Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-10-15
2000-12-12
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
51425213, 544358, 544360, 544361, 544392, 544399, 544400, A61K 31495, C07D24100, C07D40100
Patent
active
061599794
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel piperazine derivatives, processes for their preparation, and pharmaceutical compositions containing them.
WO 95/06637, WO 95/06044 and WO 95/04729 disclose a series of piperazine 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 with the advantage of a relatively fast onset of action. EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HT.sub.1D receptor antagonist activity.
A structurally distinct class of compounds have now been found to exhibit combined 5HT.sub.1A, 5HT.sub.1B and 5HT.sub.1D receptor antagonist activity. It is expected that such compounds will be useful for the treatment and prophylaxis of various CNS disorders. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof: ##STR1## in which R.sup.a is a group of formula (i) ##STR2## in which P.sup.1 is bicyclic aryl, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; R.sup.1 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, COC.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, hydroxyC.sub.1-6 alkyl, hydroxyC.sub.1-6 alkoxy, C.sub.1-6 alkoxyC.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, nitro, trifluoromethyl, cyano, SR.sup.9, SOR.sup.9, SO.sub.2 R.sup.9, SO.sub.2 NR.sup.10 R.sup.11, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, CO.sub.2 NR.sup.10 R.sup.11, CONR.sup.10 (CH.sub.2).sub.c CO.sub.2 R.sup.11, (CH.sub.2).sub.c NR.sup.10 R.sup.11, (CH.sub.2).sub.c CONR.sup.10 R.sup.11, (CH.sub.2).sub.c NR.sup.10 COR.sup.11, (CH.sub.2).sub.c CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.c OR.sup.10, NR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, NR.sup.10 CONR.sup.10 R.sup.11, CR.sup.10 .dbd.NOR.sup.11, CNR.sup.10 .dbd.NOR.sup.11, where R.sup.9, R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl and c is 1 to 4; R.sup.2 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C .sub.1-6 alkoxy, C.sub.1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are as defined for R.sup.1 ; ##STR3## wherein P.sup.2 and P.sup.3 are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, providing that at least one of P.sup.2 and P.sup.3 is a bicyclic aryl or bicyclic heterocyclic group; NR.sup.4 where R.sup.4 is hydrogen or C.sub.1-6 alkyl; heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C.sub.1-6 alkyl, halogen or C.sub.1-6 alkanoyl; C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are as defined for R.sup.1 ; and a and b are independently 1, 2 or 3; C.sub.1-6 alkyl, providing that D is nitrogen or a CH group, or G together with R.sup.b1 forms a group W where W is (CR.sup.16 R.sup.17).sub.t where t is 2, 3 or 4 and R.sup.16 and R.sup.17 are independently hydrogen or C.sub.1-6 alkyl or W is (CR.sup.16 R.sup.17).sub.u -.sup.J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR.sup.16 .dbd.CR.sup.17, CR.sup.16 .dbd.N, .dbd.CR.sup.16 O,.dbd.CR.sup.16 S or.dbd.CR.sup.16 --NR.sup.17 ; or--O--: C.sub.1-6 alkyl, trifluoromethyl, C.sub.1-6 alkoxy or aryl, or R.sup.b1 together with G forms a group W as defined above; carbon.
C.sub.1-6 alkyl groups whether alone or as part of another group may be straight chain or branched. The term `acyloxy` is used herein to describe a group--OC(O)C.sub.1-6 alkyl. The term `aryl` is used herein to describe, unless otherwise stated, a group such as phe
REFERENCES:
patent: 5556969 (1996-09-01), Chambers et al.
C. Jorand-Lebrun, et al., "Arylpiperazide Derivatives of Phenylpiperazines as a New Class of Potent and Selective 5-HT.sub.1B Receptor Antagonists", (1997), Bioorganic & Medicinal Chemistry Letters, vol. 7, No. 24, pp. 3183-3188.
Gaster Laramie Mary
Wyman Paul Adrian
King William T.
Kinzig Charles M.
Patel Sudhaker B.
Shah Mukund J.
Simon Soma G.
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