Derivatives of glycinergic r(+)-2-amino-3-hydroxypropanoic acid

• US 20050261372A1
• Filed: 08/01/2003
• Published: 11/24/2005
• Est. Priority Date: 08/14/2002
• Status: Active Grant

• Current Assignee: Prestwick Pharmaceuticals, Inc. (Bausch Health Cos., Inc.)
• Original Assignee: Prestwick Pharmaceuticals, Inc. (Bausch Health Cos., Inc.)
• Inventors: Contreras, Jean-Marie Georges, Wermuth, Camille Georges, Clarence-Smith, Kathleen, Deyon, Laurence Nathalie
• Granted Patent: US 7,488,755 B2
• Time in Patent Office: Days
• US Class Current: 514/561
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 2601/02 with a three-membered ring

Abstract

The use of R(+)-2-amino-3-hydroxypropanoic acid derivatives, nitrogen substituted by a (C₁-C₆)alkyl, (C₃-C₆)alkenyl, 3-oxo(C₅-C₆)alkyl, 3-oxo(C₄-C₆)alken-2-yl, phenyl(C₁-C₆)alkyl, phenyl(C₂-C₆)alkenyl, gem-diphenyl(C₁-C₆)alkyl, gem-diphenyl(C₂-C₆)alkenyl, (C₁-C₆)alcanoyl, optionally N-substituted alanyl, optionally N,N′-disubstituted lysinoyl, phenyl(C₁-C₆)alkylydene or gem-diphenyl(C₁-C₆)alkylidene group, and of the pharmaceutically acceptable salts thereof, for preparation of medicaments intended for the treatment of CNS diseases due to reduced glycinergic transmission, particularly for the treatment of autism, schizophrenia and Alzheimer'"'"'s disease, is described.

Claims

1. A method for treating cognitive disorders or mnestic disorders which accompany CNS diseases, comprising administering to a patient a R(+)-2-amino-3-hydroxypropanoic acid derivative of formula I

2. The method according to claim 1, wherein said CNS disease is schizophrenia.

3. The method according to claim 1, wherein said CNS disease is autism.

4. The method according to claim 1, wherein said CNS disease is Alzheimer'"'"'s disease.

5. The method according to claim 1, wherein said R(+)-2-amino-3-hydroxypropanoic acid derivative is selected from the group consisting of N-[R(+)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, N-[S(−

)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, N-[2-[S(−

)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, N-benzyl-R(+)-2-amino-3-hydroxypropanoic acid and pharmaceutically acceptable salts thereof.

13. The method according to claim 1, wherein said treatment increases glycinergic transmission in said patient.

6. A pharmaceutical composition comprising a pharmaceutically effective dose of a R(+)-2-amino-3-hydroxypropanoic acid derivative of formula II

7. The pharmaceutical composition according to claim 6, wherein said R(+)-2-amino-3-hydroxypropanoic acid derivative of formula II is selected from the group comprising 2-oxo-2-phenylethyl R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, cyclopropylmethyl R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, 4-acetylphenyl R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, N-[2-[R(+)-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, N-[2-[S(−

)-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, ethyl N-[S(−

)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, methyl N-[2-[S(−

)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, ethyl N-[2-[S(−

)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, N-[2-[R(+)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, methyl N-[2-[R(+)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, N-[2-[S(−

)-N,N′

-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic acid, the pharmaceutically acceptable salts thereof, methyl N-[2-[R(+)-N,N′

-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, methyl N-[2-[S(−

)-N,N′

-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, ethyl N-[2-[R(+)-N,N′

-bis-benzyloxycabonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable salts thereof, ethyl N-benzyl-R(+)-2-amino-3-hydroxypropanoate and pharmaceutically acceptable salts thereof.

8. A R(+)-2-amino-3-hydroxypropanoic acid derivative of formula III

9. The R(+)-2-amino-3-hydroxypropanoic acid derivative according to claim 8, where R′

is a ω

-diphenyl(C₂-C₆)alkyl group.

10. R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoic acid or a pharmaceutically acceptable salt thereof.

11. R(+)-N-[(4,4-diphenyl)-3-butenyl]-2-amino-3-hydroxypropanoic acid or a pharmaceutically acceptable salt thereof.

12. R(+)-N-[α

-phenyl-(2-hydroxy)benzylidene]-2-amino-3-hydroxypropanoic acid or a pharmaceutically acceptable salt thereof.