Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1998-01-08
1999-08-31
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514618, 514619, 564162, 564163, 564164, 564167, 564171, A61K 31165, C07C23305
Patent
active
059454547
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 2-(4-substituted)-benzylamino-2-methyl-propanamides, to their use as therapeutic agents, to a process for their preparation and to pharmaceutically compositions containing them.
WO 90/14334 discloses N-phenylalkyl substituted .alpha.-amino carboxamide derivatives active on the CNS.
It has been found that novel 2-(4-substituted)-benzylamino-2-methyl-propanamides 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 the following general formula (I) ##STR2## wherein: n is zero, 1, 2 or 3; halogen, hydroxy, C.sub.1 -C.sub.4 alkoxy or trifluoromethyl; -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl;
The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic, e.g. hydrochloric, hydrobromic, sulfuric, and phosphoric acids, or organic, e.g. acetic, propionic, lactic, oxalic, malic, maleic, tartaric, citric, benzoic, mandelic, C.sub.1 -C.sub.4 alkylsulfonic, salicylic and fumaric acids.
The compounds of the formula (I), their pharmaceutically acceptable salts may also form pharmaceutically acceptable solvates, such as mono-, di- or tri-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. Representative examples of C.sub.1 -C.sub.4 alkoxy groups include methoxy or ethoxy.
A halogen atom is e.g. chlorine, fluorine or bromine.
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 all the possible isomers of the compounds of formula (I) and their mixtures, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
Preferred compounds of the invention are the compounds of formula (I) wherein -C.sub.4 alkyl; and the pharmaceutically acceptable salts thereof.
More preferred compounds of the invention are the compounds of formula (I), wherein
Examples of specific compounds of the invention are: case, either as single (S) or (R) isomer or as a mixture thereof, and the pharmaceutically acceptable salts thereof.
The compounds of the invention and the salts thereof can be obtained by a process comprising: ##STR3## wherein n, R, R.sub.1 and X are as defined above, with a compound of formula (III) ##STR4## wherein 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 ##STR5## wherein R, R.sub.1, R.sub.3, R.sub.4, n and X are as defined above, with a compound of formula (V) or (VI) ##STR6## wherein W is a halogen atom; R'.sub.2 is a C.sub.1 -C.sub.6 alkyl and R".sub.2 is hydrogen or C.sub.1 -C.sub.5 alkyl, thus obtaining a compound of the invention in which R.sub.2 is C.sub.1 -C.sub.6 alkyl; and, if desired, converting a compound of the invention into another compound of the invention and/or, if desired, converting a compound of the invention into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound.
All the processes described hereabove are analogy processes and can be carried out according to well known methods in organic chemistry.
A compound of formula (IV) is a compound of formula (I) in which R.sub.2 is hydrogen.
The reaction of a compound of formula (II) with a compound of formula (III) to give a compound of formula (I) or (IV) is a reductive amination reaction which can be carried out according to well known methods. According to a preferred embodiment of the invention it may be performed under nitrogen atmosphere, in a suitable organic solvent, such as an alcohol, e.g. a lower alkanol, in partic
REFERENCES:
Euerby et al, Jouranal Chemical Research(M), No. 9, abstract 2419-2427, 1982.
Amici Raffaella
Bonsignori Alberto
Pevarello Paolo
Salvati Patricia
Varasi Mario
Kumar Shailendra
Pharmacia & Upjohn S.p.A.
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