Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-04-24
1999-10-26
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514291, 514364, 544126, 544142, 546 89, 548143, A61K 31535, A61K 3144, C07D41300, C07D49100
Patent
active
059729350
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel heterocyclic compounds, 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 receptor 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 is a group of formula (i): ##STR3## where 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.9, SOR.sup.9, SO.sub.2 R.sup.9, 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, N.dbd.CNR.sup.9 NR.sup.10 R.sup.11, NR.sup.10 CO(CH.sub.2).sub.a 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 a group --X--R.sup.12 where R.sup.12 is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur and X is a bond, O, S, CH.sub.2, C.dbd.O, NR.sup.13 CO or NR.sup.13 where R.sup.13 is hydrogen or C.sub.1-6 alkyl; R.sup.4 and R.sup.5 are independently hydrogen, halogen, C.sub.1-6 alkyl, 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.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; or R is a group of formula (ii): ##STR4## where R.sup.2 is hydrogen, C.sub.1-6 alkyl, optionally substituted aryl or optionally substituted heteroaryl; group (CH.sub.2).sub.q where q is 2, 3 or 4; and ##STR5## where Z is oxygen or sulphur; p is 1 or 2; four heteroatoms; saturated ring optionally containing one to three heteroatoms; and 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 1, 2 or 3 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 or 2 and J is oxygen, sulphur, CR.sup.16 .dbd.CR.sup.17, CR.sup.16 .dbd.N, CR.sup.16 NR.sup.17 or N.dbd.N; or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen; nitrogen or sulphur; 1 to 3 heteroatoms 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. Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidyl and pyrazinyl groups. Optional substituents for aryl and heteroaryl groups include C.sub.1-6 alkyl such as methyl.
Suitably R is a group of formula (i), (ii
REFERENCES:
Clitherow, et al., J. Med. Chem., vol. 37, No. 15, 1994, pp. 2253-2257.
Hartig, et al., Tips; vol. 17, No. 3, 1996, pp. 103-105.
Dustman Wayne J.
King William T.
Kinzig Charles M.
Lambkin Deborah C.
SmithKline Beecham p.l.c.
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