Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-07-25
1996-12-03
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514379, 514438, 514445, 514446, 514448, 514452, 514471, 514617, 548247, 548248, 548240, 548241, 549 62, 549 65, 549 70, 549 72, 549 76, 549362, 549475, 549479, 549487, 549495, 564182, 564183, A61K 3141, C07D26106
Patent
active
055808930
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP92/01419 filed Nov. 2, 1992.
TECHNICAL FIELD
The present invention relates to nitroxyalkylamide derivatives and pharmaceutically acceptable salts thereof having excellent vasodilator activity for the collateral vessels and anti-anginal action.
BACKGROUND ART
At present, nitroglycerin is most frequently used clinically as a therapeutic agent for cardiovascular diseases, particularly for angina pectoris.
This agent, however, has some faults such as being susceptible to undergoing the first-pass effect and having a short duration of action. Furthermore, side effects occur, such as headache and dizziness and tachycardia caused by hypotension. Against this background, therapeutic agents for angina pectoris which undergo no first-pass effect and have fewer side effects during clinical treatment have been desired.
Nitroxyalkylamide derivatives having anti-anginal action have been disclosed, for example, in U.S. Pat. No. 4200640 and Japan Kokai Hei 2-134316. However, in the latter Kokai, there is no specific description.
DISCLOSURE OF INVENTION
The present inventors have eagerly studied for many years the synthesis of nitroxy compounds and the pharmacological actions thereof.
As a result, they have found that compounds having a nitroxyalkylamide group have excellent vasodilator action on the collateral vessels, have fewer side effects and are useful as therapeutic agents for angina pectoris; they thus completed the present invention.
CONSTITUTION OF INVENTION
The present invention relates to nitroxyalkylamide derivatives having the general formula: (which may be optionally substituted or optionally condensed with a phenyl ring) containing from 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; a 5- or 6-membered heterocyclic-oxy group (which may be optionally substituted or optionally condensed with a phenyl ring) containing from 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; an optionally substituted C.sub.6 -C.sub.10 aryloxy group; or an optionally substituted C.sub.6 -C.sub.10 arylthio group (the substituents are selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups; C.sub.1 -C.sub.4 alkoxy groups; phenyl groups optionally substituted with a C.sub.1 -C.sub.4 alkyl group, with a C.sub.1 -C.sub.4 alkoxy group, or with halogen atom(s); halogen atoms; hydroxy groups; amino groups; mono- or di-C.sub.1 -C.sub.4 alkylamino groups; and nitro groups); A represents a C.sub.1 -C.sub.4 alkylene group; B' represents a C.sub.1 -C.sub.4 alkylene group; and n represents 0 or 1; heterocyclic group (which may be optionally substituted or optionally condensed with a phenyl ring) containing from 1 to 2 hetero-atoms selected from the group consisting of oxygen and sulfur atoms; a 5- or 6-membered heterocyclic-oxy group (which may be optionally substituted or optionally condensed with a phenyl ring) containing from 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; an optionally substituted C.sub.6 -C.sub.10 aryloxy group; or an optionally substituted C.sub.6 -C.sub.10 arylthio group] agent for angina pectoris comprising the nitroxyalkylamide derivatives or pharmaceutically acceptable salts thereof mentioned above as an active ingredient: and preparation of the nitroxyalkylamide derivatives or pharmaceutically acceptable salts thereof mentioned above.
The 5- or 6-membered heterocyclic group (which may be optionally substituted or optionally condensed with a phenyl ring) containing from 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms; or the heterocyclic moiety in a 5- or 6-membered heterocyclic-oxy group (which may be optionally substituted or optionally condensed with a phenyl ring) containing from 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, each represented by R.sup.1, may be a saturated or unsaturated heterocyclic group and includes, for example, the
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CA 116:46294r Antiasthmatic . . . salts. Mori et al., pp. 316-317, 1992.
CA 117:26555u Thiazolidine derivatives. Bron et al., p. 718, 1992.
Chemical Abstracts, vol. 89, No. 1, 3 Jul. 1978, Columbus, Ohio, abstract No 6236r, H. Nagano et al, "N-(Hydroxyalkyl)pyridinecarboxamide nitrate esters" p. 534, col. 1 of JP-A-78 009 775 (Chugai Pharmaceutical Co., Ltd.).
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Chemical Abstracts, vol. 106, No. 21, 25 May 1987, Columbus, Ohio, abstract No. 176137w, H. Nagano et al, "Synthesis of 4-nitro-and 5-nitro-N-(2-nitroxyethyl)nicotinamide", p. 705, col. 1, & Yakugaku Zasshi, vol. 106, No. 10, 1986, pp. 872-877.
Chemical Abstracts, vol. 114, No. 7, 18 Feb. 1991, Columbus, Ohio, abstract No. 61947h., M. Tsujimoto, "Preparation of pyridincarboxamido)alcohol esters with nitric acid as coronary vasodilators", p. 674, col. 2, of JP-A-02 207 072 (Sagami Chemical Research Centre).
Chemical Abstracts, vol. 111, No. 17, 23 Oct. 1989, Columbus, Ohio, abstract No. 153840j, Y Ito et al, "Preparation of 2-(pyrazine-2-carboxamido)ethyl, nitrate as a vasodilator", p. 729, col. 2 of JP-A-01 056 667 (Hokuriku Pharmaceutical Co. Ltd.).
Chemical Abstracts, vol. 108 No. 17, 25 Apr. 1988, Columbus, Ohio, abstract No. 150164u, H. Nagano et al, "Preparation of (nitroxyethyl)nicotinamide derivatives for treatment of angina pectoris", p. 714, col. 2 of JP-A-62 286 968 (Chugai Pharmaceutical Co., Ltd.).
Ishihara Sadao
Kataoka Mitsuru
Koike Hiroyuki
Miyake Shigeki
Mizuno Hiroshi
McKane Joseph K.
Sankyo Company Limited
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