Tricyclic spiro compounds as 5HT.sub.1D receptor antagonists

Details Tricyclic spiro compounds as 5HT.sub.1D receptor antagonists Tricyclic spiro compounds as 5HT.sub.1D receptor antagonists

1999-03-10

1999-10-26

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548131, C07D491107, A61K 3141

Patent

active

059729791

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel heterocyclic 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. 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 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 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.10, SOR.sup.10, SO.sub.2 R.sup.10, 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.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 and R.sup.13 is hydrogen, C.sub.1-6 alkyl or optionally substituted aryl; or R.sup.1 is a group --X--R where X is a bond, O, S, CH.sub.2, C.dbd.O, NHCO, NAlkylCO, NH or NAlkyl where Alkyl is C.sub.1-6 alkyl and R is an optionally substituted bicyclic heterocyclic ring or monocyclic 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 areas defined for R.sup.1 ; a group --A-- where A is (CR.sup.13 R.sup.14).sub.q where q is 2, 3 or 4 and R.sup.13 and 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 ; and R.sup.7 are joined to form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from oxygen, nitrogen or sulphur; R.sup.17 are independently hydrogen or C.sub.1-6 alkyl or E is a group S(O).sub.b where b is 1, 2 or 3;
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 means phenyl and naphthyl groups.
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 akoxy, C.sub.1-6 alkoxyC.sub.1-6 alkoxy, acyl, nitro, trifluoromethyl, cyano, SR.sup.10, SOR.sup.10, SO.sub.2 R.sup.10, 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.su

REFERENCES:
Clitherow, et al., J. of Med. Chem., 1994, vol. 37, No. 15, pp. 2253-2257.

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