Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-09-16
1999-10-26
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 514256, 514275, 514310, 514313, 514339, 514361, 514362, 514363, 514372, 514378, 514383, 514414, 514415, 544143, 544144, 544328, 544331, 544373, 544405, 546143, 546162, 546201, 5462781, C07D20908, C07D40312, C07D40112, A61K 3140
Patent
active
059729376
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
WO 95/01976 (SmithKline Beecham plc) describes indoline derivatives which are described as possessing 5HT.sub.2C receptor antagonist activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT.sub.2C receptor antagonist activity. Certain compounds of the invention also exhibit 5HT.sub.2B antagonist activity. 5HT.sub.2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof: ##STR1## wherein: P represents phenyl, a quinoline or isoquinoline residue, or a 5-membered or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; NR.sup.4 COR.sup.5, C.sub.1-6 alkylthio, cyano, nitro, halogen, CF.sub.3, OCF.sub.3, SCF.sub.3, C.sub.2 F.sub.5, NR.sup.4 R.sup.5, CONR.sup.4 R.sup.5, CHO, COR.sup.6, CH.sub.2 OR.sup.6, CO.sub.2 R.sup.6, OR.sup.6 or S(O).sub.n NR.sup.4 R.sup.5, where n is 1 or 2 and R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, C.sub.1-6 alkyl, aryl or arylC.sub.1-6 alkyl; oxygen, sulphur, C.dbd.O, CH.dbd.N--O, CONR.sup.7 or NR.sup.7 where R.sup.7 is hydrogen or C.sub.1-6 alkyl; R.sup.8 and R.sup.9 are independently hydrogen or C.sub.1-6 alkyl; p is 0 to 6 and R.sup.10 is hydroxy, C.sub.1-6 alkoxy, NR.sup.4 R.sup.5 where R.sup.4 and R.sup.5 are as defined above for R, or R.sup.4 and R.sup.5 together form a C.sub.2 -C.sub.6 methylene chain optionally containing an O, S or NR.sup.7 group and optionally substituted by NR.sup.4 R.sup.5 or C.sub.1-6 alkylNR.sup.4 R.sup.5 where R.sup.4 and R.sup.5 are independently C.sub.1-6 alkyl, or one of R.sup.4 and R.sup.5 represents an optionally substituted alicyclic amine attached directly or via a C.sub.1-6 alkyl group, or R.sup.10 is CO.sub.2 R.sup.11 where R.sup.11 is hydrogen, C.sub.1-6 alkyl or aryl; ##STR2## in which: X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR.sup.12 group or one is a CR.sup.12 group and the other is carbon or a CR.sup.12 group; hydrogen, C.sub.1-6 alkyl optionally substituted by one or more halogen atoms, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkylC.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyloxy, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-6 alkylthio, C.sub.3-6 cycloalkylthio, C.sub.3-6 cycloalkyl-C.sub.1-6 alkylthio, C.sub.1-6 alkoxy, hydroxy, halogen, nitro, CF.sub.3, C.sub.2 F.sub.5, OCF.sub.3, SCF.sub.3, SO.sub.2 CF.sub.3, SO.sub.2 F, formyl, C.sub.2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR.sup.4 R.sup.5, CONR.sup.4 R.sup.5 or CO.sub.2 R.sup.6 where where R.sup.4, R.sup.5 and R.sup.6 are as defined for R.sup.1 ; or R.sup.14 and R.sup.15 form part of an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; ##STR3## in which X and Y are both nitrogen, one is nitrogen and the other is a CR.sup.12 group or X and Y are both CR.sup.12 groups, R.sup.18 is hydrogen or C.sub.1-6 alkyl, and R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are as defined in formula (I); or ##STR4## in which R.sup.14, R.sup.15, X and Y are as defined in formula (i) and Z is O, S, CH.sub.2 or NR.sup.19 where R.sup.19 is hydrogen or C.sub.1-6 alkyl.
C.sub.1-6 Alkyl groups, whether alon
REFERENCES:
patent: 4428881 (1984-01-01), Hedrich et al.
patent: 5322951 (1994-06-01), King et al.
I.T. Forbes, "5-Methyl-1-(3-pyridylcarbamoyl)-1,2.3.5-tetrahydropyrrolo[2,3-f]indole: A Novel 5 HT.sub.2C /5-HT.sub.2B Receptor Antagonist with Improved Affinity, Selectivity, and Oral Activity", (1995), J. Med. Chem., 38(14), pp. 2524-2530.
Davies David Thomas
Gaster Laramie Mary
Mulholland Keith Raymond
Wyman Paul Adrian
Hall Linda E.
Kinzig Charles M.
Rao Deepak R.
Shah Mukund J.
SmithKline Beecham p.l.c.
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