Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-21
1998-05-26
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142338, 514364, 540552, 544105, 548131, C07D41312, A01K 3155
Patent
active
057564965
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel amide derivatives, processes for their preparation, and pharmaceutical compositions containing them.
EPA 0 533 26617/8 disclose a series of benzanilide derivatives which are said to possess .sup.5 HTlD 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 (1) or a salt thereof: ##STR1## in which A is CONR where R is hydrogen or C.sub.1-6 alkyl; Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or 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 aLkoxyC.sub.-6 alkoxy, acyl, 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.a CO.sub.2 R.sub.11, (CH.sub.2).sub.a NR.sup.10 R.sup.11, (CH.sub.2).sub.a CONR.sup.10 R.sup.11, (CH.sub.2).sub.a NR.sup.10 COR.sup.11, (CH.sub.2).sub.a CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.a OR.sup.10, NR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, NR.sup.11 CONR.sup.10 R.sup.11, CR.sup.10 =NOR.sup.11, CNR.sup.10 =NOR.sup.11, where R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl and a is 1 to 4 or R.sup.1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R.sup.2 and R.sup.3 are independently hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloallyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, acyl, 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 ; R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-6 alkyl; R.sup.6 is halogen, hydroxy, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; 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; m is 0 to 4; and n is 0, 1 or2.
C.sub.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Suitably 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, acyl, 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.hd 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.a CO.sub.2 R.sup.11, (CH.sub.2).sub.a NR.sup.10 R.sup.11, (CH.sub.2).sub.a CONR.sup.10 R.sup.11, (CH.sub.2).sub.a NR.sup.10 COR.sup.11, (CH.sub.2).sub.a CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.a 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 =NOR.sup.11, CNR.sup.10 =NOR.sup.11, where R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl and a is 1 to 4 or R.sup.1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
When R.sup.1 is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur 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. Suitable substituents for these rings inc
REFERENCES:
P.H. Hutson et al., "The effects of GR127935, a putative 5-HT1D receptor antagonist, on brain 5-HT metabolism, extracellular 5-HT concentration and behavior in the guinea pig", Neuropharmacology, 34(4), pp. 383-392 (1995).
M. Skingle et al., "Effects of the 5-HT1D receptor antagonist GR127935 on extracellular levels of 5-HT in the guinea pig frontal cortex as measured by microdialysis", Neuropharmacology, 34(4), pp. 377-382 (1995).
Duckworth David Malcolm
Gaster Laramie Mary
Ham Peter
King David Francis
Dustman Wayne J.
Gerstl Robert
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham p.l.c.
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