Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-02
1999-10-26
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514215, 514409, 540543, 546 17, 548409, A61K 31435, C07D47120
Patent
active
059729511
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel piperidine derivatives, processes for their preparation, and pharmaceutical compositions containing them.
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.
A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HT.sub.1D antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt or N-oxide thereof: ##STR2## 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.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.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl; 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;
C.sub.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Suitably 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. preferred groups include cyano, COC.sub.1-6 alkyl, CR.sup.10 .dbd.NOR.sup.11, (CH.sub.2).sub.p NR.sup.10 COR.sup.11, CO.sub.2 R.sup.10, NR.sup.10 SO.sub.2 R.sup.11, SO.sub.2 NR.sup.10 R.sup.11, CONR.sup.10 R.sup.11, CONHNR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, NR.sup.10 CONR.sup.10 R.sup.11, CONHNR.sup.10 R.sup.11 or SO.sub.2 R.sup.9. Preferably alkyl groups, including R.sup.10 and R.sup.11, are methyl and ethyl.
When R.sup.1 is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur suitable heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, iso
REFERENCES:
patent: 5358948 (1994-10-01), Bradshaw et al.
Journal of Medicinal Chemistry, (1980) vol. 23, No. 6, Washington U.S., pp. 679-682, P.A. Crooks et al., "Synthesis and analgesic properties of some conformationally restriction analogues of profadol" p. 680.
Journal of Medicinal Chemistry, (Jul. 1994) vol. 37, No. 15, 22 Washington U.S., pp. 2253-2257, J.W. Clitherow et al. Evolution of a novel series of (N, N-dimethylamino)propyl and piperazinylbenzanilides as the first selective 5-HT1D-antagonists' see table 2.
Gaster Laramie Mary
King Francis David
Wyman Paul Adrian
Dentz Bernard
Dustman Wayne J.
King William T.
Kinzig Charles M.
SmithKline Beecham Plc
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