Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-16
1999-11-23
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5462771, A61K 3144, C07D40110, C07D40310
Patent
active
059901330
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 94/04533 (SmithKline Beecham plc) describes indole and 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: ##STR3## wherein: p.sup.1 and p.sup.2 are independently phenyl, aromatic or partially saturated monocyclic or bicyclic heterocyclic rings containing up to three heteroatoms selected from nitrogen, oxygen or sulphur, alkyl or A is an optionally substituted phenyl or an optionally substituted 5- to 7-membered heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; optionally substituted by NR.sup.12 R.sup.13, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkylthio, cyano, nitro, halogen, CF.sub.3, C.sub.2 F.sub.5, NR.sup.12 R.sup.13, CONR.sup.12 R.sup.13, NR.sup.12 COR.sup.13, S(O).sub.p NR.sup.12 R.sup.13, CHO, OCF.sub.3, SCF.sub.3, COR.sup.14, CH.sub.2 OR.sup.14, CO.sub.2 R.sup.14 or OR.sup.14 where p is 1 or 2 and R.sup.12, R.sup.13 and R.sup.14 are independently hydrogen, C.sub.1-6 alkyl, optionally substituted aryl or optionally substituted arylC.sub.1-6 alkyl; ##STR4## in which: X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR.sup.5 group or one is a CR.sup.5 group and the other is carbon or a CR.sup.5 group; C.sub.1-6 alkyl optionally substituted by one or more fluorine 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, 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.12 R.sup.13, CONR.sup.12 R.sup.13 or CO.sub.2 R.sup.14 where where R.sup.12, R.sup.13 and R.sup.14 are as defined for R.sup.1 ; or R.sup.6 and R.sup.7 form part of an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; straight chain or branched
Suitably A is a bond or a chain of 1 to 5 atoms optionally substituted by C.sub.1-6 alkyl. Examples of such chains include (CH.sub.2).sub.p X or X(CH.sub.2).sub.p where p is 1 to 4 and X is CO, O, S(O).sub.x where x is 0 to 2 or A is NR, CONR, NRCO, NRCONR, CO, CH(OH), C.sub.1-6 alkyl, CH.dbd.CH, CH.dbd.CF, CF.dbd.CF, O, S(O).sub.x where x is 1 or 2, NR, or NRSO.sub.2 where R is hydrogen or C.sub.1-6 alkyl. Preferably A is a bond or a group CH.sub.2 O, OCH.sub.2, or O.
Suitably A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur. Preferably A is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidyl or pyrazinyl. Most preferably A is thiazolyl. Optional substituents when A is a phenyl or a heterocyclic group incl
Davies David Thomas
Duckworth David Malcolm
Forbes Ian Thomson
Gaster Laramie Mary
Jones Graham Elgin
Hall Linda E.
Kinzig Charles M.
Rotman Alan L.
SmithKline Beecham p.l.c.
Venetianer Stephen A.
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