Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-12-27
1998-05-05
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514212, 514213, 514215, 514217, 5142282, 5142288, 5142328, 5142338, 5142345, 5142352, 5142355, 5142358, 514301, 514258, 514267, 514291, 514292, 546 80, 546 83, 546114, 546 89, 544253, 544117, 544127, A61K 3154, A61K 31535, C07D40102, C07D40302
Patent
active
057474869
DESCRIPTION:
BRIEF SUMMARY
This is a national phase application, filed under U.S.C. .sctn. 371 of PCT/JP95/02271, filed Nov. 7, 1995.
TECHNICAL FIELD
This invention relates to a novel thienopyridine or a novel thienopyrimidine derivative or a salt thereof, which is useful as an anti-inflammatory agent, especially a therapeutic agent of arthritis, and which is useful as a prophylactic or therapeutic agent against osteoporosis.
BACKGROUND ART
Arthritis is an inflammatory disease of the joint, and, as principal diseases, are mentioned rheumatoid arthritis and related diseases with joint inflammation.
Among them, especially rheumatoid arthritis, also called chronic arthrorheumatism, is a chronic multiple arthritis characterized by inflammatory changes in the synovial membrane of the articular internal capsule layer. Arthritic diseases like rheumatoid arthritis are progressive and cause joint disorders such as deformation and ankylosis, often resulting in severe physical disorder due to lack of effective treatment and subsequent deterioration.
Traditionally, these forms of arthritis have been chemotherapeutically treated with various agents, including steroids such as cortisone and other adrenocortical hormones; non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin; gold agents such as aurothiomalate; anti-rheumatic agents such as chloroquine preparations and D-penicillamine; antipodagric agents such as colchicine; and immnunosuppressors such as cyclophosphamide, azathiopurine, methotrexate and levamisole.
However, these drugs have drawbacks such as severe adverse reactions, adverse reactions hampering the drug's long-term use, lack of sufficient efficacy and a failure to be effective against already-occurring arthritis.
Accordingly, development of a drug performing excellent prophylactic/therapeutic action on arthritis with low toxicity has still been desired from the clinical viewpoint.
Traditionally, various compounds have been synthesized as Bull. Chem. Soc. Jpn., 61, 4431 (1988), Chem. Pharm. Bull., 36, 4389 (1988), Phosphorus, Sulfur, and Silicon, 73, 127 (1992), Chem. Pharm. Bull., 40, 1376 (1992), and Khim. Geterotsikl. Soedin., 1, 124 (1987). In those compounds, the substituent at 6-position of the description of anti-inflammatory activities is given on these known thienopyridine derivatives. In Journal fuer praktische Chemie, 317, 705 group or acetoxymethyl group at 2-position is described. And, in Japanese derivatives having carboxylethyl group at 2-position. However, there has been no report of any derivative having a carbon chain substituted with heterocyclic group or amino group at 2-position of these activity of bone resorption is given on these known thienopyridine or thienopyrimidine derivatives.
DISCLOSURE OF INVENTION
The present inventors found that the novel thienopyridine or thienopyrimidine derivatives represented by the formula (I): ##STR1## have anti-arthritic activity and are useful as a joint. destruction suppressor and have inhibitory activity of bone resorption and are useful as a prophylactic or therapeutic agent against osteoporosis, and accomplished the present invention.
More specifically, the present invention relates to:
(1) A compound represented by the formula (I): ##STR2## wherein R.sup.1 and R.sup.2 independently stand for a hydrogen atom, a halogen atom or an optionally substituted alkyl group, or R.sup.1 and R.sup.2 may be combined to form a 5- to 7-membered ring; Y stands for a nitrogen atom or C-G, G stands for an optionally esterified carboxyl group; X stands for an oxygen atom, an optionally oxidized sulfur atom or --(CH.sub.2).sub.q -- (q denotes an integer of 0 to 5); R stands for an optionally substituted heterocyclic group or an optionally substituted amino group; and ring A may optionally be substituted, or a salt thereof.
(2) The compound of above item (1), wherein the optionally substituted alkyl group for R.sup.1 or R.sup.2 is independently a straight-chain or branched-chain C.sub.1-6 alkyl group; the optionally substituted 5- to 7-membered ring fo
REFERENCES:
Attaby et al., "Reactions with Cyanothioacetamide Derivatives: Synthesis Sulfur and Silicon, vol. 73:127-135, (1992).
Elgemeie et al., ".alpha.,.beta.-Unsaturated Nitriles in Heterocyclic Derivative", Bull. Chem. Soc. Jpn., vol. 61:4431-4433, (1988).
Adachi et al., "Studies on Dihydrophyridines. III. Synthesis of Activities", Chem. Pharm. Bull., vol. 36(11):4389-4402, (1988).
Toulhoat et al., "Complexes Macrocycliques Organophosphores du Palladium II, P-Alkyles et a Ponts Satures et Insatures", Phosphorus, Sulfur, and Silicon, vol. 71:127-138, (1992).
Ueno et al., "Electrochemical Oxidation of Methyl dine-5-carboxylate, a New Type of Dihydropyridine Calcium Blocker," Chem. Pharm. Bull., vol. 40(6):1376-1382 (1992).
A. A. Kpayse et al., Khim. Geterotsikl. Soedin., vol. 1:124-128 (1987). Journal fur praktische Chemie, vol. 317:705-711, (1975).
Nakanishi et al., "Studies on Psychotropic Drugs. Synthesis and diazepin-e-ones", Journal of Medicinal Chemistry, vol. 16(3):214-219 (1973).
Tinney et al., "Synthesis and Pharmacological Evaluation of Chemistry, vol. 17(6):624-630, (1974).
Baba Atsuo
Makino Haruhiko
Sohda Takashi
Grumbling Matthew V.
Takeda Chemical Industries
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