Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-06-07
1998-09-01
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514326, 514364, 544138, 546209, 548131, 548132, 548133, 548143, 548144, C07D27106, C07D27110, A61K 3141
Patent
active
058011706
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/03948 filed on Nov. 28, 1994.
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: ##STR2## 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, hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkylOC.sub.1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.9, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.9, R.sup.10 and R.sup.11 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; hydrogen, C.sub.1-6 alkyl or phenylC.sub.1-6 alkyl, or B 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 thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl 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, hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkylOC.sub.1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.9, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.9, R.sup.10 and R.sup.11 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.7 and R.sup.8 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.7 and R.sup.8 as heterocyclic rings include pyrrolidine, morpholine, piperazine and piperidine. Optional substituents for such rings include C.sub.1-6 alkyl. Preferably R.sup.7 and R.sup.8 are both C.sub.1-6 alkyl, in particular methyl.
Suitably R.sup.6 is hydrogen, halogen, hydroxy, C.sub.1-6 alkyl or C.sub.1-6 alkoxy. Preferably R.sup.6 is C.sub.1-6 alkoxy such as methoxy.
Suitably A is CONH or NHCO. Preferably A is CONH.
Suitably B is oxygen, S(O).sub.p where p is 0, 1 or 2, NR.sup.12 where R.sup.12 is hydrogen, C.sub.1-6 alkyl or phenylC.sub.1-6 alkyl, or B 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 B is oxygen, CH.sub.2 or NR.sup.12 where R.sup.12 is phenylC.sub.1-6 alkyl such as phenethyl.
Suitably m is 1 to 4, preferably m is 2
Suitably n is 1 or 2, preferably n is 1.
The groups --B(CR.sup.4 R.sup.5).sub.m NR.sup.7 R.sup.8 and R.sup.6 can be attached to the phenyl ring at any suitable position. Preferably the group --B(CR.sup.4 R.sup.5).sub.m NR.s
REFERENCES:
Korolkovas, Essentials of Medicinal Chemistry, Second Edition, John Wiley & Sons, pp. 67-85, 1988.
Gaster Laramie Mary
King Francis David
Wyman Paul Adrian
Kinzig Charles M.
Lentz Edward T.
Rao Deepak R.
Shah Mukund J.
Simon Soma G.
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