HK1090027A

HK1090027A - Amino acids with affinity for the alpha-2-delta-protein

Info

Publication number: HK1090027A
Application number: HK06110622.9A
Authority: HK
Inventors: 南希．S．巴塔; 雅各布．B．施瓦茨; 安德鲁．J．索普; 戴维．J．伍斯特罗
Original assignee: 沃纳-兰伯特公司
Priority date: 2002-03-28
Filing date: 2005-09-29
Publication date: 2006-12-15

Description

Amino acids having affinity for the alpha 2 delta protein

The present application is a divisional application of the Chinese patent application having an application date of 2003, 3/17, an application number of 03811269.8, and an invention name of "amino acid having affinity for α 2 δ -protein".

Background

The present invention relates to certain beta-amino acids that bind to the alpha-2-delta (alpha 2 delta) subunit of a calcium channel. These compounds and their pharmaceutically acceptable salts are useful in the treatment of various psychiatric, pain and other disorders.

Summary of The Invention

The present invention relates to compounds of the general formula I:

wherein R is₁Is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₂is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group; or

R₁And R₂Together with the carbon to which they are attached form a 3-6 membered cycloalkyl ring;

R₃is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-n (h) -, or pyridyl-n (h) -, wherein each of the foregoing alkyl moieties may be optionally substituted with 1-5 fluorine atoms, preferably 0-3 fluorine atoms, wherein said phenyl and said pyridyl groupPhenyl- (C)₁-C₃) Alkyl and said pyridyl- (C)₁-C₃) The phenyl and pyridyl groups in the alkyl group may each be optionally substituted with 1 to 3 substituents, preferably 0 to 2 substituents, independently selected from the group consisting of chloro, fluoro, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1-3 fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) An alkoxy group;

R₄is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₅is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group;

R₆is hydrogen or (C)₁-C₆) An alkyl group.

Particular embodiments of the present invention include the following compounds of formula I:

3-amino-5, 8-dimethyl-nonanoic acid;

3-amino-5, 5, 7-trimethyl-octanoic acid;

3-amino-5, 5, 8-trimethyl-nonanoic acid;

3-amino-5, 5, 6-trimethyl-heptanoic acid;

(3S, 5S) -3-amino-5, 8-dimethyl-nonanoic acid;

(3S, 5R) -3-amino-5, 8-dimethyl-nonanoic acid;

(3S) -3-amino-5, 5, 6-trimethyl-heptanoic acid;

(3S) -3-amino-5, 5, 7-trimethyl-octanoic acid;

(3S) -3-amino-5, 5, 8-trimethyl-nonanoic acid; and

(3S) -3-amino-5, 5, 9-trimethyl-decanoic acid.

Other examples of specific embodiments of the invention are the following compounds of formula I:

3-amino-6-cyclobutyl-5-methyl-hexanoic acid;

3-amino-7-cyclopropyl-5-methyl-heptanoic acid;

3-amino-7-cyclobutyl-5-methyl-heptanoic acid;

3-amino-7-cyclopentyl-5-methyl-heptanoic acid;

3-amino-7-cyclohexyl-5-methyl-heptanoic acid;

3-amino-8-cyclopropyl-5-methyl-octanoic acid;

3-amino-8-cyclobutyl-5-methyl-octanoic acid;

3-amino-8-cyclopentyl-5-methyl-octanoic acid;

3-amino-8-cyclohexyl-5-methyl-octanoic acid;

3-amino-6-cyclopropyl-5, 5-dimethyl-hexanoic acid;

3-amino-6-cyclobutyl-5, 5-dimethyl-hexanoic acid;

3-amino-6-cyclopentyl-5, 5-dimethyl-hexanoic acid;

3-amino-6-cyclohexyl-5, 5-dimethyl-hexanoic acid;

3-amino-7-cyclopropyl-5, 5-dimethyl-heptanoic acid;

3-amino-7-cyclobutyl-5, 5-dimethyl-heptanoic acid;

3-amino-7-cyclopentyl-5, 5-dimethyl-heptanoic acid;

3-amino-7-cyclohexyl-5, 5-dimethyl-heptanoic acid;

(3S, 5R) -3-amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5S) -3-amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S) -3-amino-6-cyclopropyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-6-cyclobutyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-6-cyclopentyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-6-cyclohexyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-7-cyclopropyl-5, 5-dimethyl-heptanoic acid;

(3S) -3-amino-7-cyclobutyl-5, 5-dimethyl-heptanoic acid;

(3S) -3-amino-7-cyclopentyl-5, 5-dimethyl-heptanoic acid; and

(3S) -3-amino-7-cyclohexyl-5, 5-dimethyl-heptanoic acid;

other embodiments of the present invention include the following compounds of formula I:

3-amino-5-methyl-heptanoic acid;

3-amino-5-methyl-octanoic acid;

3-amino-5-methyl-nonanoic acid;

3-amino-5, 5-dimethyl-nonanoic acid;

3-amino-5, 5-dimethyl-decanoic acid;

(3S) -3-amino-5, 5-dimethyl-nonanoic acid; and

(3S) -3-amino-5, 5-dimethyl-decanoic acid.

The invention also relates to compounds of general formula IA and pharmaceutically acceptable salts of such compounds:

wherein R is₁Is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₃) An alkyl group;

R₂is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₃) An alkyl group; or

R₃is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-N (H) -, or pyridyl-N (H) -, wherein each of the foregoing alkyl moieties may be optionally substituted with 1-5 fluorine atoms, preferably 0-3 fluorine atoms, wherein said phenyl and said pyridyl and said phenyl- (C)₁-C₃) Alkyl and said pyridyl- (C)₁-C₃) The phenyl and pyridyl groups in the alkyl group may each be optionally substituted with 1 to 3 substituents, preferably 0 to 2 substituents, independently selected from the group consisting of chloro, fluoro, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1-3 fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) An alkoxy group;

the condition is satisfied when R₁When is hydrogen, R₂Is not hydrogen.

The invention also relates to compounds of the general formula IA-1

Wherein R is₃The same as defined in formula I above, and pharmaceutically acceptable salts of such compounds.

Other embodiments of the present invention include the following compounds of formula IA:

3-amino-5-methyl-8-phenylamino-octanoic acid;

3-amino-5-methyl-7-phenylamino-heptanoic acid;

3-amino-5-methyl-6-phenylamino-hexanoic acid;

(3S, 5R) -3-amino-5-methyl-8-phenylamino-octanoic acid;

(3S, 5R) -3-amino-5-methyl-7-phenylamino-heptanoic acid;

(3S, 5R) -3-amino-5-methyl-6-phenylamino-hexanoic acid;

(3S, 5S) -3-amino-5-methyl-8-phenylamino-octanoic acid;

(3S, 5S) -3-amino-5-methyl-7-phenylamino-heptanoic acid;

(3S, 5S) -3-amino-5-methyl-6-phenylamino-hexanoic acid;

3-amino-5-methyl-8-phenyl-octanoic acid;

3-amino-8- (2-fluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (3-fluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (4-fluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (2-trifluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (3-trifluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (4-trifluoro-phenyl) -5-methyl-octanoic acid;

3-amino-5-methyl-8-o-tolyl-octanoic acid;

3-amino-5-methyl-8-m-tolyl-octanoic acid;

3-amino-5-methyl-8-p-tolyl-octanoic acid;

3-amino-8- (2, 3-difluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (2, 4-difluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (2, 5-difluoro-phenyl) -5-methyl-octanoic acid;

3-amino-8- (2, 6-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-5-methyl-8-phenyl-octanoic acid;

(3S, 5S) -3-amino-5-methyl-8-phenyl-octanoic acid;

(3S, 5R) -3-amino-8- (2-fluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (2-fluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (3-fluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (3-fluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (4-fluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (4-fluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (2-trifluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (2-trifluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (3-trifluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (3-trifluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (4-trifluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (4-trifluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-5-methyl-8-o-tolyl-octanoic acid;

(3S, 5S) -3-amino-5-methyl-8-o-tolyl-octanoic acid;

(3S, 5R) -3-amino-5-methyl-8-m-tolyl-octanoic acid;

(3S, 5S) -3-amino-5-methyl-8-m-tolyl-octanoic acid;

(3S, 5R) -3-amino-5-methyl-8-p-tolyl-octanoic acid;

(3S, 5S) -3-amino-5-methyl-8-p-tolyl-octanoic acid;

(3S, 5R) -3-amino-8- (2, 3-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (2, 3-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (2, 4-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (2, 4-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (2, 5-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5S) -3-amino-8- (2, 5-difluoro-phenyl) -5-methyl-octanoic acid;

(3S, 5R) -3-amino-8- (2, 6-difluoro-phenyl) -5-methyl-octanoic acid; and

(3S, 5S) -3-amino-8- (2, 6-difluoro-phenyl) -5-methyl-octanoic acid.

Preferred compounds of the present invention include compounds of formula IA-2,

IA-2

wherein R is₁，R₂And R₃The same as defined in formula I above.

An example of a more preferred compound of the invention is a compound of formula IA-2 wherein R is₁Is hydrogen, R₂Is methyl, R₃The same as defined in formula I above.

An example of a particular embodiment of the present invention is the following compound of formula IA-2:

(3S, 5R) -3-amino-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-5-methyl-octanoic acid; and

(3S, 5R) -3-amino-5-methyl-nonanoic acid.

The invention also relates to compounds of general formula IB and pharmaceutically acceptable salts thereof,

wherein R is₃As defined above, the compound is selected from the following compounds and pharmaceutically acceptable salts thereof:

3-amino-4, 5-dimethyl-hexanoic acid;

3-amino-4, 6-dimethyl-heptanoic acid;

3-amino-4, 7-dimethyl-octanoic acid;

3-amino-4, 8-dimethyl-nonanoic acid;

3-amino-4, 9-dimethyl-decanoic acid;

3-amino-4-cyclopropyl-pentanoic acid;

3-amino-4-cyclobutyl-pentanoic acid;

3-amino-4-cyclopentyl-pentanoic acid;

3-amino-4-cyclohexyl-pentanoic acid;

3-amino-5-cyclopropyl-4-methyl-pentanoic acid;

3-amino-5-cyclobutyl-4-methyl-pentanoic acid;

3-amino-5-cyclopentyl-4-methyl-pentanoic acid;

3-amino-5-cyclohexyl-4-methyl-pentanoic acid;

3-amino-6-cyclopropyl-4-methyl-hexanoic acid;

3-amino-6-cyclobutyl-4-methyl-hexanoic acid;

3-amino-6-cyclopentyl-4-methyl-hexanoic acid;

3-amino-6-cyclohexyl-4-methyl-hexanoic acid;

3-amino-7-cyclopropyl-4-methyl-heptanoic acid;

3-amino-7-cyclobutyl-4-methyl-heptanoic acid;

3-amino-7-cyclopentyl-4-methyl-heptanoic acid;

3-amino-7-cyclohexyl-4-methyl-heptanoic acid;

3-amino-8-cyclopropyl-4-methyl-octanoic acid;

3-amino-8-cyclobutyl-4-methyl-octanoic acid;

3-amino-8-cyclopentyl-4-methyl-octanoic acid;

3-amino-8-cyclohexyl-4-methyl-octanoic acid;

3-amino-9-cyclopropyl-4-methyl-nonanoic acid;

3-amino-9-cyclobutyl-4-methyl-nonanoic acid;

3-amino-9-cyclopentyl-4-methyl-nonanoic acid;

3-amino-9-cyclohexyl-4-methyl-nonanoic acid;

3-amino-4-methyl-octanoic acid;

3-amino-4-methyl-nonanoic acid;

3-amino-4-methyl-decanoic acid;

(3R, 4R) -3-amino-4, 5-dimethyl-hexanoic acid;

(3R, 4R) -3-amino-4, 6-dimethyl-heptanoic acid;

(3R, 4R) -3-amino-4, 7-dimethyl-octanoic acid;

(3R, 4R) -3-amino-4, 8-dimethyl-nonanoic acid;

(3R, 4R) -3-amino-4, 9-dimethyl-decanoic acid;

(3R, 4R) -3-amino-4-cyclopropyl-pentanoic acid;

(3R, 4R) -3-amino-4-cyclobutyl-pentanoic acid;

(3R, 4R) -3-amino-4-cyclopentyl-pentanoic acid;

(3R, 4R) -3-amino-4-cyclohexyl-pentanoic acid;

(3R, 4R) -3-amino-5-cyclopropyl-4-methyl-pentanoic acid;

(3R, 4R) -3-amino-5-cyclobutyl-4-methyl-pentanoic acid;

(3R, 4R) -3-amino-5-cyclopentyl-4-methyl-pentanoic acid;

(3R, 4R) -3-amino-5-cyclohexyl-4-methyl-pentanoic acid;

(3R, 4R) -3-amino-6-cyclopropyl-4-methyl-hexanoic acid;

(3R, 4R) -3-amino-6-cyclobutyl-4-methyl-hexanoic acid;

(3R, 4R) -3-amino-6-cyclopentyl-4-methyl-hexanoic acid;

(3R, 4R) -3-amino-6-cyclohexyl-4-methyl-hexanoic acid;

(3R, 4R) -3-amino-7-cyclopropyl-4-methyl-heptanoic acid;

(3R, 4R) -3-amino-7-cyclobutyl-4-methyl-heptanoic acid;

(3R, 4R) -3-amino-7-cyclopentyl-4-methyl-heptanoic acid;

(3R, 4R) -3-amino-7-cyclohexyl-4-methyl-heptanoic acid;

(3R, 4R) -3-amino-8-cyclopropyl-4-methyl-octanoic acid;

(3R, 4R) -3-amino-8-cyclobutyl-4-methyl-octanoic acid;

(3R, 4R) -3-amino-8-cyclopentyl-4-methyl-octanoic acid;

(3R, 4R) -3-amino-8-cyclohexyl-4-methyl-octanoic acid;

(3R, 4R) -3-amino-9-cyclopropyl-4-methyl-nonanoic acid;

(3R, 4R) -3-amino-9-cyclobutyl-4-methyl-nonanoic acid;

(3R, 4R) -3-amino-9-cyclopentyl-4-methyl-nonanoic acid;

(3R, 4R) -3-amino-9-cyclohexyl-4-methyl-nonanoic acid;

(3R, 4R) -3-amino-4-methyl-octanoic acid;

(3R, 4R) -3-amino-4-methyl-nonanoic acid;

(3R, 4R) -3-amino-4-methyl-decanoic acid;

(3R, 4S) -3-amino-4, 5-dimethyl-hexanoic acid;

(3R, 4S) -3-amino-4, 6-dimethyl-heptanoic acid;

(3R, 4S) -3-amino-4, 7-dimethyl-octanoic acid;

(3R, 4S) -3-amino-4, 8-dimethyl-nonanoic acid;

(3R, 4S) -3-amino-4, 9-dimethyl-decanoic acid;

(3R, 4S) -3-amino-4-cyclopropyl-pentanoic acid;

(3R, 4S) -3-amino-4-cyclobutyl-pentanoic acid;

(3R, 4S) -3-amino-4-cyclopentyl-pentanoic acid;

(3R, 4S) -3-amino-4-cyclohexyl-pentanoic acid;

(3R, 4S) -3-amino-5-cyclopropyl-4-methyl-pentanoic acid;

(3R, 4S) -3-amino-5-cyclobutyl-4-methyl-pentanoic acid;

(3R, 4S) -3-amino-5-cyclopentyl-4-methyl-pentanoic acid;

(3R, 4S) -3-amino-5-cyclohexyl-4-methyl-pentanoic acid;

(3R, 4S) -3-amino-6-cyclopropyl-4-methyl-hexanoic acid;

(3R, 4S) -3-amino-6-cyclobutyl-4-methyl-hexanoic acid;

(3R, 4S) -3-amino-6-cyclopentyl-4-methyl-hexanoic acid;

(3R, 4S) -3-amino-6-cyclohexyl-4-methyl-hexanoic acid;

(3R, 4S) -3-amino-7-cyclopropyl-4-methyl-heptanoic acid;

(3R, 4S) -3-amino-7-cyclobutyl-4-methyl-heptanoic acid;

(3R, 4S) -3-amino-7-cyclopentyl-4-methyl-heptanoic acid;

(3R, 4S) -3-amino-7-cyclohexyl-4-methyl-heptanoic acid;

(3R, 4S) -3-amino-8-cyclopropyl-4-methyl-octanoic acid;

(3R, 4S) -3-amino-8-cyclobutyl-4-methyl-octanoic acid;

(3R, 4S) -3-amino-8-cyclopentyl-4-methyl-octanoic acid;

(3R, 4S) -3-amino-8-cyclohexyl-4-methyl-octanoic acid;

(3R, 4S) -3-amino-9-cyclopropyl-4-methyl-nonanoic acid;

(3R, 4S) -3-amino-9-cyclobutyl-4-methyl-nonanoic acid;

(3R, 4S) -3-amino-9-cyclopentyl-4-methyl-nonanoic acid;

(3R, 4S) -3-amino-9-cyclohexyl-4-methyl-nonanoic acid;

(3R, 4S) -3-amino-4-methyl-octanoic acid;

(3R, 4S) -3-amino-4-methyl-nonanoic acid; and

(3R, 4S) -3-amino-4-methyl-decanoic acid.

The invention also relates to compounds of general formula IC and pharmaceutically acceptable salts thereof,

3-amino-6-methyl-decanoic acid;

3-amino-6-cyclopropyl-heptanoic acid;

3-amino-6-cyclobutyl-heptanoic acid;

3-amino-6-cyclopentyl-heptanoic acid;

3-amino-6-cyclohexyl-heptanoic acid;

3-amino-7-cyclopropyl-6-methyl-heptanoic acid;

3-amino-7-cyclobutyl-6-methyl-heptanoic acid;

3-amino-7-cyclopentyl-6-methyl-heptanoic acid;

3-amino-7-cyclohexyl-6-methyl-heptanoic acid;

3-amino-8-cyclopropyl-6-methyl-octanoic acid;

3-amino-8-cyclobutyl-6-methyl-octanoic acid;

3-amino-8-cyclopentyl-6-methyl-octanoic acid;

3-amino-8-cyclohexyl-6-methyl-octanoic acid;

3-amino-9-cyclopropyl-6-methyl-nonanoic acid;

3-amino-9-cyclobutyl-6-methyl-nonanoic acid;

3-amino-9-cyclopentyl-6-methyl-nonanoic acid;

3-amino-9-cyclohexyl-6-methyl-nonanoic acid;

3-amino-10-cyclopropyl-6-methyl-decanoic acid;

3-amino-10-cyclobutyl-6-methyl-decanoic acid;

3-amino-10-cyclopentyl-6-methyl-decanoic acid;

3-amino-10-cyclohexyl-6-methyl-decanoic acid;

3-amino-6-isopropyl-heptanoic acid;

3-amino-6, 8-dimethyl-nonanoic acid;

3-amino-6, 9-dimethyl-decanoic acid;

(3S, 6R) -3-amino-6-methyl-decanoic acid;

(3S, 6R) -3-amino-6-cyclopropyl-heptanoic acid;

(3S, 6R) -3-amino-6-cyclobutyl-heptanoic acid;

(3S, 6R) -3-amino-6-cyclopentyl-heptanoic acid;

(3S, 6R) -3-amino-6-cyclohexyl-heptanoic acid;

(3S, 6R) -3-amino-7-cyclopropyl-6-methyl-heptanoic acid;

(3S, 6R) -3-amino-7-cyclobutyl-6-methyl-heptanoic acid;

(3S, 6R) -3-amino-7-cyclopentyl-6-methyl-heptanoic acid;

(3S, 6R) -3-amino-7-cyclohexyl-6-methyl-heptanoic acid;

(3S, 6R) -3-amino-8-cyclopropyl-6-methyl-octanoic acid;

(3S, 6R) -3-amino-8-cyclobutyl-6-methyl-octanoic acid;

(3S, 6R) -3-amino-8-cyclopentyl-6-methyl-octanoic acid;

(3S, 6R) -3-amino-8-cyclohexyl-6-methyl-octanoic acid;

(3S, 6R) -3-amino-9-cyclopropyl-6-methyl-nonanoic acid;

(3S, 6R) -3-amino-9-cyclobutyl-6-methyl-nonanoic acid;

(3S, 6R) -3-amino-9-cyclopentyl-6-methyl-nonanoic acid;

(3S, 6R) -3-amino-9-cyclohexyl-6-methyl-nonanoic acid;

(3S, 6R) -3-amino-10-cyclopropyl-6-methyl-decanoic acid;

(3S, 6R) -3-amino-10-cyclobutyl-6-methyl-decanoic acid;

(3S, 6R) -3-amino-10-cyclopentyl-6-methyl-decanoic acid;

(3S, 6R) -3-amino-10-cyclohexyl-6-methyl-decanoic acid;

(3S, 6R) -3-amino-6-isopropyl-heptanoic acid;

(3S, 6R) -3-amino-6, 8-dimethyl-nonanoic acid;

(3S, 6R) -3-amino-6, 9-dimethyl-decanoic acid;

(3S, 6S) -3-amino-6-methyl-octanoic acid;

(3S, 6S) -3-amino-6-methyl-nonanoic acid;

(3S, 6S) -3-amino-6-methyl-decanoic acid;

(3S, 6S) -3-amino-6-cyclopropyl-heptanoic acid;

(3S, 6S) -3-amino-6-cyclobutyl-heptanoic acid;

(3S, 6S) -3-amino-6-cyclopentyl-heptanoic acid;

(3S, 6S) -3-amino-6-cyclohexyl-heptanoic acid;

(3S, 6S) -3-amino-7-cyclopropyl-6-methyl-heptanoic acid;

(3S, 6S) -3-amino-7-cyclobutyl-6-methyl-heptanoic acid;

(3S, 6S) -3-amino-7-cyclopentyl-6-methyl-heptanoic acid;

(3S, 6S) -3-amino-7-cyclohexyl-6-methyl-heptanoic acid;

(3S, 6S) -3-amino-8-cyclopropyl-6-methyl-octanoic acid;

(3S, 6S) -3-amino-8-cyclobutyl-6-methyl-octanoic acid;

(3S, 6S) -3-amino-8-cyclopentyl-6-methyl-octanoic acid;

(3S, 6S) -3-amino-8-cyclohexyl-6-methyl-octanoic acid;

(3S, 6S) -3-amino-9-cyclopropyl-6-methyl-nonanoic acid;

(3S, 6S) -3-amino-9-cyclobutyl-6-methyl-nonanoic acid;

(3S, 6S) -3-amino-9-cyclopentyl-6-methyl-nonanoic acid;

(3S, 6S) -3-amino-9-cyclohexyl-6-methyl-nonanoic acid;

(3S, 6S) -3-amino-10-cyclopropyl-6-methyl-decanoic acid;

(3S, 6S) -3-amino-10-cyclobutyl-6-methyl-decanoic acid;

(3S, 6S) -3-amino-10-cyclopentyl-6-methyl-decanoic acid;

(3S, 6S) -3-amino-10-cyclohexyl-6-methyl-decanoic acid;

(3S, 6S) -3-amino-6-isopropyl-heptanoic acid;

(3S, 6S) -3-amino-6, 8-dimethyl-nonanoic acid; and

(3S, 6S) -3-amino-6, 9-dimethyl-decanoic acid.

The invention also relates to compounds of formula II and pharmaceutically acceptable salts of such compounds:

wherein R is₁、R₂And R₃The same as defined in formula I above.

An example of a particular embodiment of the present invention is the following compound of formula IV: 2-aminomethyl-4-propyl-heptanoic acid.

The invention also relates to compounds of formula IIA and pharmaceutically acceptable salts of such compounds:

wherein R is₃The same as defined in formula I above.

Other embodiments of the present invention include the following compounds of formula IIA:

2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;

2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;

2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (2, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (3, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (2, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (3, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (2, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (3, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-ethyl-hexanoic acid;

2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-isopropyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-butyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-isobutyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- [1- (4-methyl-pentyl) -cyclopropyl ] -propionic acid;

2-aminomethyl-3- (1-methyl-cyclobutyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclobutyl) -propionic acid;

2-aminomethyl-3- (1-methyl-cyclopentyl) -propionic acid;

2-aminomethyl-3- (1-ethyl-cyclopentyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclopentyl) -propionic acid;

2-aminomethyl-3- (1-methyl-cyclohexyl) -propionic acid;

2-aminomethyl-3- (1-ethyl-cyclohexyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclohexyl) -propionic acid;

2-aminomethyl-4-ethyl-hexanoic acid;

2-aminomethyl-4-ethyl-5-methyl-hexanoic acid;

2-aminomethyl-4-ethyl-heptanoic acid;

2-aminomethyl-4-ethyl-6-methyl-heptanoic acid;

2-aminomethyl-4-ethyl-octanoic acid;

2-aminomethyl-4-ethyl-7-methyl-octanoic acid;

2-aminomethyl-4-ethyl-nonanoic acid;

2-aminomethyl-4-ethyl-8-methyl-nonanoic acid;

2-aminomethyl-4, 4-dimethyl-heptanoic acid;

2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid;

2-aminomethyl-5-ethyl-heptanoic acid;

2-aminomethyl-5-ethyl-6-methyl-heptanoic acid;

2-aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid;

2-aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid;

2-aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid;

2-aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid;

2-aminomethyl-5-ethyl-octanoic acid;

2-aminomethyl-5-ethyl-7-methyl-octanoic acid;

2-aminomethyl-5-ethyl-nonanoic acid;

2-aminomethyl-5-ethyl-8-methyl-nonanoic acid;

2-aminomethyl-4-cyclopropyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclopropyl) -butyric acid;

2-aminomethyl-4-cyclobutyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclobutyl) -butyric acid;

2-aminomethyl-4-cyclopentyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclopentyl) -butyric acid;

2-aminomethyl-4- (1-ethyl-cyclopentyl) -butyric acid;

2-aminomethyl-4-cyclohexyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclohexyl) -butyric acid;

2-aminomethyl-4- (1-ethyl-cyclohexyl) -butyric acid;

(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-ethyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-ethyl-hexanoic acid; and

(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-ethyl-hexanoic acid.

2-aminomethyl-4-methyl-hexanoic acid;

2-aminomethyl-4-methyl-heptanoic acid;

2-aminomethyl-4-methyl-octanoic acid;

2-aminomethyl-4-methyl-nonanoic acid;

2-aminomethyl-4-methyl-decanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-nonanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-decanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-nonanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-decanoic acid;

2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;

2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; and

(2R, 4R) -2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid.

The invention also relates to compounds of general formula III and pharmaceutically acceptable salts thereof,

wherein R is₃The definition is the same as that in the general formula I.

The invention also relates to compounds of general formula IV and pharmaceutically acceptable salts thereof,

wherein R is₁And R₃The definition is the same as that in the general formula I.

Other embodiments of the present invention include the following compounds of formula IV and pharmaceutically acceptable salts thereof:

2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

2-aminomethyl-5-methyl-heptanoic acid;

2-aminomethyl-5-methyl-octanoic acid;

2-aminomethyl-5-methyl-heptanoic acid;

2-aminomethyl-5-methyl-nonanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-nonanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-5-methyl-heptanoic acid; and

(2R, 6R) -2-aminomethyl-5-methyl-nonanoic acid.

The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, IA-1, IA-2, IB, IC, II, IIA, III or IV or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a disease or condition in a mammal, including a human, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from epilepsy, faintness attacks, fibromyalgia (fibrosyalgia), hypokinesia (hypokinesia), cranial disorders, hot flashes (hot flashes), essential tremor (essentia tremator), chemical dependencies and addictions (e.g., to alcohol, amphetamine (or amphetamine-like substances), caffeine, cannabis, cocaine, heroin, hallucinogens, tobacco, inhalants and aerosol propellants (propellants), nicotine, papaverines (opioids), phenylglycine (phenylglycine) derivatives, sedatives, hypnotics, benzodiazepines , and other dependency and addiction to anxiolytics), and other anxiolytics, And withdrawal symptoms (withrawallsymptoms) associated with the aforementioned dependence or addiction, addictive behaviors such as gambling; migraine, spasticity (spasticity), arthritis, Irritable Bowel Syndrome (IBS), chronic pain, acute pain, neuropathic pain (neuropathic pain), vascular headache, sinus headache, inflammatory diseases (inflimatory disorders) (e.g., rheumatoid arthritis, osteoarthritis, psoriasis), polyuria (diuresis), premenstrual syndrome, premenstrual dysphoric disorder, tinnitus (tinitis), and gastric injury.

The present invention also includes the treatment of neurodegenerative diseases known as acute brain injury. Including but not limited to: stroke, head trauma and syncope.

Stroke is associated with cerebrovascular disease and is therefore also known as cerebrovascular accident (CVA), which includes acute cerebral thrombosis stroke. Strokes include both local and systemic ischemia. In addition, transient ischemic attacks and other cerebrovascular diseases accompanied by cerebral ischemia, such as those manifested by carotid endarterectomy or other cerebrovascular or vascular surgery or vascular diagnostic treatments including cerebrovascular angiography, are also included.

The compounds of formulae I, IA-1, IA-2, IB, IC, II, IIA, III and IV are also useful in the treatment of head trauma, spinal cord trauma or injuries caused by common hypoxia, tissue hypoxia, hypoglycemia, hypotension and similar injuries that occur during joint replacement (embole), hyper-instillation (hyper-fusion), tissue hypoxia. The compounds are also useful for preventing neuronal damage during cardiac bypass surgery or in the event of intracranial hemorrhage, perinatal syncope, cardiac arrest and status epilepticus.

The invention also relates to a method of treating a disease or condition in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula I, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof, effective to treat such a disease or condition, wherein the disease or condition is selected from delirium (delirium), dementia and amnesia and other cognitive or neurodegenerative diseases, such as Parkinson's Disease (PD), Huntington's Disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory impairment, vascular dementia, and other types of dementia, such as dementia caused by HIV disease, head trauma, Parkinson's disease, Huntington's disease, pick's disease, Creutzfeldt-Jakob disease, or by a variety of etiologies; movement disorders such as akinesia, dyskinesias including familial paroxysmal dyskinesia, spasticity (spasticities), Tourette's syndrome, Scott syndrome, PALSYS, and akinetic-rigid syndrome; extrapyramidal movement disorders such as movement disorders caused by therapeutic drugs, for example Parkinsonism caused by neuroleptics (neuroleptic-induced Parkinsonism), neuroleptic malignant syndrome, acute dystonia caused by neuroleptics (neuroleptic-induced acute dystonia), acute akathisia caused by neuroleptics, tardive dyskinesia caused by neuroleptics and postural tremor caused by therapeutic drugs; down syndrome; demyelinating diseases such as Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS), peripheral neuropathies such as diabetes and neuropathies resulting from chemotherapy, and post-herpetic neuralgia, trigeminal neuralgia, segmental (sectional) or intercostal neuralgia and other neuralgias; cerebrovascular disorders due to acute or chronic cerebrovascular injury, such as cerebral infarction, subarachnoid hemorrhage or cerebral edema.

Pain refers to both acute and chronic pain. Acute pain usually occurs in a short period of time with hyperactive sympathetic nervous system. Examples of this are postoperative pain and allodynia. Chronic pain is generally defined as pain that lasts 3-6 months, including somatogenic pain and psychogenic pain. Other pain refers to pain in which pain sensation is felt.

Examples of the types of pain that can be treated by the compounds of formulae I, IA-1, IA-2, IB, IC, II, IIA, III and IV of the present invention, or pharmaceutically acceptable salts thereof, include pain caused by soft tissue and peripheral injuries, such as acute trauma, pain associated with osteoarthritis and rheumatoid arthritis, musculo-skeletal pain, such as post-traumatic pain; spinal pain, toothache, myofascial pain syndrome, vulvo-incisional pain, and pain caused by burns; deep and visceral pain, such as cardiac pain, muscular pain, ocular pain, orofacial pain, such as dental pain, abdominal pain, gynecological pain, such as dysmenorrhea, labor pain and pain associated with endometriosis; pain associated with nerve and root organ damage, such as pain associated with peripheral nerve disorders, such as compressive nerve damage (nerve entrraptor) and brachial plexus extraction, amputation, peripheral neuropathy, trigeminal neuralgia (tic doureuux), atypical facial pain, nerve root injury, trigeminal neuralgia, neuropathic lower back pain, HIV-associated neuropathic pain, cancer-associated neuropathic pain, diabetic neuralgia, and arachnoiditis; neuropathic and non-neuropathic pain associated with tumors, also commonly referred to as cancer pain; central nervous system pain, such as that caused by spinal cord or brainstem injury; lower back pain; sciatica; phantom limb pain, headache, including migraine and other vascular headaches, acute or chronic tension headaches, cluster headaches, temporomandibular (temporomandibular) pain and maxillary sinus pain; pain caused by ankylosing spondylitis and gout; pain caused by increased bladder (blader) contractions; post-operative pain; scar pain; and chronic non-neuropathic pain such as pain associated with fibromyalgia, HIV, rheumatism and osteoarthritis, anthralgia and myalgia, sprains, excessive fatigue and trauma such as bone fracture; and post-surgical pain.

Other pain is also caused by peripheral sensory nerve injury or infection. It includes, but is not limited to, peripheral nerve trauma pain, herpes virus infection, diabetes, fibromyalgia, causalgia, plexus aspiration (plexus avulsion), neuroma, amputation and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiency. Neuropathic pain includes, but is not limited to, pain caused by nerve damage, such as that sustained by diabetics.

Psychogenic pain refers to pain that occurs without an organic etiology, such as lower back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain (inflomatory pain), osteoarthritis pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, restless leg syndrome, acute herpes and post-herpetic neuralgia, causalgia, brachial plexus extraction, occipital neuralgia, gout, phantom limb, burn, and other forms of neuralgia, neuropathic and idiopathic pain syndromes.

The compounds of the present invention are also useful in the treatment of depression. Depression may originate from organ disease, secondary to stress associated with personal losses, or simply from idiopathic. There is a clear trend to find a form of depression throughout the family, suggesting the pathogenesis of at least some depression. The diagnosis of depression is based primarily on quantifying changes in the mood of the patient. Such assessment of mood as described above is typically done by a physician or quantified by a neuropsychologist using an effective Rating Scale such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Many other types of scales have been developed for quantifying and evaluating the degree of mood changes in depressed patients who present with, for example, insomnia, poor concentration, poor energy, feelings of disability, and guilt. Diagnostic criteria for depression and all psychiatric Disorders are compiled in the Diagnostic and Statistical Manual for Mental Disorders (fourth edition) published by the American society for Mental Disorders in 1994, also known as the DSM-IV-R Manual.

The present invention also relates to a method of treating a disease or condition in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof, effective to treat such a disease or condition, wherein the disease or condition is selected from mood disorders (moodsords), such as depression (depression), or more particularly depression (depressive disorders), such as single-onset (single-episode) or recurrent major depression (depressive disorders), dysthymia, depressive neurosis and neuropathic depression, melancholic depression, including anorexia, weight loss, insomnia, early morning awakening (early waking) and psychomotor retardation, atypical depression (or reactive depression), including appetite increase, hypersomnia, Psychomotor agitation or allergies, seasonal affective disorder, and childhood depression; or bipolar disorders or manic depressive disorders, such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder; conduct disorder and disruptive behavior disease; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic, specific phobias such as specific animal phobias, social anxiety disorder, social phobia, obsessive compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorder; borderline personality disorder; schizophrenia as well as other psychoses, such as schizophreniform disorders, schizoaffective disorders, delusional disorders, transient psychotic disorders (brief psychiatric disorders), shared psychogenic disorders (shared psychogenic disorders), psychosis exhibiting delusions or hallucinations, psychotic episodes of anxiety (anxiety disorders), anxiety disorders with psychosis, psychotic mood disorders such as major depression (severe major depressive disorder); mood disorders with psychoses such as acute mania and depression with bipolar disorder, mood disorders with schizophrenia; behavior disorder accompanied by delayed thinking, autism, conduct disorder.

The compounds of the present invention are also useful in the treatment of sleep disorders. Sleep disorders refer to interference phenomena that affect the ability to fall asleep and/or sleep, including hypersomnia or causing sleep-related abnormalities. Such diseases include, for example, insomnia, drug-related insomnia, hypersomnia, narcolepsy, sleep apnea syndrome, and parasomnia.

The present invention also relates to a method of treating a disease or condition in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I, IA-1, IA-2, IB, IC, II, IIA, III or IV, or a pharmaceutically acceptable salt thereof, effective to treat such a disease or condition, wherein said disease or condition is selected from the group consisting of sleep disorders (sleepdisorders) (e.g. insomnia, drug-related insomnia, REM sleep disorders, hypersomnia, narcolepsy, sleep-wake cycle disorders, sleep apnea syndrome, parasomnia and sleep disorders associated with shift work and irregular work hours).

The compounds of the formulae I, IA-1, IA-2, IB, IC, II, IIA, III and IV contain at least one chiral center and may thus exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of general formulae I, IA-1, IA-2, IB, IC, II, IIA, III and IV, including racemic mixtures of these compounds and individual enantiomeric and diastereomeric forms and mixtures thereof, to pharmaceutical compositions containing or using these compounds, respectively, and to methods of treatment as described above. The individual isomers may be obtained by known methods such as optical resolution, optically selective reactions or by chromatographic separation during the preparation of the final product or an intermediate thereof. The individual enantiomers of the compounds of the invention may be advantageous over racemic mixtures of such compounds in the treatment of various diseases or conditions.

The present invention also includes isotopically-labelled compounds, which are identical to those recited in formulas I, IA-1, IA-2, IB, IC, II, IIA, III and IV above, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the invention containing the aforementioned isotopes and/or other isotopes of other atoms, precursors thereofPharmaceutically acceptable salts of drugs, of said compounds or of said prodrugs fall within the scope of the invention. Certain isotopically-labeled compounds of the present invention, for example, those into which a radioactive isotope such as³H and¹⁴the compounds of C are useful as pharmaceuticals and/or substrates for performing tissue distribution assays. Containing tritium, i.e.³H and carbon-14 i.e.¹⁴These isotopes are particularly preferred because of their ease of preparation and detection. In addition, the use of heavy isotopes, e.g. deuterium, is also known²Substitution with H may also result in therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and thus may be preferred in some circumstances. Isotopically-labelled compounds of formula I of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below, using readily available isotopically-labelled reagents in place of non-isotopically-labelled reagents.

The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic groups, or combinations thereof. Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec-and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like.

As used herein, unless otherwise indicated, the term "alkoxy" refers to "alkyl-O-", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and pentoxy.

The term "treating" as used herein refers to reversing, alleviating, inhibiting the worsening of the disease or condition to which the term refers, or preventing one or more symptoms of such condition or disease. The term "treatment" as used herein refers to a therapeutic effect, and is as defined above for "treatment".

Since amino acids are amphoteric, their pharmacologically compatible salts may be salts of suitable inorganic or organic acids, for example salts of hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic and ascorbic acids. Starting from the corresponding hydroxides or carbonates, salts with alkali metals or alkaline earth metals, such as sodium, potassium, magnesium or calcium, can be formed. Salts with quaternary ammonium ions can also be prepared using, for example, tetramethyl-ammonium ions.

The efficacy of an oral drug depends on the effective transport of the drug across mucosal epithelial cells and its stability in the entero-hepatic circulation. Drugs that are effective after parenteral administration but have low oral efficacy or have a plasma half-life that is considered too short can be converted chemically to the prodrug form.

A prodrug is a drug that has been chemically modified to be physiologically active at its site of action, but which may be degraded or modified by one or more enzymes or other in vivo pathways to the parent, biologically active form.

Such a chemically modified drug or prodrug should have a different pharmacokinetic profile than its parent drug, be more readily absorbed through mucosal epithelial cells, form a better salt and/or be more soluble, and have improved systemic stability (e.g., prolonged plasma half-life). The chemical modification method may be

1) Ester or amide derivatives which can be cleaved by, for example, esterases or lipases. For ester derivatives, such esters are derived from the carboxylic acid groups of the drug molecule by known methods. For amide derivatives, such amides may be derived from the carboxylic acid or amine groups of the drug molecule by known methods.

2) Peptides that can be recognized by specific or non-specific proteases. The peptide may be coupled to the drug molecule by amide bond formation with an amine or carboxylic acid group of the drug molecule according to known methods.

3) The stacked derivatives are formed at their site of action by membrane selective action of the prodrug form or modified prodrug form.

4)1-3 in any combination.

Present animal experimental studies have shown that oral absorption of certain drugs can be improved by preparing "soft" quaternary salts. This quaternary salt is called a "soft" quaternary salt because it is compatible with common quaternary salts such as R-N⁺(CH₃)₃Instead, it may release the active agent by hydrolysis.

"Soft" quaternary salts have more useful physical properties than the parent drug or salt thereof. The "soft" quaternary salt can increase water solubility compared to other salts such as the hydrochloride salt, and more importantly, it can improve the intestinal absorption of the drug. The increased absorption may be due to the surface activity of the "soft" quaternary salt, which is suitable for forming micelles and unionized ion pairs with bile acids and the like, which are able to penetrate the intestinal epithelial cells more efficiently. The prodrug is absorbed and then hydrolyzed shortly after absorption to release the active parent drug.

Prodrugs of compounds of formula I, IA-1, IA-2, IB, IC, II, IIA, III and IV are included within the scope of the present invention. Prodrugs and soft drugs (soft drugs) are known in the art (Palomino E., drug of the Future, 1990; 15 (4): 361-. The last two citations are hereby incorporated by reference.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated, including hydrated forms. In general, solvate forms, including hydrate forms, are equivalent to non-solvate forms and are thus included within the scope of the present invention.

Detailed Description

The compounds of the present invention can be prepared as follows. In the reaction schemes and descriptions that follow, unless otherwise indicated, the structural formulae I, IA-1, IA-2, IB, IC, II, IIA, III and IV and the group R₁、R₂、R₃、R₄、R₅And R₆The definition is the same as above.

There are many different methods for preparing chiral and racemic β -amino acids. These methods can be found in "Enantioselective Synthesis of beta-amino Acids", Juaristi, Eusebio; editor. usa, 1997, Wiley-VCH, New York, n.y.

The methods described below are exemplary of methods that may be used to prepare such compounds and are not intended to limit the scope of the invention.

Method A

The compounds of formula IA can be prepared according to the procedure in Lazar et al, Synth. Commun, 1998, 28(2), 219-224 by heating to reflux the compounds of formula 1 in an alcoholic solvent such as ethanol in the presence of malonic acid and ammonium acetate. The aldehydes of formula 1 can be prepared from commercially available starting materials using methods well known to those skilled in the art.

The compounds that can be prepared according to the above-described process include, but are not limited to, the following compounds:

3-amino-6-cyclopropyl-5-methyl-hexanoic acid;

3-amino-6-cyclobutyl-5-methyl-hexanoic acid;

3-amino-6-cyclopentyl-5-methyl-hexanoic acid;

3-amino-6-cyclohexyl-5-methyl-hexanoic acid;

3-amino-7-cyclopropyl-5-methyl-heptanoic acid;

3-amino-7-cyclobutyl-5-methyl-heptanoic acid;

3-amino-7-cyclopentyl-5-methyl-heptanoic acid;

3-amino-7-cyclohexyl-5-methyl-heptanoic acid;

3-amino-8-cyclopropyl-5-methyl-octanoic acid;

3-amino-8-cyclobutyl-5-methyl-octanoic acid;

3-amino-8-cyclopentyl-5-methyl-octanoic acid;

3-amino-8-cyclohexyl-5-methyl-octanoic acid;

3-amino-6-cyclopropyl-5, 5-dimethyl-hexanoic acid;

3-amino-6-cyclobutyl-5, 5-dimethyl-hexanoic acid;

3-amino-6-cyclopentyl-5, 5-dimethyl-hexanoic acid;

3-amino-6-cyclohexyl-5, 5-dimethyl-hexanoic acid;

3-amino-7-cyclopropyl-5, 5-dimethyl-heptanoic acid;

3-amino-7-cyclobutyl-5, 5-dimethyl-heptanoic acid;

3-amino-7-cyclopentyl-5, 5-dimethyl-heptanoic acid; and

3-amino-7-cyclohexyl-5, 5-dimethyl-heptanoic acid.

Method B

As described in method B above, the use of a method of adding a chiral amine to an α, β -unsaturated system as a synthetic route to obtain a β -amino acid has been described in the prior art (see, e.g., S.G. Davies et al, J.chem.Soc.chem.Commun, 1153, 1993; S.G. Davies, Synlett, 1994, 117; Ishikawa et al, Synlett, 1998, 1291; Hawkins, J.Org. chem., 1985, 51, 2820). In contrast to the above-described process B, compounds of formula IA can be prepared from the corresponding compounds of formula 7, wherein PG represents the appropriate ester protecting group, which can be removed by hydrolysis or hydrogenolysis using conditions well known to those skilled in the art (see T.W.Greene and P.G.M.Wuts., "Protective groups in organic synthesis", Wiley, 1991 for a detailed description of the formation and removal of the appropriate protecting group). For example, the reaction may be carried out by: under hydrolysis conditions, at a temperature from room temperature to around the reflux temperature of the reaction mixture, preferably at reflux temperature, by treatment with a suitable acid, such as hydrochloric acid or sulfuric acid, or at a temperature from around room temperature to around the reflux temperature, preferably around room temperature, by treatment with a suitable inorganic base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide. The reaction is preferably carried out at reflux temperature using hydrochloric acid. However, if PG is tert-butyl, the reaction is preferably carried out in trifluoroacetic acid (TFA). If PG is a basic group, hydrolysis may be accomplished under basic conditions using methods well known to those skilled in the art, for example, using sodium hydroxide or potassium hydroxide.

The compounds of formula 7 may be prepared from the corresponding compounds of formula 6 using hydrogenolysis conditions well known to those skilled in the art. For example, the reaction may be accomplished by treating the compound of formula 6 with a palladium metal catalyst such as palladium hydroxide-carbon or palladium-carbon or with Raney nickel in a solvent such as methanol, ethanol or tetrahydrofuran under a hydrogen atmosphere (about 1 to 5 atmospheres) to obtain the desired compound of formula 7. The reaction is preferably accomplished using a palladium-carbon catalyst in ethanol under a hydrogen atmosphere at about 1 atmosphere of pressure.

The compounds of formula 6 can be prepared by: after treatment of the corresponding compound of formula 4 with a suitable base such as lithium diisopropylamide, N-butyllithium or lithium or potassium bis (trimethylsilyl) amide in a solvent such as diethyl ether or, preferably, Tetrahydrofuran (THF) at a temperature of about-80 ℃ to about 25 ℃, treatment with a suitable amine such as (R) - (+) -N-benzyl- α -methylbenzylamine, (S) - (-) -N-benzyl- α -methylbenzylamine, and addition of the suitable compound of formula 4. The stereochemistry of the nitrogen at the amine will determine the stereochemistry of the nitrogen at the final product. Preferably the reaction is carried out by: according to Bull, Steven D.; davies, Stephen g.; and the method described in Smith, Andrew D, J.chem.Soc., Perkin Trans.1, 2001, 22, 2931-2938, using (R) - (+) -N-benzyl- α -methylbenzylamine or (S) - (-) -N-benzyl- α -methylbenzylamine, after deprotonation using N-butyllithium in tetrahydrofuran at a temperature of about-78 ℃.

The compounds of formula 4 can be prepared from the corresponding compounds of formula 3 by treating them with the appropriate phosphonate in the presence of a suitable base such as sodium hydride, lithium diisopropylamide or triethylamine and lithium chloride or lithium bromide in a solvent such as diethyl ether or THF. Preferably, the compound of formula 3 is reacted with a phosphate (ALK ═ methyl, ethyl, isopropyl, benzyl, etc.) in the presence of lithium bromide and triethylamine in tetrahydrofuran at about room temperature. The compounds of formula 3 may be prepared from commercially available starting materials using procedures well known to those skilled in the art. It will be appreciated that the compounds of formula 3 have one or more stereogenic centers. Various compounds with specific stereochemical configurations can be prepared by the method.

(3S, 5R) -3-amino-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5R) -3-amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-amino-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5R) -3-amino-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5R) -3-amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5S) -3-amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5S) -3-amino-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5S) -3-amino-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5S) -3-amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5S) -3-amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S) -3-amino-6-cyclopropyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-6-cyclobutyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-6-cyclopentyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-6-cyclohexyl-5, 5-dimethyl-hexanoic acid;

(3S) -3-amino-7-cyclopropyl-5, 5-dimethyl-heptanoic acid;

(3S) -3-amino-7-cyclobutyl-5, 5-dimethyl-heptanoic acid;

(3S) -3-amino-7-cyclopentyl-5, 5-dimethyl-heptanoic acid; and

(3S) -3-amino-7-cyclohexyl-5, 5-dimethyl-heptanoic acid.

Method C

As a method for preparing beta-amino acids, diastereomeric alkylation of, for example, an imide of the formula 10 to give, for example, a chiral succinate analog of the formula 11 has been described in the prior art (see, for example, Evans et al, J.org.chem., 1999, 64, 6411; Sibi and Deshopande, J.chem.Soc.Perkin Trans 1., 2000, 1461; Arvanitis et al, J.chem.Soc.Perkin Trans 1., 1998, 521).

Compounds of structure 11 can be prepared from compounds of structure 10 in the presence of suitable ester derivatives (PG defined above, LG ═ Br and I or Cl), such as t-butyl bromoacetate, benzyl bromoacetate, and the like, with organometallic bases such as lithium diisopropylamide or lithium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, and the like, in solvents such as tetrahydrofuran, diethyl ether, and the like. This reaction can be accomplished using sodium bis (trimethylsilyl) amide in tetrahydrofuran at-78 deg.C, followed by treatment of the resulting anionic intermediate with t-butyl bromoacetate at-78 deg.C to-30 deg.C.

The compounds of formula 12 can be prepared by hydrolysis of the corresponding compounds of formula 11 in the presence of lithium hydroxide and hydrogen peroxide in a solvent such as water or THF at a temperature of about 0 ℃ to about room temperature. Preferably, hydrogen peroxide and lithium hydroxide are used in aqueous tetrahydrofuran at about 0 ℃ according to the methods described in the prior art (see Yuen P-W., Kanter G.D., Taylor C.P., and Vartanian M.G., bioorganic and Medicinal Chem.Lett., 1994; 4 (6): 823-826).

Treatment of a compound of formula 12 with diphenylphosphoryl azide in the presence of a suitable alcohol such as t-butanol, benzyl alcohol or p-methoxybenzyl alcohol in a suitable solvent such as toluene, benzene or THF at a temperature of about 50 deg.C to about the reflux temperature of the reaction mixture affords the corresponding compound of formula 13, wherein R is₅Is methyl, ethyl, tert-butyl, benzyl or p-methoxybenzyl. R₅Depending on the alcohol used. The reaction is preferably carried out using toluene solvent in the presence of p-methoxybenzyl alcohol under reflux conditionsShould be used.

The compounds of formula 13 may be converted to the desired compounds of formula IA by hydrolysis or hydrogenolysis using conditions well known to those skilled in the art. (see T.W.Greene and P.G.M.Wuts., "protective groups in organic synthesis", Wiley, 1991 for a detailed description of the formation and removal of suitable protecting groups). For example, the reaction may be carried out by: under hydrolysis conditions, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at reflux temperature, by treatment with a suitable acid, such as hydrochloric acid or sulfuric acid, or at a temperature from about room temperature to about the reflux temperature, preferably at about room temperature, by treatment with a suitable inorganic base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide. The reaction is preferably carried out at reflux temperature using hydrochloric acid. However, if PG is tert-butyl, the reaction is preferably carried out in trifluoroacetic acid (TFA). If PG is a basic group, hydrolysis may be accomplished under basic conditions using methods well known to those skilled in the art, for example, using sodium hydroxide or potassium hydroxide.

The compounds of formula 10 can be prepared by: the intermediate formed in situ by the reaction of the corresponding compound of formula 8 is treated with an amine base such as triethylamine in the presence of trimethylacetyl chloride in an ether solvent such as THF, followed by treatment of the previous step with a chiral oxazolidinone of formula 9. Examples of other oxazolidinones that can be used in the above process are: (4S) - (-) -4-isopropyl-2-oxazolidinone; (S) - (-) -4-benzyl-2-oxazolidinone; (4S, 5R) - (-) -4-methyl-5-phenyl-2-oxazolidinone; (R) - (+) -4-benzyl-2-oxazolidinone; (S) - (+) -4-phenyl-2-oxazolidinone; (R) - (-) -4-phenyl-2-oxazolidinone; (R) -4-isopropyl-2-oxazolidinone; and (4R, 5S) - (+) -4-methyl-5-phenyl-2-oxazolidinone and lithium chloride. Preferably the reaction is carried out by: the acid of formula 8 is treated with trimethylacetyl chloride and triethylamine in tetrahydrofuran at about-20 ℃ and then the intermediate formed in the above reaction is treated with the oxazolidinone of formula 9 and lithium chloride at about room temperature according to literature procedures (see Ho G-j. and Mathre d.j., j.org.chem., 1995; 60: 2271-one 2273).

Alternatively, the compound of formula 10 can also be prepared by treating the corresponding compound of formula 9 with an acid chloride derived from treatment of the corresponding compound of formula 8 with oxalyl chloride in a solvent such as dichloromethane in the presence of Dimethylformamide (DMF). The acids of formula 8 can be prepared from commercially available starting materials using methods known to those skilled in the art. These acids may have one or more chiral centers. The synthesis of such acids using citronellyl bromide and citronellol is described in examples 1, 2 and 3 of the present application.

The compounds which can be prepared according to the above process C include, but are not limited to, the following compounds:

(3S, 5R) -3-amino-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-5-methyl-octanoic acid;

(3S, 5R) -3-amino-5-methyl-nonanoic acid;

(3S, 5R) -3-amino-5-methyl-decanoic acid;

(3S, 5S) -3-amino-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-5-methyl-octanoic acid;

(3S, 5S) -3-amino-5-methyl-nonanoic acid;

(3S, 5S) -3-amino-5-methyl-decanoic acid;

(3S) -3-amino-5, 5-dimethyl-heptanoic acid;

(3S) -3-amino-5, 5-dimethyl-octanoic acid;

(3S) -3-amino-5, 5-dimethyl-nonanoic acid;

(3S) -3-amino-5, 5-dimethyl-decanoic acid;

(3S, 5R) -3-amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-amino-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5S) -3-amino-7-cyclopentyl-5-methyl-heptanoic acid; and

(3S, 5S) -3-amino-7-cyclohexyl-5-methyl-heptanoic acid.

Alternatively, referring to the reaction scheme below (method D), treatment of a compound of general formula 11 with an appropriate acid (when a tert-butyl ester is used, e.g., trifluoroacetic acid (TFA)) can afford the corresponding compound of general formula 14, which can then be subjected to a Curtius rearrangement (wherein R is₅As defined above) to give the corresponding compound of formula 15 (see Arvanitis et al, j. chem. soc. perkin Trans 1, 1998, 521 for a description of the method). Further hydrolysis of the imide groups (to give the corresponding compounds of formula 16) and the urethane groups gives the target amino acids of formula 11.

Compound 16 can be derived from compound 15 according to the above procedure for converting a compound of formula 11 to a compound of formula 12. Compounds of formula 17 can be prepared from the corresponding compounds of formula 16 by using strong acids such as hydrochloric acid or the like or strong bases such as sodium hydroxide or potassium hydroxide, or when R is₅Is benzyl or p-methoxybenzyl, by treatment with palladium-carbon in ethanol or THF under hydrogen atmosphere. This process, which preserves the stereochemistry of the chiral center in the compound of formula 11, which is also present in the product of formula II, is described in example 4 herein.

Method D

(2R, 4R) -2-aminomethyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-nonanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-decanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-nonanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-decanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; and

(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid.

Alternative methods of synthesizing α -substituted β -amino acids that may be used to prepare the compounds of the present invention include those described in the following references: juaristi et al, Tetrahedron asymm, 7, (8), 1996, 2233 and Seebach et al, eur.j.org.chem., 1999, 335, or Arvanitis et al, j.chem.soc.perkin Trans 1, 1998, 521, as shown in method E below:

method E

Process F below describes an alternative method for preparing compounds of formula II.

Method F

The compounds of formula 3 can be prepared from the unsaturated cyano esters of formula 2 by reduction and hydrolysis according to the method disclosed in Hoffmann-La Roche (FR 137773619641106). Cyano esters 2 can be prepared by Knoevenagel condensation of aldehyde 1 with cyanoacetate esters (e.g., Paine, j.b.; Woodward, r.b.; Dolphin, d., j.org. chem.1976, 41, 2826). The aldehydes of formula 1 can be prepared from commercially available starting materials using methods well known to those skilled in the art.

The compounds of formulae III and IV can be prepared using procedures analogous to procedure F which will be apparent to those skilled in the art. If a compound of formula III is synthesized, the starting material should be a compound similar to formula 1 in Process F except that the hydrogen attached to the carbonyl group in formula 1 is replaced with a methyl group.

The process for obtaining beta-amino acids using chiral imines has been described in the prior art as described in Process G below (see, e.g., Tang, T.P.; Ellman, J.A.J.Org.chem.1999, 64, 12-13).

Method G

The last step in the above scheme is the simultaneous hydrolysis of the sulfonamide and ester groups. The reaction is generally accomplished using a strong acid such as hydrochloric acid, hydrobromic acid or sulfuric acid in a solvent such as water or dioxane or a mixture of water and dioxane at a temperature of from about 20 ℃ to about 50 ℃, preferably at room temperature.

Methods of preparation of the compounds of the invention not specifically described in the preceding experimental section may be accomplished by a combination of the reaction methods described above, such combinations being obvious to one skilled in the art.

In each of the reactions discussed and described above, the pressure is not critical unless otherwise indicated. Pressures of from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressure, i.e., about 1 atmosphere, being preferred for convenience.

The compounds of formula 1 and group a compounds, as well as intermediates in the above reaction schemes, may be isolated and purified by conventional methods, such as recrystallization or chromatographic separation.

The binding capacity of the compounds of the invention for the α 2 δ -subunit of calcium channels can be determined using the following binding assay.

Use utilization [ 2 ]³H]The radioligand binding assay for gabapentin and The α 2 δ -subunit from porcine brain tissue (see Gee, Nicolas S et al, ` The novel antisense plunge drug, ` gabapentin ` (Neurontin), ` bins to The α 2 δ subbunit of a calcium channel ` J.biol.Chem. (1996), 271(10), ` 5768-76). The compounds of the invention have nanomolar to micromolar affinity for the α 2 δ protein. For example, R-3-amino-5, 9-dimethyl-decanoic acid has 527nM affinity for the α 2 δ protein, (3S, 5S) -3-amino-5-methyl-octanoic acid has 1uM affinity, (2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid has 29nM affinity, 2-aminomethyl-4, 4-dimethyl-heptanoic acid has 83nM affinity.

The In vivo Activity Of the compounds Of the invention can be measured In animal models Of Hyperalgesia (see Sluka, K. et al, 2001, "Universal Intramulcular Injections Of Acidic Saline product A Bilateral, Long-testing Hypergesia", Muscale New 24: 37-46; Dixon, W. 1980, "effective analysis Of experimental updates", Ann Rev Pharmacol Toxicol 20: 441-462; random L.O.and Selto J., "A Method For therapeutic Of analytical Activity injected Tissue, Arch. Pharmacol, 1957; 4: 409: 419; Harvest K., growth group Of environmental Activity injected Tissue, J., journal Of Experimental, J. P. J., journal Of Experimental active Tissue, J. D. C. D. C. D. C. D. C. D, anxiety disorders (Vogel JR, Beer B, And Clody DE, "A Simple And reusable compliance Process for testing Anti-Anxiety Agents", Psychopharmacologia 21: 1-7, 1971).

The compounds of the present invention and their pharmaceutically acceptable salts can be administered to a mammal by oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intracellular and instillation methods), rectal, buccal or intranasal administration.

The novel compounds of the present invention may be administered by any of the methods described above, alone or in combination with a pharmaceutically acceptable carrier or diluent, and may also be divided into single or multiple dose administrations. More particularly, the novel therapeutic agents of the present invention may be administered in a variety of different dosage forms, that is, they may be combined with a variety of pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, jellies, gels, pastes, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents and the like. In addition, the oral pharmaceutical composition is suitably added with sugar and/or added with perfume. In general, the weight ratio of the novel compounds of the present invention to the pharmaceutically acceptable carrier may be from about 1: 6 to about 2: 1, preferably from about 1: 4 to about 1: 1.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed in combination with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain silicate complexes and various granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are also generally very useful for tableting purposes. Solid compositions of a similar type may also be used as fillers in gel capsules; preferred materials for the attachment port also include lactose or milk sugar and high molecular weight polyethylene glycols. If aqueous suspensions and/or elixirs are suitable for oral administration, the active ingredient may be combined with various sweetening or flavouring agents, colouring matter or dyes, and if desired, emulsifying and/or suspending agents and diluents such as water, ethanol, propylene glycol, glycerin and mixtures thereof.

For parenteral administration, solutions of the compounds of the present invention in sesame or peanut oil or in aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably at a pH above 8) if necessary, and the liquid diluent should also be isotonic first. These aqueous solutions are suitable for intravenous administration. The oil solution is suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of these solutions under sterile conditions is readily accomplished according to conventional pharmaceutical procedures well known to those skilled in the art.

For intranasal or inhalational administration, the novel compounds of the present invention may be conveniently delivered in the form of a solution or suspension from a pump spray or as a spray from a closed container or nebulizer, with the aid of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized spray, the dosage unit may be controlled by a valve provided to release a metered dose of medicament. Pressurized containers or nebulizers may contain solutions or suspensions of the active compounds. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. The preparations of the active compounds according to the invention for the treatment of the above-mentioned symptoms in the average adult are preferably designed to contain 20. mu.g to 1000. mu.g of active compound per metered dose or "per" spray. For aerosols the total daily dose may be from 100. mu.g to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, such as also 1, 2 or 3 doses each time.

The compounds of the present invention may be formulated and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention may be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. In addition, the compounds of the invention may also be administered by inhalation, for example intranasally. In addition, the compounds of the present invention may be administered transdermally. It will be apparent to those skilled in the art that the following various dosage forms may contain as active ingredient a compound of formula I, IA-1, IA-2, IB, IC, II, IIA, III or IV or the corresponding pharmaceutically acceptable salts of these compounds.

For the preparation of the compounds of the present invention into pharmaceutical compositions, the pharmaceutically acceptable carrier may be either solid or liquid. Solid form preparations include powders, tablets, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid in which the finely divided active ingredient is admixed. In tablets, the active ingredient is mixed with a carrier having sufficient binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting paraffin, cocoa butter, and the like. The term "formulation" includes preparations containing the active compound in admixture with encapsulating material as a carrier for providing a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier which in turn is in association with the active ingredient. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting paraffin such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is then homogeneously dispersed therein, followed by stirring. The molten homogeneous mixture is then poured into a mold of suitable dimensions and allowed to cool and solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. Parenteral injection liquid preparations can be prepared as solutions in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and then adding suitable colorants, fragrances, stabilizers and thickeners as necessary. Aqueous suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water together with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.

Also included are solid form preparations which can be formulated as liquid preparations for oral use shortly before use. Such liquid formulations include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, colorants, fragrances, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in the form of a unit dosage form. In such dosage forms, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a small package, e.g., packeted tablets, capsules, powders in vials or ampoules, containing an individual amount of the formulation. In addition, the unit dosage form may itself be a capsule, tablet, cachet, or lozenge, or it may be the appropriate number of any of the above in a packaged form.

The amount of active ingredient in the unit formulation may be adjusted or regulated to 0.01mg to 1g, depending on certain specific applications and the potency of the active ingredient. In clinical applications, such a medicament, for example, 100 or 300mg capsules, may be taken three times a day. The pharmaceutical composition may also contain other compatible therapeutic agents, if desired.

In therapeutic applications, the compounds used in the pharmaceutical methods of the present invention are initially administered in a dosage of 0.1mg to about 1g per day. Of course, the dosage can be adjusted depending on the requirements of the patient, the severity of the condition being treated, and the compound being used. It is within the skill of the art to determine the appropriate dosage for a particular situation. Generally, treatment is initially initiated at a lower dose that is less than the optimal dose of the compound. The dose is then increased in small increments until the optimum effect under the circumstances is achieved. For convenience, the total daily dose may be divided into several portions for administration on the day, if desired.

The following examples describe the preparation of the compounds of the present invention. They are not meant to be limiting in scope. The melting point was not corrected. NMR data are given in parts per million and are referenced to deuterium trace signals from the sample solvent.

Examples

EXAMPLE 1 (3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride

(R) -2, 6-dimethyl-non-2-ene.

To a solution of (S) -citronellyl bromide (50g, 0.228mol) in THF (800mL) at 0 deg.C was added LiCl (4.3g) followed by CuCl₂(6.8 g). After 30 minutes, methylmagnesium chloride (152mL of 3M THF solution) was addedAldrich), the solution was warmed to room temperature. After 10 hours the solution was cooled to 0 ℃ and a saturated aqueous solution of ammonium chloride was carefully added. The resulting two layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrating to obtain (R) -2, 6-dimethyl-non-2-alkene. 32.6 g; 93 percent. It can be used without purification.¹HNMR(400MHz；CDCl₃)δ5.1(m，1H)，1.95(m，2H)，1.62(s，3H)，1.6(s，3H)，1.3(m，4H)，1.2(m，2H)，0.8(s，6H)；¹³C NMR(100MHz；CDCl₃)δ131.13，125.28，39.50，37.35，32.35，25.92，25.77，20.31，19.74，17.81，14.60。

(R) -4-methyl-heptanoic acid.

To a solution of (R) -2, 6-dimethyl-non-2-ene (20g, 0.13mol) in acetone (433mL) was added CrO over 50 min₃(39g, 0.39mol) of H₂SO₄(33mL)/H₂O (146mL) solution. After 6 hours, a certain amount of CrO is added₃(26g, 0.26mol) of H₂SO₄(22mL)/H₂O (100mL) solution. After 12 hours the solution was diluted with brine and extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (gradient 6: 1 to 2: 1 hexanes/EtOAc) afforded (R) -4-methyl-heptanoic acid as an oil. 12.1 g; 65 percent. MS, m/z (relative intensity): 143[ M-H, 100%]；¹H NMR(400MHz；CDCl₃)δ2.35(m，2H)，1.6(m，1H)，1.4(m，1H)，1.3(m，4H)，1.1(m，1H)，0.85(s，6H)。

(4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one.

To a solution of (R) -4-methyl-heptanoic acid (19g, 0.132mol) and triethylamine (49.9g, 0.494mol) in THF (500mL) at 0 deg.C was added trimethylacetyl chloride (20g, 0.17 mol). After 1 hour LiCl (7.1g, 0.17mol) was added followed by (4R, 5S) - (+) -4-methyl-5-phenyl-2-oxazolidinone) 3(30g, 0.17 mol). The mixture was warmed to room temperature, the filtrate was removed by filtration after 16 hours, and the solution was concentrated under reduced pressure. Flash chromatography (7: 1 hexanes/EtOAc) afforded (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one oil. 31.5 g; 79 percent. [ alpha ] to]_D＝+5.5(c 1CHCl₃A solution). MS, m/z (relative intensity): 304[ M + H, 100%]；¹H NMR(400MHz；CDCl₃)δ7.4-7.2(m，5H)，5.6(d，J＝7.32Hz，1H)，4.75(m，1H)，2.96(m，1H)，2.86(m，1H)，1.62(m，1H)，1.43(m，1H)，1.25(m，4H)，1.12(m，1H)，0.85(m，9H)；¹³C NMR(100MHz；CDCl₃)δ173.70，153.23，133.81，133.59，128.92，128.88，128.92，128.88，125.83，79.12，54.93，39.24，33.66，32.32，31.47，27.18，26.52，20.25，19.57，14.75，14.52。

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester.

To a solution of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one (12.1g, 0.04mol) in THF (200mL) at-50 ℃ was added sodium bis (trimethylsilyl) amide (48mL in 1M THF). After 30 minutes, t-butyl bromoacetate (15.6g, 0.08mol) was added. The solution was stirred at-50 ℃ for 4 hours and then warmed to room temperature. After 16 hours, a saturated aqueous solution of ammonium chloride was added and the two layers were separated. The aqueous phase was extracted with ether and the combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (9: 1 hexanes/EtOAc) afforded (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester 12g as a white solid; 72 percent. [ alpha ] to]_D＝+30.2(c1 CHCl₃A solution).¹³C NMR(100MHz；CDCl₃)δ176.47，171.24，152.72，133.63，128.87，125.86，80.85，78.88，55.34，39.98，38.77，38.15，37.58，30.60，28.23，20.38，20.13，14.50，14.28。

(S) -2- ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester.

To (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester (10.8g, 0.025mol) in H at 0 deg.C₂O (73mL) and THF (244mL) were addedContaining LiOH (51.2mL of a 0.8M solution) and H₂O₂(14.6mL of a 30% solution). After 4 hours, an additional 12.8mL LiOH (0.8M solution) and 3.65mL H were added₂O₂(30% solution). After 30 minutes, sodium bisulfite (7g), sodium sulfate (13g) and water (60mL) were added, followed by hexane (100mL) and ether (100 mL). The two layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to give an oil, which was dissolved in heptane (300 mL). The resulting solid was removed by filtration and the filtrate was dried (MgSO)₄) And concentrated to give 4-tert-butyl (S) -2- ((R) -2-methyl-pentyl) -succinate (6g, 93%) which was used without purification. MS, m/z (relative intensity): 257[ M + H, 100%]。

(3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester.

A solution of 4-tert-butyl (S) -2- ((R) -2-methyl-pentyl) -succinate (6.0g, 23.22mmol) and triethylamine (3.64mL, 26.19mmol) in toluene (200mL) was treated with diphenylphosphoryl azide (5.0mL, 23.22mL) and then stirred at room temperature for 0.5 h. After the reaction mixture was heated at reflux for 3 hours, it was briefly cooled, benzyl alcohol (7.2mL, 69.7mmol) was added and the solution was heated for an additional 3 hours. After the reaction mixture was cooled, it was diluted with ether (200mL) and saturated NaHCO₃The combined organic layers were washed with brine and dried (Na)₂SO₄). The concentrated organic fraction was purified by chromatography (MPLC) eluting with 8: 1 hexanes: ethyl acetate to give (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester (6.4g, 75.8%). MS: m + 1: 364.2, 308.2.¹HNMR(400MHz，CDCl₃) δ 0.83(t, 3H, J ═ 6.59Hz), 0.87(d, 3H, J ═ 6.59Hz), 1.08-1.34(m, 6H), 1.39(s, 9H), 1.41-1.52(m, 2H), 2.39(m, 2H), 4.02(m, 1H), 5.05(s, 2H), 5.09(m, 1H), and 7.24-7.32(m, 5H) ppm.

(3S, 5R) -3-amino-5-methyl-octanoic acid, tert-butyl ester.

A solution of (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester (2.14g, 5.88mmol) in THF (50mL) was dissolved in 50psi of H₂Next, the mixture was treated with Pd/C (0.2g) for 2 hours. The reaction mixture was then filtered and concentrated in vacuo to an oil to give (3S, 5R) -3-amino-5-methyl-octanoic acid, tert-butyl ester in quantitative yield. MS: m + 1: 230.2, 174.1.¹HNMR(400MHz，CDCl₃) δ 0.85-0.86(t and d overlap, 6H), 1.13-1.40(m, 6H), 1.44(s, 9H), 1.60(m, 1H), 2.31(dd, 1H, J ═ 7.81 and 15.86Hz), 2.38(dd, 1H, J ═ 5.13 and 15.86Hz), 3.31(m, 1H), and 3.45(br s, 2H) ppm.

(3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride.

A slurry of (3S, 5R) -amino-5-methyl-octanoic acid, tert-butyl ester (2.59g, 11.3mmol) in 6N HCl (100mL) was heated under reflux for 18 h, cooled and filtered over celite. The filtrate was concentrated in vacuo to 25mL and the resulting crystals were collected and dried to give (3S, 5R) -3-amino-5-methyl-octanoic acid hydrochloride, mp 142.5-142.7 deg.C (1.2g, 50.56%). A second crop of product (0.91g) was obtained from the filtrate. To C₉H₁₉NO₂Analytical calculation of HCl: c: 51.55, H: 9.61, N: 6.68, Cl: 16.91. measured value: c: 51.69, H: 9.72, N: 6.56, Cl: 16.63. MS: m + 1: 174.1.¹HNMR(CD₃OD) δ 0.89(t, 3H, J ═ 7.32Hz), 0.92(d, 3H, J ═ 6.35Hz), 1.12-1.18(m, 1H), 1.25-1.35(m, 2H), 1.35-1.42(m, 2H), 1.54-1.64(m, 2H), 2.50(dd, 1H, J ═ 7.81 and 17.33Hz), 2.65(dd, 1H, J ═ 4.64 and 17.32Hz), and 3.52(m, 1H) ppm.

EXAMPLE 2 (3S, 5R) -amino-5-methyl-heptanoic acid

(S) -3, 7-dimethyl-oct-6-enyl methanesulfonate.

To CH of S- (-) -citronellol (42.8g, 0.274mol) and triethylamine (91mL, 0.657mol) at 0 deg.C₂Cl₂(800mL) solution was added methanesulfonyl chloride (26mL, 0.329mol) in CH₂Cl₂(200mL) of the solution. After 2 hours, the solution was washed with 1N HCl at 0 ℃ followed by brine. The organic phase was dried (MgSO)₄) And concentrated to give the title compound as an oil (60.5g, 94%) which was used without further treatmentAnd (5) purifying. MS, m/z (relative intensity): 139[ 100%]，143[100％]。¹H NMR(400MHz；CDCl₃)δ5.05(1H，m)，4.2(2H，m)，2.95(3H，s)，1.98(2H，m)，1.75(1H，m)，1.6(3H，s)，1.5(4H，m)，1.35(2H，m)，1.2(1H，m)，0.91(3H，d，J＝6.5Hz)。

(R) -2, 6-dimethyl-oct-2-ene.

To a solution of (S) -3, 7-dimethyl-oct-6-enyl methanesulfonate (60g, 0.256mol) in THF (1L) was added lithium aluminum hydride (3.8g, 0.128mol) at 0 ℃. After 7 hours, 3.8g of lithium aluminium hydride are again added and the solution is warmed to room temperature. After 18 hours, a further 3.8g of lithium aluminium hydride are added. After a further 21 hours, the reaction was carefully quenched with 1N citric acid and the solution was washed further with brine. The resulting phases were separated and the organic phase was dried (MgSO)₄) And concentrated to give the title compound as an oil, which was used without purification. MS, m/z (relative intensity): 139[ M + H, 100%]。

(R) -4-methyl-hexanoic acid.

Using a procedure analogous to that for the synthesis of (R) -4-methyl-heptanoic acid, acid was obtained as an oil (9.3g, 56%). IR (film) 2963, 2931, 2877, 2675, 1107, 1461, 1414cm^-1(ii) a MS, m/z (relative intensity): 129[ M-H, 100%]；¹H NMR(400MHz；CDCl₃)δ2.35(m，2H)，1.66(m，1H)，1.37(m，4H)，1.29(m，1H)，0.86(m，6H)；¹³C NMR(100MHz；CDCl₃)δ181.02，34.09，32.12，31.39，29.29，18.94，11.44。

(4R, 5S) -4-methyl-3- ((R) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one.

Using a procedure analogous to the synthesis of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one, the title compound was obtained as an oil (35.7g, 95%). MS, m/z (relative intensity): 290[ M + H, 100%]；¹H NMR(400MHz；CDCl₃)δ7.4-7.25(m，5H)，5.6(d，J＝7.32Hz，1H)，4.75(m，1H)，2.97(m，1H)，2.85(m，1H)，1.68(m，1H)，1.43(m，2H)，1.12(m，2H)，0.87(m，9H)；¹³C NMR(100MHz；CDCl₃)δ173.71，153.24，133.56，128.94，128.90，125.83，79.14，54.95，34.22，33.72，31.07，29.45，27.20，26.52，19.19，19.15，14.77，14.53，11.54。

(3S, 5R) -5-methyl-3- [1- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -formyl (methanoyl) ] -heptanoic acid tert-butyl ester.

Using a procedure analogous to the preparation of tert-butyl (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate, the title compound was obtained as an oil (7.48 g; 31%). IR (film) 2967, 2934, 1770, 1716, 1696, 1344, 1148, 1121, 1068, 1037, 947cm^-1(ii) a MS, m/z (relative intensity): 178[ 100%]，169[100％]；[α]_D＝+21.6(c1 CHCl₃A solution).

(S) -2- ((R) -2-methyl-butyl) -succinic acid 4-tert-butyl ester.

To (3S, 5R) -5-methyl-3- [1- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -formyl (methanoyl) at 0 deg.C]-tert-butyl heptanoate (7.26g, 0.018mol) in H₂O (53mL) and THF (176mL) were added to a solution containing LiOH (37mL of 0.8M solution) and H₂O₂(10.57mL of a 30% solution) and the solution was warmed to room temperature. After 2 hours, sodium bisulfite (7g), sodium sulfate (13g), and water (60mL) were added, the two layers were separated, and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil, which was dissolved in heptane (200 mL). The resulting solid was removed by filtration, and the filtrate was dried (MgSO)₄) And concentrated to give the title compound as an oil (4.4g), which was used without purification. MS, m/z (relative intensity): 243[ 100%]；¹HNMR(400MHz；CDCl₃)δ2.88(m，1H)，2.59(m，1H)，2.36(m，1H)，1.65(m，1H)，1.41(s，9H)，1.20(m，4H)，0.84(m，6H)。

(3S, 5R) -3-benzyloxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester.

The compoundPrepared according to the procedure described above starting from (S) -2- ((R) -2-methyl-butyl) succinic acid, 4-tert-butyl ester to give (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester as an oil (73.3% yield).¹H NMR(400MHz；CDCl₃) δ 0.84(t, 3H, J ═ 7.33Hz), 0.89(d, 3H, J ═ 6.60Hz), 1.12-1.38(m, 4H), 1.41(s, 9H), 1.43-1.59(m, 2H), 2.42(m, 2H), 4.05(m, 1H), 5.07(t, 2H J ═ 12.95Hz), and 7.28-7.34(m, 5H).

(3S, 5R) -amino-5-methyl-heptanoic acid, tert-butyl ester.

This compound was prepared according to the procedure described above starting from (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-heptanoic acid, tert-butyl ester instead of (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester to give the title compound.¹H NMR(400MHz；CDCl₃) δ 0.84(t and d overlap, 6H), 1.08-1.16(m, 2H), 1.27-1.30(m, 2H), 1.42(s, 9H), 1.62(br s, 2H), 2.15(dd, 1H, J ═ 8.54 and 15.62Hz), 2.29(dd, 1H, J ═ 4.15 and 15.37Hz), and 3.20(br s, 2H).

(3S, 5R) -amino-5-methyl-heptanoic acid hydrochloride.

A slurry of (3S, 5R) -amino-5-methyl-heptanoic acid, tert-butyl ester (1.44g, 6.69mmol) in 3N HCl was heated at reflux for 3h, filtered through celite, and concentrated to dryness. The resulting solid was pulverized in diethyl ether to give (3S, 5R) -3-amino-5-methyl-heptanoic acid hydrochloride, (0.95g, 85%) mp 126.3-128.3 ℃.¹HNMR(400MHz；CD₃OD) δ 0.92(t, 3H, J ═ 7.32Hz), 0.92(d, 3H, J ═ 6.35Hz), 1.15-1.24(m, 1H), 1.33-1.43(m, 2H), 1.44-1.52(m, 1H), 1.60-1.67(m, 1H), 2.57(ddd, 1H, J ═ 7.3217.67 and 5.12Hz), 2.69(ddd, 1H, J ═ 0.97, 4.88 and 17.32Hz), and 3.28(m, 1H). To C₈H₁₇NO₂·HCl·0.1H₂Analytical calculation of O: c: 48.65, H: 9.29, N: 7.09, Cl: 17.95. measured value: c: 48.61, H: 9.10, N: 7.27, Cl: 17.87 MS: m + 1: 160.2.

example 3 (3S, 5R) -3-amino-5-methyl-nonanoic acid

(R) -4-methyl-octanoic acid.

Lithium chloride (0.39g, 9.12mmol) and copper (I) chloride (0.61g, 4.56mmol) were dissolved together in 45mL THF at ambient temperature, stirred for 15 minutes, then cooled to 0 deg.C at which time ethylmagnesium bromide (1M in THF, 45mL, 45mmol) was added. (S) -citronellyl bromide (5.0g, 22.8mmol) was added dropwise and the solution was slowly warmed to ambient temperature and stirred overnight. By careful addition of saturated NH₄Cl (aq) quench the reaction and use Et₂O and saturated NH₄Cl (aq) stirred for 30 minutes. The phases were separated and the organic phase was dried (MgSO)₄) And concentrated. The crude product (R) -2, 6-dimethyl-dec-2-ene was used as such without purification. To a solution of (R) -2, 6-dimethyl-dec-2-ene (3.8g, 22.8mmol) in 50mL of acetone at 0 deg.C was added Jones reagent (2.7M H)₂SO₄(aq), 40mL, 108mmol), the solution was slowly warmed to room temperature and stirred overnight. The mixture is in Et₂O and H₂The phases are separated, the organic phase is washed with brine and dried (MgSO)₄) And then concentrated. The residue was purified by flash chromatography (8: 1 hexanes: EtOAc) to give 2.14g (59%) of the title compound as a colorless oil: LRMS: m/z 156.9 (M)⁺)；¹H NMR(400MHz；CDCl₃): δ 2.33(m, 2H), 1.66(m, 1H), 1.43(m, 2H), 1.23(m, 5H), 1.10(m, 1H), 0.86(m, 6H). By mixing 26.7g CrO₃、23mL H₂SO₄Mixing and then using H₂O was diluted to 100mL to prepare a 2.7M solution of jones reagent.

(4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one.

To a solution of (R) -4-methyl-octanoic acid (2.14g, 13.5mmol) in 25mL CH at 0 deg.C₂Cl₂To the solution was added slowly 3 drops of DMF followed by addition of oxalyl chloride (1.42mL, 16.2mmol) to allow vigorous gas flow. The solution was warmed directly to ambient temperature, stirred for 30 minutes and concentrated. At the same time, to oxazolidinone (2.64g, 14.9mmol) at-78 deg.CTo a solution of 40mL in THF was added n-butyllithium (1.6M in hexane, 9.3mL, 14.9mmol) dropwise. The mixture was stirred for 10 minutes, at which time a 10mL THF solution of the acid chloride was added dropwise. The reaction was stirred at-78 ℃ for 30 minutes, then warmed directly to room temperature and quenched with saturated NH₄The Cl quenched. The mixture is in Et₂O and saturated NH₄The phases were separated by separation between Cl (aq), the phases were separated and the organic phase was dried (MgSO)₄) Then, it was concentrated to give 3.2g of the title compound as a colorless oil. LRMS: m/z 318.2 (M)⁺)；¹H NMR(400MHz；CDCl₃): 7.34(m, 5H), 5.64(d, J ═ 7.3Hz, 1H), 4.73 (quintuple, J ═ 6.8Hz, 1H), 2.96(m, 1H), 2.86(m, 1H), 1.66(m, 1H), 1.47(m, 2H), 1.26(m, 5H), 1.13(m, 1H), 0.88(m, 9H). The crude product was used as such without purification.

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester.

To a solution of diisopropylamine (1.8mL, 12.6mmol) in 30mL THF at-78 deg.C was added n-butyllithium (1.6M in hexane, 7.6mL, 12.1mmol) and the mixture was stirred for 10 minutes at which time a solution of (4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one (3.2g, 10.1mmol) in 10mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8mL, 12.1mmol) was added dropwise rapidly at-50 ℃ and the mixture was slowly warmed to 10 ℃ over 3 hours. The mixture is in Et₂O and saturated NH₄The phases were separated by separation between Cl (aq), the phases were separated and the organic phase was dried (MgSO)₄) And concentrated. The residue was purified by flash chromatography (16: 1 to 8: 1 hexane: EtOAc) to give 2.65g (61%) of the title compound as a colourless, crystalline solid, mp-84-86 ℃. [ alpha ] to]_D ²³+17.1(c＝1.00，CHCl₃)；¹H NMR(400MHz；CDCl₃): δ 7.34(m, 5H), 5.62(d, J ═ 7.3Hz, 1H), 4.73 (quintuple, J ═ 6.8Hz, 1H), 4.29(m, 1H), 2.67(dd, J ═ 9.8, 16.4Hz, 1H), 2.40(dd, J ═ 5.1, 16.4Hz, 1H), 1.69(m, 1H), 1.38(s, 9H), 1.28(m, 7H), 1.08(m, 1H), 0.88(m, 9H);¹³C NMR(400MHz；CDCl₃)δ176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. To C₂₅H₃₇NO₅Analytical calculation of (a): c, 69.58; h, 8.64; and N, 3.25. Measured value: c, 69.37; h, 8.68; and N, 3.05.

(S) -2- ((R) -2-methyl-hexyl) -succinic acid 4-tert-butyl ester.

To a solution of (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester (2.65g, 6.14mmol) in 20mL THF at 0 deg.C was added pre-cooled (0 deg.C) LiOH monohydrate (1.0g, 23.8mmol) and hydrogen peroxide (30 wt% aqueous solution, 5.0mL) in 10mL H₂And (4) O solution. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred for 90 minutes. At 0 deg.C by adding 100mL of 10% NaHSO₃(aq) quench the reaction and use Et₂And (4) extracting. The phases were separated and the organic phase was washed with brine and dried (MgSO)₄) And (4) concentrating. The title compound was used as is without purification.

(3S, 5R) -3-benzyloxycarbonylamino-5-methylnonanoic acid, tert-butyl ester.

This compound was prepared in analogy to the procedure described above, starting from (S) -2- ((R) -2-methylhexyl) succinic acid, 4-tert-butyl ester instead of (S) -2- ((R) -2-methylpentyl) succinic acid, 4-tert-butyl ester to give the title compound as an oil (71.6% yield).¹HNMR(400MHz；CDCl₃) δ 0.81(t, 3H, J ═ 4.40Hz), 0.85(d, 3H, J ═ 6.55Hz), 1.06-1.20(m, 7H), 1.36(s, 9H), 1.38-1.50(m, 2H), 2.36(m, 2H), 3.99(m, 1H), 5.02(m + s, 3H), and 7.28-7.28(m, 5H).

(3S, 5R) -3-amino-5-methyl-nonanoic acid, tert-butyl ester.

This compound is prepared as described above except that (3S, 5R) -benzyloxycarbonylamino-5-methyl-nonanoic acid, tert-butyl ester is substituted for (3S, 5R) -3-benzyloxycarbonylamino-5-methyl-octanoic acid, tert-butyl esterAnd starting. The yield was 97%.¹HNMR(400MHz；CDCl₃) δ 0.82(d and t overlap, 6H), 1.02-1.08(m, 1H), 1.09-1.36(m, 6H), 1.39(s, 9H), 1.47(br s, 1H), 1.80(s, 2H), 2.13(dd, 1H, J ═ 8.54 and 15.61Hz), and 2.27(dd, 1H, J ═ 4.15 and 15.38 Hz).

(3S, 5R) -3-amino-5-methyl-nonanoic acid hydrochloride.

A mixture of (3S, 5R) -3-amino-5-methyl-nonanoic acid, tert-butyl ester (1.50g, 6.16mmol) in 3N HCl (100mL) was heated at reflux for 3h, filtered hot through celite, and concentrated in vacuo to 30 mL. The resulting crystals were collected, washed with 3N HCl and dried to give the title compound, mp 142.5-143.3 ℃. From the filtrate, another 1.03g (70.4%) of the product was obtained.¹HNMR(400MHz；CD₃OD) δ is 0.91(t, 3H, J is 6.84Hz), 0.92(d, 3H, J is 6.35Hz), 1.16-1.26(m, 1H), 1.27-1.35(m, 4H), 1.38-1.45(m, 1H), 1.61(br s, 1H), 1.63-1.68(m, 1H), 2.58(dd, 1H, J is 7.32 and 17.34Hz), 2.69(dd, 1H, J is 5.13 and 17.59Hz), and 3.59(m, 1H). To C₁₀H₂₁NO₂Analytical calculation of HCl: c: 53.68, H: 9.91, N: 6.26, Cl: 15.85. measured value: c: 53.89, H: 10.11, N: MS: m + 1: 188.1.

EXAMPLE 4 (2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid

5R-methyl-3R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) octanoic acid.

A solution of (3R, 5R) -5-methyl-3- ((4S, 5R) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester (3.9g, 9.34mmol) in dichloromethane (150mL) was treated with trifluoroacetic acid (7.21mL, 93.4mL) and stirred at ambient temperature for 18 h. After removal of the solvent and reagents in vacuo, the resulting residue was triturated in 100mL hexane to yield 3.38g of the title compound (100%) mp 142-143 ℃. MS M +1 ═ 362.1.¹H NMR(400MHz；CDCl₃) δ 0.85(2t, 6H, J ═ 7.1Hz), 0.93(d, 3H, J ═ 6.1Hz), 1.14(m, 1H), 1.2-1.49(m, 6H), 2.56(dd, 1H, J ═ 4.15 and 17.57Hz), 2.81(dd, 1H, J ═ 17.33 and 10.74Hz), 4.28(m, 1H), 4.74 (quintuple, 1H, J ═ 6.84Hz), 5.64(d, 1H, J ═ 7.32Hz), 7.29-7.43(m, 5H).

Benzyl [ 4R-methyl-2R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) heptyl ] carbamate.

A solution of 5R-methyl-3R- (4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl) octanoic acid (1.98g, 5.48mmol) and triethylamine (0.92mL, 6.57mmol) was treated with diphenylphosphonyl azide (1.2mL, 5.48mmol), stirred at ambient temperature for 30 minutes, and then heated to reflux for 3 hours. After brief cooling, the reaction mixture was treated with benzyl alcohol (2.8mL, 27.4mmol) and heated at reflux for an additional 3 hours. The reaction mixture was cooled, diluted with ether (150mL), then saturated NaHCO₃And brine, dried (MgSO)₄) And concentrated in vacuo to give an oil. Chromatography (MPLC, eluting with 4: 1 hexanes: ethyl acetate) afforded the title compound as an oil (2.0g, 78.3%). MS M + 1-467.1.¹H NMR(400MHz；CDCl₃) δ 0.86(2t, 6H, J ═ 7.1Hz), 0.93(d, 3H, J ═ 5.9Hz), 1.14(m, 1H), 1.09-1.36(m, 6H), 1.50(d, 1H, J ═ 5.2Hz), 3.49(t, 1H, J ═ 6.1Hz), 4.10(m, 1H), 4.71 (quintuple, 1H, J ═ 6.61Hz), 5.06(d, 2H, J ═ 3.42Hz), 5.20(t, 1H, J ═ 5.61Hz), 5.64(d, 1H, J ═ 7.08Hz), 7.29-7.43(m, 10H).

2R- (benzyloxycarbonylaminomethyl) -4R-methylheptanoic acid.

Mixing 4R-methyl-2R- (4S-methyl-2-oxo-5R-phenyl oxazolidine-3-carbonyl) heptyl]Benzyl carbamate (4.12g, 8.83mmol) in 3: 1 THF/water (100mL) solution was cooled to 0 deg.C and then treated with a solution containing 0.8N LiOH (17.5mL, 14mmol) and 30% H₂O₂(4.94mL, 44mmol) of the mixture. After the reaction mixture was left to cool and stirred for 3 hours, NaHSO was used₃(2.37g) and Na₂SO₃(4.53g) quench as a slurry in water (30mL) and stir for 1 hour. The reaction mixture was diluted with ether (200mL), the layers were separated, the organic layer was washed with brine, and dried (MgSO)₄). ConcentrationThe condensed organic extract was chromatographed (MPLC) using ethyl acetate to give 1.25g of 2R- (benzyloxycarbonylaminomethyl) -4R-methylheptanoic acid (46%). MSM +1 is 308.1.¹H NMR(400MHz；CDCl₃)δ0.83(t，3H，J＝6.84Hz)，0.87(t，3H，J＝6.35Hz)，1.14(m，1H)，1.06-1.54(m，7H)，2.7(br s，1H)，3.30(m，2H)，5.05(q，2H，J＝12.2Hz)，5.14(t，1H，J＝5.61Hz)，7.30(br s，5H)。

(2R, 4R) -2-amino-4-methyl-heptanoic acid hydrochloride.

A mixture of 2R- (benzyloxycarbonylaminomethyl) -4R-methyl-heptanoic acid (1.25g, 4.07mmol) and Pd/C (20%, 0.11g) in methanol (50mL) was hydrogenated at 50psi for 18 h. After removal of the catalyst by filtration, the solvent was removed in vacuo and the resulting solid was triturated in ether to give (2S, 4R) -2-amino-4-methyl-heptanoic acid hydrochloride (0.28g, 40%) mp 226.3-228.0 ℃. MS M +1 ═ 174.0.¹H NMR(400MHz；CD₃OD) δ 0.89(t + d, 6H, J ═ 6.35Hz), 1.11(m, 1H), 1.25-1.40(m, 4H), 1.47-1.62(m, 2H), 2.48(br s, 1H), 2.93(m, 2H). To C₉H₁₉NO₂·0.1 H₂Analytical calculation of O: c: 61.75H: 11.06N: 8.00. measured value: c: 61.85H: 10.83N: 8.01.

example 5.2-aminomethyl-4, 4-dimethyl-heptanoic acid hydrochloride

2-cyano-4, 4-dimethyl-hepta-2, 6-dienoic acid ethyl ester.

A solution of 2, 2-dimethyl-pent-4-enal (5.0g, 44mmol), cyano-ethyl acetate (5.12mL, 48mmol), piperidine (1.3mL, 14mmol), and acetic acid (4.52mL, 80mmol) in 170mL toluene was heated to reflux in a flask equipped with a dean-Stark trap for 18 hours. Several milliliters of water were collected in the trap. The reaction was cooled and then successively treated with 1N HCl, NaHCO₃And a brine wash. Na for organic layer₂SO₄Dried and concentrated to give an oil. This oil was chromatographed, eluting with 20% EtOAc in hexane to give a two-part mixture, 8.3g (91%) total weight.¹H NMR(400MHz；CDCl₃)1.28(s，6H)，1.32(t，3H，J＝7Hz)，2.26(d，2H，J＝7.6Hz)，4.27(q，2H，J＝7.2Hz)，5.08(d，1H，J＝12Hz)，5.10(d，1H，J＝4Hz)，5.72(m，1H)。

2-aminomethyl-4, 4-dimethyl-heptanoic acid hydrochloride.

2-cyano-4, 4-dimethyl-hepta-2, 6-dienoic acid ethyl ester (5.88g, 28mmol) was dissolved in a mixture containing 91mL of ethanol and 6mL of HCl, then 0.4g of PtO was used₂And (6) processing. The reaction was carried out at 100psi of hydrogen at room temperature for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give 3.8g of ethyl 2-aminomethyl-4, 4-dimethyl-heptanoate as an oil as the desired product. Ms (apci): 216.2(M +1)⁺. The oil was refluxed in 75mL of 6N HCl for 18 hours. While the reaction was cooling, a precipitate formed. The solid was filtered, washed with additional HCl solution and triturated with ether to give the title compound neat. Ms (apci): 188.1(M +1)⁺。186.1(M-1)⁺。¹H NMR(400MHz；CD₃OD): 0.91(9H, m), 1.30(5H, m), 1.81(dd, 1H, J ═ 7.2Hz, 14.4Hz), 2.72(1H, m), 3.04(2H, m); to C₁₀H₂₁NO₂Analytical calculation of HCl: c: 53.68, H: 9.91, N: 6.26, Cl: 15.85; measured value: c: 53.83, H: 10.15, N: 6.22, Cl: 15.40. MP: 229.5-231.0 ℃.

Example 6 (S) -3-amino-5, 5-dimethyl-octanoic acid

3- (4, 4-dimethyl-heptanoyl) - (R) -4-methyl- (S) -5-phenyl-oxazolidin-2-one: a solution of 4, 4-dimethyl-heptanoic acid (1.58g, 10mmol) and triethylamine (4.6mL) in 50mL THF was cooled to 0 deg.C and then treated with 2, 2-dimethyl-propionyl chloride (1.36 mL). After 1h, 4R-methyl-5S-phenyl-oxazolidin-2-one (1.95g, 11mmol) and lithium chloride (0.47g, 11mmol) were added and the mixture stirred for 18 h. The precipitate was filtered and washed well with additional THF. The filtrate was concentrated in vacuo to give an oily solid. Dissolving the solid in 200mLEt₂In O, saturated NaHCO is used in turn₃Washed with 0.5N HCl and saturated NaCl and dried (MgSO)₄) And concentrated in vacuo to give the title compound as an oil (3.0g, 95%).¹HNMR(400MHz；CDCl₃)：0.73-0.84(m，2H)，1.10-1.22(m，4H)，1.46-1.54(m，2H)，2.75-2.87(m，2H)，4.70(m，1H，J＝7Hz)，5.59(d，1H，J＝7Hz)，7.22-7.37(m，5H)。

5, 5-dimethyl- (S) -3- ((R) -4-methyl-2-oxo- (S) -5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester: from 5.07g (16mmol) of 3- (4, 4-dimethyl-heptanoyl) -4-methyl-5-phenyl-oxazolidin-2-one, 18mL (1N, 18mmol) of NaHMDS solution and 4.72mL (32mmol) of tert-butyl bromoacetate according to example 1, 3.40g (49.3%) of the title compound are obtained as crystalline solid.¹HNMR(400MHz；CDCl₃)：0.85-0.89(m，12H)，1.18-1.32(m，6H)，1.41(s，9H)，1.88(dd，1H，J＝6Hz，8.4Hz)，2.41(dd，1H，J＝6Hz，16Hz)，2.62(dd，1H，J＝8.4Hz，16Hz)，4.30-4.40(m，1H)，4.72(m，1H)，5.62(d，1H，J＝7Hz)，7.30-7.40(m，5H)。m.p.：83-85℃。

(S) -2- (2, 2-dimethyl-pentyl) -succinic acid 4-tert-butyl ester: according to example 1, starting from 3.4g (7.9mmol) of tert-butyl 5, 5-dimethyl-3- (4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate, 16mL (12.8mmol) of 0.8N LiOH and 4.5mL of 30% H₂O₂2.42g (> 100%) of the title compound are obtained as an oil.¹HNMR(400MHz；CDCl₃)：0.77-0.82(m，9H)，1.14-1.29(m，5H)，1.42(s，9H)，1.77(dd，1H，J＝8Hz，16Hz)，2.36(dd，1H，J＝6Hz，16Hz)，2.59(dd，1H，J＝8Hz，16Hz)，2.75-2.85(m，1H)。

(S) -3-benzyloxycarbonylamino-5, 5-dimethyl-octanoic acid tert-butyl ester: according to example 1, from 2.14g (7.9mmol) 4-tert-butyl 2- (2, 2-dimethyl-pentyl) -succinate, 1.7mL DPPA, 1.1mL Et₃N and 2.44mL BnOH gave 1.63g (54.8% in two steps) of the title compound as an oil.¹HNMR(400MHz；CDCl₃)：0.78-0.89(m，9H)，1.10-1.30(m，5H)，1.36(s，9H)，2.39(t，2H，J＝5Hz)，4.95-4.05(m，1H)，5.00(s，2H)，5.09(d，1H，J＝9.6Hz)，7.22-7.30(m，5H)。

(S) -3-amino-5, 5-dimethyl-octanoic acid tert-butyl ester: the title compound was obtained from 1.63g of tert-butyl 3-benzyloxycarbonylamino-5, 5-dimethyl-octanoate and 0.2g of 20% Pd/C according to example 1.¹HNMR(400MHz；CDCl₃)：0.84-0.89(m，9H)，1.13-1.39(m，6H)，1.43(s，9H)，2.25(dd，1H，J＝8.4Hz，15.6Hz)，2.35(dd，1H，J＝4.4Hz，15.6Hz)，2.79(s，br，2H)，3.25-3.35(m，1H)。MS，m/z，244.2(M+1)⁺。

(S) -3-amino-5, 5-dimethyl-octanoate hydrochloride: according to example 1, tert-butyl 3-amino-5, 5-dimethyl-octanoate is treated with 3N HCl to yield 286mg of the title compound as a solid.¹HNMR(400MHz；CD₃OD)：0.87-0.93(m，9H)，1.18-1.31(m，4H)，1.51(dd，1H，J＝4Hz，14.4Hz)，1.62(dd，1H，J＝6.8Hz，14.4Hz)，2.60(dd，1H，J＝8Hz，17.6Hz)，2.73(dd，1H，J＝4Hz，7.6Hz)，3.55-3.60(m，1H)。MS(APCI)，m/z：188.1(M+1)⁺，186.1(M-1)⁺. To C₁₀H₂₁NO₂·HCl·0.12H₂Analytical calculation of O: c: 53.17, H: 9.92, N: 6.20, Cl: 15.69; measured value: c: 53.19, H: 10.00, N: 6.08, Cl: 15.25. α ═ 20 ° (MeOH). MP: 194.2-195.2 ℃.

Example 7.2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid

2-cyano-3- (1-methyl-cyclopropyl) -acrylic acid ethyl ester.

To 1-methylcyclopropane-methanol (Aldrich, 1.13mL, 11.6mmol) in 50mL CH₂Cl₂To the solution was added neutral aluminium (2.5g) and PCC (2.5g, 11.6mmol) was added and the mixture stirred at ambient temperature for 3 hours. The mixture was filtered under vacuum through a 1cm plug size silica gel and Et₂And (4) flushing. The filtrate was concentrated to a total volume of about 5 mL. To the residue was added THF (10mL), ethyl cyanoacetate (1.2mL, 11.3mmol), piperidine (5 drops), and finally acetic acid (5 drops). The whole mixture was stirred at ambient temperature overnight and then in Et₂O and saturationNaHCO₃The layers were separated between the aqueous solutions. The phases were separated and the organic phase was washed with brine and dried (MgSO)₄) And (4) concentrating. Flash chromatography of the residue (10-15% EtOAc/hexanes) afforded 0.53g (25%) of the ester as a colorless oil which crystallized upon standing, mp35-37 ℃.¹H NMR(CDCl₃)δ6.99(s，1H)，4.27(q，J＝7.3Hz，2H)，1.55(s，3H)，1.32(t，J＝7.3Hz，3H)，1.14(s，2H)，1.07(s，2H)。¹³C NMR δ 170.44, 162.90, 115.17, 103.69, 62.52, 21.24, 21.07(2C), 20.71, 14.35. To C₁₀H₁₃NO₂Analytical calculation of (a): c, 67.02; h, 7.31; and N, 7.82. Measured value: c, 66.86; h, 7.47; and N, 7.70.

2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid ethyl ester.

To a solution of 2-cyano-3- (1-methyl-cyclopropyl) -acrylic acid ethyl ester (0.45g, 2.51mmol) in 16mL ETOH: THF (1: 1) was added RaNi (0.4g), and the mixture was hydrogenated in a Parr shaker at 48psi for 15.5 h. Pearlman's catalyst (0.5g) was then added and hydrogenation was continued for 15 hours. The mixture was filtered and concentrated, and the residue was flash chromatographed with 2 → 3 → 4 → 5 → 6 → 8% MeOH/CH₂Cl₂Elution provided 0.25g (54%) of the amino ester as a colorless oil.¹H NMR(CDCl₃)δ3.97(m，2H)，2.67(m，2H)，2.46(m，1H)，1.28(d，J＝7.3Hz，2H)，1.19(bs，2H)，1.09(t，J＝7.3Hz，3H)，0.85(s，3H)，0.04(m，4H)。LRMS：m/z 186.1(M+1)。

2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid.

To 10mL of 2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid ethyl ester (0.25g, 1.35mmol) in methanol at 0 deg.C was added 10% NaOH solution (10 mL). The mixture was stirred at ambient temperature overnight and then concentrated to remove methanol. The residue was cooled to 0 ℃ and acidified to pH 2 with concentrated HCl. After warming to room temperature, the mixture was loaded on DOWEX-50WX8-100 ion exchange resin using H₂O elutes until neutral to litmus. Continued with 5% NH₄OH (100mL) solution was eluted and concentratedThe basic fraction gave 0.15g (71%) of the amino acid as a colorless solid.¹H NMR(CDCl₃)δ2.72(m，2H)，2.42(m，1H)，1.34(dd，J＝8.5，13.9Hz，1H)，1.19(dd，J＝6.1，13.9Hz，1H)，0.82(s，3H)，0.05(m，4H)。LRMS：m/z 158.0(M+1)。

EXAMPLE 8 (3S, 5R) -3-amino-5-methyl-octanoic acid

(5S) -5-methyl-octa-2, 6-dienoic acid tert-butyl ester.

(S) -3-methyl-hex-4-enoic acid ethyl ester dropwise within 5 minutes at-78 ℃^*DIBAH (1.0M in THF, 6.4mL) was added to a solution of (1.0g, 6.4mmol) in 30mL of toluene. The mixture was stirred at-78 ℃ for 45 minutes while adding 5 drops of methanol to allow vigorous H evolution₂And (4) streaming. Methanol was added until no more gas evolution was observed (approximately 5 mL). At this point the cold bath was removed and approximately 5mL of saturated Na tartrate solution was added⁺K⁺A salt solution. When the mixture reached room temperature, additional saturated Na tartrate was added⁺K⁺Salt solution and Et₂O, stirring was continued until both phases were substantially clear (about 1 hour). The phases were separated and the organic phase was washed with brine and dried (MgSO)₄) It was concentrated by evaporation to a total volume of about 10 mL. The crude mixture was mixed with another portion of aldehyde prepared from 10mmol of ester as described above and the entire mixture was used without purification. To a suspension of sodium hydride (60% dispersion in mineral oil) in 25mL THF was added dropwise over 1 hour, tert-butyl P, P-dimethylphosphonoacetate (3.0mL, 15mmol) so that H could be controlled₂Escape of (3). After the addition was complete, a solution of the crude aldehyde in toluene (total volume about 20mL) was added dropwise rapidly and the mixture was stirred at room temperature overnight. The mixture was added to Et₂O and saturated NH₄The phases were separated by separation between the Cl solutions, the organic phase was washed with brine and dried (MgSO)₄) And concentrated. The residue was flash chromatographed (0 → 3 → 5% EtOAc/hexanes) to give 1.0g (29%, two steps) of the unsaturated ester as a pale yellow oil:¹H NMR(CDCl₃)δ6.75(m，1H)，5.66(m，1H)，5.30(m，2H)，2.03-2.29(m，3H)，1.58(d，J＝6.1Hz，3H)，1.41(s，9H)，0.91(d，J＝6.6Hz，3H)。

^*ethyl (S) -3-methyl-hex-4-enoate was prepared from (S) -trans-3-penten-2-ol [ Liang, j.; hoard, d.w.; van Khau, v.; martinelli, m.j.; moher, e.d.; moore, r.e.; tius, m.a.j.org.chem., 1999, 64, 1459]By Johnson-Claisen rearrangement with triethyl orthoacetate according to literature methods [ Hill, r.k.; soman, r.; sawada, s., j.org.chem., 1972, 37, 3737]And (4) preparing.

(3R, 5S) -3- [ benzyl- (1-phenyl-ethyl) -amino ] -5-methyl-oct-6-enoic acid tert-butyl ester.

To a solution of (S) - (-) -N-benzyl- α -methylbenzylamine (0.6mL, 2.85mmol) in 9.0mL THF at-78 deg.C was added N-butyllithium (1.6M in hexane, 1.6mL) rapidly and dropwise and a dark pink color appeared. The mixture was stirred at-78 ℃ for 30 minutes while slowly adding dropwise a solution of (5S) -5-methyl-octa-2, 6-dienoic acid tert-butyl ester (0.5g, 2.38mmol) in 1.0mL of THF to give a light brown color, which was left to stand in the dark for 3 hours. The mixture was stirred at-78 ℃ for 3 hours and then saturated NH was added₄The Cl solution was quenched. The mixture was warmed to room temperature, stirred overnight, then placed in EtOAc and saturated NH₄The layers were separated between the Cl solutions. The phases were concentrated and the organic phase was dried (MgSO)₄) And concentrated. Flash chromatography of the residue (3 → 5% EtOAc/hexanes) afforded 0.52g (52%) of the amino ester as a yellow oil.¹H NMR(CDCl₃)δ7.34(m，2H)，7.20(m，8H)，5.27(m，2H)，3.74(m，1H)，3.72(d，J＝15.9Hz，1H)，3.41(d，J＝14.9Hz，1H)，3.27(m，1H)，2.38(m，1H)，1.98(dd，J＝3.7，14.2Hz，1H)，1.81(dd，J＝9.3，14.4Hz，1H)，1.54(d，J＝4.9Hz，3H)，1.32(s，9H)，1.24(d，J＝7.1Hz，3H)，0.99(m，2H)，0.74(d，J＝6.6Hz，3H)。

(3S, 5R) -3-amino-5-methyl-octanoic acid.

To (3R, 5S) -3- [ benzyl- (1-phenyl-ethyl) -amino]-5-methyl-oct-6-enoic acid tert-butyl ester (0.92g, 2.18 mm)ol) was added to 20% Pd/C (0.20g) in 50mL MeOH and the mixture was hydrogenated on a Parr shaker at 48psi for 23 h. The mixture was filtered and concentrated. To the crude amino ester 10mL CH₂Cl₂To the solution was added 1.0mL of trifluoroacetic acid and the solution was stirred at ambient temperature overnight. The mixture was concentrated and the residue was dissolved in a small amount of H₂O, loaded on DOWEX-50WX8-100 ion exchange resin. Column H₂Eluting with 5% NH until neutral to litmus₄OH (100mL) solution was eluted. Concentration of the basic fraction gave 0.25g (66%, two steps) of the amino acid as an off-white solid.¹H NMR(CD₃OD)δ3.41(m，1H)，2.36(dd，J＝5.1，16.6Hz，1H)，2.25(dd，J＝8.1，16.6Hz，1H)，1.42(m，2H)，1.24(m，1H)，1.12(m，2H)，1.00(m，1H)，0.73(d，J＝6.4Hz，3H)，0.68(t，J＝6.8Hz，3H)。LRMS：m/z 172.1(M-1)。

Example 9.2-aminomethyl-8-methyl-nonanoic acid

2-aminomethyl-8-methyl-nonanoic acid is prepared from 6-methyl-1-heptanol using a process analogous to that for the preparation of 2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid, M/z 202.1(M +).

2-aminomethyl-4, 8-dimethyl-nonanoic acid

(R) -2, 6-dimethylhept-1-ol: magnesium turnings (2.04g, 84mmol) and crystals of iodine were suspended in 5mL THF, then 1-bromo-3-methylbutane (0.3mL, pure) was added. The mixture is heated to initiate the Grignard formation reaction. The remaining 1-bromo-3-methylbutane (8.63mL, 72mmol) was diluted in THF (60mL) and then added dropwise. The mixture was stirred at ambient temperature for 2 hours and cooled to-5 ℃. A solution of copper chloride (1.21g, 9mmol) and LiCl (0.76g, 18mmol) in THF (50mL) was added dropwise while maintaining the temperature below 0 ℃. The resulting mixture was stirred for 20 minutes and a solution of (R) -3-bromo-2-methylpropanol in THF (20mL) was added dropwise while maintaining the temperature below 0 ℃. The mixture was allowed to slowly reach ambient temperature overnight. The reaction mixture was quenched with ammonium hydroxide and water. The mixture was diluted with EtOAc and extracted 3X 20mL EtOAc. The organic phase is washed with brine and dried (MgSO₄) Filtered and concentrated. The residual oil was purified by silica gel chromatography (90/10 hexane/EtOAc) to give 2.67g of (R) -2, 6-dimethylheptan-1-ol.

(R) -1-iodo-2, 6-dimethylheptane: at 0 deg.C, to dissolve in CH₂Cl₂To a mixture of the carrier triphenylphosphine (6.55g, 19.67mmol) in (1.33g, 19.67mmol) was added iodine (4.99g, 19.67mmol) and imidazole (1.33g, 19.67 mmol). The mixture was warmed to ambient temperature, stirred for 1 hour, cooled to 0 ℃ and the CH of (R) -2, 6-dimethylheptan-1-ol was added dropwise₂Cl₂(5 mL). The mixture was allowed to reach ambient temperature, stirred for 1 hour while being filtered through a pad of celite, and the solid was taken up with CH₂Cl₂And (6) washing. The filtrate was concentrated and the crude product was purified by silica gel chromatography to give (R) -1-iodo-2, 6-dimethylheptane (2.44 g).

(4R) -4, 8-Dimethylnonanoic acid tert-butyl ester: to a solution of diisopropylamine (0.827mL, 5.9mmol) in THF (8mL) at-78 deg.C was added n-butyllithium (2.65mL of a 2.6M solution in pentane). The solution was stirred at-78 deg.C for 30 minutes, followed by the addition of n-butyl acetate (0.8mL, 5.9 mmol). The mixture was stirred at-78 deg.C for 2 hours, then (R) -1-iodo-2, 6-dimethylheptane (0.3g, 1.18mmol) and HMPA (1.5mL) in THF (1mL) were added. The reaction was stirred at-78 ℃ and slowly brought to ambient temperature overnight, then heated to 35 ℃ to complete the reaction. The reaction was quenched by the addition of ammonium chloride (saturated aqueous solution) and the mixture was extracted with EtOAc (2X 10 mL). The combined organic phases were washed with water and dried (MgSO)₄) Filtered and concentrated. Chromatography on silica gel (98/2 hexane/EtOAc) afforded 0.25g of tert-butyl (4R) -4, 8-dimethylnonanoate.

(4R) -4, 8-Dimethylnonanoic acid: at 0 deg.C, (4R) -4, 8-dimethyl nonanoic acid tert-butyl ester at 25mLCH₂Cl₂The solution in (a) was treated with TFA (6 mL). The mixture was allowed to stand at ambient temperature and stirred overnight. The solvent was removed by rotary evaporation and the mixture was chromatographed on silica gel (95/5 hexane/EtOAc) to give 0.962g of (4R) -4, 8-dimethylnonanoic acid. M/z 185 (M-).

3- (4R, 8-dimethyl-nonanoyl) -4- (S) -methyl-5 (R) -phenyl-oxazolidin-2-one: using a procedure analogous to (4R, 5S) -4-methyl-3- (R) -4-methyl-heptanoyl) -5-oxazolidin-2-one, 3- (4R, 8-dimethyl-nonanoyl) -4- (S) -methyl-5 (R) -phenyl-oxazolidin-2-one (1.35g) M/z 346.5(M +).

[4R, 8-dimethyl-2R- (4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbonyl) -nonyl]-benzyl carbamate: to 3- (4(R), 8-dimethyl-nonanoyl) -4(S) -methyl-5 (R) -phenyl-oxazolidin-2-one (1.05g, 3.04mmol) in CH at-20 deg.C₂Cl₂(12mL) and TiCl₄(3.04mL of 1M CH₂Cl₂Solution) was added diisopropylethylamine (0.55mL, 3.19 mmol). The resulting dark red solution was stirred at-20 ℃ for 30 minutes, then N-methoxymethylbenzylcarbamate (0.652g, 3.34mmol) was added in CH₂Cl₂(3.5mL) and TiCl₄(3.34 mL). The mixture was stirred at 0 ℃ for 4 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. CH for the mixture₂Cl₂(3X 15 mL). The organic phase was collected, washed with 1N HCl, neutralized with NaOH, and then washed with brine. The organic phase was dried (MgSO)₄) Filtered, concentrated and purified by silica gel chromatography (95/5 hexanes/EtOAc) to give 0.555g of [4R, 8-dimethyl-2R- (4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbonyl) -nonyl]-benzyl carbamate.

2(R) - (benzyloxycarbonylamino-methyl) -4(R), 8-dimethyl-nonanoic acid: using a procedure analogous to the preparation of tert-butyl (S) -2- ((R) -2-methyl-pentyl) succinate, 0.198g of 2(R) - (benzyloxycarbonylamino-methyl) -4(R), 8-dimethyl-nonanoic acid are obtained.

2-aminomethyl-4, 8-dimethylnonanoic acid: 2(R) - (benzyloxycarbonylamino-methyl) -4(R), 8-dimethyl-nonanoic acid (0.148g, 0.566mmol) was treated with hydrogen in the presence of 20% pd/C to give 0.082g of 2-aminomethyl-4, 8-dimethyl-nonanoic acid, which was purified by chromatography on silica gel after filtration (85/15 CH)₂Cl₂/MeOH)。M/z 216.3(M+)。

Example 10.2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid

2, 2, 6-trimethyl-heptanoic acid methyl ester: to a solution of diisopropylamine (1.54mL, 11.03mmol) in THF (22mL) at-78 deg.C was added n-butyllithium (6.89mL of a 1.6M solution in hexane). The solution was stirred at-78 ℃ for 30 minutes, followed by the addition of methyl isobutyrate (0.97mL, 8.48 mmol). The mixture was stirred at-78 deg.C for 2 hours, then a solution of 1-iodo-4-methylpentane (1.8g, 8.48mmol) and DMPU (0.55mL, 4.24mmol) in THF (6mL) was added. The reaction was stirred at-78 ℃ and allowed to stand slowly for 16 hours to ambient temperature. The reaction was quenched by the addition of ammonium chloride (saturated aqueous solution) and the mixture was extracted with EtOAc (2X 10 mL). The combined organic phases were washed with water and dried (MgSO)₄) Filtered and concentrated. Chromatography on silica gel (99/1 hexanes/EtOAc) afforded 1.57g of methyl 2, 2, 6-trimethyl-heptanoate.

2, 2, 6-trimethyl-heptan-1-ol: methyl 2, 2, 6-trimethyl-heptanoate (1.97g, 10.6mmol) was dissolved in toluene (65mL) and cooled to-78 ℃. DiBALH (12.7mL of a 1N solution in toluene) was added dropwise. After 45 minutes, 1.5mL of DiBALH was added. After 2 hours, the reaction was quenched by the addition of 15mL of MeOH at-78 ℃. The mixture was warmed to ambient temperature and then cooled again to-78 ℃ before 10mL of 1N HCl was added. The mixture was extracted with EtOAc (3X 15 mL). The combined organic phases were washed with brine and dried (MgSO)₄) Filtered and concentrated. The residual oil was chromatographed on silica gel (95/5 hexanes/EtOAc) to give 2, 2, 6-trimethyl-heptan-1-ol (0.88 g). M/z 159(M +).

2, 2, 6-trimethyl-heptanal: pyridinium chlorochromate (PCC, 4.17g, 19.4mmol) and neutral aluminum (14.6g) in CH₂Cl₂The solution was mixed and stirred at ambient temperature for 15 minutes. Using alcohol with CH₂Cl₂Dilute and the mixture stirred at ambient temperature for 2 hours. The solution was filtered through a pad of silica and the solids were treated with CH₂Cl₂And (6) washing. The filtrate was evaporated to give 1.05g of 2, 2, 6-trimethylheptanal M/z 157(M +). It was used as is without purification.

2-cyano-4, 4, 8-trimethyl-non-2-enoic acid benzyl ester: to a solution containing 2, 2, 6-trimethyl-heptanal (1.05g,glacial acetic acid (0.72g, 12.1mmol) was added to a solution of a mixture of 6.73mmol, piperidine (0.19mL, 2.01mmol) and benzyl cyanoacetate (1.29g, 7.4mmol) in toluene (50 mL). The flask was fitted with a dean-stark trap and the mixture was heated to reflux 18. After cooling the mixture, it was treated with dilute hydrochloric acid and the layers were separated. The organic layer was washed successively with saturated sodium bicarbonate solution and brine, dried (MgSO)₄) Filtered and concentrated. The residual oil was purified by silica gel chromatography (98/2 hexanes/EtOAc) to give 1.3g benzyl 2-cyano-4, 4, 8-trimethyl-non-2-enoate M/z 314(M +).

2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid: a solution of benzyl 2-cyano-4, 4, 8-trimethyl-nonan-2-enoate (1.3g, 4.14mmol) in THF (50mL) was treated with hydrogen in the presence of 20% Pd/C to give a mixture of cyanoacids and cyanomethyl esters. The mixture was purified by silica gel chromatography to give 278mg 80105X 41-1-2. The acid was treated with hydrogen in MeOH/NH of Raney nickel₄Treatment of the OH solution gives 0.16g of 2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid. M/z 230.3(M +).

Example 11.2-aminomethyl-4-ethyl-octanoic acid

2-aminomethyl-4-ethyl-octanoic acid is prepared from 2-ethylhexanal using procedures analogous to those for 2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid. M/z 202.1(M +).

Example 12.2-aminomethyl-4-ethyl-8-methyl-nonanoic acid

2-aminomethyl-8-methyl-nonanoic acid is prepared from 2, 6-di-tert-butyl-4-methylphenyl cyclopropyl carboxylate using procedures analogous to those used for the preparation of 2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid. M/z 230.2(M +).

Example 13.3-amino-2- [1- (4-methyl-pentyl) -cyclopropylmethyl ] -propionic acid

2-aminomethyl-8-methyl-nonanoic acid is prepared from 2, 6-di-tert-butyl-4-methylphenyl cyclopropyl carboxylate using procedures analogous to those used for the preparation of 2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid. M/z 228.2(M +).

Example 14.2-aminomethyl-4-ethyl-hexanoic acid

2-aminomethyl-4-ethyl-hexanoic acid was prepared from 4-ethylhexanoic acid using a procedure similar to that used to prepare 2-aminomethyl-4, 8-dimethyl-nonanoic acid. m/z 174.1.

Example 15.3(S) -amino-3, 5-dimethyl-heptanoic acid

2-methyl-propane-2 (S) -sulfinic acid (1, 3-dimethyl-pentylidene) -amide: a solution of (S) - (-) -2-methyl-2-propanesulfonamide (500mg, 4.1mmol), 4-methyl-2-hexanone (470mg, 4.1mmol) and titanium (IV) ethoxide (1.7mL, 8.3mmol) was heated under reflux for 18 hours. The reaction mixture was poured into 20mL of brine and stirred rapidly. The resulting solution was filtered through celite and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2X 20 mL). The combined organic layers were dried (Na)₂SO₄) Filtered and concentrated. The resulting oil was purified by silica gel chromatography (25% EtOAc in hexanes) to give 575mg of 2-methyl-propane-2 (S) -sulfinic acid (1, 3-dimethyl-pentylidene) -amide as a yellow oil.

3, 5-dimethyl-3- (2-methyl-propane-2 (S) -sulfinylamino) -heptanoic acid methyl ester: to a solution of lithium bis (trimethylsilyl) amide (5.1mL of a 1M solution in THF) at-78 deg.C in THF (6mL) was added methyl acetate (0.41mL, 5.1mmol) dropwise. After stirring for 20 minutes, a solution of triisopropyltitanium oxychloride (2.5mL, 10mmol) in THF (3mL) was added dropwise. After 1 hour, a solution of 2-methyl-propane-2 (S) -sulfinic acid (1, 3-dimethyl-pentylidene) -amide (560mg, 2.6mmol) in THF (3mL) was added dropwise at-78 ℃. The reaction was stirred at-78 ℃ for 5 hours, then quenched by the addition of 10mL ammonium chloride and warmed to room temperature. The mixture was diluted with 10mL of water and filtered. The aqueous layer was extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The resulting oil was purified by silica gel chromatography (30% EtOAc in hexanes) to give 360mg of methyl 3, 5-dimethyl-3- (2-methyl-propane-2 (S) -sulfinylamino) -heptanoate.

3(S) -amino-3, 5-dimethyl-heptanoic acid: methyl 3, 5-dimethyl-3- (2-methyl-propane-2 (S) -sulfinylamino) -heptanoate (360mg, 1.2mmol) was dissolved in 6N HCl (2mL) and dioxane (2mL) and heated at 100 ℃ for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (15 mL). The organic phase was purified by ion exchange chromatography to give 3(S) -amino-3, 5-dimethyl-heptanoic acid (270mg), which was then purified by silica gel chromatography (70: 25: 5 CH)₂Cl₂/MeOH/NH₄OH) to yield 203mg of 3(S) -amino-3, 5-dimethyl-heptanoic acid as a white solid. m/z 174 (C)₉H₁₉NO₂+H)。

Example 16.3(S) -amino-3, 5-dimethyl-nonanoic acid

3(S) -amino-3, 5-dimethyl-nonanoic acid is prepared analogously to the preparation of 3(S) -amino-3, 5-dimethyl-heptanoic acid. m/z 202.1 (C)₁₁H₂₃NO₂+H)。

Example 17.3(S) -amino-3, 5-dimethyl-octanoic acid

3(S) -amino-3, 5-dimethyl-nonanoic acid is prepared using a procedure analogous to that used to prepare 3(S) -amino-3, 5-dimethyl-heptanoic acid. m/z 188.1 (C)₁₀H₂₁NO₂+H)。

Claims

1. A compound of formula II:

R₂is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₃) An alkyl group;

R₃is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-n (h) -, or pyridyl-n (h) -, wherein each of the foregoing alkyl moieties may be optionally substituted with 1-5 fluorine atoms, and wherein each of the foregoing phenyl and pyridyl moieties is optionally substituted with 1-3 substituents independently selected from chlorine, fluorine, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1-3 fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) An alkoxy group;

provided that when R is₁When is hydrogen, R₂Is not hydrogen.

2. A compound according to claim 1 represented by formula IIA, including pharmaceutically acceptable salts thereof:

wherein R is₃Is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-N (H) -or pyridyl-N (H) -wherein each of the foregoing alkyl moieties is optionally substituted with 1-5 fluorine atoms, and wherein each of the foregoing phenyl and pyridyl moieties is optionally substituted with 1-3 substituents independently selected from the group consisting of chlorine, fluorine, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1-3 fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) An alkoxy group.

3. A compound according to claim 1 selected from the following compounds and their pharmaceutically acceptable salts:

2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;

2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;

2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (2, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-7- (3, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (2, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7- (3, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-7- (4-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (3-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (2-fluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (2, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7- (3, 4-difluoro-phenyl) -4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (2-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (3-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7- (4-trifluoromethyl-phenyl) -heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-ethyl-hexanoic acid;

2-aminomethyl-4-ethyl-hexanoic acid;

2-aminomethyl-4-ethyl-5-methyl-hexanoic acid;

2-aminomethyl-4-ethyl-heptanoic acid;

2-aminomethyl-4-ethyl-6-methyl-heptanoic acid;

2-aminomethyl-4-ethyl-octanoic acid;

2-aminomethyl-4-ethyl-7-methyl-octanoic acid;

2-aminomethyl-4-ethyl-nonanoic acid;

2-aminomethyl-4-ethyl-8-methyl-nonanoic acid;

2-aminomethyl-4, 4-dimethyl-heptanoic acid;

2-aminomethyl-4, 6-dimethyl-heptanoic acid;

2-aminomethyl-4, 4, 8-trimethyl-nonanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-ethyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-ethyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-ethyl-hexanoic acid;

2-aminomethyl-4-methyl-hexanoic acid;

2-aminomethyl-4-methyl-heptanoic acid;

2-aminomethyl-4-methyl-octanoic acid;

2-aminomethyl-4-methyl-nonanoic acid;

2-aminomethyl-4-methyl-decanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-nonanoic acid;

(2R, 4R) -2-aminomethyl-4-methyl-decanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-nonanoic acid;

(2R, 4S) -2-aminomethyl-4-methyl-decanoic acid;

2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;

2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;

(2R, 4S) -2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

(2R, 4R) -2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

(2R, 4R) -2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; and

(2R, 4R) -2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid.

4. A compound of formula III:

wherein R is₃Is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl radicals-(C₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-N (H) -or pyridyl-N (H) -wherein each of the foregoing alkyl moieties is optionally substituted with 1-5 fluorine atoms, and wherein each of the foregoing phenyl and pyridyl moieties is optionally substituted with 1-3 substituents independently selected from the group consisting of chlorine, fluorine, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1-3 fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) An alkoxy group.

5. A compound of formula IV:

wherein R is₁Is hydrogen or optionally substituted by 1 to 5 fluorine atoms (C)₁-C₆) An alkyl group; and

R₃is (C)₁-C₆) Alkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl- (C)₁-C₃) Alkyl, phenyl- (C)₁-C₃) Alkyl, pyridyl- (C)₁-C₃) Alkyl, phenyl-N (H) -or pyridyl-N (H) -wherein each of the foregoing alkyl moieties is optionally substituted with 1-5 fluorine atoms, and wherein each of the foregoing phenyl and pyridyl moieties is optionally substituted with 1-3 substituents independently selected from the group consisting of chlorine, fluorine, amino, nitro, cyano, (C)₁-C₃) Alkylamino, optionally substituted by 1-3 fluorine atoms (C)₁-C₃) Alkyl and optionally substituted by 1 to 3 fluorine atoms (C)₁-C₃) An alkoxy group.

6. A compound according to claim 5, selected from the following compounds and their pharmaceutically acceptable salts:

2-aminomethyl-5-ethyl-heptanoic acid;

2-aminomethyl-5-ethyl-6-methyl-heptanoic acid;

2-aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid;

2-aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid;

2-aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid;

2-aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid;

2-aminomethyl-5-ethyl-octanoic acid;

2-aminomethyl-5-ethyl-7-methyl-octanoic acid;

2-aminomethyl-5-ethyl-nonanoic acid;

2-aminomethyl-5-ethyl-8-methyl-nonanoic acid;

2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

2-aminomethyl-5-methyl-heptanoic acid;

2-aminomethyl-5-methyl-octanoic acid;

2-aminomethyl-5-methyl-nonanoic acid;

2-aminomethyl-8-methyl-nonanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-heptanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-octanoic acid;

(2R, 6S) -2-aminomethyl-5-methyl-nonanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(2R, 6R) -2-aminomethyl-5-methyl-heptanoic acid;

(2R, 6R) -2-aminomethyl-5-methyl-octanoic acid; and

(2R, 6R) -2-aminomethyl-5-methyl-nonanoic acid.

7. A compound selected from the group consisting of:

2-aminomethyl-3- (1-methyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-isopropyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-butyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- (1-isobutyl-cyclopropyl) -propionic acid;

2-aminomethyl-3- [1- (4-methyl-pentyl) -cyclopropyl ] -propionic acid;

2-aminomethyl-3- (1-methyl-cyclobutyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclobutyl) -propionic acid;

2-aminomethyl-3- (1-methyl-cyclopentyl) -propionic acid;

2-aminomethyl-3- (1-ethyl-cyclopentyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclopentyl) -propionic acid;

2-aminomethyl-3- (1-methyl-cyclohexyl) -propionic acid;

2-aminomethyl-3- (1-ethyl-cyclohexyl) -propionic acid;

2-aminomethyl-3- (1-propyl-cyclohexyl) -propionic acid;

2-aminomethyl-4-cyclopropyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclopropyl) -butyric acid;

2-aminomethyl-4-cyclobutyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclobutyl) -butyric acid;

2-aminomethyl-4-cyclopentyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclopentyl) -butyric acid;

2-aminomethyl-4- (1-ethyl-cyclopentyl) -butyric acid;

2-aminomethyl-4-cyclohexyl-butyric acid;

2-aminomethyl-4- (1-methyl-cyclohexyl) -butyric acid; and

2-aminomethyl-4- (1-ethyl-cyclohexyl) -butyric acid.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

9. A method of treatment of a disease or condition in a mammal, including a human, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from inflammatory pain, chronic pain, acute pain, neuropathic pain, sleep disorders, hot flashes, fibromyalgia and anxiety.

10. The method according to claim 9, wherein the disease or condition is neuropathic pain.

11. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammatory pain, chronic pain, acute pain, neuropathic pain, sleep disorders, hot flashes, fibromyalgia or anxiety.

12. Use according to claim 11, wherein the medicament is for the treatment of neuropathic pain.