N-(4-substituted-benzyl)-2-aminolactam derivatives

Details N-(4-substituted-benzyl)-2-aminolactam derivatives N-(4-substituted-benzyl)-2-aminolactam derivatives

1998-01-08

1999-06-15

McKane, Joseph K.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514212, 514327, 514424, 540364, 540527, 546216, 548550, A61K 31395, C07D205085, C07D20726

Patent

active

059122420

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel N-(4-substituted-benzyl)-2-aminolactams, to their use as therapeutic agents, to a process for their preparation and to pharmaceutically compositions containing them.
It has been found that novel N-(4-substituted-benzyl)-2-aminolactam derivatives as herein defined have valuable biological properties, in particular as antiepileptic, anti-Parkinson, neuroprotective, anti-depressant, antispastic and/or hypnotic agent.
The present invention provides novel compounds of formula (I) ##STR1## wherein:
m is zero, 1, 2 or 3;
n is zero, 1, 2 or 3;
X is --O--, --S--, --CH.sub.2 -- or --NH--;
each of R and R.sub.1 independently is hydrogen, C.sub.1 -C.sub.6 alkyl, halogen, hydroxy, C.sub.1 -C.sub.4 alkoxy or trifluoromethyl;
each of R.sub.2, R.sub.3 and R.sub.4 independently is hydrogen, C.sub.1 -C.sub.6 alkyl optionally substituted by a hydroxy group, or C.sub.3 -C.sub.7 cycloalkyl;
and the pharmaceutically acceptable salts thereof.
The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic, e.g. hydrochloric, hydrobromic, sulphuric, and phosphoric acids, or organic, e.g. acetic, propionic, lactic, oxalic, malic, maleic, tartaric, citric, benzoic, mandelic, salicylic, C.sub.1 -C.sub.4 alkylsulfonic and fumaric acids.
The compounds of the formula (I), their pharmaceutically acceptable salts may also form pharmaceutically acceptable solvates, such as hydrates, which are also object of the present invention.
The alkyl and alkoxy groups may be branched or straight groups.
A C.sub.1 -C.sub.6 alkyl group is preferably a C.sub.1 -C.sub.4 alkyl group, in particular methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, more preferably methyl or ethyl.
A C.sub.1 -C.sub.6 alkyl group substituted by hydroxy is typically hydroxymethyl.
Representative examples of C.sub.1 -C.sub.4 alkoxy groups include methoxy or ethoxy.
A halogen atom is e.g. chlorine, fluorine, bromine, in particular chlorine and fluorine, more preferably fluorine.
A C.sub.3 -C.sub.7 cycloalkyl group is, for instance, a cyclopropyl, cyclohexyl or cycloheptyl group, in particular cyclopropyl.
The present invention also include within its scope both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
Compounds of formula (I) contain an asymmetric carbon atom and have optical l and d isomers. Accordingly, the invention includes all the possible isomers, in particular l and d isomers and their mixtures.
Preferred compounds of the invention are the compounds of formula (I) wherein
m is 1 or 2;
n is 1 or 2;
X is --O--, --S--or --NH--;
R is hydrogen;
R.sub.1 is hydrogen or halogen;
each of R.sub.2 and R.sub.4 independently is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.3 is hydrogen or C.sub.1 -C.sub.4 alkyl optionally substituted by a hydroxy group; and the pharmaceutically acceptable salts thereof.
More preferred compounds of the invention are the compounds of formula (I), wherein
m is 1;
n is 1;
X is --O-- or --NH--;
R.sub.1 is hydrogen or halogen;
R.sub.2 is hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sub.3 is hydrogen or C.sub.1 -C.sub.4 alkyl optionally substituted by hydroxy;
R and R.sub.4 are hydrogen; and the pharmaceutically acceptable salts thereof.
Examples of specific compounds of the invention are: ne; and the pharmaceutically acceptable salts thereof.
The compounds of the invention and the salts thereof can be obtained by a process comprising: ##STR2## wherein n, R, R.sub.1 and X are as defined above, with a compound of formula (III) ##STR3## wherein m, R.sub.3 and R.sub.4 are as defined above, thus obtaining a compound of formula (I) in which R.sub.2 is hydrogen; or ##STR4## wherein R, R.sub.1, R.sub.3, R.sub.4, m, n and X are as defined above, with a compound of formula (V) or (VI) R".sub.2 is hydrogen or C.sub.1 -C.sub.3 alkyl, thus obtaining a compound of the invention in which R.sub.2 is C.sub.1 -C.sub.4 alkyl; and, if desired, converting a compound of the invention into another c

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