U.S. patent application number 11/480010 was filed with the patent office on 2006-11-02 for methods for using amino acids with affinity for the alpha2delta-protein.
Invention is credited to Candace Bramson, George M. Haig, Denis J. Schrier, Fong Wang.
Application Number | 20060247282 11/480010 |
Document ID | / |
Family ID | 34393101 |
Filed Date | 2006-11-02 |
United States Patent
Application |
20060247282 |
Kind Code |
A1 |
Bramson; Candace ; et
al. |
November 2, 2006 |
Methods for using amino acids with affinity for the
alpha2delta-protein
Abstract
This 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 a variety of psychiatric, pain
and other disorders.
Inventors: |
Bramson; Candace; (Ann
Arbor, MI) ; Haig; George M.; (Perrysburg, OH)
; Schrier; Denis J.; (Ann Arbor, MI) ; Wang;
Fong; (Ann Arbor, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
34393101 |
Appl. No.: |
11/480010 |
Filed: |
June 30, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10950094 |
Sep 24, 2004 |
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11480010 |
Jun 30, 2006 |
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60506003 |
Sep 25, 2003 |
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Current U.S.
Class: |
514/357 ;
514/521; 514/561; 514/567 |
Current CPC
Class: |
A61P 25/34 20180101;
A61P 25/04 20180101; A61P 25/06 20180101; A61P 21/06 20180101; A61P
29/00 20180101; A61P 3/00 20180101; A61P 19/02 20180101; A61P 25/30
20180101; A61P 25/22 20180101; A61P 25/14 20180101; A61P 25/08
20180101; A61P 25/00 20180101; A61K 31/44 20130101; A61P 25/28
20180101; A61K 31/198 20130101; A61K 31/275 20130101; A61P 25/16
20180101; A61K 31/197 20130101 |
Class at
Publication: |
514/357 ;
514/561; 514/567; 514/521 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 31/198 20060101 A61K031/198; A61K 31/277 20060101
A61K031/277 |
Claims
1-5. (canceled)
6. A method of treating a disorder or condition in a mammal,
including a human, the disorder or condition selected from
epilepsy, abstinence from addictive substances and dependencies,
smoking cessation, post herpetic neuralgia, chronic headache, lower
back pain, and surgical pain, the method comprising administering
to the mammal in need of such treatment a therapeutically effective
amount of a compound represented by having the formula IA ##STR18##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is
hydrogen or (C.sub.1-C.sub.3)alkyl optionally substituted with from
one to five fluorine atoms; R.sub.2 is hydrogen or
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to five
fluorine atoms; and R.sub.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, or
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, wherein each of
the foregoing alkyl moieties can be optionally substituted with
from one to five fluorine atoms with the proviso that when R.sub.1
is hydrogen, R.sub.2 is not hydrogen.
7. (canceled)
8. A method according to claim 6, the compound represented by
formula IA-1 ##STR19## or a pharmaceutically acceptable salt
thereof, wherein R.sub.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, or
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, wherein each of
the foregoing alkyl moieties can be optionally substituted with
from one to five fluorine atoms.
9. (canceled)
10. A method according to claim 6, the compound represented by
formula IA-2 ##STR20## or a pharmaceutically acceptable salt
thereof, wherein R.sub.1 is hydrogen or (C.sub.1-C.sub.3)alkyl
optionally substituted with from one to five fluorine atoms;
R.sub.2 is hydrogen or (C.sub.1-C.sub.3)alkyl optionally
substituted with from one to five fluorine atoms; and R.sub.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, wherein each of
the foregoing alkyl moieties can be optionally substituted with
from one to five fluorine atoms with the proviso that when R.sub.1
is hydrogen, R.sub.2 is not hydrogen.
11-12. (canceled)
13. A method according to claim 6, wherein the compound is selected
from: 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,5
S)-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;
(3S)-3-Amino-5,5,9-trimethyl-decanoic acid;
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;
(3S)-3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid;
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;
(3S)-3-Amino-5,5-dimethyl-decanoic acid; and their pharmaceutically
acceptable salts.
14. A method according to claim 6, wherein the compound is selected
from: 3-Amino-5-methyl-heptanoic acid; 3-Amino-5-methyl-octanoic
acid; 3-Amino-5-methyl-nonanoic acid;
(3S,5R)-3-Amino-5-methyl-heptanoic acid;
(3S,5R)-3-Amino-5-methyl-octanoic acid;
(3S,5R)-3-Amino-5-methyl-nonanoic acid; and their pharmaceutically
acceptable salts.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/506,003, filed Sep. 25, 2003, the complete
disclosure of which is herein incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] This 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 a variety of psychiatric, pain
and other disorders.
SUMMARY OF THE INVENTION
[0003] This invention relates to compounds of the formula I
##STR1## wherein R.sub.1 is hydrogen or (C.sub.1-C.sub.6)alkyl
optionally substituted with from one to five fluorine atoms;
[0004] R.sub.2 is hydrogen or (C.sub.1-C.sub.6)alkyl optionally
substituted with from one to five fluorine atoms; or
[0005] R.sub.1 and R.sub.2, together with the carbon to which they
are attached, form a three to six membered cycloalkyl ring;
[0006] R.sub.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, phenyl,
phenyl-(C.sub.1-C.sub.3)alkyl, pyridyl,
pyridyl-(C.sub.1-C.sub.3)alkyl, phenyl-N(H)--, or pyridyl-N(H)--,
wherein each of the foregoing alkyl moieties can be optionally
substituted with from one to five fluorine atoms, preferably with
from zero to three fluorine atoms, and wherein said phenyl and said
pyridyl and the phenyl and pyridyl moieties of said
phenyl-(C.sub.1-C.sub.3)alkyl and said
pyridyl-(C.sub.1-C.sub.3)alkyl, respectively, can be optionally
substituted with from one to three substituents, preferably with
from zero to two substituents, independently selected from chloro,
fluoro, amino, nitro, cyano, (C.sub.1-C.sub.3)alkylamino,
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to
three fluorine atoms and (C.sub.1-C.sub.3)alkoxy optionally
substituted with from one to three fluorine atoms;
[0007] R.sub.4 is hydrogen or (C.sub.1-C.sub.6)alkyl optionally
substituted with from one to five fluorine atoms;
[0008] R.sub.5 is hydrogen or (C.sub.1-C.sub.6)alkyl optionally
substituted with from one to five fluorine atoms; and
[0009] R.sub.6 is hydrogen or (C.sub.1-C.sub.6)alkyl;
[0010] and the pharmaceutically acceptable salts of such
compounds.
[0011] Specific embodiments of this invention include the following
compounds of the formula I and their pharmaceutically acceptable
salts: [0012] 3-Amino-5,8-dimethyl-nonanoic acid; [0013]
3-Amino-5,5,7-trimethyl-octanoic acid; [0014]
3-Amino-5,5,8-trimethyl-nonanoic acid; [0015]
3-Amino-5,5,6-trimethyl-heptanoic acid; [0016]
(3S,5S)-3-Amino-5,8-dimethyl-nonanoic acid; [0017]
(3S,5R)-3-Amino-5,8-dimethyl-nonanoic acid; [0018]
(3S)-3-Amino-5,5,6-trimethyl-heptanoic acid; [0019]
(3S)-3-Amino-5,5,7-trimethyl-octanoic acid; [0020]
(3S)-3-Amino-5,5,8-trimethyl-nonanoic acid; and [0021]
(3S)-3-Amino-5,5,9-trimethyl-decanoic acid.
[0022] Other examples of specific embodiments of this invention are
the following compounds of the formula I and their pharmaceutically
acceptable salts: [0023] 3-Amino-6-cyclobutyl-5-methyl-hexanoic
acid; [0024] 3-Amino-7-cyclopropyl-5-methyl-heptanoic acid; [0025]
3-Amino-7-cyclobutyl-5-methyl-heptanoic acid; [0026]
3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; [0027]
3-Amino-7-cyclohexyl-5-methyl-heptanoic acid; [0028]
3-Amino-8-cyclopropyl-5-methyl-octanoic acid; [0029]
3-Amino-8-cyclobutyl-5-methyl-octanoic acid; [0030]
3-Amino-8-cyclopentyl-5-methyl-octanoic acid; [0031]
3-Amino-8-cyclohexyl-5-methyl-octanoic acid; [0032]
3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid; [0033]
3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid; [0034]
3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid; [0035]
3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid; [0036]
3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid; [0037]
3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid; [0038]
3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; [0039]
3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid; [0040]
(3S,5R)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid; [0041]
(3S,5R)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid; [0042]
(3S,5R)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid; [0043]
(3S,5R)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; [0044]
(3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid; [0045]
(3S,5R)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid; [0046]
(3S,5R)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid; [0047]
(3S,5R)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid; [0048]
(3S,5R)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid; [0049]
(3S,5S)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid; [0050]
(3S,5S)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid; [0051]
(3S,5S)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid; [0052]
(3S,5S)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; [0053]
(3S,5S)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid; [0054]
(3S,5S)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid; [0055]
(3S,5S)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid; [0056]
(3S,5S)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid; [0057]
(3S,5S)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid; [0058]
(3S)-3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid; [0059]
(3S)-3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid; [0060]
(3S)-3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid; [0061]
(3S)-3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid; [0062]
(3S)-3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid; [0063]
(3S)-3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid; [0064]
(3S)-3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and [0065]
(3S)-3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid;
[0066] Other specific embodiments of this invention include the
following compounds of the formula I and their pharmaceutically
acceptable salts: [0067] 3-Amino-5-methyl-heptanoic acid; [0068]
3-Amino-5-methyl-octanoic acid; [0069] 3-Amino-5-methyl-nonanoic
acid; [0070] 3-Amino-5,5-dimethyl-nonanoic acid; [0071]
3-Amino-5,5-dimethyl-decanoic acid; [0072]
(3S)-3-Amino-5,5-dimethyl-nonanoic acid; and [0073]
(3S)-3-Amino-5,5-dimethyl-decanoic acid.
[0074] This invention also relates to compounds of the formula IA:
##STR2## wherein R.sub.1 is hydrogen or (C.sub.1-C.sub.3)alkyl
optionally substituted with from one to five fluorine atoms;
[0075] R.sub.2 is hydrogen or (C.sub.1-C.sub.3)alkyl optionally
substituted with from one to five fluorine atoms; or
[0076] R.sub.1 and R.sub.2, together with the carbon to which they
are attached, form a three to six membered cycloalkyl ring;
[0077] R.sub.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl, phenyl,
phenyl-(C.sub.1-C.sub.3)alkyl, pyridyl,
pyridyl-(C.sub.1-C.sub.3)alkyl, phenyl-N(H)--, or pyridyl-N(H)--,
wherein each of the foregoing alkyl moieties can be optionally
substituted with from one to five fluorine atoms, preferably with
from zero to three fluorine atoms, and wherein said phenyl and said
pyridyl and the phenyl and pyridyl moieties of said
phenyl-(C.sub.1-C.sub.3)alkyl and said
pyridyl-(C.sub.1-C.sub.3)alkyl, respectively, can be optionally
substituted with from one to three substituents, preferably with
from zero to two substituents, independently selected from chloro,
fluoro, amino, nitro, cyano, (C.sub.1-C.sub.3)alkylamino,
(C.sub.1-C.sub.3)alkyl optionally substituted with from one to
three fluorine atoms and (C.sub.1-C.sub.3)alkoxy optionally
substituted with from one to three fluorine atoms;
[0078] with the proviso that when R.sub.1 is hydrogen, R.sub.2 is
not hydrogen; and the pharmaceutically acceptable salts of such
compounds.
[0079] This invention also relates to compounds of the formula IA-1
##STR3## wherein R.sub.3 is defined as for formula I above, and the
pharmaceutically acceptable salts of such compounds.
[0080] Other specific embodiments of this invention include the
following compounds of the formula IA and their pharmaceutically
acceptable salts: [0081] 3-Amino-5-methyl-8-phenylamino-octanoic
acid; [0082] 3-Amino-5-methyl-7-phenylamino-heptanoic acid; [0083]
3-Amino-5-methyl-6-phenylamino-hexanoic acid; [0084]
(3S,5R)-3-Amino-5-methyl-8-phenylamino-octanoic acid; [0085]
(3S,5R)-3-Amino-5-methyl-7-phenylamino-heptanoic acid; [0086]
(3S,5R)-3-Amino-5-methyl-6-phenylamino-hexanoic acid; [0087]
(3S,5S)-3-Amino-5-methyl-8-phenylamino-octanoic acid; [0088]
(3S,5S)-3-Amino-5-methyl-7-phenylamino-heptanoic acid; [0089]
(3S,5S)-3-Amino-5-methyl-6-phenylamino-hexanoic acid; [0090]
3-Amino-5-methyl-8-phenyl-octanoic acid; [0091]
3-Amino-8-(2-fluoro-phenyl)-5-methyl-octanoic acid; [0092]
3-Amino-8-(3-fluoro-phenyl)-5-methyl-octanoic acid; [0093]
3-Amino-8-(4-fluoro-phenyl)-5-methyl-octanoic acid; [0094]
3-Amino-8-(2-trifluoro-phenyl)-5-methyl-octanoic acid; [0095]
3-Amino-8-(3-trifluoro-phenyl)-5-methyl-octanoic acid; [0096]
3-Amino-8-(4-trifluoro-phenyl)-5-methyl-octanoic acid; [0097]
3-Amino-5-methyl-8-o-tolyl-octanoic acid; [0098]
3-Amino-5-methyl-8-m-tolyl-octanoic acid; [0099]
3-Amino-5-methyl-8-p-tolyl-octanoic acid; [0100]
3-Amino-5-methyl-8-p-tolyl-octanoic acid; [0101]
3-Amino-8-(2,3-difluoro-phenyl)-5-methyl-octanoic acid; [0102]
3-Amino-8-(2,4-difluoro-phenyl)-5-methyl-octanoic acid; [0103]
3-Amino-8-(2,5-difluoro-phenyl)-5-methyl-octanoic acid; [0104]
3-Amino-8-(2,6-difluoro-phenyl)-5-methyl-octanoic acid; [0105]
(3S,5R)-3-Amino-5-methyl-8-phenyl-octanoic acid; [0106]
(3S,5S)-3-Amino-5-methyl-8-phenyl-octanoic acid; [0107]
(3S,5R)-3-Amino-8-(2-fluoro-phenyl)-5-methyl-octanoic acid; [0108]
(3S,5S)-3-Amino-8-(2-fluoro-phenyl)-5-methyl-octanoic acid; [0109]
(3S,5R)-3-Amino-8-(3-fluoro-phenyl)-5-methyl-octanoic acid; [0110]
(3S,5S)-3-Amino-8-(3-fluoro-phenyl)-5-methyl-octanoic acid; [0111]
(3S,5R)-3-Amino-8-(4-fluoro-phenyl)-5-methyl-octanoic acid; [0112]
(3S,5S)-3-Amino-8-(4-fluoro-phenyl)-5-methyl-octanoic acid; [0113]
(3S,5R)-3-Amino-8-(2-trifluoro-phenyl)-5-methyl-octanoic acid;
[0114] (3S,5S)-3-Amino-8-(2-trifluoro-phenyl)-5-methyl-octanoic
acid; [0115]
(3S,5R)-3-Amino-8-(3-trifluoro-phenyl)-5-methyl-octanoic acid;
[0116] (3S,5S)-3-Amino-8-(3-trifluoro-phenyl)-5-methyl-octanoic
acid; [0117]
(3S,5R)-3-Amino-8-(4-trifluoro-phenyl)-5-methyl-octanoic acid;
[0118] (3S,5S)-3-Amino-8-(4-trifluoro-phenyl)-5-methyl-octanoic
acid; [0119] (3S,5R)-3-Amino-5-methyl-8-o-tolyl-octanoic acid;
[0120] (3S,5S)-3-Amino-5-methyl-8-o-tolyl-octanoic acid; [0121]
(3S,5R)-3-Amino-5-methyl-8-m-tolyl-octanoic acid; [0122]
(3S,5S)-3-Amino-5-methyl-8-m-tolyl-octanoic acid; [0123]
(3S,5R)-3-Amino-5-methyl-8-p-tolyl-octanoic acid; [0124]
(3S,5S)-3-Amino-5-methyl-8-p-tolyl-octanoic acid; [0125]
(3S,5R)-3-Amino-8-(2,3-difluoro-phenyl).sub.5-methyl-octanoic acid;
[0126]
(3S,5S)-3-Amino-8-(2,3-difluoro-phenyl).sub.5-methyl-octanoic acid;
[0127]
(3S,5R)-3-Amino-8-(2,4-difluoro-phenyl).sub.5-methyl-octanoic acid;
[0128]
(3S,5S)-3-Amino-8-(2,4-difluoro-phenyl).sub.5-methyl-octanoic acid;
[0129]
(3S,5R)-3-Amino-8-(2,5-difluoro-phenyl).sub.5-methyl-octanoic acid;
[0130]
(3S,5S)-3-Amino-8-(2,5-difluoro-phenyl).sub.5-methyl-octanoic acid;
[0131] (3S,5R)-3-Amino-8-(2,6-difluoro-phenyl)-5-methyl-octanoic
acid; and [0132]
(3S,5S)-3-Amino-8-(2,6-difluoro-phenyl)-5-methyl-octanoic acid.
[0133] Preferred compounds of this invention include those of the
formula IA-2, ##STR4## wherein R.sub.1, R.sub.2, and R.sub.3 are
defined as for formula I above.
[0134] Examples of more preferred compounds of this invention are
compounds of the formula IA-2 wherein R.sub.1 is hydrogen, R.sub.2
is methyl and R.sub.3 is defined as for formula I above.
[0135] Examples of specific embodiments of this invention are the
following compounds of the formula IA-2 and their pharmaceutically
acceptable salts: [0136] (3S,5R)-3-Amino-5-methyl-heptanoic acid;
[0137] (3S,5R)-3-Amino-5-methyl-octanoic acid; and [0138]
(3S,5R)-3-Amino-5-methyl-nonanoic acid.
[0139] This invention also relates to compounds of the formula IB
##STR5## and their pharmaceutically acceptable salts wherein
R.sub.3 is defined as above and wherein said compounds are selected
from the following compounds and their pharmaceutically acceptable
salts: [0140] 3-Amino-4,5-dimethyl-hexanoic acid; [0141]
3-Amino-4,6-dimethyl-heptanoic acid; [0142]
3-Amino-4,7-dimethyl-octanoic acid; [0143]
3-Amino-4,8-dimethyl-nonanoic acid; [0144]
3-Amino-4,9-dimethyl-decanoic acid; [0145]
3-Amino-4-cyclopropyl-pentanoic acid; [0146]
3-Amino-4-cyclobutyl-pentanoic acid; [0147]
3-Amino-4-cyclopentyl-pentanoic acid; [0148]
3-Amino-4-cyclohexyl-pentanoic acid; [0149]
3-Amino-5-cyclopropyl-4-methyl-pentanoic acid; [0150]
3-Amino-5-cyclobutyl-4-methyl-pentanoic acid; [0151]
3-Amino-5-cyclopentyl-4-methyl-pentanoic acid; [0152]
3-Amino-5-cyclohexyl-4-methyl-pentanoic acid; [0153]
3-Amino-6-cyclopropyl-4-methyl-hexanoic acid; [0154]
3-Amino-6-cyclobutyl-4-methyl-hexanoic acid; [0155]
3-Amino-6-cyclopentyl-4-methyl-hexanoic acid; [0156]
3-Amino-6-cyclohexyl-4-methyl-hexanoic acid; [0157]
3-Amino-7-cyclopropyl-4-methyl-heptanoic acid; [0158]
3-Amino-7-cyclobutyl-4-methyl-heptanoic acid; [0159]
3-Amino-7-cyclopentyl-4-methyl-heptanoic acid; [0160]
3-Amino-7-cyclohexyl-4-methyl-heptanoic acid; [0161]
3-Amino-8-cyclopropyl-4-methyl-octanoic acid; [0162]
3-Amino-8-cyclobutyl-4-methyl-octanoic acid; [0163]
3-Amino-8-cyclopentyl-4-methyl-octanoic acid; [0164]
3-Amino-8-cyclohexyl-4-methyl-octanoic acid; [0165]
3-Amino-9-cyclopropyl-4-methyl-nonanoic acid; [0166]
3-Amino-9-cyclobutyl-4-methyl-nonanoic acid; [0167]
3-Amino-9-cyclopentyl-4-methyl-nonanoic acid; [0168]
3-Amino-9-cyclohexyl-4-methyl-nonanoic acid; [0169]
3-Amino-4-methyl-octanoic acid; [0170] 3-Amino-4-methyl-nonanoic
acid; [0171] 3-Amino-4-methyl-decanoic acid; [0172]
(3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid; [0173]
(3R,4R)-3-Amino-4,6-dimethyl-heptanoic acid; [0174]
(3R,4R)-3-Amino-4,7-dimethyl-octanoic acid; [0175]
(3R,4R)-3-Amino-4,8-dimethyl-nonanoic acid; [0176]
(3R,4R)-3-Amino-4,9-dimethyl-decanoic acid; [0177]
(3R,4R)-3-Amino-4-cyclopropyl-pentanoic acid; [0178]
(3R,4R)-3-Amino-4-cyclobutyl-pentanoic acid; [0179]
(3R,4R)-3-Amino-4-cyclopentyl-pentanoic acid; [0180]
(3R,4R)-3-Amino-4-cyclohexyl-pentanoic acid; [0181]
(3R,4R)-3-Amino-5-cyclopropyl-4-methyl-pentanoic acid; [0182]
(3R,4R)-3-Amino-5-cyclobutyl-4-methyl-pentanoic acid; [0183]
(3R,4R)-3-Amino-5-cyclopentyl-4-methyl-pentanoic acid; [0184]
(3R,4R)-3-Amino-5-cyclohexyl-4-methyl-pentanoic acid; [0185]
(3R,4R)-3-Amino-6-cyclopropyl-4-methyl-hexanoic acid; [0186]
(3R,4R)-3-Amino-6-cyclobutyl-4-methyl-hexanoic acid; [0187]
(3R,4R)-3-Amino-6-cyclopentyl-4-methyl-hexanoic acid; [0188]
(3R,4R)-3-Amino-6-cyclohexyl-4-methyl-hexanoic acid; [0189]
(3R,4R)-3-Amino-7-cyclopropyl-4-methyl-heptanoic acid; [0190]
(3R,4R)-3-Amino-7-cyclobutyl-4-methyl-heptanoic acid; [0191]
(3R,4R)-3-Amino-7-cyclopentyl-4-methyl-heptanoic acid; [0192]
(3R,4R)-3-Amino-7-cyclohexyl-4-methyl-heptanoic acid; [0193]
(3R,4R)-3-Amino-8-cyclopropyl-4-methyl-octanoic acid; [0194]
(3R,4R)-3-Amino-8-cyclobutyl-4-methyl-octanoic acid; [0195]
(3R,4R)-3-Amino-8-cyclopentyl-4-methyl-octanoic acid; [0196]
(3R,4R)-3-Amino-8-cyclohexyl-4-methyl-octanoic acid; [0197]
(3R,4R)-3-Amino-9-cyclopropyl-4-methyl-nonanoic acid; [0198]
(3R,4R)-3-Amino-9-cyclobutyl-4-methyl-nonanoic acid; [0199]
(3R,4R)-3-Amino-9-cyclopentyl-4-methyl-nonanoic acid; [0200]
(3R,4R)-3-Amino-9-cyclohexyl-4-methyl-nonanoic acid; [0201]
(3R,4R)-3-Amino-4-methyl-octanoic acid; [0202]
(3R,4R)-3-Amino-4-methyl-nonanoic acid; [0203]
(3R,4R)-3-Amino-4-methyl-decanoic acid; [0204]
(3R,4S)-3-Amino-4,5-dimethyl-hexanoic acid; [0205]
(3R,4S)-3-Amino-4,6-dimethyl-heptanoic acid; [0206]
(3R,4S)-3-Amino-4,7-dimethyl-octanoic acid; [0207]
(3R,4S)-3-Amino-4,8-dimethyl-nonanoic acid; [0208]
(3R,4S)-3-Amino-4,9-dimethyl-decanoic acid; [0209]
(3R,4S)-3-Amino-4-cyclopropyl-pentanoic acid; [0210]
(3R,4S)-3-Amino-4-cyclobutyl-pentanoic acid; [0211]
(3R,4S)-3-Amino-4-cyclopentyl-pentanoic acid; [0212]
(3R,4S)-3-Amino-4-cyclohexyl-pentanoic acid; [0213]
(3R,4S)-3-Amino-5-cyclopropyl-4-methyl-pentanoic acid; [0214]
(3R,4S)-3-Amino-5-cyclobutyl-4-methyl-pentanoic acid; [0215]
(3R,4S)-3-Amino-5-cyclopentyl-4-methyl-pentanoic acid; [0216]
(3R,4S)-3-Amino-5-cyclohexyl-4-methyl-pentanoic acid; [0217]
(3R,4S)-3-Amino-6-cyclopropyl-4-methyl-hexanoic acid; [0218]
(3R,4S)-3-Amino-6-cyclobutyl-4-methyl-hexanoic acid; [0219]
(3R,4S)-3-Amino-6-cyclopentyl-4-methyl-hexanoic acid; [0220]
(3R,4S)-3-Amino-6-cyclohexyl-4-methyl-hexanoic acid; [0221]
(3R,4S)-3-Amino-7-cyclopropyl-4-methyl-heptanoic acid; [0222]
(3R,4S)-3-Amino-7-cyclobutyl-4-methyl-heptanoic acid; [0223]
(3R,4S)-3-Amino-7-cyclopentyl-4-methyl-heptanoic acid; [0224]
(3R,4S)-3-Amino-7-cyclohexyl-4-methyl-heptanoic acid; [0225]
(3R,4S)-3-Amino-8-cyclopropyl-4-methyl-octanoic acid; [0226]
(3R,4S)-3-Amino-8-cyclobutyl-4-methyl-octanoic acid; [0227]
(3R,4S)-3-Amino-8-cyclopentyl-4-methyl-octanoic acid; [0228]
(3R,4S)-3-Amino-8-cyclohexyl-4-methyl-octanoic acid; [0229]
(3R,4S)-3-Amino-9-cyclopropyl-4-methyl-nonanoic acid; [0230]
(3R,4S)-3-Amino-9-cyclobutyl-4-methyl-nonanoic acid; [0231]
(3R,4S)-3-Amino-9-cyclopentyl-4-methyl-nonanoic acid; [0232]
(3R,4S)-3-Amino-9-cyclohexyl-4-methyl-nonanoic acid; [0233]
(3R,4S)-3-Amino-4-methyl-octanoic acid; [0234]
(3R,4S)-3-Amino-4-methyl-nonanoic acid; and [0235]
(3R,4S)-3-Amino-4-methyl-decanoic acid.
[0236] This invention also relates to the compounds of the formula
IC ##STR6## and their pharmaceutically acceptable salts wherein
R.sub.3 is defined as above and wherein said compounds are selected
from the following compounds and their pharmaceutically acceptable
salts:
[0237] 3-Amino-6-methyl-decanoic acid; [0238]
3-Amino-6-cyclopropyl-heptanoic acid; [0239]
3-Amino-6-cyclobutyl-heptanoic acid; [0240]
3-Amino-6-cyclopentyl-heptanoic acid; [0241]
3-Amino-6-cyclohexyl-heptanoic acid; [0242]
3-Amino-7-cyclopropyl-6-methyl-heptanoic acid; [0243]
3-Amino-7-cyclobutyl-6-methyl-heptanoic acid; [0244]
3-Amino-7-cyclopentyl-6-methyl-heptanoic acid; [0245]
3-Amino-7-cyclohexyl-6-methyl-heptanoic acid; [0246]
3-Amino-8-cyclopropyl-6-methyl-octanoic acid; [0247]
3-Amino-8-cyclobutyl-6-methyl-octanoic acid; [0248]
3-Amino-8-cyclopentyl-6-methyl-octanoic acid; [0249]
3-Amino-8-cyclohexyl-6-methyl-octanoic acid; [0250]
3-Amino-9-cyclopropyl-6-methyl-nonanoic acid; [0251]
3-Amino-9-cyclobutyl-6-methyl-nonanoic acid; [0252]
3-Amino-9-cyclopentyl-6-methyl-nonanoic acid; [0253]
3-Amino-9-cyclohexyl-6-methyl-nonanoic acid; [0254]
3-Amino-10-cyclopropyl-6-methyl-decanoic acid; [0255]
3-Amino-10-cyclobutyl-6-methyl-decanoic acid; [0256]
3-Amino-10-cyclopentyl-6-methyl-decanoic acid; [0257]
3-Amino-10-cyclohexyl-6-methyl-decanoic acid; [0258]
3-Amino-6-isopropyl-heptanoic acid; [0259]
3-Amino-6,8-dimethyl-nonanoic acid; [0260]
3-Amino-6,9-dimethyl-decanoic acid; [0261]
(3S,6R)-3-Amino-6-methyl-decanoic acid; [0262]
(3S,6R)-3-Amino-6-cyclopropyl-heptanoic acid; [0263]
(3S,6R)-3-Amino-6-cyclobutyl-heptanoic acid; [0264]
(3S,6R)-3-Amino-6-cyclopentyl-heptanoic acid; [0265]
(3S,6R)-3-Amino-6-cyclohexyl-heptanoic acid; [0266]
(3S,6R)-3-Amino-7-cyclopropyl-6-methyl-heptanoic acid; [0267]
(3S,6R)-3-Amino-7-cyclobutyl-6-methyl-heptanoic acid; [0268]
(3S,6R)-3-Amino-7-cyclopentyl-6-methyl-heptanoic acid; [0269]
(3S,6R)-3-Amino-7-cyclohexyl-6-methyl-heptanoic acid; [0270]
(3S,6R)-3-Amino-8-cyclopropyl-6-methyl-octanoic acid; [0271]
(3S,6R)-3-Amino-8-cyclobutyl-6-methyl-octanoic acid; [0272]
(3S,6R)-3-Amino-8-cyclopentyl-6-methyl-octanoic acid; [0273]
(3S,6R)-3-Amino-8-cyclohexyl-6-methyl-octanoic acid; [0274]
(3S,6R)-3-Amino-9-cyclopropyl-6-methyl-nonanoic acid; [0275]
(3S,6R)-3-Amino-9-cyclobutyl-6-methyl-nonanoic acid; [0276]
(3S,6R)-3-Amino-9-cyclopentyl-6-methyl-nonanoic acid; [0277]
(3S,6R)-3-Amino-9-cyclohexyl-6-methyl-nonanoic acid; [0278]
(3S,6R)-3-Amino-10-cyclopropyl-6-methyl-decanoic acid; [0279]
(3S,6R)-3-Amino-10-cyclobutyl-6-methyl-decanoic acid; [0280]
(3S,6R)-3-Amino-10-cyclopentyl-6-methyl-decanoic acid; [0281]
(3S,6R)-3-Amino-10-cyclohexyl-6-methyl-decanoic acid; [0282]
(3S,6R)-3-Amino-6-isopropyl-heptanoic acid; [0283]
(3S,6R)-3-Amino-6,8-dimethyl-nonanoic acid; [0284]
(3S,6R)-3-Amino-6,9-dimethyl-decanoic acid; [0285]
(3S,6S)-3-Amino-6-methyl-octanoic acid; [0286]
(3S,6S)-3-Amino-6-methyl-nonanoic acid; [0287]
(3S,6S)-3-Amino-6-methyl-decanoic acid; [0288]
(3S,6S)-3-Amino-6-cyclopropyl-heptanoic acid; [0289]
(3S,6S)-3-Amino-6-cyclobutyl-heptanoic acid; [0290]
(3S,6S)-3-Amino-6-cyclopentyl-heptanoic acid; [0291]
(3S,6S)-3-Amino-6-cyclohexyl-heptanoic acid; [0292]
(3S,6S)-3-Amino-7-cyclopropyl-6-methyl-heptanoic acid; [0293]
(3S,6S)-3-Amino-7-cyclobutyl-6-methyl-heptanoic acid; [0294]
(3S,6S)-3-Amino-7-cyclopentyl-6-methyl-heptanoic acid; [0295]
(3S,6S)-3-Amino-7-cyclohexyl-6-methyl-heptanoic acid; [0296]
(3S,6S)-3-Amino-8-cyclopropyl-6-methyl-octanoic acid; [0297]
(3S,6S)-3-Amino-8-cyclobutyl-6-methyl-octanoic acid; [0298]
(3S,6S)-3-Amino-8-cyclopentyl-6-methyl-octanoic acid; [0299]
(3S,6S)-3-Amino-8-cyclohexyl-6-methyl-octanoic acid; [0300]
(3S,6S)-3-Amino-9-cyclopropyl-6-methyl-nonanoic acid; [0301]
(3S,6S)-3-Amino-9-cyclobutyl-6-methyl-nonanoic acid; [0302]
(3S,6S)-3-Amino-9-cyclopentyl-6-methyl-nonanoic acid; [0303]
(3S,6S)-3-Amino-9-cyclohexyl-6-methyl-nonanoic acid; [0304]
(3S,6S)-3-Amino-10-cyclopropyl-6-methyl-decanoic acid; [0305]
(3S,6S)-3-Amino-10-cyclobutyl-6-methyl-decanoic acid; [0306]
(3S,6S)-3-Amino-10-cyclopentyl-6-methyl-decanoic acid; [0307]
(3S,6S)-3-Amino-10-cyclohexyl-6-methyl-decanoic acid; [0308]
(3S,6S)-3-Amino-6-isopropyl-heptanoic acid; [0309]
(3S,6S)-3-Amino-6,8-dimethyl-nonanoic acid; and [0310]
(3S,6S)-3-Amino-6,9-dimethyl-decanoic acid.
[0311] This invention also relates to compounds of the formula II:
##STR7## wherein R.sub.1, R.sub.2, and R.sub.3 are defined as for
formula I above, and the pharmaceutically acceptable salts of such
compounds.
[0312] Examples of specific embodiments of this invention are the
following compound of formula IV and its pharmaceutically
acceptable salts: 2-aminomethyl-4-propyl-heptanoic acid.
[0313] This invention also relates to compounds of the formula IIA
##STR8## wherein R.sub.3 is defined as for formula I above, and the
pharmaceutically acceptable salts of such compounds.
[0314] Other specific embodiments of this invention include the
following compounds of the formula II and their pharmaceutically
acceptable salts: [0315] 2-Aminomethyl-4-methyl-7-phenyl-heptanoic
acid; [0316] 2-Aminomethyl-4-methyl-6-phenyl-hexanoic acid; [0317]
2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid; [0318]
2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid; [0319]
2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid; [0320]
2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid;
[0321] 2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic
acid; [0322]
2-Aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoic acid;
[0323]
2-Aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic acid;
[0324]
2-Aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic acid;
[0325] 2-Aminomethyl-4-methyl-6-phenylamino-hexanoic acid; [0326]
2-Aminomethyl-4-methyl-7-phenylamino-heptanoic acid; [0327]
2-Aminomethyl-4-methyl-8-phenylamino-octancoic acid; [0328]
(2R,4R)-2-Aminomethyl-4-methyl-7-phenyl-heptanoic acid; [0329]
(2R,4R)-2-Aminomethyl-4-methyl-6-phenyl-hexanoic acid; [0330]
(2R,4R)-2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid;
[0331] (2R,4R)-2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic
acid; [0332]
(2R,4R)-2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid;
[0333]
(2R,4R)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic
acid; [0334]
(2R,4R)-2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic
acid; [0335]
(2R,4R)-2-Aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-hepta-
noic acid; [0336]
(2R,4R)-2-Aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid; [0337]
(2R,4R)-2-Aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid; [0338] (2R,4R)-2-Aminomethyl-4-methyl-6-phenylamino-hexanoic
acid; [0339] (2R,4R)-2-Aminomethyl-4-methyl-7-phenylamino-heptanoic
acid; [0340] (2R,4R)-2-Aminomethyl-4-methyl-8-phenylamino-octancoic
acid; [0341] (2R,4S)-2-Aminomethyl-4-methyl-7-phenyl-heptanoic
acid; [0342] (2R,4S)-2-Aminomethyl-4-methyl-6-phenyl-hexanoic acid;
[0343] (2R,4S)-2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic
acid; [0344]
(2R,4S)-2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid;
[0345] (2R,4S)-2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic
acid; [0346]
(2R,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic
acid; [0347]
(2R,4S)-2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic
acid; [0348]
(2R,4S)-2-Aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-hepta-
noic acid; [0349]
(2R,4S)-2-Aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid; [0350]
(2R,4S)-2-Aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid; [0351] (2R,4S)-2-Aminomethyl-4-methyl-6-phenylamino-hexanoic
acid; [0352] (2R,4S)-2-Aminomethyl-4-methyl-7-phenylamino-heptanoic
acid; [0353] (2R,4S)-2-Aminomethyl-4-methyl-8-phenylamino-octanoic
acid; [0354] (2R,4S)-2-Aminomethyl-6-cyclohexyl-4-ethyl-hexanoic
acid; [0355] 2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid;
[0356] 2-Aminomethyl-3-(1-ethyl-cyclopropyl)-propionic acid; [0357]
2-Aminomethyl-3-(1-propyl-cyclopropyl)-propionic acid; [0358]
2-Aminomethyl-3-(1-isopropyl-cyclopropyl)-propionic acid; [0359]
2-Aminomethyl-3-(1-butyl-cyclopropyl)-propionic acid; [0360]
2-Aminomethyl-3-(1-isobutyl-cyclopropyl)-propionic acid; [0361]
2-Aminomethyl-3-[1-(4-methyl-pentyl)-cyclopropyl]-propionic acid;
[0362] 2-Aminomethyl-3-(1-methyl-cyclobutyl)-propionic acid; [0363]
2-Aminomethyl-3-(1-ethyl-cyclobutyl)-propionic acid; [0364]
2-Aminomethyl-3-(1-propyl-cyclobutyl)-propionic acid; [0365]
2-Aminomethyl-3-(1-methyl-cyclopentyl)-propionic acid; [0366]
2-Aminomethyl-3-(1-ethyl-cyclopentyl)-propionic acid; [0367]
2-Aminomethyl-3-(1-propyl-cyclopentyl)-propionic acid; [0368]
2-Aminomethyl-3-(1-methyl-cyclohexyl)-propionic acid; [0369]
2-Aminomethyl-3-(1-ethyl-cyclohexyl)-propionic acid; [0370]
2-Aminomethyl-3-(1-propyl-cyclohexyl)-propionic acid; [0371]
2-Aminomethyl-4-ethyl-hexanoic acid; [0372]
2-Aminomethyl-4-ethyl-5-methyl-hexanoic acid; [0373]
2-Aminomethyl-4-ethyl-heptanoic acid; [0374]
2-Aminomethyl-4-ethyl-6-methyl-heptanoic acid; [0375]
2-Aminomethyl-4-ethyl-octanoic acid; [0376]
2-Aminomethyl-4-ethyl-7-methyl-octanoic acid; [0377]
2-Aminomethyl-4-ethyl-nonanoic acid; [0378]
2-Aminomethyl-4-ethyl-8-methyl-nonanoic acid; [0379]
2-Aminomethyl-4,4-dimethyl-heptanoic acid; [0380]
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid; [0381]
2-Aminomethyl-5-ethyl-heptanoic acid; [0382]
2-Aminomethyl-5-ethyl-6-methyl-heptanoic acid; [0383]
2-Aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid; [0384]
2-Aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid; [0385]
2-Aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid; [0386]
2-Aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid; [0387]
2-Aminomethyl-5-ethyl-octanoic acid; [0388]
2-Aminomethyl-5-ethyl-7-methyl-octanoic acid; [0389]
2-Aminomethyl-5-ethyl-nonanoic acid; [0390]
2-Aminomethyl-5-ethyl-8-methyl-nonanoic acid; [0391]
2-Aminomethyl-4-cyclopropyl-butyric acid; [0392]
2-Aminomethyl-4-(1-methyl-cyclopropyl)-butyric acid; [0393]
2-Aminomethyl-4-(1-ethyl-cyclopropyl)-butyric acid; [0394]
2-Aminomethyl-4-cyclobutyl-butyric acid; [0395]
2-Aminomethyl-4-(1-methyl-cyclobutyl)-butyric acid; [0396]
2-Aminomethyl-4-(1-ethyl-cyclobutyl)-butyric acid; [0397]
2-Aminomethyl-4-cyclopentyl-butyric acid; [0398]
2-Aminomethyl-4-(1-methyl-cyclopentyl)-butyric acid; [0399]
2-Aminomethyl-4-(1-ethyl-cyclopentyl)-butyric acid; [0400]
2-Aminomethyl-4-cyclohexyl-butyric acid; [0401]
2-Aminomethyl-4-(1-methyl-cyclohexyl)-butyric acid; [0402]
2-Aminomethyl-4-(1-ethyl-cyclohexyl)-butyric acid; [0403]
(2R,4S)-2-Aminomethyl-6-cyclopentyl-4-ethyl-hexanoic acid; [0404]
(2R,4S)-2-Aminomethyl-6-cyclobutyl-4-ethyl-hexanoic acid; and
[0405] (2R,4S)-2-Aminomethyl-6-cyclopropyl-4-ethyl-hexanoic
acid.
[0406] Other specific embodiments of this invention include the
following compounds of the formula IIA and their pharmaceutically
acceptable salts: [0407] 2-Aminomethyl-4-methyl-hexanoic acid;
[0408] 2-Aminomethyl-4-methyl-heptanoic acid; [0409]
2-Aminomethyl-4-methyl-octanoic acid; [0410]
2-Aminomethyl-4-methyl-nonanoic acid; [0411]
2-Aminomethyl-4-methyl-decanoic acid; [0412]
(2R,4R)-2-Aminomethyl-4-methyl-hexanoic acid; [0413]
(2R,4R)-2-Aminomethyl-4-methyl-heptanoic acid; [0414]
(2R,4R)-2-Aminomethyl-4-methyl-octanoic acid; [0415]
(2R,4R)-2-Aminomethyl-4-methyl-nonanoic acid; [0416]
(2R,4R)-2-Aminomethyl-4-methyl-decanoic acid; [0417]
(2R,4S)-2-Aminomethyl-4-methyl-hexanoic acid; [0418]
(2R,4S)-2-Aminomethyl-4-methyl-heptanoic acid; [0419]
(2R,4S)-2-Aminomethyl-4-methyl-octanoic acid; [0420]
(2R,4S)-2-Aminomethyl-4-methyl-nonanoic acid; [0421]
(2R,4S)-2-Aminomethyl-4-methyl-decanoic acid; [0422]
2-Aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid; [0423]
2-Aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid; [0424]
2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid; [0425]
2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid; [0426]
2-Aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid; [0427]
2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid; [0428]
2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; [0429]
2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid; [0430]
2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid; [0431]
2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid; [0432]
2-Aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid; [0433]
2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid; [0434]
2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid; [0435]
2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid; [0436]
2-Aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; [0437]
2-Aminomethyl-8-cyclohexyl-4-methyl-octanoic acid; [0438]
(2R,4S)-2-Aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid; [0439]
(2R,4S)-2-Aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid; [0440]
(2R,4S)-2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid; [0441]
(2R,4S)-2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid; [0442]
(2R,4S)-2-Aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid; [0443]
(2R,4S)-2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid; [0444]
(2R,4S)-2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; [0445]
(2R,4S)-2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid; [0446]
(2R,4S)-2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid; [0447]
(2R,4S)-2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid; [0448]
(2R,4S)-2-Aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid; [0449]
(2R,4S)-2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid; [0450]
(2R,4S)-2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid; [0451]
(2R,4S)-2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid; [0452]
(2R,4S)-2-Aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; [0453]
(2R,4S)-2-Aminomethyl-8-cyclohexyl-4-methyl-octanoic acid; [0454]
(2R,4R)-2-Aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid; [0455]
(2R,4R)-2-Aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid; [0456]
(2R,4R)-2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid; [0457]
(2R,4R)-2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid; [0458]
(2R,4R)-2-Aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid; [0459]
(2R,4R)-2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid; [0460]
(2R,4R)-2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; [0461]
(2R,4R)-2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid; [0462]
(2R,4R)-2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid; [0463]
(2R,4R)-2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid; [0464]
(2R,4R)-2-Aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid; [0465]
(2R,4R)-2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid; [0466]
(2R,4R)-2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid; [0467]
(2R,4R)-2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid; [0468]
(2R,4R)-2-Aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; and
[0469] (2R,4R)-2-Aminomethyl-8-cyclohexyl-4-methyl-octanoic
acid.
[0470] This invention also relates to compounds of the formula III
##STR9## and their pharmaceutically acceptable salts, wherein
R.sub.3 is defined as for formula I above.
[0471] This invention also relates to compounds of the formula IV
##STR10## and their pharmaceutically acceptable salts, wherein
R.sub.1 and R.sub.3 are defined as for compounds of the formula I
above.
[0472] Other specific embodiments of this invention include the
following compounds of the formula IV and their pharmaceutically
acceptable salts: [0473]
2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; [0474]
2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; [0475]
2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; [0476]
2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; [0477]
2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; [0478]
2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; [0479]
2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; [0480]
2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; [0481]
2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; [0482]
2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; [0483]
2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; [0484]
2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; [0485]
2-Aminomethyl-5-methyl-heptanoic acid; [0486]
2-Aminomethyl-5-methyl-octanoic acid; [0487]
2-Aminomethyl-5-methyl-heptanoic acid; [0488]
2-Aminomethyl-5-methyl-nonanoic acid; [0489]
(2R,6S)-2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; [0490]
(2R,6S)-2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; [0491]
(2R,6S)-2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; [0492]
(2R,6S)-2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; [0493]
(2R,6S)-2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; [0494]
(2R,6S)-2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; [0495]
(2R,6S)-2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; [0496]
(2R,6S)-2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; [0497]
(2R,6S)-2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; [0498]
(2R,6S)-2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; [0499]
(2R,6S)-2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; [0500]
(2R,6S)-2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; [0501]
(2R,6S)-2-Aminomethyl-5-methyl-heptanoic acid; [0502]
(2R,6S)-2-Aminomethyl-5-methyl-octanoic acid; [0503]
(2R,6S)-2-Aminomethyl-5-methyl-heptanoic acid; [0504]
(2R,6S)-2-Aminomethyl-5-methyl-nonanoic acid; [0505]
(2R,6R)-2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; [0506]
(2R,6R)-2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; [0507]
(2R,6R)-2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; [0508]
(2R,6R)-2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; [0509]
(2R,6R)-2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; [0510]
(2R,6R)-2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; [0511]
(2R,6R)-2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; [0512]
(2R,6R)-2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; [0513]
(2R,6R)-2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; [0514]
(2R,6R)-2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; [0515]
(2R,6R)-2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; [0516]
(2R,6R)-2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; [0517]
(2R,6R)-2-Aminomethyl-5-methyl-heptanoic acid; [0518]
(2R,6R)-2-Aminomethyl-5-methyl-octanoic acid; [0519]
(2R,6R)-2-Aminomethyl-5-methyl-heptanoic acid; and [0520]
(2R,6R)-2-Aminomethyl-5-methyl-nonanoic acid.
[0521] This invention also relates to a pharmaceutical composition
comprising a therapeutically effective amount of a compound of the
formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III, or IV, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0522] This invention also relates to a method of treating a
disorder or condition selected from epilepsy, faintness attacks,
fibromyalgia, hypokinesia, cranial disorders, hot flashes,
essential tremor, chemical dependencies and addictions, (e.g.,
dependencies on or addictions to alcohol, amphetamines (or
amphetamine-like substances), caffeine, cannabis, cocaine, heroin,
hallucinogens, tobacco, inhalants and aerosol propellants,
nicotine, opioids, phenylglycidine derivatives, sedatives,
hypnotics, benzodiazepines and other anxiolytics), and withdrawal
symptoms associated with such dependencies or addictions, addictive
behaviors such as gambling; migraine, spasticity including muscle
spasticity and hypotonia with paralysis, arthritis, irritable bowel
syndrome (IBS), chronic pain, acute pain, neuropathic pain,
vascular headache, sinus headache, inflammatory disorders (e.g.,
rheumatoid arthritis, osteoarthritis, disease modification of
osteoarthritis disease, cartilage damage, psoriasis), diuresis,
premenstrual syndrome, premenstrual dysphoric disorder, tinnitus,
and gastric damage in a mammal, including a human, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of the formula I,
IA, IA-1, IA-2, IB, IC, II, IIA, III, or IV, or a pharmaceutically
acceptable salt thereof.
[0523] The present invention also relates to a method for cessation
of smoking, abstinence from addictive substances and dependencies,
promoting weight gain in a mammal having or suffering from
anorexia, cancer, old age and/or frailty, in a mammal, including
humans, comprising administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of the
formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III; or IV, or a
pharmaceutically acceptable salt thereof.
[0524] The present invention also covers treating neurodegenerative
disorders termed acute brain injury. These include but are not
limited to: stroke, head trauma, and asphyxia.
[0525] Stroke refers to a cerebral vascular disease and may also be
referred to as a cerebral vascular incident (CVA) and includes
acute thromboembolic stroke. Stroke includes both focal and global
ischemia. Also, included are transient cerebral ischemic attacks
and other cerebral vascular problems accompanied by cerebral
ischemia, such as those that occur in patients undergoing carotid
endarterectomy or other cerebrovascular or vascular surgical
procedures, or diagnostic vascular procedures including cerebral
angiography and the like.
[0526] Compounds of the formulas I, IA, IA-1, IA-2, IB, IC, II,
IIA, III, and IV, are also useful in the treatment of head trauma,
spinal cord trauma, or injury from general anoxia, hypoxia,
hypoglycemia, hypotension as well as similar injuries seen during
procedures from embole, hyperfusion, and hypoxia. They are also
useful in preventing neuronal damage that occurs during cardiac
bypass surgery, in incidents of intracranial hemorrhage, in
perinatal asphyxia, in cardiac arrest, and status epilepticus.
[0527] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of
delirium, dementia, and amnestic and other cognitive or
neurodegenerative disorders, such as Parkinson's disease (PD),
Huntington's disease (HD), Alzheimer's disease, senile dementia,
dementia of the Alzheimers type, memory disorder, vascular
dementia, and other dementias, for example, due to HIV disease,
head trauma, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies;
movement disorders such as akinesias, dyskinesias, including
familial paroxysmal dyskinesias, spasticities, Tourette's syndrome,
Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptc malignant
syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced
acute akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremour; Down's syndrome; demyelinating
diseases such as multiple sclerosis (MS) and amylolateral sclerosis
(ALS), peripheral neuropathy, for example diabetic and
chemotherapy-induced-neuropathy, and postherpetic neuralgia,
trigeminal neuralgia, segmental or intercostal neuralgia and other
neuralgias; and cerebral vascular disorders due to acute or chronic
cerebrovascular damage such as cerebral infarction, subarachnoid
haemorrhage or cerebral oedema in a mammal, including a human,
comprising administering to said mammal an amount of a compound of
the formula I, IA, IA-1, IA-2, IB, IC, II, IIA, III, or IV, or a
pharmaceutically acceptable salt thereof, that is effective in
treating such disorder or condition.
[0528] Cognition can also be enhanced in those having fibromyalgia,
Alzheimer's disease, and Parkinson's disease by enhancing sleep in
a mammal, including a human, suffering therefrom by administering
to a mammal in need of such treatment a therapeutically effective
amount of a compound of the formula I, IA, IA-1, IA-2, IB, IC, II,
IIA, III, or IV, or a pharmaceutically acceptable salt thereof.
[0529] Pain refers to acute as well as chronic pain. Acute pain is
usually short-lived and is associated with hyperactivity of the
sympathetic nervous system. Examples are postoperative pain and
allodynia. Chronic pain is usually defined as pain persisting from
3 to 6 months and includes somatogenic pain and psychogenic pain.
Other pain is nociceptive.
[0530] Examples of the types of pain that can be treated with the
compounds of formulas I, IA, IA-1, IA-2, IB, IC, II, IIA, III, and
IV of the present invention and their pharmaceutically acceptable
salts include pain resulting from soft tissue and peripheral
damage, such as acute trauma, pain associated with osteoarthritis
and rheumatoid arthritis, musculo-skeletal pain, such as pain
experienced after trauma; spinal pain, dental pain, myofascial pain
syndromes, episiotomy pain, and pain resulting from burns; deep and
visceral pain, such as heart pain, muscle pain, eye pain, orofacial
pain, for example, odontalgia, abdominal pain, gynaecological pain,
for example, dysmenorrhoea, labour pain and pain associated with
endometriosis; pain associated with nerve and root damage, such as
pain associated with peripheral nerve disorders, for example, nerve
entrapment and brachial plexus avulsions, amputation, peripheral
neuropathies, tic douloureux, atypical facial pain, nerve root
damage, trigeminal neuralgia, neuropathic lower back pain, HIV
related neuropathic pain, cancer related neuropathic pain, diabetic
neuropathic pain, and arachnoiditis; neuropathic and
non-neuropathic pain associated with carcinoma, often referred to
as cancer pain; central nervous system pain, such as pain due to
spinal cord or brain stem damage; lower back pain; sciatica;
phantom limb pain, headache, including migraine and other vascular
headaches, acute or chronic tension headache, cluster headache,
temperomandibular pain and maxillary sinus pain; pain resulting
from ankylosing spondylitis and gout; pain caused by increased
bladder contractions; post operative pain; scar pain; and chronic
non-neuropathic pain such as pain associated with fibromyalgia,
HIV, rheumatoid and osteoarthritis, anthralgia and myalgia,
sprains, strains and trauma such as broken bones; and post surgical
pain.
[0531] Still other pain is caused by injury or infection of
peripheral sensory nerves. It includes, but is not limited to pain
from peripheral nerve trauma, herpes virus infection, diabetes
mellitus, fibromyalgia, causalgia, plexus avulsion, neuroma, limb
amputation, and vasculitis. Neuropathic pain is also caused by
nerve damage from chronic alcoholism, human immunodeficiency virus
infection, hypothyroidism, uremia, or vitamin deficiencies.
Neuropathic pain includes, but is not limited to pain caused by
nerve injury such as, for example, the pain diabetics suffer
from.
[0532] Psychogenic pain is that which occurs without an organic
origin such as low back pain, atypical facial pain, and chronic
headache.
[0533] Other types of pain are: inflammatory pain, osteoarthritic
pain, trigeminal neuralgia, cancer pain, diabetic neuropathy,
restless leg syndrome, acute herpetic and postherpetic neuralgia,
causalgia, brachial plexus avulsion, occipital neuralgia, gout,
phantom limb, burn, and other forms of neuralgia, neuropathic and
idiopathic pain syndrome.
[0534] The compounds of the invention are also useful in the
treatment of depression. Depression can be the result of organic
disease, secondary to stress associated with personal loss, or
idiopathic in origin. There is a strong tendency for familial
occurrence of some forms of depression suggesting a mechanistic
cause for at least some forms of depression. The diagnosis of
depression is made primarily by quantification of alterations in
patients' mood. These evaluations of mood are generally performed
by a physician or quantified by a neuropsychologist using validated
rating scales, such as the Hamilton Depression Rating Scale or the
Brief Psychiatric Rating Scale. Numerous other scales have been
developed to quantify and measure the degree of mood alterations in
patients with depression, such as insomnia, difficulty with
concentration, lack of energy, feelings of worthlessness, and
guilt. The standards for diagnosis of depression as well as all
psychiatric diagnoses are collected in the Diagnostic and
Statistical Manual of Mental Disorders (Fourth Edition) referred to
as the DSM-IV-R manual published by the American Psychiatric
Association, 1994.
[0535] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of mood
disorders, such as depression, or more particularly, depressive
disorders, for example, single episodic or recurrent major
depressive disorders, dysthymic disorders, depressive neurosis and
neurotic depression, melancholic depression, including anorexia,
weight loss, insomnia, early morning waking and psychomotor
retardation, atypical depression (or reactive depression),
including increased appetite, hypersomnia, psychomotor agitation or
irritability, seasonal affective disorder and pediatric depression;
or bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder; conduct
disorder and disruptive behavior disorder; anxiety disorders, such
as panic disorder with or without agoraphobia, agoraphobia without
history of panic disorder, specific phobias, for example, specific
animal phobias, fear of flying, social anxiety disorder, social
phobia, obsessive-compulsive disorder, stress disorders, including
post-traumatic stress disorder and acute stress disorder, and
generalized anxiety disorders; borderline personality disorder;
schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder, mood disorders
associated with schizophrenia; behavioral disturbances associated
with mental retardation, autistic disorder, and conduct disorder in
a mammal, including a human, comprising administering to said
mammal an amount of a compound of the formula I, IA, IA-1, IA-2,
IB, IC, II, IIA, III, or IV, or a pharmaceutically acceptable salt
thereof, that is effective in treating such disorder or
condition.
[0536] The compounds of the invention are also useful in the
treatment of sleep disorders. Sleep disorders are disturbances that
affect the ability to fall and/or stay asleep, that involves
sleeping too much, or that result in abnormal behavior associated
with sleep. The disorders include, for example, insomnia,
drug-associated sleeplessness, hypersomnia, narcolepsy, sleep apnea
syndromes, and parasomnias.
[0537] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of sleep
disorders (e.g., insomnia, drug-associated sleeplessness, REM sleep
disorders, hypersomnia, narcolepsy, sleep-wake cycle disorders,
sleep apnea syndromes, parasomnias, restless leg syndrome, jet lag,
periodic limb movement disorder, altered sleep architecture, and
sleep disorders associated with shift work and irregular work
hours) in a mammal, including a human, comprising administering to
said mammal an amount of a compound of the formula I, IA, IA-1,
IA-2, IB, IC, II, IIA, III, or IV, or a pharmaceutically acceptable
salt thereof, that is effective in treating such disorder or
condition.
[0538] Compounds of formulas I, IA, IA-1, IA-2, IB, IC, II, IIA,
Ill, and IV contain at least one chiral center and therefore may
exist in different enantiomeric and diastereomeric forms. This
invention relates to all optical isomers and all stereoisomers of
compounds of the formulas I, IA, IA-1, IA-2, IB, IC, II, IIA, III,
and IV, both as racemic mixtures and as individual enantiomers and
diastereoisomers of such compounds, and mixtures thereof, and to
all pharmaceutical compositions and methods of treatment defined
above that contain or employ them, respectively. Individual isomers
can be obtained by known methods, such as optical resolution,
optically selective reaction, or chromatographic separation in the
preparation of the final product or its intermediate. Individual
enantiomers of the compounds of this invention may have advantages,
as compared with the racemic mixtures of these compounds, in the
treatment of various disorders or conditions.
[0539] The present invention also includes isotopically labelled
compounds, which are identical to those recited in formulas I, IA,
IA-1, IA-2, IB, IC, II, IIA, III, and IV, but for the fact 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 present invention include isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.11C, .sup.14C,
.sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, and .sup.36Cl, respectively. Compounds of the present
invention, prodrugs thereof, and pharmaceutically acceptable salts
of said compounds or of said prodrugs which contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically labelled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
formula I of this 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, by substituting a
readily available isotopically labelled reagent for a
non-isotopically labelled reagent.
[0540] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight, branched or cyclic moieties or combinations
thereof. Examples of "alkyl" groups 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.
[0541] The term "alkoxy", as used herein, unless otherwise
indicated, means "alkyl-O--", wherein "alkyl" is as defined above.
Examples of "alkoxy" groups include, but are not limited to,
methoxy, ethoxy, propoxy, butoxy and pentoxy.
[0542] The term "treating", as used herein, refers to protecting,
reversing, alleviating, inhibiting the progress of, or preventing
the disorder or condition to which such term applies, or preventing
one or more symptoms of such condition or disorder. The term
"treatment", as used herein, refers to the act of treating, as
"treating" is defined immediately above.
[0543] Because amino acids are amphoteric, pharmacologically
compatible salts can be salts of appropriate inorganic or organic
acids, for example, hydrochloric, sulphuric, phosphoric, acetic,
oxalic, lactic, citric, malic, salicylic, malonic, maleic,
succinic, and ascorbic. Starting from corresponding hydroxides or
carbonates, salts with alkali metals or alkaline earth metals, for
example, sodium, potassium, magnesium, or calcium are formed. Salts
with quaternary ammonium ions can also be prepared with, for
example, the tetramethyl-ammonium ion.
[0544] The effectiveness of an orally administered drug is
dependent upon the drug's efficient transport across the mucosal
epithelium and its stability in entero-hepatic circulation. Drugs
that are effective after parenteral administration but less
effective orally, or whose plasma half-life is considered too
short, may be chemically modified into a prodrug form.
[0545] A prodrug is a drug that has been chemically modified and
may be biologically inactive at its site of action, but which may
be degraded or modified by one or more enzymatic or other in vivo
processes to the parent bioactive form.
[0546] This chemically modified drug, or prodrug, should have a
different pharmacokinetic profile than the parent drug, enabling
easier absorption across the mucosal epithelium, better salt
formulation and/or solubility, improved systemic stability (for an
increase in plasma half-life, for example). These chemical
modifications may be [0547] 1) ester or amide derivatives which may
be cleaved by, for example, esterases or lipases. For ester
derivatives, the ester is derived from the carboxylic acid moiety
of the drug molecule by known means. For amide derivatives, the
amide may be derived from the carboxylic acid moiety or the amine
moiety of the drug molecule by known means. [0548] 2) peptides
which may be recognized by specific or nonspecific proteinases. A
peptide may be coupled to the drug molecule via amide bond
formation with the amine or carboxylic acid moiety of the drug
molecule by known means. [0549] 3) derivatives that accumulate at a
site of action through membrane selection of a prodrug form or
modified prodrug form, [0550] 4) any combination of 1 to 3.
[0551] Current research in animal experiments has shown that the
oral absorption of certain drugs may be increased by the
preparation of "soft" quaternary salts. The quaternary salt is
termed a "soft" quaternary salt since, unlike normal quaternary
salts, e.g., R--N.sup.+(CH.sub.3).sub.3, it can release the active
drug upon hydrolysis.
[0552] "Soft" quaternary salts have useful physical properties
compared with the basic drug or its salts. Water solubility may be
increased compared with other salts, such as the hydrochloride, but
more important there may be an increased absorption of the drug
from the intestine. Increased absorption is probably due to the
fact that the "soft" quaternary salt has surfactant properties and
is capable of forming micelles and unionized ion pairs with bile
acids, etc., which are able to penetrate the intestinal epithelium
more effectively. The prodrug, after absorption, is rapidly
hydrolyzed with release of the active parent drug.
[0553] Prodrugs of compounds of formulas I, IA, IA-1, IA-2, IB, IC,
II, IIA, III, and IV are included within the scope of this
invention. Prodrugs and soft drugs are known in the art (Palomino
E., Drugs of the Future, 1990; 15(4):361-368). The last two
citations are hereby incorporated by reference.
[0554] Certain of the compounds of the present invention can exist
in unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms, including hydrated forms,
are equivalent to unsolvated forms and are intended to be
encompassed within the scope of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0555] The compounds of this invention can be prepared as described
below. In the reaction schemes and discussion that follow,
structural formulas I, IA, IA-1, IA-2, IB, IC, II, IIA, III, and
IV, and the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
and R.sub.6, unless otherwise indicated, are defined as above.
[0556] Diverse methods exist for the preparation of chiral and
racemic .beta.-amino acids. Such methods can be found in
"Enantioselective Synthesis of .beta.-Amino Acids", Juaristi,
Eusebio; Editor. USA, 1997, Wiley-VCH, New York, N.Y.
[0557] The methods described below are illustrative of methods that
can be utilized for the preparation of such compounds but are not
limiting in scope. ##STR11##
[0558] According to the procedure of Lazar, et al, Synth. Commun,
1998, 28(2), 219-224, compounds of the formula IA can be prepared
by heating to reflux compounds of the formula I in a alcoholic
solvent such as ethanol, in the presence of malonic acid and
ammonium acetate. Aldehydes of the formula I can be prepared from
commercially available materials using methods well known to those
of skill in the art.
[0559] Compounds that can be made by the above method include, but
are not limited to the following: [0560]
3-Amino-6-cyclopropyl-5-methyl-hexanoic acid; [0561]
3-Amino-6-cyclobutyl-5-methyl-hexanoic acid; [0562]
3-Amino-6-cyclopentyl-5-methyl-hexanoic acid; [0563]
3-Amino-6-cyclohexyl-5-methyl-hexanoic acid; [0564]
3-Amino-7-cyclopropyl-5-methyl-heptanoic acid; [0565]
3-Amino-7-cyclobutyl-5-methyl-heptanoic acid; [0566]
3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; [0567]
3-Amino-7-cyclohexyl-5-methyl-heptanoic acid; [0568]
3-Amino-8-cyclopropyl-5-methyl-octanoic acid [0569]
3-Amino-8-cyclobutyl-5-methyl-octanoic acid; [0570]
3-Amino-8-cyclopentyl-5-methyl-octanoic acid; [0571]
3-Amino-8-cyclohexyl-5-methyl-octanoic acid; [0572]
3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid; [0573]
3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid; [0574]
3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid; [0575]
3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid; [0576]
3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid; [0577]
3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid; [0578]
3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and [0579]
3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid. ##STR12##
[0580] The use of chiral amine additions to
.alpha.,.beta.-unsaturated systems as a synthetic approach to
.beta.-amino acids, as illustrated in Method B above, has been
described previously (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). Referring to Method B above, compounds of the formula IA
can be prepared from the corresponding compounds of the formula 7,
wherein PG represents a suitable ester protecting group that can be
removed by hydrolysis or hydrogenolysis, using conditions well
known to those of skill in the art. (See T. W. Greene and P. G. M.
Wuts., "Protective groups in organic synthesis", Wiley, 1991 for a
detailed description for the formation and removal of suitable
protecting groups). For example, this reaction can be conducted
under hydrolytic conditions by treatment with an appropriate acid,
such as hydrochloric acid or sulfuric acid, at a temperature from
about room temperature to about the reflux temperature of the
reaction mixture, preferably at the reflux temperature, or by
treatment with an appropriate inorganic base, such as sodium
hydroxide, potassium hydroxide, or lithium hydroxide, preferably
sodium hydroxide, at a temperature from about room temperature to
about the reflux temperature, preferably at about room temperature.
This reaction is preferably carried out using hydrochloric acid at
the reflux temperature. When PG is t-butyl, however, the reaction
is preferably carried out in trifluoroacetic acid (TFA). When PG is
a basic group, the hydrolysis can be carried out under basic
conditions, using methods well known to those of skill in the art,
for example, using sodium or potassium hydroxide.
[0581] Compounds of the formula 7 can be prepared from the
corresponding compounds of the formula 6 using hydrogenolysis
conditions that are well known to those of skill in the art. For
example, this reaction can be carried out by treating the compounds
of formula 6 with a palladium metal catalyst, such as, for example,
palladium hydroxide on carbon, or palladium on carbon, or with
Raney Nickel, in a solvent such as, for example, methanol, ethanol
or tetrahydrofuran, under an atmosphere of hydrogen (between about
1 and 5 atmospheres of pressure) to give the desired compound of
formula 7. Preferably, the reaction is carried out using palladium
on carbon in ethanol under about 1 atmosphere of hydrogen.
[0582] Compounds of the formula 6 can be prepared by treating the
corresponding compounds of formula 4 with an appropriate amine such
as (R)-(+)-N-benzyl-.alpha.-methylbenzylamine,
(S)-(-)-N-benzyl-.alpha.-methylbenzylamine after treatment with an
appropriate base such as lithium diisopropylamide, n-butyl lithium,
or lithium or potassium bis(trimethylsilyl)amide, in a solvent such
as ethyl ether, or, preferably, tetrahydrofuran (THF), at a
temperature from about -80.degree. C. to about 25.degree. C., and
then adding the appropriate compound of formula formula 4. The
stereochemistry about the nitrogen of the amine will determine the
stereochemistry about the nitrogen of the final product.
Preferably, this reaction is carried out using either
(R)-(+)-N-benzyl-.alpha.-methylbenzylamine,
(S)-(-)-N-benzyl-.alpha.-methylbenzylamine, after deprotonation
with n-butyl-lithium in tetrahydrofuran, at a temperature of about
-78.degree. C., according to method described by Bull, Steven D.;
Davies, Stephen G.; and Smith, Andrew D, J. Chem. Soc., Perkin
Trans. 1, 2001, 22, 2931-2938. Preferably, this reaction is carried
out using either (R)-(+)-N-benzyl-.alpha.-methylbenzylamine, or
(S)-(-)-N-benzyl-.alpha.-methylbenzylamine, after deprotonation
with n-butyl-lithium in tetrahydrofuran, at a temperature of about
-78.degree. C., according to method described by Bull, Steven D.;
Davies, Stephen G.; and Smith, Andrew D, J. Chem. Soc., Perkin
Trans. 1, 2001, 22, 2931-2938.
[0583] Compounds of the formula 4 can be prepared from the
corresponding compounds of formula 3 by treating them with an
appropriate phosphonate ester in the presence of a suitable base
such as sodium hydride, lithium diisopropylamide, or triethyl amine
and either lithium chloride or lithium bromide, in a solvent such
as ether or THF. Preferably, the compound of formula 3 is reacted
with a phosphonate ester (ALK=methyl, ethyl, isopropyl, benzyl or
the like) in the presence of lithium bromide and triethylamine in
tetrahydrofuran at about room temperature. Compounds of the formula
3 can be prepared from commercially available materials using
methods well known to those of skill in the art. It will be
appreciated that compounds of the formula 3 may possess one or more
stereogenic centers. Using the above described method, compounds
with specific stereochemical configurations can be prepared.
[0584] Compounds that can be made by this method include, but are
not limited to the following: [0585]
(3S,5R)-3-Amino-6-cyclopropyl-5-methyl-hexanoic acid; [0586]
(3S,5R)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid; [0587]
(3S,5R)-3-Amino-6-cyclopentyl-5-methyl-hexanoic acid; [0588]
(3S,5R)-3-Amino-6-cyclohexyl-5-methyl-hexanoic acid; [0589]
(3S,5R)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid; [0590]
(3S,5R)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid; [0591]
(3S,5R)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid; [0592]
(3S,5R)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid; [0593]
(3S,5S)-3-Amino-6-cyclopropyl-5-methyl-hexanoic acid; [0594]
(3S,5S)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid; [0595]
(3S,5S)-3-Amino-6-cyclopentyl-5-methyl-hexanoic acid; [0596]
(3S,5S)-3-Amino-6-cyclohexyl-5-methyl-hexanoic acid; [0597]
(3S,5S)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid; [0598]
(3S,5S)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid; [0599]
(3S,5S)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid; [0600]
(3S,5S)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid; [0601]
(3S)-3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid; [0602]
(3S)-3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid; [0603]
(3S)-3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid; [0604]
(3S)-3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid; [0605]
(3S)-3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid; [0606]
(3S)-3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid; [0607]
(3S)-3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and [0608]
(3S)-3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid.
##STR13##
[0609] The diastereoalkylation of imides such as those of formula
10 to afford chiral succinate analogs such as those of formula 11
has been previously described as an approach to preparing
.beta.-amino acids (see, e.g., Evans et al, J. Org. Chem., 1999,
64, 6411; Sibi and Deshpande, J. Chem. Soc. Perkin Trans 1., 2000,
1461; Arvanitis et al, J. Chem. Soc. Perkin Trans 1., 1998,
521).
[0610] Compounds of structure 11 can be prepared from compounds of
structure 10 in the presence of a suitably derived ester (PG as
defined above, LG=Br or I or Cl) such as, for example, t-butyl
bromoacetate, benzyl bromoacetate with an organometallic base such
as, for example, lithium diisopropylamide or lithium
bis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide and the
like in a solvent such as, for example, tetrahydrofuran, ether, and
the like. The reaction can be carried out using sodium
bis(trimethylsilyl)amide in tetrahydrofuran at -78.degree. C. and
treatment of the resultant anion intermediate with t-butyl
bromoacetate at -78.degree. C. to -30.degree. C.
[0611] Compounds of the formula 12 can be prepared by hydrolysing
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 from about 0.degree. C. to about room
temperature. Preferably, this reaction is carried out using
hydrogen peroxide and lithium hydroxide in aqueous tetrahydrofuran
at about 0.degree. C. according to the method described in the
literature (See Yuen P-W., Kanter G. D., Taylor C. P., and
Vartanian M. G., Bioorganic and Medicinal Chem. Lett., 1994;
4(6):823-826).
[0612] Treatment of a compound of the formula 12 with
diphenylphosphorylazide 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
from about 50.degree. C. to about the reflux temperature of the
reation mixture yields the corresponding compound of formula 13
wherein R.sub.5 is methyl, ethyl, t-butyl, benzyl, or
p-methoxybenzyl. R.sub.5 is dependent on the choice of the alcohol
used. Preferably, this reaction is carried out using a toluene
solvent in the presence of p-methoxybenzyl alcohol under refluxing
conditions.
[0613] Compounds of the formula 13 can be converted into the
desired compounds of formula IA by hydrolysis or hydrogenolysis,
using conditions well known to those of skill in the art. (See T.
W. Greene and P. G. M. Wuts., "Protective groups in organic
synthesis", Wiley, 1991 for a detailed description for the
formation and removal of suitable protecting groups). For example,
this reaction can be conducted under hydrolytic conditions by
treatment with an appropriate acid, such as hydrochloric acid or
sulfuric acid, at a temperature from about room temperature to
about the reflux temperature of the reaction mixture, preferably at
the reflux temperature, or by treatment with an appropriate
inorganic base, such as sodium hydroxide, potassium hydroxide, or
lithium hydroxide, preferably sodium hydroxide, at a temperature
from about room temperature to about the reflux temperature,
preferably at about room temperature. This reaction is preferably
carried out using hydrochloric acid at the reflux temperature. When
PG is t-butyl, however, the reaction is preferably carried out in
trifluoroacetic acid (TFA). When PG is a basic group, the
hydrolysis can be carried out under basic conditions, using methods
well known to those of skill in the art, for example, using sodium
or potassium hydroxide.
[0614] Compounds of the formula 10 can be prepared by treating the
corresponding compounds of formula 8 with an amine base such as
triethylamine, in the presence of trimethylacetylchloride, in an
ethereal solvent such as THF, and then treating the intermediates
formed by this reaction [in situ] with a chiral oxazolidinone of
the formula 9. Examples of other oxazolidonones that can be used in
this method 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, this reaction is carried out by treating an
acid of the formula 8 with trimethylacetylchloride and
triethylamine in tetrahydrofuran at about -20.degree. C., followed
by treatment of the intermediate formed in such reaction with an
oxazolidinone of the 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; 60:2271-2273).
[0615] Alternatively, compounds of the formula 10 can be prepared
by treating the corresponding compounds of the formula 9 with the
acid chloride derived from treatment of the corresponding compound
of the formula 8 with oxalyl chloride, in a solvent such as
dichloromethane, in the presence of dimethylformamide (DMF). Acids
of the formula 8 can be prepared from commercially available
materials using methods well known to those of skill in the art.
These acids may possess one or more chiral centers. The use of
citronellyl bromide and citronellol in the synthesis of such acids
is described in Examples 1, 2 and 3 of this application.
[0616] Compounds that can be prepared by the above Method C
include, but are not limited to the following: [0617]
(3S,5R)-3-Amino-5-methyl-heptanoic acid; [0618]
(3S,5R)-3-Amino-5-methyl-octanoic acid; [0619]
(3S,5R)-3-Amino-5-methyl-nonanoic acid; [0620]
(3S,5R)-3-Amino-5-methyl-decanoic acid; [0621]
(3S,5S)-3-Amino-5-methyl-heptanoic acid; [0622]
(3S,5S)-3-Amino-5-methyl-octanoic acid; [0623]
(3S,5S)-3-Amino-5-methyl-nonanoic acid; [0624]
(3S,5S)-3-Amino-5-methyl-decanoic acid; [0625]
(3S)-3-Amino-5,5-dimethyl-heptanoic acid; [0626]
(3S)-3-Amino-5,5-dimethyl-octanoic acid; [0627]
(3S)-3-Amino-5,5-dimethyl-nonanoic acid; [0628]
(3S)-3-Amino-5,5-dimethyl-decanoic acid; [0629]
(3S,5R)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid; [0630]
(3S,5R)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid; [0631]
(3S,5R)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; [0632]
(3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid; [0633]
(3S,5S)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid; [0634]
(3S,5S)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid; [0635]
(3S,5S)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; and [0636]
(3S,5S)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid.
[0637] Alternatively, referring to the reaction scheme (Method D)
below, compounds of the formula 11 can be treated with an
appropriate acid (for example, trifluoroacetic acid (TFA) when the
t-butyl ester is used) to yield the corresponding compounds of
formula 14, which can then be subjected to a Curtius rearrangement
(where R.sub.5 is defined as above) to yield the corresponding
compounds of formula 15 (See Arvanitis et al, J. Chem. Soc. Perkin
Trans 1., 1998, 521 for a description of this approach). Further
hydrolysis of the imide group (to yield the corresponding compound
of formula 16) and the carbamate group gives the desired
.alpha.-amino acids of formula 11.
[0638] Compound 16 can be derived from compound 15 as described
above for the conversion of compounds of the formula 11 into
compounds of the formula 12. Compounds of the formula 17 can be
prepared from corresponding compounds of the formula 16 through
treatment with a strong acid, such as hydrochloric acid or the
like, or a strong base, such as sodium or potassium hydroxide or,
if R.sub.5 is benzyl or p-methoxybenzyl, through hygrogenolytic
conditions, using palladium on carbon in ethanol or THF under a
hydrogen atmosphere. This approach, which preserves the
stereochemistry about the chiral center in the compounds of formula
11, which is also present in the product of formula II, is
described in Example 4 of this application. ##STR14##
[0639] Compounds that can be made by this method include, but are
not limited to the following: [0640]
(2R,4R)-2-Aminomethyl-4-methyl-hexanoic acid; [0641]
(2R,4R)-2-Aminomethyl-4-methyl-heptanoic acid; [0642]
(2R,4R)-2-Aminomethyl-4-methyl-octanoic acid; [0643]
(2R,4R)-2-Aminomethyl-4-methyl-nonanoic acid; [0644]
(2R,4R)-2-Aminomethyl-4-methyl-decanoic acid; [0645]
(2R,4S)-2-Aminomethyl-4-methyl-hexanoic acid; [0646]
(2R,4S)-2-Aminomethyl-4-methyl-heptanoic acid; [0647]
(2R,4S)-2-Aminomethyl-4-methyl-octanoic acid; [0648]
(2R,4S)-2-Aminomethyl-4-methyl-nonanoic acid; [0649]
(2R,4S)-2-Aminomethyl-4-methyl-decanoic acid; [0650]
(2R,4S)-2-Aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid; [0651]
(2R,4S)-2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid; [0652]
(2R,4S)-2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; and
[0653] (2R,4S)-2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic
acid.
[0654] Other alternative approaches to synthesizing
.alpha.-substituted .beta.-amino acids that can be utilized for
preparing the compounds of this invention include those described
by Juaristi et al Tetrahedron Asymm., 7, (8), 1996, 2233 and
Seebach et al, Eur. J. Org. Chem., 1999, 335, or by Arvanitis et
al, J. Chem. Soc. Perkin Trans 1., 1998, 521, as shown in Method E
below: ##STR15##
[0655] Method F below illustrates an alternate method of preparing
compounds of the formula II. ##STR16##
[0656] According to the procedure disclosed by Hoffmann-La Roche
(FR 1377736 19641106), compounds of formula 3 can be prepared from
unsaturated cyanoesters of formula 2 by reduction and hydrolysis.
In turn, cyanoesters 2 can be prepared via Knoevenagel condensation
of aldehydes 1 with cyanoacetic esters (e.g. Paine, J. B.;
Woodward, R. B.; Dolphin, D., J. Org. Chem. 1976, 41, 2826).
Aldehydes of the formula 1 can be prepared from commercially
available materials by methods known to those skilled in the
art.
[0657] Compounds of the formulas III and IV can be prepared using
procedures analogous to those of Method F that will be obvious to
those of skill in the art. When synthesizing a compound of the
formula II, the starting material should be a compound similar to
formula I in Method F, but wherein the hydrogen attached to the
carbonyl group in formula I is replaced by a methyl group.
[0658] The use of chiral imines to afford .beta.-amino acids, as
illustrated in Method G below, has been described previously (see,
e.g Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12-13).
##STR17##
[0659] The final step in the above scheme is a hydrolysis of both
the sulfonamide and ester groups. This reaction is generally
carried out 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 from
about 20.degree. C. to about 50.degree. C., preferably at about
room temperature.
[0660] The preparation of compounds of this invention that are not
specifically described in the foregoing experimental section can be
accomplished using combinations of the reactions described above
that will be apparent to those skilled in the art.
[0661] In each of the reactions discussed or illustrated above,
pressure is not critical unless otherwise indicated. Pressures from
about 0.5 atmospheres to about 5 atmospheres are generally
acceptable, and ambient pressure, i.e., about 1 atmosphere, is
preferred as a matter of convenience.
[0662] The compounds of formula I, IA, IA-1, IA-2, IB, IC, II, IIA,
III, or IV, and intermediates shown in the above reaction schemes
can be isolated and purified by conventional procedures, such as
recrystallization or chromatographic separation.
[0663] The ability of compounds of the present invention to bind to
the .alpha.2.delta.-subunit of a calcium channel can be determined
using the following binding assay.
[0664] The radioligand binding assay using [.sup.3H]-gabapentin and
the .alpha.2.delta.-subunit derived from porcine brain tissue was
used (See, Gee, Nicolas S et al. "The novel anticonvulsant drug,
gabapentin (Neurontin), binds to the .alpha.2.delta. subunit of a
calcium channel". J. Biol. Chem. (1996), 271 (10), 5768-76).
Compounds of the invention bind with nanomolar to micromolar
affinity for the .alpha.2.delta. protein. For example,
R-3-amino-5,9-dimethyl-decanoic acid binds with 527 nM affinity to
the .alpha.2.delta. protein, (3S,5S)-3-amino-5-methyl-octanoic acid
binds with 1 uM affinity, (2R,4R)-2-Aminomethyl-4-methyl-heptanoic
acid binds with 29 nM affinity,
2-Aminomethyl-4,4-dimethyl-heptanoic acid binds with 83 nM
affinity.
[0665] The In vivo activity of compounds of this invention can be
determined in animal models. See, e.g., Sluka, K., et al.,
"Unilateral Intramuscular Injections Of Acidic Saline Produce A
Bilateral, Long-Lasting Hyperalgesia," Muscle Nerve 24: 37-46
(2001); Dixon, W., "Efficient analysis of experimental
observations," Ann Rev Pharmacol Toxicol 20:441-462, (1980);
Randall L. O. and Selitto J. J., "A Method For Measurement Of
Analgesic Activity On Inflamed Tissue," Arch. Int. Pharmacodyn;
4:409-419, (1957); Hargreaves K., Dubner R., Brown F., Flores C.,
and Joris J. "A New And Sensitive Method For Measuring Thermal
Nociception In Cutaneous Hyperalgesia," Pain. 32:77-88 (1988)
(hyperalgesia). See also, Vogel J R, Beer B, and Clody D E, "A
Simple And Reliable Conflict Procedure For Testing Anti-Anxiety
Agents," Psychopharmacologia 21:1-7 (1971) (anxiety).
[0666] The compounds of the present invention, and their
pharmaceutically acceptable salts, can be administered to mammals
via either the oral, parenteral (such as subcutaneous, intravenous,
intramuscular, intrasternal and infusion techniques), rectal,
buccal or intranasal routes.
[0667] The novel compounds of the present invention may be
administered alone or in combination with pharmaceutically
acceptable carriers or diluents by any of the routes previously
indicated, and such administration may be carried out in single or
multiple doses. More particularly, the novel therapeutic agents of
this invention can be administered in a wide variety of different
dosage forms, i.e., they may be combined with various
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, etc. Moreover, oral pharmaceutical compositions can be
suitably sweetened and/or flavored. In general, the weight ratio of
the novel compounds of this invention to the pharmaceutically
acceptable carrier will be in the range from about 1:6 to about
2:1, and preferably from about 1:4 to about 1:1.
[0668] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the active ingredient may be
combined with various sweetening or flavoring agents, coloring
matter or dyes, and, if so desired, emulsifying and/or suspending
agents as well, together with such diluents as water, ethanol,
propylene glycol, glycerin and various like combinations
thereof.
[0669] For parenteral administration, solutions of a compound of
the present invention in either sesame or peanut oil or in aqueous
propylene glycol may be employed. The aqueous solutions should be
suitably buffered (preferably pH greater than 8) if necessary and
the liquid diluent first rendered isotonic. These aqueous solutions
are suitable for intravenous injection purposes. The oily solutions
are suitable for intra-articular, intra-muscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
[0670] For intranasal administration or administration by
inhalation, the novel compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound. 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.
Formulations of the active compounds of this invention for
treatment of the conditions referred to above in the average adult
human are preferably arranged so that each metered dose or "puff"
of aerosol contains 20 .mu.g to 1000 .mu.g of active compound. The
overall daily dose with an aerosol will be within the range 100
.mu.g to 10 mg. Administration may be several times daily, for
example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses
each time.
[0671] The compounds of the present invention can be prepared and
administered in a wide variety of oral and parenteral dosage forms.
Thus, the compounds of the present invention can be administered by
injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, or
intraperitoneally. Also, the compounds of the present invention can
be administered by inhalation, for example, intranasally.
Additionally, the compounds of the present invention can be
administered transdermally. It will be obvious to those skilled in
the art that the following dosage forms may comprise as the active
component, either a compound of formula I, IA, IA-1, IA-2, IB, IC,
II, IIA, III, or IV or a corresponding pharmaceutically acceptable
salt of such compound.
[0672] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material. In
powders, the carrier is a finely divided solid which is in a
mixture with the finely divided active component. In tablets, the
active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0673] The powders and tablets preferably contain from five or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as a
carrier providing a capsule in which the active component with or
without other carriers, is surrounded by a carrier, which is thus
in association with it. Similarly, cachets and lozenges are
included. Tablets, powders, capsules, pills, cachets, and lozenges
can be used as solid dosage forms suitable for oral
administration.
[0674] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0675] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water propylene glycol solutions.
For parenteral injection liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution. Aqueous solutions
suitable for oral use can be prepared by dissolving the active
component in water and adding suitable colorants, flavors,
stabilizing and thickening agents as desired. Aqueous suspensions
suitable for oral use can be made by dispersing the finely divided
active component in water with viscous material, such as natural or
synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, and other well-known suspending agents.
[0676] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0677] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsules, tablet, cachet, or lozenge itself, or it
can be the appropriate number of any of these in packaged form.
[0678] The quantity of active component in a unit dose preparation
may be varied or adjusted from 0.01 mg to 1 g according to the
particular application and the potency of the active component. In
medical use the drug may be administered three times daily as, for
example, capsules of 100 or 300 mg. The composition can, if
desired, also contain other compatible therapeutic agents.
[0679] In therapeutic use, the compounds utilized in the
pharmaceutical method of this invention are administered at the
initial dosage of about 0.1 mg to about 1 g daily. The dosages,
however, may be varied depending upon the requirements of the
patient, the severity of the condition being treated, and the
compound being employed. Determination of the proper dosage for a
particular situation is within the skill of the art. Generally,
treatment is initiated with smaller dosages which are less than the
optimum dose of the compound. Thereafter, the dosage is increased
by small increments until the optimum effect under the
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day, if
desired.
[0680] The following Examples illustrate the preparation of the
compounds of the present invention. They are not meant to be
limiting in scope. Melting points are uncorrected. NMR data are
reported in parts per million and are referenced to the deuterium
lock signal from the sample solvent.
EXAMPLES
Example 1
[0681] (3S,5R)-3-Amino-5-methyl-octanoic acid hydrochloride
(R)-2,6-Dimethyl-non-2-ene. To (S)-citronellyl bromide (50 g, 0.228
mol) in THF (800 mL) at 0.degree. C. was added LiCl (4.3 g)
followed by CuCl.sub.2 (6.8 g). After 30 minutes methylmagnesium
chloride (152 mL of a 3 M solution in THF, Aldrich) was added and
the solution warmed to room temperature. After 10 hours the
solution was cooled to 0.degree. C. and a saturated aqueous
solution of ammonium chloride carefully added. The resultant two
layers were separated and the aqueous phase extracted with ether.
The combined organic phases were dried (MgSO.sub.4) and
concentrated to give (R)-2,6-dimethyl-non-2-ene. 32.6 g; 93%. Used
without further purification. .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 5.1 (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); .sup.13C NMR (100 MHz;
CDCl.sub.3) .delta. 131.13, 125.28, 39.50, 37.35, 32.35, 25.92,
25.77, 20.31, 19.74, 17.81, 14.60.
[0682] (R)-4-Methyl-heptanoic acid. To (R)-2,6-dimethyl-non-2-ene
(20 g, 0.13 mol) in acetone (433 mL) was added a solution of
CrO.sub.3 (39 g, 0.39 mol) in H.sub.2SO.sub.4 (33 mL)/H.sub.2O (146
mL) over 50 minutes. After 6 hours a further amount of CrO.sub.3
(26 g, 0.26 mol) in H.sub.2SO.sub.4 (22 mL)/H.sub.2O (100 mL) was
added. After 12 hours the solution was diluted with brine and the
solution extracted with ether. The combined organic phases were
dried (MgSO.sub.4) and concentrated. Flash chromatography (gradient
of 6:1 to 2:1 hexane/EtOAc) gave (R)-4-methyl-heptanoic acid as an
oil. 12.1 g; 65%. MS, m/z (relative intensity): 143 [M-H, 100%];
.sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 2.35 (m, 2H), 1.6 (m,
1H), 1.4 (m, 1H), 1.3 (m, 4H), 1.1 (m, 1H), 0.85 (s, 6H).
[0683]
(4R,5S)-4-Methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2--
one. To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and
triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0.degree. C.
was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour
LiCl (7.1 g, 0.17 mol) was added followed by
(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) (30 g, 0.17 mol).
The mixture was warmed to room temperature and after 16 hours the
filtrate was removed by filtration and the solution concentrated
under reduced pressure. Flash chromatography (7:1 hexane/EtOAc)
gave
(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one
as an oil. 31.5 g; 79%. [.alpha.].sub.D=+5.5 (c 1 in CHCl.sub.3).
MS, m/z (relative intensity): 304 [M+H, 100%]; .sup.1H NMR (400
MHz; CDCl.sub.3) .delta. 7.4-7.2 (m, 5H), 5.6 (d, J=7.32 Hz, 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); .sup.13C NMR (100
MHz; CDCl.sub.3) 8173.70, 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.
[0684]
(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3--
carbonyl)-octanoic acid tert-butyl ester. To
(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one
(12.1 g, 0.04 mol) in THF (200 ml) at -50.degree. C. was added
sodium bis(trimethylsilyl)amide (48 mL of a 1 M solution in THF).
After 30 min t-butylbromoaceate (15.6 g, 0.08 mol) was added. The
solution was stirred for 4 hours at -50.degree. C. and then warmed
to room temperature. After 16 hours a saturated aqueous solution of
ammonium chloride was added and the two layers separated. The
aqueous phase was extracted with ether and the combined organic
phases dried (MgSO.sub.4) and concentrated. Flash chromatography
(9:1 hexane/EtOAc) gave
(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbony-
l)-octanoic acid tert-butyl ester as a white solid 12 g; 72%.
[.alpha.].sub.D=+30.2 (c 1 in CHCl.sub.3). .sup.13C NMR (100 MHz;
CDCl.sub.3) .delta. 176.47, 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.
[0685] (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-carbony-
l)-octanoic acid tert-butyl ester (10.8 g, 0.025 mol) in H.sub.2O
(73 mL) and THF (244 mL) at 0.degree. C. was added a premixed
solution of LiOH (51.2 mL of a 0.8 M solution) and H.sub.2O.sub.2
(14.6 mL of a 30% solution). After 4 hours a further 12.8 mL LiOH
(0.8 M solution) and 3.65 mL of H.sub.2O.sub.2 (30% solution) was
added. After 30 minutes sodium bisulfite (7 g), sodium sulfite (13
g), and water (60 mL) was added followed by hexane (100 mL) and
ether (100 mL). The two layers were separated and the aqueous layer
extracted with ether. The combined organic phases were concentrated
to an oil that was dissolved in heptane (300 mL). The resultant
solid was filtered off and the filtrate dried (MgSO.sub.4) and
concentrated to afford (S)-2-((R)-2-methyl-pentyl)-succinic acid
4-tert-butyl ester (6 g, 93%) which was used immediately without
further purification. MS, m/z (relative intensity): 257 [M+H,
100%].
[0686] (3S,5R)-3-Benzyoxycarbonylamino-5-methyl-octanoic acid,
tert-butyl ester. A solution of
(S)-2-((R)-2-methyl-pentyl)-succinic acid 4-tert-butyl ester (6.0
g, 23.22 mmol) and triethylamine (3.64 mL, 26.19 mmol) in toluene
(200 mL) was treated with diphenylphosphoryl azide (5.0 mL, 23.22
mL) and stirred at room temperature for 0.5 hours. After the
reaction mixture was then heated at reflux for 3 h and cooled
briefly, benzyl alcohol was added (7.2 mL, 69.7 mmol) and the
solution heated for another 3 h. After the reaction mixture was
allowed to cool, it was diluted with ethyl ether (200 mL) and the
combined organic layer was washed successively with saturated
NaHCO.sub.3 and brine and dried (Na.sub.2SO.sub.4). The
concentrated organic component was purified by chromatography
(MPLC) eluting with 8:1 hexanes:ethyl acetate to provide
(3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butyl
ester (6.4 g, 75.8%). MS: M+1: 364.2, 308.2. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 0.83 (t, 3H, J=6.59 Hz), 0.87 (d, 3H, J=6.59
Hz), 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.
[0687] (3S,5R)-3-Amino-5-methyl-octanoic acid, tert-butyl ester. A
solution of (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid,
tert-butyl ester (2.14 g, 5.88 mmol) in THF (50 mL) was treated
with Pd/C (0.2 g) and H.sub.2 at 50 psi for 2 hours. The reaction
mixture was then filtered and concentrated to an oil in vacuo to
give (3S,5R)-3-amino-5-methyl-octanoic acid, tert-butyl ester in
quantitative yield. MS: M+1: 230.2, 174.1. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 0.85-0.86 (overlapping t and d, 6H), 1.13-1.40
(m, 6H), 1.44 (s, 9H), 1.60 (m, 1H), 2.31 (dd, 1H, J=7.81 and 15.86
Hz), 2.38(dd, 1H, J=5.13 and 15.86 Hz), 3.31 (m, 1H), and 3.45(br
s, 2H) ppm.
[0688] (3S,5R)-3-Amino-5-methyl-octanoic acid hydrochloride. A
slurry of (3S,5R)-amino-5-methyl-octanoic acid, tert-butyl ester
(2.59 g, 11.3 mmol) in 6N HCl (100 mL) was heated under reflux 18
hours, cooled, and filtered over Celite. The filtrate was
concentrated in vacuo to 25 mL and the resulting crystals were
collected and dried to provide (3S,5R)-3-amino-5-methyl-octanoic
acid hydrochloride, mp 142.5-142.7.degree. C. (1.2 g, 50.56%). A
second crop (0.919) was obtained from the filtrate. Anal. Calc'd
for C.sub.9H.sub.19NO.sub.2.HCl: C, 51.55; H, 9.61, N, 6.68, Cl:
16.91. Found: C, 51.69; H: 9.72, N, 6.56, Cl: 16.63. MS: M+1:
174.1. .sup.1HNMR (CD.sub.3OD) .delta. 0.89 (t, 3H, J=7.32 Hz),
0.92 (d, 3H, J=6.35 Hz), 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
17.33 Hz), 2.65 (dd, 1H, J=4.64 and 17.32 Hz), and 3.52 (m, 1H)
ppm.
[0689] (3S,5R)-3-Amino-5-methyl-octanoic acid hydrochloride acid
salt. 5.3 g of 2S-(2R-methyl-pentyl)-succinic acid-4-tert-butyl
ester contained in 30 mL methyltertbutyl ether is reacted at room
temperature with 3.5 mL triethylamine followed by 6.4 g of
diphenylphosphoryl azide. After allowing the reaction to exotherm
to 45.degree. C. and stirring for at least 4 hours, the reaction
mixture is allowed to cool to room temperature and stand while the
phases separated. The lower layer is discarded and the upper layer
is washed with water, followed by dilute aqueous HCl. The upper
layer is then combined with 10 mL of 6 N aqueous HCl, and stirred
at 45-65.degree. C. The reaction mixture is concentrated by vacuum
distillation to about 10-14 mL and allowed to crystallize while
cooling to about 5.degree. C. After collecting the product by
filtration, the product is washed with toluene and reslurried in
toluene. The product is dried by heating under vacuum resulting in
2.9 g (67%) of white crystalline product. The product may be
recrystallized from aqueous HCl. mp 137.degree. C., HNMR (400 MHz,
D6 DMSO) delta 0.84-0.88 (overlapping d and t, 6H), 1.03-1.13 (m,
1H), 1.16-1.37 (m,4H), 1.57-1.68 (m, 2H), 2.55 (dd, 1H, J=7.17 Hz),
2.67 (dd, 1H, J=6, 17 Hz), 3.40 (m, 1H), 8.1 (brs, 3H), 12.8 (brs,
1H).
Example 2
(3S,5R)-Amino-5-methyl-heptanoic acid
[0690] Methanesulfonic acid (S)-3,7-dimethyl-oct-6-enyl ester. To
S-(-)-citronellol (42.8 g, 0.274 mol) and triethylamine (91 mL,
0.657 mol) in CH.sub.2Cl.sub.2 (800 mL) at 0.degree. C. was added
methanesulphonyl chloride (26 mL, 0.329 mol) in CH.sub.2Cl.sub.2
(200 mL). After 2 hours at 0.degree. C. the solution was washed
with 1N HCl then brine. The organic phase was dried (MgSO.sub.4)
and concentrated to afford the titled compound as an oil (60.5 g,
94%) which was used without further purification. MS, m/z (relative
intensity): 139 [100%], 143 [100%]. .sup.1H NMR (400 MHz;
CDCl.sub.3) .delta.5.05 (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=6.5 Hz).
[0691] (R)-2,6-Dimethyl-oct-2-ene. To methanesulfonic acid
(S)-3,7-dimethyl-oct-6-enyl ester (60 g, 0.256 mol) in THF (1 L) at
0.degree. C. was added lithium aluminum hydride (3.8 g, 0.128 mol).
After 7 hours, a further 3.8 g of lithium aluminum hydride was
added and the solution warmed to room temperature. After 18 hours,
a further 3.8 g of lithium aluminum hydride was added. After a
further 21 hours, the reaction was carefully quenched with 1N
citric acid and the solution diluted further with brine. The
resultant two phases were separated and the organic phase was dried
(MgSO.sub.4) and concentrated to afford the titled compound as an
oil which was used without further purification. MS, m/z (relative
intensity): 139 [M+H, 100%].
[0692] (R)-4-Methyl-hexanoic acid. A procedure similar to the
synthesis of (R)-4-methyl-heptanoic acid was utilized giving the
acid as an oil (9.3 g, 56%). IR (film) 2963, 2931, 2877, 2675,
1107, 1461, 1414 cm.sup.-1; MS, m/z (relative intensity): 129 [M-H,
100%]; .sup.1H NMR (400 MHz; CDCl.sub.3) .delta.2.35 (m, 2H), 1.66
(m, 1H), 1.37 (m, 4H), 1.29 (m, 1H), 0.86 (m, 6H); .sup.13C NMR
(100 MHz; CDCl.sub.3) .delta. 181.02, 34.09, 32.12, 31.39, 29.29,
18.94, 11.44.
[0693]
(4R,5S)-4-Methyl-3-((R)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-o-
ne. A procedure similar to the synthesis of
(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one
was utilized giving the titled compound as an oil (35.7 g, 95%).
MS, m/z (relative intensity): 290 [M+H, 100%]; .sup.1H NMR (400
MHz; CDCl.sub.3) .delta. 7.4-7.25 (m, 5H), 5.6 (d, J=7.32 Hz, 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); .sup.13C NMR (100 MHz; CDCl.sub.3)
6173.71, 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.
[0694]
(3S,5R)-5-Methyl-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3--
yl)-methanoyl]-heptanoic acid tert-butyl ester. A procedure similar
to the preparation of
(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbony-
l)-octanoic acid tert-butyl ester was followed giving the titled
compound as an oil (7.48 g; 31%). IR (film) 2967, 2934, 1770, 1716,
1696, 1344, 1148, 1121, 1068, 1037, 947 cm.sup.-1; MS, m/z
(relative intensity): 178 [100%], 169 [100%]; [.alpha.].sub.D=+21.6
(c 1 in CHCl.sub.3).
[0695] (S)-2-((R)-2-Methyl-butyl)-succinic acid 4-tert-butyl ester.
(3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-m-
ethanoyl]-heptanoic acid tert-butyl ester (7.26 g, 0.018 mol) in
H.sub.2O (53 mL) and THF (176 mL) at 0.degree. C. was added a
premixed solution of LiOH (37 mL of a 0.8 M solution) and
H.sub.2O.sub.2 (10.57 mL of a 30% solution) and the solution warmed
to room temperature. After 2 hours sodium bisulfite (7 g), sodium
sulfite (13 g), and water (60 mL) was added and the two layers were
separated and the aqueous layer extracted with ether. The combined
organic phases were concentrated to an oil that was dissolved in
heptane (200 mL). The resultant solid was filtered off and the
filtrate dried (MgSO.sub.4) and concentrated to afford the titled
compound as an oil (4.4 g) that was used without further
purification. MS, m/z (relative intensity): 243 [100%]; .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta.2.88 (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)
[0696] (3S,5R)-3-Benzyoxycarbonylamino-5-methyl-heptanoic acid,
tert-butyl ester--This compound was prepared as described above
starting with (S)-2-((R)-2-methyl-butyl) succinic acid,
4-tert-butyl ester to give
(3S,5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl
ester as an oil (73.3% yield). .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 0.84(t, 3H, J=7.33 Hz), 0.89(d, 3H, J=6.60 Hz), 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=12.95 Hz), and 7.28-7.34 (m, 5H).
[0697] (3S,5R)-Amino-5-methyl-heptanoic acid, tert-butyl
ester--This compound was prepared as described above starting with
(3S,5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl
ester instead of (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic
acid, tert-butyl ester to give the titled compound. .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 0.84 (overlapping t and d, 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 15.62 Hz), 2.29(dd, 1H, J=4.15 and 15.37
Hz), and 3.20(br s, 2H).
[0698] (3S,5R)-Amino-5-methyl-heptanoic acid hydrochloride--A
slurry of (3S,5R)-amino-5-methyl-heptanoic acid, tert-butyl ester
(1.44 g, 6.69 mmol) in 3N HCl was heated at reflux for 3 hours,
filtered hot over Celite, and concentrated to dryness. Trituration
of the resulting solid in ethyl ether provided
(3S,5R)-3-amino-5-methyl-heptanoic acid hydrochloride, (0.95 g,
85%) mp 126.3-128.3.degree. C. .sup.1H NMR (400 MHz; CD.sub.3OD)
.delta. 0.92 (t, 3H, J=7.32 Hz), 0.92 (d, 3H, J=6.35 Hz), 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=7.32 17.67 and 5.12 Hz), 2.69 (ddd, 1H, J=0.97,
4.88 and 17.32 Hz), and 3.28 (m, 1H). Anal. Calc'd for
C.sub.8H.sub.17NO.sub.2.HCl.0.1H.sub.2O: C, 48.65; H, 9.29, N,
7.09, Cl: 17.95. Found: C, 48.61; H, 9.10, N, 7.27, Cl: 17.87MS:
M+1: 160.2
Example 3
(3S,5R)-3-Amino-5-methyl-nonanoic acid
[0699] (R)-4-Methyl-octanoic acid. Lithium chloride (0.39 g, 9.12
mmol) and copper (I) chloride (0.61 g, 4.56 mmol) were combined in
45 ml THF at ambient temperature and stirred 15 minutes, then
cooled to 0.degree. C. at which time ethylmagnesium bromide (1 M
solution in THF, 45 mL, 45 mmol) was added. (S)-citronellyl bromide
(5.0 g, 22.8 mmol) was added dropwise and the solution was allowed
to warm slowly to ambient temperature with stirring overnight. The
reaction was quenched by cautious addition of sat. NH.sub.4Cl (aq),
and stirred with Et.sub.2O and sat. NH.sub.4Cl (aq) for 30 minutes.
The phases were separated and the organic phase dried (MgSO.sub.4)
and concentrated. The crude (R)-2,6-dimethyl-dec-2-ene was used
without purification. To a solution of (R)-2,6-dimethyl-dec-2-ene
(3.8 g, 22.8 mmol) in 50 mL acetone at 0.degree. C. was added
Jones' reagent (2.7 M in H.sub.2SO.sub.4 (aq), 40 mL, 108 mmol) and
the solution was allowed to warm slowly to ambient temperature with
stirring overnight. The mixture was partitioned between Et.sub.2O
and H.sub.2O, the phases were separated, and the organic phase
washed with brine, dried (MgSO.sub.4), and concentrated. The
residue was purified by flash chromatography (8:1 hexanes:EtOAc) to
afford 2.14 g (59%) of the titled compound as a colorless oil:
LRMS: m/z 156.9 (M+); .sup.1H NMR (400 MHz; CDCl.sub.3):
.delta.2.33 (m, 2H), 1.66 (m, 1H), 1.43 (m, 2H), 1.23 (m, 5H), 1.10
(m, 1H), 0.86 (m, 6H). Jones' reagent was prepared as a 2.7M
solution by combining 26.7 g CrO.sub.3, 23 mL H.sub.2SO.sub.4, and
diluting to 100 mL with H.sub.2O.
[0700]
(4R,5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-o-
ne. To (R)-4-methyl-octanoic acid (2.14 g, 13.5 mmol) in 25 mL
CH.sub.2Cl.sub.2 at 0.degree. C. was added 3 drops DMF, followed by
oxalyl chloride (1.42 mL, 16.2 mmol) resulting in vigorous gas
evolution. The solution was warmed directly to ambient temperature,
stirred 30 minutes, and concentrated. Meanwhile, to a solution of
the oxazolidinone (2.64 g, 14.9 mmol) in 40 mL THF at -78.degree.
C. was added n-butyllithium (1.6 M soln in hexanes, 9.3 mL, 14.9
mmol) dropwise. The mixture was stirred for 10 minutes at which
time the acid chloride in 10 mL THF was added dropwise. The
reaction was stirred 30 minutes at -78.degree. C., then warmed
directly to ambient temperature and quenched with sat. NH.sub.4Cl.
The mixture was partitioned between Et.sub.2O and sat. NH.sub.4Cl
(aq), the phases were separated, and the organic phase dried
(MgSO.sub.4), and concentrated to furnish 3.2 g of the titled
compound as a colorless oil. LRMS: m/z 318.2 (M+); .sup.1H NMR (400
MHz; CDCl.sub.3): 7.34 (m, 5H), 5.64 (d, J=7.3 Hz, 1H), 4.73
(quint, J=6.8 Hz, 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 without purification.
[0701]
(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 (1.8 mL, 12.6 mmol) in 30 mL THF at -78.degree. C.
was added n-butyllithium (1.6 M soln in hexanes, 7.6 mL, 12.1
mmol), and the mixture stirred 10 minutes at which time
(4R,5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one
(3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution
was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1
mmol) was added quickly dropwise at -50.degree. C., and the mixture
was allowed to warm slowly to 10.degree. C. over 3 hours. The
mixture was partitioned between Et.sub.2O and sat. NH.sub.4Cl (aq),
the phases were separated, and the organic phase dried
(MgSO.sub.4), and concentrated. The residue was purified by flash
chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%)
of the titled compound as a colorless crystalline solid,
mp=84-86.degree. C. [.alpha.].sub.D.sup.23+17.1 (c=1.00,
CHCl.sub.3); .sup.1H NMR (400 MHz; CDCl.sub.3): 7.34 (m, 5H), 5.62
(d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67
(dd, J=9.8, 16.4 Hz, 1H), 2.40 (dd, J=5.1, 16.4 Hz, 1H), 1.69 (m,
1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H);
.sup.13C NMR (400 MHz; CDCl.sub.3) 176.45, 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. Anal. Calcd for
C.sub.25H.sub.37NO.sub.5: C, 69.58; H, 8.64; N, 3.25. Found: C,
69.37; H, 8.68; N, 3.05.
[0702] (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-carbony-
l)-nonanoic acid tert-butyl ester (2.65 g, 6.14 mmol) in 20 mL THF
at 0.degree. C. was added a precooled (0.degree. C.) solution of
LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt %
aqueous soln, 5.0 mL) in 10 mL H.sub.2O. The mixture was stirred
vigorously for 90 minutes, then warmed to ambient temperature and
stirred 90 minutes. The reaction was quenched at 0.degree. C. by
addition of 100 mL 10% NaHSO.sub.3 (aq), then extracted with
Et.sub.2O. The phases were separated, and the organic phase washed
with brine, dried (MgSO.sub.4), and concentrated. The titled
compound was used without purification.
[0703] (3S,5R)-3-Benzyoxycarbonylamino-5-methylnonanoic acid,
tert-butyl ester. This compound was prepared similarly as described
above starting with (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 provide the titled compound as an oil
(71.6% yield). .sup.1HNMR (400 MHz; CDCl.sub.3) .delta. 0.81(t, 3H,
J=4.40 Hz), 0.85(d, 3H, J=6.55 Hz), 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).
[0704] (3S,5R)-3-Amino-5-methyl-nonanoic acid, tert-butyl ester.
This compound was prepared as described above starting with
(3S,5R)-benzyoxycarbonylamino-5-methyl-nonanoic acid, tert-butyl
ester instead of (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic
acid, tert-butyl ester. Yield=97%. .sup.1HNMR (400 MHz; CDCl.sub.3)
.delta. 0.82(overlapping d and t, 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 15.61 Hz), and 2.27(dd, 1H, J=4.15 and
15.38 Hz).
[0705] (3S,5R)-3-Amino-5-methyl-nonanoic acid hydrochloride. A
mixture of (3S,5R)-3-amino-5-methyl-nonanoic acid, tert-butyl ester
(1.50 g, 6.16 mmol) in 3N HCl (100 mL) was heated at reflux for 3
hours, filtered hot over Celite, and concentrated to 30 mL in
vacuo. The resulting crystals were collected, washed with
additional 3N HCl, and dried to provide the title compound, mp
142.5-143.3.degree. C. Additional crops were obtained from the
filtrate to provide 1.03 g (70.4%). .sup.1HNMR (400 MHz;
CD.sub.3OD) .delta.=0.91 (t, 3H, J=6.84 Hz), 0.92(d, 3H, J=6.35
Hz), 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=7.32 and 17.34 Hz),
2.69(dd, 1H, J=5.13 and 17.59 Hz), and 3.59(m, 1H). Anal. Calc'd
for C.sub.10H.sub.21NO.sub.2.HCl: C, 53.68; H, 9.91, N, 6.26, Cl:
15.85. Found: C, 53.89; H, 10.11, N, 6.13. MS: M+1: 188.1.
Example 4
(2R,4R)-2-Aminomethyl-4-methyl-heptanoic acid
[0706]
5R-Methyl-3R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)octa-
noic acid. A solution of
(3R,5R)-5-Methyl-3-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbony-
l)-octanoic acid tert-butyl ester (3.9 g, 9.34 mmol) in
dichloromethane (150 mL) was treated with trifluoroacetic acid
(7.21 mL, 93.4 mL) and stirred 18 hours at ambient temperature.
After the solvents and reagent were removed in vacuo, the resulting
residue was tritrurated in 100 mL hexanes to provide 3.38 g of the
title compound (100%) mp 142-143.degree. C. MS M+1=362.1. .sup.1H
NMR (400 MHz; CDCl.sub.3) .delta. 0.85(2t, 6H, J=7.1 Hz), 0.93(d,
3H, J=6.1 Hz), 1.14(m, 1H), 1.2-1.49(m, 6H), 2.56(dd, 1H, J=4.15
and 17.57 Hz), 2.81(dd, 1H, J=17.33 and 10.74 Hz), 4.28(m, 1H),
4.74(quint, 1H, J=6.84 Hz), 5.64(d, 1H, J=7.32 Hz), 7.29-7.43(m,
5H).
[0707]
[4R-Methyl-2R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)hep-
tyl]carbamic acid benzyl ester. A solution of
5R-methyl-3R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)octanoic
acid (1.98 g, 5.48 mmol) and triethylamine (0.92 mL, 6.57 mmol) was
treated with diphenylphosphorylazide (1.2 mL, 5.48 mmol), stirred
30 min at ambient temperature and then heated at reflux for 3
hours. After cooling briefly, the reaction mixture was treated with
benzyl alcohol (2.8 mL, 27.4 mmol) and heated for an additional 3 h
at reflux. The reaction mixture was cooled, diluted with ethyl
ether (150 mL), washed successively with sat'd NaHCO.sub.3 and
brine, dried (MgSO.sub.4) and concentrated in vacuo to an oil.
Chromatography (MPLC, elution with 4:1 hexanes:ethyl acetate)
provided the title compound (2.0 g, 78.3%) as an oil. MS M+1=467.1.
.sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 0.86(2t, 6H, J=7.1 Hz),
0.93(d, 3H, J=5.9 Hz), 1.14(m, 1H), 1.09-1.36(m, 6H), 1.50(d, 1H,
J=5.2 Hz), 3.49(t, 1H, J=6.1 Hz), 4.10(m, 1H), 4.71 (quint, 1H,
J=6.61 Hz), 5.06(d, 2H, J=3.42 Hz), 5.20(t, 1H, J=5.61 Hz), 5.64(d,
1H, J=7.08 Hz), 7.29-7.43(m, 10H).
[0708] 2R-(Benzyloxycarbonylaminomethyl)-4R-methylheptanoic acid. A
solution of
4R-methyl-2R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)heptyl]carb-
amic acid benzyl ester (4.12 g, 8.83 mmol) in 3:1 THF:water (100
mL) was cooled to 0.degree. C. and treated with a mixture of 0.8 N
LiOH (17.5 mL, 14 mmol) and 30% H.sub.2O.sub.2 (4.94 mL, 44 mmol).
After the reaction mixture was stirred in the cold 3 hours, it was
quenched with a slurry of NaHSO.sub.3 (2.37 g) and Na.sub.2SO.sub.3
(4.53 g) in water (30 mL) and stirred 1 hour. The reaction mixture
was diluted with ethyl ether (200 mL), partitioned, and the organic
layer washed with brine and dried (MgSO.sub.4). The concentrated
organic extract was chromatographed (MPLC) eluting with ethyl
acetate to give 1.25 g of
2R-(benzyloxycarbonylaminomethyl)-4R-methylheptanoic acid (46%). MS
M+1=308.1. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 0.83(t, 3H,
J=6.84 Hz), 0.87(t, 3H, J=6.35 Hz), 1.14(m, 1H), 1.06-1.54(m, 7H),
2.7(br s, 1H), 3.30(m, 2H), 5.05(q, 2H, J=12.2 Hz), 5.14(t, 1H,
J=5.61 Hz), 7.30(br s, 5H).
[0709] (2R,4R)-2-Amino-4-methyl-heptanoic acid hydrochloride. A
mixture of 2R-(benzyloxycarbonylaminomethyl)-4R-methyl-heptanoic
acid (1.25 g, 4.07 mmol) and Pd/C (20%, 0.11 g) in methanol (50 mL)
was hydrogenated at 50 psi for 18 hours. After the catalyst was
removed by filtration, the solvent was removed in vacuo and the
resulting solid triturated in ether to provide
(2S,4R)-2-amino-4-methyl-heptanoic acid hydrochloride (0.28 g, 40%)
mp 226.3-228.0.degree. C. MS M+1=174.0. .sup.1H NMR (400 MHz;
CD.sub.3OD) .delta. 0.89(t+d, 6H, J=6.35 Hz), 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).
Anal. Calc'd for C.sub.9H.sub.19NO.sub.2.0.1H.sub.2.degree. C.:
61.75H, 11.06 N, 8.00. Found C, 61.85; H: 10.83 N, 8.01.
Example 5
2-Aminomethyl-4,4-dimethyl-heptanoic acid hydrochloride
[0710] 2-Cyano-4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester. A
solution of 2,2-dimethyl-pent-4-enal (5.0 g, 44 mmol), cyano-acetic
acid ethyl ester (5.12 mL, 48 mmol), piperidine (1.3 mL, 14 mmol)
and acetic acid (4.52 mL, 80 mmol) in 170 mL of toluene was heated
under reflux for 18 hours in a flask equipped with a Dean-Stark
separator. Several mL of water was collected in the trap. The
reaction was cooled and washed with 1N HCl, NaHCO.sub.3 and brine,
successively. The organic layers were dried over Na.sub.2SO.sub.4
and concentrated to an oil. This oil was chromatographed eluting
with 20% of EtOAc in hexane to give a combination of two lots total
8.3 g (91%). .sup.1H NMR (400 MHz; CDCl.sub.3) 1.28 (s, 6H), 1.32
(t, 3H, J=7 Hz), 2.26 (d, 2H, J=7.6 Hz), 4.27 (q, 2H, J=7.2 Hz),
5.08 (d, 1H, J=12 Hz), 5.10 (d, 1H, J=4 Hz), 5.72 (m, 1H).
[0711] 2-Aminomethyl-4,4-dimethyl-heptanoic acid hydrochloride.
2-Cyano-4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester (5.88 g, 28
mmol) was dissolved in the mixture of 91 mL of ethanol and 6 mL of
HCl and treated with 0.4 g of PtO.sub.2. The reaction was carried
out under 100 psi of hydrogen pressure at room temperature for 15
hours. The catalyst was filtered and filtrate was concentrated to
give 3.8 g of the desired product
2-aminomethyl-4,4-dimethyl-heptanoic acid ethyl ester as an oil. MS
(APCl): 216.2 (M+1).sup.+. This oil was refluxed in 75 mL of 6N HCl
for 18 hours. While the reaction was cooled, a precipitate formed.
The solid was filtered, washed with additional HCl solution and
triturated with ether to give the clean title compound. MS (APCl):
188.1 (M+1).sup.+. 186.1 (M-1).sup.+. .sup.1H NMR (400 MHz;
CD.sub.3OD): 0.91 (9H, m), 1.30 (5H, m), 1.81 (dd, 1H, J=7.2 Hz,
14.4 Hz), 2.72 (1H, m), 3.04 (2H, m); Anal. Calc'd for
C.sub.10H.sub.21NO.sub.2.HCl: C, 53.68; H, 9.91, N, 6.26, Cl:
15.85; Found: C, 53.83; H, 10.15, N, 6.22, Cl: 15.40. MP:
229.5-231.0.degree. C.
Example 6
(S)-3-Amino-5,5-dimethyl-octanoic acid
[0712]
3-(4,4-Dimethyl-heptanoyl)-(R)-4-methyl-(S)-5-phenyl-oxazolidin-2--
one. A solution of 4,4-dimethyl-heptanoic acid (1.58 g, 10 mmol)
and triethylamine (4.6 mL) in 50 mL THF was cooled to 0.degree. C.
and treated with 2,2-dimethyl-propionyl chloride (1.36 mL). After
one hour, 4R-methyl-5S-phenyl-oxazolidin-2-one (1.95 g, 11 mmol)
and lithium chloride (0.47 g, 11 mmol) was added and the mixture
was stirred for 18 hours. The precipitate was filtered and washed
thoroughly with additional THF. The filtrate was concentrated in
vacuo to give an oily solid. This solid was dissolved in 200 mL
Et.sub.2O, washed successively with saturated NaHCO.sub.3, 0.5N HCl
and saturated NaCl, dried (MgSO.sub.4) and concentrated in vacuo to
give the title compound as an oil (3.0 g, 95%). .sup.1HNMR (400
MHz; CDCl.sub.3): 0.73-0.84 (m, 12H), 1.10-1.22 (m, 4H), 1.46-1.54
(m, 2H), 2.75-2.87 (m, 2H), 4.70 (m, 1H, J=7 Hz), 5.59 (d, 1H, J=7
Hz), 7.22-7.37 (m, 5H).
[0713]
5,5-Dimethyl-(S)-3-((R)-4-methyl-2-oxo-(S)-5-phenyl-oxazolidine-3--
carbonyl)-octanoic acid tert-butyl ester. According to example 1,
5.07 g (16 mmol) of
3-(4,4-dimethyl-heptanoyl)-4-methyl-5-phenyl-oxazolidin-2-one, 18
mL (1N, 18 mmol) of NaHMDS solution and 4.72 mL (32 mmol) of
bromo-acetic acid tert-butyl ester gave 3.40 g (49.3%) of the title
compound as a crystalline solid. .sup.1HNMR (400 MHz; CDCl.sub.3):
0.85-0.89 (m, 12H), 1.18-1.32 (m, 6H), 1.41 (s, 9H), 1.88 (dd, 1H,
J=6 Hz, 8.4 Hz), 2.41 (dd, 1H, J=6 Hz, 16 Hz), 2.62 (dd, 1H, J=8.4
Hz, 16 Hz), 4.30-4.40 (m, 1H), 4.72 (m, 1H), 5.62 (d, 1H, J=7 Hz),
7.30-7.40 (m, 5H). m.p.: 83-85.degree. C.
[0714] (S)-2-(2,2-Dimethyl-pentyl)-succinic acid 4-tert-butyl
ester. According to example 1, 3.4 g (7.9 mmol) of
5,5-dimethyl-3-(4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic
acid tert-butyl ester, 16 mL (12.8 mmol) of 0.8N LiOH and 4.5 mL of
30% H.sub.2O.sub.2 gave 2.42 g (>100%) of the title compound as
an oil. .sup.1HNMR (400 MHz; CDCl.sub.3): 0.77-0.82 (m, 9H),
1.14-1.29 (m, 5H), 1.42 (s, 9H), 1.77 (dd, 1H, J=8 Hz, 16 Hz), 2.36
(dd, 1H, J=6 Hz, 16 Hz), 2.59 (dd, 1H, J=8 Hz, 16 Hz), 2.75-2.85
(m, 1H).
[0715] (S)-3-Benzyloxycarbonylamino-5,5-dimethyl-octanoic acid
tert-butyl ester. According to example 1, 2.14 g (7.9 mmol) of
2-(2,2-dimethyl-pentyl)-succinic acid 4-tert-butyl ester, 1.7 mL of
DPPA, 1.1 mL of Et.sub.3N and 2.44 mL of BnOH provided 1.63 g
(54.8% in two steps) of the title compound as an oil. .sup.1HNMR
(400 MHz; CDCl.sub.3): 0.78-0.89 (m, 9H), 1.10-1.30 (m, 5H), 1.36
(s, 9H), 2.39 (t, 2H, J=5 Hz), 4.95-4.05 (m, 1H), 5.00 (s, 2H),
5.09 (d, 1H, J=9.6 Hz), 7.22-7.30 (m, 5H).
[0716] (S)-3-Amino-5,5-dimethyl-octanoic acid tert-butyl ester.
According to example 1, 1.63 g of
3-benzyloxycarbonylamino-5,5-dimethyl-octanoic acid tert-butyl
ester and 0.2 g of 20% Pd/C furnished the title compound.
.sup.1HNMR (400 MHz; CDCl.sub.3): 0.84-0.89 (m, 9H), 1.13-1.39 (m,
6H), 1.43 (s, 9H), 2.25 (dd, 1H, J=8.4 Hz, 15.6 Hz), 2.35 (dd, 1H,
J=4.4 Hz, 15.6 Hz), 2.79 (s, br, 2H), 3.25-3.35 (m, 1H). MS, m/z,
244.2 (M+1).sup.+.
[0717] (S)-3-Amino-5,5-dimethyl-octanoic acid hydrochloride.
According to example 1,3-amino-5,5-dimethyl-octanoic acid
tert-butyl ester was treated with 3N HCl to provide 286 mg of the
title compound as a solid. .sup.1HNMR (400 MHz; CD.sub.3OD):
0.87-0.93 (m, 9H), 1.18-1.31 (m, 4H), 1.51 (dd, 1H, J=4 Hz, 14.4
Hz), 1.62 (dd, 1H, J=6.8 Hz, 14.4 Hz), 2.60 (dd, 1H, J=8 Hz, 17.6
Hz), 2.73 (dd, 1H, J=4 Hz, 7.6 Hz), 3.55-3.60 (m, 1H). MS (APCl),
m/z: 188.1 (M+1).sup.+. 186.1 (M-1).sup.+. Anal. Calc'd for
C.sub.10H.sub.21NO.sub.2.HCl.0.12H.sub.2O: C, 53.17; H, 9.92, N,
6.20, Cl: 15.69; Found: C, 53.19; H, 10.00, N, 6.08, Cl: 15.25.
.alpha.=+200 (MeOH). MP: 194.2-195.2.degree. C.
Example 7
2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid
[0718] 2-Cyano-3-(1-methyl-cyclopropyl)-acrylic acid ethyl ester.
To 1-methylcyclopropane-methanol (Aldrich, 1.13 mL, 11.6 mmol) in
50 mL CH.sub.2Cl.sub.2 was added neutral alumina (2.5 g) and then
PCC (2.5 g, 11.6 mmol), and the mixture stirred 3 h at ambient
temperature. The mixture was filtered through a 1 cm plug of silica
gel under vacuum, and rinsed with Et.sub.2O. The filtrate was
concentrated to ca. 5 mL total volume. To the residue was added THF
(10 mL), ethyl cyanoacetate (1.2 mL, 11.3 mmol), piperidine (5
drops), and finally acetic acid (5 drops). The whole was stirred at
ambient temperature overnight, then partitioned between Et.sub.2O
and sat. aq. NaHCO.sub.3. The phases were separated and the organic
phase washed with brine, dried (MgSO.sub.4), and concentrated.
Flash chromatography of the residue (1 0.fwdarw.15% EtOAc/hexanes)
provided 0.53 g (25%) of the ester as a colorless oil that
crystallized on standing, mp 35-37.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.99 (s, 1H), 4.27 (q, J=7.3 Hz, 2H), 1.55 (s,
3H), 1.32 (t, J=7.3 Hz, 3H), 1.14 (s, 2H), 1.07 (s, 2H). .sup.13C
NMR .delta.. 170.44, 162.90, 115.17, 103.69, 62.52, 21.24, 21.07
(2C), 20.71, 14.35. Anal. Calcd for C.sub.10H.sub.13NO.sub.2: C,
67.02; H, 7.31; N, 7.82. Found: C, 66.86; H, 7.47; N, 7.70.
[0719] 2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid ethyl
ester. To 2-cyano-3-(1-methyl-cyclopropyl)-acrylic acid ethyl ester
(0.45 g, 2.51 mmol) in 16 mL EtOH:THF (1:1) was added RaNi (0.4 g),
and the mixture was hydrogenated in a Parr shaker at 48 psi for
15.5 h. Pearlman's catalyst (0.5 g) was then added and
hydrogenation was continued for an additional 15 h. The mixture was
filtered and concentrated. Flash chromatography of the residue
2.fwdarw.3.fwdarw.4.fwdarw.6.fwdarw.8% MeOH/CH.sub.2Cl.sub.2
provided 0.25 g (54%) of the aminoester as a colorless oil. .sup.1H
NMR (CDCl.sub.3) .delta. 3.97 (m, 2H), 2.67 (m, 2H), 2.46 (m, 1H),
1.28 (d, J=7.3 Hz, 2H), 1.19 (bs, 2H), 1.09 (t, J=7.3 Hz, 3H), 0.85
(s, 3H), 0.04 (m, 4H). LRMS: m/z 186.1 (M+1).
[0720] 2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid. To a
solution of 2-aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid
ethyl ester (0.25 g, 1.35 mmol) in 10 mL methanol at 0.degree. C.
was added 10% aq. NaOH (10 mL). The mixture was stirred at ambient
temperature overnight, then concentrated to remove the methanol.
The residue was cooled to 0.degree. C. and acidified to pH 2 with
conc. HCl. After allowing to warm to ambient temperature the
mixture was loaded onto DOWEX-50WX8-100 ion exchange resin and
eluted with H.sub.2O until neutral to litmus. Elution was continued
with 5% aq. NH.sub.4OH (100 mL) and the alkaline fractions
concentrated to provide 0.15 g (71%) of the amino acid as a
colorless solid. .sup.1H NMR (CDCl.sub.3) .delta. 2.72 (m, 2H),
2.42 (m, 1H), 1.34 (dd, J=8.5, 13.9 Hz, 1H), 1.19 (dd, J=6.1, 13.9
Hz, 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
[0721] (5S)-5-Methyl-octa-2,6-dienoic acid tert-butyl ester. To a
solution of (S)-3-methyl-hex-4-enoic acid ethyl ester* (1.0 g, 6.4
mmol) in 30 mL toluene at -78.degree. C. was added DIBAH (1.0M in
THF, 6.4 mL) dropwise over 5 min. The mixture was stirred at
-78.degree. C. 45 min at which time 5 drops of methanol were added,
resulting in vigorous H.sub.2 evolution. Methanol was added until
no more gas evolution was observed (ca. 5 mL). At this time the
cold bath was removed and ca. 5 mL of sat. aq. Na.sup.+ K.sup.+
tartrate was added. When the mixture reached room temperature,
additional sat. aq. Na.sup.+ K.sup.+ tartrate and Et.sub.2O were
added and stirring was continued until the phases were mostly clear
(ca. 1 h). The phases were separated, and the organic phase washed
with brine, dried (MgSO.sub.4), and concentrated to ca. 10 mL total
volume owing to volatility concerns. The crude mixture was combined
with an additional batch of aldehyde prepared from 10 mmol of the
ester by the method described above and the whole used without
purification. To a suspension of sodium hydride (60% dispersion in
mineral oil) in 25 mL THF was added
t-butyl-P,P-dimethylphosphonoacetate (3.0 mL, 15 mmol) dropwise
over 1 h such that the evolution of H.sub.2 was under control.
After the addition was complete, the crude aldehyde in toluene (ca.
20 mL total volume) was added quickly dropwise and the mixture
stirred at ambient temperature overnight. The mixture was
partitioned between Et.sub.2O and sat. aq. NH.sub.4Cl, the phases
separated, the organic phase washed with brine, dried (MgSO.sub.4),
and concentrated. Flash chromatography of the residue
(0.fwdarw.3.fwdarw.5% EtOAc/hexanes) afforded 1.0 g (29%, two
steps) of the unsaturated ester as a pale yellow oil: .sup.1H NMR
(CDCl.sub.3) .delta. 6.75 (m, 1H), 5.66 (m, 1H), 5.30 (m, 2H),
2.03-2.29 (m, 3H), 1.58 (d, J=6.1 Hz, 3H), 1.41 (s, 9H), 0.91 (d,
J=6.6 Hz, 3H).
[0722] *(S)-3-methyl-hex-4-enoic acid ethyl ester 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] via Johnson-Claisen rearrangement with
triethylorthoacetate according to the literature protocol [Hill, R.
K.; Soman, R.; Sawada, S., J. Org. Chem., 1972, 37, 3737].
[0723]
(3R,5S)-3-[Benzyl-(1-phenyl-ethyl)-amino]-5-methyl-oct-6-enoic acid
tert-butyl ester. To a solution of
(S)-(-)-N-benzyl-.alpha.-methylbenzylamine (0.60 mL, 2.85 mmol) in
9.0 mL THF at -78.degree. C. was added n-butyllithium (1.6M in
hexanes, 1.6 mL) quickly dropwise resulting in a deep pink color.
The mixture was stirred at -78.degree. C. for 30 min at which time
(5S)-5-Methyl-octa-2,6-dienoic acid tert-butyl ester (0.5 g, 2.38
mmol) in 1.0 mL THF was added slowly dropwise, resulting in a pale
tan color which darkened over 3 h. The mixture was stirred 3 h at
-78.degree. C., then quenched with sat. aq. NH.sub.4Cl. The mixture
was allowed to warm to rt and stirred overnight, then partitioned
between EtOAc and sat. aq. NH.sub.4Cl. The phases were
concentrated, and the organic phase dried (MgSO.sub.4), and
concentrated. Flash chromatography of the residue (3.fwdarw.5%
EtOAc/hexanes) provided 0.52 g (52%) of the aminoester as a yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.34 (m, 2H), 7.20 (m, 8H),
5.27 (m, 2H), 3.74 (m, 1H), 3.72 (d, J=15.9 Hz, 1H), 3.41 (d,
J=14.9 Hz, 1H), 3.27 (m, 1H), 2.38 (m, 1H), 1.98 (dd, J=3.7, 14.2
Hz, 1H), 1.81 (dd, J=9.3, 14.4 Hz, 1H), 1.54 (d, J=4.9 Hz, 3H),
1.32 (s, 9H), 1.24 (d, J=7.1 Hz, 3H), 0.99 (m, 2H), 0.74 (d, J=6.6
Hz, 3H).
[0724] (3S,5R)-3-Amino-5-methyl-octanoic acid. To a solution of
(3R,5S)-3-[Benzyl-(1-phenyl-ethyl)-amino]-5-methyl-oct-6-enoic acid
tert-butyl ester (0.92 g, 2.18 mmol) in 50 mL MeOH was added 20%
Pd/C (0.20 g), and the mixture was hydrogenated in a Parr shaker at
48 psi for 23 h. The mixture was filtered and concentrated. To the
crude aminoester in 10 mL CH.sub.2Cl.sub.2 was added 1.0 mL
trifluoroacetic acid, and the solution stirred at ambient
temperature overnight. The mixture was concentrated, and the
residue dissolved in the minimum amount of H.sub.2O, and loaded
onto DOWEX-50WX8-100 ion exchange resin. The column was eluted with
H.sub.2O until neutral to litmus, then continued with 5% aq.
NH.sub.4OH (100 mL). The alkaline fractions were concentrated to
provide 0.259 (66%, two steps) of the amino acid as an off-white
solid. .sup.1H NMR (CD3OD) .delta. 3.41 (m, 1H), 2.36 (dd, J=5.1,
16.6 Hz, 1H), 2.25 (dd, J=8.1, 16.6 Hz, 1H), 1.42 (m, 2H), 1.24 (m,
1H), 1.12 (m, 2H), 1.00 (m, 1H), 0.73 (d, J=6.4 Hz, 3H), 0.68 (t,
J=6.8 Hz, 3H). LRMS: m/z 172.1 (M-1).
Example 9
2-Aminomethyl-8-methyl-nonanoic acid
[0725] A procedure similar to that of
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare
2-Aminomethyl-8-methyl-nonanoic acid from 6-methyl-1-heptanol m/z
202.1 (M+).
[0726] 2-Aminomethyl-4,8-dimethyl-nonanoic acid (R)-2,6-dimethyl
heptan-1-ol. Magnesium turnings (2.04 g, 84 mmol) and a crystal of
iodine were suspended in 5 mL THF for the addition of
1-bromo-3-methyl butane (0.3 mL, neat). The mixture was heated to
start the Grignard formation. The remaining 1-bromo-3-methyl butane
(8.63 mL, 72 mmol) was diluted in THF (60 mL) and added dropwise.
The mixture was stirred at ambient temperature for 2 hours and
cooled to -5.degree. C. A solution of copper chloride (1.21 g, 9
mmol) and LiCl (0.76 g, 18 mmol) in THF (50 mL) was added dropwise
keeping the temperature below 0.degree. C. The resulting mixture
was stirred for 20 min, and (R)-3-bromo-2-methylpropanol in THF (20
mL) was added dropwise while keeping the temperature below
0.degree. C. 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 with 3.times.20 mL EtOAc. The organics were washed
with brine, dried (MgSO.sub.4), filtered and concentrated. The
residual oil was purified via silica gel chromatography (90/10
Hexane/EtOAc) to give 2.67 g (R)-2,6-dimethyl heptan-1-ol.
[0727] (R)-1-iodo-2,6-dimethyl heptane. To a mixture of supported
triphenyl phosphine (6.55 g, 19.67 mmol) in CH.sub.2Cl.sub.2 at
0.degree. C. was added iodine (4.99 g, 19.67 mmol) and imidazole
(1.33 g, 19.67 mmol). The mixture was warmed to ambient
temperature, stirred for 1 h and cooled to 0.degree. C. for the
dropwise addition of (R)-2,6-dimethyl heptan-1-ol in
CH.sub.2Cl.sub.2 (5 mL). The mixture was allowed to reach ambient
temperature and stirred for 1 h, at which time it was filtered
through a pad of celite and the solids were washed with
CH.sub.2Cl.sub.2. The filtrated was concentrated, and the crude
product was purified via silica gel chromatography to give
(R)-1-iodo-2,6-dimethyl heptane (2.44 g).
[0728] (4R)-4,8-dimethyl nonanoic acid t-butyl ester. To
diisopropyl amine (0.827 mL, 5.9 mmol) in THF (8 mL) at -78.degree.
C. was added nBuLi (2.65 mL of a 2.6 M solution in pentane). The
solution was stirred for 30 min at -78.degree. C., followed by the
addition of t-butyl acetate (0.8 mL, 5.9 mmol). The mixture was
stirred at -78.degree. C. for 2 h, and then (R)-1-iodo-2,6-dimethyl
heptane (0.3 g, 1.18 mmol) and HMPA (1.5 mL) in THF (1 mL) was
added. The reaction was stirred at -78.degree. C. and allowed to
slowly reach ambient temperature overnight, then heated at
35.degree. C. to drive the reaction to completion. The reaction was
quenched by the addition of ammonium chloride (saturated aqueous
solution), and the mixture was extracted with EtOAc (2.times.10
mL). The organics were combined, washed with water, dried
(MgSO.sub.4), filtered and concentrated. Silica gel chromatography
(98/2 hexane/EtOAc) provided 0.25 g of (4R)-4,8-dimethyl nonanoic
acid t-butyl ester.
[0729] (4R)-4,8-dimethyl nonanoic acid. (4R)-4,8-dimethyl nonanoic
acid t-butyl ester in 25 mL CH.sub.2Cl.sub.2 at 0.degree. C. was
treated with TFA (6 mL). The mixture was allowed to reach ambient
temperature and stir overnight. The solvent was removed by rotary
evaporation, and the mixture was purified by silica gel
chromatography (95/5 hexane/EtOAc) to give 0.962 g
(4R)-4,8-dimethyl nonanoic acid. m/z 185 (M-).
[0730]
3-(4R,8-Dimethyl-nonanoyl)-4(S)-methyl-5(R)-phenyl-oxazolidin-2-on-
e. A procedure similar to
(4R,5S)-4-Methyl-3-(R)-4-methyl-heptanoyl)-5-oxazolidin-2-one was
utilized to give
3-(4R,8-Dimethyl-nonanoyl)-4(S)-methyl-5(R)-phenyl-oxazolidin-2-one
(1.35 g) m/z 346.5 (M+).
[0731]
[4R,8-Dimethyl-2R-(4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbony-
l)-nonyl]-carbamic acid benzyl ester. To a solution of
3-(4(R),8-Dimethyl-nonanoyl)-4(S)-methyl-5(R)-phenyl-oxazolidin-2-one
(1.05 g, 3.04 mmol) in CH.sub.2Cl.sub.2 (12 mL) and TiCl.sub.4
(3.04 mL of a 1 M solution in CH.sub.2Cl.sub.2) was added
diisopropyl ethyl amine (0.55 mL, 3.19 mmol) at -20.degree. C. The
resulting dark red solution was stirred at -20.degree. C. for 30
min prior to the addition of a solution of N-methoxymethyl benzyl
carbamate (0.652 g, 3.34 mmol) in CH.sub.2Cl.sub.2 (3.5 mL) and
TiCl.sub.4 (3.34 mL). The mixture was stirred at 0.degree. C. for 4
h. The reaction was quenched by the addition of saturated aqueous
ammonium chloride solution. The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.15 mL). The organics were combined and
washed with 1 N HCl and neutralized with NaOH, followed by washing
with brine. The organics were dried (MgSO.sub.4), filtered,
concentrated and purified by silica gel chromatography (95/5
hexane/EtOAc) to give 0.555 g
[4R,8-Dimethyl-2R-(4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbonyl)-nony-
l]-carbamic acid benzyl ester.
[0732]
2(R)-(Benzyloxycarbonylamino-methyl)-4(R),8-dimethyl-nonanoic acid.
A procedure similar to that of (S)-2-((R)-2-Methyl=pentyl)succinic
acid t-butyl ester was utilized to provide 0.198 g
2(R)-(Benzyloxycarbonylamino-methyl)-4(R),8-dimethyl-nonanoic
acid.
[0733] 2-aminomethyl-4,8-dimethyl nonanoic acid.
2(R)-(Benzyloxycarbonylamino-methyl)-4(R),8-dimethyl-nonanoic acid
(0.148 g, 0.566 mmol) was treated with hydrogen in the presence of
20% pd/C to give 0.082 g of 2-aminomethyl-4,8-dimethyl nonanoic
acid after filtration and purification via silica gel
chromatography (85/15 CH.sub.2Cl.sub.2/MeOH). m/z 216.3 (M+).
Example 10
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid
[0734] 2,2,6-Trimethyl-heptanoic acid methyl ester. To diisopropyl
amine (1.54 mL, 11.03 mmol) in THF (22 mL) at -78.degree. C. was
added nBuLi (6.89 mL of a 1.6 M solution in hexane). The solution
was stirred for 30 min at -78.degree. C., followed by the addition
of methyl isobutyrate (0.97 mL, 8.48 mmol). The mixture was stirred
at -78.degree. C. for 2 h, and then 1-iodo-4-methyl pentane (1.8 g,
8.48 mmol) and DMPU (0.55 mL, 4.24 mmol) in THF (6 mL) was added.
The reaction was stirred at -78.degree. C. and allowed to slowly
reach ambient temperature over 16 h. The reaction was quenched by
the addition of ammonium chloride (saturated aqueous solution), and
the mixture was extracted with EtOAc (2.times.10 mL). The organics
were combined, washed with water, dried (MgSO.sub.4), filtered and
concentrated. Silica gel chromatography (99/1 hexane/EtOAc)
provided 1.57 g of 2,2,6-Trimethyl-heptanoic acid methyl ester.
[0735] 2,2,6-Trimethyl-heptan-1-ol. 2,2,6-Trimethyl-heptanoic acid
methyl ester (1.97 g, 10.6 mmol) was taken up in toluene (65 mL)
and cooled to -78.degree. C. DiBALH (12.7 mL of a 1 N solution in
toluene) was added dropwise. After 45 min, 1.5 mL DIBALH was added.
After 2 h, the reaction was quenched by the addition of 15 mL MeOH
at -78.degree. C. The mixture was warmed to ambient temperature,
and then cooled again to -78.degree. C. for the addition of 10 mL 1
N HCl. The mixture was extracted with EtOAc (3.times.15 mL). The
combined organics were washed with brine, dried (MgSO.sub.4),
filtered and concentrated. The residual oil was purified via silica
gel chromatography (95/5 Hexane/EtOAc) to give
2,2,6-Trimethyl-heptan-1-ol (0.88 g). m/z 159 (M+).
[0736] 2,2,6-Trimethyl-heptanal. Pyridinium chlorochromate (PCC,
4.17 g, 19.4 mmol) was combined with neutral alumina (14.6 g) in
CH.sub.2Cl.sub.2 and stirred at ambient temperature for 15 min. The
alcohol was diluted in CH.sub.2Cl.sub.2, and the mixture was
stirred at ambient temperature for 2 h. The solution was filtered
through a pad of silica, and the solids were washed with
CH.sub.2Cl.sub.2. The filtrate was evaporated to give 1.05 g m/z
157 (M+). 2,2,6-Trimethyl-heptanal which was carried on without
further purification.
[0737] 2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester. To a
mixture of 2,2,6-Trimethyl-heptanal (1.05 g, 6.73 mmol), piperidine
(0.19 mL, 2.01 mmol) and benzyl cyanoacetate (1.29 g, 7.4 mmol) in
toluene (50 mL) was added glacial acetic acid (0.72 g, 12.1 mmol).
The flask was fitted with a Dean-Stark trap, and the mixture was
heated at reflux for 18. The mixture was cooled, treated with
dilute HCl, and the layers were separated. The organics were washed
with a saturated sodium bicarbonate solution followed by brine, and
dried (MgSO.sub.4), filtered and concentrated. The residual oil was
purified by silica gel chromatography (98/2 hexane/EtOAc) to give
1.3 g of 2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester m/z
314 (M+).
[0738] 2-aminomethyl-4,4,8-trimethyl-nonanoic acid.
2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester (1.3 g, 4.14
mmol) in THF (50 mL) was treated with hydrogen in the presence of
20% Pd/C to give a mixture of the cyano acid and the cyano methyl
ester. The mixture was purified by silica gel chromatography to
give 278 mg of cyano acid. The acid was then treated with hydrogen
in the presence of Raney Ni in MeOH/NH4OH to give 0.16 g of
2-aminomethyl-4,4,8-trimethyl-nonanoic acid. m/z 230.3 (M+).
Example 11
2-Aminomethyl-4-ethyl-octanoic acid
[0739] A procedure similar to that of
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare
2-Aminomethyl-4-ethyl-octanoic acid from 2-ethylhexanal. m/z 202.1
(M+).
Example 12
2-Aminomethyl-4-ethyl-8-methyl-nonanoic acid
[0740] A procedure similar to that of
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare
2-Aminomethyl-8-methyl-nonanoic acid from
2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 230.2
(M+).
Example 13
3-Amino-2-[1-(4-methyl-pentyl)-cyclopropylmethyl]-propionic
acid
[0741] A procedure similar to that of
2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare
2-Aminomethyl-8-methyl-nonanoic acid from
2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 228.2
(M+).
Example 14
2-Aminomethyl-4-ethyl-hexanoic acid
[0742] A procedure similar to 2-aminomethyl-4,8-dimethyl-nonanoic
acid was used to prepare 2-aminomethyl-4-ethyl-hexanoic acid from
4-ethyl hexanoic acid. m/z 174.1.
Example 15
3(S)-Amino-3,5-dimethyl-heptanoic acid
[0743] 2-Methyl-propane-2(S)-sulfinic acid
(1,3-dimethyl-pentylidene)-amide.
[0744] A solution of (S)-(-)-2-methyl-2-propanesulfonamide (500 mg,
4.1 mmol), 4-methyl-2-hexanone (470 mg, 4.1 mmol), and Titanium(IV)
ethoxide (1.7 mL, 8.3 mmol) was heated at reflux for 18 h. The
reaction mixture was poured into 20 mL brine with rapid stirring.
The resulting solution was filtered through celite, and the organic
layer was separated. The aqueous layer was extracted with ethyl
acetate (2.times.20 mL). The combined organics were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The resultant oil
was purified by silica gel chromatography (25% EtOAc in hexane) to
give 575 mg of 2-Methyl-propane-2(S)-sulfinic acid
(1,3-dimethyl-pentylidene)-amide as a yellow oil.
[0745]
3,5-Dimethyl-3-(2-methyl-propane-2(S)-sulfinylamino)-heptanoic acid
methyl ester. To a -78.degree. C. solution of lithium
bis(trimethylsilyl)amide (5.1 ml of a 1 M solution in THF) in THF
(6 mL) was added methyl acetate ((0.41 mL, 5.1 mmol) dropwise.
After stirring for 20 min, a solution of chlorotitanium
triisopropoxide (2.5 ml, 10 mmol) in THF (3 mL) was added dropwise.
After 1 hour, 2-Methyl-propane-2(S)-sulfinic acid
(1,3-dimethyl-pentylidene)-amide (560 mg, 2.6 mmol) in THF (3 mL)
was added dropwise at -78.degree. C. The reaction was stirred at
-78.degree. C. for 5 h, and then quenched by the addition of 10 mL
ammonium chloride solution and warmed to room temperature. The
mixture was diluted with 10 mL water, and filtered. The aqueous
layer was extracted with ethyl acetate (2.times.20 mL). The
combined organics were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The resultant oil was purified by
silica gel chromatography (30% EtOAc in hexane) to give 360 mg of
3,5-Dimethyl-3-(2-methyl-propane-2(S)-sulfinylamino)-heptanoic acid
methyl ester.
[0746] 3(S)-Amino-3,5-dimethyl-heptanoicacid.
3,5-Dimethyl-3-(2-methyl-propane-2(S)-sulfinylamino)-heptanoic acid
methyl ester (360 mg, 1.2 mmol) was dissolved in 6 N HCl (2 mL) and
dioxane (2 mL) and heated at 100 C for 6 h. The mixture was cooled
to room temperature, diluted with water, and extracted with EtOAc
(15 mL). The organics were purified by ion exchange chromatography
to give 3(S)-Amino-3,5-dimethyl-heptanoic acid (270 mg) and then
repurification by silica gel chromatography (70:25:5
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) to give 203 mg of
3(S)-Amino-3,5-dimethyl-heptanoic acid as a white solid. m/z 174
(C.sub.9H.sub.19NO.sub.2+H).
Example 16
3(S)-Amino-3,5-dimethyl-nonanoic acid
[0747] A procedure similar to that of
3(S)-Amino-3,5-dimethyl-heptanoic acid was used to prepare
3(S)-Amino-3,5-dimethyl-nonanoic acid. m/z 202.1
(C.sub.11H.sub.23NO.sub.2+H).
Example 17
3(S)-Amino-3,5-dimethyl-octanoic acid
[0748] A procedure similar to that of
3(S)-Amino-3,5-dimethyl-heptanoic acid was used to prepare
3(S)-Amino-3,5-dimethyl-nonanoic acid. m/z 188.1
(C.sub.10H.sub.21NO.sub.2+H).
* * * * *