Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1999-02-18
2000-09-05
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514617, 514620, 564142, 564164, 564165, 564193, 564197, A61K 31165, C07C23305
Patent
active
06114391&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to .alpha.-amino acid amides, processes for the preparation thereof and pharmaceutical compositions containing them.
More precisely, the invention relates to serinamide, glycinamide alaninamide and phenylalaninamide derivatives of general fonmula (I): ##STR2## wherein R is a straight or branched alkyl cycloalkyl; arylalkyl or phenylalkyl optionally substituted at the ring with alkyl, halogen or haloalkyl; fused or non-fused aryl optionally substituted with alkyl, alkoxy, halogen or haloalkyl; phenylalkyl, when R is alkyl, cycloalkyl, arylalkyl; or R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, optionally acylated C.sub.1 -C.sub.4 hydroxyalkyl or phenylalkyl when R is aryl
An alkyl group if not otherwise specified is preferably a C.sub.1 -C.sub.10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, 2-ethylpentyl, 1-ethylheptyl, 1-methyloctyl, 4-heptyl.
A cycloalkylalkyl group is preferably a group having 1 to 3 carbon atoms in the alkyl moiety and 3 to 7 carbon atoms in the cycloalkyl moiety such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-(5-norbornylenyl)ethyl.
An optionally substituted arylalkyl or phenylalkyl group is preferably 2-naphthalenylmethyl, benzyl, phenethyl, phenylpropyl, phenylbutyl, 3-(4-methylphenyl)propyl, 3-(4-fluorophenyl)propyl, 3-(4-chlorophenyl)propyl, 3-(4-trifluoromethylphenyl)propyl, 3-phenyl-1-methylpropyl, 2-phenyl-1-methylethyl, 3-phenyl-3-methyl-propyl, 1-phenylethyl.
A fused or non-fused aryl group is preferably 1,2,3,4-tetrahydro-2-naphthalenyl, 2-indanyl optionally substituted by one or more alkoxy, halogen or haloalkyl groups.
An acylated C.sub.1 -C.sub.4 hydroxyalkyl group is preferably acetoxyalkyl, propanoyloxyalkyl, 2-methylpropanoyloxyalkyl, benzoyloxyalkyl group.
A class of preferred compounds is that wherein: phenylalkyl, 1,2,3,4-tetrahydro-2-naphthalenyl or 2-indanyl optionally substituted with alkyl, alkoxy, halogen or haloalkyl; R' is hydrogen or methyl and R.sub.2 is hydrogen or methyl.
A particularly preferred sub-class is that wherein R.sub.1 is CH.sub.2 OH; R is phenyl-(C.sub.2 -C.sub.3)-alkyl or 1,2,3,4-tetrahydro-2-naphthalenyl, or 2-indanyl optionally substituted by one or more alkoxy, halogen, haloalkyl groups; R' and R.sub.2 are hydrogen.
A second class of preferred compounds is that wherein R.sub.1 is hydrogen or methyl, R is 1,2,3,4-tetrahydro-2-naphthalenyl or 2-indanyl optionally substituted by one or more alkoxy, halogen, haloalkyl groups and R' and R.sub.2 are hydrogen.
The compounds of the invention can be in the form of organic or inorganic acid addition salts.
Moreover they can have one or more asymmetric carbon atoms, therefore they can be used both in the form of mixtures containing more diastereoisomers in any ratio, and in the form of racemic mixtures containing couples of enantiomers in equal or different ratios, and in the form of optically pure compounds.
The compounds of the invention can be used in the treatment of chronic neurodegenerative diseases, such as Alzheimer's disease, various forms of dementia, Parkinson's disease, Huntingdon's disease or acute neurodegenerative impairments such as stroke and head injuries; in the treatment of epilepsy and depression.
GB patent 2048852 (Continental Pharma S.A.) discloses 2-aminoacetamide (commonly referred to as glycinamide) derivatives which can be used in the treatment of epilepsy, in the treatment of dyskinesias such as Parkinsons's disease, in the treatment of memory disorders and possibly in the treatment of depression.
Some of the disclosed compounds, orally administered in doses of 10-100 mg/kg, showed anticonvulsive effects against bicuculline-induced tonic convulsions in mouse.
2-n-Pentylaminoacetamide (in the following referred to with the nonproprietary name milacemide) and its hydrochloride were particularly studied.
Milacemide was used as the reference compound to test the pharmacological activity of the compounds of the present invention.
EP-B1-0400495 (Farmitalia C
REFERENCES:
patent: 5198547 (1993-03-01), Bailey et al.
Altamura et al, J. Med. Chem, vol. 38, pp. 4244-4256, 1995.
Pevarello et al, The New Journal of Organic Synthesis, pp. 179-183, 1996.
Armani Elisabetta
Chiesi Paolo
De Fanti Renato
Del Canale Maurizio
Pietra Claudio
Chiesi Farmaceutici S.p.A.
Kumar Shailendra
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