Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-26
1997-12-09
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544364, 544367, 544373, A61K 31495, C07D40310, C07D40314, C07D41314
Patent
active
056961227
DESCRIPTION:
BRIEF SUMMARY
The present application is filed under .sctn. 371 and is based on PCT application number PCT/EP94/02663, filed on Aug. 9, 1993, which, in turn, is based on Great Britain application number 9318325.9, filed on Sep. 3, 1993, Great Britain application number 9318337.4, filed on Sep. 3, 1993, Great Britain application number 9322251.1, filed on Oct. 28, 1993, Great Britain application number 9322252.9, filed on Oct. 28, 1993 and Great Britain application number 9325753.3, filed on Dec. 16, 1993.
The present invention relates to novel urea derivatives, 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 alleged to be of use in the treatment of various CNS disorders such as depression.
A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HT.sub.1D antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof: ##STR4## in which R is a group of formula (i): ##STR5## in which P.sup.1 is a phenyl or a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;, and C.sub.1-6 alkoxy, hydroxyC.sub.1-6 alkyl, acyl, nitro, trifluoromethyl, cyano, SR.sup.5, SOR.sup.5, SO.sub.2 R.sup.5, SO.sub.2 NR.sup.5 R.sup.6, CO.sub.2 R.sup.5, CONR.sup.5 R.sup.6, CONR.sup.5 (CH.sub.2).sub.x CO.sub.2 R.sup.6, NR.sup.5 R.sup.6, NR.sup.5 CO.sub.2 R.sup.6, CR.sup.5 .dbd.NO 1 to 3; ##STR6## in which P.sup.2 is phenyl or biphenyl; P.sup.3 is phenyl or a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;, R.sup.8 is oxygen, S(O).sub.m where m is 0 to 2, carbonyl, CO.sub.2 or CH.sub.2 and p and q are independently 0 to 3; and R.sup.9 and R.sup.10 are independently hydrogen or C.sub.1-6 alkyl.
C.sub.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched.
The groups P.sup.1, P.sup.2, and P.sup.3 can be aromatic or saturated heterocyclic rings. Examples of aromatic heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, isothiazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. Examples of saturated rings include piperidine, morpholine and piperazine rings. Each of the groups P.sup.1, P.sup.2, and P.sup.3 can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom.
When R is a group of formula (i) P.sup.1 is preferably phenyl, R.sup.1 is preferably halogen and R.sup.2 is preferably C.sub.1-6 alkyl, for example methyl.
Preferred groups of formula (ii) include those in which P.sup.2 and P.sup.3 are both phenyl and A is oxygen and those in which P.sup.2 is biphenyl, A is a bond and P.sup.3 is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. More preferably P.sup.3 is a 5-membered ring containing 3 heteroatoms, in particular a 1,2,4-oxadiazol-3-yl group. When R is a group of formula (ii) R.sup.1 and R.sup.2 are preferably C.sub.1-6 alkyl in particular methyl. When P.sup.2 is a biphenyl group one or more R.sup.2 substituents can be present.
Most preferably R is a group of formula (ii) having the following structure: ##STR7##
Suitably R.sup.3 is hydrogen, halogen, hydroxy, C.sub.1-6 alkyl or C.sub.1-6 alkoxy. Preferably R.sup.3 is C.sub.1-6 alkoxy such as methoxy.
Preferably n is 1.
Suitably R.sup.4 is hydrogen or C.sub.1-6 alkyl. Preferably R.sup.4 is hydrogen or C.sub.1-4 alkyl such as methyl.
Preferably R.sup.9 and R.sup.10 are both hydrogen such that the group B forms part of an indole or indoline ring.
Particularly preferred compounds include: azinyl)!1H-indole, )-1-H-indole, phene-4'-ylcarbonyl!indole, e, l) benzoyl!-6-(4-methyl-1-piperazinyl)-1H-indole, -(4-methyl-1-piperazinyl)-1H-indole, or l) benzoyl!-6-(1-piperazinyl)-1H-indole,
Preferred salts of the compounds of formula (
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Chemical Abstracts, vol. 68, No. 15, 8 Apr. 1968, abstract No. 68881x, p. 6645.
Duckworth David Malcolm
Gaster Laramie Mary
Jenkins Sarah Margaret
Wyman Paul Adrian
Dustman Wayne J.
Kinzig Charles M.
Lentz Edward T.
Qazi Sabiha N.
Shah Mukund J.
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