Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-23
2001-04-10
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S083000
Reexamination Certificate
active
06214838
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP99/03155, filed on Jun. 14, 1999.
TECHNICAL FIELD
The present invention relates to a new thienodipyridine derivative which shows anti-inflammatory activity, bone resorption inhibitory activity and activity on inhibiting production of immunocytokines and which is useful as a therapeutic agent for arthritis, or a salt thereof, production thereof and use thereof.
BACKGROUND ART
Arthritis, an inflammatory disease of the joint, occurs in various forms such as rheumatoid arthritis and in related diseases with joint inflammation.
Rheumatoid arthritis, also called chronic rheumatoid arthritis, in particular, is a chronic multiple arthritis characterized by inflammatory changes in the synovial membrane of the particular capsule inner layer. Arthritis like rheumatoid arthritis are progressive and cause joint disorders such as deformation and acampsia, often resulting in severe physical disorders due to a lack of effective treatment and subsequent deterioration.
Traditionally, these forms of arthritis have been chemotherapeutically treated with various agents, including steroids and other adrenocortical hormones (e.g., cortisone), non-steroidal anti-inflammatory agents (e.g., aspirin, piroxicam, indomethacin), gold agents (e.g., auro-thiomalate), antirheumaticagents (e.g., chloroquine preparations, D-penicillamine), anti-gout agents (e.g., colchicine), and immunosuppressors (e.g., cyclophosphamide, azathioprine, methotrexate, levamisole).
Japanese laid-open Publication No. 10-36374 (1998) or PCT International Application Laid-Open No. WO97/40050 show thienopyridine derivatives or thienodipyridine, derivatives as an anti-inflammatory agent, especially as a therapeutic agent for arthritis.
However, steroids such as adrenocortical hormones and non-steroidal anti-inflammatory agents have drawbacks such as severe adverse reactions and adverse reactions hampering the drug's long-term use.
Although thienopyridine derivatives and thienodipyridine derivatives concretely disclosed in Japanese laid-open Publication No. 10-36374 (1998) or PCT International Application Laid-Open No. WO97/40050 have an anti-inflammatory activity, and especially therapeutical effect for arthritis, they tend to be affected by the metabolism of the body, so that, ratio of non-metabolized form of these derivatives in a body also tends to be lower.
Accordingly, there is a need for the development of a drug which is stable to metabolism by the body and exhibits excellent anti-inflammatory activity, bone resorption inhibitory activity and activity in inhibiting production of immunocytokines.
DISCLOSURE OF INVENTION
The present inventors studied in accordance with the above states, and found that thienodipyridine derivatives having succinimidomethyl group at the 2-position and non-substituted or alkanoyl group as a protective group at the 7-position show strong anti-inflammatory activity, especially anti-arthritic activity, and that these derivatives are stable to metabolism by the body. The inventors made investigations based on these findings, and developed the present invention.
The present invention relates to
(1) a compound of the formula (I):
wherein R is hydrogen or C
2-6
alkanoyl; X is halogen; and ring A is benzene ring which is optionally substituted by 1 to 4 substituents selected from {circle around (1)} halogen, {circle around (2)} hydroxy, {circle around (3)} C
1-6
alkoxy optionally substituted by halogen or phenyl, {circle around (4)} C
1-6
alkylthio optionally substituted by halogen or phenyl, {circle around (5)} C
1-6
alkyl optionally substituted by halogen, {circle around (6)} C
2-6
alkanoylamino or {circle around (7)} carboxy optionally esterified by C
1-6
alkyl, or a salt thereof;
(2) a compound of the above (1) wherein R is hydrogen;
(3) a compound of the above (1) wherein ring A is benzene ring which is optionally substituted by 1 to 2 substituents selected from {circle around (1)} hydroxy, {circle around (2)} C
1-6
alkoxy optionally substituted by halogen or {circle around (3)} C
1-6
alkylthio optionally substituted by halogen;
(4) a compound of the above (1) wherein R is hydrogen; and ring A is benzene ring which is optionally substituted by 1 to 2 substituents selected from {circle around (1)} C
1-6
alkoxy optionally substituted by halogen or {circle around (2)} C
1-6
alkylthio optionally substituted by halogen;
(5) a compound of the above (1) wherein R is hydrogen; X is chlorine; and ring A is benzene ring which is optionally substituted by 1 to 2 C
1-6
alkoxy groups, or a salt thereof;
(6) a compound of the above (5) wherein ring A is benzene ring substituted by C
1-6
alkoxy group at the 4-position and optionally substituted by C
1-6
alkoxy group at the other position;
(7) a compound of the above (1) wherein R is hydrogen; X is chlorine; and ring A is benzene ring which is optionally substituted by 1 to 2 methoxy groups;
(8) a compound of the above (1) wherein R is C
2-6
alkanoyl; and ring A is benzene ring which is optionally substituted by 1 to 2 substituents selected from {circle around (1)} hydroxy, {circle around (2)} C
1-6
alkoxy optionally substituted by halogen or {circle around (3)} C
1-6
alkylthio optionally substituted by halogen;
(9) a pro-drug of the compound of the above (1);
(10) 3-chloro-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, 3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, or a salt thereof;
(11) 3-chloro-4-(4-ethoxyphenyl)-5,6,7,8-tetrahydro-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, 3-bromo-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, or a salt thereof;
(12) 7-acetyl-3-chloro-5,6,7,8-tetrahydro-4-(4-hydroxy-3-methoxyphenyl)-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, 7-acetyl-3-chloro-5,6,7,8-tetrahydro-4-(4-hydroxyphenyl)-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, or a salt thereof;
(13) 7-acetyl-3-chloro-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, 7-acetyl-3-chloro-4-(4-ethoxyphenyl)-5,6,7,8-tetrahydro-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, 7-acetyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(succinimidomethyl)thieno[2,3-b:5,4-c′]dipyridine, or a salt thereof;
(14) a method for production of a compound of the formula (I-2):
wherein X is halogen atom; and ring A is benzene ring which is optionally substituted by 1 to 4 substituents selected from {circle around (1)} halogen, {circle around (2)} hydroxy, {circle around (3)} C
1-6
alkoxy optionally substituted by halogen or phenyl, {circle around (4)} C
1-6
alkylthio optionally substituted by halogen or phenyl, {circle around (5)} C
1-6
alkyl optionally substituted by halogen, By {circle around (6)} C
2-6
alkanoylamino or {circle around (7)} carboxyl optionally esterified by C
1-6
alkyl, or a salt thereof,
which comprises subjecting a compound of the formula:
wherein M is a protective group of a nitrogen atom; the other symbols are the same defined above, or a salt thereof, to deprotection;
(15) a method for production of a compound of the formula (I-3):
wherein R
1
is C
2-6
alkanoyl; X is halogen; ring A is benzene ring which is optionally substituted by 1 to 4 substituents selected from {circle around (1)} halogen, {circle around (2)} hydroxy, {circle around (3)} C
1-6
alkoxy optionally substituted by halogen or phenyl, {circle around (4)} C
1-6
alkylthio optionally substituted by halogen or phenyl {circle around (5)} C
1-6
alkyl optionally substituted by halogen {circle around (6)} C
2-6
alkanoylamino or {circle around (7)} carboxyl optionally esterified by C
1-6
alkyl, or a salt thereof,
which comprises subjecting a compound of the formula (I-2):
wherein each a symbol is the same defined above, or a salt thereof, to acy
Baba Atsuo
Makino Haruhiko
Sohda Takashi
Yamane Taihei
Chao Mark
Huang Evelyn Mei
Riesen Philippe Y.
Takeda Chemical Industries Ltd.
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