Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-30
1999-07-13
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514313, 514314, 546196, 546197, 546198, 546199, A01N 4342, C07D40100
Patent
active
059227338
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 92/05170, WO 94/04533, WO 94/14801, WO 95/01976 and J. Med. Chem., 1995, 38, 2524-2530 (SmithKline Beecham plc) describe indole and indoline derivatives which are described as possessing 5HT.sub.2C receptor antagonist activity. Indole-3-carboxylic acid compounds having 5HT.sub.3 antagonist activity are diclosed in JPA 03 161 470. Indole derivatives having activity as tyrosine kinase inhibitors are disclosed in J. Med. Chem., 1995, 38, 58-57. Quinoline and indoline derivatives having potassium channel activating activity are disclosed in EPA 0 610 553 (E. R. Squibb).
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.
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; C.dbd.O, CH, CH.sub.2 or NR.sup.4 where R.sup.4 is hydrogen or C.sub.1-6 alkyl; bonds; or OR.sup.9 where R.sup.7, R.sup.8 and R.sup.9 are independently hydrogen or C.sub.1-6 alkyl; one or more halogen atoms, C.sub.2-6 alkenyl, 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 cycloalkylC.sub.1-6 alkylthio, halogen, nitro, CF.sub.3, OCF.sub.3, SCF.sub.3, SO.sub.2 CF.sub.3, SO.sub.2 F, formyl, C.sub.2-6 alkanoyl, cyano, phenyl or thienyl optionally substituted by C.sub.1-6 alkyl, halogen, CF.sub.3, NR.sup.7 R.sup.8 or OR.sup.9 where R.sup.7, R.sup.8 and R.sup.9 are independently hydrogen or C.sub.1-6 alkyl, or R.sup.3 is NR.sup.7 R.sup.8, CONR.sup.7 R.sup.8, or OR.sup.9 where R.sup.7, R.sup.8 and R.sup.9 are as defined for R.sup.1, CO.sub.2 R.sup.10 where R.sup.10 is hydrogen or C.sub.1-6 alkyl, provided that:
C.sub.1-6 Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
The amide 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 amide moiety can be attached at any position of the ring, preferably to the 4- or 5-position. Preferably P is 3-pyridyl, in particular 3-pyridyl.
Suitably X and Y are independently selected from oxygen, sulphur, carbon, nitrogen, C.dbd.O, CH, CH.sub.2 or NR.sup.4 where R.sup.4 is hydrogen or C.sub.1-6 alkyl and Z is selected from carbon, CH or nitrogen such that X, Y and Z together with the phenyl group to which they are attached form a 5,6 bicyclic ring system. Examples of such ring systems include benzothiophene, benzofuran, indene and indole. Preferably X is oxygen, sulphur or NR.sup.4, Z is carbon and Y is CH, i.e. Z-Y is a C.dbd.CH group such that X, Y and Z together with the phenyl group to which they are attached
REFERENCES:
patent: 4686224 (1987-08-01), Melvin, Jr.
patent: 4730004 (1988-03-01), Kadin
Forbes, et al., 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.
Palmer, et al., "Tyrosine Kinase Inhibitors. 4. Structure-Activity Relationships among N-and 3-Substituted 2,2'-Dithiobis(1H-indoles) for in vitro Inhibition of Receptor and Nonreceptor Protein Tyrosine Kinases", (1995), J. Med. Chem. 38(1), pp. 58-67.
Davies David Thomas
Forbes Ian Thomson
Ham Peter
Jones Graham Elgin
King Francis David
Hall Linda E.
Kinzig Charles M.
Shah Mukund J.
SmithKline Beecham p.l.c.
Truong Tamthom N.
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