Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-11-08
1998-01-13
Lambkin, Deborah
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514622, 564180, 564142, 564139, 564134, 562405, 568327, A61K 31165, C07C23308, C07C 5911, C07C 5964
Patent
active
057080330
DESCRIPTION:
BRIEF SUMMARY
This appln is a 371 of PCT/GB55/01040 May 9, 1995.
The present invention relates to a group of substituted carbocyclic amides, to pharmaceutical compositions which contain them, to methods for their preparation and their use in therapy, in particular in the treatment of inflammatory conditions.
We have found that a novel group of substituted carbocyclic amides have beneficial anti-inflammatory and analgesic properties. These compounds are relatively free of other pharmacological properties.
Accordingly, the present invention provides a compound of the formula (I): ##STR2## or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, wherein .sup.1 and R.sup.2 are the same or different and each is chloro, fluoro, bromo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkyl provided that R.sup.1 and R.sup.2 are not both fluoro;
R.sup.3 and R.sup.4 are independently selected from hydrogen and C.sub.1-6 alkyl.
Suitably R.sup.1 and R.sup.2 are independently selected from chloro, fluoro, bromo or C.sub.1-4 alkyl; preferably chloro, fluoro, bromo or methyl. Particularly preferred compounds of formula (I) include those wherein at least one of .sup.1 and R.sup.2 is chloro. Most preferably R.sup.1 is chloro and R.sup.2 is chloro, fluoro, bromo or methyl.
Preferably at least one of R.sup.1 and R.sup.2 is chloro.
Suitably R.sup.3 and R.sup.4 are independently selected from hydrogen or C.sub.1-4 alkyl; preferably hydrogen, methyl or ethyl.
A preferred group of compounds of the formula (I) is that of the formula (IA): ##STR3## or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, wherein R.sup.1a is chloro, R.sup.2a is chloro, fluoro, bromo or methyl, R.sup.3 and R.sup.4 are the same or different and each is hydrogen, methyl or ethyl.
Preferred compounds of the present invention include:
As used herein the term:
a) "C.sub.1-6 alkyl" means an alkyl group having from 1 to 6 carbon atoms containing straight, branched chain or cyclic alkyl groups. Such alkyl groups preferably have 1 to 3 carbon atoms and are more preferably methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2-yl cyclopropyl or cyclobutyl. Alkyl groups are most preferably methyl or ethyl, or cyclopropyl.
b) "C.sub.1-6 alkoxy" as a group or part of a group means a monovalent straight or branched chain radical having from 1 to 6 carbon atoms which are attached to the parent moiety through an oxygen atom. Such alkoxy groups preferably have 1 to 4 carbon atoms and are more preferably methoxy or ethoxy, most preferably methoxy.
c) "haloalkyl" means alkyl substituted by 1 to 5 fluoro or chloro atoms preferably fluoro atoms.
d) "physiologically functional derivatives" means any other physiologically acceptable derivative of a compound of the present invention, for example an ester, which, upon administration to the recipient, such as a human, is capable of providing (directly or indirectly) the said compound or an active metabolite or residue thereof.
e) "salt" means base salts as further defined herein below.
f) "solvate" means a combination, in definite proportions, of a compound of the present invention with its solvent.
It will be appreciated that the compounds of formula (I) can exist in various geoisomeric forms and as mixtures thereof in any proportions. The present invention includes within its scope such geoisomeric forms or mixtures of geoisomers, including the individual E and Z isomers of the compounds of formula (I) as well as mixtures of such isomers, in any proportions. Preferred compounds of formula (I) are those wherein the group adjacent to the exo double bond and the carbonyl group are on opposite sides of the exo double bond. The compounds of formula (I) may exist in forms wherein one or more carbon centres is/are chiral. The present invention includes within its scope each possible optical isomer substantially free, i.e., associated with less than 5%, of any other optical isomer(s), as well as mixtures of one or more optical isomers in any proportion,
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A.G. Anderson et al., "The Synthesis of 20 Apr. 1973, vol. 38, No. 8, pp. 1439-1444.
Lahiri et al, "Synthesis and Pharmocology of Some Indanamines", CA 69:35792, (1968).
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Kelley James Leroy
Musso David Lee
Glaxo Wellcome Inc.
Hrubiec Robert T.
Lambkin Deborah
Makujina Shah R.
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