Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-20
1997-12-23
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546250, 548131, A61K 3141
Patent
active
057008183
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel amide 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 said to be of use in the treatment of various CNS disorders.
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: ##STR1## in which P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.8, CONR.sup.9 R.sup.10, NR.sup.9 R.sup.10 where R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen or C.sub.1-6 alkyl; or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; where R.sup.11 and R.sup.12 are independently hydrogen or C.sub.1-6 alkyl and p is 2 or 3 and q is 1, 2 or 3; R.sup.10 is hydrogen or C.sub.1-6 alkyl, or D is CR.sup.4 .dbd.CR.sup.5 or CR.sup.4 R.sup.5 where R.sup.4 and R.sup.5 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.
Suitably P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Examples of suitable heterocyclic rings include pyridyl, thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimldyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Preferably P is oxadiazolyl.
Suitably R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.8, CONR.sup.9 R.sup.10, NR.sup.9 R.sup.10 where R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen or C.sub.1-6 alkyl. Preferably R.sup.1 and R.sup.2 are C.sub.1-6 alkyl, in particular methyl. Preferably R.sup.3 is hydrogen.
Suitably R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-6 alkyl. Preferably R.sup.4 and R.sup.5 are both hydrogen.
Suitably R.sup.6 and R.sup.7 are independently hydrogen, C.sub.1-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur. Examples of R.sup.6 and R.sup.7 heterocyclic rings include morpholine, piperazine and piperidine. Examples of R.sup.6 and R.sup.7 aralkyl groups include benzyl. Optional substituents for such rings include C.sub.1-6 alkyl. Preferably R.sup.6 ,and R.sup.7 are both C.sub.1-6 alkyl, in particular methyl.
Suitably A is CONH or NHCO, preferably A is CONH.
Suitably B is --(CR.sup.11 R.sup.12).sub.p -- or --O(CR.sup.11 R.sup.12).sub.q -- where R.sup.11 and R.sup.12 are independently hydrogen or C.sub.1-6 alkyl and p is 2 or 3 and q is 1, 2 or 3. Preferably B is --(CR.sup.11 R.sup.12).sub.p-- where R.sup.11 and R.sup.12 are both hydrogen and p is 2, that is to say, B forms part of a dihydrobenzofuran ring.
Suitably D is oxygen, S(O).sub.n where n is 0, 1 or 2, or D is NR.sup.10 where R.sup.10 is hydrogen or C.sub.1-6 alkyl or D is CR.sup.4 .dbd.CR.sup.5 or CR.sup.4 R.sup.5 where R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-6 alkyl. Preferably D is oxygen, NH or CH.sub.2.
Suitably m is 1 to 4, preferably m is 2.
The group --D(CR.sup.4 R.sup.5).sub.m NR.sup.6 R.sup.7 can be attached to the phenyl ring at any suitable position. Prefe
Bucknum Michael
Dustman Wayne J.
Kinzig Charles M.
Lentz Edward T.
Shah Mukund J.
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