Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-09-18
2000-08-08
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 16, 546 17, A61K 3144, C07D22120
Patent
active
061002720
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. 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. Compounds of the invention exhibit certain advantages when compared with 5HT.sub.1B receptor antagonists known in the art, for example greater selectivity for the 5HT.sub.1B receptor over the 5HT.sub.1D receptor. 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 is a group NR.sup.1 COR.sup.2 where R.sup.1 is hydrogen, C.sub.1-6 alkyl or together with R.sup.3 forms a group (C.sub.2).sub.k where k is 2, 3 or 4 and R.sup.2 is hydrogen, C.sub.1-6 alkyl or optionally substituted aryl; or R is an optionally substituted saturated or partially saturated bicyclic heterocyclic ring or monocyclic saturated or partially saturated 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.11, CONR.sup.12 R.sup.13, NR.sup.12 R.sup.13 where R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or C.sub.1-6 alkyl, or R.sup.4 and R.sup.5 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) 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 ; alkenyl or C.sub.1-6 alkylC.sub.3-6 cycloalkyl; 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 n is 1, 2 or 3; X and Y are independently CR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are as defined above; and m 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 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.4 /R.sup.5.
Suitably R is a group NR.sup.1 COR.sup.2 where R.sup.1 is hydrogen, C.sub.1-6 alkyl or together with R.sup.3 forms a group (C.sub.2).sub.k where k is 2, 3 or 4 and R.sup.2 is hydrogen, C.sub.1-6 alkyl or optionally substituted aryl; or R is an optionally substituted saturated or partially saturated bicyclic heterocyclic ring or monocyclic 5 to 7-membered heterocyclic ring. The bicyclic and momocyclic R groups can contain 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur. Preferred rings are those having an oxo or thioxo moiety such as lactams and thiolactams. 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.4 and R.sup.5 groups as defined above.
When R is a group NR.sup.1 COR.sup.2 preferred groups include those where R
REFERENCES:
patent: 5591849 (1997-01-01), Kato et al.
Rubini et al. "SAynthesis of isoteric methylene-oxy pseudopiptide . . . " Tetrahedron V. 42, p.6039-45, 1986.
Gaster et al. "Preparation of azaspiro compounds as 5HT1B . . . "CA 127:331477, 1997.
Gaster "Preparation of spiroazabicyclic compounds and . . . " CA 128:13254, 1997.
Gaster Laramie Mary
Ham Peter
King Francis David
Wyman Paul Adrian
Chang Ceila
Kanagy James M.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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