Tricyclic spiro compounds process for their preparation and thei

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

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514278, 514409, 540543, 546 16, 546 17, 548409, C07D491107, C07D49510, A61K 31435, A61K 3155

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059523255

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BRIEF SUMMARY
The present invention relates to novel amide 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 thereof: ##STR2## in which R.sup.1 is NR.sup.9 CONR.sup.10 R.sup.11, NR.sup.10 SO.sub.2 R.sup.11, SO.sub.2 NR.sup.10 R.sup.11, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, CO.sub.2 NR.sup.10 R.sup.11, CONR.sup.10 (CH.sub.2).sub.a CO.sub.2 R.sup.11, (CH.sub.2).sub.a NR.sup.10 R.sup.11, (CH.sub.2).sub.a CONR.sup.10 R.sup.11, (CH.sub.2).sub.a NR.sup.10 COR.sup.11, (CH.sub.2).sub.a CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.a OR.sup.10, NR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, CONHNR.sup.10 R.sup.11, CR10.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 a 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, 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.13 and R.sup.14 are independently hydrogen or C.sub.1-6 alkyl;
C.sub.1-6 alkyl groups, whether alone or as part of another groups may be straight chain or branched.
Suitably R.sup.1 is NR.sup.9 CONR.sup.10 R.sup.11, NR.sup.10 SO.sub.2 R.sup.11, SO.sub.2 NR.sup.10 R.sup.11, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, CO.sub.2 NR.sup.10 R.sup.11, CONR.sup.10 (CH.sub.2).sub.a CO.sub.2 R.sup.11, (CH.sub.2).sub.a NR.sup.10 R.sup.11, (CH.sub.2).sub.a CONR.sup.10 R.sup.11, (CH.sub.2).sub.a NR.sup.10 COR.sup.11, (CH.sub.2).sub.a CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.a OR.sup.10, NR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, CONHNR.sup.10 R.sup.11, CR10.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 a 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.
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-1,2,4-oxadiazol-3-yl group.
Suitably R.sup.2 and R.sup.3 are independently hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, hydroxy C.sub.1-6 alkyl, C.sub.1-6 alkylOC.sub.1-6 alkyl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.9, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.9, R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl. Preferably R.sup.1 and R.sup.2 are 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. Preferably R.sup.4 is methyl.
Suitably R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-6 alkyl. Prefe

REFERENCES:
patent: 5756496 (1998-05-01), Ham et al.
patent: 5817833 (1998-10-01), Gaster
J. W. Clitherow et al., Journal of Medicinal Chemistry, vol. 37, No. 15, pp. 2253-2257 (1994).

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