave the title
compound (180 mg, 41.%) as white crystals.
*H NMR (CDCls) 5 1.41-1.55 (2H, m), 1.71 (2H, d, J= 11.7 Hz), 2.07 (2H,
d, J= 12.4 Hz), 2.63 (2H, q, J= 11.1 Hz), 3.70-3.82 (4H, m), 4.84 (2H, s),
4.90-5.06 (1H, m), 5.29 (2H, s), 6.91 (2H, t, J= 8.1 Hz), 7.13 (lH, s), 7.25-
7.33 (1H, m), 7.47 (2H, d, J= 8.4 Hz), 7.58 (2H, d, J= 9.0 Hz), 7.63 (lH, s).
Reference Example 21
Production of N-(4-(5-chloromethyM-(2,6-difluorobenzyD-3-(5-
fluoropyridin-2 -yl)* 1,2,3,4-tetrahydro-2,4-dioxothieno[2,3 -d]pyrimidin-6 -
yDphenyl) -N'-methoxyurea

The similar reaction as described in Example 5 by using 4-(N*
benzyl-N-methylaminometh.yl)-2-CN-(2,6-difluorobenzyl)-N-
ethoxycarbonyl3Uunino}5-(4-(3-methoxyureido)phenyl)thiophene-3-
carboxylic acid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine(3.51 g,
31.30 mmol) gave N-(4-(5-((benzyKmethyl)amino)methyl)-l-(2,6-
difluorobenzyl)-3-(5-fluoropyridin-2-yl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3*dIpyrimidin-6-yl)phenyl-N'-methoxyurea (3.39 g,
32 %) as white solids. The similar reaction as described in Reference
Example 18 by using the compound (l.O g, 1.46 mmol) gave the title
compound (560 mg, 64 %) as white solids.
iH NMR (CDCla) 8 3.83 (lH, s), 4.79 (2H, br), 5.34 (2H, br), 6.93 (2H, t, J=
8.0 Hz), 7.14 (IH, s), 7.29-7.40 (2H, m), 7.50-7.65 (5H, m), 8.51 (lH, d, J=
3.0 Hz).
Reference Example 22
Production of N-(4- (5-chloromethyl-l-(2,6-difluorobenzyD-1,2,3,4-
tetrahydro-2,4-dioxo-3-(pyridin-2-yl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-
N'-methoxyurea
The similar reaction as described in Reference Example 18 by
using compound (500 mg, 0.75 mmol) obtained in Example 1 gave the
title compound (270 mg, 62 %) as white solids.
iH NMR (DMDO-de) 5 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13
(2H, t, J= 8.3 Hz), 7.41-7.54 (4H, m), 7.78 (2H, d, J= 8.4 Hz), 8.01 (1H, t,
J= 8.0 Hz), 8.30 (1H, s), 8.59-8.61 (lH, m), 9.14 (lH, s), 9.66 (lH, s)
Reference Example 23
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-5-
(methylamino)methyl-l,2,3,4-tetrahydro-2,4-dioxo-thieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea
The similar reaction as described in Reference Example 14 by
using N-(4-(5-((benzyl(methyl)amino)methyl)- l-(2,6-difluorobenzyl)-3-(4-
hydroxycydohexy0-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-dlpyrimidin-6-
yl)phenyl-N'-methoxyurea(5.20 g, 48 %) obtained in Reference Example
20 gave the title compound (5.20 g, 48 %) as white crystals.
*H NMR (DMDQ-de) 5 3.63 (3H, s), 4.85 (2H, s), 5.10-5.24 (2H, br), 7.13
(2H, t, J= 8.3 Hz), 7.41-7.54 (4H, m), 7.78 (2H, d, J= 8.4 Hz), 8.01 (lH, t,
J= 8.0 Hz), 8.30 (1H, s), 8.59-8.61 (lH, m), 9.14 (lH, s), 9.66 (lH, s)
Reference Example 24
Production of N-(2-methoxy- l-methylethyl)-N-methylamine

A mixture of a solution of methoxyacetone (2.92 g, 33.14 mmol) and
methylamine in 2.0 M THF (100 ml, 200.0 mmol) and a solution of acetic
acid (0.5 ml) in THF (100 ml) was stirred under ice cooling for 30
minutes. To the mixture was added triacetoxy sodium borohydride
(14.05 g, 66.28 mmol), and the mixture was stirred at room temperature
for 4 days. To the reaction mixture were added saturated aqueous
solution of sodium bicarbonate (100 ml), ethyl acetate ethyl acetate (100
ml) and benzyloxycarbonylchloride (8.48 g, 49.71 mmol), successively,
and the mixture was stirred at room temperature for 5 hours. The
reaction mixture was distributed between saturated aqueous solution of
sodium bicarbonate and ethyl acetate. The ethyl acetate layer was
washed with saturated brine and dried over magnesium sulfate, and the
solvent was distilled off. The residue was purified by silica gel
chromatography (eluent- ethyl acetate/hexane; from 6/1 to 4/1) to obtain
colorless liquid (4.24 g, 54 %). A mixed solution of the colorless liquid
(0.94 g, 3.96 mmol) and 10 % palladium-carbon (94 mg) in ethanol (10 ml)
was stirred at room temperature under hydrogen atmosphere for 2 hours,
and subjected to filtration. The filtrate was concentrated under
reduced pressure to give the title compound (220 mg, 54 %) as pale yellow
liquid.
iH NMR (CDCls) 5 1.15 (3H, d, J= 6.6 Hz), 2.50 (3H, s), 2.90-2.99 (lH, m),
3.29-3.44 (5H, m).
Reference Example 25
Production of N-(4-(5-methylaminomethyl-l-(2,6-difluorobenzyl)-1,2,3,4-
tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrinudin-6-
yDphenyl)-N'-methoxyureahydrochloride

A mixed solution of N-(4-(5-((benzyl(methyl)amino)methyl)-l-(2,6-
difluorobenzyD-3-(4-methoxyphenyD-2,4-dioxo-l,2,3,4-
tetxahydrothieno^^-dJpyrimidin-G-yDphenyl-N'-metlioxyurea (2.0 g, 2.87
mmol) synthesized in Reference Example 19, 10 %-palladium-carbon (200
mg), IN hydrochloric acid (3 ml) in ethanol (40 ml) was stirred under
hydrogen atmosphere at room temperature for 72 hours. The reaction
mixture was subjected to filtration and the filtrate was concentrated to
dryness to give the title compound (1.77 g, 96 %) as white powders.
iH NMR (CDCls) 5 2.73 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 4.00-4.18 (2H,
br), 5.35 (2H, s), 5.37 (2H, s), 6.90-7.08 (4H, m), 7.20-7.38 (5H, m), 7.61
(4H, s), 7.77 (1H, s), 7.95 (1H, s).
Reference Example 26
Production of N-(4-(5-(((lR)-l-phenylethyl(methyDamino)methyD-1-(2,6-
difluorobenzyl)-l,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-
d]pyrinridin-6-yl)phenyl)-N'-methoxyurea

A solution of the compound (100 mg, 0.17 mmol) obtained in
Reference Example 18, (R)-(+)-N-a-dimethylbenzylamine (28 mg, 0.21
mmol) and N-ethyldiisopropylamine (29 mg, 0.22 mmol) in DMF (200 ml)
was stirred at room temperature for 24 hours. The reaction mixture was
diluted with saturated aqueous solution of sodium bicabonate and
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous solution of sodium chloride, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (eluent: from ethyl
acetate/chloroform(2/3) to chloroform/methanol(20/l)) and recrystallized
from chloroform/diethylether to give the title compound (58 mg, 50 %) as
white crystals.
iH NMR (CDCb) 5 1.25 (3H, d, J= 6.6 Hz), 1.89 (3H, s), 3.82 (3H, s), 3.82-
3.87 (IH, m), 3.91 (2H, d, J= 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.3 Hz),
7.14-7.30 (9H, m), 7.43-7.61 (8H, m).
mp 192-193 °C.
Reference Example 27
Production of N-(4-(5-((lS)-l-phenylethyl(methyl)amino)methyl)-1-(2,6-
difluorobenzyl)-l,2,3,4-tetraliydro-2,4*clioxo-3-phenylthieno[2,3-
d]pyrinridin-6-yl)phenyD-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using compound (100 mg, 0.17 mmol) obtained in Reference Example 18
and (S)-0-N-a-dimethylbenzylamine(28 mg, 0.21 mmol) gave the title
compound (61 mg, 53 %) as white crystals.
iH NMR (CDCla) 5 1.25 (3H, d, J= 6.6 Hz), 1.89 (3H, s), 3.82 (3H, s), 3.82-
3.90 (1H, m), 3.91 (2H, d, J= 4.5 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.0 Hz),
7.19-7.30 (9H, m), 7.43-7.61 (8H, m).
mp 191-192 °C.
Reference Example 28
Production of N-(4-(5-(((lR)- l-phenylethylamino)methyl)-1"(2,6-
difluorobenzyl)-l,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using compound (100 mg, 0.17 mmol) obtained in Reference Example 18
and (R)-(+)-l-phenylethylamine (25 mg, 0.21 mmol) gave the title
compound (56 mg, 49 %) as white crystals.
*H NMR (CDCla) 5 1.32 (3H, d, J= 6.6 Hz), 3.59 (lH, d, J= 12.0 Hz), 3.65-
3.82 (5H, m), 5.25-5.46 (2H, AB), 6.90 (2H, t, J= 8.1 Hz), 7.11-7.59 (13H,
m).
Elemental analysis CaaHsiFssNeCXS • 0.2H2O
Calcd.: C, 64.41; H, 4.71; N, 10.43.
Found: C, 64.29; H, 4.64; N, 10.46.
mp 180-182 °C.
Reference Example 29
Production of N-(4-(5-(((lS)- l-phenylethylamino)methyl)-1-(2,6-
diQuorobenzyD-l,2,3,4-tetrahydro-2,4-dioxo-3-phenyltbieno[2,3-
d]pyrimidin-6-yDphenyl)-N,-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (100 mg, 0.17 mmol) obtained in Reference Example
18 and (S)-(-)-l-phenylethylamine (25 mg, 0.21 mmol) gave the title
compound (56 mg, 49 %) as white crystals.
m NMR (CDCla) 5 1.31 (3H, d, J= 6.6 Hz), 3.58 (lH, d, J= 12.3 Hz), 3.72-
3.82 (5H, m), 5.24-5.46 (2H, AB), 6.90 (2H, t, J= 8.1 Hz), 7.12 (lH, s),
7.16-7.37 (8H, m), 7.43-7.56 (4H, m).
Elemental analysis C36H31F2N5O4S
Calcd.: C, 64.76; H, 4.68; N, 10.49.
Found: C, 64.46; H, 4.57; N, 10.60.
mp 182-185 °C.
Reference Example 30
Production of N-(4-(5-(methyl(l-phenylpropylamino)methyl)-l-(2,6-
difluorobenzyD-l,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

Under ice cooling, to a solution of 1 -phenyl-1 -propanol (1.0 g, 7.34
mmol) and N-ethyldiisopropylamine (1.42 g, 11.01 mmol) in
dichloromethane (10 ml) was added methanesulfonyl chloride (690 //1,
8.81 mmoD, and the mixture was stirred at room temperature for 5 hours.
The reaction mixture was diluted with saturated aqueous solution of
sodium bicarbonate and extracted with ethyl acetate. The extract was
washed with saturated brine, dried over magnesium sulfate, and solvent
was distilled off under reduced pressure. The residue was purified by
silica gel chromatography (eluenfrethyl acetate/hexane:5/l) to give 1-
chloro-1-phenylpropane (610 mg, 54 %) as pale yellow liquid.
The similar reaction as described in Reference Example 26 by
using the compound (100 mg, 0.17 mmol) obtained in Reference Example
15 and the 1-chloro-l-phenylpropane (32 mg, 0.21 mmol) obtained above
gave the title compound (45 mg, 38 %) as white crystals.
iH NMR (CDCla) 5 0.67 (3H, t, J= 7.2 Hz), 1.63-1.91 (5H, m), 3.52-3.57
(1H, m), 3.73-3.93 (5H, m), 3.91 (2H, d, J= 4.5 Hz), 5.35 (2H, s), 6.91.(2H,
t, J= 8.1 Hz), 7.08-7.34 (8H, m), 7.41-7.55 (8H, m), 7.64 (1H, s).
mp 171-172 °C.
Reference Example 31
Production of methyl (((l-(2,6-difluorobenzyl)-6-(4-
(((methoxyammo)carbonyDamino)phenyl)-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahy drothieno[2,3 ¦ dJpyrimidin-5-
yl)methyl)(methyDamino)(phenyl)acetic acid

The similar reaction as described in Example 20 by using the
compound (150 mg, 0.17 mmol) obtained in Reference Example 15 and or
bromophenylmethyl acetate (71 mg, 0.31 mmol) gave the title compound
(73 mg, 39 %) as white crystals.
iH NMR (CDCla) 8 2.08 (3H, s), 3.54 (32H, s), 3.79 (3H, s), 3.89-4.20 (2H,
AB), 4.67 (1H, s), 5.35 (2H, brs), 6.92 (2H, t, J= 8.2 Hz), 7.22-7.37 (6H,
m), 7.44-7.56 (7H, m) 7.71 (2H, d, J= 8.0 Hz).
Elemental analysis C88H33F2N5O6S
Calcd.: C, 62.89; H, 4.58; N, 9.65.
Found: C, 62.70; H, 4.61; N, 9.78.
mp 147-149 °C.
Reference Example 32
Production of N-(4-(l-(2,6-difluorobenzyl)-5-((2-methoxy-1-
phenylethyl(methyl)amino)methyl)- l,2,3,4-tetrahydro-2,4-dioxo-3-
phenyltliieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

A solution of methylphenethylether (l.O g, 7.34 mmoD, NBS (1.96
g, 11.01 mmol) and AIBN (240 mg, 1.47 mmol) in carbon tetrachloride (30
ml) was heated under reflux for 2 hours. After cooling, the reaction
mixture was diluted with saturated aqueous solution of sodium
bicarbonate and extracted with chloroform. The extract was washed
with saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure to give a crude 2-methoxy-l-phenylbromoethane
(1.33 g, 84 %) as brown liquid.
The similar reaction as described in Example 14 by using the
compound (200 mg, 0.34 mmol) obtained in Reference Example 15 and
the crude bromide (50 mg) obtained above gave the title compound (42
mg, 18 %) as white crystals.
m NMR (CDCk) 8 1.97 (3H, s), 3.24 (3H, s), 3.55-3.61 (lH, m), 3.80 (3H,
s), 3.86-3.96 (3H, m), 4.67 (lH, s), 5.36 (2H, s), 6.91 (2H, t, J= 8.1 Hz),
7.14-7.31 (8H, m), 7.33-7.56 (8H, m), 7.63 (lH, s).
Elemental analysis C38H35F2N5O5S • 0.2H2O
Calcd.: C, 63.80; H, 4.99; N, 9.79.
Found: C, 63.64; H, 4.95; N, 9.89.
mp 169-172 °C.
Reference Example 33
Production of N-(4-(l-(2,6-difluorobenzyl)-5-(methyl(l-pyridin-2-
ylethyDamino)methyD- l,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-
d]pyrimidin-6-yl)phenyI)-N'-methoxyiirea

A solution of 2-ethylpyridine (10.0 g, 93.34 mmol), N-
bromosuccinimide (17.44 g, 98.00 mmol) and azobisisobutyronitrile (1.53
g, 9.33 mmol) in carbon tetrachloride (300 ml) was stirred at 90 °C for 1
hour. After cooling, the reaction mixture was subjected to filtration.
The filtrate was washed with saturated aqueous solution of sodium
bicabonate and saturated aqueous solution of sodium chloride, dried over
magnesium sulfate and concentrated. The residue was purified by silica
gel chromatography to give a bromide (15.68 g, 90 %) as pale yellow
liquid.
The similar reaction as described in Example 14 by using the
compound (160 mg, 0.26 mmol) obtained in Reference Example 15 and
the above bromide (62 mg, 0.33 mmol) obtained above gave the title
compound (133 mg, 75 %) as white crystals.
*H NMR (CDCla) 8 1.30 (3H, d, J= 6.9 Hz), 1.92 (3H, s), 3.80 (3H, s), 4.00
(2H, s), 4.04 (1H, q, J= 6.6 Hz), 5.35 (2H, s), 6.91 (2H, t, J= 8.0 Hz), 7.02-
7.06 (1H, m), 7.24-7.30 (4H, m), 7.40-7.54 (8H, m), 7.65 (1H, s), 8.44 (lH,
d,J=5.7Hz).
mp 146-148 °C.
The title compound (40 mg) was optically resolved by a preparative
HPLC by using CHIRALPAK AD (50 mmI.D.x500 mmL), in which mobile
phase is hexane/2-propanol(=3/2), to obtain 19 mg of an optical isomer
having an retention time of 25 minutes (99.9 % ee) and 19 mg of another
isomer having retention time of 29 minutes (99.0 % ee) in an analysis
using CHIRALPAK AD (4.6 mmI.D.x250 mmL), both of which are white
powders.
Reference Example 34
Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-methoxyl-
methylethyl)methylamino)methyl)- l,2,3,4-tetrahydro-2,4-dioxo-3-
phenylthieno[2,3-dJpyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (100 mg, 0.17 mmol) obtained in Reference Example
18 and the compound (21 mg, 0.21 mmol) obtained in Reference Example
24 gave the title compound (24 mg, 21 %) as white crystals.
!H NMR (CDCla) 8 0.90 (3H, d, J= 6.3 Hz), 2.04 (3H, s), 3.06-3.16 (2H, m),
3.26 (3H, s), 3.40-3.46 (1H, m), 3.51-3.98 (4H, m), 5.35 (2H, s), 6.90 (2H, t,
J= 8.4 Hz), 7.09 (1H, s), 7.25-7.32 (5H, m), 7.39-7.60 (6H, m).
Elemental analysis CssHssFjsNsOsS • O.3H2O
Calcd.: C, 60.50; H, 5.17; N, 10.69.
Found: C, 60.28; H, 5.21; N, 10.53.
mp 154-155 °C.
The title compound (48 nig) was optically resolved by preparative
HPLC by using CHIRALPAK AD(50 mmI.D.x500 mmL), in which mobile
phase is hexane/2-propanol (65/35), to obtain 22 mg of an optical isomer
having an retention time of 49 minutes (99.0 % ee) and 21 mg of another
isomer having retention time of 54 minutes (99.0 % ee) in an analysis
using CHIRALPAK OD (4.6 mmI.D.x250 mmL), both of which are white
powders.
Reference Example 35
Production of N-(4- (l-(2,6-difluorobenzyD-5-((methyl(l-pyridin-2-
ylethyl)amino)methyl)- l,2,3,4-tetrahydro-2,4-dioxo-3-(pyridin-2-
yl)thieno[2,3 - d]pyrimidin-6 -yl)phenyl) -N'-methoxyurea

The similar reaction as described in Reference Example 33 by
using the compound (100 mg, 0.17 mmol) obtained in Reference Example
14 gave the title compound (31 mg, 27 %) as white crystals.
iH NMR (CDCla) 8 1.30 (3H, d, J= 6.9 Hz), 1.92 (3H, s), 3.80 (3H, s), 3.98-
4.10 (3H, m), 5.33 (2H, brs), 6.90 (2H, t, J= 8.1 Hz), 7.01-7.06 (lH, m),
7.23-7.42 (5H, m), 7.49-7.56 (4H, m) 7.65 (lH, s), 7.90 (lH, t, J= 7.8 Hz),
8.44 (1H, d, J= 3.9 Hz), 8.68 (lH, d, J= 5.7 Hz),
mp 143-144 °C.
The title compound (20 mg) was optically resolved by a preparative
HPLC by using CHIRALPAK AD (50 mmI.D.x500 mmL), in which mobile
phase is hexane/2-propanol (l/l), to obtain 10 mg of an optical isomer
having an retention time of 23 minutes (99.9 % ee) and 11 mg of another
isomer having retention time of 28 minutes (99.2 % ee) in an analysis
using CHIRALPAK AD (4.6 mmI.D.x250 mmL), each of which is colorless
oily substance.
Reference Example 36
Production of N-(4- (l-(2,6-difluorobenzyD-3-(4-hydroxycyclohexyl)-5-((l-
pyridin-2 -ylethyl)methylamino)methyl) - 1,2,3,4-tetrahydro-2,4-
dioxothieno[2,3-d]pyrimidin-6-yDphenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 33 by
using the compound (100 mg, 0.17 mmol) obtained in Reference Example
23 gave the title compound (17 mg, 14 %) as white crystals.
iH NMR (CDCls) 5 1.35 (3H, d, J= 6.9 Hz), 1.43-1.54 (2H, m), 1.91 (3H, s),
2.09 (2H, d, J= 12.3 Hz), 2.65 (2H, q, J= 12.8 Hz), 3.73-3.81 (4H, m), 3.98-
4.13 (3H, m), 4.60 (lH, t, J= 12.0 Hz), 5.28 (2H, brs), 6.88 (2H, t, J= 8.1
Hz), 6.89-7.08 (1H, m), 7.22-7.31 (3H, m), 7.40-7.54 (4H, m) 7.62 (lH, s),
8.45 (1H, d, J= 4.89 Hz).
mp 144-145 °C.
Reference Example 37
Production of N-(4-(5-(((lR)- l-phenylethylamino)methyD-1-(2,6-
difluorobenzyl)-3-(4-hydroxycyclohexyD-l,2,3,4-tetrahydro-2,4-
dioxothieno[2,3-d]pyrimi'din-6-yDphenyD-N,-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (180 mg, 0.30 mmol) obtained in Reference Example
20 gave the title compound (77 mg, 37 %) as white crystals.
iH NMR (CDCls) 5 1.30 (3H, d, J= 6.6 Hz), 1.43-1.57 (2H, m), 1.71 (2H, d,
J= 9.9 Hz), 1.88 (3H, s), 2.04-2.15 (2H, m), 2.62-2.71 (2H, m), 3.70-3.93
(7H, m), 4.90-5.10 (lH, m), 5.28 (2H, s), 6.89 (2H, t, J= 8.1 Hz), 7.11-7.30
(8H, m), 7.51 (3H, s), 7.60 (lH, s).
Elemental analysis C37H39F2N5O5S • I.5H2O
Calcd.: C, 60.81; H, 5.79; N, 9.58.
Found: C, 60.77; H, 5.72; N, 9.41.
mp 137-138 °C.
Reference Example 38
Production of N-(4-(5-(((lR)-l-phenylethyDmethylaniino)methyl)-1-(2,6-
difluorobenzyl)U,2,3,4-tetrahydro-2,4-dioxo-3-pyridin-2-ylthieno[2,3'
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (270 mg, 0.46 mmol) obtained in Reference Example
22 gave the title compound (178 mg, 57 %) as white crystals.
m NMR (CDCla) 8 1.27 (3H, d, J= 6.8 Hz), 1.91 (3H, s), 2.04-2.15 (2H, m),
2.62-2.71 (2H, m), 3.75-4.00 (4H, m), 5.30 (2H, brs), 6.91 (2H, t, J= 8.1
Hz), 7.13-7.42 (10H, m), 7.54 (2H, d, J= 8.6 Hz), 7.61 (2H, d, J= 8.5 Hz),
7.91 (1H, t, J= 7.7 Hz), 8.70 (lH, d, J= 4.8 Hz).
Elemental analysis C36H32F2N6O4S • O.5H2O
Calcd.: C, 62.51; H, 4.81; N, 12.15.
Found: C, 62.34; H, 4.71; N, 12.12.
mp 168-170 °C.
Reference Example 39
Production of N-(4-(5-(((lR)- l-phenylethylamino)methyl)-1-(2,6-
dMuorobenzyl)-l,2,3,4-tetrahydro-2,4-dioxo-3-(5-fluoropyridin-2-
yDthieno[2,3-d]pyrimidin-6-yl)phenyD-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (280 mg, 0.46 mmol) obtained in Reference Example
21 gave the title compound (187 mg, 58 %) as white crystals.
iH NMR (CDCls) 8 1.27 (3H, d, J= 6.6 Hz), 1.90 (3H, s), 3.78-3.99 (5H, m),
5.33 (2H, brs), 6.91 (2H, t, J= 8.1 Hz), 7.12-7.38 (9H, m), 7.51-7.63 (5H,
m), 8.52 (1H, d, J= 3.0 Hz).
Elemental analysis CseHsiFsNeC^S • 0.2H2O
Calcd.: C, 61.39; H, 4.49; N, 11.93.
Found: C, 61.22; H, 4.56; N, 11.96.
mp 128-130 °C.
Reference Example 40
Production of N-(4-(5-((2-methoxyethyDmethylamino)methyl)-1-(2,6-
difluorobenzyD-l,2,3,4-tetrahydro-2,4-dioxo-3-(4-
methoxyphenyl)tMeno[2,3-dJpyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 4 by using the
compound (800 mg, 1.24 mmol) obtained in Reference Example 25 and 2-
bromoethylethylether (207 mg, 1.49 mmol) gave the title compound (407
mg, 58 %) as white solids.
*H NMR (CDCla) 5 2.13 (3H, s), 2.64 (2H, t, J= 5.7 Hz), 3.27(3H, s), 3.41
(2H, t, J= 5.6 Hz), 3.82 (3H, s), 3.84 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J=
8.1 Hz), 7.01 (2H, d, J= 8.7 Hz), 7.11 81H, s), 7.19 (2H, d, J= 8.7 Hz),
7.26-7.33 (3H, m), 7.53-7.70 (5H, m).
mp 181-184°C
Reference Example 41
Production of l-amino-2-methyl-2-propanol

To a suspension of lithium aluminum hydride (2.85 g, 75 mmol) in
diethylether (120 ml) was dropwise added a solution of acetone
cyanhydrin (4.73 g, 50 mmol) in diethylether (30 ml) under ice cooling.
The reaction liquid was stirred at room temperature for 4 hours. To the
reaction liquid were dropwise added water (2.85 ml), IN sodium
hydroxide (2.85 ml) and water (8.55 ml), successively. Insoluble matters
are filtered off, and the filtrate was concentrated to give the title
compound (1.32 g, 30 %) as colorless oily substance.
iH-NMR(CDCls) 5: 1.17 (6H, s), 2.60 (2H, s).
Reference Example 42
Production of tert-butyl(3-ethoxy-2,2-dimethylpropoxy)dimethylsilane

To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-
dimethylpropan-1-ol (Registry No. 117932-70-4) (2.18 g, 10 mmol) in THF
(30 ml) were added triethylamine (1.67 ml, 12 mmol) and
methanesulfonyl chloride (0.85 ml, 11 mmol) under ice cooling. The
reaction liquid was stirred at room temperature for 30 minutes, and to
the reaction liquid was added an aqueous solution of sodium bicarbonate.
The mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to give the title compound (2.98 g,
quant.) as colorless oily substance.
iH-NMRteDCla) 8: 0.04 (6H, s), 0.89 (9H, s), 0.93 (6H, s), 2.98 (3H, s),
3.34 (9H, s), 4.00 (2H, s).
Reference Example 43
Production of 2-(3-{[tert-butyl(dimethyDsilyl]oxy}-2,2-dimethylpropyl)-
lH-isoindol-l,3(2H)-dione

To a solution of compound (2.96 g, 10 mmol) obtained in Reference
Example 42 in DMF (10 ml) was added potassium phthalimide (1.85 g, 10
mmoD. The reaction liquid was stirred at 140 °C for 30 hours, and water
was added. The mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluenfcethyl acetate/hexane=l/10) to
give the title compound (2.79 g, 80 %) as pale yellow oily substance.
i H-NMRCCDCla) 8: 0.01 (6H, s), 0.87 (9H, s), 0.93 (6H, s), 3.39 (2H, s),
3.61 (2H, s), 7.65-7.75 (2H, m), 7.8-7.9 (2H, m).
Reference Example 44
Production of 3-amino-2,2-dimethylpropan-l-ol hydrochloride

A mixture of compound (1.395 g, 4.0 mmol) obtained in Reference
Example 43, concentrated hydrochloric acid (10 ml), acetic acid (7 ml) and
water (10 ml) was refluxed for 24 hours. The reaction liquid was
concentrated and water was added. The precipitated phthalic acid was
filtered off and filtrate was concentrated. The residue was recrystallized
from ethyl acetate to give the title compound (257.2 mg, 46 %) as pale
purple crystals.
i H-NMR(CDCl3+ CDsOD) 8- 2.91 (2H, brs), 3.38 (6H, brs), 3.52 (2H, brs).
Reference Example 45
Production of [l-({[tert-
butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol

To a solution of lithium aluminum hydride (9.34 g, 246 mmol) in
THF (150 ml) was dropwise added a solution of dimethylcyclopropane-
1,1-dicarboxylate (25.95 g, 164.1 mmol) in THF (150 ml) under ice
cooling. The solution was stirred at 0 °C for 2 hours, and to the solution
were slowly added water (9.5 ml), 15 % aqueous solution of NaOH (9.5
ml) and water (30 ml), successively. Insoluble matters were filtered off,
and the filtrate was concentrated to give cyclopropane-1,1-
dimethylmethanol as colorless oily substance.
To a solution of the above oily substance in 1,2-dimethoxyethane
(150 ml) was added sodium hydride (60 % oil, 6.56 g, 164 mmol), and the
mixture was stirred at room temperature for 1 hour. To the reaction
liquid was dropwise added a solution of tert-butylchlorodimethylsilane
(24.7 g, 164 mmol) in 1,2-dimethoxyethane (100 ml), and the mixture was
stirred at room temperature over night. The reaction liquid was poured
into water and extracted twice with ethyl acetate. The organic layer was
dried over magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silicagel column chromatography
(eluentJethyl acetate/hexane=l/15-l/9) to give the title compound (28.19
g, 79 %) as colorless oily substance.
iH-NMR(CDCl3) 8: 0.07 (6H, s), 0.45-0.54 (4H, m), 0.91 (9H, s), 2.35 (lH,
brs), 3.56 (2H, s), 3.61 (2H, s).
IR(neat) 3361, 2953, 2856, 1466, 1254, 1088, 1030, 837, 777cm i.
Reference Example 46
Production of tert-butyl{[l-
(ethoxymethyl)cyclopropyl] methoxy} dimethylsilane

The similar reaction as described in Reference Example 42 by
using the compound (4.33 g, 20 mmol) obtained in Reference Example 45
gave the title compound (5.71 g, 97 %) as colorless oily substance,
i H-NMR(CDCL») 5: 0.05 (6H, s), 0.55-0.65 (4H, m), 0.89 (9H, s), 3.01 (3H,
s), 3.52 (2H,s), 4.17 (2H,s).
Reference Example 47
Production of 2-{[l-({[tert-
butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl} - lH-isoindol-1,3(2H) -
dione

The similar reaction as described in Reference Example 43 by
using the compound (5.71 g, 19.39 mmol) obtained in Reference Example
46 gave the title compound (5.02 g, 75 %) as colorless oily substance.
iH-NMR(CDCls) 5: -0.07 (6H, s), 0.45-0.55 (2H, m), 0.65-0.75 (2H, m),
0.79 (9H, s), 3.53 (2H, s), 3.74 (2H, s), 7.65-7.75 (2H, m), 7.80-7.90 (2H,
m).
Reference Example 48
Production of l-[l-({[tert-
butyl(dimethyDsilyl]oxy}methyl)cydopropyl]methanamine

To a solution of compound (2.0 g, 5.79 mmol) obtained in Reference
Example 47 in ethanol (20 ml) was added hydrazine monohydrate (0.42
ml, 8.68 mmol) and the mixture was refluxed for 2 hours. Insoluble
matters were filtered off and the filtrate was concentrated. The residue
was distributed between ethyl acetate and aqueous solution of lN-sodium
hydroxide, and extracted with ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate and concentrated to
give the title compound (1.15 g, 92 %) as pale yellow oily substance.
iH-NMR(CDCl3) 8: 0.0-0.1 (6H, m), 0.3-0.4 (4H, m), 0.85 (9H, s), 2.61 (2H,
s), 3.49 (2H, s).
Reference Example 49
Production of N-(4- (5-chloromethyl-l-(2,6-difluorobenzyl)-1,2,3,4-
tetrahydro-2,4-dioxo-3-(6-methoxy-3-pyridiny0thieno[2,3-d]pyrimidin-6-
yDphenyD -N'-methoxyurea

The similar reaction as described in Reference Example 18 by
using the N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyD(methyl)amino)methyl) -3- (6 -methoxy-3-pyridinyl) -2,4-
dioxo-l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea (49.3 mg, 0.074 mmol) gave the title compound (44.1 mg,
quant.) as white powders.
iH-NMR(CDCls) 5: 3.83 (3H, s), 3.97 (3H, s), 4.83 (2H, s), 5.37 (2H, s),
6.87 (1H, d, J = 9.0 Hz), 6.94 (2H, t, J = 8.4 Hz), 7.13 (1H, s), 7.25-7.35
(1H, m), 7.5-7.6 (3H, m), 7.52 (2H, d, J = 9.0 Hz), 7.66 (lH, s), 8.1-8.15
(1H, m).
Reference Example 50
Production of N-(4-(5-chloromethyl-l-(2,6-difluorobenzyD-1,2,3,4-
tetrahydro-2,4-dioxo-3-(6-methoxy-3-pyridazinyI)thieno[2,3-d]pyrimidin-
6 -yl)phenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 18 by
using the N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxy ethyD (methyDamino)methyl) -3-(6-methoxy-3-p yridazinyl) -2,4-
dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea (1.34 g, 2 mmol) gave the title compound (888.5 mg, 71 %)
as pale yellow powders.
iH-NMR(CDCl3) 5: 3.83 (3H, s), 4.19 (3H, s), 4.7-4.9 (2H, brm), 5.3-5.45
(2H, m), 6.93 (2H, t, J = 8.0 Hz), 7.14 (lH, d, J = 9.0 Hz), 7.16 (lH, s), 7.2-
7.4 (1H, m), 7.42(1H, d, J = 9.0 Hz), 7.52(2H, d, J = 8.6 Hz), 7.62 (2H, d, J
= 8.6 Hz), 7.69 (1H, s).
Reference Example 51
Production of N-(4-(l-(2,6-difluorobeiizyl)-3-(4-hydroxycyclohexyl)-5-
((methylamino)methyl)-2,4-dioxo- l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Reference Example 14 by
using the compound (1.75 g, 2.54 mmol) obtained in Example 69
described later gave the title compound (1.60 g, quant.) as colorless
crystals.
iH-NMR(CDCla) 8: 1.4-1.9 (3H, m), 2.0-2.2 (2H, m), 2.40 (3H, s), 2.5-2.75
(2H, m), 3.77 (2H, s), 3.7-3.85 (lH, m), 3.82 (3H, s), 4.9-5.1 (1H, m), 5.30
(2H, s), 6.90 (2H, t, J = 8.0 Hz), 7.2-7.35 (2H, m), 7.38 (2H, d, J = 8.4 Hz),
7.54 (2H, d, J = 8.4 Hz), 7.61 (lH, s).
Reference Example 52
Production of KN-(4-(l-(2,6-difluorobenzyD-3-(2-hydroxypropyD-5-
((methylamino)methyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyD-N'-methoxyurea

The similar reaction as described in Reference Example 14 by
using the compound (360 mg, 0.554 mmol) obtained in Example 72
described later gave the title compound (281 mg, 91 %) as white powders,
i H-NMR(CDCl3) 8: 1.29 (3H, d, J = 6.0 Hz), 2.39 (3H, s), 3.80 (2H, s), 3.82
(3H, s), 4.1-4.25 (3H, m), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.25-7.35
(2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.63 (lH, s).
Reference Example 53
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(2-hydroxy-2-methylpropyl)-
5-((methylamino)methyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyriinidin-6-y])phenyD-N,-methoxyurea

The similar reaction as described in Reference Example 14 by
using the compound (310 mg, 0.467 mmol) obtained in Example 73
described later gave the title compound (241 mg, 90 %) as white powders.
iH-NMR(CDCl3) 5: 1.28 (6H, s), 2.38 (3H, s), 3.80 (2H, s), 3.82 (3H, s),
3.88 (1H, brs), 4.26 (2H, s), 5.37 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.25-7.35
(2H, m), 7.40 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.63 (1H, s).
Reference Example 54
Production of N-(4-(l-(2,6*difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-5-
((methylamino)methyD'2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
dlpyrimidin -6 -yDphenyl) -N'-methoxyurea

The similar reaction as described in Reference Example 14 by
using the compound (320 mg, 0.457 mmol) obtained in Example 77
described later gave the title compound (138 mg, 50 %) as white powders.
iH-NMR(CDCl3) 8: 2.34 (3H, s), 3.77 (2H, s), 3.82 (3H, s), 4.19 (3H, s),
5.35 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.14 (lH, t, J = 9.2 Hz), 7.25-7.5 (5H,
m), 7.57 (2H, d, J = 8.6 Hz), 7.64 (lH, s).
Reference Example 55
Production of N-{4-[l-(2,6*difluorobenzy0-5-[(dimethylamino)methyl]-3-
(4-methoxypheny0-2,4-dioxo-l,2,3,4-tetrahydrotMeno[2,3-dJpyrimidin-6-
yl]phenyl}-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (130 mg, 0.192 mmol) obtained in Reference
Example 19 described later and a solution of dimethylamine in THF (0.96
ml, 1.92 mmol) gave the title compound (43.4 mg, 36 %) as colorless
crystals.
iH-NMR(CDCl3) 6: 2.14 (6H, s), 3.70 (2H, s), 3.82 (3H, s), 3.83 (3H, s),
5.36 (2H, s), 6.92 (2H, t, J = 7.8 Hz), 7.01 (lH, d, J = 8.7 Hz), 7.1-7.35
(4H, m), 7.51 (2H, d, J = 8.7 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.63 (1H, s).
Reference Example 56
Production of N-{4-[l-(2,6-difluorobenzyD-3-(6-methoxypyridazin-3-yD-
2,4-dioxo-5-(pyrrolidin-l-ylmethyl)-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl]phenyl}-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (110 mg, 0.175 mmol) obtained in Reference
Example 50 and pyrrolidine (124 mg, 1.75 mmoD gave the title compound
(68.1 mg, 60 %) as colorless crystals.
iH-NMR(CDCl3) 5: 1.5-1.7 (4H, m), 2.35-2.5 (4H, m), 3.82 (3H, s), 3.89
(2H, brs), 4.18 (3H, s), 5.34 (2H, brs), 6.92 (2H, t, J = 8.8 Hz), 7.12 (2H, d,
J = 9.2 Hz), 7.2-7.35 (2H, m), 7.41 (lH, d, J = 9.2 Hz), 7.57.6 (3H, m),
7.64 (1H, s).
Reference Example 57
Production of N-{4-[l 0norpholin-4-ylmethyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
dJpyrimidin-6-yl]phenyl}-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (110 mg, 0.175 mmol) obtained in Reference
Example 50 and morpholine (152 mg, 1.75 mmol) gave the title compound
(78.0 mg, 67 %) as colorless crystals.
iH-NMR(CDCl3) 5: 2.35-2.5 (4H, m), 3.5-3.65 (4H, m), 3.76 (2H, s), 3.83
(3H, s), 4.19 (3H, s), 5.35 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.1-7.2 (2H, m),
7.2-7.3 (1H, m), 7.40 (lH, d, J = 9.0 Hz), 7.5-7.7 (5H, m).
Reference Example 58
Production of N-(4-(5-((benzyl(2-methoxyethyl)amino)methyl)-1-(2,6-
difluorobenzyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-
tetrahy drothieno[2,3 - d]pyrimidin-6 -yl)phenyl) -N' -methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (120 mg, 0.191 mmol) obtained in Reference
Example 50 and N-benzyl-N-(2-methoxyethyl)amine (316 mg, 1.91 mmol)
gave the title compound (105.1 mg, 74 %) as white powders.
1 HNMR(CDCl3) 5: 2.67 (2H, t, J = 6.2 Hz), 3.18 (3H, s), 3.34 (2H, t, J =
6.2 Hz), 3.65 (2H, s), 3.83 (3H, s), 4.03 (2H, s), 4.20 (3H, s), 5.32 (2H, brs),
6.92 (2H, t, J = 8.2 Hz), 7.1-7.25 (6H, m), 7.25-7.35 (2H, m), 7.40 (lH, d, J
= 9.0 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.64 (1H, s), 7.75 (2H, d, J = 8.7 Hz).
Elemental analysis Cs 7 H$s F2 N7 Oe S • I.OH2 O
Calcd.: C, 58.34; H, 4.90; N, 12.87.
Found: C, 58.51; H, 4.58; N, 12.56.
Reference Example 59
Production of N-(4-(l-(2,6-difLuorobenzyl)-5-(((2-
methoxyethyl)amino)methyl) - 3 -(6 -methoxy- 3 -pyridazinyD -2,4- dioxo -
1,2,3,4-tetrahy drothieno[2,3 - dlpyrimidin -6 -yDphenyl) -N'-methoxyurea

The similar reaction, as described in Reference Example 14 by
using the compound (400 mg, 0.538 mmol) obtained in Reference
Example 58 gave the title compound (215.9 mg, 61 %) as colorless
crystals.
iH-NMR(CDCl3) 5: 2.72 (2H, t, J = 5.6 Hz), 3.28 (3H, s), 3.40 (2H, t, J =
5.6 Hz), 3.82(3H, s), 3.86 (2H, s), 4.19 (3H, s), 5.35 (2H, brs), 6.92 (2H, t, J
= 8.4 Hz), 7.14 (2H, d, J = 9.0 Hz), 7.25-7.35 (lH, m), 7.39 (2H, d, J = 9.0
Hz), 7.43 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.64 (lH, s).
Elemental analysis C3 0 H2 9 F2 N7 Oe S • O.5H2 O
Calcd.: C, 54.38; H, 4.56; N, 14.80.
Found: C, 54.62; H, 4.39; N, 14.62.
Example 61
Production of N-(4-(l-(2,6-difiuorobenzyl)-3-(2-hydroxypropyl)-5-(((2-
methoxyethy0(methyl)amino)methyl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (1.82 g, 3 mmol) obtained in Reference Example 7 and 1-
amino-2-propanol (0.45 g, 6 mmol) gave the title compound (l.ll g, 60 %)
as white powders.
iH-NMR(CDCl3) 5: 1.27 (3H, d, J = 5.6 Hz), 2.12 (3H, s), 2.64 (2H, t, J =
5.8 Hz), 2.9-3.05 (1H, m), 3.30 (3H, s), 3.45 (2H, d, J = 5.8 Hz), 3.82 (5H,
s), 4.05-4.25 (1H, m), 4.18 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz),
7.2-7.4 (1H, m), 7.5-7.6 (3H, m), 7.63 (1H, s).
Elemental analysis C2 9 Ha 3 F2 N6 Oe S • 0.7H2 O
Calcd.: C, 55.26; H, 5.50; N, 11.11.
Found: C, 55.42; H, 5.52; N, 10.75.
Example 62
Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-
methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-oxopropyl)-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyD-N'-methoxyurea

To a solution of oxalyl chloride (0.20 g, 1.58 mmol) in
dichloromethane (2 ml) was dropwise added a solution of
dimethylsulfoxide (163 mg, 2.09 mmol) in dichloromethane (2 ml) under
cooling at -78°C. After stirring for 10 minutes, a solution of the
compound (308 mg, 0.5 mmol) obtained in Example 61 in
dichloromethane (2 ml) was dropwise added. After stirring for further
30 minutes, triethylamine (0.40 ml, 2.88 mmol) was dropwise added, and
the mixture was stirred at 0 °C for 2 hours. To the mixture was added
an aqueous solution of ammonium chloride at 0 °C, and the mixture was
extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and concentrated with under
reduced pressure. The residue was purified by NH-silica gel (Produced
by Fuji Silysia Chemical Ltd.) column chromatography (eluent;ethyl
acetate), and the obtained powders was washed with diisopropyl ether
and hexane to give the title compound (40.7 mg, 13 %) as pale yellow
powders.
iH-NMR(CDCl3) 6: 2.13 (3H, s), 2.27 (3H, s), 2.55-2.65 (2H, m), 3.29 (3H,
s), 3.4-3.5 (2H, m), 3.82 (5H, s), 4.88 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J =
8.0 Hz), 7.2-7.35 (1H, m), 7.5-7.65 (4H, m).
Example 63
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(3,3-dimethyl-2-oxobutyl)-5-
(((2-methoxyethyl)(methyl)amino)methyD-2,4-dioxo-l,2,3,4-
tetrahy6^otMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (303 mg, 0.5 mmol) obtained in Reference Example 7 and 3,3-
dimethyl-2-oxobutylamine hydrochloride (U.S.P 6,096,688) (152 mg, 1
mmol) gave the title compound (195.7 mg, 60 %) as pale yellow crystals.
iH-NMR(CDCl3) 5: 1.30 (9H, s), 2.12 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.29
(3H, s), 3.44 (2H, d, J = 5.8 Hz), 3.80 (2H, s), 3.82 (3H, s), 5,04 (2H, s),
5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.14 (lH,s), 7.2-7.3 (lH, m), 7.5-7.6
(4H, m), 7.61 (1H, s).
Elemental analysis Ca 2 Hs 7 F2 Ns Os S
Calcd.: C, 58.43; H, 5.67; N, 10.65.
Found: C, 58.15; H, 5.71; N, 10.42.
Example 64
Production of N-(4-(l-(2,6-difluorobenzyD*5-(((2-
methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2,2,2-trifluoroethyl)-
l,2,3,4-tetrahydrothieno[2,3-dJpyiimidin-6-yl)plienyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (303 mg, 0.5 mmol) obtained in Reference Example 7 and
2,2,2-trifluoroethylamine (99 mg, 1 mmol) gave the title compound (52.9
mg, 16 %) as colorless crystals.
1 H-NMrtfCDCls) 5: 2.12 (3H, s), 2.65 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.45
(2H, d, J = 6.0 Hz), 3.82 (5H, s), 4.75-4.85 (2H, m), 5.36 (2H, s), 6.92 (2H,
t, J = 8.2 Hz), 7.13 (lH,s), 7.2-7.35 (lH, m), 7.55-7.6 (4H, m), 7.62 (lH, s).
Elemental analysis C2 s H2 a Fs Ns Os S • I.OH2 O
Calcd.: C, 50.98; H, 4.58; N, 10.62.
Found: C, 51.14; H, 4.44; N, 10.34.
Example 65
Production of N(4-(l-(2,6-difluorobenzyl)-3-(2-hydroxy-3,3-
dimethylbutyJ)-5-(((2-methoxyethy0(methy0amino)methyD-2,4-dioxo-
l^^^-tetrahydrothieno^.S-dJps^rinudin-G-yDphenyD-N'-methoxyurea

To a mixed solution of compound (120 mg, 0.182 mmol) obtained in
Example 63 in methanol (6 ml) and THF (4 ml) was added sodium
borohydride (6.9 mg, 0.182 mmol) under ice cooling. The reaction liquid
was stirred at room temperature for 1.5 hours and concentrated under
reduced pressure. The residue was distributed between water and ethyl
acetate, and the organic layer was extracted. The extract was washed
with brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by NH-silica gel
(Produced by Fuji Silysia Chemical Ltd.) column chromatography
(eluent.'ethyl acetate), and recrystallized from ethyl acetate and
diethylether to give the title compound (81.1 mg, 68 %) as colorless
crystals.
1 H-NMR(CDCl3) 6: 1.04 (9H, s), 2.12 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 2.96
(1H, d, J = 6.0 Hz), 3.31 (3H, s), 3.46 (2H, d, J = 6.0 Hz), 3.5-3.6 (1H, m),
3.82 (3H, s), 3.75-3.9 (2H, m), 4.05-4.2 (lH, m), 4.3-4.45 (lH, m), 5.25-
5.45(2H, m), 6.91 (2H, t, J = 8.2 Hz), 7.14 (lH,s), 7.2-7.35 (1H, m), 7.5-7.6
(4H, m), 7.61 (1H, s).
Elemental analysis C3 2 Hs 9 F2 Ns Oe S • 0.2H2 O
Calcd.: C, 57.94; H, 5.99; N, 10.56.
Found: C, 57.89; H, 5.91; N, 10.43.
Example 66
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(2-hydroxy-2-methylpropyD-
5-(((2-methoxyethyl)(methyl)amino)methyD-2,4-dioxo-l,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (303 mg, 0.5 mmol) obtained in Reference Example 7 and
compound (89 mg, 1 mmol) obtained in Reference Example 41 gave the
title compound (133.9 mg, 42 %) as colorless crystals,
i H-NMR(CDCl3) 5= 1.28 (6H, s), 2.3 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 3.30
(3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.99 (lH, s), 4.25 (2H, s),
5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.12 (lH,s), 7.2-7.4 (lH, m), 7.5-7.6
(4H, m), 7.61 (1H, s).
Elemental analysis Cs 0 Ha b F2 NB Oe S • 0. IH2 O
Calcd.: C, 56.88; H, 5.60; N, 11.06.
Found: C, 56.65; H, 5.54; N, 10.85.
Example 67
Production of N-[4-(l-(2,6-difluorobenzyl)-3-(3-hydroxy-2,2-
dimethylpropyD-5-{[(2-methoxyetiiyO(methyl)amino]methyl}-2,4-dioxo-
l,2,3,4-tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl]-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (303 mg, 0.5 mmol) obtained in Reference Example 7 and
compound (140 mg, 1 mmol) obtained in Reference Example 44 gave the
title compound (36.8 mg, 11 %) as pale yellow crystals.
iH-NMR(CDCla) 6- 0.96 (6H, s), 2.13 (3H, s), 2.64 (2H, t, J = 6.2 Hz),
3.13(2H, s), 3.30(3H, s), 3.46 (2H, t, J = 6.2 Hz), 3.82 (5H, s), 3.95-
4.15(2H, brm), 5.1-5.5 (2H, br), 6.91 (2H, t, J = 8.2 Hz), 7.14 (lH,s), 7.2-
7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (lH, s).
HPLC (220 nm) Purity 90 % (Retention time 1.83 minutes)
MS (ESI+, m/e) 646 (M+l)
Example 68
Production of N-(4-(l-(2,6-difLuorobenzyl)-3-((l-
(hydroxymethyDcyclopropyl)methyl)-5-(((2-
methoxyethyD^ethyDamino^ethyD^^-dioxo-l^^^-
tetrahydrotMeno[2,3-dJpyrimidin-6-yDphenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (606 mg, 1 mmoD obtained in Reference Example 7 and
compound (431 mg, 2 mmol) obtained in Reference Example 47 gave the
thienopyrimidine cyclized form (549.3 mg, 72 %). The above cyclized
form was dissolved in THF (10 ml), and a solution of
tetrabutylammoniumfluoride in 1M THF (1.7 ml, 1.7 mmol) was added.
The mixture was stirred at room temperature for 20 hours. The reaction
liquid was distributed between water and ethyl acetate, and the organic
layer was extracted. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by NH-silica gel (Produced by Fuji
Silysia Chemical Ltd.) column chromatography (eluent,"ethyl acetate),
and recrystallized from ethyl acetate and diethylether to give the title
compound (196.1 mg, 43 %) as colorless crystals.
i H-NMR(CDCls) 8- 0.46 (2H, t, J = 5.4 Hz), 0.85 (2H, t, J = 5.4 Hz), 2.11
(3H, s), 2.64 (2H, t, J = 6.0 Hz), 3.25(2H, s), 3.3l(3H, s), 3.46 (2H, t, J =
6.0 Hz), 3.82 (5H, s), 3.95-4.15(1H, br), 4.14 (2H, s), 5.37 (2H, s), 6.91
(2H, t, J = 8.0 Hz), 7.12 (lH,s), 7.2-7.4 (lH, m), 7.54 (4H, s), 7.61 (lH, s).
Elemental analysis Cs i Ha s F2 N5 Os S
Calcd.: C, 57.84; H, 5.48; N, 10.88.
Found: C, 57.63; H, 5.46; N, 10.86.
Example 69
Production of N-(4-(5-((benzyl(methyl)amino)methyl)-l-(2,6-
difluorobenzyl)-3-(4-hydroxycydohexyl)-2,4-dioxo-l,2,3,4-
tetr ahy drothieno[2,3 - djpyrimidin -6 -yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using 4-(N-
benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyD-N-
ethoxycarbonylJaminq}5 - [4- (3 -methoxyureido)phenyl] thiophene-3 -
carboxylic acid (3.19 g, 5 mmol) and trans-4-aminocyclohexanol (1.44 g,
12.5 mmol) gave the title compound (1.80 g, 52 %) as colorless crystals.
iH-NMItfCDCla) 5: 1.35-1.65 (3H, m), 1.65-1.8 (2H, m), 2.07 (3H, s), 2.5-
2.8 (2H, m), 3.58 (2H, s), 3.7-3.9 (1H, m), 3.82 (3H, s), 3.9l(2H, s), 4.9-5.1
(1H, m), 5.29 (2H, s), 6.90 (2H, t, J = 7.8 Hz), 7.13 (lH,s), 7.15-7.35 (6H,
m), 7.53 (2H, d, J = 8.6 Hz), 7.61 (lH, s), 7.66 (2H, d, J = 8.6 Hz).
Elemental analysis Cs e Ha 7 F2 Ns Oe S • 0.5Hz O
Calcd.: C, 61.09; H, 5.55; N, 9.89.
Found: C, 61.415 H, 5.65; N, 9.56.
Example 70
Production of N-[4-(l-(2,6-difluorobenzyD-3-(4-hydroxycyclohexyl)-5-{[(2-
methoxyethyl)(methyDamino]methyl}-2,4-dioxo-l,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl]-N'-methoxyiirea

The similar reaction as described in Example 4 by using the
compound (300 mg, 0.5 mmol) obtained in Reference Example 51 and 2-
bromoethylmethylether (0.69 g, 5 mmol) gave the title compound (75.1
mg, 23 %) as colorless crystals.
iH-NMItfCDCla) 6: 1.2-1.6 (3H, m), 1.6-1.8 (2H, m), 2.0-2.1 (2H, m), 2.14
(3H, s), 2.5-2.75 (4H, m), 3.31 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.65-3.85
(3H, m), 3.82 (3H, s), 4.9-5.05 (lH, br), 5.30 (2H, s), 6.90 (2H, t, J = 8.0
Hz), 7.12 (1H, s), 7.25-7.4 (lH, m), 7.5-7.6 (4H, m), 7.60 (lH, s).
Elemental analysis C3 2 Ha 7 F2 Ns Oe S • O.5H2 O
Calcd.: C, 57.65; H, 5.74; N, 10.50.
Found: C, 57.54; H, 5.75; N, 10.64.
Example 71
Production of N-{4-[l-(2,6-difluorobenzyl)-5-{[(2-
methoxyethyl)(methy0amino]methyl}-3-(6-methylpyridazin-3-yl)-2,4-
dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N'-
methoxyurea

The similar reaction as described in Example 5 by using the
compound (303 mg, 0.5 mmol) obtained in Reference Example 7 and 3-
ammo-6-methylpyridazine (136 mg, 1.25 mmol) gave the title compound
(48.3 mg, 15 %) as colorless crystals.
i H-NMRCCDCIa) 5: 2.13 (3H, s), 2.61 (2H, t, J = 5.8 Hz), 2.79 (3H, s), 3.26
(3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.75-3.85 (2H, m), 3.82 (3H, s), 5.25-5.45
(2H, brm), 6.92 (2H, t, J = 8.2 Hz), 7.18 (lH, s), 7.2-7.7 (8H, m).
Example 72
Production of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-
difluorobenzyD-3-(2-hydroxypropyl)-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-dJpyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 5 by using 4-(N-
benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyD-N-
ethoxycarbonyl|amin^-5-[4-(3-methoxyureido)phenyl]thiophene-3-
carboxylic acid (639 mg, 1 mmol) and l-amino-2-propanol (0.19 g, 2.5
mmol) gave the title compound (409.7 mg, 63 %) as colorless crystals.
1 HNMR(CDCl3) 5: 1.30 (3H, d, J = 6.0 Hz), 2.06 (3H, s), 2.90 (1H, d, J =
5.2 Hz), 3.57 (2H, s), 3.82 (3H, s), 3.91 (2H, s), 4.1-4.25 (lH, m), 4.20 (2H,
s), 5.34 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.16 (lH, s), 7.2-7.4 (6H, m), 7.54
(2H, d, J = 8.8 Hz), 7.62 (lH, s), 7.67 (2H, d, J = 8.8 Hz).
Elemental analysis Ca 3 Hs s F2 N5 O5 S
Calcd.: C, 61.00; H, 5.12; N, 10.78.
Found: C, 60.82; H, 5.21; N, 10.68.
Example 73
Production of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-
difluorobenzyl)-3-(2-hydro^-2-methyipropyl)-2,4-dioxo-l,2,3,4-
tetrahy(kothienp[2,3-d]pyrimidin-6-yl)phenyD_N'-methoxyurea

The similar reaction as described in Example 5 by using the 4-(N-
benzyl-N-methylaminomethyD-2-[N-(2,6-difluorobenzyl)_N-
etiioxycarbonylfemino]5-[4-(3-methoxyureido)phenyl]thiophene-3-
carboxylic acid (639 mg, 1 mmol) and compound (0.22 g, 2.5 mmol)
obtained in Reference Example 41 gave the title compound (360.9 mg,
54 %) as colorless crystals.
^-NMItfCDCls) 6: 1.29 (6H, s), 2.06 (3H, s), 3.56 (2H, s), 3.83 (3H, s),
3.91 (2H, s), 3.96 (lH, s), 4.28 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2
Hz), 7.13 (1H, s), 7.2-7.35 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (lH, s),
7.67 (2H, d, J = 8.8 Hz).
Elemental analysis Cs 4 Hs s F2 Ns Os S
Calcd.: C, 61.53; H, 5.32; N, 10.55.
Found: C, 61.30; H, 5.32; N, 10.32.
Example 74
Production of N-(4-(l-(2,6-difluorobenzyl)-3-(2-hydroxypropyD-5-
((methyl(2-(2-pyridinyl)ethy0amino)methy0-2,4-dioxo-l,2,3,4-
tetr ahy drothieno[2,3 -d]pyrimidin-6 -yDphenyl) -N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound (260 mg, 0.465 mmol) obtained in Reference Example 52 and
2-(2-hydroxyethy])pyridine (400 mg, 1.63 mmol) gave the title compound
(195.9 mg, 63 %) as colorless crystals.
iH-NMR(CDCl3) 8: 1.28 (3H, d, J = 5.8 Hz), 2.21 (3H, s), 2.75-2.95 (4H,
m), 3.0-3.1 (1H, m), 3.82 (5H, s), 4.1-4.2 (lH, m), 4.17 (2H, s), 5.34 (2H, s),
6.91 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 (lH, s), 7.2-7.4 (lH, m),
7.4-7.55 (5H, m), 7.59 (lH, s), 8.43 (lH, d, J = 5.0 Hz).
Elemental analysis C3 s Ha 4 F2 N6 Os S ¦ 0.2H2 O
Calcd.: C, 59.31; H, 5.19; N, 12.57.
Found: C, 59.24; H, 5.29; N, 12.32.
Example 75
Production of N-(4-(l-(2,6-difluorobenzyD-3-(2-hydroxy-2-methylpropyD-
5-((methyl(2-(2-pyridinyDethyDamino)methy0-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-dJpyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound (220 mg, 0.384 mmol) obtained in Reference Example 53 and
2-(2-hydroxyethyDpyridine (800 mg, 3.25 mmol) gave the title compound
(138.2 mg, 53 %) as colorless crystals.
iH-NMR(CDCl3) 8: 1.26 (6H, s), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.82 (5H,
s), 3.99 (1H, s), 4.24 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.1
(2H, m), 7.13 (1H, s), 7.2-7.35 (lH, m), 7.45-7.55 (5H, m), 7.59 (lH, s),
8.43 (1H, d, J = 4.0 Hz).
Elemental analysis C3 a Ha e F2 Ns Os S • 0. IH2 O
Calcd.: C, 59.85; H, 5.38; N, 12.32.
Found: C, 59.81; H, 5.45; N, 12.03.
Example 76
Production of N-(4-(l-(2,6-difluorobenzyD-5-(((2-
methoxyethyl)(methy0amino)methyl)-2,4-dioxo-3-(2-pyrazinyl)-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyD-N'-methoxyurea

The similar reaction as described in Example 5 by using the
compound (303 mg, 0.5 mmoD obtained in Reference Example 7 and
aminopyrazine (119 mg, 1.25 mmol) gave the title compound (35.2 mg,
11 %) as colorless crystals.
*H-NMR(CDCl3) 8: 2.13 (3H, s), 2.62 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.41
(2H, t, J = 6.0 Hz), 3.79 (2H, s), 3.83 (lH, s), 5.36 (2H, s), 6.94 (2H, t, J =
8.0 Hz), 7.12 (1H, s), 7.2-7.4 (lH, m), 7.5-7.65 (5H, m), 8.65-8.7 (3H, m).
Elemental analysis Ca 0 H2 9 F2 N? Os S • 0. IH2 O
Calcd.: C, 56.35; H, 4.60; N, 15.33.
Found: C, 56.20; H, 4.52; N, 15.16.
Example 77
Production of N-(4-(5-((benzyl(methyDamino)methyl)-1 -(2,6-
difluorobenzy0-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-l,2,3,4"
tetrahydrotMeno[2,3-dJpyrimidin-6-yl)phenyl)-N'-metiioxyurea

The similar reaction as described in Example 5 by using 4-(N-
benzyl-N-methylaminomethyD-2-[N-(2,6-difluorobenzyl)-N-
ethoxycarbonylJaminqj-5 - [4- (3 -methoxyureido)phenyl]thiophene - 3 -
carboxylic acid (1.28 g, 2 mmol) and 6-chloro-3-aminopyridazine (648 mg,
5 mmol) gave the title compound (0.36 g, 26 %) as colorless crystals.
iH-NMR(CDCls) 5: 2.06 (3H, s), 3.55 (2H, s), 3.83 (3H, s), 3.87 (2H, s),
4.19 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.45 (9H, m), 7.55
(2H, d, J = 8.4 Hz), 7.63 (lH, s), 7.72 (2H, d, J = 8.4 Hz).
Example 78
Production of N-(4-(l-(2,6-difluorobenzyD-3-(6-methoxy-3-pyridazinyD-5-
((methyl(2-(2-pyridinyl)ethyl)amino)methyD-2,4-dioxo-l,2,3,4-
tetrahydrotMeno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound (135 mg, 0.221 mmoD obtained in Reference Example 54 and
2-(2-hydroxyethyDpyridine (272 mg, 2.21 mmol) gave the title compound
(79.6 mg, 50 %) as colorless crystals.
1H-NMR(CDCl3) 5: 2.20 (3H, s), 2.7-2.9 (4H, m), 3.78 (2H, s), 3.82 (3H, s),
4.19 (3H, s), 5.34 (2H, s), 6.85-7.2 (5H, m), 7.25-7.45 (2H, m), 7.45-7.7
(7H, m), 8.42 (lH, d, J = 4.0 Hz).
Elemental analysis C3 5 H3 2 F2 N3 O5 S . 1.OH2 O
Calcd.: C, 57.37; H, 4.68; N, 15.29.
Found: C, 57.29; H, 4.60; N, 15.15.
Example 79
Production of N-(4- (5-((2-pyridin-2-ylethyl)methylamino)methyl)-l-(2,6-
difluorobenzyl)-l,2,3,4-tetrahydro-2,4-dioxo-3-(4-
methoxyphenyl)tbieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 2 by using the
compound (800 mg, 1.24 mmol) obtained in Reference Example 25 and 2-
(2-hydroxyethyDpyridine (300 mg, 1.49 mmol) gave the title compound
(407 mg, 58 %) as white solids.
iH NMR (CDCI3) 52.20 (3H, s), 2.86 (4H, m), 3.82-3.84 (8H,m), 5.36 (2H,
s), 6.92 (2H, t, J= 8.3 Hz), 7.00-7.06 (4H, m), 7.14-7.33 (4H, m), 7.46-7.51
(5H, m), 7.61 (1H, s), 8.42 (lH, d, J= 5.7 Hz).
Elemental analysis C37H34F2N6O5S O.7H2O
Calcd.: C, 61.26; H, 4.92; N, 11.59.
Found: C, 61.06; H, 4.86; N, 11.52.
Example 80
Production of N-[4-(l-(2,6-difluorobenzyl)-3-(6-hydroxypyridazin-3-yl)-5-
{[(2-methoxyethyl)(methyl)amino]methyl}-2,4-dioxo-1,2,3,4-
tetrahydrothieno[2,3-dlpyrimidin-6-yl)phenyl]-N'-methoxyurea

To a solution of the compound (1.34 g, 2 mmol) obtained in
Example 57 in THF (30 ml) was added a solution of 4N HC1 in acetic acid
(2 ml, 8 mmol), and the mixture was stirred at room temperature for 20
hours, at 50 °C for 10 hours and further at 60 °C for 3 hours. The
reaction liquid was distributed between aqueous solution of sodium
bicarbonate and ethyl acetate, and the organic layer was extracted. The
aqueous layer was subjected to salting-out, and extracted with ethyl
acetate. The organic layers were collected and combined and the organic
layer was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by NH-silica gel
(Produced by Fuji Silysia Chemical Ltd.) column chromatography
(eluentJethyl acetate/methanol=8/l). To the eluate was added
diisopropylether to give powders. The powders were collected by
filtration, washed with diisopropylether to obtain the title compound (539
mg, 41 %) as a pale yellow powder.
1 H-NMR(CDCl3)d: 2.12 (3H, s), 2.63 (2H, t, J = 5.8 Hz), 3.28 (3H, s), 3.43
(2H, t, J = 5.8 Hz), 3.79 (2H, s), 3.83 (3H, s), 5.35 (2H, s), 6.94 (2H, t, J =
8.2 Hz), 7.0-7.1 (1H, m), 7.2-7.4 (3H, m), 7.5-7.65 (4H, m), 7.63 (1H, s),
10.510.6 (1H.brs).
Elemental analysis C30 H2 9 F2 N7 O6 S • 2.OH2O
Calcd.: C, 52.24; H, 4.82; N, 14.22.
Found: C, 52.24; H, 4.57; N, 14.06.
Example 81
Production of N-{4-[l-(2,6-difluorobenzyl)-5-{[(2-
hydroxyethyl)(methyl)aminolmethyl}-3-(6-methoxypyridazin-3-yl)-2,4-
dioxo-1,2,3,4,-tetrahydrothieno[2,3,-d]pyrimidin-6-yl]phenyl}-N'-
methoxyurea

The similar reaction as described in Example 4 by using the
compound (305 mg, 0.5 mmol) obtained in Reference Example 54 and 2-
bromoethanol (0.62 g, 5 mmol) gave the title compound (145.7 mg, 45 %)
as colorless crystals.
1H-NMR(CDCl3) d: 1.98 (3H, s), 2.45-2.5 (2H, m), 2.9-3.2 (1H, m), 3.5-3.55
(2H, m), 3.65-3.85 (2H, brm), 3.82 (3H, s), 4.18 (3H, s), 5.34 (2H, s), 6.93
(2H, t, J = 8.0 Hz), 7.11 (1H, d, J = 9.0 Hz), 7.18 (lH, s), 7.25-7.35 (1H,
m), 7.35-7.45 (3H, m), 7.57 (2H, d, J = 8.7 Hz), 7.66 (lH, s).
Elemental analysis C3 0 H2 9 F2 N7 O6 S • O.6H2 O
Calcd.: C, 54.23; H, 4.58; N, 14.76.
Found: C, 53.98; H, 4.61; N, 14.72.
Example 82
Production of N{4-[l-(2,6-difluorobenzyl)-5-{[(2-
hydroxyethyl)(methyl)amino]methyl}-3-(4-methoxyphenyl)-2,4-dioxo-
l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N'-methoxyurea

The similar reaction as described in Example 4 by using the
compound (123 mg, 0.191 mmol) obtained in Reference Example 25 and
2-bromoethanol (239 mg, 1.91 mmoD gave the title compound (47.1 mg,
39 %) as colorless crystals.
1H-NMR(CDCl3) d: 1.99 (3H, s), 2.45-2.55 (2H, m), 3.5-3.6 (2H, m), 3.79
(2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.0 Hz),
6.99 (2H, d, J = 8.8 Hz), 7.1-7.3 (4H, m), 7.39 (2H, d, J = 8.8 Hz), 7.56
(2H, d, J = 8.8 Hz), 7.64 (lH, s).
Example 83
Production of N-(4-(l-(2,6-difluorobenzy1)-5-((dimethylamino)methy1)-3-
(6-methoxy-3-pyridaziny1)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea

The similar reaction as described in Example 4 by using the
compound (100 mg, 0.164 mmol) obtained in Reference Example 54 and
methyl iodide (0.010 ml, 0.164 mmol) gave the title compound (17.3 mg,
17 %) as colorless crystals.
1 H-NMR(CDCl3) d: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s),
5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (lH, d, J = 8.8 Hz), 7.2-7.65
(7H, m), 7.69 (lH, s).
Example 84
Production of N-{4-[l-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-
(6-methoxypyridin-3-yl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl]phenyl}-N'-methoxyurea

The similar reaction as described in Reference Example 26 by
using the compound (41.1 mg, 0.067 mmol) obtained in Reference
Example 49 and a solution of dimethylamine in THF (0.67 ml, 1.34 mmo1)
gave the title compound (18.4 mg, 44 %) as white powders.
1H-NMR(CDCl3) d: 2.13 (6H, s), 3.68 (2H, s), 3.83 (3H, s), 3.96 (3H, s),
5.36 (2H, s), 6.8-7.0 (3H, m), 7.13 (1H, s), 7.2-7.4 (1H, m), 7.45-7.65 (6H,
m),8.10(lH, d, J = 2.6 Hz).
Preparation 1
By a conventional manner, tablet is prepared by using the
compound obtained in Example 40 (100 mg), lactose (165 mg), corn starch
(25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (l mg).
Preparation 2
The compound obtained in Example 40 (5 g) was dissolved in
distilled water for injection to make the total volume to 100 ml. The
solution was subjected to sterile filtration by using membrane filter
having a diameter of 0.22 urn (Produced by Sumitomo Electric Industries,
Ltd. or Sartorius K.K.), 2 ml each of the solution is poured into a
sterilized vial, and is freeze dried in a conventional manner to give
freeze-dried injectable preparation.
Preparation 3
By a conventional manner a tablet is prepared by using compound .
obtained in Example 41 (100 mg), lactose (165 mg), corn starch (25 mg),
polyvinyl alcohol (4 mg) and magnesium stearate (l mg).
Preparation 4
The compound obtained in Example 41 (5 g) was dissolved in
distilled water for injection to make the total volume to 100 ml. The
solution was subjected to sterile filtration by using membrane filter
having a diameter of 0.22 µm (Produced by Sumitomo Electric Industries,
Ltd. or Sartorius K.K.), 2 ml each of the solution is poured into a
sterilized vial, and is freeze dried in a conventional manner to give
freeze-dried injectable preparation.
Preparation 5
(1) Compound obtained in Example 40 or Example 41 5 g
(2) lactose • crystalline cellulose (grain) 330 g
(3) D-mannito1 29 g
(4) low substituted hydroxypropylcellulose 20 g
(5) talc 25 g
(6) hydroxypropylcellulose 50 g
(7) aspartame 3 g
(8) dipotassium glycyrrhizinate 3 g
(9) hydroxypropylmethylcellulose 2910 30 g
(10) titanium oxide 3.5 g
(l l) ferric oxide yellow 0.5 g
(12) light silicic acid anhydride 1 g
The above (1), (3), (4), (5), (6), (7) and (8) are suspended or
dissolved in purified water, nuclear particles of (2) are coated with the
solution to prepare crude fine grains. The crude fine grains are coated
with (9) to (11) to prepare coated fine grains. They are mixed with (12)
to prepare 1 % KM05283 fine grains (500 g). 500 mg each of the fine
grains are wrapped, separately.
Experimental Example 1
(1) Preparation of 125I-leuprorelin
To a tube containing 10 ul of a 3 x 10 4M aqueous solution of
leuprorelin and 10 ul of 0.01 mg/ml lactoperoxidase was added 10 ul (37
MBq) of a solution of Na125I. After stirring, 10 ul of 0.001 % H2O2 was
added, and a reaction was carried out at room temperature for 20
minutes. By adding 700 ul of a 0.05 % TFA solution, the reaction was
stopped, followed by purification by reversed-phase HPLC. The HPLC
conditions used are shown below. 125I-leuprorelin was eluted at a
retention time of 26 to 27 minutes.
Column: TSKgel ODS-80™ (TM indicates a registered trademark; the
same applies below) CTR (4.6 mm x 10 cm)
Eluents: Solvent A (0.05 % TFA)
Solvent B (40 % CH3CN-0.05 % TFA)
0 minute (100 % Solvent A) - 3 minutes (100 % Solvent A) - 7
minutes (50 % Solvent A + 50 % Solvent B) - 40 minutes (100 % Solvent
B)
Eluting temperature: Room temperature
Elution rate: 1 ml/min
(2) Preparation of CHO (Chinese hamster ovarian) cell membrane
fraction containing monkey GnRH receptor
Monkey GnRH receptor-expressing CHO cells (109 cells) were
suspended in phosphate-buffered saline supplemented with 5 mM EDTA
(PBS-EDTA) and centrifuged at 100 x g for 5 minutes. To the cell pellet,
10 ml of a cell homogenate buffer (10 mM NaHCO3, 5 mM EDTA, pH 7.5)
was added, followed by homogenization using the Polytron homogenizer.
After centrifugation at 400 x g for 15 minutes, the supernatant was
transferred to an ultracentrifugation tube and centrifuged at 100,000 x g
for 1 hour to yield a membrane fraction precipitate. This precipitate was
suspended in 2 ml of an assay buffer and centrifuged at 100,000 x g for 1
hour. The membrane fraction recovered as a precipitate was again
suspended in 20 ml of the assay buffer, dispensed, and stored at -80 °C
before use upon thawing.
(3) Preparation of CHO (Chinese hamster ovarian) cell membrane
fraction containing human GnRH receptor
Human GnRH receptor-expressing CHO cells (109 cells) were
suspended in phosphate-buffered saline supplemented with 5 mM EDTA
(PBS-EDTA) and centrifuged at 100 x g for 5 minutes. To the cell pellet,
10 ml of a cell homogenate buffer (10 mM NaHCO3, 5 mM EDTA, pH 7.5)
was added, followed by homogenization using the Polytron homogenizer.
After centrifugation at 400 x g for 15 minutes, the supernatant was
transferred to an ultracentrifugation tube and centrifuged at 100,000 x g
for 1 hour to yield a membrane fraction precipitate. This precipitate was
suspended in 2 ml of an assay buffer and centrifuged at 100,000 x g for 1
hour. The membrane fraction recovered as a precipitate was again
suspended in 20 ml of the assay buffer, dispensed, and stored at -80 °C
before use upon thawing.
(4) Determination of 125I-leuprorelin binding inhibition rate
The monkey and human membrane fractions prepared in the
above (2) and (3) were diluted with the assay buffer to yield a 200 ug/ml
dilution, each of which was then dispensed at 188 ul per tube. To a tube
containing the cell membrane fraction of the CHO with monkey GnRH
receptors expressed were added 2 ul of a solution of 20 mM compound in
60 % DMSO and 10 ul of 38 nM 125I-leuprorelin. To a tube containing
the cell membrane fraction of the CHO with human GnRH receptors
expressed were added 2 ul of a solution of 2 mM compound in 60 %
DMSO and 10 ul of 38 nM 125I-leuprorelin. To determine maximum
binding quantity, a reaction mixture containing 2 ul of 60 % DMSO and
10 ul of 38 nM 125Heuprorelin was prepared. To determine non-specific
binding amount, a reaction mixture containing 2 ul of a solution of 100
uM leuprorelin in 60 % DMSO and 10 ul of 38 nM 125I-leuprorelin was
prepared.
Where the membrane fraction of the CHO with monkey and
human GnRH receptors expressed was used, the reaction was carried out
at 25 °C for 60 minutes. After each reaction, the reaction mixture was
aspirated and filtered through a polyethyleneimine-treated Whatman
glass filter (GF-F). After this filtration, the radioactivity of 125I-
leuprorelin remaining on the filter paper was measured with a y-counter.
The expression (TB-SB)/(TB-NSB) x 100 (where SB = radioactivity
with the compound added, TB = maximum bound radioactivity, NSB =
nonspecifically bound radioactivity) was calculated to find the binding
inhibition rate of each test compound. Furthermore, the inhibition rate
was determined by varying the concentration of the test substance and
the 50 % inhibitory concentration GC50 value) of the compound was
calculated from Hill plot. The results are shown in below.

Industrial Applicability
The compound of the present invention possesses excellent
gonadotropin-releasing hormone antagonizing activity. It is also good in
oral absorbability and excellent in stability and pharmacokinetics. With
low toxicity, it is also excellent in safety. Therefore, for example, the
compound of the present invention can be used as a preventing or
treating agent for hormone-dependent diseases. Concretely, for
example, it is effective as a preventing or treating agent for sex hormone-
dependent cancers (e.g., prostatic cancer, uterine cancer, breast cancer,
pituitary tumor, and the like), prostatic hypertrophy, hysteromyoma,
endometriosis, metrofibroma, precocious puberty, amenorrhea syndrome,
premenstrual syndrome, multilocular ovary syndrome, polycystic ovary
syndrome, acne , alopecia, Alzheimer's disease, and the like; as a
pregnancy regulator (e.g., contraceptive, etc.), infertility remedy or
menstruation regulator, as a preventing or treating agent for irritable
bowel syndrome; or as a preventing agent for postoperative recurrence of
sex hormone-dependent cancer, as medicament. It is also effective as an
animal estrous regulator, food meat quality improving agent or animal
growth regulator in the field of animal husbandry, and as a fish
spawning promoter in the field of fishery.
Claims
1. A compound of the formula-'
5
wherein
R1 is a C1- 4 alkyl;
R2is
(1) a C1-6 alkyl which may have a substituent selected from the group
10 consisting of (l') a hydroxy group, (2') a C1- 4 alkoxy, (3') a C1- 4 alkoxy-
carbonyl, (4') a di-C1- 4 alkyl-carbamoyl, (5') a 5- to 7-membered nitrogen-
containing heterocyclic group, (6') a C1- 4 alkyl-carbonyl and (7') a halogen,
(2) a C3- 8 cycloalkyl which may have (D a hydroxy group or (2') a mono-
C1- 4 alkyl-carbonylamino,
15 (3) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (D a halogen,
(2') a hydroxy group, (30 a C1- 4 alkyl and (4') a C1- 4 alkoxy,
(4) a phenyl which may have a substituent selected from the group
consisting of (l') a halogen, (2') a C1- 4 alkoxy-C1- 4 alkyl, (3') a mono-C1- 4
20 alkyl-carbamoyl-C1- 4 alkyl, (4') a C1- 4 alkoxy and (5') a mono-C1- 4
alkylcarbamoyl-C1- 4 alkoxy, or
(5) a C1- 4 alkoxy;
R3 is a C1- 4 alkyl;
R4is
25 (l) a hydrogen atom,
(2) a C1- 4 alkoxy,
(3) a C6-10 aryI,
(4) a N-1- 4 alkyl-N-C1- 4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (l') oxo, (2') a C1- 4
alkyl, (3') a hydroxy-C1- 4 alkyl, (4') a C1- 4 alkoxy-carbonyl, (5') a mono-C1- 4
alkyl-carbamoyl and (6') a C1- 4 alkylsulfonyl;
n is an integer of 1 to 4',
10 provided that when R2 is a phenyl which may have a substituent, R4 is a
5- to 7-membered nitrogen-containing heterocyclic group which may have
a substituent selected from the group consisting of (l) oxo, (2) a hydroxy-
C1- 4 alkyl, (3) a C1- 4 alkoxy-carbonyl, (4) a mono-C1- 4 alkyl-carbamoyl and
(5) a C1- 4 alkylsulfonyl; or a salt thereof.
15 2. A compound as claimed in claim 1, wherein
R2is
(1) a C1- 4 alkyl which may have a substituent selected from the group
consisting of (l') a hydroxy group, (2') a C1- 4 alkoxy, (3') a C1- 4 alkoxy-
carbonyl, (4') a di-C1- 4 alkyl-carbamoyl and (5') a 5 to 7-membered
20 nitrogen-containing heterocyclic group,
(2) a C3-8a cycloalkyl which may have (D a hydroxy group or (2') a mono-
C1- 4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (l') a halogen,
25 (2') a hydroxy group, (3') a C1- 4 alkyl and (4') a C1- 4 alkoxy,
(4) a phenyl which may have a substituent selected from the group
consisting of (l') a halogen, (2') a C1- 4 alkoxy-C1- 4 alkyl, (3') a mono-C1- 4
alkyl-carbamoyl-C1- 4 alkyl and (4') a mono-C1- 4 alkylcarbamoyl-C1- 4 alkoxy,
or
30 (5) a C1- 4 alkoxy;
R4is
(1) a C1- 4 alkoxy,
(2) a Ce 10 aryl,
(3) a N-C1- 4alkyl-N-C1- 4alkylsulfonylamino or
(4) a 5- to 7-membered nitrogen-containing heterocyclic group which may
have a substituent selected from the group consisting of (D oxo, (2') a
5 hydroxy-C1- 4 alkyl, (30 a C1- 4 alkoxy-carbonyl, (4') a mono-C1- 4 alkyl-
carbamoyl and (5') a C1- 4 alkylsulfonyl.
3. A compound as claimed in claim 1, wherein R1 is methyl.
4. A compound as claimed in claim 1, wherein R2 is a 5- to 7-membered
nitrogen-containing heterocyclic group which may have a substituent
10 selected from the group consisting of (l) a halogen, (2) a hydroxy group,
(3) a C1- 4 alkyl and (4) a C1- 4 alkoxy.
5. A compound as claimed in claim 1, wherein R3 is methyl.
6. A compound as claimed in claim 1, wherein R4 is a C1- 4 alkoxy.
7. A compound as claimed in claim 1, wherein n is 2.
15 8. A compound as claimed in claim 1, wherein R3 is methyl, R4 is a
hydrogen atom and n is 1.
9. N-(4-(l-(2,6-difluorobenzyl)-5-(((2-
methoxyethyl)(methy)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-
tetrahydrotlueno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, N-(4-(l-
20 (2,6-di£luorobenzyl)-5-(((2-ethoxyethyl)(methyl)amino)methyl)-2,4-dioxo-
3-(2-pyridmyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea, N-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-
(6-methoxy-3-pyridazinyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or N-(4-(l-(2,6-difluorobenzyl)-
25 5-((dimethylamino)methyl)-3-(6-methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-
tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N,-methoxyurea, or a salt
thereof.
10. N-(4-(5-((2-methoxyethyl)methylamino)methyl)-1-(2,6-
difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-
30 methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or
N-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(4-
methoxyphenyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-
yl)phenyl)-N'methoxyurea, or a salt thereof.
11. A pharmaceutical which comprises the compound as claimed in claim 1.
12. A pharmaceutical as claimed in claim 11, which is a gonadotropin-releasing
hormone antagonist.
13. A pharmaceutical as claimed in claim 11, which is for preventing or treating a
sex hormone dependent disease.
14. A pharmaceutical as claimed in claim 11, which is for preventing or treating sex
hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer,
prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious
puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary
syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease,
infertility, irritable bowel syndrome, benign or malignant tumor which is
hormone independent and LH-RH sensitive or hot flash; reproduction regulator;
contraceptive agent; ovulation inducer; or for prevention of postoperative
recurrence of sex hormone-dependent cancer.
15. A compound of the formula:
wherein
Ra is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents
selected from group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino,
(v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy,
(vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an
alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a
heterocyclic group which may have a substituent;
Rb is a nitrogen-containing heterocyclic group which may have a substituent;
Rc is an amino group which may have a substituent;
Rd is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof.
16. N-(4-(l-(2,6-difluorobenzyl)-3-(4-(l-hydroxy-l-methylethyl)phenyl)-5-(((2-
methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl)phenyl)-N'-methoxyurea,
N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-( 1-hydroxy-
l-methylethyl)phenyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)
phenyl)-N'-(methoxyurea or N-(4-(l-(2,6-difluorobenzyl)-3-((l-
(hydroxymethyl)cyclopropyl)methyl)-5-(((2-methoxyethyl)(methyl)amino)
methyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-
N -methoxyurea, or a salt thereof.
17. N-(4-(l-(2,6-difluorobenzyl)-5-(((2-methoxyethyl) (methyl) amino)methyl)-2,4-
dioxo-3-(2-pyridinyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea or a salt thereof.
18. N-(4-(l-(2,6-difluorobenzyl)-5-(((2-ethoxyethyl)(methyl)amino)methyl)-2,4-
dioxo-3-(2-pyridinyl)-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea or a salt thereof.
19. N-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-
pyridazinyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-
N'-methoxyurea or a salt thereof.
20. N-(4-( 1 -(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridin-3-
yl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea or a salt thereof.
21. N-(4-(5-((2-methoxyethyl)methylamino)methyl)-1 -(2,6-difluorobezyl)-1,2,3,4-
tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-
N'-methoxyurea or a salt thereof.
22. N-(4-( 1 -(2,6-difluorobenzyl)-5 -((dimethylamino)methyl)-3 -(4-methoxypheny 1)-
2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyridin-6-yl)phenyl)-N'-methoxyurea or a salt thereof.

The present invention provides a compound represented by the formula:
wherein R1 is a C1- 4 alkyl; R2 is (l) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from
the group consisting of (1') a halogen, (2') a hydroxy group, (3') a C1- 4 alkyl
and (4') a C1- 4 alkoxy, (2) a phenyl which may have a substituent selected from the group consisting of (1') a halogen, (2') a C1- 4 alkoxy-C1- 4 alkyl, (3') a mono-C1- 4 alkyl-carbamoyl-C1- 4 alkyl, (4') a C1- 4 alkoxy and (5') a mono-C1- 4 alkylcarbamoyl-C1- 4 alkoxy, or the like; R3 is a C1- 4 alkyl; R4 is a C1- 4
alkoxy, or the like; n is an integer of 1 to 4; or a salt thereof, as a thienopyrimidine compound having gonadotropin-releasing hormone
antagonistic activity.

Documents:

1636-kolnp-2005-abstract.pdf

1636-kolnp-2005-claims.pdf

1636-kolnp-2005-correspondence.pdf

1636-kolnp-2005-description (complete).pdf

1636-kolnp-2005-examination report.pdf

1636-kolnp-2005-form 1.pdf

1636-kolnp-2005-form 13.pdf

1636-kolnp-2005-form 18.pdf

1636-kolnp-2005-form 2.pdf

1636-kolnp-2005-form 3.pdf

1636-kolnp-2005-form 5.pdf

1636-KOLNP-2005-FORM-27-1.pdf

1636-KOLNP-2005-FORM-27.pdf

1636-kolnp-2005-gpa.pdf

1636-kolnp-2005-granted-abstract.pdf

1636-kolnp-2005-granted-claims.pdf

1636-kolnp-2005-granted-correspondence.pdf

1636-kolnp-2005-granted-description (complete).pdf

1636-kolnp-2005-granted-examination report.pdf

1636-kolnp-2005-granted-form 1.pdf

1636-kolnp-2005-granted-form 13.pdf

1636-kolnp-2005-granted-form 18.pdf

1636-kolnp-2005-granted-form 2.pdf

1636-kolnp-2005-granted-form 3.pdf

1636-kolnp-2005-granted-form 5.pdf

1636-kolnp-2005-granted-gpa.pdf

1636-kolnp-2005-granted-reply to examination report.pdf

1636-kolnp-2005-granted-specification.pdf

1636-kolnp-2005-reply to examination report.pdf

1636-kolnp-2005-specification.pdf


Patent Number 235678
Indian Patent Application Number 1636/KOLNP/2005
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 29-Jul-2009
Date of Filing 16-Aug-2005
Name of Patentee TAKEDA PHARMACEUTICAL COMPANY LIMITED
Applicant Address 1-1, DOSHOMACHI 4-CHOME, CHUO-KU, OSAKA-SHI, OSAKA
Inventors:
# Inventor's Name Inventor's Address
1 CHO, NOBUO C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA 532-8686
2 IMADA, TAKASHI C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA 532-8686
3 HITAKA, TAKENORI C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA 532-8686
4 MIWA, KAZUHIRO C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA 532-8686
5 KUSAKA, MASAMI C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED, 17-85, JUSOHONMACHI 2-CHOME, YODOGAWA-KU, OSAKA-SHI, OSAKA 532-8686
6 SUZUKI, NOBUHIRO C/O TAKEDA PHARMACEUTICAL COMPANY LIMITED, 10, WADAI, TSUKUBA-SHI, IBARAKI 300-4293
PCT International Classification Number C07D 495/04
PCT International Application Number PCT/JP2004/000741
PCT International Filing date 2004-01-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 020854/2003 2003-01-29 Japan