U.S. patent application number 09/908507 was filed with the patent office on 2002-02-14 for thienopyridine derivatives, their intermediates and production thereof.
Invention is credited to Akita, Masahiro, Fukuoka, Koichiro, Furuya, Shuichi, Ishimaru, Yoichiro, Kawakami, Junichi, Miki, Shokyo.
Application Number | 20020019529 09/908507 |
Document ID | / |
Family ID | 26522789 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020019529 |
Kind Code |
A1 |
Miki, Shokyo ; et
al. |
February 14, 2002 |
Thienopyridine derivatives, their intermediates and production
thereof
Abstract
The present invention provides an intermediate for producing a
thienopyridine derivative useful as a GnRH antagonist as well as an
efficient and safe method for producing the same in an industrial
scale at a high yield.
Inventors: |
Miki, Shokyo; (Osaka,
JP) ; Fukuoka, Koichiro; (Osaka, JP) ; Akita,
Masahiro; (Osaka, JP) ; Kawakami, Junichi;
(Nara, JP) ; Furuya, Shuichi; (Ibaraki, JP)
; Ishimaru, Yoichiro; (Hyogo, JP) |
Correspondence
Address: |
TAKEDA PHARMACEUTICALS NORTH AMERICA, INC
INTELLECTUAL PROPERTY DEPARTMENT
475 HALF DAY ROAD
SUITE 500
LINCOLNSHIRE
IL
60069
US
|
Family ID: |
26522789 |
Appl. No.: |
09/908507 |
Filed: |
July 18, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09908507 |
Jul 18, 2001 |
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09446542 |
Dec 22, 1999 |
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6313301 |
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09446542 |
Dec 22, 1999 |
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PCT/JP98/03575 |
Aug 11, 1998 |
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Current U.S.
Class: |
546/114 |
Current CPC
Class: |
C07D 495/04
20130101 |
Class at
Publication: |
546/114 |
International
Class: |
C07D 498/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 13, 1997 |
JP |
9-218862 |
Aug 13, 1997 |
JP |
9-218863 |
Claims
1. A compound of the formula: 54wherein R.sup.11a represents
hydrogen or halogen, and R.sup.41a represents c.sub.1-6 alkyl,
c.sub.1-6 alkoxy or c.sub.6-10 aryl, with proviso that R.sup.41a is
not ethoxy when R.sup.11a is hydrogen, or a salt thereof.
2. A compound of claim 1 or a salt thereof, wherein R.sup.11a is
hydrogen or bromo.
3. A compound of claim 1 or a salt thereof, which is
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylth-
ieno[2,3-b]pyridine.
4. A compound of claim 1 or a salt thereof, which is
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxo-2-phe-
nylthieno[2,3-b]pyridine.
5. A compound of claim 1 or a salt thereof, which is
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-4-oxo-2-phenylthieno[2,3-
-b]pyridine-5-carboxylic acid ethyl ester.
6. A process for producing a compound of the formula: 55wherein X
represents halogen, R.sup.12a represents a divalent hydrocarbon
group which may be substituted, R.sup.3a represents a hydrocarbon
group which may be substituted, R.sup.4a represents a hydrocarbon
group or a hydrocarbon-oxy group, and R.sup.22a represents a
hydrocarbon group substituted by nitro, or a salt thereof, which
comprises subjecting a compound of the formula: 56wherein R.sup.21a
represents a hydrocarbon group and other symbols are as defined
above, or a salt thereof to nitration.
7. A process of claim 6, wherein R.sup.12a is methylene, R.sup.21a
is phenyl, R.sup.22a is nitrophenyl, R.sup.3a is
difluorophenyl-methyl, and R.sup.4a is isopropyl or ethoxy.
8. A process for producing a compound of the formula: 57wherein X
represents halogen, R.sup.12a represents a divalent hydrocarbon
group, and R.sup.4a represents a hydrocarbon group or a
hydrocarbon-oxy group, or a salt thereof, which comprises
subjecting a compound of the formula: 58wherein R.sup.1a represents
a hydrocarbon group which may be substituted and the other symbol
is as defined above, or a salt thereof to halogenation.
9. A process of claim 8, wherein the halogenation is carried out in
the presence of methyl acetate.
10. A process of claim 8, wherein X is bromo, R.sup.1a is methyl,
R.sup.12a is methylene, and R.sup.4a is isopropyl or ethoxy.
11. A process for producing a compound of the formula: 59wherein X
represents halogen, R.sup.12a represents a divalent hydrocarbon
group which may be substituted, R.sup.3a represents a hydrocarbon
group which may be substituted, R.sup.4a represents a hydrocarbon
group or a hydrocarbon-oxy group, and R.sup.22a represents a
hydrocarbon group substituted by nitro, or a salt thereof, which
comprises subjecting a compound of the formula: 60wherein R.sup.1a
and R.sup.2a each represents a hydrocarbon group which may be
substituted and other symbols are as defined above, or a salt
thereof to halogenation to obtain a compound of the formula:
61wherein each symbol is as defined above, or a salt thereof, and
then subjecting the resultant compound to nitration.
12. A process of claim 11, wherein R.sup.1a is methyl, R.sup.12a is
methylene, R.sup.2a is phenyl, R.sup.22a is nitrophenyl, R.sup.3a
is difluorophenyl-methyl, and R.sup.4a is isopropyl or ethoxy.
13. A process for producing a compound of the formula: 62wherein
R.sup.1a, R.sup.2a and R.sup.3a each represents a hydrocarbon group
which may be substituted, and R.sup.5a and R.sup.6a each represents
a hydrocarbon group, or a salt thereof, which comprises reacting a
compound of the formula: 63wherein each symbol is as defined above,
or a salt thereof with a compound of the formula: 64wherein each
symbol is as defined above, or a salt thereof.
14. A process of claim 13, wherein R.sup.1a is methyl which may be
substituted by N-benzyl-N-methylamino, R.sup.2a is phenyl which may
be substituted by isobutyrylamino, R.sup.3a is
difluorophenyl-methyl, and R.sup.5a and R.sup.6a are methyl.
15. A compound of the formula: 65wherein R.sup.11 represents
C.sub.1-6 alkyl, R.sup.21 represents phenyl which may be
substituted, or R.sup.11 and R.sup.21 form, taken together with
adjacent two carbon atoms, a 5- to 7-membered ring which may be
substituted, R.sup.3 represents a hydrocarbon group which may be
substituted, and R.sup.5 represents hydrogen or a hydrocarbon
group, or a salt thereof.
16. A compound of claim 15 or a salt thereof, wherein the
substituent of the phenyl which may be substituted for R.sup.21 is
isobutyrylamino or methoxy.
17. A compound of claim 15 or a salt thereof, which is
4-hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine.
18. A compound of claim 15 or a salt thereof, which is
4-hydroxy-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methylthieno[2,3-b]p-
yridine.
19. A process for producing a compound of the formula: 66wherein
R.sup.1 and R.sup.2 each represents a hydrocarbon group which may
be substituted, or R.sup.1 and R.sup.2 form, taken together with
adjacent two carbon atoms, a 5- to 7-membered ring which may be
substituted, R.sup.3 represents a hydrocarbon group which may be
substituted, and R.sup.5 represents hydrogen or a hydrocarbon
group, or a salt thereof, which comprises subjecting a compound of
the formula: 67wherein R.sup.4 represents a hydrocarbon group and
other symbols are as defined above, or a salt thereof to
cyclization.
20. A process of claim 19, wherein R.sup.1 is methyl, R.sup.2 is
phenyl which may be substituted by isobutyrylamino or methoxy, or
R.sup.1 and R.sup.2 form, taken together with adjacent two carbon
atoms, tetrahydrobenzene ring, R.sup.3 is methyl, isopropyl or
phenyl, R.sup.4 is ethyl, and R.sup.5 is hydrogen.
21. A compound of the formula: 68wherein R.sup.1 and R.sup.2 each
represents a hydrocarbon group which may be substituted, or R.sup.1
and R.sup.2 form, taken together with adjacent two carbon atoms, a
5- to 7-membered ring which may be substituted, R.sup.3 represents
a hydrocarbon group which may be substituted, R.sup.4 represents a
hydrocarbon group, and R.sup.5 represents hydrogen or a hydrocarbon
group, or a salt thereof.
22. A compound of claim 21 or a salt thereof, wherein R.sup.1 is
methyl, R.sup.2 is phenyl which may be substituted by
isobutyrylamino, methoxy or nitro, or R.sup.1 and R.sup.2 form,
taken together with adjacent two carbon atoms, tetrahydrobenzene
ring, R.sup.3 is methyl, isopropyl or phenyl, R.sup.4 is ethyl, and
R.sup.5 is hydrogen.
23. A compound of claim 21 or a salt thereof, which is
4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-phenylthiophene-3-carb-
oxylic acid ethyl ester.
24. A compound of claim 21 or a salt thereof, which is
5-(4-isobutyrylaminophenyl)-4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)ami-
no]thiophene-3-carboxylic acid ethyl ester.
25. A process for producing a compound of the formula: 69wherein
R.sup.1 and R.sup.2 each represents a hydrocarbon group which may
be substituted, or R.sup.1 and R.sup.2 form, taken together with
adjacent two carbon atoms, a 5- to 7-membered ring which may be
substituted, R.sup.3 represents a hydrocarbon group which may be
substituted, R.sup.4 represents a hydrocarbon group, and R.sup.5
represents hydrogen or a hydrocarbon group, or a salt thereof,
which comprises reacting a compound of the formula: 70wherein each
symbol is as defined above, or a salt thereof, with a compound of
the formula: 71wherein R.sup.6 represents hydrogen, sodium,
potassium or a hydrocarbon group and other symbols are as defined
above, or a salt thereof.
26. A process of claim 25, wherein R.sup.1 is methyl, R.sup.2 is
phenyl which may be substituted by isobutyrylamino, methoxy or
nitro, or R.sup.1 and R.sup.2 form, taken together with adjacent
two carbon atoms, tetrahydrobenzene ring, R.sup.3 is methyl,
isopropyl or phenyl, R.sup.4 is ethyl, and R.sup.5 is hydrogen.
27. A process for producing a compound of the formula: 72wherein
R.sup.1 and R.sup.2 each represents a hydrocarbon group which may
be substituted, or R.sup.1 and R.sup.2 form, taken together with
adjacent two carbon atoms, a 5- to 7-membered ring which may be
substituted, R.sup.3 represents a hydrocarbon group which may be
substituted, and R.sup.5 represents hydrogen or a hydrocarbon
group, or a salt thereof, which comprises reacting a compound of
the formula: 73wherein R.sup.4 is a hydrocarbon group and other
symbols are as defined above, or a salt thereof with a compound of
the formula: 74wherein R.sup.6 represents hydrogen, sodium,
potassium or a hydrocarbon group, and other symbols are as defined
above, or a salt thereof, to obtain a compound of the formula:
75wherein each symbol is as defined above, or a salt thereof, and
then subjecting the resultant compound to cyclization.
28. A process of claim 27, wherein R.sup.1 is methyl, R.sup.2 is
phenyl which may be substituted by isobutyrylamino or methoxy, or
R.sup.1 and R.sup.2 form, taken together with adjacent two carbon
atoms, tetrahydrobenzene ring, R.sup.3 is methyl, isopropyl or
phenyl, R.sup.4 is ethyl, and R.sup.5 is hydrogen.
29. A compound of the formula: 76wherein R.sup.22 represents
isobutyrylamino or methoxy, or a salt thereof.
30. A compound of claim 29 or a salt thereof, which is
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-isobutyrylaminopheny-
l)-3-methyl-4-oxothieno[2,3-b]pyridine.
31. A process for producing a compound of the formula: 77wherein
R.sup.23 represents phenyl which may be substituted by
isobutyrylamino or methoxy, and R.sup.3 represents a hydrocarbon
group which may be substituted, or a salt thereof, which comprises
reacting a compound of the formula; 78wherein each symbol is as
defined above, or a salt thereof, with a compound of the formula:
79wherein X represents halogen, or a salt thereof.
32. A dibasic acid salt of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-
-2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-4-oxothieno[2,3-b]pyri-
dine.
Description
TECHNICAL FIELD
[0001] The present invention relates to synthetic intermediates for
production of compounds having thienopyridine skeleton and being
useful for medicines, agricultural chemicals, and so forth,
especially thienopyridine derivatives exhibiting gonadotropin
releasing hormone (GnRH) antagonizing activity, and their
production.
[0002] As a basic structure of a thienopyridine,
4,7-dihydro-4-oxo-thieno[- 2,3-b]pyridine of the formula: 1
[0003] or thieno[2,3-b]pyridine of the formula: 2
[0004] is exemplified.
BACKGROUND ART
[0005] Thienopyridines are known to have antibacterial activities
as well as other activities, found recently such as angiotensine II
antagonistic activities and GnRH antagonistic activities, due to
which they are expected to be used widely in the fields of
medicines and agricultural industries. Concerning the synthetic
method for 5-acyl-4-hydroxythieno[2,- 3-b]pyridine derivative, one
of such thienopyridines, there are examples reported on a direct
synthesis of 5-acetyl-4-hydroxythieno[2,3-b]pyridine from
2-aminothiophene by a method called Gould-Jacobs method
characterized by employing an ethoxymethylene compound of an active
methylene compound as shown below [M. A. Khan et al., J.
Heterocyclic Chem., Vol.14, p. 807 (1977)]: 3
[0006] a synthesis from a corresponding acyl group-containing
polysubstituted pyridine as shown below (F. A. Abu-Shanab et al.,
J. Chem. Soc. Perkin Trans. 1, 1994, page 1449): 4
[0007] and a synthesis through functional group conversion in the
5-position of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine
derivative or a 5-cyano-substituted derivative thereof obtained by
a conventional procedure as shown below [WO 95/28405
(JP-A-8-295693)]: 5
[0008] wherein R.sup.51 represents hydrogen or a group through a
carbon, nitrogen, oxygen or sulfur atom, R.sup.52 represents
hydrogen or alkyl, R.sup.53 a hydrocarbon group, and R.sup.54
represents phenylalkylene which may be substituted
[0009] In order to produce a thienopyridine derivative having a
GnRH antagonistic effect, a compound having a nitrophenyl in the
2-position and a halogenomethyl in the 3-position is produced as an
intermediate in WO 95/28405 (JP-A-8-295693). In the production of
this compound, a nitro group is first introduced into the phenyl of
the compound having a phenyl in the 2-position and a methyl in the
3-position and then the methyl in the 3-position is converted into
a halogenomethyl.
[0010] Also in WO 95/28405 (JP-A-8-295693), a compound having an
acid amide in the 5-position is produced from a compound having a
carboxylic acid ester in the 5-position.
[0011] In the method by M. A. Khan et al. described above, the
product is provided via an undesirable step such as the involvement
of an organotin compound in an attempt to avoid the formation of an
unstable 2-aminothiophene as an intermediate, while the method by
F. A. Abu-Shanab et al. provides a O-ethylated product and involves
a limitation in terms of the substituents on the thiophene ring,
because of which the range of the application is limited.
[0012] On the other hand, the method for obtaining a 5-acyl form by
the functionality conversion of a
5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyri- dine derivative or a
5-cyano-substituted derivative thereof which are obtained by a
conventional method involves a less efficient multiple-stage
synthesis. In the production of a GnRH antagonistic thienopyridine
derivative employing this conventional method disclosed in WO
95/28405 (JP-A-8-295693) involves a large number of the production
steps, which also make this method less efficient.
[0013] Accordingly, there has still been a desire to develop a
method for producing a 5-acyl-4-hydroxythieno[2,3-b]pyridine
skeleton conveniently and efficiently.
[0014] In the method disclosed in WO 95/28405 (JP-A-8-295693) which
involves a conversion of the methyl in the 3-position of a compound
having a nitrophenyl in the 2-position and the methyl in the
3-position into a halogenomethyl, carbon tetrachloride is employed
as a solvent (see Example 6 in this publication). Since carbon
tetrachloride has a high toxicity, an industrial or safety and
sanitary consideration encourages to use a method employing no
carbon tetrachloride. Nevertheless, no use of carbon tetrachloride
results in a disadvantageous intermission of a brominating
reaction.
[0015] In the method disclosed in WO 95/28405 (JP-A-8-295693), for
producing a compound having an acid amide structure in the
5-position from a compound having a carboxylic acid ester in the
5-position, trimethylaluminum is used (see Example 50 in this
publication). Since this trimethylaluminum is readily flashing and
flammable, highly toxic and should be free from water, it should be
handled with a great care. Industrially, a safe production method
requiring no use of trimethylaluminum is desired.
DISCLOSURE OF THE INVENTION
[0016] We made an effort under the circumstance mentioned above and
finally found that by halogenating the methyl in the 3-position of
4,7-dihydro-4-oxothieno[2,3-b]pyridine represented by the formula:
6
[0017] having a phenyl in the 2-position and a methyl in the
3-position followed by introducing a nitro group into the phenyl in
the 2-position of a resultant compound, a rapid halogenation in a
solvent other than carbon tetrachloride, such as an easily-handled
solvent such as ethyl acetate, under a gentle and convenient
condition is possible in a halogenation process, and an
easily-operable nitration by dissolving said halogenated compound
in a solvent such as methanesulfonic acid followed by reacting with
various nitrates in a nitration process is also possible.
[0018] It is also found that by producing a compound having an acid
amide structure in the 5-position from a compound having a free
carboxylate in the 5-position a target compound can be produced
safely and conveniently in a high yield and a high purity without
requiring the use of dangerous trimethylaluminum.
[0019] Also, the present inventors found out that a compound of the
formula: 7
[0020] or a salt thereof, is obtained in high yield by subjecting a
compound of the formula: 8
[0021] or a salt thereof to cyclization.
[0022] The inventors conducted further investigation based on this
finding, and developed the present invention.
[0023] The present invention, therefore, relates to:
[0024] (1) a compound of the formula: 9
[0025] wherein R.sup.11a represents hydrogen or halogen, and
R.sup.41a represents C.sub.1-6 alkyl, C.sub.1-6 alkoxy or
C.sub.6-10 aryl, with proviso that R.sup.41a is not ethoxy when
R.sup.11a is hydrogen, or a salt thereof;
[0026] (2) a compound of the above (1) or a salt thereof, wherein
R.sup.11a is hydrogen or bromo;
[0027] (3) a compound of the above (1) or a salt thereof, which is
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylth-
ieno[2,3-b]pyridine;
[0028] (4) a compound of the above (1) or a salt thereof, which is
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxo-2-phe-
nylthieno[2,3-b]pyridine;
[0029] (5) a compound of the above (1) or a salt thereof, which is
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-4-oxo-2-phenylthieno[2,3-
-b]pyridine-5-carboxylic acid ethyl ester;
[0030] (6) a process for producing a compound of the formula:
10
[0031] wherein X represents halogen, R.sup.12a represents a
divalent hydrocarbon group which may be substituted, R.sup.3a
represents a hydrocarbon group which may be substituted, R.sup.4a
represents a hydrocarbon group or a hydrocarbon-oxy group, and
R.sup.22a represents a hydrocarbon group substituted by nitro, or a
salt thereof, which comprises subjecting a compound of the formula:
11
[0032] wherein R.sup.21a represents a hydrocarbon group and other
symbols are as defined above, or a salt thereof to nitration;
[0033] (7) a process of the above (6), wherein R.sup.12a is
methylene, R.sup.21a is phenyl, R.sup.22a is nitrophenyl, R.sup.3a
is difluorophenylmethyl, and R.sup.4a is isopropyl or ethoxy;
[0034] (8) a process for producing a compound of the formula:
12
[0035] wherein X represents halogen, R.sup.12a represents a
divalent hydrocarbon group, and R.sup.4a represents a hydrocarbon
group or a hydrocarbon-oxy group, or a salt thereof, which
comprises subjecting a compound of the formula: 13
[0036] wherein R.sup.1a represents a hydrocarbon group which may be
substituted and the other symbol is as defined above, or a salt
thereof to halogenation;
[0037] (9) a process of the above (8), wherein the halogenation is
carried out in the presence of methyl acetate;
[0038] (10) a process of the above (8), wherein X is bromo,
R.sup.1a is methyl, R.sup.12a is methylene, and R.sup.4a is
isopropyl or ethoxy;
[0039] (11) a process for producing a compound of the formula:
14
[0040] wherein X represents halogen, R.sup.12a represents a
divalent hydrocarbon group which may be substituted, R.sup.3a
represents a hydrocarbon group which may be substituted, R.sup.4a
represents a hydrocarbon group or a hydrocarbon-oxy group, and
R.sup.22a represents a hydrocarbon group substituted by nitro, or a
salt thereof, which comprises subjecting a compound of the formula:
15
[0041] wherein R.sup.1a and R.sup.2a each represents a hydrocarbon
group which may be substituted and other symbols are as defined
above, or a salt thereof to halogenation to obtain a compound of
the formula: 16
[0042] wherein each symbol is as defined above, or a salt thereof,
and then subjecting the resultant compound to nitration;
[0043] (12) a process of the above (11), wherein R.sup.1a is
methyl, R.sup.12a is methylene, R.sup.2a is phenyl, R.sup.22a is
nitrophenyl, R.sup.3a is difluorophenyl-methyl, and R.sup.4a is
isopropyl or ethoxy;
[0044] (13) a process for producing a compound of the formula:
17
[0045] wherein R.sup.1a, R.sup.2a and R.sup.3a each represents a
hydrocarbon group which may be substituted, and R.sup.5a and
R.sup.6a each represents a hydrocarbon group, or a salt thereof,
which comprises reacting a compound of the formula: 18
[0046] wherein each symbol is as defined above, or a salt thereof
with a compound of the formula: 19
[0047] wherein each symbol is as defined above, or a salt
thereof;
[0048] (14) a process of the above (13), wherein R.sup.1a is methyl
which may be substituted by N-benzyl-N-methylamino, R.sup.2a is
phenyl which may be substituted by isobutyrylamino, R.sup.3a is
difluorophenyl-methyl, and R.sup.5a and R.sup.6a are methyl;
[0049] (15) a compound of the formula: 20
[0050] wherein R.sup.11 represents C.sub.1-6 alkyl, R.sup.21
represents phenyl which may be substituted, or R.sup.11 and
R.sup.21 form, taken together with adjacent two carbon atoms, a 5-
to 7-membered ring which may be substituted, R.sup.3 represents a
hydrocarbon group which may be substituted, and R.sup.5 represents
hydrogen or a hydrocarbon group, or a salt thereof;
[0051] (16) a compound of the above (15) or a salt thereof, wherein
the substituent of the phenyl which may be substituted for R.sup.21
is isobutyrylamino or methoxy;
[0052] (17) a compound of the above (15) or a salt thereof, which
is
4-hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine;
[0053] (18) a compound of the above (15) or a salt thereof, which
is
4-hydroxy-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methylthieno[2,3-b]p-
yridine;
[0054] (19) a process for producing a compound of the formula:
21
[0055] wherein R.sup.1 and R.sup.2 each represents a hydrocarbon
group which may be substituted, or R.sup.1 and R.sup.2 form, taken
together with adjacent two carbon atoms, a 5- to 7-membered ring
which may be substituted, R.sup.3 represents a hydrocarbon group
which may be substituted, and R.sup.5 represents hydrogen or a
hydrocarbon group, or a salt thereof, which comprises subjecting a
compound of the formula: 22
[0056] wherein R.sup.4 represents a hydrocarbon group and other
symbols are as defined above, or a salt thereof to cyclization;
[0057] (20) a process of the above (19), wherein R.sup.1 is methyl,
R.sup.2 is phenyl which may be substituted by isobutyrylamino or
methoxy, or R.sup.1 and R.sup.2 form, taken together with adjacent
two carbon atoms, tetrahydrobenzene ring, R.sup.3 is methyl,
isopropyl or phenyl, R.sup.4 is ethyl, and R.sup.5 is hydrogen;
[0058] (21) a compound of the formula: 23
[0059] wherein R.sup.1 and R.sup.2 each represents a hydrocarbon
group which may be substituted, or R.sup.1 and R.sup.2 form, taken
together with adjacent two carbon atoms, a 5- to 7-membered ring
which may be substituted, R.sup.3 represents a hydrocarbon group
which may be substituted, R.sup.4 represents a hydrocarbon group,
and R.sup.5 represents hydrogen or a hydrocarbon group, or a salt
thereof;
[0060] (22) a compound of the above (21) or a salt thereof, wherein
R.sup.1 is methyl, R.sup.2 is phenyl which may be substituted by
isobutyrylamino, methoxy or nitro, or R.sup.1 and R.sup.2 form,
taken together with adjacent two carbon atoms, tetrahydrobenzene
ring, R.sup.3 is methyl, isopropyl or phenyl, R.sup.4 is ethyl, and
R.sup.5 is hydrogen;
[0061] (23) a compound of the above (21) or a salt thereof, which
is
4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-phenylthiophene-3-carb-
oxylic acid ethyl ester;
[0062] (24) a compound of the above (21) or a salt thereof, which
is
5-(4-isobutyrylaminophenyl)-4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)ami-
no]thiophene-3-carboxylic acid ethyl ester;
[0063] (25) a process for producing a compound of the formula:
24
[0064] wherein R.sup.1 and R.sup.2 each represents a hydrocarbon
group which may be substituted, or R.sup.1 and R.sup.2 form, taken
together with adjacent two carbon atoms, a 5- to 7-membered ring
which may be substituted, R.sup.3 represents a hydrocarbon group
which may be substituted, R.sup.4 represents a hydrocarbon group,
and R.sup.5 represents hydrogen or a hydrocarbon group, or a salt
thereof, which comprises reacting a compound of the formula: 25
[0065] wherein each symbol is as defined above, or a salt thereof,
with a compound of the formula: 26
[0066] wherein R.sup.6 represents hydrogen, sodium, potassium or a
hydrocarbon group and other symbols are as defined above, or a salt
thereof;
[0067] (26) a process of the above (25), wherein R.sup.1 is methyl,
R.sup.2 is phenyl which may be substituted by isobutyrylamino,
methoxy or nitro, or R.sup.1 and R.sup.2 form, taken together with
adjacent two carbon atoms, tetrahydrobenzene ring, R.sup.3 is
methyl, isopropyl or phenyl, R.sup.4 is ethyl, and R.sup.5 is
hydrogen;
[0068] (27) a process for producing a compound of the formula:
27
[0069] wherein R.sup.1 and R.sup.2 each represents a hydrocarbon
group which may be substituted, or R.sup.1 and R.sup.2 form, taken
together with adjacent two carbon atoms, a 5- to 7-membered ring
which may be substituted, R.sup.3 represents a hydrocarbon group
which may be substituted, and R.sup.5represents hydrogen or a
hydrocarbon group, or a salt thereof, which comprises reacting a
compound of the formula: 28
[0070] wherein R.sup.4 is a hydrocarbon group, and other symbols
are as defined above, or a salt thereof with a compound of the
formula: 29
[0071] wherein R.sup.6 represents hydrogen, sodium, potassium or a
hydrocarbon group, and other symbols are as defined above, or a
salt thereof, to obtain a compound of the formula: 30
[0072] wherein each symbol is as defined above, or a salt thereof,
and then subjecting the resultant compound to cyclization;
[0073] (28) a process of the above (27), wherein R.sup.1 is methyl,
R.sup.2 is phenyl which may be substituted by isobutyrylamino or
methoxy, or R.sup.1 and R.sup.2 form, taken together with adjacent
two carbon atoms, tetrahydrobenzene ring, R.sup.3 is methyl,
isopropyl or phenyl, R.sup.4 is ethyl, and R.sup.5 is hydrogen;
[0074] (29) a compound of the formula: 31
[0075] wherein R.sup.22 represents isobutyrylamino or methoxy, or a
salt thereof;
[0076] (30) a compound of the above (29) or a salt thereof, which
is
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-isobutyrylaminopheny-
l)-3-methyl-4-oxothieno[2,3-b]pyridine;
[0077] (31) a process for producing a compound of the formula:
32
[0078] wherein R.sup.23 represents phenyl which may be substituted
by isobutyrylamino or methoxy, and R.sup.3 represents a hydrocarbon
group which may be substituted, or a salt thereof, which comprises
reacting a compound of the formula; 33
[0079] wherein each symbol is as defined above, or a salt thereof,
with a compound of the formula: 34
[0080] wherein X represents halogen, or a salt thereof; and
[0081] (32) a dibasic acid salt of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-is-
obutyryl-2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-4-oxothieno[2,-
3-b]pyridine.
BEST MODE FOR CARRYING OUT THE INVENTION
[0082] In the above formulae, halogen for R.sup.11a includes, for
example, fluoro, chloro, bromo, iodo. Among others, bromo is
especially preferred.
[0083] In the above formulae, C.sub.1-6 alkyl for R.sup.41a
includes, for example, methyl, ethyl, n-propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and so forth. Among
others, C.sub.1-3 alkyl is preferred.
[0084] In the above formulae, C.sub.1-6 alkoxy for R.sup.41a
includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy, t-butoxy, and so forth. Among
others, C.sub.1-3 alkoxy is preferred.
[0085] In the above formulae, C.sub.6-10 aryl for R.sup.41a
includes, for example, phenyl, 1-naphthyl, 2-naphthyl, and so
forth. Among others, phenyl is preferred.
[0086] In the above formulae, halogen for X includes, for example,
fluoro, chloro, bromo, iodo. Among others, bromo is especially
preferred.
[0087] In the above formulae, preferred is a C.sub.1-20 hydrocarbon
group as the hydrocarbon group of the hydrocarbon group which may
be substituted for R.sup.1a, R.sup.2a or R.sup.3a, the hydrocarbon
group for R.sup.4a, R.sup.5a or R.sup.6a, and the hydrocarbon group
of the hydrocarbon-oxy for R.sup.4a.
[0088] The above C.sub.1-20 hydrocarbon group includes, for
example, (1) C.sub.1-15 alkyl (e.g., methyl, ethyl, n-propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,
heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,
tetradecyl, pentadecyl, etc., preferably C.sub.1-6 alkyl, etc.),
(2) C.sub.3-10 cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,
etc.), (3) C.sub.2-10 alkenyl (e.g., vinyl, allyl, 1-butenyl,
2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl,
3-octenyl, etc.), (4) C.sub.2-10 alkynyl (e.g., ethynyl, propargyl,
2-propynyl, isopropynyl, 2-butynyl, 3-hexynyl, etc.), (5)
C.sub.3-10 cycloalkenyl (e.g., cyclopropenyl, cyclopentenyl,
cyclohexenyl), (6) C.sub.6-14 aryl (e.g., phenyl, naphthyl,
anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.), (7)
C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-6 alkyl such as benzyl,
phenethyl, benzhydryl, and trityl), and so forth.
[0089] The divalent hydrocarbon group of the divalent hydrocarbon
group which may be substituted for R.sup.12a, includes preferably,
for example, a divalent C.sub.1-20 hydrocarbon group such as (1)
C.sub.1-15 alkylene (e.g., methylene, ethylene, n-propylene,
isopropylene, butylene, isobutylene, sec-butylene, pentylene, and
hexylene, preferably C.sub.1-6 alkylene, etc.), (2) C.sub.2-10
alkenylene (e.g., vinylene, allylene, 1-butenylene, 2-butenylene,
butadienylene, isopropenylene, 2-methylallylene, hexatrienylene,
3-octenylene, etc., preferably C.sub.2-6 alkenylene), (3)
C.sub.2-10 alkynylene (e.g., ethynylene, propargylene,
2-propynylene, isopropynylene, 2-butynylene, 3-hexynylene, etc.,
preferably C.sub.2-6 alkynylene), and so forth.
[0090] The hydrocarbon group which may be substituted for R.sup.1a,
R.sup.2a or R.sup.3a, and the divalent hydrocarbon group which may
be substituted for R.sup.12a may have 1 to 6, preferably 1 to 5,
more preferably 1 to 3, especially 1 or 2 substituents at possible
positions of the hydrocarbon group.
[0091] The substituents of the hydrocarbon group which may be
substituted for R.sup.1a, R.sup.2a or R.sup.3a, include, for
example, (1) halogen (e.g., fluoro, chloro, bromo, and iodo), (2)
nitro, (3) nitroso, (4) cyano or isocyano, (5) amino which may be
substituted [e.g., an amino of the formula: --NR.sup.30aR.sup.31a
wherein R.sup.30a and R.sup.31a each represents hydrogen,
C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-10 alkenyl,
C.sub.6-14 aryl, C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-5
alkyl, etc.), C.sub.1-10 acyl (C.sub.1-10 alkanoyl), C.sub.1-6
alkoxy-carbonyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl,
C.sub.1-6 alkylsulfinyl or a heterocyclic group (a 5- to 8-membered
saturated or unsaturated heterocyclic group containing 1 to 4
hetero atoms selected from the group consisting of oxygen, sulfur
and nitrogen atoms, or a condensed heterocyclic group thereof, as
mentioned below)], (6) hydroxy which may be substituted by
substituent(s) selected from the group consisting of (i) C.sub.1-6
alkyl [this C.sub.1-6 alkyl maybe substituted by halogen, hydroxy,
C.sub.1-6 alkoxy, C.sub.2-10 alkenyl, C.sub.3-10 cycloalkyl,
C.sub.1-3 alkylthio, C.sub.1-6 alkyl-carbonyl, carboxy, carbamoyl,
C.sub.1-6 alkyl-carbamoyl, a heterocyclic group (a 5- to 8-membered
saturated or unsaturated heterocyclic group containing 1 to 4
hetero atoms selected from the group consisting of oxygen, sulfur
and nitrogen atoms, or a condensed heterocyclic group thereof, as
mentioned below) or halogen], (ii) C.sub.1-4 acyl (C.sub.1-4
alkanoyl), (iii) C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-5
alkyl; this group may be substituted by halogen, C.sub.1-3 alkoxy
or C.sub.1-4 alkyl), (iv) C.sub.6-14 aryl (this may be substituted
by halogen), (v) C.sub.2-6 alkenyl, (vi) C.sub.3-7 cycloalkyl,
(vii) C.sub.1-3 alkoxy-carbonyl, (viii) mono- or di-C.sub.1-6
alkylamino, (ix) C.sub.2-6 alkenylamino, (x) C.sub.1-6
alkylcarbonyl, (xi) C.sub.3-6 cycloalkyloxycarbonyl, and (xii)
trifluorosulfonyl, (7) a group of the formula: --S(O)n-R.sup.32a
wherein n represents an integer of 0 to 2, and R.sup.32a represents
hydrogen or a hydrocarbon group which may be substituted by
substituents such as halogen, nitro, cyano, hydroxy, oxo, thioxo,
carboxy, cyano-C.sub.6-14 aryl, halogeno-C.sub.6-14 aryl, etc.; in
this hydrocarbon group, C.sub.1-20 hydrocarbon group is preferred,
especially, C.sub.1-6 alkyl, C.sub.6-14 aryl, and C.sub.7-19
aralkyl (C.sub.6-14 aryl-C.sub.1-5 alkyl) are preferred, (8)
carbamoyl which may be substituted (the substituents of this
carbamoyl include, for example, mono- or di-C.sub.1-6 alkyl,
preferably mono- or di-C.sub.1-3 alkyl, etc.), (9) a group through
carbonyl [e.g., a group of the formula: --CO--R.sup.33a wherein
R.sup.33a represents (i) hydrogen, (ii) hydroxy, (iii) C.sub.1-6
alkyl, (iv) C.sub.1-6 alkoxy (this alkoxy may be substituted by
C.sub.6-14 aryl which may be substituted by halogen or nitro,
etc.), (v) C.sub.3-6 cycloalkyl, (vi) C.sub.6-14 aryl, (vii)
C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-6 alkyl), (viii) amino
which may be substituted (e.g. the above amino) or (ix) a
heterocyclic group (a5- to 8-membered saturated or unsaturated
heterocyclic group containing 1 to 4 hetero atoms selected from the
group consisting of oxygen, sulfur and nitrogen atoms, or a
condensed heterocyclic group thereof, as mentioned below)], (10) a
5- to 8-membered saturated or unsaturated heterocyclic group
containing 1 to 4 hetero atoms selected from the group consisting
of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic
group thereof, as mentioned below, (this heterocyclic group may be
substituted by (i) halogen, (ii) C.sub.1-4 alkyl, (iii) C.sub.1-3
alkoxy, (iv) C.sub.1-4 alkylthio, or (v) phenoxy which may be
substituted by halogen), (11) sulfo, (12) C.sub.6-14 aryl (e.g.,
phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl,
etc.; this aryl may be substituted by 1 to 4 substituents selected
from the group consisting of (a) hydroxy, (b) amino, (c) mono- or
di-C.sub.1-6 alkylamino (e.g., methylamino, ethylamino,
propylamino, dimethylamino, diethylamino, etc.), (d) C.sub.1-6
alkoxy (e.g., methoxy, ethoxy, propoxy, hexyloxy, etc.) and (e)
halogen (fluoro, chloro, bromo and iodo ), (13) aryloxy [this aryl
is same as the above (12)], (14) C.sub.3-7 cycloalkyl, (15)
C.sub.1-6 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy,
propylenedioxy, etc.), (16) oxo, (17) thioxo, (18) C.sub.3-4
alkynyl (e.g., propargyl, 2-butynyl, etc.), (19) C.sub.3-10
cycloalkyl, (20) C.sub.2-10 alkenyl (e.g., vinyl, allyl,
isopropenyl, 1-butenyl, 2-butenyl, butadienyl, hexatrienyl,
3-octenyl, etc.; C.sub.2-6 alkenyl is preferred.), (21) C.sub.7-19
aralkyl (C.sub.6-14 aryl-C.sub.1-6 alkyl), (22) amidino, (23)
azido, and so forth.
[0092] The substituents of the above-mentioned hydrocarbon group
which may be substituted, may further have 1 to 3, preferably 1 or
2 substituents at possible positions. Said substituents, which the
substituents may further have, include, for example, 1 to 4,
preferably 1 or 2 substituents selected from the group consisting
of (1) hydroxy, (2) amino, (3) mono- or di-C.sub.1-4 alkylamino
(e.g., methylamino, ethylamino, propylamino, dimethylamino,
diethylamino etc.), (4) C.sub.1-4 alkoxy, preferably C.sub.1-3
alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), (5) halogen (fluoro,
chloro, bromo, and iodo), and nitro, and so forth.
[0093] When the hydrocarbon group is cycloalkyl, alkenyl, alkynyl,
cycloalkenyl, aryl or aralkyl, this hydrocarbon group may be
substituted by 1 to 3 C.sub.1-6 alkyl, preferably C.sub.1-4 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), and this
C.sub.1-6 alkyl may be further substituted by 1 to 3 hydroxy, oxo,
C.sub.1-3 alkoxy (e.g., methoxy, ethoxy, ethoxy, n-propoxy,
isopropoxy etc.), C.sub.1-3 alkylthio, halogen, and carbamoyl,
etc.
[0094] The substituted C.sub.1-6 alkyl includes formyl (methyl
substituted by an oxo), carboxy (methyl substituted by an oxo and a
hydroxy), C.sub.1-6 alkoxycarbonyl (methyl substituted by an oxo
and an alkoxy) (e.g., C.sub.1-6 alkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.),
hydroxy-C.sub.1-6 alkyl (e.g., hydroxymethyl, hydroxyethyl,
hydroxybutyl, hydroxypropyl, etc.), C.sub.1-3 alkoxy-C.sub.1-6
alkyl(e.g., methoxymethyl, ethoxymethyl, ethoxybutyl,
propoxymethyl, propoxyhexyl, etc.), and so forth.
[0095] The number of the above substituents is 1 to 6, preferably 1
to 5, more preferably 1 to 3, especially 1 or 2. The number of the
substituents which substituents may further have, is 1 to 3,
preferably 1 to 2.
[0096] In the definitions of the above-mentioned groups, C.sub.1-10
alkyl includes, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,
hexyl, etc. Among others, preferred is C.sub.1-6 alkyl, and more
preferred is C.sub.1-4 alkyl or C.sub.1-3 alkyl. The C.sub.1-6
alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl,
neopentyl, hexyl, etc. The C.sub.1-4 alkyl includes, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl
and t-butyl. The C.sub.1-3 alkyl includes, for example, methyl,
ethyl, n-propyl, and isopropyl.
[0097] In the definitions of the above-mentioned groups, as
cycloalkyl preferred is C.sub.3-10 cycloalkyl such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclononyl, etc. Among others, C.sub.3-7 cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
etc.), and C.sub.3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, etc.) are preferred.
[0098] In the definitions of the above-mentioned groups, C.sub.2-10
alkenyl includes, for example, vinyl, allyl, 1-butenyl, 2-butenyl,
butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, 3-octenyl,
etc. Among others, preferred is C.sub.2-6 alkenyl (e.g., vinyl,
allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl,
2-methylallyl, hexatrienyl etc.).
[0099] In the definitions of the above-mentioned groups, C.sub.6-14
aryl includes, for example, phenyl, naphthyl, anthryl, phenanthryl,
acenaphthyl, anthracenyl, etc.
[0100] In the definitions of the above-mentioned groups, C.sub.7-19
aralkyl includes, for example, C.sub.6-14 aryl-C.sub.1-5 alkyl such
as benzyl, phenethyl, benzhydryl, and trityl.
[0101] In the definitions of the above-mentioned groups, C.sub.1-6
alkoxy includes, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc. Among
others, C.sub.1-4 alkoxy or C.sub.1-3 alkoxy (e.g., methoxy,
ethoxy, n-propoxy, and isopropoxy) is preferred.
[0102] In the definitions of the above-mentioned groups, C.sub.1-10
acyl includes, for example, C.sub.1-10 alkanoyl (e.g., formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl, and hexanoyl).
Among others, preferred is C.sub.1-4 acyl [e.g., C.sub.1-4 alkanoyl
(e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, etc.)].
[0103] In the definitions of the above-mentioned groups, the
heterocyclic group includes, for example, a 5- to 8-membered
saturated or unsaturated heterocyclic group containing 1 to 4
hetero atoms selected from the group consisting of oxygen, sulfur
and nitrogen atoms, or a condensed heterocyclic group thereof.
[0104] The examples of the above heterocyclic group include (1) a
5-membered heterocyclic group containing 1 to 4 hetero atoms
selected from the group consisting of oxygen, sulfur and nitrogen
atoms in addition to carbon atoms, such as 2- or 3-thienyl, 2- or
3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-,4- or
5-thiazolyl, 3-,4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4-
or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or
5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or
5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or
5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1H- or 2H-tetrazolyl, succinimido, etc., (2) a
6-membered heterocyclic group containing 1 to 4 hetero atoms
selected from the group consisting of oxygen, sulfur and nitrogen
atoms in addition to carbon atoms, such as 2-, 3- or 4-pyridyl, 2-,
4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyl, thiomorpholinyl,
morpholinyl, oxoimidazinyl, triazinyl, pyrrolidinyl, piperidinyl,
pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl,
piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl,
pyrazinyl, 3- or 4-pyridazinyl, etc., (3) a bi- or tri-cyclic
condensed heterocyclic group containing 1 to 4 hetero atoms
selected from the group consisting of oxygen, sulfur and nitrogen
atoms in addition to carbon atoms, such as benzofuryl,
benzothiazolyl, benzoxazolyl, tetrazolo[1,5-b]pyridazinyl,
triazolo[4,5-b]pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,
quinolizinyl, 1,8-naphthylizinyl, purinyl, pteridinyl,
dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, cromanyl,
banzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalimido, etc.
[0105] Preferable examples of the above heterocyclic group include
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,4-thiazinyl,
imidazolinyl, succinimido, phthalimido, etc.
[0106] Preferred examples of the substituents of the hydrocarbon
group which may be substituted for R.sup.1a include (1) nitro, (2)
amino which may be substituted by C.sub.1-10 alkyl, C.sub.1-10 acyl
(C.sub.1-10 alkanoyl) or C.sub.1-6 alkoxy-carbonyl, etc., (3)
hydroxy which may be substituted by C.sub.1-6 alkyl, C.sub.1-4 acyl
(C.sub.1-4 alkanoyl), C.sub.1-3 alkoxy-carbonyl, C.sub.1-6
alkylcarbonyl, C.sub.3-6 cycloalkyl-oxycarbonyl or
trifluorosulfonyl, etc., (4) a group of the formula:
--S(O)n-R.sup.32a wherein n represents an integer of 0 to 2, and
R.sup.32a represents hydrogen or a C.sub.1-10 hydrocarbon group
(preferably C.sub.1-6 alkyl), (5) succinimido, (6) phthalimido, and
so forth.
[0107] R.sup.1a preferably is (1) a C.sub.1-20 hydrocarbon group
(preferably C.sub.1-6 alkyl), and (2) a C.sub.1-20 hydrocarbon
group (preferably C.sub.1-6 alkyl) substituted by (i) amino which
may be substituted by C.sub.1-10 alkyl, C.sub.1-10 acyl (C.sub.1-10
alkanoyl) or C.sub.1-6 alkoxy-carbonyl, (ii) succinimido or (iii)
phthalimido. More preferably, R.sup.1a is (1) C.sub.1-6 alkyl, and
(2) N--C.sub.7-19 aralkyl-N--C.sub.1-6 alkylamino-C.sub.1-6 alkyl
(N--C.sub.6-14 aryl-C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino-C.sub.1-6 alkyl), etc.
[0108] Preferred examples of the substituents of the hydrocarbon
group which may be substituted for R.sup.2a include (1) nitro, (2)
halogen, (3) amino which may be substituted by C.sub.1-10 acyl
(C.sub.1-10 alkanoy) or C.sub.1-6 alkoxy-carbonyl, (4) hydroxy
which may be substituted by C.sub.1-6 alkyl, C.sub.1-4 acyl
(C.sub.1-4 alkanoyl), C.sub.1-3 alkoxy-carbonyl, C.sub.1-6
alkylcarbonyl, C.sub.3-6 cycloalkyl-oxycarbonyl or
trifluorosulfonyl, (5) a group of the formula: --S(O)n-R.sup.32a
wherein n represents an integer of 0 to 2, and R.sup.32a represents
hydrogen or a C.sub.1-6 hydrocarbon group which may be substituted
(preferably C.sub.1-6 aryl), (6) carbamoyl, (7) a group through
carbonyl (e.g., C.sub.1-6 alkoxy-carbonyl, etc.), (8) succinimido,
(9) phthalimido, and so forth.
[0109] R.sup.2a preferably is (1) a C.sub.1-20 hydrocarbon group
(preferably C.sub.1-6 alkyl or C.sub.6-10 aryl), and (2) a
C.sub.1-20 hydrocarbon group (preferably C.sub.1-6 alkyl or
C.sub.6-10 aryl, more preferably C.sub.6-10 aryl) substituted by
(i) amino which may be substituted by C.sub.1-10 acyl (C.sub.1-10
alkanoyl) or C.sub.1-6 alkoxy-carbonyl, (ii) hydroxy which may be
substituted by C.sub.1-6 alkyl, C.sub.1-4 acyl (C.sub.1-4
alkanoyl), C.sub.1-3 alkoxy-carbonyl, C.sub.1-6 alkylcarbonyl or
C.sub.3-6 cycloalkyl-oxycarbonyl, etc., (iii) succinimido or (iv)
phthalimido. More preferably, R.sup.2a is (1) C.sub.6-14 aryl, (2)
C.sub.1-8 alkanoylamino-C.sub.6-14 aryl, (3) C.sub.2-10
alkenyl-C.sub.1-6 alkoxy-C.sub.6-14 aryl, and so forth.
[0110] Preferred examples of the substituents of the hydrocarbon
group which may be substituted for R.sup.3a include (1) nitro, (2)
halogen, (3) amino which may be substituted, (4) hydroxy which may
be substituted, (5) a group of the formula: --S(O)n-R.sup.32 a
wherein n represents an integer of 0 to 2, and R.sup.32a represents
hydrogen or a C.sub.1-20 hydrocarbon group which may be substituted
(preferably C.sub.1-6 alkyl), (6) carbamoyl which may be
substituted, (7) a group through carbonyl (e.g., C.sub.1-6
alkoxy-carbonyl, etc.), and so forth.
[0111] Especially R.sup.3a preferably is, phenyl-C.sub.1-3 alkyl
which may be substituted by halogen.
[0112] Preferred examples of the divalent hydrocarbon group which
may be substituted for R.sup.12a include C.sub.1-6 alkylene. More
preferred is methylene or ethylene.
[0113] Preferred examples of the hydrocarbon group for R.sup.4a or
the hydrocarbon group of the hydrocarbon-oxy for R.sup.4a include
C.sub.1-6 alkyl.
[0114] Preferred examples of the hydrocarbon group of the
hydrocarbon group substituted by nitro for R.sup.22a include
C.sub.1-6 alkyl.
[0115] Preferred examples of the hydrocarbon group for R.sup.5a or
R.sup.6a include C.sub.1-6 alkyl.
[0116] R.sup.11a preferably is hydrogen or halogen (preferably
bromo, etc.).
[0117] R.sup.41a preferably is C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
and phenyl. More preferred is C.sub.1-3 alkyl, ethoxy, phenyl, and
so forth.
[0118] The following are processes of the present invention.
[0119] 1. Halogenation in the present invention is carried out by
reacting a material compound of the formula: 35
[0120] wherein each symbols is as defined above, with a
halogenating reagent to obtain a compound of the formula: 36
[0121] wherein each symbols is as defined above.
[0122] The halogenating reagent includes N-halosuccinimide (e.g.,
N-bromosuccinimide, N-bromophthalimide, 1,
3-dibromo-5,5-dimethylhydantoi- n), etc.
[0123] In this reaction, a radical initiator is advantageously
used. The radical initiator includes, for example,
2,2'-azobisisobutyronitrile, benzoyl peroxide,
2,2'-azobis(2,4-dimethylvaleronitrile), and so forth.
[0124] The amount of the halogenating reagent to be used is about 1
to 1.5 mol, preferably about 1 to 1.2 mol relative to one mol of
the material compound. The amount of the radical initiator to be
used is about 0 to 0.5 mol, preferably 0.01 to 0.1 mol relative to
one mol of the material compound.
[0125] In this reaction, a solvent is advantageously used. There is
no particular limitation on the kind of solvent that can be used
unless the reaction is interfered with. Among others, preferably
used are hydrocarbons (e.g., n-hexane, benzene, toluene, xylene,
etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), and
mixtures of those solvents.
[0126] The reaction time is advantageously from about 10 minutes to
5 hours, preferably from 1 to 3 hours. The reaction temperature is
selected according to boiling point of the solvent that can be used
in the reaction, for example, about 35.degree. C. to reflux
temperature, preferably about 70.degree. C. to reflux temperature,
more preferably about 70 to 80.degree. C. When methyl acetate is
used, the reaction temperature is about 40.degree. C. to reflux
temperature, preferably about 50 to 60.degree. C. When ethyl
acetate is used, the reaction temperature is, for example, about
40.degree. C. to reflux temperature, preferably about 70.degree. C.
to reflux temperature, more preferably bout 70 to 80.degree. C.
[0127] 2. Nitration in the present invention is carried out by
subjecting a material compound of the formula: 37
[0128] wherein each symbol is as defined above, to nitration to
obtain a compound of the formula: 38
[0129] wherein each symbol is as defined above.
[0130] Said nitration is carried out according to an ordinary
nitration method of aromatic compound. In this reaction, as a
nitrating agent, (1) nitric acid, alkali metal of nitric acid
(e.g., sodium nitrate, potassium nitrate, etc.) or ammonium salt of
nitric acid (e.g., ammonium nitrate, etc.), or mixture with a
strong acid is added. As for said strong acid, any acid may be used
as far as it can generate nitronium ion from nitric acid. Among
them, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid,
methanesulfonic acid and trifluoromethanesulfonic acid, which have
a high solubility against organic compound, are preferable and used
as solvents at the same time.
[0131] At addition, it is preferable to drop said nitrating agent
comprising 1 mole of nitric acid or nitrate to said strong acid
solution of 1 mole of a material compound under said
temperature.
[0132] This reaction may be carried out without a solvent or in the
presence of a solvent. When a solvent is used, the solvent
includes, for example, ketones (e.g., acetone, methyl ethyl ketone,
etc.), nitriles (e.g., acetonitrile, etc.), sulfoxides (e.g.,
dimethylsulfoxide, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, etc.), esters (e.g., ethyl acetate, etc.),
carboxylic acids (e.g., acetic acid, propionic acid),
dimethoxyethane, etc., and mixtures of those solvents.
[0133] The reaction temperature is about -40 to 40.degree. C.,
preferably about 0 to 20.degree. C. The reaction time is about 10
minutes to 10 hours, preferably 1 to 2 hours.
[0134] 3. The reaction of converting a carboxylic acid derivative
to a N-substituted amide derivative, of the present invention is
carried out by reacting a material compound of the formula: 39
[0135] wherein each symbol is as defined above, with a
N,O-dihydrocarbonhydroxylamine derivative of the formula: 40
[0136] wherein each symbol is as defined above, or salt thereof, to
obtain a compound of the formula: 41
[0137] wherein each symbol is as defined above.
[0138] In this reaction, the amount of the
N,O-dihydrocarbonhydroxylamine derivative or its salt is about 1 to
5 equivalents, preferably 1 to 3 equivalents, relative to one mol
of the material compound or its salt.
[0139] To this reaction system, advantageously added are about 1 to
5 equivalents, preferably about 1 to 3 equivalents of amines (e.g.,
triethylamine), about 1 to 5 equivalents, preferably about 1 to 3
equivalents of 1-hydroxybenzotriazole (HOBT), and about 1 to 5
equivalents, preferably 2 to 3 equivalents of
1-ethyl-3-(3-dimethylaminop- ropyl)carbodiimide (WSC).
[0140] This reaction is usually carried out in a solvent that does
not interfere with the reaction. Such solvents include, for
example, ethers (e.g., dioxane, tetrahydrofuran,
1,2-dimethoxyethane, etc.), ketones (e.g., acetone, etc.), nitrites
(e.g., acetonitrile, etc.), amides (e.g., dimethylformamide,
dimethylacetamide, etc.), dimethylsulfoxide, sulfolane, etc. and
mixtures of those solvents.
[0141] This reaction is carried out at about 0 to 100.degree. C.,
preferably about 50 to 60.degree. C., for about 1 to 10 hours,
preferably about 5 to 7 hours.
[0142] The material carboxylic acid derivative is obtained by for
example, subjecting a compound of the formula: 42
[0143] wherein R.sup.41a represents a hydrocarbon group and the
other symbols are as defined above, which is disclosed in
JP-A-8-295693 (WO 95/28405), to hydrolysis.
[0144] The hydrolysis is carried out by adding an acid (e.g.,
hydrochloric acid, sulfuric acid, etc.) or an alkali (e.g., sodium
hydroxide, potassium hydroxide, lithium hydroxide, etc.) to the
reaction followed by stirring.
[0145] The solvents to be used include, for example, water,
alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, etc.),
tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane,
dioxane, etc.), and so forth. The reaction temperature is usually
about 0 to 100.degree. C., preferably about 50 to 80.degree. C. The
reaction time is preferably about 0.5 to 10 hours, preferably,
about 1 to 4 hours.
[0146] 4. The reaction of converting the resultant acid amide
derivative as mentioned above to a ketone derivative, is carried
out by reacting a material compound of the formula: 43
[0147] wherein each symbol is as defined above, or a salt thereof
with Grignard reagent [e.g., isopropyl magnesium chloride (2M-THF
solution), isopropyl magnesium bromide, etc.] to obtain a material
compound of the formula: 44
[0148] wherein R.sup.42a represents a hydrocarbon group and other
symbols are as defined above, or a salt thereof.
[0149] The amount of the Grignard reagent is about 1 to 10
equivalents, preferably about 2 to 4 equivalents relative to one
mol of the material compound or a salt thereof.
[0150] This reaction may be carried out in the presence of a
solvent, which can be used unless the reaction is interfered with.
The solvent includes, for example, the same ones used in the above
reaction for obtaining an acid amide derivative.
[0151] The reaction temperature is about -10 to 0.degree. C.,
preferably about -5 to 0.degree. C. The reaction time is about 30
minutes to 5 hours, preferably about 40 to 50 minutes.
[0152] Salts of compounds used in these reactions and salts of
compounds obtained in these reactions (hereinafter, referred to as
"compound of the present invention") are preferably physiologically
acceptable acid addition salts. Such salts include, for example,
salts with inorganic acids (e.g., hydrochloric acid, phosphoric
acid, hydrobromic acid, sulfuric acid, etc.), salts with organic
acids (e.g., acetic acid, formic acid, propionic acid, fumaric
acid, maleic acid, succinic acid, tartaric acid, citric acid, malic
acid, oxalic acid, benzoic acid, methanesulfonic acid,
benzenesulfonic acid, etc.), and so forth. For example, when a
compound of the present invention has an acidic group such as
carboxylic acid, it may form a physiologically acceptable salt with
an inorganic base (e.g., alkali metals or alkaline earth metals
such as sodium, potassium, calcium and magnesium, ammonia, etc.) or
an organic base (e.g., tri-C.sub.1-3 alkylamine such as
triethylamine, etc.). The compound in free form can be converted to
a salt and the one in salt form can be converted to a free form by
per se known methods or analogous thereto.
[0153] When the compound has a double bond, and there exist
stereoisomers of Z- or E-form, Z-form, E-form and their mixture may
be used.
[0154] When the compound has a chiral carbon atom, and there exist
stereoisomers of R- or S-form, R-form, S-form and their mixture are
within the scope of the present invention.
[0155] When the compound of the present invention or a salt thereof
is an optically active compound, it can be resolved into the d- and
l-forms by the conventional optical resolution techniques.
[0156] Thus obtained compounds or salt thereof may be isolated and
purified by ordinary means of separation such as solvent
extraction, concentration under reduced pressure, crystallization,
recrystallization, distillation chromatography, and the like.
[0157] The compound obtained in the present invention or a salt
thereof can be submitted to the next reaction either as the
reaction mixture or after partial purification.
[0158] The compound obtained in the present invention or a salt
thereof is used for production of thienopyridine derivatives being
useful as GnRH antagonists, according to the methods described in,
for example, JP-A-8-295693 (WO 95/28405) or analogous methods
thereto.
[0159] Therefore, the compound obtained in the present invention or
a salt thereof can be used as synthetic intermediates for
thienopyridine derivatives being useful as GnRH antagonists, which
is described in, for example, JP-A-8-295693 (WO 95/28405).
[0160] Material compounds and salts thereof used in methods of the
present invention can be produced, for example, by the methods
described in WO 95/28405 (JP-A-8-295693) or analogous methods
thereto.
[0161] In the above formulae, C.sub.1-6 alkyl for R.sup.11
includes, for example, methyl, ethyl, n-propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., preferably
methyl, ethyl, n-isopropyl, more preferably methyl.
[0162] In the above formulae, the 5- to 7-membered ring of the "5-
to 7-membered ring which may be substituted" which R.sup.11 and
R.sup.21 form, taken together with adjacent two carbon atoms, and
the 5- to 7-membered ring of the "5- to 7-membered ring which may
be substituted" which R.sup.1 and R.sup.1 form, taken together with
adjacent two carbon atoms include a 5- to 7-membered ring which may
contain 1 to 4 nitrogen atoms, sulfur atoms and/or oxygen atoms.
Such examples are
[0163] (1) a ring of the formula: 45
[0164] wherein R.sup.7 represents --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, --C.dbd.C--C.dbd.C--,
--CH.sub.2--R.sup.8--CH.sub.2--, --R.sup.8--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--R.sup.8--,
--CH.sub.2--R.sup.8--CH.sub.2--CH.sub.2-- -,
--CH.sub.2--CH.sub.2--R.sup.8--CH.sub.2--,
--R.sup.8--CH.sub.2--CH.sub.- 2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--R.sup.8--,
--CH.sub.2--R.sup.8--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--R.sup.8-- -CH.sub.2--,
--R.sup.8--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--R.sup.8-- wherein R.sup.8
represents (i) --NH--, (ii) --S(O)m-- wherein m represents an
integer of 0 to 2, or (iii) --O--,
[0165] (2) a 5-membered heterocycle containing 1 to 4 hetero atoms
selected form oxygen atom, sulfur atom, nitrogen atom, etc., in
addition to carbon atoms, such as thiophene, furan, oxazole,
thiazole, pyrazole, imidazole, isoxazole, isothiazole,
1,2,3-thiadiazole, 1,2,5-thiadiazole, 1,2,3-triazole, etc., and
[0166] (3) a 6-membered heterocycle containing 1 to 4 hetero atoms
selected form oxygen atom, sulfur atom, nitrogen atom, etc., in
addition to carbon atoms, such as pyridine, pyridazine, pyrimidine,
triazine, pyrrolidine, pyran, pyrazine, etc.
[0167] Substituents which the 5- to 7-membered ring may have
include halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, nitro, oxo,
thioxo, alkylthio, cyano, C.sub.1-6 alkylcarbonyl, C.sub.1-4
alkoxycarbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl,
di-C.sup.1-6 alkylcarbamoyl, C.sup.1-10 acylamino (e.g., C.sub.1-10
alkanoylamino, etc.), di-C.sub.1-6 alkylamino, C.sub.6-14 aryl,
C.sub.6-14 aryloxy, heterocyclic group (the above-mentioned "5- to
8-membered saturated or unsaturated heterocyclic group containing 1
to 4 hetero atoms selected from the group consisting of oxygen,
sulfur and nitrogen atoms, or a condensed heterocyclic group
thereof"), and so forth.
[0168] The above 5- to 7-membered ring may have 1 to 3 substituents
above-mentioned at possible positions.
[0169] In the above formulae, as the hydrocarbon group of the
hydrocarbon group which may be substituted for R.sup.1, R.sup.2 or
R.sup.3, and as the hydrocarbon group for R.sup.4, R.sup.5 or
R.sup.6, preferred is a C.sub.1-20 hydrocarbon group.
[0170] The C.sub.1-20 hydrocarbon group includes, for example, (1)
C.sub.1-15 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl,
nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
etc.), (2) C.sub.3-10 cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,
etc.), (3) C.sub.2-10 alkenyl (e.g., vinyl, allyl, 1-butenyl,
2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl,
3-octenyl, etc.), (4) C.sub.2-10 alkynyl (e.g., ethynyl, propargyl,
2-propynyl, isopropynyl, 2-butynyl, 3-hexynyl, etc.), (5)
C.sub.3-10 cycloalkenyl (e.g., cyclopropenyl, cyclopentenyl,
cyclohexenyl), (6) C.sub.6-14 aryl (e.g., phenyl, naphthyl,
anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.), (7)
C.sub.7-19 aralkyl (e.g., C.sub.6-14 aryl-C.sub.1-5 alkyl such as
benzyl, phenethyl, benzhydryl, trityl, etc.), and the like.
[0171] Substituents of the hydrocarbon group which may be
substituted for R.sup.1, R.sup.2 or R.sup.3 include, for example,
(1) halogen (e.g., fluoro, chloro, bromo, and iodo ),(2) nitro, (3)
nitroso, (4) cyano or isocyano, (5) substituted amino [e.g., a
substituted amino of the formula: --NR.sup.30R.sup.31 wherein
R.sup.30 and R.sup.31 each is hydrogen, C.sub.1-10
alkyl,C.sub.3-10cycloalkyl, C.sub.2-10 alkenyl, C.sub.6-14 aryl,
C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-6 alkyl etc.)
C.sub.1-10 acyl (C.sub.1-10 alkanoyl, preferably C.sub.1-4 alkanoyl
), C.sub.1-6 alkoxy-carbonyl, a group of the formula:
--S(O)p-R.sup.32 wherein p represents 1 or 2, and R.sup.32
represents C.sub.1-6 alkyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylsulfinyl, or heterocyclic group (the above-mentioned 5- to
8-membered saturated or unsaturated heterocyclic group containing 1
to 4 hetero atoms selected from the group consisting of oxygen,
sulfur and nitrogen atoms, or a condensed heterocyclic group
thereof); provided that R.sup.30 and R.sup.31 are not hydrogen at
the same time], (6) hydroxy which may be substituted by (i)
C.sub.1-6 alkyl [this C.sub.1-6 alkyl may be substituted by
halogen, C.sub.1-6 alkoxy, C.sub.2-10 alkenyl, C.sub.3-10
cycloalkyl, C.sub.1-3 alkylthio, oxy-C.sub.1-3 alkoxy, C.sub.1-6
alkyl-carbonyl, carbamoyl, C.sub.1-6 alkyl-carbamoyl, heterocyclic
group (the above-mentioned 5- to 8-membered saturated or
unsaturated heterocyclic group containing 1 to 4 hetero atoms
selected from the group consisting of oxygen, sulfur and nitrogen
atoms, or a condensed heterocyclic group thereof) or halogen], (ii)
C.sub.1-4 acyl, (iii) C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-5
alkyl; this C.sub.7-19 aralkyl may be substituted by halogen,
C.sub.1-3 alkoxy or C.sub.1-4 alkyl), (iv) C.sub.6-14 aryl (this
C.sub.6-14 aryl may be substituted by halogen), (v) C.sub.2-6
alkenyl, (vi) C.sub.3-7 cycloalkyl, (vii) C.sub.1-3
alkoxy-carbonyl, (viii) di-C.sub.1-6 alkylaminocarbonyl, (ix)
C.sub.1-3 alkoxy-carbonyl, (x) C.sub.1-6 alkylcarbonyl, (xi)
C.sub.3-6 cycloalkyl-oxycarbonyl and (xii) C.sub.1-6 alkylsulfonyl
or C.sub.6-14 arylsulfonyl each of which may be substituted by
halogen, (7) a group of the formula: --S(O)n-R.sup.33 wherein n
represents an integer of 0 to 2, and R.sup.33 represents hydrogen
or a hydrocarbon group which may be substituted by substituent(s)
(e.g., halogen, nitro, cyano, oxo, thioxo, cyano-C.sub.6-14 aryl,
halogeno-C.sub.6-14 aryl etc.); the hydrocarbon group includes
C.sub.1-20 hydrocarbon group, preferably C.sub.1-6 alkyl,
C.sub.6-14 aryl, C.sub.7-19 aralkyl (C.sub.6-14 aryl-C.sub.1-6
alkyl), (8) carbamoyl which may be substituted (such substituent(s)
includes, for example, mono- or di-C.sub.1-6 alkyl, preferably
mono- or di-C.sub.1-3 alkyl, etc.), (9) a group through carbonyl
[e.g., a group of the formula: --CO--R.sup.34 wherein R.sup.34
represents (i) hydrogen, (ii) C.sub.1-6 alkyl, (iii) C.sub.1-6
alkoxy (this alkoxy may be substituted by C.sub.6-14 aryl which may
be substituted by halogen or nitro, etc.), (v) C.sub.3-6
cycloalkyl, (vi) C.sub.6-14 aryl, (vii) C.sub.7-19 aralkyl
(C.sub.6-14 aryl-C.sub.1-6 alkyl) or (viii) heterocyclic group (the
above-mentioned 5- to 8-membered saturated or unsaturated
heterocyclic group containing 1 to 4 hetero atoms selected from the
group consisting of oxygen, sulfur and nitrogen atoms, or a
condensed heterocyclic group thereof)], (10) heterocyclic group
(the above-mentioned 5- to 8-membered saturated or unsaturated
heterocyclic group containing 1 to 4 hetero atoms selected from the
group consisting of oxygen, sulfur and nitrogen atoms, or a
condensed heterocyclic group thereof); this heterocyclic group may
be substituted by (i) halogen, (ii) C.sub.1-4 alkyl, (iii)
C.sub.1-3 alkoxy, (iv) C.sub.1-4 alkylthio or (v) phenoxy which may
be substituted by halogen, (11) C.sub.6-14 aryl [e.g., phenyl,
naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.;
this aryl may be substituted by 1 to 4 substituents selected form
the group consisting of (a) C.sub.1-6 alkoxy (e.g., methoxy,
ethoxy, propoxy, hexyloxy, etc.), (b) halogen (fluoro, chloro,
bromo, and iodo ) and (c)di-C.sub.1-4 alkylamino (e.g.,
dimethylamino, diethylamino etc.) etc.], (12) C.sub.6-14 aryloxy
[this C.sub.6-14 aryl is as same as the above (11)], (13) C.sub.3-7
cycloalkyl, (14) C.sub.1-6 alkylenedioxy(e.g., methylenedioxy,
ethylenedioxy, propylenedioxy, 2,2-dimethylenedioxy etc.), (15)
oxo, (16) thioxo, (17) C.sub.3-4 alkynyl (e.g., propargyl,
2-butynyl, etc.), (18) C.sub.3-10 cycloalkyl, (19) C.sub.2-10
alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl,
butadienyl, hexatrienyl, 3-octenyl etc., preferably C.sub.2-6
alkenyl), (20) C.sub.7-19 aralkyl, (21) azido, and so forth.
[0172] The substituents of the above-mentioned hydrocarbon group
which may be substituted, may further have 1 to 3, preferably 1 or
2 substituents at possible positions. Said substituents, which the
substituents may further have, include, for example, 1 to 4,
preferably 1 or 2 substituents selected from the group consisting
of C.sub.1-4 alkoxy(e.g.,methoxy,ethoxy, propoxy, etc.), halogen
(fluoro, chloro, bromo and iodo), nitro and di-C.sub.1-4 alkylamino
(e.g., dimethylamino, diethylamino, etc.), etc.
[0173] When the hydrocarbon group is cycloalkyl, alkenyl, alkynyl,
cycloalkenyl, aryl or aralkyl, this hydrocarbon group maybe
substituted 1 to 3 C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, etc.), and this C.sub.1-6 alkyl may be further
substituted by 1 to 3 oxo, C.sub.1-3 alkoxy (e.g., methoxy, ethoxy,
ethoxy, n-propoxy, isopropoxy etc.), C.sub.1-3 alkylthio, halogen,
and carbamoyl, etc.
[0174] The substituted C.sub.1-6 alkyl includes, formyl (methyl
substituted by an oxo), C.sub.1-6 alkoxycarbonyl (methyl
substituted by an oxo and an alkoxy) (e.g., C.sub.1-6
alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,
t-butoxycarbonyl, etc.), C.sub.1-3 alkoxy-C.sub.1-6 alkyl (e.g.,
methoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl,
propoxyhexyl, etc.), and so forth.
[0175] The number of the above substituents is 1 to 6, preferably 1
to 5, more preferably 1 to 3, especially 1 or 2. The t number of
the substituents which substituents may further have, is 1 to 3,
preferably 1 to 2.
[0176] In the definitions of the above-mentioned groups, C.sub.1-10
alkyl includes, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,
hexyl, etc., preferably C.sub.1-6 alkyl, more preferably C.sub.1-4
alkyl or C.sub.1-3 alkyl. The C.sub.1-6 alkyl includes, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl,etc. The
C.sub.1-4 alkyl includes,for example,methyl,ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The C.sub.1-3
alkyl includes, for example, methyl, ethyl, n-propyl, and
isopropyl.
[0177] In the definitions of the above-mentioned groups, C.sub.3-10
cycloalkyl includes, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.,
preferably C.sub.3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, etc.), more preferably
C.sub.3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, etc.).
[0178] In the definitions of the above-mentioned groups, C.sub.2-10
alkenyl includes, for example, vinyl, allyl, 1-butenyl, 2-butenyl,
butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, 3-octenyl,
etc., preferably C.sub.2-6 alkenyl (e.g., vinyl, allyl, 1-butenyl,
2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl,
etc.).
[0179] In the definitions of the above-mentioned groups, C.sub.6-14
aryl includes, for example, phenyl, naphthyl, anthryl, phenanthryl,
acenaphthyl, anthracenyl, etc. Preferred is C.sub.6-10 aryl.
[0180] In the definitions of the above-mentioned groups, C.sub.7-19
aralkyl includes, for example, benzyl, phenethyl, benzhydryl,
trityl, etc.
[0181] In the definitions of the above-mentioned groups, C.sub.1-10
alkoxy includes, for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc. Among
others preferred is C.sub.1-4 alkoxy or C.sub.1-3 alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, and isopropoxy).
[0182] In the definitions of the above-mentioned groups, C.sub.1-10
acyl includes, for example, C.sub.1-10 alkanoyl (e.g., formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl), etc.
Among others, preferred is C.sub.1-4 acyl [e.g., C.sub.1-4 alkanoyl
(e.g., formyl, acetyl, propionyl, butyryl, isobutyryl etc.)].
[0183] Preferred examples of the substituents of the hydrocarbon
group which may be substituted for R.sup.1 include (1) nitro, (2)
amino which may be substituted by C.sub.1-10 alkyl, C.sub.1-10 acyl
(C.sub.1-10 alkanoyl) or C.sub.1-6 alkoxy-carbonyl, (3) hydroxy
which may be substituted by C.sub.1-6 alkyl, C.sub.1-4 acyl
(C.sub.1-4 alkanoyl ), C.sub.1-3 alkoxy-carbonyl, C.sub.1-6
alkylcarbonyl, C.sub.3-6 cycloalkyloxycarbonyl or
trifluorosulfonyl, (4) a group of the formula: --S(O)n-R.sup.12
wherein n represents an integer of 0 to 2, and R.sup.12 represents
hydrogen or C.sub.1-20 hydrocarbon group (preferably C.sub.1-6
alkyl), and so forth.
[0184] R.sup.1 is preferably (1) C.sub.1-20 hydrocarbon group
(preferably C.sub.1-6 alkyl) and (2) C.sub.1-20 hydrocarbon group
(preferably C.sub.1-6 alkyl) substituted by amino which may be
substituted by C.sub.1-6 alkyl, C.sub.7-19 aralkyl (C.sub.6-14
aryl-C.sub.1-6 alkyl), etc. More preferably R.sup.1 is (1)
C.sub.1-6 alkyl and (2) N--C.sub.7-19 aralkyl-N--C.sub.1-6
alkylamino-C.sub.1-6 alkyl (N--C.sub.6-14 aryl-C.sub.1-5
alkyl-N--C.sub.1-6 alkylamino-C.sub.1-6 alkyl) etc.
[0185] Preferred examples of the substituents of the hydrocarbon
group which may be substituted for R.sup.2 include (1) nitro, (2)
halogen, (3) a group of the formula: --S(O)n-R.sup.12 wherein n
represents an integer of 0 to 2, and R.sup.12 represents hydrogen
or C.sub.1-20 hydrocarbon group (preferably C.sub.1-6 alkyl), (4)
carbamoyl, (5) a group through carbonyl (e.g., C.sub.1-6
alkoxy-carbonyl, etc.), and so forth.
[0186] R.sup.2 is preferably C.sub.1-20 hydrocarbon group (e.g.,
C.sub.6-14 aryl). More preferably R.sup.2 is (1) C.sub.6-14 aryl,
(2) C.sub.1-8 alkanoyl -amino-C.sub.6-14 aryl, (3) C.sub.2-10
alkenyl-C.sub.1-6 alkoxy-C.sub.6-14 aryl, and so forth.
[0187] In the formulae, the halogen for X includes fluoro, chloro,
bromo and iodo. Among others, preferred is bromo.
[0188] R.sup.3 is preferably C.sub.1-20 hydrocarbon group (e.g.,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.6-14 aryl, etc.). More
preferred is methyl, isopropyl or phenyl.
[0189] R.sup.4 is preferably C.sub.1-20 hydrocarbon group (e.g.,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.6-14 aryl, etc.). More
preferred is ethyl, etc.
[0190] R.sup.5 is preferably hydrogen.
[0191] R.sup.6 represents hydrogen, sodium, potassium or a
hydrocarbon group. R.sup.6 is preferably C.sub.1-20 hydrocarbon
group (e.g., C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.6-14 aryl,
etc.).
[0192] The production of the present invention is as follows.
46
[0193] wherein R.sup.1' and R.sup.2' each represents a hydrocarbon
group which may be substituted, R.sup.1" and R.sup.2" form, taken
together with adjacent two carbon atoms, a 5- to 7-membered ring
which may be substituted, and other symbols are as defined
above.
[0194] The above "hydrocarbon group which may be substituted" and
the "5- to 7-membered ring which may be substituted" are as defined
above, respectively. The compound of the above formula (VIII') is
sometimes refereed as compound (VIII'). The compound of the above
formula (VIII") is sometimes refereed as compound (VIII").
[0195] 1. Cyclization is Carried Out as Follows
[0196] (1) Firstly, Thiophene Compound (II) is Reacted with
Compound (III) to Produce Compound (IV)
[0197] In this reaction, about 1 to 5 mol, preferably 1 to 2 mol of
compound (III) is used relative to one mol of compound (II).
[0198] In this reaction, there is no particular limitation on the
kind of solvent that can be used unless the reaction is interfered
with. Such solvent includes, for example, hydrocarbons (e.g.,
n-hexane, benzene, toluene, xyxlene, etc.), halogenated
hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane,
chloroform, carbon tetrachloride, etc.), ethers (e.g., diethyl
ether, diisopropyl ether, ethylene glycol dimethyl ether,
tetrahydrofuran, dioxane, etc.), nitrites (e.g., acetonitrile,
etc.), esters (e.g., ethylacetate, etc.), amides (e.g.,
N,N-dimethylformamide, etc.), ketones (e.g., acetone, methyl ethyl
ketone, etc.), sulfoxides (e.g., dimethylsulfoxide, etc.) and
mixtures of those solvents. This reaction is preferably carried out
in the presence of an acid to promote this reaction. The acid
includes an inorganic acid such as hydrochloric acid, hydrobromic
acid, sulfuric acid and phosphoric acid, an organic acid such as
acetic acid, trifluoroacetic acid, methanesulfonic acid,
benzenesulfonic acid and p-toluenesulfonic acid. The amount of the
acid is about 0 to 5 equivalents, preferably about 0.01 to 0.5
equivalents relative to one mol of compound (II).
[0199] The reaction temperature is about 0 to 180.degree. C.,
preferably about 10 to 50.degree. C. The reaction time is about 10
minutes to 24 hours, preferably about 1 to 2 hours.
[0200] Compound (II) is produced by the per se known method, for
example, the method described in K. Gewald, et. al., Chem. Ber. 99,
94, 1966, or analogue methods thereto. Compound (III) is produced
by the per se known method, for example, methods described in J.
Dabrowski, et. al., Bull. Chem. Soc,. Jpn. 48, 1310, 1975, or U.
Lienhard, et. al., Helv. Chim. Acta, 61, 1609, 1978, or analogous
methods thereto. (2) The reaction in which compound (IV) is
subjected to cyclization to produce compound (V) is carried out by
heating compound (IV).
[0201] The reaction is carried out by heating compound (IV) at
about 100 to 300.degree. C., preferably about 200 to 280.degree.
C., for about 30 minutes to 30 hours, preferably about 1 to 6
hours, with distilling off an alcohol (e.g., ethanol, etc.) which
is produced during the reaction.
[0202] This reaction may be carried out without a solvent or in the
presence of a solvent. When a solvent is used, preferred is a
solvent which does not interfere with the cyclization and has a
high boiling point (e.g., a solvent having b.p. 100.degree. C. or
more). Such solvent includes, for example, diethylene glycol
dibutyl ether, diphenyl ether, diethyl phthalate, etc.
[0203] 2. A Compound of the Formula 47
[0204] wherein each symbol is as defined above, can be produced
[hereinafter, sometimes referred to as compound (VIII)] by
introducing a difluorophenyl-methyl group to the 7-position of
compound (V).
[0205] In this reaction about 1 to 2 mol, preferably about 1 to 1.2
mol of halogenated difluorophenyl-methyl compound is added relative
to one mol of compound (V).
[0206] This reaction is advantageously carried out in the presence
of a base. Such base includes, for example, an inorganic base such
as an alkali metal or alkaline earth metal hydrogencarbonate (e.g.,
sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), an
alkali metal or alkaline earth metal carbonate (e.g., sodium
carbonate, potassium carbonate, etc.), an alkali metal or alkaline
earth metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,
calcium hydroxide, etc.) and an organic base such as an alkylamine
(e.g., triethylamine, diisopropylethylamine, etc.), and so forth.
The amount of the base to be used is about 1 to 2 mol relative to
one mol of compound (V).
[0207] In this reaction, there is no particular limitation on the
kind of solvent that can be used unless the reaction is interfered
with. Among others, preferred are ethers (e.g., diethyl ether,
diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran,
dioxane, etc.), nitrites (e.g., acetonitrile, etc.), amides (e.g.,
N,N-dimethylformamide etc.), ketones (e.g., acetone, methyl ethyl
ketone, etc.), etc.
[0208] The reaction temperature is about 0 to 100.degree. C.,
preferably about 20 to 50.degree. C. The reaction time is about 1
to 24 hours, preferably about 2 to 3 hours.
[0209] Salts of compounds used in these reactions and salts of
compounds obtained in these reactions (hereinafter, referred to as
"compound of the present invention") are preferably physiologically
acceptable acid addition salts. Such salts include, for example,
salts with inorganic acids (e.g., hydrochloric acid, phosphoric
acid, hydrobromic acid, sulfuric acid, etc.), salts with organic
acids (e.g., acetic acid, formic acid, propionic acid, fumaric
acid, maleic acid, succinic acid, tartaric acid, citric acid, malic
acid, oxalic acid, benzoic acid, methanesulfonic acid,
benzenesulfonic acid, etc.), and so forth. For example, when a
compound of the present invention has an acidic group such as
carboxylic acid, it may form a physiologically acceptable salt with
an inorganic base (e.g., alkali metals or alkaline earth metals
such as sodium, potassium, calcium and magnesium; ammonia; etc.) or
an organic base (e.g., tri-C.sub.1-3 alkylamine such as
triethylamine, etc.). The compound in free form can be converted to
a salt and the one in salt form can be converted to a free form by
per se known methods or analogous thereto.
[0210] In JP-A-8-295693 (WO 95/28405),
2-(4-aminophenyl)-3-(N-benzyl-N-met-
hylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothien-
o[2,3-b]pyridine is shown merely as an amorphous. In the present
invention,
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difl-
uorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine can
be obtained as a stable crystalline salt according to, for example,
the following examples. The above crystalline salts include
physiologically acceptable acid addition salts such as salts with
inorganic acids (e.g., hydrochloric acid, phosphoric acid,
hydrobromic acid, sulfuric acid, etc.), salts with organic acids
(e.g., acetic acid, formic acid, propionic acid, fumaric acid,
maleic acid, succinic acid, tartaric acid, citric acid, malic acid,
oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic
acid, etc.), and so forth. Preferably, the crystalline salts are
salts with hydrochloric acid, methanesulfonic acid, dibasic acid
(e.g., fumaric acid, oxalic acid, malonic acid, succinic acid,
malic acid, etc.), or tribasic acid (e.g.,
1,2,3-propanetricarboxylic acid, etc.), more preferably, salts with
dibasic acid (preferably, fumaric acid, malonic acid, succinic
acid, malic acid, etc.).
[0211] Crystalline salt of
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminometh-
yl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyri-
dine, of the present invention is stable so that it can be easily
isolated and purified and it can be preserved in stable condition
for long term.
[0212] When the compound has a double bond, and there exist
stereoisomers of Z- or E-form, Z-form, E-form and their mixture may
be used.
[0213] When the compound has a chiral carbon atom, and there exist
stereoisomers, each of them and their mixture are within the scope
of the present invention.
[0214] When the compound of the present invention or a salt thereof
is an optically active compound, it can be resolved into the d- and
l-forms by the conventional optical resolution techniques.
[0215] Thus obtained compound or its salt may be isolated and
purified by ordinary means of separation such as solvent
extraction, concentration under reduced pressure, crystallization,
recrystallization, distillation chromatography, and the like.
[0216] The compound obtained in the present invention or a salt
thereof can be submitted to the next reaction either as the
reaction mixture or after partial purification.
[0217] Compound (VIII) obtained by the methods of the present
invention or a salt thereof can be used as a synthetic intermediate
for production of thienopyridine derivatives having GnRH
antagonistic activity or compounds containing such derivative as
partial structure [hereinafter, sometimes referred to as compound
(IX)].
[0218] Thienopyridine derivatives having GnRH antagonistic activity
[hereinafter, referred to as compound (IX')] or their salts can be
produced from thienopyridine derivatives in compound (VIII)
[hereinafter, referred to as compound (VIII')] or their salts,
according to methods descried in JP-A-8-295693 (WO 95/28405) or
analogous methods thereto.
[0219] Since a compound of Formula (VIII) wherein a ring formed by
R.sup.1 and R.sup.2 together with adjacent two carbon atoms has a
substituent [hereinafter, referred to as compound (VIII")] or its
salt can be used in a manner similar to that described in
JP-A-8-295693 (WO 95/28405) by converting the substituent in said
compound or by further introducing a substituent thereinto to
produce a GnRH antagonistic compound [sometimes abbreviated as
compound (IX"), which means a compound having as a part a
thienopyridine derivative described above] or its salt, compound
(VIII") or its salt can be used as an intermediate for producing
compound (IX") or its salt.
[0220] Since compound (IX) or its salt has a GnRH antagonistic
activity with a low toxicity, it can be used as a GnRH antagonist
in a manner similar to that described in JP-A-8-295693 (WO
95/28405).
[0221] A thienopyridine derivative described above (compound (IX)
or its salt) produced from a compound obtained by a method of the
invention has an excellent GnRH antagonistic activity and has a low
toxicity. Accordingly, said thienopyridine derivative suppresses
the secretion of a gonadotropin through its GnRH receptor
antagonism in a mammal (for example, human, monkey, cattle, horse,
dog, cat, rabbit, rat, mouse, etc.) to provide a control of the
blood levels of sex hormones, due to which it can safely be
employed in the prophylaxis and the treatment of a androgenic
hormone- or estrogenic hormone-dependent disease or a disease
attributable to the hypersecretion of such hormone.
[0222] For example, said thienopyridine derivative is useful in the
prophylaxis and the treatment of a sex hormone-dependent cancer
(e.g., prostatic cancer, uterine cancer, mammary cancer, pituitary
tumor, etc.) as well as prostatomegaly, hysteromyoma,
endometriosis, precocious puberty, amenorrhea, premenstrual
syndrome, multilocular ovary syndrome, acne and the like. It is
useful also in the preoperative treatment before a surgery of any
disease listed above as well as in the postoperative prevention of
a recurrence. Said thienopyridine derivative is useful also in
controlling the reproduction in males and females (e.g., pregnancy
regulator, menstrual period regulator, etc.). A thienopyridine
derivative may be used also as a contraceptive in males and females
or as an ovulation-promoting agent in females. Said thienopyridine
derivative may be used in the treatment of a sterility by utilizing
the rebound effect thereof after discontinuation.
[0223] Said thienopyridine derivative of the invention is useful
also in a field of stockbreeding for controlling an estrus of an
animal, improving the texture of a meat, or promoting the growth of
an animal. Said thienopyridine derivative is useful also as a
oviposition-promoting agent in fish.
[0224] The following examples merely illustrate this invention in
further detail and should by no means be construed as defining the
scope of the invention.
EXAMPLE 1
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-4-oxo-2-phe-
nylthieno[2,3-b]pyridine-5-carboxylic acid ethyl ester
[0225]
7-(2,6-difluorobenzyl-4,7-dihydro-3-methyl-4-oxo-2-phenylthieno[2,3-
-b]pyridine-5-carboxylic acid ethyl ester obtained as in Example
3(13) in WO 95/28405 (JP-A-8-295693) (1200 g), N-bromosuccinimide
(589 g), 2,2'-azobisisobutylonitrile (AIBN) (45.3 g) were suspended
in ethyl acetate (13.3 L) and the mixture was stirred under reflux
for 2.5 hours. After dissolving once, a crystal of the title
compound was precipitated slowly. The mixture was allowed to cool
with stirring, and then cooled with water and then on ice. The
crystal was recovered by a filtration, washed with ethyl acetate (1
L) (twice) and a purified water (2.7 L)(twice) and then dried at
50.degree. C. for 9 hours to obtain 1295 g of the title compound
(yield: 92%).
[0226] m.p. 206-206.degree. C.
EXAMPLE 2
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-2-(4-nitrop-
henyl)-4-oxothieno[2,3-b]pyridine-5-carboxylic acid ethyl ester
[0227] To methanesulfonic acid (4.5 L), 900 g of the compound
obtained in Example 1 described above was added over a period of 30
minutes (internal temperature 19 to 23.degree. C.). After cooling
on ice with stirring, sodium nitrate (147 g)/methanesulfonic acid
(1.98 L) was added dropwise over a period of 2 hours (internal
temperature 12 to 14.degree. C.). Subsequently, the reaction
mixture was stirred for 1.5 hours at 11 to 12.degree. C., and was
added to 155 L of an ice-water, and the precipitated crystal was
recovered by a filtration, washed with water and then dried. The
crystal was dried in vacuo for 26 hours at 50.degree. C. to obtain
944 g of a crude product of the title compound (yield: 75%, HPLC).
The crystal was suspended in ethyl acetate (2.9 L), and the mixture
was stirred under reflux for 30 minutes, at room temperature for 30
minutes, and then stirred with cooling on ice for 1 hour and 20
minutes. The crystal was recovered by a filtration, washed with
cool ethyl acetate (0.8 L), dried under reduced pressure for 8
hours at 50.degree. C. to obtain 837 g of the title compound
(yield: 86%).
[0228] m.p. 200-202.degree. C.
EXAMPLE 3
Production of
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7--
dihydro-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-carboxyli-
c acid
[0229] (1) The compound obtained in Example 2 described above was
subjected to the process described in Example 26(2) in WO 95/28405
(JP-A-8-295693) and the process described in Example 27(2) in the
same reference to obtain
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7--
(2,6-difluorobenzyl)-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic
acid ethyl ester.
[0230] (2) The compound obtained in the above step (1) was admixed
with a slightly excess of isobutyrylchloride in pyridine and
stirred at room temperature for 2 hours to obtain
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-
-difluorobenzyl)-4,7-dihydro-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b-
]pyridine-5-carboxylic acid ethyl ester.
[0231] m.p. 185-186.degree. C.
[0232] (3) The compound (735 g) obtained in the above step (2) was
dissolved in ethanol (11 L) and combined with 2.5 N NaOH (4.57 L),
and stirred for 3 hours at an internal temperature of
40.+-.5.degree. C. After distilling ethanol off under reduced
pressure, the residue was combined with water (7.4 L) and adjusted
with concentrated hydrochloric acid (989 ml) to pH 5.4. After
extraction with 2-butanone (14.5 L, 7.4 L; twice), the organic
phase was washed with saturated saline and then concentrated under
reduced pressure. While suspended in 2-butanone (1.6 L) with
stirring, isopropylether (3.3 L) was added dropwise. After cooling
on ice and then recovering by filtration, washing was performed
with diisopropylether. After drying in air and drying at 50.degree.
C. for 9 hours under reduced pressure, 605 g of the title compound
(yield: 93%) was obtained.
[0233] NMR (CDCl.sub.3, .delta.): 1.27(d,6H,J=6.8 Hz), 2.20(s,3H),
2.63(m,1H), 3.75(s,2H), 4.20(s,2H), 5.41(s,2H), 6.9-7.7(m,12H),
8.69(s,1H).
EXAMPLE 4
Production of
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7--
dihydro-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridine-5-(N-methyl-
-O-methyl)hydroxamic acid
[0234] A mixture of the compound obtained in Example 3 described
above (574 g), acetonitrile (4.6 L), N,O-dimethylhydroxylamine
hydrochloride (182 g), triethylamine (261 ml), hydroxybenzotriazole
(HOBT) (253 g) and 1-(3-dimetylaminopropyl)-3-ethylcarbodiimide
hydrochloride (WSC) (179 g) was stirred with heating at 50 to
59.degree. C. WSC (250 g) was further added in 4 portions.
Acetonitrile was distilled off under reduced pressure, and the
residue was combined with 2-butanone (12 L) and saturated saline (8
L) and the mixture was stirred vigorously. After separating the
organic phase, the aqueous phase was extracted with 2-butanone. The
organic phases were combined and washed twice with saturated saline
(5.6 L). After drying over magnesium sulfate followed by distilling
the solvent off under reduced pressure, ethyl acetate was added and
then concentrated again under reduced pressure. After concentrating
to about 1.6 L followed by cooling on ice, the precipitated crystal
was recovered by a filtration. Then, after washing with cool ethyl
acetate (640 ml) followed by drying at 50.degree. C. under reduced
pressure for 9 hours, 556 g of the title compound (yield: 91%) was
obtained.
[0235] m.p. 152-154 C.
EXAMPLE 5
Production of
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7--
dihydro-2-(4-isobutyrylaminophenyl)-5-isobutyryl-4-oxothieno[2,3-b]pyridin-
e hydrochloride
[0236] The compound obtained in the above Example 4 is subjected to
the procedure described in Reference 18 in JP-A-9-169766 to obtain
the title compound.
EXAMPLE 6
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-3-methyl-4-oxo-2-phenylth-
ieno[2,3-b]pyridine-5-carboxylic acid
[0237]
7-(2,6-Difluorobenzyl-4,7-dihydro-3-methyl-4-oxo-2-phenylthieno[2,3-
-b]pyridine-5-carboxylic acid ethyl ester obtained as in Example
3(13) in WO 95/28405 (JP-A-8-295693)(200.0 g) was dissolved in
ethanol (3.0 L) and combined with 8 N NaOH (170.7 ml), and stirred
with heating under reflux for 1 hour. After distilling ethanol off
under reduced pressure, the residue was combined with water (2 L)
and the pH was then adjusted to5with concentrated hydrochloric
acid(117ml). The crystal precipitated was recovered by a
filtration, washed with water, dried in air and then at 50.degree.
C. under reduced pressure for 9 hours to obtain 184.6 g of the
title compound (yield: 98.6%).
[0238] m.p. 286-289.degree. C.
EXAMPLE 7
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-3-methyl-4-oxo-2-phenylth-
ieno[2,3-b]pyridine-5-(N-methyl-O-methyl)hydroxamic acid
[0239] The compound obtained in the procedure of the above Example
6 (1.0 g) was dissolved in a dried tetrahydrofuran (THF) and the
reaction vessel was purged with an argon gas. While stirring with
cooling on ice, thionyl chloride (0.24 ml) was added and the
mixture was stirred at room temperature for 4 hours and then
concentrated to dryness under reduced pressure to obtain
7-(2,6-difluorobenzyl)-4,7-dihydro-3-methyl-4-oxo-2-ph-
enylthio[2,3-b]pyridine-5-carboxylic acid chloride as a residue,
which was then dissolved in a dried THF.
[0240] A mixture of N,O-dimethylhydroxylamine (0.30 g),
triethylamine (0.34 ml) and a dried THF was stirred with cooling on
ice, and treated dropwise with the solution of the acid chloride
described above in a dried THF. To the reaction mixture, chloroform
(40 ml) and water (30 ml) were added and the mixture was stirred
vigorously and then the organic phase was separated. The organic
phase was washed with saturated saline (30 ml) and dried over
magnesium sulfate, and the solvent was distilled off under reduced
pressure. To the residue, 2-butanone (3 ml) and diisopropylether (6
ml) were added, and after allowing a crystal to be precipitated,
the mixture was stirred with cooling on ice. The crystal was
recovered by a filtration, and washed with diisopropyl ether. After
drying at 40.degree. C. under reduced pressure for 6 hours, 1.07 g
of the title compound was obtained (yield: 97%).
[0241] m.p. 247-250.degree. C.
EXAMPLE 8
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-o-
xo-2-phenylthieno[2,3-b]pyridine
[0242] Using the compound obtained in Example 7, the title compound
was obtained in the manner similar to that in Example 5.
[0243] m.p. 204-207.degree. C.
EXAMPLE 9
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-4-oxo-2-phenylthieno[2,3-b]pyridine
[0244] Using the compound obtained in the above Example 8, the
title compound was obtained in the manner similar to that in the
above Example 1.
[0245] m.p. 189-192.degree. C.
EXAMPLE 10
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine
[0246] Using the compound obtained in the above Example 9, the
title compound was obtained in the manner similar to that in
Example 2.
[0247] m.p. 202-204.degree. C.
EXAMPLE 11
Production of
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7--
dihydro-5-isobutyryl-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridin-
e hydrochloride:
[0248] The compound obtained in the above Example 10 is subjected
to the method in Example 47(2) in WO 95/28405 (JP-A-8-295693)
followed by the method in Example 55 in the same reference, and
further followed by the method in Example 57(10) in the same
reference to obtain the title compound.
[0249] The chemical structure of the compounds obtained in Examples
1, 2, 4 and 7 to 10 are shown in Table 1.
1TABLE 1 48 Ex. No. R.sup.1a R.sup.2a R.sup.45a 1 bromomethyl
phenyl ethoxycarbonyl 2 bromomethyl 4-nitrophenyl ethoxycarbonyl 4
N-benzyl-N- 4-isobutyrylamino- (N-methyl-O-methyl)-
methylaminomethyl phenyl hydroxamic acid 7 methyl phenyl
(N-methyl-O-methyl)- hydroxamic acid 8 methyl phenyl isopropyl 9
bromomethyl phenyl isopropyl 10 bromomethyl 4-nitrophenyl
isopropyl
EXAMPLE 12
Production of
2-amino-5-(4-isobutyrylaminophenyl)-4-methylthiophene-3-carb-
oxylic acid ethyl ester
[0250] 4-Isobutyrylaminophenylacetone (5 g), ethyl cyanoacetate
(3.09 g), ammonium acetate (0.53 g) and acetic acid (30 ml)were
admixed and heated under reflux for 4 hours. After distilling
acetic acid off under reduced pressure, the residue was partitioned
between ethyl acetate (50 ml) and a 5% aqueous solution of sodium
hydrogencarbonate (50 ml). The organic phase was washed with a 5%
aqueous solution of sodium hydrogen carbonate (50 ml) and a 5%
saline (50 ml), and the solvent was distilled off under reduced
pressure, and the residue was heated azeotropically with ethyl
acetate (10 ml) and ethanol (10 ml). The residue was dissolved in
ethanol (43 ml) and combined with diethylamine (1.67 g) and sulfur
(0.73 g), and the mixture was stirred at room temperature for 3
hours. The reaction mixture was partitioned between ethyl acetate
(100 ml) and a 5% saline (50 ml), and then the organic phase was
washed successively with a 5% saline (50 ml), a 5% aqueous solution
of sodium hydrogen carbonate (50 ml) and then a 5% saline (50 ml).
The solvent was distilled off under reduced pressure to obtain a
residue, which was subjected to a column chromatography on a silica
gel (ethyl acetate/hexane=7/3) followed by a recrystallization from
diisopropylether/hexane=1/1 (100 ml) to obtain the title compound
(4.85 g).
[0251] .sup.1HNMR(300 MHz,CDCl.sub.3) .delta.; 1.27(d,6H,J=6.9 Hz),
1.37(t,3H,J=7.1 Hz), 2.30(s,3H), 2.52(sept,1H,J=6.9 Hz),
4.31(q,2H,J=7.1 Hz), 6.08(bs,2H), 7.18(bs,1H), 7.29(d,2H,J=8.5 Hz),
7.54(d,2H,J=8.5 Hz).
EXAMPLE 13
Production of
4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-phenylthi-
ophene-3-carboxylic acid ethyl ester
[0252] 2-Amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl
ester [m.p. 93-95.degree. C., a compound obtained by a method
similar to that described in WO 95/28405 (JP-A-8-295693),
hereinafter the same is applied analogously.] (10 g), a 85% pure of
1-methoxy-4-methyl-1-penten-3-one (6.9 g), p-toluenesulfonic acid
monohydrate (0.219 g) and toluene (100 ml) were mixed and the
mixture was stirred at room temperature for 2.5 hours. The reaction
mixture was diluted with ethyl acetate and washed with a saturated
aqueous solution of sodium hydrogen carbonate and the aqueous layer
(wash) was extracted with ethyl acetate. The organic phases were
combined and washed with a saturated saline, and then dried over
anhydrous magnesium sulfate. The residue (precipitate) was
triturated with hexane and the filter cake was washed with hexane
to obtain the title compound (12.64 g, 92.4%).
[0253] m.p. 104-108.degree. C.
EXAMPLE 14
Production of
4-hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridin- e
[0254] The compound obtained in Example 13 (50 g) and diphenylether
(500 ml) were mixed and the ethanol formed as the reaction
proceeded was distilled off while continuing the heating under
reflux for 4 hours. After allowing to cool followed by distilling
diphenylether off under reduced pressure a crude crystal was
precipitated and washed with n-hexane to obtain the title compound
(35.1 g, 80.6%).
[0255] m.p. 114-117.degree. C.
EXAMPLE 15
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-o-
xo-2-phenylthieno[2,3-b]pyridine
[0256] The compound obtained in Example 14 (35 g), potassium
carbonate (18.6 g) and N,N-dimethylformamide (280 ml) were mixed,
and 2,6-difluorobenzyl bromide (27.9 g) was added, and the mixture
was stirred at room temperature for 4 hours. Water (560 ml) was
added dropwise to the reaction mixture, and the mixture was stirred
for 30 minutes,-cooled on ice, and then stirred further for 1 hour.
The crude crystal was recovered by a filtration, washed with water,
dried in air, and then suspended in a 1:1 solvent mixture (250 ml)
of ethyl acetate and diisopropylether, and the suspension was
stirred at 25 to 40.degree. C. for 1 hour, and then stirred with
cooling on ice for 1 hour, and the crystal precipitated out was
recovered by a filtration and washed with the solvent mixture
described above (125 ml) to obtain the title compound (44.6 g,
91.7%).
[0257] m.p. 205-207.degree. C.
EXAMPLE 16
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-4-oxo-2-phenylthieno[2,3-b]pyridine
[0258] The compound obtained in Example 15 (1.8 g) was admixed with
N-bromosuccinimide (0.88 g), azobisisobutyronitrile (70 mg) and
ethyl acetate (18 ml) and the mixture was heated under reflux for 2
hours. At the time when about 1 hour and 30 minutes had elapsed
during this procedure, the suspension turned into a solution. The
suspension obtained after allowing to cool was cooled on ice, and
the precipitated crystal was recovered by a filtration, washed with
cool ethyl acetate and water to obtain the title compound (1.68 g,
79.1%).
[0259] m.p. 189-192.degree. C.
EXAMPLE 17
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine
[0260] The compound obtained in Example 16 (1 g) was dissolved in
methanesulfonic acid (5 ml) with cooling at 10 to 12.degree. C. and
then treated dropwise with a solution of sodium nitrate (0.165 g)
in methanesulfonic acid (2.5 ml). The mixture was stirred as it was
for 2 hours, and then poured into a cool water, and the crystal
precipitated was recovered by a filtration, washed with water and
diisopropylether, dried in vacuo to obtain a crude crystal (1.04
g). This was suspended in ethyl acetate (15 ml) with stirring and
then cooled on ice, and the crystal precipitated was recovered by a
filtration, washed with a cool ethyl acetate to obtain the title
compound (0.647 g, 59.5%).
[0261] m.p. 202-204.degree. C. (recrystallized from methanol).
EXAMPLE 18
Production of
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7--
dihydro-5-isobutyryl-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b]pyridin-
e hydrochloride
[0262] The compound obtained in the above Example 17 is subjected
to the method in Example 47(2) in WO 95/28405 (JP-A-8-295693)
followed by the method in Example 55 in the same reference, and
further followed by the method in Example 57(10) in the same
reference to obtain the title compound.
EXAMPLE 19
Production of
4-methyl-2-[(3-oxo-1-buten-1-yl)amino]-5-phenylthiophene-3-c-
arboxylic acid ethyl ester
[0263] From 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid
ethyl ester (5 g) and commercially available
4-methoxy-3-buten-2-one (2.55 g), the title compound (6.06 g) was
obtained similarly as in Example 13.
[0264] m.p. 111-114.degree. C.
EXAMPLE 20
Production of
5-acetyl-4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine
[0265] From the compound obtained in the above Example 19 (1 g),
the title compound (0.754 g) was obtained similarly as in Example
14.
[0266] .sup.1HNMR (300 MHz, CDCl.sub.3) .delta.; 2.65(3H,s),
2.73(3H,s), 7.35-7.60(5H,m), 8.80(1H,s), 13.81(1H,s).
EXAMPLE 21
Production of
4-methyl-2-[(3-oxo-3-phenyl-1-propen-1-yl)amino]-5-phenylthi-
ophene-3-carboxylic acid ethyl ester
[0267] From 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid
ethyl ester (1 g) and 3-methoxy-1-phenyl-2-propen-1-one (0.93 g),
the title compound (1.166 g) was obtained similarly as in Example
13.
[0268] m.p. 106-108.degree. C.
EXAMPLE 22
Production of
5-benzoyl-4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine
[0269] From the compound obtained in Example 21 (1 g), the title
compound (0.727 g) was obtained similarly as in Example 14.
[0270] m.p. 159-161.degree. C. (recrystallized from
acetonitrile).
EXAMPLE 23
Production of 5-
(4-methoxyphenyl)-4-methyl-2-[(4-methyl-3-oxo-1-penten-1--
yl)amino]thiophene-3-carboxylic acid ethyl ester
[0271] From
2-amino-5-(4-methoxyphenyl)-4-methylthiophene-3-carboxylic acid
ethyl ester [
[0272] m.p. 84-86.degree. C., obtained in a manner similar to that
described in WO 95/28405 (JP-A-8-295693)] (1 g), the title compound
(0.872 g) was obtained similarly as in Example 13.
[0273] m.p. 121-122.degree. C.
EXAMPLE 24
Production of
4-hydroxy-5-isobutyryl-2-(4-methoxyphenyl)-3-methylthieno[2,-
3-b]pyridine
[0274] From the compound obtained in Example 23 (0.5 g), the title
compound (0.327 g) was obtained similarly as in Example 14.
[0275] m.p. 129-133.degree. C.
EXAMPLE 25
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-methoxy-
phenyl)-3-methyl-4-oxothieno[2,3-b]pyridine
[0276] From the compound obtained in Example 24 (0.25 g), the title
compound (0.32 g) was obtained similarly as in Example 29 described
below.
[0277] m.p. 183-186.degree. C.
EXAMPLE 26
Production of
4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-(4-nitrop-
henyl)thiophene-3-carboxylic acid ethyl ester
[0278] 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic
acid ethyl ester [
[0279] m.p. 168-171.degree. C., obtained in a manner similar to
that described in WO 95/28405 (JP-A-8-295693)] was produced and the
resultant compound (2.95 g) was subjected to the similar method as
Example 13 to obtain the title compound (3.24 g, 83.4%).
[0280] m.p. 117-119.degree. C.
EXAMPLE 27
Production of
5-(4-isobutyrylaminophenyl)-4-methyl-2-[(4-methyl-3-oxo-1-pe-
nten-1-yl)amino]thiophene-3-carboxylic acid ethyl ester
[0281] From the compound obtained in the above Example 12 (2 g),
the title compound (2.43 g, 95.1%) was obtained similarly as in
Example 13.
[0282] m.p. 181-184.degree. C.
EXAMPLE 28
Production of
4-hydroxy-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methylt-
hieno[2,3-b]pyridine
[0283] The compound obtained in Example 27 (1.236 g) and
diphenylether (12 ml) were mixed and the mixture was heated under
reflux for 7 hours. After allowing to cool, the crystal
precipitated was recovered by a filtration, washed with
diisopropylether to obtain the title compound (0.798 g).
[0284] m.p. 247-249.degree. C.
EXAMPLE 29
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-isobuty-
rylaminophenyl)-3-methyl-4-oxothieno[2,3-b]pyridine
[0285] The compound obtained in Example 28 (1 g), potassium
carbonate (0.349 g) and N,N-dimethylformamide (5 ml) were mixed and
2,6-difluorobenzyl bromide (0.783 g) was added and the reaction
mixture was stirred at room temperature overnight (15 hours). The
reaction mixture was concentrated under reduced pressure to obtain
a residue, which was partitioned between ethyl acetate-methyl ethyl
ketone and water, and the aqueous layer was extracted with ethyl
acetate. The organic layers were combined and washed with a
saturated saline and then dried over anhydrous magnesium sulfate.
The residue obtained after concentration was washed with
diisopropylether to obtain the title compound (1.2 g, 91.0%).
[0286] m.p. 219-222.degree. C.
EXAMPLE 30
Production of
4,5,6,7-tetrahydro-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]be-
nzo[b]thiophene-3-carboxylic acid ethyl ester
[0287] From a commercially available ethyl
2-amino-4,5,6,7-tetrahydrobenzo- [b]thiophene-3-carboxylate (1 g),
the title compound (1.384 g) was obtained similarly as in Example
13.
[0288] m.p. 78-80.degree. C.
EXAMPLE 31
Production of
4,5,6,7-tetrahydro-1-hydroxy-2-isobutyryl[1]benzothiolo[2,3--
b]pyridine
[0289] From the compound obtained in Example 30 (1 g), the title
compound (0.645 g) was obtained similarly as in Example 14.
[0290] m.p. 156-159.degree. C.
EXAMPLE 32
Production of
4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-phenylthi-
ophene-3-carboxylic acid ethyl ester
[0291] 2-Amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl
ester [m.p. 93-95.degree. C., a compound obtained by a method
similar to that described in WO 95/28405 (JP-A-8-295693),
hereinafter the same is applied analogously.] (50 g),
1-methoxy-4-methyl-1-penten-3-one (31 g), p-toluenesulfonic acid
monohydrate (1.1 g) and toluene (500 ml) were mixed and the
reaction mixture was stirred at room temperature for 6 hours. The
reaction mixture was diluted with methyl ethyl ketone (170 ml), and
washed with a saturated aqueous solution of sodium
hydrogencarbonate, and the aqueous layer (wash) was extracted with
a 3:1 mixture (200 ml) of ethyl acetate and methyl ethyl ketone.
The organic layers were combined and washed with a saturated saline
(300 ml) and then dried over anhydrous magnesium sulfate (20 g).
The residue after concentration (precipitated crystal) was
triturated with hexane (300 ml) and the mixture was stirred at room
temperature for 1 hour and then with cooling at 10.degree. C. for
further 1 hour, and subsequently the crystal was recovered by a
filtration, washed with hexane (200 ml) which was cooled at
10.degree. C., and then dried in vacuo at 40.degree. C. for 5 hours
to obtain the title compound (60.2 g, 88.0%).
[0292] m.p. 104-108.degree. C.
EXAMPLE 33
Production of
4-hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridin- e
[0293] A compound obtained in an example,
4-methyl-2-[(4-methyl-3-oxo-1-pe-
nten-1-yl)amino]-5-phenylthiophene-3-carboxylic acid ethyl ether
(50 g) and diphenylether (500 ml) were mixed and the reaction
mixture was heated under reflux for 5.5 hours while removing the
ethanol, which was formed as the reaction proceeded, by means of a
distillation. After distilling diphenylether off under reduced
pressure followed by allowing to cool to about 100.degree. C., at
which time (before solidification), a water-containing 90% ethanol
(250 ml) was added and the mixture was heated under reflux for 30
minutes. After allowing the mixture to cool followed by stirring
with cooling on ice for 1 hour, the crystal precipitated was
recovered by a filtration, washed with an ice-cooled
water-containing 90% ethanol (200 ml), dried in vacuo at 40.degree.
C. for 5 hours to obtain the title compound (35.8 g, 82.2%).
[0294] m.p. 115-117.degree. C.
EXAMPLE 34
Production of
7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-o-
xo-2-phenylthieno[2,3-b]pyridine
[0295]
4-Hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine (35
g), potassium carbonate (18.6 g) and N,N-dimethylformamide (280 ml)
were mixed and 2,6-difluorobenzyl bromide (27.9 g) was added and
the reaction mixture was stirred at 40 to 50.degree. C. for 2
hours. The reaction mixture was treated dropwise with water (560
ml), and the mixture was stirred for 1 hour and then cooled on ice,
and then stirred further for 1 hour. The crude crystal was
recovered by a filtration, washed with water (about 1000 ml), dried
in air, suspended in a 1:1 solvent mixture (250 ml) of ethyl
acetate and diisopropylether, and then the mixture was stirred at
room temperature for 1 hour, and then stirred with cooling on ice
for 1 hour. The crystal obtained by a filtration was washed with
the same solvent mixture (180 ml), dried in vacuo at 40.degree. C.
for 5 hours to obtain the title compound (46.53 g, 94.6%).
[0296] m.p. 205-207.degree. C.
EXAMPLE 35
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-4-oxo-2-phenylthieno[2,3-b]pyridine
[0297]
7-(2,6-Difluorobenzyl-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phe-
nylthieno[2,3-b]pyridine (46 g), N-bromosuccinimide (22.5 g),
azobisisobutyronitrile (1.73 g) and ethyl acetate (460 ml) were
mixed and the reaction mixture was heated under reflux for 2 hours.
The reaction mixture was allowed to cool with stirring over a
period of 2 hours, and then stirred with cooling on ice for 1.5
hours, the precipitated crystal was recovered by a filtration, and
washed with a 1:1 solvent mixture (320 ml) of ice-cooled hexane and
ethyl acetate and water (300 ml), dried in vacuo at 40.degree. C.
for 6 hours to obtain the title compound (40.82 g, 75.2%).
[0298] m.p. 189-192.degree. C.
EXAMPLE 36
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-4-oxo-2-phenylthieno[2,3-b]pyridine
[0299]
7-(2,6-Difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-ph-
enylthieno[2,3-b]pyridine (10 g), N-bromosuccinimide (4.86 g),
2,2'-azobis(2,4-dimethylvaleronitrile (0.56 g) and methyl acetate
(100 ml) were mixed and the reaction mixture was heated under
reflux for 2 hours. The reaction mixture was allowed to cool with
stirring over a period of 2 hours, water (50 ml) was added and then
the mixture was stirred with cooling on ice for 1.5 hours. The
crystal precipitated was recovered by a filtration, washed with an
ice-cooled methyl acetate (30 ml) and water (30 ml), dried in vacuo
at 40.degree. C. for 6 hours to obtain the title compound (10.61 g,
87.1%).
[0300] m.p. 189-192.degree. C.
EXAMPLE 37
Production of
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyry-
l-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine
[0301]
3-Bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxo-
-2-phenylthieno[2,3-b]pyridine (40 g) was dissolved in
methanesulfonic acid (200 ml) with cooling at 13 to 15.degree. C.
and then treated dropwise with a solution of sodium nitrate (6.59
g) in methanesulfonic acid (100 ml) over a period of 1 hour. The
mixture was stirred as it was for 2.5 hours, and then poured into a
cool water (2800 ml), and the crystal precipitated was recovered by
a filtration, washed with water until the pH of the wash became 5
to 6, and then dried in vacuo at 50.degree. C. for 24 hours. The
rude crystal thus obtained was suspended in ethyl acetate (300 ml),
and the reaction mixture was stirred at 50.degree. C. for 1 hour
and then with cooling on ice for 1 hour, and the crystal was
recovered by a filtration, washed with a cooled ethyl acetate (100
ml), dried in vacuo at 40.degree. C. for 5 hours to obtain the
title compound (32.4 g, 74.5%).
[0302] m.p. 202-204.degree. C.
EXAMPLE 38
Production of
3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7--
dihydro-5-isobutyryl-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine
[0303]
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4--
nitrophenyl)-4-oxothieno[2,3-b]pyridine (32 g),
N,N-dimethylformamide (64 ml) and N-ethyldiisopropylamine (8.84 g)
were mixed and treated dropwise with N-methylbenzylamine (8.29 g)
with cooling on ice, and the reaction mixture was stirred at 30 to
40.degree. C. for 5 hours. The reaction mixture was poured into a
mixture of a solution of potassium carbonate (9.5 g) in water (320
ml) and diisopropylether (320 ml) and the reaction mixture was
stirred at room temperature for 2 hours and then with cooling on
ice for 1 hour, and the crystal precipitated was recovered by a
filtration, washed with water (600 ml) and diisopropylether (160
ml), dried in vacuo at 50.degree. C. for 4 hours to obtain the
title compound (33.58 g, 97.9%).
[0304] m.p. 158-162.degree. C.
EXAMPLE 39
Production of
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-di-
fluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine
fumarate
[0305]
3-(N-Benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-
-5-isobutyryl-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine (33 g),
iron powder (12.3 g) and ethanol (132 ml) were mixed and treated
dropwise with concentrated hydrochloric acid (55.5 g) diluted with
water (19 ml) over a period of 2 hours with cooling on ice, and the
reaction mixture was stirred as it was for 2 hours. The reaction
mixture was poured into a solution of sodium hydrogencarbonate
(55.3 g) in water (450 ml) and the mixture was stirred for 1 hour
together with ethyl acetate (825 ml), and filtered through a Hyflo
Super Cell to remove insoluble materials. The aqueous layer was
extracted with ethyl acetate (500 ml) and then the organic layers
were combined, and washed with a saturated saline (1000 ml), dried
over anhydrous magnesium sulfate (35 g) and then concentrated into
dryness to obtain a crude product of
2-(4-aminophenyl)-3-(N-benzyl-N-
-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxot-
hieno[2,3-b]pyridine (32.3 g). This was dissolved in methanol (200
ml) and admixed with a solution of fumaric acid (6.56 g) in
methanol (200 ml) and the mixture was concentrated under reduced
pressure to about 150 g. The precipitated suspension thus obtained
was diluted with ethyl acetate (300 ml) and the mixture was stirred
at room temperature for 1 hour and then the crystal was recovered
by a filtration. After washing with ethyl acetate (200 ml) followed
by drying in vacuo at 50.degree. C. for 3 hours, the title compound
(33.38 g, 88.5%) was obtained.
[0306] m.p. 222-225.degree. C.
EXAMPLE 40
Production of
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-di-
fluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine
trimethanesulfonate
[0307] From the crude product of
2-(4-aminophenyl)-3-(N-benzyl-N-methylami-
nomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3--
b]pyridine obtained in Example 39 (500 mg) and methanesulfonic acid
(168 mg), the title compound (619 mg, 82.3%) was obtained similarly
as in Example 39. However, as a solvent, ethanol was used instead
of methanol.
[0308] m.p. 131-135.degree. C.
EXAMPLE 41
Production of
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-di-
fluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine
oxalate
[0309] From the crude product of
2-(4-aminophenyl)-3-(N-benzyl-N-methylami-
nomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3--
b]pyridine obtained in Example 39 (500 mg) and oxalic acid (79 mg),
the title compound (499 mg, 82.6%) was obtained similarly as in
Example 40.
[0310] m.p. 159-163.degree. C.
EXAMPLE 42
Production of 2-(4-aminophenyl)-3-
(N-benzyl-N-methylaminomethyl)-7-(2,6-d-
ifluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine
malonate
[0311] From the crude product of
2-(4-aminophenyl)-3-(N-benzyl-N-methylami-
nomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3--
b]pyridine obtained in Example 39 (500 mg) and malonic acid (91
mg), the title compound (533 mg, 90.2%) was obtained similarly as
in Example 40.
[0312] m.p. 144-146.degree. C.
EXAMPLE 43
Production of
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-di-
fluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine
succinate
[0313] From the crude product of
2-(4-aminophenyl)-3-(N-benzyl-N-methylami-
nomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3--
b]pyridine obtained in Example 39 (500 mg) and succinic acid (103
mg), the title compound (573 mg, 95.0%) was obtained similarly as
in Example 40.
[0314] m.p. 183-188.degree. C.
EXAMPLE 44
Production of
2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-di-
fluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine
oxalate.
[0315] From the crude product of
2-(4-aminophenyl)-3-(N-benzyl-N-methylami-
nomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3--
b]pyridine obtained in Example 39 (500 mg) and malic acid (117 mg),
the title compound (545 mg, 88.3%) was obtained similarly as in
Example 40.
[0316] m.p. 169-174.degree. C.
[0317] The chemical structures of the compounds obtained in the
above Examples 13 to 15 and 19 to 31 are shown in Table 2 to Table
4.
2TABLE 2 49 Ex. No. R.sup.1 R.sup.2 R.sup.3 13 methyl phenyl
isopropyl 19 methyl phenyl methyl 21 methyl phenyl phenyl 23 methyl
4-methoxyphenyl isopropyl 26 methyl 4-nitrophenyl isopropyl 27
methyl 4-isobutyrylaminophenyl isopropyl 30 50 isopropyl
[0318]
3TABLE 3 51 Ex. No. R.sup.1 R.sup.2 R.sup.3 14 methyl phenyl
isopropyl 20 methyl phenyl methyl 22 methyl phenyl phenyl 24 methyl
4-methoxyphenyl isopropyl 28 methyl 4-isobutyrylaminophenyl
isopropyl 31 52 isopropyl
[0319]
4TABLE 4 53 Ex. No. R.sup.22 15 hydrogen 25 methoxy 29
isobutyrylamino
[0320] Industrial Applicability
[0321] According to the present invention, an intermediate for a
thienopyridine derivative useful as a GnRH antagonist can be
produced at a high yield.
[0322] Thus, by haloganating the hydrocarbon in the 3-position of a
thienopyridine derivative followed by nitrating, the use of carbon
tetrachloride which has been essential can be avoided, and a nitro
form can safely be produced under a gentle condition.
[0323] By converting a compound having a carboxylic acid in the
5-position of a thienopyridine derivative into an acid amide
derivative which was then converted into a ketone body, the use of
a dangerous trimethylaluminum can be avoided, and a target product
can safely be produced.
[0324] Also according to the invention,
5-acyl-4-hydroxythieno[2,3-b]pyrid- ine skeleton useful as an
intermediate for a pharmaceutical can be produced in a simple
process at a high yield.
* * * * *