Azaspiro derivatives with 5HT.sub.1B activity

Details Azaspiro derivatives with 5HT.sub.1B activity Azaspiro derivatives with 5HT.sub.1B activity

1998-05-08

2000-05-23

Rotman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546 17, A61K 31435, C07D47110, C07D48710, C07D49110, C07D49510

Patent

active

060666447

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. The 5HT.sub.1D.beta. receptor has now been reclassified as the 5HT.sub.1D 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: ##STR2## in which R.sup.1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; 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 ; is OR.sup.16 or SR.sup.16 where R.sup.16 is hydrogen or C.sub.1-6 alkyl or R.sup.15 is 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.19 are independently hydrogen or C.sub.1-6 alkyl or B is a group S(O).sub.b where b is 1, 2 or 3;
C.sup.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched.
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, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Suitable substituents for these rings include R.sup.2 and R.sup.3 groups as defined above. Preferably R.sup.1 is optionally substituted oxadiazolyl. Preferred substituents for such oxadiazolyl groups include C.sub.1-6 alkyl such as methyl or ethyl. Most preferably R.sup.1 is a 5-methyl-1,3,4-oxadiazol-2-yl group.
Preferably R.sup.2 is C.sub.1-6 alkyl, in particular methyl. Preferably R.sup.3 is hydrogen. Suitably R.sup.4 is hydrogen or C.sub.1-6 alkyl and R.sup.5 is hydrogen or C.sub.1-6 alkyl or R.sup.4 and R.sup.5 together form 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. Preferably R.sup.4 and R.sup.5 form a group --A--. Preferably A is (CH.sub.2).sub.2. Preferably R.sup.6 is a group --(CH.sub.2).sub.p --R.sup.15 where p is 2 and R.sup.15 is hydroxy. Preferably R.sup.7 and R.sup.8 are both hydrogen. Preferably m is 2 forming a spiropiperidine ring. Preferably B is oxygen. Preferably n is 1.
Particularly preferred compounds of the invention include: -4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine], -4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3 -f]indole-3,4'-piperidine], phenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidin e], -4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]or pharmaceutically acceptable salts thereof.
Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acctates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates. Tautome

REFERENCES:
patent: 5356893 (1994-10-01), Bradshaw et al.
patent: 5952325 (1999-09-01), Wayman et al.
patent: 5972951 (1999-10-01), Gaster

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