Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-30
2000-12-05
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548411, A61K 3140, C07D20954
Patent
active
061567833
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel azabicyclic 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. PCT/EP/95/04889 discloses further 5HT.sub.1D receptor antagonists having a spiropiperidine structure. 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.
A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HT.sub.1B receptor antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt or N-oxide thereof: ##STR1## in which P.sup.1 and P.sup.2 are independently phenyl, bicyclic aryl, a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or a bicyclic heterocyclic ring containing one to three heteroatoms selected from oxygen, nitrogen or sulphur; 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, N.dbd.CNR.sup.9 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, or NR.sup.12 COR.sup.13 where R.sup.9, R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl, p is 1 to 4, R.sup.12 is hydrogen, C.sub.1-6 alkyl or together with R.sup.2' forms a group (CH.sub.2).sub.k where k is 2, 3 or 4 or R.sup.13 is hydrogen, C.sub.1-6 alkyl or optionally substituted aryl; 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, or R.sup.2 and R.sup.3 together form a group --(CH.sub.2).sub.r --R.sup.14 --(CH.sub.2).sub.s -- where R.sup.14 is O, S, CH.sub.2 or NR.sup.15 where R.sup.15 is hydrogen or C.sub.1-6 alkyl and r and s are independently 0, 1 or 2; alkyl, C.sub.1-6 alkoxy or halogen or R.sup.6 together with R.sup.7 forms a group --A-- where A is (CR.sup.16 R.sup.17).sub.t where t is 2, 3 or 4 and R.sup.16 and R.sup.17 are independently hydrogen or C.sub.1-6 alkyl or A is (CR.sup.16 R.sup.17).sub.u --J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR.sup.16 .dbd.CR.sup.17, CR.sup.16 .dbd.N, .dbd.CR.sup.16 O, .dbd.CR.sup.16 S or .dbd.CR.sup.16 --NR.sup.17 ; R.sup.20 are independently hydrogen or C.sub.1-6 alkyl or E is S(O).sub.v where v is 0, 1 or 2; independently hydrogen or C.sub.1-6 alkyl; and containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulphur.
C.sub.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched. As used herein the term aryl includes phenyl and naphthyl. Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidyl and pyrazinyl groups. Optional substituents for aryl and heteroaryl groups include those groups listed above for R.sup.2 /R.sup.3.
Suitably P.sup.1 and P.sup.2 are independently selected from p
Kanagy James M.
Kinzig Charles M.
Lambkin Deborah C.
SmithKline Beecham p.l.c.
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