Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-17
1999-02-02
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514254, 514332, 544300, 546113, 546255, C07D47104, C07D21375, A61K 3144
Patent
active
058665862
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/03944 filed Oct. 5, 1995.
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. Some or all of the compounds of the invention also exhibit 5HT.sub.2B antagonist activity. 5HT.sub.2B/2C 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: 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; halogen, CF.sub.3, NR.sup.8 R.sup.9, CONR.sup.8 R.sup.9, CO.sub.2 R.sup.10 or OR.sup.10 where R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen, ##STR2## in which: X and Y are both nitrogen or one is nitrogen and the other is carbon or a CH group; substituted by one or more halogen atoms, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyloxy, C.sub.3-6 cycloalkylC.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, 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.8 R.sup.9, CONR.sup.8 R.sup.9, or OR.sup.10 where R.sup.8, R.sup.9 and R.sup.10 are as defined for R.sup.1, CO.sub.2 R.sup.11 where R.sup.11 is hydrogen or C.sub.1-6 alkyl; or R.sup.4 and R.sup.5 form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring; ##STR3## in which R.sup.4 and R.sup.5 are as defined in formula (i), X and Y are both nitrogen or one is nitrogen and the other is a CH group;
C.sub.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched.
The urea moiety can be attached to a carbon or any available nitrogen atom of the ring P, preferably it is attached to a carbon atom. Suitable moieties when the ring P is a 5-membered aromatic heterocyclic ring include isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. Suitable moieties when the ring P is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrimidyl or pyrazinyl. When P is quinoline, or an isoquinoline residue, the urea moiety can be attached at any position of the ring, preferably to the 4- or 5-position. Preferably P is 3-pyridyl.
Preferably R.sup.1 is hydrogen.
Preferably R.sup.2 is hydrogen.
Preferably R.sup.3 is a group of formula (i) where R.sup.6 and R.sup.7 are hydrogen and X is carbon or a CH group and Y is nitrogen.
Preferably R.sup.4 is trifluoromethyl or halogen. Most preferably R.sup.4 is halogen, in particular chloro.
Preferably R.sup.5 is C.sub.1-6 alkylthio, in particular thiomethyl, or C.sub.1-6 alkoxy, in particular methoxy. Most preferably R.sup.4 is thiomethyl.
When R.sup.4 and R.sup.5 form part of an aromatic ring suitable rings include thiophene, furan and pyrrole rings. Optional subtituents for such rings include
REFERENCES:
Stanovnik, et al., "Heteroacyl Azides as Acylating Agents for Aromatic or Heteroaromatic Amines (1)", J. Heterocyclic Chem., vol. 17, pp. 733-736, 1980.
Forbes Ian Thomson
Jones Graham Elgin
Davis Zinna Northington
Hall Linda E.
SmithKline Beecham p.l.c.
Venetianer Stephen A.
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