Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-07-01
2000-08-22
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514409, 514410, 514413, A01N 4338, A61K 3140
Patent
active
061073288
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel method of medical treatment, in particular the treatment and prevention of angina.
EPA 0 533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HT.sub.1D receptor antagonist activity. These compounds are said to be of use in the treatment of various CNS disorders.
The 5HT.sub.1D.beta. receptor has now been reclassified as the 5HT.sub.1B receptor (P. R. Hartig et al Trends in Pharmacological Science, 1996, 17, 103-105. It has now been found that 5-HT.sub.1B receptors are present in smooth muscle. It is expected, as a consequence, that compounds which exhibit 5-HT.sub.1B antagonist activity will be useful in treating vascular disease such as angina, Raynaud's syndrome, peripheral vascular disease and portal hypertension.
The present invention therefore provides, in a first aspect, the use of a compound having 5-HT.sub.1B antagonist activity in the treatment of vascular disease. Preferred compounds are those which are selective for the 5-HT.sub.1B receptor.
Preferred 5-HT.sub.1B antagonists include those compounds disclosed in WO 96/1947, that is to say, compounds of formula (I): ##STR1## in which R.sup.1 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, COC.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, hydroxyC.sub.1-6 alkyl, hydroxyC.sub.1-6 alkoxy, C.sub.1-6 alkoxyC.sub.1-6 alkoxy, acyl, nitro, trifluoromethyl, cyano, SR.sup.9, SOR.sup.9, SO.sub.2 R.sup.9, SO.sub.2 NR.sup.10 R.sup.11, CO.sub.2 R.sup.10, NR.sup.10 SO.sub.2 R.sup.11, CONR.sup.10 R.sup.11, CO.sub.2 NR.sup.10 R.sup.11, CONR.sup.10 (CH.sub.2).sub.p CO.sub.2 R.sup.11, (CH.sub.2 .sub.p NR.sup.10 R.sup.11, (CH.sub.2).sub.p CONR.sup.10 R.sup.11, (CH.sub.2).sub.p NR.sup.10 COR.sup.11, (CH.sub.2).sub.p CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.p OR.sup.10, CONHNR.sup.10 R.sup.11, NR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, NR.sup.10 CO(CH.sub.2).sub.p NR.sup.10 R.sup.11, NR.sup.10 CONR.sup.10 R.sup.11, CR.sup.10 .dbd.NOR.sup.11, CNR.sup.10 .dbd.NOR.sup.11, where R.sup.9, R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl and p is 1 to 4; or R.sup.1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkylOC.sub.1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.14 are independently hydrogen or C.sub.1-6 alkyl or A is (CR.sup.13 R.sup.14 .sub.r -D where r is 0, 1, 2 or 3 and D is oxygen, sulphur or CR.sup.13 .dbd.CR.sup.14. R.sup.17 are independently hydrogen or C.sub.1-6 alkyl or B is S(O).sub.b where b is 0, 1 or 2;
Particularly preferred compounds of formula (I) include 1'-methyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbon yl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine.
Other preferred compounds of the invention include the 5-HT.sub.1D antagonists generically and specifically dissolved in WO 95/04729, WO 95/06044, WO95/06644, WO 95/06637, WO 95/11243, WO 95/17401, WO 95/17398, PCT/EP95/0090, PCT/EP95/03226, in particular WO 95/15954, PCT/EP95/01578 and PCT/EP95/01890..
Further preferred compounds of the invention include the 5-HT.sub.1B antagonists generically and specifically disclosed in EPA 0 533 266/7/8, GB 2 276 160, GB 2 276 161, GB 2 276162, GB 2 276 163, GB 2 276 164, GB 2 276 165, GB 2 273 930, and WO 94/15920.
Certain compounds exhibiting 5-HT.sub.1B antagonist activity are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention.
Compounds exhibiting 5-HT.sub.1B antagonist activity are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mi
REFERENCES:
patent: 4814346 (1989-03-01), Albert et al.
:Leonard, B. E., "Sub-types of serotonin receptors: biochemical changes and pharmacological consequences", International Clinical Psychopharmacology, 7, pp. 13-21, 1992.
Hartig, et al., TiPS; vol. 17, 1996, pp. 103-105.
Jones Dwayne C.
Kanagy James M.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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