Thienopyridine derivatives, their production and use

Details Thienopyridine derivatives, their production and use Thienopyridine derivatives, their production and use

2002-08-22

2003-11-25

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S232800, C514S291000, C514S278000, C546S080000, C546S089000, C544S126000

Reexamination Certificate

active

06653476

ABSTRACT:

This application is the National Phase filing of International Patent Application No. PCT/JP01/01483, filed Feb. 28, 2001.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel thienopyridine derivatives or salts thereof, which have anti-inflammatory activity, bone resorption suppressive activity, immune cytokine production suppressive activity, etc., and are useful as medicaments such as anti-arthritis drugs, etc., and to their production and use.
PRIOR ART
Arthritis is an inflammatory disease of joints, which includes, as major diseases, rheumatoid arthritis and related diseases with inflammation observed in joints.
Among them, rheumatoid arthritis, also called chronic rheumatoid arthritis, is a chronic polyarthritis that is characterized by inflammatory changes in the synovia in the internal capsules of joints as the major lesion. Arthritis such as rheumatoid arthritis is a progressive disease, which brings about joint dysfunctions such as joint deformity, arthrokleisis, and the like, and often leads to serious disability if it is exacerbated without being treated effectively.
Heretofore, drugs available for treating these arthritides have been steroids such as corticosteroids (e.g., cortisone, etc.), non-steroidal anti-inflammatory drugs (e.g., aspirin, piroxicam, indomethacin, etc.), gold compounds (e.g., aurothiomalate, etc.), antirheumatic drugs (e.g., chloroquine preparation, D-penicillamine, etc.), gout suppressants (e.g., colchicines, etc.), immunosuppressants (e.g., cyclophosphamide, azathioprine, methotrexate, levamisole, etc.) and the like. However, some of these drugs have been problematic such as serious adverse reactions, adverse reactions precluding a long-term administration, insufficient efficacy, lack of effect on established arthritis or the like.
Thienopyridine derivatives or thienodipyridine derivatives have been reported as anti-inflammatory drugs, especially as remedies for arthritis, in JP 8-225577 A (PCT International Application Publication No. WO96/14319); JP 10-36374 A (PCT International Application Publication No. WO97/40050), and PCT International Application Publication No. WO97/65916 and the like.
OBJECTS OF THE INVENTION
Medicaments with superior prophylactic and therapeutic efficacy against arthritis and the like have been still desired for the clinical treatment of arthritis and the like.
SUMMARY OF THE INVENTION
Under these circumstances, the present inventors have studied intensively and, as a result, the present inventors have found that novel thienopyridine derivatives, which are represented by the following formula (I) and are characteristic in ring B and group G in the 3-position, are useful as suppressants of joint destruction by possessing potent anti-inflammatory activity, in particular antiarthritic activity, are useful as bone resorption suppressants by possessing the excellent bone resorption suppressing activity with direct effect on the bone, and further are useful as immunosuppressants. The present inventors have further studied based on these findings. Thus the present invention has been completed.
That is, the present invention relates to:
(1) A compound represented by the formula (I):
wherein G represents a halogen atom, hydroxyl group, an optionally substituted amino group, an optionally substituted lower alkyl group or an optionally substituted alkoxy group; alk represents an optionally substituted lower alkylene group; X represents oxygen atom, an optionally oxidized sulfur atom, or —(CH
2
)
q
— (q represents an integer of 0 to 5); R represents an optionally substituted amino group or an optionally substituted heterocyclic group; ring B represents an optionally substituted Y-containing 5- to 8-membered ring whose ring constituent atoms contain no nitrogen atom; Y represents oxygen atom, an optionally oxidized sulfur atom,
(wherein Ra and Rb are the same or different and, respectively, represent hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group, or Ra and Rb may be combined each other to form a 5- to 7-membered ring; and Rc represents hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, or an optionally substituted heterocyclic group); and ring A represents an optionally substituted benzene ring, or a salt thereof;
(2) The compound according to the above (1), wherein alk is methylene;
(3) The compound according to the above (1), wherein G is a halogen atom;
(4) The compound according to the above (1), wherein G is chlorine atom;
(5) The compound according to the above (1), wherein X is —(CH
2
)
q
— (q represents an integer of 0 to 5);
(6) The compound according to the above (1), wherein X is a bond;
(7) The compound according to the above (1), wherein the optionally substituted amino group represented by R is —N(R
1
) (R
2
) (wherein R
1
and R
2
, which may be the same or different, respectively, represent hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted acyl, sulfonyl, sulfinyl, or heterocyclic group, or R
1
and R
2
may be combined each other to form an optionally substituted nitrogen-containing 5- to 7-membered heterocyclic group);
(8) The compound according to the above (7), wherein R
1
and R
2
are combined each other to form a nitrogen-containing optionally substituted 5- to 7-membered heterocyclic group;
(9) The compound according to the above (7), wherein R
1
and R
2
are acyl groups;
(10) The compound according to the above (1), wherein R is an optionally substituted nitrogen-containing heterocyclic group;
(11) The compound according to the above (1), wherein the substituent on the optionally substituted heterocyclic group represented by R is oxo group;
(12) The compound according to the above (1), wherein R is
wherein ring C represents a 5- to 7-membered heterocyclic group optionally containing one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms, in addition to the nitrogen atom;
(13) The compound according to the above (1), wherein ring B is an optionally substituted 6-membered ring containing Y;
(14) The compound according to the above (1), wherein the substituents on ring B are one to four substituents selected from a C
1-6
alkyl group and a halogen atom;
(15) The compound according to the above (1), wherein ring B is a ring represented by the formula:
wherein Y′ and Y″ represent carbon atom, sulfur atom or oxygen atom, respectively; n represents an integer of 0 to 4; and Y is as defined in the above 1, which may be substituted with one to four substituents selected from a C
1-6
alkyl group and a halogen atom;
(16) The compound according to the above (1), wherein Y is an optionally oxidized sulfur atom or
(17) The compound according to the above (1), wherein ring A is benzene ring which may be substituted with one to four substituents selected from a halogen atom, nitro group, an optionally substituted alkyl group, an optionally substituted hydroxyl, an optionally substituted thiol group, an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group, and an optionally substituted aromatic ring group;
(18) The compound according to the above (1), wherein the substituent on ring A is a C
1-6
alkoxy group or hydroxyl group;
(19) The compound according to the above (1), wherein the compound represented by

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