U.S. patent application number 10/949908 was filed with the patent office on 2005-06-09 for amino acids with affinity for the alpha2delta-protein.
Invention is credited to Deur, Christopher James, Henegar, Kevin E., Kolz, Christine Nylund, Miller, Jonathan Mark, Osuma, Augastine Tobi, Plummer, Mark Stephen, Samas, Brian, Schwarz, Jacob Bradley, Thorpe, Andrew J., Wustrow, David J..
Application Number | 20050124668 10/949908 |
Document ID | / |
Family ID | 34396281 |
Filed Date | 2005-06-09 |
United States Patent
Application |
20050124668 |
Kind Code |
A1 |
Deur, Christopher James ; et
al. |
June 9, 2005 |
Amino acids with affinity for the alpha2delta-protein
Abstract
Certain .beta.-amino acids that bind to the alpha-2-delta
(.alpha.2.delta.) subunit of a calcium channel are disclosed. These
compounds and their pharmaceutically acceptable salts are useful in
the treatment of a variety of psychiatric, pain and other
disorders.
Inventors: |
Deur, Christopher James;
(Ann Arbor, MI) ; Henegar, Kevin E.; (Ann Arbor,
MI) ; Kolz, Christine Nylund; (Dexter, MI) ;
Miller, Jonathan Mark; (Ann Arbor, MI) ; Osuma,
Augastine Tobi; (Canton, MI) ; Plummer, Mark
Stephen; (Dexter, MI) ; Samas, Brian; (Ann
Arbor, MI) ; Schwarz, Jacob Bradley; (Ann Arbor,
MI) ; Thorpe, Andrew J.; (Whitmore Lake, MI) ;
Wustrow, David J.; (Ann Arbor, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
34396281 |
Appl. No.: |
10/949908 |
Filed: |
September 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60505953 |
Sep 25, 2003 |
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60507443 |
Sep 30, 2003 |
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Current U.S.
Class: |
514/357 ;
514/522; 514/561; 514/567; 546/335; 558/410; 562/443 |
Current CPC
Class: |
A61P 25/08 20180101;
C07C 229/08 20130101; A61P 23/00 20180101; A61P 25/00 20180101;
A61P 43/00 20180101; A61P 19/00 20180101; A61P 25/32 20180101; A61P
25/36 20180101; C07C 229/28 20130101; A61P 9/02 20180101; C07C
2601/04 20170501; A61P 27/16 20180101; A61P 25/34 20180101; C07C
227/32 20130101; C07C 229/34 20130101; A61P 25/28 20180101; A61P
25/06 20180101; C07D 263/26 20130101; A61P 25/18 20180101; A61P
25/20 20180101; C07C 2601/14 20170501; A61P 11/00 20180101; A61P
25/16 20180101; A61P 25/30 20180101; C07C 2601/08 20170501; A61P
9/00 20180101; A61P 13/02 20180101; C07B 2200/07 20130101; A61P
3/10 20180101; A61P 25/04 20180101; Y02P 20/582 20151101; A61P
19/02 20180101; A61P 25/02 20180101; A61P 25/14 20180101; A61P
21/00 20180101; A61P 31/18 20180101; A61P 15/00 20180101; A61P
25/24 20180101; C07C 2601/02 20170501; A61P 25/22 20180101; A61P
7/10 20180101; A61P 29/00 20180101; A61P 1/00 20180101; A61P 17/06
20180101 |
Class at
Publication: |
514/357 ;
514/522; 514/567; 514/561; 558/410; 562/443; 546/335 |
International
Class: |
A61K 031/44; C07D
213/55; A61K 031/277; A61K 031/198 |
Claims
What is claimed is:
1. A compound of formula I 15or a pharmaceutically acceptable salt
thereof, wherein R.sub.1 is a hydrogen atom or
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to five
fluorine atoms; R.sub.2 is a hydrogen atom or
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to five
fluorine atoms; or R.sub.1 and R.sub.2, together with the carbon to
which they are attached, form a three- to six-membered cycloalkyl
ring; R.sub.3 is a hydrogen atom, (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, or
pyridyl-(C.sub.1-C.sub.3)alkyl, wherein the alkyl and cycloalkyl
moieties or substituents are optionally substituted with from one
to five fluorine atoms, and the phenyl and pyridyl substituents and
the phenyl and pyridyl moieties of the
phenyl-(C.sub.1-C.sub.3)alkyl and the
pyridyl-(C.sub.1-C.sub.3)alkyl substituents are optionally
substituted with from one to five substituents independently
selected from chloro, fluoro, amino, nitro, cyano, hydroxy,
(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; R.sub.4 is a hydrogen atom or
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to five
fluorine atoms; R.sub.5 is a hydrogen atom or
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to five
fluorine atoms; R.sub.4 and R.sub.5, together with the carbon to
which they are attached, form a three- to six-membered cycloalkyl
ring; and R.sub.6 is a hydrogen atom or (C.sub.1-C.sub.6)alkyl;
with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are not simultaneously hydrogen atoms.
2. A compound of claim 1 having a structure represented by formula
II 16or a pharmaceutically acceptable salt thereof, wherein
R.sub.1, R.sub.3, and R.sub.4 are defined as in claim 1 with the
proviso that R.sub.1 is not a hydrogen atom.
3. A compound of claim 1 having a structure represented by formula
III 17or a pharmaceutically acceptable salt thereof, wherein R. and
R.sub.3 are defined as in claim 1 with the proviso that R. and
R.sub.3 are not hydrogen atoms.
4. A compound of claim 3 having a structure represented by formula
IV 18or a pharmaceutically acceptable salt thereof, wherein R.sub.3
is defined as in claim 1 with the proviso that R.sub.3 is not a
hydrogen atom.
5. A compound of claim 1 having a structure represented by formula
V 19or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined as in claim 1
with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 are not simultaneously hydrogen atoms.
6. A compound of claim 1 having a structure represented by formula
VI 20or a pharmaceutically acceptable salt thereof, wherein
R.sub.3, R.sub.4, and R.sub.5 are defined as in claim 1 with the
proviso that R.sub.3, R.sub.4, and R.sub.5 are not simultaneously
hydrogen atoms.
7. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
8. A method of treating a disorder or condition in a mammal,
including a human, the disorder or condition selected from:
epilepsy, faintness attacks, fibromyalgia, hypokinesia, cranial
disorders, hot flashes, and essential tremor; chemical dependencies
and 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; withdrawal symptoms associated with the
dependencies, addictions, or addictive behaviors, including
gambling; and migraine, spasticity, muscle spasticity, hypotonia
with paralysis, arthritis, irritable bowel syndrome, chronic pain,
acute pain, neuropathic pain, post herpetic neuralgia, lower back
pain, surgical pain, vascular headache, sinus headache, chronic
headache, inflammatory disorders, rheumatoid arthritis,
osteoarthritis, psoriasis, disease modification of osteoarthritis
disease, diuresis, premenstrual syndrome, premenstrual dysphoric
disorder, tinnitus, and gastric damage; the method comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
9. A method of treating a disorder or condition in a mammal,
including a human, the disorder or condition selected from:
delirium, dementia, and amnestic or other cognitive or
neurodegenerative disorders, including Parkinson's disease,
Huntington's disease, Alzheimer's disease, senile dementia,
dementia of the Alzheimer's type, memory disorder, vascular
dementia, and other dementias, including dementia 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 including akinesias, dyskinesias,
including familial paroxysmal dyskinesias, spasticities, Tourette's
syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome;
extra-pyramidal movement disorders including medication-induced
movement disorders, including neuroleptic-induced Parkinsonism,
neuroleptic malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; Down's
syndrome; demyelinating diseases including multiple sclerosis and
amylolateral sclerosis, peripheral neuropathy, including diabetic
and chemotherapy-induced-neuropathy, or postherpetic neuralgia,
trigeminal neuralgia, segmental or intercostal neuralgia and other
neuralgias; and cerebral vascular disorders due to acute or chronic
cerebrovascular damage including cerebral infarction, subarachnoid
haemorrhage or cerebral oedema; the method comprising administering
to the mammal in need of such treatment a therapeutically effective
amount of a compound of claim 1 or a pharmaceutically acceptable
salt thereof.
10. A method of treating a disorder or condition in a mammal,
including a human, the disorder or condition selected from sleep
disorders, 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, or
sleep disorders associated with shift work and irregular work
hours, the method comprising administering to the mammal in need of
such treatment a therapeutically effective amount of a compound of
claim 1 or a pharmaceutically acceptable salt thereof.
11. A method of treating a disorder or condition in a mammal,
including a human, the disorder or condition selected from: mood
disorders, including depression or depressive disorders, including
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; bipolar disorders or manic depression,
including bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder and disruptive behavior disorder;
anxiety disorders, including panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, including specific animal phobias, social
anxiety, 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,
including 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 including severe major depressive
disorder; mood disorders associated with psychotic disorders
including acute mania and depression associated with bipolar
disorder, mood disorders associated with schizophrenia; and
behavioral disturbances associated with mental retardation,
autistic disorder, and conduct disorder; the method comprising
administering to the mammal in need of such treatment a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
12. A compound selected from the following compounds and their
pharmaceutically acceptable salts: 3-Amino-4,5-dimethyl-hexanoic
acid; 3-Amino-4,5-dimethyl-heptanoic acid;
3-Amino-4,5-dimethyl-octanoic acid; 3-Amino-4,5-dimethyl-nonanoic
acid; 3-Amino-4,5-dimethyl-decanoic acid;
3-Amino-4-ethyl-5-methyl-heptanoic acid;
3-Amino-4-ethyl-5-methyl-octanoi- c acid;
3-Amino-4-ethyl-5-methyl-nonanoic acid; 3-Amino-4-ethyl-5,6-dimeth-
yl-heptanoic acid; 3-Amino-4-ethyl-5,7-dimethyl-octanoic acid;
3-Amino-4-ethyl-5,8-dimethyl-nonanoic acid;
3-Amino-5-ethyl-4-methyl-octa- noic acid;
3-Amino-5-ethyl-4-methyl-nonanoic acid; 3-Amino-4,5-diethyl-hep-
tanoic acid; 3-Amino-4,5-diethyl-octanoic acid;
3-Amino-4,5-diethyl-nonano- ic acid;
3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
3-Amino-4,5-diethyl-6-methyl-- heptanoic acid;
3-Amino-4,5-diethyl-7-methyl-octanoic acid;
3-Amino-4,5-diethyl-8-methyl-nonanoic acid;
3-Amino-4,5,6-trimethyl-hepta- noic acid;
3-Amino-4,5,7-trimethyl-octanoic acid; 3-Amino-4,5,8-trimethyl--
nonanoic acid; 3-Amino-4-ethyl-5-methyl-hexanoic acid;
3-Amino-5-ethyl-4-methyl-octanoic acid;
3-Amino-5-ethyl-4-methyl-heptanoi- c acid;
3-Amino-4-methyl-5-propyl-octanoic acid; 3-Amino-4-methyl-6-ethyl--
octanoic acid; 3-Amino-4-methyl-6-ethyl-nonanoic acid;
3-Amino-4,6-diethyl-octanoic acid; 3-Amino-4,6-diethyl-nonanoic
acid; 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
3-Amino-7-cyclopentyl-4- ,5-dimethyl-heptanoic acid;
3-Amino-5-ethyl-4,6-dimethyl-heptanoic acid;
3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
3-Amino-5-ethyl-4,8-dimethyl-- nonanoic acid;
(3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
(3R,4R,5R)-3-Amino-4,5-di- methyl-octanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid;
3-Amino-5-cyclopropyl-4-et- hyl-hexanoic acid;
3-Amino-6-cyclopropyl-4-ethyl-5-methyl-hexanoic acid;
3-Amino-5-cyclobutyl-4-ethyl-hexanoic acid;
3-Amino-6-cyclobutyl-4-ethyl-- 5-methyl-hexanoic acid;
3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
3-Amino-6-cyclopentyl-4-ethyl-5-methyl-hexanoic acid;
3-Amino-5-cyclohexyl-4-ethyl-hexanoic acid;
3-Amino-6-cyclohexyl-4-ethyl-- 5-methyl-hexanoic acid;
3-Amino-5-cyclopropyl-4-methyl-hexanoic acid;
3-Amino-6-cyclopropyl-4,5-dimethyl-hexanoic acid;
3-Amino-5-cyclobutyl-4-- methyl-hexanoic acid;
3-Amino-6-cyclobutyl-4,5-dimethyl-hexanoic acid;
3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
3-Amino-6-cyclopentyl-4,5-d- imethyl-hexanoic acid;
3-Amino-5-cyclohexyl-4-methyl-hexanoic acid;
3-Amino-6-cyclohexyl-4,5-dimethyl-hexanoic acid;
3-Amino-8-cyclohexyl-4,5- -dimethyl-octanoic acid;
3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid;
3-Amino-4,6-dimethyl-heptanoic acid; 3-Amino-4,6-dimethyl-octanoic
acid; 3-Amino-4,6-dimethyl-nonanoic acid;
3-Amino-4,6-dimethyl-decanoic acid;
3-Amino-4,6,7-trimethyl-octanoic acid;
3-Amino-4,6,8-trimethyl-nonanoic acid;
3-Amino-4,6,9-trimethyl-decanoic acid;
3-Amino-6-cyclopropyl-4-meth- yl-heptanoic acid;
3-Amino-6-cyclobutyl-4-methyl-heptanoic acid;
3-Amino-6-cyclopentyl-4-methyl-heptanoic acid;
3-Amino-6-cyclohexyl-4-met- hyl-heptanoic acid;
3-Amino-7-cyclopropyl-4,6-dimethyl-heptanoic acid;
3-Amino-7-cyclobutyl-4,6-dimethyl-heptanoic acid;
3-Amino-7-cyclopentyl-4- ,6-dimethyl-heptanoic acid;
3-Amino-7-cyclohexyl-4,6-dimethyl-heptanoic acid;
3-Amino-8-cyclopropyl-4,6-dimethyl-octanoic acid;
3-Amino-8-cyclobutyl-4,6-dimethyl-octanoic acid;
3-Amino-8-cyclopentyl-4,- 6-dimethyl-octanoic acid;
3-Amino-8-cyclohexyl-4,6-dimethyl-octanoic acid;
3-Amino-6-(3-chloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-6-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-4-methyl-6-(3-trifluoromethyl-phenyl)-heptanoic acid;
3-Amino-4-methyl-6-(4-trifluoromethyl-phenyl)-heptanoic acid;
3-Amino-7-(3-chloro-phenyl)-4,6-dimethyl-heptanoic acid;
3-Amino-7-(3,4-dichloro-phenyl)-4,6-dimethyl-heptanoic acid;
3-Amino-4,6-dimethyl-7-(3-trifluoromethyl-phenyl)-heptanoic acid;
3-Amino-4,6-dimethyl-7-(4-trifluoromethyl-phenyl)-heptanoic acid;
3-Amino-8-(3-chloro-phenyl)-4,6-dimethyl-octanoic acid;
3-Amino-8-(3,4-dichloro-phenyl)-4,6-dimethyl-octanoic acid;
3-Amino-4,6-dimethyl-8-(3-trifluoromethyl-phenyl)-octanoic acid;
3-Amino-4,6-dimethyl-8-(4-trifluoromethyl-phenyl)-octanoic acid;
3-Amino-4-ethyl-6-methyl-octanoic acid;
3-Amino-4-ethyl-6-methyl-nonanoic acid;
3-Amino-4-ethyl-6-methyl-decanoic acid;
3-Amino-4-ethyl-6,7-dimethy- l-octanoic acid;
3-Amino-4-ethyl-6,8-dimethyl-nonanoic acid;
3-Amino-4-ethyl-6,9-dimethyl-decanoic acid;
3-Amino-6-cyclopropyl-4-ethyl- -heptanoic acid;
3-Amino-6-cyclobutyl-4-ethyl-heptanoic acid;
3-Amino-6-cyclopentyl-4-ethyl-heptanoic acid;
3-Amino-6-cyclohexyl-4-ethy- l-heptanoic acid;
3-Amino-7-cyclopropyl-4-ethyl-6-methyl-heptanoic acid;
3-Amino-7-cyclobutyl-4-ethyl-6-methyl-heptanoic acid;
3-Amino-7-cyclopentyl-4-ethyl-6-methyl-heptanoic acid;
3-Amino-7-cyclohexyl-4-ethyl-6-methyl-heptanoic acid;
3-Amino-8-cyclopropyl-4-ethyl-6-methyl-octanoic acid;
3-Amino-8-cyclobutyl-4-ethyl-6-methyl-octanoic acid;
3-Amino-8-cyclopentyl-4-ethyl-6-methyl-octanoic acid;
3-Amino-8-cyclohexyl-4-ethyl-6-methyl-octanoic acid;
3-Amino-6-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
3-Amino-6-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
3-Amino-4-ethyl-6-(3-trifluoromethyl-phenyl)-heptanoic acid;
3-Amino-4-ethyl-6-(4-trifluoromethyl-phenyl)-heptanoic acid;
3-Amino-7-(3-chloro-phenyl)-4-ethyl-6-methyl-heptanoic acid;
3-Amino-7-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-heptanoic acid;
3-Amino-4-ethyl-6-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
3-Amino-4-ethyl-6-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid; 3-Amino-8-(3-chloro-phenyl)-4-ethyl-6-methyl-octanoic acid;
3-Amino-8-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-octanoic acid;
3-Amino-4-ethyl-6-methyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid;
3-Amino-4-ethyl-6-methyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid; 3-Amino-4-methyl-heptanoic acid;
3-Amino-4,6-dimethyl-heptanoic acid; 3-Amino-4,7-dimethyl-octanoic
acid; 3-Amino-4,8-dimethyl-nonanoic acid; 3-Amino-4-methyl-hexanoic
acid; 3-Amino-4-methyl-heptanoic acid; 3-Amino-4-methyl-octanoic
acid; 3-Amino-4-methyl-nonanoic acid;
3-Amino-5-cyclopropyl-4-methyl-pentanoic acid;
3-Amino-6-cyclopropyl-4-me- thyl-hexanoic acid;
3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;
3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;
3-Amino-6-cyclobutyl-4-meth- yl-hexanoic acid;
3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;
3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;
3-Amino-6-cyclopentyl-4-me- thyl-hexanoic acid;
3-Amino-7-cyclopentyl-4-methyl-heptanoic acid;
3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;
3-Amino-6-cyclohexyl-4-meth- yl-hexanoic acid;
3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;
3-Amino-5-cyclopropyl-4-ethyl-pentanoic acid;
3-Amino-6-cyclopropyl-4-eth- yl-hexanoic acid;
3-Amino-7-cyclopropyl-4-ethyl-heptanoic acid;
3-Amino-5-cyclobutyl-4-ethyl-pentanoic acid;
3-Amino-6-cyclobutyl-4-ethyl- -hexanoic acid;
3-Amino-7-cyclobutyl-4-ethyl-heptanoic acid;
3-Amino-5-cyclopentyl-4-ethyl-pentanoic acid;
3-Amino-6-cyclopentyl-4-eth- yl-hexanoic acid;
3-Amino-7-cyclopentyl-4-ethyl-heptanoic acid;
3-Amino-5-cyclohexyl-4-ethyl-pentanoic acid;
3-Amino-6-cyclohexyl-4-ethyl- -hexanoic acid;
3-Amino-7-cyclohexyl-4-ethyl-heptanoic acid;
3-Amino-4,4,5-trimethyl-heptanoic acid;
3-Amino-4,4,5-trimethyl-octanoic acid;
3-Amino-4,4,5-trimethyl-hexanoic acid;
3-Amino-4,5,5-trimethyl-hept- anoic acid;
3-Amino-4,5,5-trimethyl-octanoic acid; 3-Amino-4,5,5-trimethyl-
-hexanoic acid; 3-Amino-4-methyl-5-phenyl-pentanoic acid;
3-Amino-4-methyl-6-phenyl-hexanoic acid;
3-Amino-4-methyl-7-phenyl-heptan- oic acid;
3-Amino-5-(2-chloro-phenyl)-4-methyl-pentanoic acid;
3-Amino-5-(3-chloro-phenyl)-4-methyl-pentanoic acid;
3-Amino-5-(4-chloro-phenyl)-4-methyl-pentanoic acid;
3-Amino-5-(2,4-dichloro-phenyl)-4-methyl-pentanoic acid;
3-Amino-5-(3,4-dichloro-phenyl)-4-methyl-pentanoic acid;
3-Amino-4-(2-chloro-benzyl)-hexanoic acid;
3-Amino-4-(3-chloro-benzyl)-he- xanoic acid;
3-Amino-4-(4-chloro-benzyl)-hexanoic acid;
3-Amino-4-(2,4-dichloro-benzyl)-hexanoic acid;
3-Amino-4-(3,4-dichloro-be- nzyl)-hexanoic acid;
3-Amino-6-(2-chloro-phenyl)-4-methyl-hexanoic acid;
3-Amino-6-(3-chloro-phenyl)-4-methyl-hexanoic acid;
3-Amino-6-(4-chloro-phenyl)-4-methyl-hexanoic acid;
3-Amino-6-(2,4-dichloro-phenyl)-4-methyl-hexanoic acid;
3-Amino-6-(3,4-dichloro-phenyl)-4-methyl-hexanoic acid;
3-Amino-6-(2-chloro-phenyl)-4-ethyl-hexanoic acid;
3-Amino-6-(3-chloro-phenyl)-4-ethyl-hexanoic acid;
3-Amino-6-(4-chloro-phenyl)-4-ethyl-hexanoic acid;
3-Amino-6-(2,4-dichloro-phenyl)-4-ethyl-hexanoic acid;
3-Amino-6-(3,4-dichloro-phenyl)-4-ethyl-hexanoic acid;
3-Amino-7-(2-chloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-7-(3-chloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-7-(4-chloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-7-(2,4-dichloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-7-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
3-Amino-7-(2-chloro-phenyl)-4-ethyl-heptanoic acid;
3-Amino-7-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
3-Amino-7-(4-chloro-phenyl)-4-ethyl-heptanoic acid;
3-Amino-7-(2,4-dichloro-phenyl)-4-ethyl-heptanoic acid; and
3-Amino-7-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid.
2-Aminomethyl-4-(2-fluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-fluo- ro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-fluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-difluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-difluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-difluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-difluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-difluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-difluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4,5-tetrafluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4,6-tetrafluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5,6-tetrafluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-pentafluorophenyl-pentanoic acid;
2-Aminomethyl-4-(2-fluo- ro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-fluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-fluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-dif- luoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-difluoro-phenyl)-hexanoi- c acid;
2-Aminomethyl-4-(2,5-difluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-difluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-difluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-difluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4,5-tetrafluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4,6-tetrafluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5,6-tetrafluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-pentafluorophenyl-hexanoic acid;
2-Aminomethyl-5-(2-fluor- o-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-fluoro-phenyl)-4-met- hyl-pentanoic acid;
2-Aminomethyl-5-(4-fluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-difluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,5-difluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,6-difluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,4-difluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,5-difluoro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrafluoro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrafluoro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrafluoro-phenyl)-pentanoic
acid; 2-Aminomethyl-4-methyl-5-pentafluorophenyl-pentanoic acid;
2-Aminomethyl-5-(2-fluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-fluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-fluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrafluoro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrafluoro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrafluoro-phenyl)-hexanoic
acid; 2-Aminomethyl-4-methyl-5-pentafluorophenyl-hexanoic acid;
2-Aminomethyl-6-(2-fluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3-fluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(4-fluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,3-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,4-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,5-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,6-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,4-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,5-difluoro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,4-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,5-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,4,5-tetrafluoro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,4,6-tetrafluoro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,5,6-tetrafluoro-phenyl)-hexanoic
acid; 2-Aminomethyl-4-methyl-6-pentafluorophenyl-hexanoic acid;
2-Aminomethyl-5-(2-fluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-fluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-fluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-difluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,5-difluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,6-difluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,4-difluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,5-difluoro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-trifluoro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetrafluoro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetrafluoro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetrafluoro-phenyl)-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-pentafluorophenyl-pentanoic acid;
2-Aminomethyl-6-(2-fluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-fluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-fluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-difluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,4-difluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,5-difluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,6-difluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,4-difluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,5-difluoro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-trifluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4,5-tetrafluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4,6-tetrafluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5,6-tetrafluoro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-pentafluorophenyl-hexanoic acid;
2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,3-difluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,5-difluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,6-difluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,5-difluoro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4,5-tetrafluoro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,4,6-tetrafluoro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,5,6-tetrafluoro-phenyl)-heptanoic
acid; 2-Aminomethyl-4-methyl-7-pentafluorophenyl-heptanoic acid;
2-Aminomethyl-7-(2-fluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-fluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-fluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-difluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,5-difluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,6-difluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,5-difluoro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-trifluoro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4,5-tetrafluoro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,4,6-tetrafluoro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,5,6-tetrafluoro-phenyl)-heptanoic
acid; 2-Aminomethyl-4-ethyl-7-pentafluorophenyl-heptanoic acid;
2-Aminomethyl-4-(2-chloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-chlo- ro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-chloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-dichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-dichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-dichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-dichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-dichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-dichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4,5-tetrachloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4,6-tetrachloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5,6-tetrachloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-pentachlorophenyl-pentanoic acid;
2-Aminomethyl-4-(2-chlo- ro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-chloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-chloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-dic- hloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-dichloro-phenyl)-hexanoi- c acid;
2-Aminomethyl-4-(2,5-dichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-dichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-dichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-dichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4,5-tetrachloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4,6-tetrachloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5,6-tetrachloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-pentachlorophenyl-hexanoic acid;
2-Aminomethyl-5-(2-chlor- o-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-chloro-phenyl)-4-met- hyl-pentanoic acid;
2-Aminomethyl-5-(4-chloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrachloro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrachloro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrachloro-phenyl)-pentanoic
acid; 2-Aminomethyl-4-methyl-5-pentachlorophenyl-pentanoic acid;
2-Aminomethyl-5-(2-chloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-chloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-chloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrachloro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrachloro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrachloro-phenyl)-hexanoic
acid; 2-Aminomethyl-4-methyl-5-pentachlorophenyl-hexanoic acid;
2-Aminomethyl-5-(2-chloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-chloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-chloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrachloro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrachloro-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrachloro-phenyl)-hexanoic
acid; 2-Aminomethyl-4-methyl-5-pentachlorophenyl-hexanoic acid;
2-Aminomethyl-5-(2-chloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-chloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-chloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-trichloro-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetrachloro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetrachloro-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetrachloro-phenyl)-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-pentachlorophenyl-pentanoic acid;
2-Aminomethyl-6-(2-chloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-chloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-chloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dichloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dichloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dichloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dichloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dichloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dichloro-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-trichloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4,5-tetrachloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4,6-tetrachloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5,6-tetrachloro-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-pentachlorophenyl-hexanoic acid;
2-Aminomethyl-7-(2-chloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3-chloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(4-chloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dichloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dichloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dichloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dichloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dichloro-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4,5-tetrachloro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,4,6-tetrachloro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,5,6-tetrachloro-phenyl)-heptanoic
acid; 2-Aminomethyl-4-methyl-7-pentachlorophenyl-heptanoic acid;
2-Aminomethyl-7-(2-chloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-chloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dichloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dichloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dichloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dichloro-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-trichloro-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4,5-tetrachloro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,4,6-tetrachloro-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,5,6-tetrachloro-phenyl)-heptanoic
acid; 2-Aminomethyl-4-ethyl-7-pentachlorophenyl-heptanoic acid;
2-Aminomethyl-4-(2-methoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-methoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-methoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-dimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-dimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-dimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-dimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-dimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-dimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2-methoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-meth- oxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-methoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-dimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-dimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,5-dimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-dimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-dimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-dimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-methoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-methoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(4-methoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dimethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dimethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dimethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dimethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dimethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dimethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-5-(2-methoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-methoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-methoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-6-(2-methoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3-methoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(4-methoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dimethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,4-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,5-trimethoxy-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-methoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-methoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-methoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dimethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dimethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dimethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dimethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dimethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dimethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-trimethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetramethoxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetramethoxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetramethoxy-phenyl)-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-pentamethoxyphenyl-pentanoic acid;
2-Aminomethyl-6-(2-methoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-methoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-methoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dimethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dimethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dimethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dimethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dimethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dimethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-trimethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-7-(2-methoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3-methoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(4-methoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dimethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dimethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dimethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dimethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dimethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dimethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-7-(2-methoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-methoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-methoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dimethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dimethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dimethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dimethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dimethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dimethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-trimethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-(2-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-di-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-di-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-di-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-di-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-di-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-di-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-tri-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-tri-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-tri-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-tri-trifluoromethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-di-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-di-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,5-di-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-di-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-di-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-di-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-tri-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-tri-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-trifluoromethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,4-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,5-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,6-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(3,4-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethyl-phenyl)-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethyl-phenyl)-pentano-
ic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethyl-phenyl)-penta-
noic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethyl-phenyl)-pen-
tanoic acid;
2-Aminomethyl-5-(2-trifluoromethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(2,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(2,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(2,6-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(3,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethyl-phenyl)-hexano-
ic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethyl-phenyl)-hexan-
oic acid;
2-Aminomethyl-6-(2-trifluoromethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3-trifluoromethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(4-trifluoromethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,3-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,6-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(3,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(3,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
2-Aminomethyl-4-methyl-6-(2,3,6-tri-trifluoromethyl-phenyl)-hexano-
ic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-tri-trifluoromethyl-phenyl)-hexan-
oic acid;
2-Aminomethyl-5-(2-trifluoromethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,4-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,5-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,6-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(3,4-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(3,5-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-tri-trifluoromethyl-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-tri-trifluoromethyl-phenyl)-pentanoi-
c acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-tri-trifluoromethyl-phenyl)-pentano-
ic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-tri-trifluoromethyl-phenyl)-pentan-
oic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetra-trifluoromethyl-phenyl)-p-
entanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetra-trifluoromethyl-phen-
yl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetra-trifluoromethyl-
-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-penta-trifluoromethylphen- yl-pentanoic
acid; 2-Aminomethyl-6-(2-trifluoromethyl-phenyl)-4-ethyl-hexa- noic
acid; 2-Aminomethyl-6-(3-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid; 2-Aminomethyl-6-(4-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,3-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,4-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,5-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,6-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(3,4-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(3,5-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoic
acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoic
acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-tri-trifluoromethyl-phenyl)-hexanoic
acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-tri-trifluoromethyl-phenyl)-hexanoic
acid; 2-Aminomethyl-7-(2-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid; 2-Aminomethyl-7-(3-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid; 2-Aminomethyl-7-(4-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,3-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,4-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,5-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,6-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(3,4-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(3,5-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,4-tri-trifluoromethyl-phenyl)-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,5-tri-trifluoromethyl-phenyl)-heptano-
ic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-tri-trifluoromethyl-phenyl)-hepta-
noic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-tri-trifluoromethyl-phenyl)-hep-
tanoic acid;
2-Aminomethyl-7-(2-trifluoromethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-trifluoromethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-trifluoromethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,4-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,5-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,6-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(3,4-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(3,5-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-tri-trifluoromethyl-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-tri-trifluoromethyl-phenyl)-heptanoi-
c acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-tri-trifluoromethyl-phenyl)-heptano-
ic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-tri-trifluoromethyl-phenyl)-heptan-
oic acid; 2-Aminomethyl-4-(2-trifluoromethoxy-phenyl)-pentanoic
acid; 2-Aminomethyl-4-(3-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-di-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-di-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-di-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-di-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-di-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-di-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-tri-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-tri-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-tri-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-tri-trifluoromethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-di-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-di-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,5-di-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-di-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-di-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-di-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-tri-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-tri-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-tri-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-tri-trifluoromethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(3-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(4-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-5-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethoxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethoxy-phenyl)-pentan-
oic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethoxy-phenyl)-pen-
tanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethoxy-phenyl)--
pentanoic acid;
2-Aminomethyl-5-(2-trifluoromethoxy-phenyl)-4-ethyl-pentan- oic
acid; 2-Aminomethyl-5-(3-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid; 2-Aminomethyl-5-(4-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,3-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,4-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,5-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(2,6-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(3,4-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-5-(3,5-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-tri-trifluoromethoxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-tri-trifluoromethoxy-phenyl)-pentano-
ic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-tri-trifluoromethoxy-phenyl)-penta-
noic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-tri-trifluoromethoxy-phenyl)-pen-
tanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetra-trifluoromethoxy-pheny-
l)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetra-trifluoromethoxy-
-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetra-trifluorom-
ethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-penta-trifluorometh- oxyphenyl-pentanoic
acid; 2-Aminomethyl-5-(2-trifluoromethoxy-phenyl)-4-me-
thyl-hexanoic acid;
2-Aminomethyl-5-(3-trifluoromethoxy-phenyl)-4-methyl-h- exanoic
acid; 2-Aminomethyl-5-(4-trifluoromethoxy-phenyl)-4-methyl-hexanoi-
c acid;
2-Aminomethyl-5-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-5-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethoxy-phenyl)-hexa-
noic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethoxy-phenyl)-he-
xanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethoxy-phenyl)--
hexanoic acid;
2-Aminomethyl-6-(2-trifluoromethoxy-phenyl)-4-methyl-hexano- ic
acid; 2-Aminomethyl-6-(3-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid; 2-Aminomethyl-6-(4-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-6-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,4-tri-trifluoromethoxy-phenyl)-hexanoic
acid;
2-Aminomethyl-4-methyl-6-(2,3,5-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
2-Aminomethyl-4-methyl-6-(2,3,6-tri-trifluoromethoxy-phenyl)-hexa-
noic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-tri-trifluoromethoxy-phenyl)-he-
xanoic acid;
2-Aminomethyl-6-(2-trifluoromethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-trifluoromethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-trifluoromethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,4-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,5-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(2,6-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(3,4-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-6-(3,5-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-tri-trifluoromethoxy-phenyl)-hexanoic
acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-tri-trifluoromethoxy-phenyl)-hexanoi-
c acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-tri-trifluoromethoxy-phenyl)-hexan-
oic acid;
2-Aminomethyl-7-(2-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(3-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(4-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-7-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
2-Aminomethyl-4-methyl-7-(2,3,4-tri-trifluoromethoxy-phenyl)-heptan-
oic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-tri-trifluoromethoxy-phenyl)-hep-
tanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-tri-trifluoromethoxy-phenyl)--
heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-tri-trifluoromethoxy-pheny-
l)-heptanoic acid;
2-Aminomethyl-7-(2-trifluoromethoxy-phenyl)-4-ethyl-hep- tanoic
acid; 2-Aminomethyl-7-(3-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid; 2-Aminomethyl-7-(4-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,3-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,4-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,5-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(2,6-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(3,4-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-7-(3,5-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-tri-trifluoromethoxy-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-tri-trifluoromethoxy-phenyl)-heptano-
ic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-tri-trifluoromethoxy-phenyl)-hepta-
noic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-tri-trifluoromethoxy-phenyl)-hep-
tanoic acid; 2-Aminomethyl-4-(2-ethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-ethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-etho- xy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-diethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-diethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-diethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-diethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-diethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-diethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2-ethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-ethox- y-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-ethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-diethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-diethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,5-diethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-diethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-diethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-diethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-ethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-ethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(4-ethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-diethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,4-diethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,5-diethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,6-diethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,4-diethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,5-diethoxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-5-(2-ethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-ethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-ethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-diethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,4-diethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,5-diethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,6-diethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,4-diethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,5-diethoxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-triethoxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetraethoxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetraethoxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetraethoxy-phenyl)-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-pentaethoxyphenyl-pentanoic acid;
2-Aminomethyl-5-(2-ethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-ethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-ethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-6-(2-ethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3-ethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(4-ethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,3-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,4-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,5-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,6-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,4-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,5-diethoxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,4-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,5-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-6-(2-ethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-ethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-ethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-diethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,4-diethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,5-diethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,6-diethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,4-diethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,5-diethoxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-triethoxy-phenyl)-hexanoic acid;
2-Aminomethyl-7-(2-ethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3-ethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(4-ethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,3-diethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,4-diethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,5-diethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,6-diethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,4-diethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,5-diethoxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-7-(2-ethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-ethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-ethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-diethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,4-diethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,5-diethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,6-diethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,4-diethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,5-diethoxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-triethoxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-(2-methyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-meth- yl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-methyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-dimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-dimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-dimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-dimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-dimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-dimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2-methyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-methy- l-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-methyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-dimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-dimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,5-dimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-dimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-dimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-dimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-methyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-methyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(4-methyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dimethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dimethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dimethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dimethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dimethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dimethyl-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-5-(2-methyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-methyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-methyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dimethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dimethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dimethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dimethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dimethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dimethyl-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-trimethyl-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetramethyl-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetramethyl-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetramethyl-phenyl)-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-pentamethylphenyl-pentanoic acid;
2-Aminomethyl-5-(2-methyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-methyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-methyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-6-(2-methyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3-methyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(4-methyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dimethyl-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,4-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,5-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-6-(2-methyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-methyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-methyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dimethyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dimethyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dimethyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dimethyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dimethyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dimethyl-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-trimethyl-phenyl)-hexanoic acid;
2-Aminomethyl-7-(2-methyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3-methyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(4-methyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dimethyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dimethyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dimethyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dimethyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dimethyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dimethyl-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-7-(2-methyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-methyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-methyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dimethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dimethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dimethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dimethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dimethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dimethyl-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-trimethyl-phenyl)-heptanoic acid;
2-Aminomethyl-4-(2-hydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3-hydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(4-hydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3-dihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4-dihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,5-dihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,6-dihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,4-dihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(3,5-dihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,4-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,5-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,3,6-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2,4,6-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-(2-hydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3-hydr- oxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(4-hydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3-dihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4-dihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,5-dihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,6-dihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,4-dihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(3,5-dihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,4-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,5-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,3,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-(2,4,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-hydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3-hydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(4-hydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dihydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dihydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dihydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dihydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dihydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dihydroxy-phenyl)-4-methyl-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-5-(2-hydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3-hydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(4-hydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,3-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,4-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,5-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(2,6-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,4-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-5-(3,5-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,4-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,5-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,3,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-5-(2,4,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-6-(2-hydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3-hydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(4-hydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dihydroxy-phenyl)-4-methyl-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,4-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,5-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,3,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-methyl-6-(2,4,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-5-(2-hydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3-hydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(4-hydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,3-dihydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,4-dihydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,5-dihydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(2,6-dihydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,4-dihydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-5-(3,5-dihydroxy-phenyl)-4-ethyl-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,5-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,6-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,4,6-trihydroxy-phenyl)-pentanoic acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetrahydroxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetrahydroxy-phenyl)-pentanoic
acid;
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetrahydroxy-phenyl)-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-pentahydroxyphenyl-pentanoic acid;
2-Aminomethyl-6-(2-hydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3-hydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(4-hydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,3-dihydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,4-dihydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,5-dihydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(2,6-dihydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,4-dihydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-6-(3,5-dihydroxy-phenyl)-4-ethyl-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,4-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,5-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,3,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-4-ethyl-6-(2,4,6-trihydroxy-phenyl)-hexanoic acid;
2-Aminomethyl-7-(2-hydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3-hydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(4-hydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dihydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dihydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dihydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dihydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dihydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dihydroxy-phenyl)-4-methyl-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,4-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,5-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,3,6-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-methyl-7-(2,4,6-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-7-(2-hydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3-hydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(4-hydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,3-dihydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,4-dihydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,5-dihydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(2,6-dihydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,4-dihydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-7-(3,5-dihydroxy-phenyl)-4-ethyl-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,5-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,6-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,4,6-trihydroxy-phenyl)-heptanoic acid;
2-Aminomethyl-4-ethyl-7-(2,3,4,5-tetrahydroxy-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,4,6-tetrahydroxy-phenyl)-heptanoic
acid;
2-Aminomethyl-4-ethyl-7-(2,3,5,6-tetrahydroxy-phenyl)-heptanoic
acid; 2-Aminomethyl-4-ethyl-7-pentahydroxyphenyl-heptanoic acid;
(2R,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic acid;
(2S,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic acid;
(2R,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
(2S,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid; (2R,4S)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(3,5-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(2-fluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-pentanoic
acid; (2S)-2-Aminomethyl-5-(2,4-difluoro-phenyl)-pentanoic acid;
(2S,4S)-2-Aminomethyl-4-(2,6-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(4-fluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(2,5-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(3-fluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-pentafluorophenylmethyl-hexanoic acid;
(2S,4R)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid; (2S,4S)-2-Aminomethyl-4-(4-trifluoromethyl-benzyl)-hexanoic
acid; 2-Aminomethyl-4-(4-methoxy-2-methyl-benzyl)-hexanoic acid;
2-Aminomethyl-5-(4-methoxy-2-methyl-phenyl)-4-methyl-pentanoic
acid; 2-Aminomethyl-4-(4-methoxy-3-methyl-benzyl)-hexanoic acid;
2-Aminomethyl-5-(4-methoxy-3-methyl-phenyl)-4-methyl-pentanoic
acid; 2-Aminomethyl-4-ethyl-5-methyl-hexanoic acid;
2-Aminomethyl-4-ethyl-3-met- hyl-hexanoic acid;
2-Aminomethyl-3,4-dimethyl-hexanoic acid;
2-Aminomethyl-3-ethyl-4-methyl-hexanoic acid;
2-Aminomethyl-4-ethyl-3-met- hyl-heptanoic acid;
2-Aminomethyl-3,4-dimethyl-octanoic acid;
2-Aminomethyl-3-methyl-pentanoic acid;
2-Aminomethyl-3-methyl-hexanoic acid;
2-Aminomethyl-3-methyl-heptanoic acid;
2-Aminomethyl-3,4-dimethyl-p- entanoic acid;
2-Aminomethyl-3,5-dimethyl-hexanoic acid;
2-Aminomethyl-3,6-dimethyl-heptanoic acid;
2-Aminomethyl-3,5,5-trimethyl-- hexanoic acid;
2-Aminomethyl-3-cyclopropyl-butyric acid;
2-Aminomethyl-3-cyclopentyl-butyric acid;
2-Aminomethyl-3-cyclohexyl-buty- ric acid;
2-Aminomethyl-4-cyclohexyl-3-methyl-butyric acid;
2-Aminomethyl-5-cyclohexyl-3-methyl-pentanoic acid;
2-Aminomethyl-3-methyl-4-(4-methyl-cyclohexyl)-butyric acid;
2-Aminomethyl-3-ethyl-pentanoic acid;
2-Aminomethyl-3-ethyl-hexanoic acid;
2-Aminomethyl-3-ethyl-heptanoic acid;
2-Aminomethyl-3-ethyl-4-methy- l-pentanoic acid;
2-Aminomethyl-3-cyclohexylmethyl-pentanoic acid;
2-Aminomethyl-5-(4-methoxy-cyclohexyl)-3-methyl-pentanoic acid;
2-Aminomethyl-5-(4-methoxy-phenyl)-3-methyl-pentanoic acid;
2-Aminomethyl-4-(2-methoxy-phenyl)-3-methyl-butyric acid;
2-Aminomethyl-4-(4-methoxy-phenyl)-3-methyl-butyric acid;
2-Aminomethyl-3-phenyl-butyric acid;
2-Aminomethyl-3-methyl-4-phenyl-buty- ric acid;
2-Aminomethyl-3-methyl-5-phenyl-pentanoic acid;
2-Aminomethyl-3-methyl-4-(3-trifluoromethyl-phenyl)-butyric acid;
2-Aminomethyl-3-(4-ethyl-phenyl)-butyric acid;
2-Aminomethyl-3-(2,5-dimet- hyl-phenyl)-butyric acid;
2-Aminomethyl-3-methyl-4-p-tolyl-butyric acid;
2-Aminomethyl-3-m-tolyl-butyric acid;
2-Aminomethyl-3-benzyl-pentanoic acid;
2-Aminomethyl-4-(4-fluoro-phenyl)-3-methyl-butyric acid;
2-Aminomethyl-5-cyclopropyl-hexanoic acid;
2-Aminomethyl-5-cyclobutyl-hex- anoic acid;
2-Aminomethyl-5-cyclopentyl-hexanoic acid;
2-Aminomethyl-5-cyclohexyl-hexanoic acid;
2-Aminomethyl-5-phenyl-hexanoic acid;
2-Aminomethyl-5-(3-chloro-phenyl)-hexanoic acid;
2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-hexanoic acid;
2-Aminomethyl-5-cyclopropyl-heptanoic acid;
2-Aminomethyl-5-cyclobutyl-he- ptanoic acid;
2-Aminomethyl-5-cyclopentyl-heptanoic acid;
2-Aminomethyl-5-cyclohexyl-heptanoic acid;
2-Aminomethyl-5-phenyl-heptano- ic acid;
2-Aminomethyl-5-(3-chloro-phenyl)-heptanoic acid;
2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-heptanoic acid;
2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-heptanoic acid;
2-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
2-Aminomethyl-6-(3-chloro-- phenyl)-5-methyl-hexanoic acid;
2-Aminomethyl-5-methyl-6-(3-trifluoromethy- l-phenyl)-hexanoic
acid; 2-Aminomethyl-5-methyl-6-(4-trifluoromethyl-pheny-
l)-hexanoic acid; 2-Aminomethyl-5-cyclopropylmethyl-heptanoic acid;
2-Aminomethyl-5-cyclobutylmethyl-heptanoic acid;
2-Aminomethyl-5-cyclopen- tylmethyl-heptanoic acid;
2-Aminomethyl-5-cyclohexylmethyl-heptanoic acid;
2-Aminomethyl-5-benzyl-heptanoic acid;
2-Aminomethyl-5-(3-chloro-benzyl)-- heptanoic acid;
2-Aminomethyl-5-(3-trifluoromethyl-benzyl)-heptanoic acid;
2-Aminomethyl-5-(4-trifluoromethyl-benzyl)-heptanoic acid;
2-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
2-Aminomethyl-7-(3-chloro- -phenyl)-5-methyl-heptanoic acid;
2-Aminomethyl-5-methyl-7-(3-trifluoromet- hyl-phenyl)-heptanoic
acid; 2-Aminomethyl-5-methyl-7-(4-trifluoromethyl-ph-
enyl)-heptanoic acid; 2-Aminomethyl-7-cyclopropyl-5-ethyl-heptanoic
acid; 2-Aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid;
2-Aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid;
2-Aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid;
2-Aminomethyl-5-ethyl-7-phenyl-heptanoic acid;
2-Aminomethyl-7-(3-chloro-- phenyl)-5-ethyl-heptanoic acid;
2-Aminomethyl-5-ethyl-7-(3-trifluoromethyl- -phenyl)-heptanoic
acid; 2-Aminomethyl-5-ethyl-7-(4-trifluoromethyl-phenyl-
)-heptanoic acid; 2-Aminomethyl-5,5-dimethyl-heptanoic acid;
2-Aminomethyl-5,5-dimethyl-octanoic acid; and
2-Aminomethyl-5,5-dimethyl-- nonanoic acid.
13. A compound selected from the following compounds and their
pharmaceutically acceptable salts:
(3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
(3S,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
(3R,4R,5R)-3-Amino-4,5-- dimethyl-heptanoic acid;
(3S,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
(3R,4S,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
(3R,4R,5S)-3-Amino-4,5-di- methyl-heptanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
(3S,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
(3R,4S,5R)-3-Amino-4,5-dim- ethyl-octanoic acid;
(3R,4R,5S)-3-Amino-4,5-dimethyl-octanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
(3S,4R,5R)-3-Amino-4,5-dim- ethyl-nonanoic acid;
(3R,4S,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
(3R,4R,5S)-3-Amino-4,5-dimethyl-nonanoic acid;
(3R,4R,5R)-3-Amino-4,5-dim- ethyl-decanoic acid;
(3S,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid;
(3R,4S,5R)-3-Amino-4,5-dimethyl-decanoic acid;
(3R,4R,5S)-3-Amino-4,5-dim- ethyl-decanoic acid; and opposite
enantiomers thereof.
14. A compound selected from the following compounds and their
pharmaceutically acceptable salts:
(3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
(3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
(3R,4R,5R)-3-Amino-4,5-dim- ethyl-nonanoic acid; and
(3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid.
15. A compound selected from the following compounds and their
pharmaceutically acceptable salts:
(2R,4R)-2-Aminomethyl-4-(2,4-difluoro-- benzyl)-hexanoic acid;
(2S,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexan- oic acid;
(2R,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
(2S,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid; (2R,4S)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(3,5-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(2-fluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-pentanoic
acid; (2S)-2-Aminomethyl-5-(2,4-difluoro-phenyl)-pentanoic acid;
(2S,4S)-2-Aminomethyl-4-(2,6-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(4-fluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(2,5-difluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-(3-fluoro-benzyl)-hexanoic acid;
(2S,4S)-2-Aminomethyl-4-pentafluorophenylmethyl-hexanoic acid;
(2S,4R)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid; and
(2S,4S)-2-Aminomethyl-4-(4-trifluoromethyl-benzyl)-hexanoic
acid.
16. A compound selected from a succinic acid complex of
(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and a succinic acid
complex of (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid.
17. The compound of claim 16, wherein the molar ratio of succinic
acid to (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid or to
(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid is 1:6.
18. The compound of claim 16, wherein the succinic acid complex of
(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid or the succinic acid
complex of (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid is a
hydrate.
19. The compound of claim 18, wherein the molar ratio of succinic
acid to water and to (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid
or to (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid is 1:1:6.
20. A compound selected from a sulfuric acid salt of
(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and a sulfuric acid
salt of (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/505,953, filed Sep. 25, 2003, and U.S.
Provisional Application No. 60/507,443, filed Sep. 30, 2003, the
complete disclosures of which are 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 provides compounds of formula I, 1
[0004] and their pharmaceutically acceptable salts, wherein
[0005] R.sub.1 is a hydrogen atom or (C.sub.1-C.sub.6)alkyl
optionally substituted with from one to five fluorine atoms;
[0006] R.sub.2 is a hydrogen atom or (C.sub.1-C.sub.6)alkyl
optionally substituted with from one to five fluorine atoms; or
[0007] R.sub.1 and R.sub.2, together with the carbon to which they
are attached, form a three- to six-membered cycloalkyl ring;
[0008] R.sub.3 is a hydrogen atom, (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, or
pyridyl-(C.sub.1-C.sub.3)alkyl, wherein the alkyl and cycloalkyl
moieties or substituents are optionally substituted with from one
to five fluorine atoms, preferably with from zero to three fluorine
atoms, and the phenyl and pyridyl substituents and the phenyl and
pyridyl moieties of the phenyl-(C.sub.1-C.sub.3)alkyl and the
pyridyl-(C.sub.1-C.sub.3)alkyl substituents are optionally
substituted with from one to five substituents, preferably with
from zero to two substituents, independently selected from chloro,
fluoro, amino, nitro, cyano, hydroxy, (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;
[0009] R.sub.4 is a hydrogen atom or (C.sub.1-C.sub.6)alkyl
optionally substituted with from one to five fluorine atoms;
[0010] R.sub.5 is a hydrogen atom or (C.sub.1-C.sub.6)alkyl
optionally substituted with from one to five fluorine atoms;
[0011] R.sub.4 and R.sub.5, together with the carbon to which they
are attached, form a three- to six-membered cycloalkyl ring;
and
[0012] R.sub.6 is a hydrogen atom or (C.sub.1-C.sub.6)alkyl;
[0013] with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are not simultaneously hydrogen atoms.
[0014] Specific compounds of formula I include the following
compounds and their pharmaceutically acceptable salts:
[0015] 3-Amino-4,5-dimethyl-hexanoic acid;
[0016] 3-Amino-4,5-dimethyl-heptanoic acid;
[0017] 3-Amino-4,5-dimethyl-octanoic acid;
[0018] 3-Amino-4,5-dimethyl-nonanoic acid;
[0019] 3-Amino-4,5-dimethyl-decanoic acid;
[0020] 3-Amino-4-ethyl-5-methyl-heptanoic acid;
[0021] 3-Amino-4-ethyl-5-methyl-octanoic acid;
[0022] 3-Amino-4-ethyl-5-methyl-nonanoic acid;
[0023] 3-Amino-4-ethyl-5,6-dimethyl-heptanoic acid;
[0024] 3-Amino-4-ethyl-5,7-dimethyl-octanoic acid;
[0025] 3-Amino-4-ethyl-5,8-dimethyl-nonanoic acid;
[0026] 3-Amino-5-ethyl-4-methyl-octanoic acid;
[0027] 3-Amino-5-ethyl-4-methyl-nonanoic acid;
[0028] 3-Amino-4,5-diethyl-heptanoic acid;
[0029] 3-Amino-4,5-diethyl-octanoic acid;
[0030] 3-Amino-4,5-diethyl-nonanoic acid;
[0031] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[0032] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[0033] 3-Amino-4,5-diethyl-6-methyl-heptanoic acid;
[0034] 3-Amino-4,5-diethyl-7-methyl-octanoic acid;
[0035] 3-Amino-4,5-diethyl-8-methyl-nonanoic acid;
[0036] 3-Amino-4,5,6-trimethyl-heptanoic acid;
[0037] 3-Amino-4,5,7-trimethyl-octanoic acid;
[0038] 3-Amino-4,5,8-trimethyl-nonanoic acid;
[0039] 3-Amino-4-ethyl-5-methyl-hexanoic acid;
[0040] 3-Amino-5-ethyl-4-methyl-octanoic acid;
[0041] 3-Amino-5-ethyl-4-methyl-heptanoic acid;
[0042] 3-Amino-4-methyl-5-propyl-octanoic acid;
[0043] 3-Amino-4-methyl-6-ethyl-octanoic acid;
[0044] 3-Amino-4-methyl-6-ethyl-nonanoic acid;
[0045] 3-Amino-4,6-diethyl-octanoic acid;
[0046] 3-Amino-4,6-diethyl-nonanoic acid;
[0047] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[0048] 3-Amino-7-cyclopentyl-4,5-dimethyl-heptanoic acid;
[0049] 3-Amino-5-ethyl-4,6-dimethyl-heptanoic acid;
[0050] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[0051] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[0052] (3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
[0053] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
[0054] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
[0055] (3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
[0056] (3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid;
[0057] 3-Amino-5-cyclopropyl-4-ethyl-hexanoic acid;
[0058] 3-Amino-6-cyclopropyl-4-ethyl-5-methyl-hexanoic acid;
[0059] 3-Amino-5-cyclobutyl-4-ethyl-hexanoic acid;
[0060] 3-Amino-6-cyclobutyl-4-ethyl-5-methyl-hexanoic acid;
[0061] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[0062] 3-Amino-6-cyclopentyl-4-ethyl-5-methyl-hexanoic acid;
[0063] 3-Amino-5-cyclohexyl-4-ethyl-hexanoic acid;
[0064] 3-Amino-6-cyclohexyl-4-ethyl-5-methyl-hexanoic acid;
[0065] 3-Amino-5-cyclopropyl-4-methyl-hexanoic acid;
[0066] 3-Amino-6-cyclopropyl-4,5-dimethyl-hexanoic acid;
[0067] 3-Amino-5-cyclobutyl-4-methyl-hexanoic acid;
[0068] 3-Amino-6-cyclobutyl-4,5-dimethyl-hexanoic acid;
[0069] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[0070] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[0071] 3-Amino-5-cyclohexyl-4-methyl-hexanoic acid;
[0072] 3-Amino-6-cyclohexyl-4,5-dimethyl-hexanoic acid;
[0073] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid;
[0074] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid;
[0075] 3-Amino-4,6-dimethyl-heptanoic acid;
[0076] 3-Amino-4,6-dimethyl-octanoic acid;
[0077] 3-Amino-4,6-dimethyl-nonanoic acid;
[0078] 3-Amino-4,6-dimethyl-decanoic acid;
[0079] 3-Amino-4,6,7-trimethyl-octanoic acid;
[0080] 3-Amino-4,6,8-trimethyl-nonanoic acid;
[0081] 3-Amino-4,6,9-trimethyl-decanoic acid;
[0082] 3-Amino-6-cyclopropyl-4-methyl-heptanoic acid;
[0083] 3-Amino-6-cyclobutyl-4-methyl-heptanoic acid;
[0084] 3-Amino-6-cyclopentyl-4-methyl-heptanoic acid;
[0085] 3-Amino-6-cyclohexyl-4-methyl-heptanoic acid;
[0086] 3-Amino-7-cyclopropyl-4,6-dimethyl-heptanoic acid;
[0087] 3-Amino-7-cyclobutyl-4,6-dimethyl-heptanoic acid;
[0088] 3-Amino-7-cyclopentyl-4,6-dimethyl-heptanoic acid;
[0089] 3-Amino-7-cyclohexyl-4,6-dimethyl-heptanoic acid;
[0090] 3-Amino-8-cyclopropyl-4,6-dimethyl-octanoic acid;
[0091] 3-Amino-8-cyclobutyl-4,6-dimethyl-octanoic acid;
[0092] 3-Amino-8-cyclopentyl-4,6-dimethyl-octanoic acid;
[0093] 3-Amino-8-cyclohexyl-4,6-dimethyl-octanoic acid;
[0094] 3-Amino-6-(3-chloro-phenyl)-4-methyl-heptanoic acid;
[0095] 3-Amino-6-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
[0096] 3-Amino-4-methyl-6-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[0097] 3-Amino-4-methyl-6-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[0098] 3-Amino-7-(3-chloro-phenyl)-4,6-dimethyl-heptanoic acid;
[0099] 3-Amino-7-(3,4-dichloro-phenyl)-4,6-dimethyl-heptanoic
acid;
[0100] 3-Amino-4,6-dimethyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[0101] 3-Amino-4,6-dimethyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[0102] 3-Amino-8-(3-chloro-phenyl)-4,6-dimethyl-octanoic acid;
[0103] 3-Amino-8-(3,4-dichloro-phenyl)-4,6-dimethyl-octanoic
acid;
[0104] 3-Amino-4,6-dimethyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid;
[0105] 3-Amino-4,6-dimethyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid;
[0106] 3-Amino-4-ethyl-6-methyl-octanoic acid;
[0107] 3-Amino-4-ethyl-6-methyl-nonanoic acid;
[0108] 3-Amino-4-ethyl-6-methyl-decanoic acid;
[0109] 3-Amino-4-ethyl-6,7-dimethyl-octanoic acid;
[0110] 3-Amino-4-ethyl-6,8-dimethyl-nonanoic acid;
[0111] 3-Amino-4-ethyl-6,9-dimethyl-decanoic acid;
[0112] 3-Amino-6-cyclopropyl-4-ethyl-heptanoic acid;
[0113] 3-Amino-6-cyclobutyl-4-ethyl-heptanoic acid;
[0114] 3-Amino-6-cyclopentyl-4-ethyl-heptanoic acid;
[0115] 3-Amino-6-cyclohexyl-4-ethyl-heptanoic acid;
[0116] 3-Amino-7-cyclopropyl-4-ethyl-6-methyl-heptanoic acid;
[0117] 3-Amino-7-cyclobutyl-4-ethyl-6-methyl-heptanoic acid;
[0118] 3-Amino-7-cyclopentyl-4-ethyl-6-methyl-heptanoic acid;
[0119] 3-Amino-7-cyclohexyl-4-ethyl-6-methyl-heptanoic acid;
[0120] 3-Amino-8-cyclopropyl-4-ethyl-6-methyl-octanoic acid;
[0121] 3-Amino-8-cyclobutyl-4-ethyl-6-methyl-octanoic acid;
[0122] 3-Amino-8-cyclopentyl-4-ethyl-6-methyl-octanoic acid;
[0123] 3-Amino-8-cyclohexyl-4-ethyl-6-methyl-octanoic acid;
[0124] 3-Amino-6-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
[0125] 3-Amino-6-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
[0126] 3-Amino-4-ethyl-6-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[0127] 3-Amino-4-ethyl-6-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[0128] 3-Amino-7-(3-chloro-phenyl)-4-ethyl-6-methyl-heptanoic
acid;
[0129] 3-Amino-7-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-heptanoic
acid;
[0130]
3-Amino-4-ethyl-6-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[0131]
3-Amino-4-ethyl-6-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[0132] 3-Amino-8-(3-chloro-phenyl)-4-ethyl-6-methyl-octanoic
acid;
[0133] 3-Amino-8-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-octanoic
acid;
[0134]
3-Amino-4-ethyl-6-methyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid;
[0135]
3-Amino-4-ethyl-6-methyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid;
[0136] 3-Amino-4-methyl-heptanoic acid;
[0137] 3-Amino-4,6-dimethyl-heptanoic acid;
[0138] 3-Amino-4,7-dimethyl-octanoic acid;
[0139] 3-Amino-4,8-dimethyl-nonanoic acid;
[0140] 3-Amino-4-methyl-hexanoic acid;
[0141] 3-Amino-4-methyl-heptanoic acid;
[0142] 3-Amino-4-methyl-octanoic acid;
[0143] 3-Amino-4-methyl-nonanoic acid;
[0144] 3-Amino-5-cyclopropyl-4-methyl-pentanoic acid;
[0145] 3-Amino-6-cyclopropyl-4-methyl-hexanoic acid;
[0146] 3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;
[0147] 3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;
[0148] 3-Amino-6-cyclobutyl-4-methyl-hexanoic acid;
[0149] 3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;
[0150] 3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;
[0151] 3-Amino-6-cyclopentyl-4-methyl-hexanoic acid;
[0152] 3-Amino-7-cyclopentyl-4-methyl-heptanoic acid;
[0153] 3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;
[0154] 3-Amino-6-cyclohexyl-4-methyl-hexanoic acid;
[0155] 3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;
[0156] 3-Amino-5-cyclopropyl-4-ethyl-pentanoic acid;
[0157] 3-Amino-6-cyclopropyl-4-ethyl-hexanoic acid;
[0158] 3-Amino-7-cyclopropyl-4-ethyl-heptanoic acid;
[0159] 3-Amino-5-cyclobutyl-4-ethyl-pentanoic acid;
[0160] 3-Amino-6-cyclobutyl-4-ethyl-hexanoic acid;
[0161] 3-Amino-7-cyclobutyl-4-ethyl-heptanoic acid;
[0162] 3-Amino-5-cyclopentyl-4-ethyl-pentanoic acid;
[0163] 3-Amino-6-cyclopentyl-4-ethyl-hexanoic acid;
[0164] 3-Amino-7-cyclopentyl-4-ethyl-heptanoic acid;
[0165] 3-Amino-5-cyclohexyl-4-ethyl-pentanoic acid;
[0166] 3-Amino-6-cyclohexyl-4-ethyl-hexanoic acid;
[0167] 3-Amino-7-cyclohexyl-4-ethyl-heptanoic acid;
[0168] 3-Amino-4,4,5-trimethyl-heptanoic acid;
[0169] 3-Amino-4,4,5-trimethyl-octanoic acid;
[0170] 3-Amino-4,4,5-trimethyl-hexanoic acid;
[0171] 3-Amino-4,5,5-trimethyl-heptanoic acid;
[0172] 3-Amino-4,5,5-trimethyl-octanoic acid; and
[0173] 3-Amino-4,5,5-trimethyl-hexanoic acid.
[0174] Other compounds of formula I include the following
compounds, and their pharmaceutically acceptable salts:
[0175] 3-Amino-4-methyl-5-phenyl-pentanoic acid;
[0176] 3-Amino-4-methyl-6-phenyl-hexanoic acid;
[0177] 3-Amino-4-methyl-7-phenyl-heptanoic acid;
[0178] 3-Amino-5-(2-chloro-phenyl)-4-methyl-pentanoic acid;
[0179] 3-Amino-5-(3-chloro-phenyl)-4-methyl-pentanoic acid;
[0180] 3-Amino-5-(4-chloro-phenyl)-4-methyl-pentanoic acid;
[0181] 3-Amino-5-(2,4-dichloro-phenyl)-4-methyl-pentanoic acid;
[0182] 3-Amino-5-(3,4-dichloro-phenyl)-4-methyl-pentanoic acid;
[0183] 3-Amino-4-(2-chloro-benzyl)-hexanoic acid;
[0184] 3-Amino-4-(3-chloro-benzyl)-hexanoic acid;
[0185] 3-Amino-4-(4-chloro-benzyl)-hexanoic acid;
[0186] 3-Amino-4-(2,4-dichloro-benzyl)-hexanoic acid;
[0187] 3-Amino-4-(3,4-dichloro-benzyl)-hexanoic acid;
[0188] 3-Amino-6-(2-chloro-phenyl)-4-methyl-hexanoic acid;
[0189] 3-Amino-6-(3-chloro-phenyl)-4-methyl-hexanoic acid;
[0190] 3-Amino-6-(4-chloro-phenyl)-4-methyl-hexanoic acid;
[0191] 3-Amino-6-(2,4-dichloro-phenyl)-4-methyl-hexanoic acid;
[0192] 3-Amino-6-(3,4-dichloro-phenyl)-4-methyl-hexanoic acid;
[0193] 3-Amino-6-(2-chloro-phenyl)-4-ethyl-hexanoic acid;
[0194] 3-Amino-6-(3-chloro-phenyl)-4-ethyl-hexanoic acid;
[0195] 3-Amino-6-(4-chloro-phenyl)-4-ethyl-hexanoic acid;
[0196] 3-Amino-6-(2,4-dichloro-phenyl)-4-ethyl-hexanoic acid;
[0197] 3-Amino-6-(3,4-dichloro-phenyl)-4-ethyl-hexanoic acid;
[0198] 3-Amino-7-(2-chloro-phenyl)-4-methyl-heptanoic acid;
[0199] 3-Amino-7-(3-chloro-phenyl)-4-methyl-heptanoic acid;
[0200] 3-Amino-7-(4-chloro-phenyl)-4-methyl-heptanoic acid;
[0201] 3-Amino-7-(2,4-dichloro-phenyl)-4-methyl-heptanoic acid;
[0202] 3-Amino-7-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
[0203] 3-Amino-7-(2-chloro-phenyl)-4-ethyl-heptanoic acid;
[0204] 3-Amino-7-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
[0205] 3-Amino-7-(4-chloro-phenyl)-4-ethyl-heptanoic acid;
[0206] 3-Amino-7-(2,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
and
[0207] 3-Amino-7-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid.
[0208] This invention also provides compounds of formula II 2
[0209] and their pharmaceutically acceptable salts, wherein
R.sub.1, R.sub.3, and R.sub.4 are as defined above in formula I,
with the proviso that R.sub.1 is not a hydrogen atom.
[0210] Specific compounds of formula II include the following
compounds and their pharmaceutically acceptable salts:
[0211] 3-Amino-4,5-dimethyl-hexanoic acid;
[0212] 3-Amino-4,5-dimethyl-heptanoic acid;
[0213] 3-Amino-4,5-dimethyl-octanoic acid;
[0214] 3-Amino-4,5-dimethyl-nonanoic acid;
[0215] 3-Amino-4-ethyl-5-methyl-heptanoic acid;
[0216] 3-Amino-4-ethyl-5-methyl-octanoic acid;
[0217] 3-Amino-4-ethyl-5-methyl-nonanoic acid;
[0218] 3-Amino-4-ethyl-5,6-dimethyl-heptanoic acid;
[0219] 3-Amino-4-ethyl-5,7-dimethyl-octanoic acid;
[0220] 3-Amino-4-ethyl-5,8-dimethyl-nonanoic acid;
[0221] 3-Amino-5-ethyl-4-methyl-octanoic acid;
[0222] 3-Amino-5-ethyl-4-methyl-nonanoic acid;
[0223] 3-Amino-4,5-diethyl-heptanoic acid;
[0224] 3-Amino-4,5-diethyl-octanoic acid;
[0225] 3-Amino-4,5-diethyl-nonanoic acid;
[0226] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[0227] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[0228] 3-Amino-4,5-diethyl-6-methyl-heptanoic acid;
[0229] 3-Amino-4,5-diethyl-7-methyl-octanoic acid;
[0230] 3-Amino-4,5-diethyl-8-methyl-nonanoic acid;
[0231] 3-Amino-4,5,6-trimethyl-heptanoic acid;
[0232] 3-Amino-4,5,7-trimethyl-octanoic acid;
[0233] 3-Amino-4,5,8-trimethyl-nonanoic acid;
[0234] 3-Amino-4-ethyl-5-methyl-hexanoic acid;
[0235] 3-Amino-5-ethyl-4-methyl-octanoic acid;
[0236] 3-Amino-5-ethyl-4-methyl-heptanoic acid;
[0237] 3-Amino-4-methyl-5-propyl-octanoic acid;
[0238] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[0239] 3-Amino-7-cyclopentyl-4,5-dimethyl-heptanoic acid;
[0240] 3-Amino-5-ethyl-4,6-dimethyl-heptanoic acid;
[0241] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[0242] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[0243] (3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
[0244] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
[0245] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
[0246] (3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
[0247] (3R,4R,5R)-3-Amino-4,5-decanoic acid;
[0248] 3-Amino-5-cyclopropyl-4-ethyl-hexanoic acid;
[0249] 3-Amino-6-cyclopropyl-4-ethyl-5-methyl-hexanoic acid;
[0250] 3-Amino-5-cyclobutyl-4-ethyl-hexanoic acid;
[0251] 3-Amino-6-cyclobutyl-4-ethyl-5-methyl-hexanoic acid;
[0252] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[0253] 3-Amino-6-cyclopentyl-4-ethyl-5-methyl-hexanoic acid;
[0254] 3-Amino-5-cyclohexyl-4-ethyl-hexanoic acid;
[0255] 3-Amino-6-cyclohexyl-4-ethyl-5-methyl-hexanoic acid;
[0256] 3-Amino-5-cyclopropyl-4-methyl-hexanoic acid;
[0257] 3-Amino-6-cyclopropyl-4,5-dimethyl-hexanoic acid;
[0258] 3-Amino-5-cyclobutyl-4-methyl-hexanoic acid;
[0259] 3-Amino-6-cyclobutyl-4,5-dimethyl-hexanoic acid;
[0260] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[0261] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[0262] 3-Amino-5-cyclohexyl-4-methyl-hexanoic acid;
[0263] 3-Amino-6-cyclohexyl-4,5-dimethyl-hexanoic acid;
[0264] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid and
[0265] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid.
[0266] This invention also provides compounds of formula III 3
[0267] and their pharmaceutically acceptable salts, wherein R.sub.1
and R.sub.3 are as defined above in formula I, with the proviso
that R.sub.1 and R.sub.3 are not hydrogen atoms.
[0268] Specific compounds of formula III include the following
compounds and their pharmaceutically acceptable salts:
[0269] 3-Amino-4,5-dimethyl-hexanoic acid;
[0270] 3-Amino-4,5-dimethyl-heptanoic acid;
[0271] 3-Amino-4,5-dimethyl-octanoic acid;
[0272] 3-Amino-4,5-dimethyl-nonanoic acid;
[0273] 3-Amino-4,5,6-trimethyl-heptanoic acid;
[0274] 3-Amino-4,5,7-trimethyl-octanoic acid;
[0275] 3-Amino-4,5,8-trimethyl-nonanoic acid;
[0276] 3-Amino-4-methyl-5-propyl-octanoic acid;
[0277] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[0278] 3-Amino-7-cyclopentyl-4,5-dimethyl-heptanoic acid;
[0279] 3-Amino-5-ethyl-4,6-dimethyl-heptanoic acid;
[0280] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[0281] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[0282] (3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
[0283] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
[0284] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
[0285] (3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
[0286] (3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid;
[0287] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[0288] 3-Amino-5-cyclopropyl-4-methyl-hexanoic acid;
[0289] 3-Amino-6-cyclopropyl-4,5-dimethyl-hexanoic acid;
[0290] 3-Amino-5-cyclobutyl-4-methyl-hexanoic acid;
[0291] 3-Amino-6-cyclobutyl-4,5-dimethyl-hexanoic acid;
[0292] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[0293] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[0294] 3-Amino-5-cyclohexyl-4-methyl-hexanoic acid;
[0295] 3-Amino-6-cyclohexyl-4,5-dimethyl-hexanoic acid;
[0296] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid and
[0297] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid.
[0298] This invention also provides compounds of formula IV 4
[0299] and their pharmaceutically acceptable salts, wherein R.sub.3
is as defined above in formula I, with the proviso that R.sub.3 is
not a hydrogen atom.
[0300] Specific compounds of formula IV include the following
compounds and their pharmaceutically acceptable salts:
[0301] (3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
[0302] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
[0303] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
[0304] (3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid and
[0305] (3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid.
[0306] This invention also relates to compounds of formula V 5
[0307] and their pharmaceutically acceptable salts, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as defined
above in formula I, with the proviso that R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are not simultaneously hydrogen
atoms.
[0308] Specific compounds of formula V include the following
compounds and their pharmaceutically acceptable salts:
[0309] 2-Aminomethyl-4-(2-fluoro-phenyl)-pentanoic acid;
[0310] 2-Aminomethyl-4-(3-fluoro-phenyl)-pentanoic acid;
[0311] 2-Aminomethyl-4-(4-fluoro-phenyl)-pentanoic acid;
[0312] 2-Aminomethyl-4-(2,3-difluoro-phenyl)-pentanoic acid;
[0313] 2-Aminomethyl-4-(2,4-difluoro-phenyl)-pentanoic acid;
[0314] 2-Aminomethyl-4-(2,5-difluoro-phenyl)-pentanoic acid;
[0315] 2-Aminomethyl-4-(2,6-difluoro-phenyl)-pentanoic acid;
[0316] 2-Aminomethyl-4-(3,4-difluoro-phenyl)-pentanoic acid;
[0317] 2-Aminomethyl-4-(3,5-difluoro-phenyl)-pentanoic acid;
[0318] 2-Aminomethyl-4-(2,3,4-trifluoro-phenyl)-pentanoic acid;
[0319] 2-Aminomethyl-4-(2,3,5-trifluoro-phenyl)-pentanoic acid;
[0320] 2-Aminomethyl-4-(2,3,6-trifluoro-phenyl)-pentanoic acid;
[0321] 2-Aminomethyl-4-(2,4,6-trifluoro-phenyl)-pentanoic acid;
[0322] 2-Aminomethyl-4-(2,3,4,5-tetrafluoro-phenyl)-pentanoic
acid;
[0323] 2-Aminomethyl-4-(2,3,4,6-tetrafluoro-phenyl)-pentanoic
acid;
[0324] 2-Aminomethyl-4-(2,3,5,6-tetrafluoro-phenyl)-pentanoic
acid;
[0325] 2-Aminomethyl-4-pentafluorophenyl-pentanoic acid;
[0326] 2-Aminomethyl-4-(2-fluoro-phenyl)-hexanoic acid;
[0327] 2-Aminomethyl-4-(3-fluoro-phenyl)-hexanoic acid;
[0328] 2-Aminomethyl-4-(4-fluoro-phenyl)-hexanoic acid;
[0329] 2-Aminomethyl-4-(2,3-difluoro-phenyl)-hexanoic acid;
[0330] 2-Aminomethyl-4-(2,4-difluoro-phenyl)-hexanoic acid;
[0331] 2-Aminomethyl-4-(2,5-difluoro-phenyl)-hexanoic acid;
[0332] 2-Aminomethyl-4-(2,6-difluoro-phenyl)-hexanoic acid;
[0333] 2-Aminomethyl-4-(3,4-difluoro-phenyl)-hexanoic acid;
[0334] 2-Aminomethyl-4-(3,5-difluoro-phenyl)-hexanoic acid;
[0335] 2-Aminomethyl-4-(2,3,4-trifluoro-phenyl)-hexanoic acid;
[0336] 2-Aminomethyl-4-(2,3,5-trifluoro-phenyl)-hexanoic acid;
[0337] 2-Aminomethyl-4-(2,3,6-trifluoro-phenyl)-hexanoic acid;
[0338] 2-Aminomethyl-4-(2,4,6-trifluoro-phenyl)-hexanoic acid;
[0339] 2-Aminomethyl-4-(2,3,4,5-tetrafluoro-phenyl)-hexanoic
acid;
[0340] 2-Aminomethyl-4-(2,3,4,6-tetrafluoro-phenyl)-hexanoic
acid;
[0341] 2-Aminomethyl-4-(2,3,5,6-tetrafluoro-phenyl)-hexanoic
acid;
[0342] 2-Aminomethyl-4-pentafluorophenyl-hexanoic acid;
[0343] 2-Aminomethyl-5-(2-fluoro-phenyl)-4-methyl-pentanoic
acid;
[0344] 2-Aminomethyl-5-(3-fluoro-phenyl)-4-methyl-pentanoic
acid;
[0345] 2-Aminomethyl-5-(4-fluoro-phenyl)-4-methyl-pentanoic
acid;
[0346] 2-Aminomethyl-5-(2,3-difluoro-phenyl)-4-methyl-pentanoic
acid;
[0347] 2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-pentanoic
acid;
[0348] 2-Aminomethyl-5-(2,5-difluoro-phenyl)-4-methyl-pentanoic
acid;
[0349] 2-Aminomethyl-5-(2,6-difluoro-phenyl)-4-methyl-pentanoic
acid;
[0350] 2-Aminomethyl-5-(3,4-difluoro-phenyl)-4-methyl-pentanoic
acid;
[0351] 2-Aminomethyl-5-(3,5-difluoro-phenyl)-4-methyl-pentanoic
acid;
[0352] 2-Aminomethyl-4-methyl-5-(2,3,4-trifluoro-phenyl)-pentanoic
acid;
[0353] 2-Aminomethyl-4-methyl-5-(2,3,5-trifluoro-phenyl)-pentanoic
acid;
[0354] 2-Aminomethyl-4-methyl-5-(2,3,6-trifluoro-phenyl)-pentanoic
acid;
[0355] 2-Aminomethyl-4-methyl-5-(2,4,6-trifluoro-phenyl)-pentanoic
acid;
[0356]
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrafluoro-phenyl)-pentanoic
acid;
[0357]
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrafluoro-phenyl)-pentanoic
acid;
[0358]
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrafluoro-phenyl)-pentanoic
acid;
[0359] 2-Aminomethyl-4-methyl-5-pentafluorophenyl-pentanoic
acid;
[0360] 2-Aminomethyl-5-(2-fluoro-phenyl)-4-methyl-hexanoic
acid;
[0361] 2-Aminomethyl-5-(3-fluoro-phenyl)-4-methyl-hexanoic
acid;
[0362] 2-Aminomethyl-5-(4-fluoro-phenyl)-4-methyl-hexanoic
acid;
[0363] 2-Aminomethyl-5-(2,3-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0364] 2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0365] 2-Aminomethyl-5-(2,5-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0366] 2-Aminomethyl-5-(2,6-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0367] 2-Aminomethyl-5-(3,4-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0368] 2-Aminomethyl-5-(3,5-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0369] 2-Aminomethyl-4-methyl-5-(2,3,4-trifluoro-phenyl)-hexanoic
acid;
[0370] 2-Aminomethyl-4-methyl-5-(2,3,5-trifluoro-phenyl)-hexanoic
acid;
[0371] 2-Aminomethyl-4-methyl-5-(2,3,6-trifluoro-phenyl)-hexanoic
acid;
[0372] 2-Aminomethyl-4-methyl-5-(2,4,6-trifluoro-phenyl)-hexanoic
acid;
[0373]
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrafluoro-phenyl)-hexanoic
acid;
[0374]
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrafluoro-phenyl)-hexanoic
acid;
[0375]
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrafluoro-phenyl)-hexanoic
acid;
[0376] 2-Aminomethyl-4-methyl-5-pentafluorophenyl-hexanoic
acid;
[0377] 2-Aminomethyl-6-(2-fluoro-phenyl)-4-methyl-hexanoic
acid;
[0378] 2-Aminomethyl-6-(3-fluoro-phenyl)-4-methyl-hexanoic
acid;
[0379] 2-Aminomethyl-6-(4-fluoro-phenyl)-4-methyl-hexanoic
acid;
[0380] 2-Aminomethyl-6-(2,3-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0381] 2-Aminomethyl-6-(2,4-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0382] 2-Aminomethyl-6-(2,5-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0383] 2-Aminomethyl-6-(2,6-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0384] 2-Aminomethyl-6-(3,4-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0385] 2-Aminomethyl-6-(3,5-difluoro-phenyl)-4-methyl-hexanoic
acid;
[0386] 2-Aminomethyl-4-methyl-6-(2,3,4-trifluoro-phenyl)-hexanoic
acid;
[0387] 2-Aminomethyl-4-methyl-6-(2,3,5-trifluoro-phenyl)-hexanoic
acid;
[0388] 2-Aminomethyl-4-methyl-6-(2,3,6-trifluoro-phenyl)-hexanoic
acid;
[0389] 2-Aminomethyl-4-methyl-6-(2,4,6-trifluoro-phenyl)-hexanoic
acid;
[0390]
2-Aminomethyl-4-methyl-6-(2,3,4,5-tetrafluoro-phenyl)-hexanoic
acid;
[0391]
2-Aminomethyl-4-methyl-6-(2,3,4,6-tetrafluoro-phenyl)-hexanoic
acid;
[0392]
2-Aminomethyl-4-methyl-6-(2,3,5,6-tetrafluoro-phenyl)-hexanoic
acid;
[0393] 2-Aminomethyl-4-methyl-6-pentafluorophenyl-hexanoic
acid;
[0394] 2-Aminomethyl-5-(2-fluoro-phenyl)-4-ethyl-pentanoic
acid;
[0395] 2-Aminomethyl-5-(3-fluoro-phenyl)-4-ethyl-pentanoic
acid;
[0396] 2-Aminomethyl-5-(4-fluoro-phenyl)-4-ethyl-pentanoic
acid;
[0397] 2-Aminomethyl-5-(2,3-difluoro-phenyl)-4-ethyl-pentanoic
acid;
[0398] 2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-ethyl-pentanoic
acid;
[0399] 2-Aminomethyl-5-(2,5-difluoro-phenyl)-4-ethyl-pentanoic
acid;
[0400] 2-Aminomethyl-5-(2,6-difluoro-phenyl)-4-ethyl-pentanoic
acid;
[0401] 2-Aminomethyl-5-(3,4-difluoro-phenyl)-4-ethyl-pentanoic
acid;
[0402] 2-Aminomethyl-5-(3,5-difluoro-phenyl)-4-ethyl-pentanoic
acid;
[0403] 2-Aminomethyl-4-ethyl-5-(2,3,4-trifluoro-phenyl)-pentanoic
acid;
[0404] 2-Aminomethyl-4-ethyl-5-(2,3,5-trifluoro-phenyl)-pentanoic
acid;
[0405] 2-Aminomethyl-4-ethyl-5-(2,3,6-trifluoro-phenyl)-pentanoic
acid;
[0406] 2-Aminomethyl-4-ethyl-5-(2,4,6-trifluoro-phenyl)-pentanoic
acid;
[0407]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetrafluoro-phenyl)-pentanoic
acid;
[0408]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetrafluoro-phenyl)-pentanoic
acid;
[0409]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetrafluoro-phenyl)-pentanoic
acid;
[0410] 2-Aminomethyl-4-ethyl-5-pentafluorophenyl-pentanoic
acid;
[0411] 2-Aminomethyl-6-(2-fluoro-phenyl)-4-ethyl-hexanoic acid;
[0412] 2-Aminomethyl-6-(3-fluoro-phenyl)-4-ethyl-hexanoic acid;
[0413] 2-Aminomethyl-6-(4-fluoro-phenyl)-4-ethyl-hexanoic acid;
[0414] 2-Aminomethyl-6-(2,3-difluoro-phenyl)-4-ethyl-hexanoic
acid;
[0415] 2-Aminomethyl-6-(2,4-difluoro-phenyl)-4-ethyl-hexanoic
acid;
[0416] 2-Aminomethyl-6-(2,5-difluoro-phenyl)-4-ethyl-hexanoic
acid;
[0417] 2-Aminomethyl-6-(2,6-difluoro-phenyl)-4-ethyl-hexanoic
acid;
[0418] 2-Aminomethyl-6-(3,4-difluoro-phenyl)-4-ethyl-hexanoic
acid;
[0419] 2-Aminomethyl-6-(3,5-difluoro-phenyl)-4-ethyl-hexanoic
acid;
[0420] 2-Aminomethyl-4-ethyl-6-(2,3,4-trifluoro-phenyl)-hexanoic
acid;
[0421] 2-Aminomethyl-4-ethyl-6-(2,3,5-trifluoro-phenyl)-hexanoic
acid;
[0422] 2-Aminomethyl-4-ethyl-6-(2,3,6-trifluoro-phenyl)-hexanoic
acid;
[0423] 2-Aminomethyl-4-ethyl-6-(2,4,6-trifluoro-phenyl)-hexanoic
acid;
[0424]
2-Aminomethyl-4-ethyl-6-(2,3,4,5-tetrafluoro-phenyl)-hexanoic
acid;
[0425]
2-Aminomethyl-4-ethyl-6-(2,3,4,6-tetrafluoro-phenyl)-hexanoic
acid;
[0426]
2-Aminomethyl-4-ethyl-6-(2,3,5,6-tetrafluoro-phenyl)-hexanoic
acid;
[0427] 2-Aminomethyl-4-ethyl-6-pentafluorophenyl-hexanoic acid;
[0428] 2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic
acid;
[0429] 2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic
acid;
[0430] 2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic
acid;
[0431] 2-Aminomethyl-7-(2,3-difluoro-phenyl)-4-methyl-heptanoic
acid;
[0432] 2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic
acid;
[0433] 2-Aminomethyl-7-(2,5-difluoro-phenyl)-4-methyl-heptanoic
acid;
[0434] 2-Aminomethyl-7-(2,6-difluoro-phenyl)-4-methyl-heptanoic
acid;
[0435] 2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic
acid;
[0436] 2-Aminomethyl-7-(3,5-difluoro-phenyl)-4-methyl-heptanoic
acid;
[0437] 2-Aminomethyl-4-methyl-7-(2,3,4-trifluoro-phenyl)-heptanoic
acid;
[0438] 2-Aminomethyl-4-methyl-7-(2,3,5-trifluoro-phenyl)-heptanoic
acid;
[0439] 2-Aminomethyl-4-methyl-7-(2,3,6-trifluoro-phenyl)-heptanoic
acid;
[0440] 2-Aminomethyl-4-methyl-7-(2,4,6-trifluoro-phenyl)-heptanoic
acid;
[0441]
2-Aminomethyl-4-methyl-7-(2,3,4,5-tetrafluoro-phenyl)-heptanoic
acid;
[0442]
2-Aminomethyl-4-methyl-7-(2,3,4,6-tetrafluoro-phenyl)-heptanoic
acid;
[0443]
2-Aminomethyl-4-methyl-7-(2,3,5,6-tetrafluoro-phenyl)-heptanoic
acid;
[0444] 2-Aminomethyl-4-methyl-7-pentafluorophenyl-heptanoic
acid;
[0445] 2-Aminomethyl-7-(2-fluoro-phenyl)-4-ethyl-heptanoic
acid;
[0446] 2-Aminomethyl-7-(3-fluoro-phenyl)-4-ethyl-heptanoic
acid;
[0447] 2-Aminomethyl-7-(4-fluoro-phenyl)-4-ethyl-heptanoic
acid;
[0448] 2-Aminomethyl-7-(2,3-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[0449] 2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[0450] 2-Aminomethyl-7-(2,5-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[0451] 2-Aminomethyl-7-(2,6-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[0452] 2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[0453] 2-Aminomethyl-7-(3,5-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[0454] 2-Aminomethyl-4-ethyl-7-(2,3,4-trifluoro-phenyl)-heptanoic
acid;
[0455] 2-Aminomethyl-4-ethyl-7-(2,3,5-trifluoro-phenyl)-heptanoic
acid;
[0456] 2-Aminomethyl-4-ethyl-7-(2,3,6-trifluoro-phenyl)-heptanoic
acid;
[0457] 2-Aminomethyl-4-ethyl-7-(2,4,6-trifluoro-phenyl)-heptanoic
acid;
[0458]
2-Aminomethyl-4-ethyl-7-(2,3,4,5-tetrafluoro-phenyl)-heptanoic
acid;
[0459]
2-Aminomethyl-4-ethyl-7-(2,3,4,6-tetrafluoro-phenyl)-heptanoic
acid;
[0460]
2-Aminomethyl-4-ethyl-7-(2,3,5,6-tetrafluoro-phenyl)-heptanoic
acid;
[0461] 2-Aminomethyl-4-ethyl-7-pentafluorophenyl-heptanoic
acid;
[0462] 2-Aminomethyl-4-(2-chloro-phenyl)-pentanoic acid;
[0463] 2-Aminomethyl-4-(3-chloro-phenyl)-pentanoic acid;
[0464] 2-Aminomethyl-4-(4-chloro-phenyl)-pentanoic acid;
[0465] 2-Aminomethyl-4-(2,3-dichloro-phenyl)-pentanoic acid;
[0466] 2-Aminomethyl-4-(2,4-dichloro-phenyl)-pentanoic acid;
[0467] 2-Aminomethyl-4-(2,5-dichloro-phenyl)-pentanoic acid;
[0468] 2-Aminomethyl-4-(2,6-dichloro-phenyl)-pentanoic acid;
[0469] 2-Aminomethyl-4-(3,4-dichloro-phenyl)-pentanoic acid;
[0470] 2-Aminomethyl-4-(3,5-dichloro-phenyl)-pentanoic acid;
[0471] 2-Aminomethyl-4-(2,3,4-trichloro-phenyl)-pentanoic acid;
[0472] 2-Aminomethyl-4-(2,3,5-trichloro-phenyl)-pentanoic acid;
[0473] 2-Aminomethyl-4-(2,3,6-trichloro-phenyl)-pentanoic acid;
[0474] 2-Aminomethyl-4-(2,4,6-trichloro-phenyl)-pentanoic acid;
[0475] 2-Aminomethyl-4-(2,3,4,5-tetrachloro-phenyl)-pentanoic
acid;
[0476] 2-Aminomethyl-4-(2,3,4,6-tetrachloro-phenyl)-pentanoic
acid;
[0477] 2-Aminomethyl-4-(2,3,5,6-tetrachloro-phenyl)-pentanoic
acid;
[0478] 2-Aminomethyl-4-pentachlorophenyl-pentanoic acid;
[0479] 2-Aminomethyl-4-(2-chloro-phenyl)-hexanoic acid;
[0480] 2-Aminomethyl-4-(3-chloro-phenyl)-hexanoic acid;
[0481] 2-Aminomethyl-4-(4-chloro-phenyl)-hexanoic acid;
[0482] 2-Aminomethyl-4-(2,3-dichloro-phenyl)-hexanoic acid;
[0483] 2-Aminomethyl-4-(2,4-dichloro-phenyl)-hexanoic acid;
[0484] 2-Aminomethyl-4-(2,5-dichloro-phenyl)-hexanoic acid;
[0485] 2-Aminomethyl-4-(2,6-dichloro-phenyl)-hexanoic acid;
[0486] 2-Aminomethyl-4-(3,4-dichloro-phenyl)-hexanoic acid;
[0487] 2-Aminomethyl-4-(3,5-dichloro-phenyl)-hexanoic acid;
[0488] 2-Aminomethyl-4-(2,3,4-trichloro-phenyl)-hexanoic acid;
[0489] 2-Aminomethyl-4-(2,3,5-trichloro-phenyl)-hexanoic acid;
[0490] 2-Aminomethyl-4-(2,3,6-trichloro-phenyl)-hexanoic acid;
[0491] 2-Aminomethyl-4-(2,4,6-trichloro-phenyl)-hexanoic acid;
[0492] 2-Aminomethyl-4-(2,3,4,5-tetrachloro-phenyl)-hexanoic
acid;
[0493] 2-Aminomethyl-4-(2,3,4,6-tetrachloro-phenyl)-hexanoic
acid;
[0494] 2-Aminomethyl-4-(2,3,5,6-tetrachloro-phenyl)-hexanoic
acid;
[0495] 2-Aminomethyl-4-pentachlorophenyl-hexanoic acid;
[0496] 2-Aminomethyl-5-(2-chloro-phenyl)-4-methyl-pentanoic
acid;
[0497] 2-Aminomethyl-5-(3-chloro-phenyl)-4-methyl-pentanoic
acid;
[0498] 2-Aminomethyl-5-(4-chloro-phenyl)-4-methyl-pentanoic
acid;
[0499] 2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-methyl-pentanoic
acid;
[0500] 2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-methyl-pentanoic
acid;
[0501] 2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-methyl-pentanoic
acid;
[0502] 2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-methyl-pentanoic
acid;
[0503] 2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-methyl-pentanoic
acid;
[0504] 2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-methyl-pentanoic
acid;
[0505] 2-Aminomethyl-4-methyl-5-(2,3,4-trichloro-phenyl)-pentanoic
acid;
[0506] 2-Aminomethyl-4-methyl-5-(2,3,5-trichloro-phenyl)-pentanoic
acid;
[0507] 2-Aminomethyl-4-methyl-5-(2,3,6-trichloro-phenyl)-pentanoic
acid;
[0508] 2-Aminomethyl-4-methyl-5-(2,4,6-trichloro-phenyl)-pentanoic
acid;
[0509]
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrachloro-phenyl)-pentanoic
acid;
[0510]
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrachloro-phenyl)-pentanoic
acid;
[0511]
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrachloro-phenyl)-pentanoic
acid;
[0512] 2-Aminomethyl-4-methyl-5-pentachlorophenyl-pentanoic
acid;
[0513] 2-Aminomethyl-5-(2-chloro-phenyl)-4-methyl-hexanoic
acid;
[0514] 2-Aminomethyl-5-(3-chloro-phenyl)-4-methyl-hexanoic
acid;
[0515] 2-Aminomethyl-5-(4-chloro-phenyl)-4-methyl-hexanoic
acid;
[0516] 2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0517] 2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0518] 2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0519] 2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0520] 2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0521] 2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0522] 2-Aminomethyl-4-methyl-5-(2,3,4-trichloro-phenyl)-hexanoic
acid;
[0523] 2-Aminomethyl-4-methyl-5-(2,3,5-trichloro-phenyl)-hexanoic
acid;
[0524] 2-Aminomethyl-4-methyl-5-(2,3,6-trichloro-phenyl)-hexanoic
acid;
[0525] 2-Aminomethyl-4-methyl-5-(2,4,6-trichloro-phenyl)-hexanoic
acid;
[0526]
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrachloro-phenyl)-hexanoic
acid;
[0527]
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrachloro-phenyl)-hexanoic
acid;
[0528]
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrachloro-phenyl)-hexanoic
acid;
[0529] 2-Aminomethyl-4-methyl-5-pentachlorophenyl-hexanoic
acid;
[0530] 2-Aminomethyl-5-(2-chloro-phenyl)-4-methyl-hexanoic
acid;
[0531] 2-Aminomethyl-5-(3-chloro-phenyl)-4-methyl-hexanoic
acid;
[0532] 2-Aminomethyl-5-(4-chloro-phenyl)-4-methyl-hexanoic
acid;
[0533] 2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0534] 2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0535] 2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0536] 2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0537] 2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0538] 2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-methyl-hexanoic
acid;
[0539] 2-Aminomethyl-4-methyl-5-(2,3,4-trichloro-phenyl)-hexanoic
acid;
[0540] 2-Aminomethyl-4-methyl-5-(2,3,5-trichloro-phenyl)-hexanoic
acid;
[0541] 2-Aminomethyl-4-methyl-5-(2,3,6-trichloro-phenyl)-hexanoic
acid;
[0542] 2-Aminomethyl-4-methyl-5-(2,4,6-trichloro-phenyl)-hexanoic
acid;
[0543]
2-Aminomethyl-4-methyl-5-(2,3,4,5-tetrachloro-phenyl)-hexanoic
acid;
[0544]
2-Aminomethyl-4-methyl-5-(2,3,4,6-tetrachloro-phenyl)-hexanoic
acid;
[0545]
2-Aminomethyl-4-methyl-5-(2,3,5,6-tetrachloro-phenyl)-hexanoic
acid;
[0546] 2-Aminomethyl-4-methyl-5-pentachlorophenyl-hexanoic
acid;
[0547] 2-Aminomethyl-5-(2-chloro-phenyl)-4-ethyl-pentanoic
acid;
[0548] 2-Aminomethyl-5-(3-chloro-phenyl)-4-ethyl-pentanoic
acid;
[0549] 2-Aminomethyl-5-(4-chloro-phenyl)-4-ethyl-pentanoic
acid;
[0550] 2-Aminomethyl-5-(2,3-dichloro-phenyl)-4-ethyl-pentanoic
acid;
[0551] 2-Aminomethyl-5-(2,4-dichloro-phenyl)-4-ethyl-pentanoic
acid;
[0552] 2-Aminomethyl-5-(2,5-dichloro-phenyl)-4-ethyl-pentanoic
acid;
[0553] 2-Aminomethyl-5-(2,6-dichloro-phenyl)-4-ethyl-pentanoic
acid;
[0554] 2-Aminomethyl-5-(3,4-dichloro-phenyl)-4-ethyl-pentanoic
acid;
[0555] 2-Aminomethyl-5-(3,5-dichloro-phenyl)-4-ethyl-pentanoic
acid;
[0556] 2-Aminomethyl-4-ethyl-5-(2,3,4-trichloro-phenyl)-pentanoic
acid;
[0557] 2-Aminomethyl-4-ethyl-5-(2,3,5-trichloro-phenyl)-pentanoic
acid;
[0558] 2-Aminomethyl-4-ethyl-5-(2,3,6-trichloro-phenyl)-pentanoic
acid;
[0559] 2-Aminomethyl-4-ethyl-5-(2,4,6-trichloro-phenyl)-pentanoic
acid;
[0560]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetrachloro-phenyl)-pentanoic
acid;
[0561]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetrachloro-phenyl)-pentanoic
acid;
[0562]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetrachloro-phenyl)-pentanoic
acid;
[0563] 2-Aminomethyl-4-ethyl-5-pentachlorophenyl-pentanoic
acid;
[0564] 2-Aminomethyl-6-(2-chloro-phenyl)-4-ethyl-hexanoic acid;
[0565] 2-Aminomethyl-6-(3-chloro-phenyl)-4-ethyl-hexanoic acid;
[0566] 2-Aminomethyl-6-(4-chloro-phenyl)-4-ethyl-hexanoic acid;
[0567] 2-Aminomethyl-6-(2,3-dichloro-phenyl)-4-ethyl-hexanoic
acid;
[0568] 2-Aminomethyl-6-(2,4-dichloro-phenyl)-4-ethyl-hexanoic
acid;
[0569] 2-Aminomethyl-6-(2,5-dichloro-phenyl)-4-ethyl-hexanoic
acid;
[0570] 2-Aminomethyl-6-(2,6-dichloro-phenyl)-4-ethyl-hexanoic
acid;
[0571] 2-Aminomethyl-6-(3,4-dichloro-phenyl)-4-ethyl-hexanoic
acid;
[0572] 2-Aminomethyl-6-(3,5-dichloro-phenyl)-4-ethyl-hexanoic
acid;
[0573] 2-Aminomethyl-4-ethyl-6-(2,3,4-trichloro-phenyl)-hexanoic
acid;
[0574] 2-Aminomethyl-4-ethyl-6-(2,3,5-trichloro-phenyl)-hexanoic
acid;
[0575] 2-Aminomethyl-4-ethyl-6-(2,3,6-trichloro-phenyl)-hexanoic
acid;
[0576] 2-Aminomethyl-4-ethyl-6-(2,4,6-trichloro-phenyl)-hexanoic
acid;
[0577]
2-Aminomethyl-4-ethyl-6-(2,3,4,5-tetrachloro-phenyl)-hexanoic
acid;
[0578]
2-Aminomethyl-4-ethyl-6-(2,3,4,6-tetrachloro-phenyl)-hexanoic
acid;
[0579]
2-Aminomethyl-4-ethyl-6-(2,3,5,6-tetrachloro-phenyl)-hexanoic
acid;
[0580] 2-Aminomethyl-4-ethyl-6-pentachlorophenyl-hexanoic acid;
[0581] 2-Aminomethyl-7-(2-chloro-phenyl)-4-methyl-heptanoic
acid;
[0582] 2-Aminomethyl-7-(3-chloro-phenyl)-4-methyl-heptanoic
acid;
[0583] 2-Aminomethyl-7-(4-chloro-phenyl)-4-methyl-heptanoic
acid;
[0584] 2-Aminomethyl-7-(2,3-dichloro-phenyl)-4-methyl-heptanoic
acid;
[0585] 2-Aminomethyl-7-(2,4-dichloro-phenyl)-4-methyl-heptanoic
acid;
[0586] 2-Aminomethyl-7-(2,5-dichloro-phenyl)-4-methyl-heptanoic
acid;
[0587] 2-Aminomethyl-7-(2,6-dichloro-phenyl)-4-methyl-heptanoic
acid;
[0588] 2-Aminomethyl-7-(3,4-dichloro-phenyl)-4-methyl-heptanoic
acid;
[0589] 2-Aminomethyl-7-(3,5-dichloro-phenyl)-4-methyl-heptanoic
acid;
[0590] 2-Aminomethyl-4-methyl-7-(2,3,4-trichloro-phenyl)-heptanoic
acid;
[0591] 2-Aminomethyl-4-methyl-7-(2,3,5-trichloro-phenyl)-heptanoic
acid;
[0592] 2-Aminomethyl-4-methyl-7-(2,3,6-trichloro-phenyl)-heptanoic
acid;
[0593] 2-Aminomethyl-4-methyl-7-(2,4,6-trichloro-phenyl)-heptanoic
acid;
[0594]
2-Aminomethyl-4-methyl-7-(2,3,4,5-tetrachloro-phenyl)-heptanoic
acid;
[0595]
2-Aminomethyl-4-methyl-7-(2,3,4,6-tetrachloro-phenyl)-heptanoic
acid;
[0596]
2-Aminomethyl-4-methyl-7-(2,3,5,6-tetrachloro-phenyl)-heptanoic
acid;
[0597] 2-Aminomethyl-4-methyl-7-pentachlorophenyl-heptanoic
acid;
[0598] 2-Aminomethyl-7-(2-chloro-phenyl)-4-ethyl-heptanoic
acid;
[0599] 2-Aminomethyl-7-(3-chloro-phenyl)-4-ethyl-heptanoic
acid;
[0600] 2-Aminomethyl-7-(4-chloro-phenyl)-4-ethyl-heptanoic
acid;
[0601] 2-Aminomethyl-7-(2,3-dichloro-phenyl)-4-ethyl-heptanoic
acid;
[0602] 2-Aminomethyl-7-(2,4-dichloro-phenyl)-4-ethyl-heptanoic
acid;
[0603] 2-Aminomethyl-7-(2,5-dichloro-phenyl)-4-ethyl-heptanoic
acid;
[0604] 2-Aminomethyl-7-(2,6-dichloro-phenyl)-4-ethyl-heptanoic
acid;
[0605] 2-Aminomethyl-7-(3,4-dichloro-phenyl)-4-ethyl-heptanoic
acid;
[0606] 2-Aminomethyl-7-(3,5-dichloro-phenyl)-4-ethyl-heptanoic
acid;
[0607] 2-Aminomethyl-4-ethyl-7-(2,3,4-trichloro-phenyl)-heptanoic
acid;
[0608] 2-Aminomethyl-4-ethyl-7-(2,3,5-trichloro-phenyl)-heptanoic
acid;
[0609] 2-Aminomethyl-4-ethyl-7-(2,3,6-trichloro-phenyl)-heptanoic
acid;
[0610] 2-Aminomethyl-4-ethyl-7-(2,4,6-trichloro-phenyl)-heptanoic
acid;
[0611]
2-Aminomethyl-4-ethyl-7-(2,3,4,5-tetrachloro-phenyl)-heptanoic
acid;
[0612]
2-Aminomethyl-4-ethyl-7-(2,3,4,6-tetrachloro-phenyl)-heptanoic
acid;
[0613]
2-Aminomethyl-4-ethyl-7-(2,3,5,6-tetrachloro-phenyl)-heptanoic
acid;
[0614] 2-Aminomethyl-4-ethyl-7-pentachlorophenyl-heptanoic
acid;
[0615] 2-Aminomethyl-4-(2-methoxy-phenyl)-pentanoic acid;
[0616] 2-Aminomethyl-4-(3-methoxy-phenyl)-pentanoic acid;
[0617] 2-Aminomethyl-4-(4-methoxy-phenyl)-pentanoic acid;
[0618] 2-Aminomethyl-4-(2,3-dimethoxy-phenyl)-pentanoic acid;
[0619] 2-Aminomethyl-4-(2,4-dimethoxy-phenyl)-pentanoic acid;
[0620] 2-Aminomethyl-4-(2,5-dimethoxy-phenyl)-pentanoic acid;
[0621] 2-Aminomethyl-4-(2,6-dimethoxy-phenyl)-pentanoic acid;
[0622] 2-Aminomethyl-4-(3,4-dimethoxy-phenyl)-pentanoic acid;
[0623] 2-Aminomethyl-4-(3,5-dimethoxy-phenyl)-pentanoic acid;
[0624] 2-Aminomethyl-4-(2,3,4-trimethoxy-phenyl)-pentanoic
acid;
[0625] 2-Aminomethyl-4-(2,3,5-trimethoxy-phenyl)-pentanoic
acid;
[0626] 2-Aminomethyl-4-(2,3,6-trimethoxy-phenyl)-pentanoic
acid;
[0627] 2-Aminomethyl-4-(2,4,6-trimethoxy-phenyl)-pentanoic
acid;
[0628] 2-Aminomethyl-4-(2-methoxy-phenyl)-hexanoic acid;
[0629] 2-Aminomethyl-4-(3-methoxy-phenyl)-hexanoic acid;
[0630] 2-Aminomethyl-4-(4-methoxy-phenyl)-hexanoic acid;
[0631] 2-Aminomethyl-4-(2,3-dimethoxy-phenyl)-hexanoic acid;
[0632] 2-Aminomethyl-4-(2,4-dimethoxy-phenyl)-hexanoic acid;
[0633] 2-Aminomethyl-4-(2,5-dimethoxy-phenyl)-hexanoic acid;
[0634] 2-Aminomethyl-4-(2,6-dimethoxy-phenyl)-hexanoic acid;
[0635] 2-Aminomethyl-4-(3,4-dimethoxy-phenyl)-hexanoic acid;
[0636] 2-Aminomethyl-4-(3,5-dimethoxy-phenyl)-hexanoic acid;
[0637] 2-Aminomethyl-4-(2,3,4-trimethoxy-phenyl)-hexanoic acid;
[0638] 2-Aminomethyl-4-(2,3,5-trimethoxy-phenyl)-hexanoic acid;
[0639] 2-Aminomethyl-4-(2,3,6-trimethoxy-phenyl)-hexanoic acid;
[0640] 2-Aminomethyl-4-(2,4,6-trimethoxy-phenyl)-hexanoic acid;
[0641] 2-Aminomethyl-5-(2-methoxy-phenyl)-4-methyl-pentanoic
acid;
[0642] 2-Aminomethyl-5-(3-methoxy-phenyl)-4-methyl-pentanoic
acid;
[0643] 2-Aminomethyl-5-(4-methoxy-phenyl)-4-methyl-pentanoic
acid;
[0644] 2-Aminomethyl-5-(2,3-dimethoxy-phenyl)-4-methyl-pentanoic
acid;
[0645] 2-Aminomethyl-5-(2,4-dimethoxy-phenyl)-4-methyl-pentanoic
acid;
[0646] 2-Aminomethyl-5-(2,5-dimethoxy-phenyl)-4-methyl-pentanoic
acid;
[0647] 2-Aminomethyl-5-(2,6-dimethoxy-phenyl)-4-methyl-pentanoic
acid;
[0648] 2-Aminomethyl-5-(3,4-dimethoxy-phenyl)-4-methyl-pentanoic
acid;
[0649] 2-Aminomethyl-5-(3,5-dimethoxy-phenyl)-4-methyl-pentanoic
acid;
[0650] 2-Aminomethyl-4-methyl-5-(2,3,4-trimethoxy-phenyl)-pentanoic
acid;
[0651] 2-Aminomethyl-4-methyl-5-(2,3,5-trimethoxy-phenyl)-pentanoic
acid;
[0652] 2-Aminomethyl-4-methyl-5-(2,3,6-trimethoxy-phenyl)-pentanoic
acid;
[0653] 2-Aminomethyl-4-methyl-5-(2,4,6-trimethoxy-phenyl)-pentanoic
acid;
[0654] 2-Aminomethyl-5-(2-methoxy-phenyl)-4-methyl-hexanoic
acid;
[0655] 2-Aminomethyl-5-(3-methoxy-phenyl)-4-methyl-hexanoic
acid;
[0656] 2-Aminomethyl-5-(4-methoxy-phenyl)-4-methyl-hexanoic
acid;
[0657] 2-Aminomethyl-5-(2,3-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0658] 2-Aminomethyl-5-(2,4-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0659] 2-Aminomethyl-5-(2,5-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0660] 2-Aminomethyl-5-(2,6-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0661] 2-Aminomethyl-5-(3,4-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0662] 2-Aminomethyl-5-(3,5-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0663] 2-Aminomethyl-4-methyl-5-(2,3,4-trimethoxy-phenyl)-hexanoic
acid;
[0664] 2-Aminomethyl-4-methyl-5-(2,3,5-trimethoxy-phenyl)-hexanoic
acid;
[0665] 2-Aminomethyl-4-methyl-5-(2,3,6-trimethoxy-phenyl)-hexanoic
acid;
[0666] 2-Aminomethyl-4-methyl-5-(2,4,6-trimethoxy-phenyl)-hexanoic
acid;
[0667] 2-Aminomethyl-6-(2-methoxy-phenyl)-4-methyl-hexanoic
acid;
[0668] 2-Aminomethyl-6-(3-methoxy-phenyl)-4-methyl-hexanoic
acid;
[0669] 2-Aminomethyl-6-(4-methoxy-phenyl)-4-methyl-hexanoic
acid;
[0670] 2-Aminomethyl-6-(2,3-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0671] 2-Aminomethyl-6-(2,4-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0672] 2-Aminomethyl-6-(2,5-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0673] 2-Aminomethyl-6-(2,6-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0674] 2-Aminomethyl-6-(3,4-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0675] 2-Aminomethyl-6-(3,5-dimethoxy-phenyl)-4-methyl-hexanoic
acid;
[0676] 2-Aminomethyl-4-methyl-6-(2,3,4-trimethoxy-phenyl)-hexanoic
acid;
[0677] 2-Aminomethyl-4-methyl-6-(2,3,5-trimethoxy-phenyl)-hexanoic
acid;
[0678] 2-Aminomethyl-4-methyl-6-(2,3,6-trimethoxy-phenyl)-hexanoic
acid;
[0679] 2-Aminomethyl-4-methyl-6-(2,4,6-trimethoxy-phenyl)-hexanoic
acid;
[0680] 2-Aminomethyl-5-(2-methoxy-phenyl)-4-ethyl-pentanoic
acid;
[0681] 2-Aminomethyl-5-(3-methoxy-phenyl)-4-ethyl-pentanoic
acid;
[0682] 2-Aminomethyl-5-(4-methoxy-phenyl)-4-ethyl-pentanoic
acid;
[0683] 2-Aminomethyl-5-(2,3-dimethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0684] 2-Aminomethyl-5-(2,4-dimethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0685] 2-Aminomethyl-5-(2,5-dimethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0686] 2-Aminomethyl-5-(2,6-dimethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0687] 2-Aminomethyl-5-(3,4-dimethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0688] 2-Aminomethyl-5-(3,5-dimethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0689] 2-Aminomethyl-4-ethyl-5-(2,3,4-trimethoxy-phenyl)-pentanoic
acid;
[0690] 2-Aminomethyl-4-ethyl-5-(2,3,5-trimethoxy-phenyl)-pentanoic
acid;
[0691] 2-Aminomethyl-4-ethyl-5-(2,3,6-trimethoxy-phenyl)-pentanoic
acid;
[0692] 2-Aminomethyl-4-ethyl-5-(2,4,6-trimethoxy-phenyl)-pentanoic
acid;
[0693]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetramethoxy-phenyl)-pentanoic
acid;
[0694]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetramethoxy-phenyl)-pentanoic
acid;
[0695]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetramethoxy-phenyl)-pentanoic
acid;
[0696] 2-Aminomethyl-4-ethyl-5-pentamethoxyphenyl-pentanoic
acid;
[0697] 2-Aminomethyl-6-(2-methoxy-phenyl)-4-ethyl-hexanoic
acid;
[0698] 2-Aminomethyl-6-(3-methoxy-phenyl)-4-ethyl-hexanoic
acid;
[0699] 2-Aminomethyl-6-(4-methoxy-phenyl)-4-ethyl-hexanoic
acid;
[0700] 2-Aminomethyl-6-(2,3-dimethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0701] 2-Aminomethyl-6-(2,4-dimethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0702] 2-Aminomethyl-6-(2,5-dimethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0703] 2-Aminomethyl-6-(2,6-dimethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0704] 2-Aminomethyl-6-(3,4-dimethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0705] 2-Aminomethyl-6-(3,5-dimethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0706] 2-Aminomethyl-4-ethyl-6-(2,3,4-trimethoxy-phenyl)-hexanoic
acid;
[0707] 2-Aminomethyl-4-ethyl-6-(2,3,5-trimethoxy-phenyl)-hexanoic
acid;
[0708] 2-Aminomethyl-4-ethyl-6-(2,3,6-trimethoxy-phenyl)-hexanoic
acid;
[0709] 2-Aminomethyl-4-ethyl-6-(2,4,6-trimethoxy-phenyl)-hexanoic
acid;
[0710] 2-Aminomethyl-7-(2-methoxy-phenyl)-4-methyl-heptanoic
acid;
[0711] 2-Aminomethyl-7-(3-methoxy-phenyl)-4-methyl-heptanoic
acid;
[0712] 2-Aminomethyl-7-(4-methoxy-phenyl)-4-methyl-heptanoic
acid;
[0713] 2-Aminomethyl-7-(2,3-dimethoxy-phenyl)-4-methyl-heptanoic
acid;
[0714] 2-Aminomethyl-7-(2,4-dimethoxy-phenyl)-4-methyl-heptanoic
acid;
[0715] 2-Aminomethyl-7-(2,5-dimethoxy-phenyl)-4-methyl-heptanoic
acid;
[0716] 2-Aminomethyl-7-(2,6-dimethoxy-phenyl)-4-methyl-heptanoic
acid;
[0717] 2-Aminomethyl-7-(3,4-dimethoxy-phenyl)-4-methyl-heptanoic
acid;
[0718] 2-Aminomethyl-7-(3,5-dimethoxy-phenyl)-4-methyl-heptanoic
acid;
[0719] 2-Aminomethyl-4-methyl-7-(2,3,4-trimethoxy-phenyl)-heptanoic
acid;
[0720] 2-Aminomethyl-4-methyl-7-(2,3,5-trimethoxy-phenyl)-heptanoic
acid;
[0721] 2-Aminomethyl-4-methyl-7-(2,3,6-trimethoxy-phenyl)-heptanoic
acid;
[0722] 2-Aminomethyl-4-methyl-7-(2,4,6-trimethoxy-phenyl)-heptanoic
acid;
[0723] 2-Aminomethyl-7-(2-methoxy-phenyl)-4-ethyl-heptanoic
acid;
[0724] 2-Aminomethyl-7-(3-methoxy-phenyl)-4-ethyl-heptanoic
acid;
[0725] 2-Aminomethyl-7-(4-methoxy-phenyl)-4-ethyl-heptanoic
acid;
[0726] 2-Aminomethyl-7-(2,3-dimethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0727] 2-Aminomethyl-7-(2,4-dimethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0728] 2-Aminomethyl-7-(2,5-dimethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0729] 2-Aminomethyl-7-(2,6-dimethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0730] 2-Aminomethyl-7-(3,4-dimethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0731] 2-Aminomethyl-7-(3,5-dimethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0732] 2-Aminomethyl-4-ethyl-7-(2,3,4-trimethoxy-phenyl)-heptanoic
acid;
[0733] 2-Aminomethyl-4-ethyl-7-(2,3,5-trimethoxy-phenyl)-heptanoic
acid;
[0734] 2-Aminomethyl-4-ethyl-7-(2,3,6-trimethoxy-phenyl)-heptanoic
acid;
[0735] 2-Aminomethyl-4-ethyl-7-(2,4,6-trimethoxy-phenyl)-heptanoic
acid;
[0736] 2-Aminomethyl-4-(2-trifluoromethyl-phenyl)-pentanoic
acid;
[0737] 2-Aminomethyl-4-(3-trifluoromethyl-phenyl)-pentanoic
acid;
[0738] 2-Aminomethyl-4-(4-trifluoromethyl-phenyl)-pentanoic
acid;
[0739] 2-Aminomethyl-4-(2,3-di-trifluoromethyl-phenyl)-pentanoic
acid;
[0740] 2-Aminomethyl-4-(2,4-di-trifluoromethyl-phenyl)-pentanoic
acid;
[0741] 2-Aminomethyl-4-(2,5-di-trifluoromethyl-phenyl)-pentanoic
acid;
[0742] 2-Aminomethyl-4-(2,6-di-trifluoromethyl-phenyl)-pentanoic
acid;
[0743] 2-Aminomethyl-4-(3,4-di-trifluoromethyl-phenyl)-pentanoic
acid;
[0744] 2-Aminomethyl-4-(3,5-di-trifluoromethyl-phenyl)-pentanoic
acid;
[0745] 2-Aminomethyl-4-(2,3,4-tri-trifluoromethyl-phenyl)-pentanoic
acid;
[0746] 2-Aminomethyl-4-(2,3,5-tri-trifluoromethyl-phenyl)-pentanoic
acid;
[0747] 2-Aminomethyl-4-(2,3,6-tri-trifluoromethyl-phenyl)-pentanoic
acid;
[0748] 2-Aminomethyl-4-(2,4,6-tri-trifluoromethyl-phenyl)-pentanoic
acid;
[0749] 2-Aminomethyl-4-(2-trifluoromethyl-phenyl)-hexanoic
acid;
[0750] 2-Aminomethyl-4-(3-trifluoromethyl-phenyl)-hexanoic
acid;
[0751] 2-Aminomethyl-4-(4-trifluoromethyl-phenyl)-hexanoic
acid;
[0752] 2-Aminomethyl-4-(2,3-di-trifluoromethyl-phenyl)-hexanoic
acid;
[0753] 2-Aminomethyl-4-(2,4-di-trifluoromethyl-phenyl)-hexanoic
acid;
[0754] 2-Aminomethyl-4-(2,5-di-trifluoromethyl-phenyl)-hexanoic
acid;
[0755] 2-Aminomethyl-4-(2,6-di-trifluoromethyl-phenyl)-hexanoic
acid;
[0756] 2-Aminomethyl-4-(3,4-di-trifluoromethyl-phenyl)-hexanoic
acid;
[0757] 2-Aminomethyl-4-(3,5-di-trifluoromethyl-phenyl)-hexanoic
acid;
[0758] 2-Aminomethyl-4-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0759] 2-Aminomethyl-4-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0760] 2-Aminomethyl-4-(2,3,6-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0761] 2-Aminomethyl-4-(2,4,6-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0762]
2-Aminomethyl-5-(2-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0763]
2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0764]
2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0765]
2-Aminomethyl-5-(2,3-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0766]
2-Aminomethyl-5-(2,4-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0767]
2-Aminomethyl-5-(2,5-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0768]
2-Aminomethyl-5-(2,6-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0769]
2-Aminomethyl-5-(3,4-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0770]
2-Aminomethyl-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-pentanoic
acid;
[0771]
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethyl-phenyl)-pentano-
ic acid;
[0772]
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethyl-phenyl)-pentano-
ic acid;
[0773]
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethyl-phenyl)-pentano-
ic acid;
[0774]
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethyl-phenyl)-pentano-
ic acid;
[0775] 2-Aminomethyl-5-(2-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0776] 2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0777] 2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0778]
2-Aminomethyl-5-(2,3-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0779]
2-Aminomethyl-5-(2,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0780]
2-Aminomethyl-5-(2,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0781]
2-Aminomethyl-5-(2,6-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0782]
2-Aminomethyl-5-(3,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0783]
2-Aminomethyl-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0784]
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0785]
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0786]
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0787]
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0788] 2-Aminomethyl-6-(2-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0789] 2-Aminomethyl-6-(3-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0790] 2-Aminomethyl-6-(4-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0791]
2-Aminomethyl-6-(2,3-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0792]
2-Aminomethyl-6-(2,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0793]
2-Aminomethyl-6-(2,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0794]
2-Aminomethyl-6-(2,6-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0795]
2-Aminomethyl-6-(3,4-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0796]
2-Aminomethyl-6-(3,5-di-trifluoromethyl-phenyl)-4-methyl-hexanoic
acid;
[0797]
2-Aminomethyl-4-methyl-6-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0798]
2-Aminomethyl-4-methyl-6-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0799]
2-Aminomethyl-4-methyl-6-(2,3,6-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0800]
2-Aminomethyl-4-methyl-6-(2,4,6-tri-trifluoromethyl-phenyl)-hexanoi-
c acid;
[0801] 2-Aminomethyl-5-(2-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0802] 2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0803] 2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0804]
2-Aminomethyl-5-(2,3-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0805]
2-Aminomethyl-5-(2,4-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0806]
2-Aminomethyl-5-(2,5-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0807]
2-Aminomethyl-5-(2,6-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0808]
2-Aminomethyl-5-(3,4-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0809]
2-Aminomethyl-5-(3,5-di-trifluoromethyl-phenyl)-4-ethyl-pentanoic
acid;
[0810]
2-Aminomethyl-4-ethyl-5-(2,3,4-tri-trifluoromethyl-phenyl)-pentanoi-
c acid;
[0811]
2-Aminomethyl-4-ethyl-5-(2,3,5-tri-trifluoromethyl-phenyl)-pentanoi-
c acid;
[0812]
2-Aminomethyl-4-ethyl-5-(2,3,6-tri-trifluoromethyl-phenyl)-pentanoi-
c acid;
[0813]
2-Aminomethyl-4-ethyl-5-(2,4,6-tri-trifluoromethyl-phenyl)-pentanoi-
c acid;
[0814]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetra-trifluoromethyl-phenyl)-pent-
anoic acid;
[0815]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetra-trifluoromethyl-phenyl)-pent-
anoic acid;
[0816]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetra-trifluoromethyl-phenyl)-pent-
anoic acid;
[0817]
2-Aminomethyl-4-ethyl-5-penta-trifluoromethylphenyl-pentanoic
acid;
[0818] 2-Aminomethyl-6-(2-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0819] 2-Aminomethyl-6-(3-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0820] 2-Aminomethyl-6-(4-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0821]
2-Aminomethyl-6-(2,3-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0822]
2-Aminomethyl-6-(2,4-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0823]
2-Aminomethyl-6-(2,5-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0824]
2-Aminomethyl-6-(2,6-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0825]
2-Aminomethyl-6-(3,4-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0826]
2-Aminomethyl-6-(3,5-di-trifluoromethyl-phenyl)-4-ethyl-hexanoic
acid;
[0827]
2-Aminomethyl-4-ethyl-6-(2,3,4-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0828]
2-Aminomethyl-4-ethyl-6-(2,3,5-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0829]
2-Aminomethyl-4-ethyl-6-(2,3,6-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0830]
2-Aminomethyl-4-ethyl-6-(2,4,6-tri-trifluoromethyl-phenyl)-hexanoic
acid;
[0831]
2-Aminomethyl-7-(2-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0832]
2-Aminomethyl-7-(3-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0833]
2-Aminomethyl-7-(4-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0834]
2-Aminomethyl-7-(2,3-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0835]
2-Aminomethyl-7-(2,4-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0836]
2-Aminomethyl-7-(2,5-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0837]
2-Aminomethyl-7-(2,6-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0838]
2-Aminomethyl-7-(3,4-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0839]
2-Aminomethyl-7-(3,5-di-trifluoromethyl-phenyl)-4-methyl-heptanoic
acid;
[0840]
2-Aminomethyl-4-methyl-7-(2,3,4-tri-trifluoromethyl-phenyl)-heptano-
ic acid;
[0841]
2-Aminomethyl-4-methyl-7-(2,3,5-tri-trifluoromethyl-phenyl)-heptano-
ic acid;
[0842]
2-Aminomethyl-4-methyl-7-(2,3,6-tri-trifluoromethyl-phenyl)-heptano-
ic acid;
[0843]
2-Aminomethyl-4-methyl-7-(2,4,6-tri-trifluoromethyl-phenyl)-heptano-
ic acid;
[0844] 2-Aminomethyl-7-(2-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0845] 2-Aminomethyl-7-(3-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0846] 2-Aminomethyl-7-(4-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0847]
2-Aminomethyl-7-(2,3-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0848]
2-Aminomethyl-7-(2,4-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0849]
2-Aminomethyl-7-(2,5-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0850]
2-Aminomethyl-7-(2,6-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0851]
2-Aminomethyl-7-(3,4-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0852]
2-Aminomethyl-7-(3,5-di-trifluoromethyl-phenyl)-4-ethyl-heptanoic
acid;
[0853]
2-Aminomethyl-4-ethyl-7-(2,3,4-tri-trifluoromethyl-phenyl)-heptanoi-
c acid;
[0854]
2-Aminomethyl-4-ethyl-7-(2,3,5-tri-trifluoromethyl-phenyl)-heptanoi-
c acid;
[0855]
2-Aminomethyl-4-ethyl-7-(2,3,6-tri-trifluoromethyl-phenyl)-heptanoi-
c acid;
[0856]
2-Aminomethyl-4-ethyl-7-(2,4,6-tri-trifluoromethyl-phenyl)-heptanoi-
c acid;
[0857] 2-Aminomethyl-4-(2-trifluoromethoxy-phenyl)-pentanoic
acid;
[0858] 2-Aminomethyl-4-(3-trifluoromethoxy-phenyl)-pentanoic
acid;
[0859] 2-Aminomethyl-4-(4-trifluoromethoxy-phenyl)-pentanoic
acid;
[0860] 2-Aminomethyl-4-(2,3-di-trifluoromethoxy-phenyl)-pentanoic
acid;
[0861] 2-Aminomethyl-4-(2,4-di-trifluoromethoxy-phenyl)-pentanoic
acid;
[0862] 2-Aminomethyl-4-(2,5-di-trifluoromethoxy-phenyl)-pentanoic
acid;
[0863] 2-Aminomethyl-4-(2,6-di-trifluoromethoxy-phenyl)-pentanoic
acid;
[0864] 2-Aminomethyl-4-(3,4-di-trifluoromethoxy-phenyl)-pentanoic
acid;
[0865] 2-Aminomethyl-4-(3,5-di-trifluoromethoxy-phenyl)-pentanoic
acid;
[0866]
2-Aminomethyl-4-(2,3,4-tri-trifluoromethoxy-phenyl)-pentanoic
acid;
[0867]
2-Aminomethyl-4-(2,3,5-tri-trifluoromethoxy-phenyl)-pentanoic
acid;
[0868]
2-Aminomethyl-4-(2,3,6-tri-trifluoromethoxy-phenyl)-pentanoic
acid;
[0869]
2-Aminomethyl-4-(2,4,6-tri-trifluoromethoxy-phenyl)-pentanoic
acid;
[0870] 2-Aminomethyl-4-(2-trifluoromethoxy-phenyl)-hexanoic
acid;
[0871] 2-Aminomethyl-4-(3-trifluoromethoxy-phenyl)-hexanoic
acid;
[0872] 2-Aminomethyl-4-(4-trifluoromethoxy-phenyl)-hexanoic
acid;
[0873] 2-Aminomethyl-4-(2,3-di-trifluoromethoxy-phenyl)-hexanoic
acid;
[0874] 2-Aminomethyl-4-(2,4-di-trifluoromethoxy-phenyl)-hexanoic
acid;
[0875] 2-Aminomethyl-4-(2,5-di-trifluoromethoxy-phenyl)-hexanoic
acid;
[0876] 2-Aminomethyl-4-(2,6-di-trifluoromethoxy-phenyl)-hexanoic
acid;
[0877] 2-Aminomethyl-4-(3,4-di-trifluoromethoxy-phenyl)-hexanoic
acid;
[0878] 2-Aminomethyl-4-(3,5-di-trifluoromethoxy-phenyl)-hexanoic
acid;
[0879] 2-Aminomethyl-4-(2,3,4-tri-trifluoromethoxy-phenyl)-hexanoic
acid;
[0880] 2-Aminomethyl-4-(2,3,5-tri-trifluoromethoxy-phenyl)-hexanoic
acid;
[0881] 2-Aminomethyl-4-(2,3,6-tri-trifluoromethoxy-phenyl)-hexanoic
acid;
[0882] 2-Aminomethyl-4-(2,4,6-tri-trifluoromethoxy-phenyl)-hexanoic
acid;
[0883]
2-Aminomethyl-5-(2-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0884]
2-Aminomethyl-5-(3-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0885]
2-Aminomethyl-5-(4-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0886]
2-Aminomethyl-5-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0887]
2-Aminomethyl-5-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0888]
2-Aminomethyl-5-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0889]
2-Aminomethyl-5-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0890]
2-Aminomethyl-5-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0891]
2-Aminomethyl-5-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-pentanoic
acid;
[0892]
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethoxy-phenyl)-pentan-
oic acid;
[0893]
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethoxy-phenyl)-pentan-
oic acid;
[0894]
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethoxy-phenyl)-pentan-
oic acid;
[0895]
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethoxy-phenyl)-pentan-
oic acid;
[0896]
2-Aminomethyl-5-(2-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0897]
2-Aminomethyl-5-(3-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0898]
2-Aminomethyl-5-(4-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0899]
2-Aminomethyl-5-(2,3-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0900]
2-Aminomethyl-5-(2,4-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0901]
2-Aminomethyl-5-(2,5-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0902]
2-Aminomethyl-5-(2,6-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0903]
2-Aminomethyl-5-(3,4-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0904]
2-Aminomethyl-5-(3,5-di-trifluoromethoxy-phenyl)-4-ethyl-pentanoic
acid;
[0905]
2-Aminomethyl-4-ethyl-5-(2,3,4-tri-trifluoromethoxy-phenyl)-pentano-
ic acid;
[0906]
2-Aminomethyl-4-ethyl-5-(2,3,5-tri-trifluoromethoxy-phenyl)-pentano-
ic acid;
[0907]
2-Aminomethyl-4-ethyl-5-(2,3,6-tri-trifluoromethoxy-phenyl)-pentano-
ic acid;
[0908]
2-Aminomethyl-4-ethyl-5-(2,4,6-tri-trifluoromethoxy-phenyl)-pentano-
ic acid;
[0909]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetra-trifluoromethoxy-phenyl)-pen-
tanoic acid;
[0910]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetra-trifluoromethoxy-phenyl)-pen-
tanoic acid;
[0911]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetra-trifluoromethoxy-phenyl)-pen-
tanoic acid;
[0912]
2-Aminomethyl-4-ethyl-5-penta-trifluoromethoxyphenyl-pentanoic
acid;
[0913]
2-Aminomethyl-5-(2-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0914]
2-Aminomethyl-5-(3-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0915]
2-Aminomethyl-5-(4-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0916]
2-Aminomethyl-5-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0917]
2-Aminomethyl-5-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0918]
2-Aminomethyl-5-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0919]
2-Aminomethyl-5-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0920]
2-Aminomethyl-5-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0921]
2-Aminomethyl-5-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0922]
2-Aminomethyl-4-methyl-5-(2,3,4-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0923]
2-Aminomethyl-4-methyl-5-(2,3,5-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0924]
2-Aminomethyl-4-methyl-5-(2,3,6-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0925]
2-Aminomethyl-4-methyl-5-(2,4,6-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0926]
2-Aminomethyl-6-(2-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0927]
2-Aminomethyl-6-(3-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0928]
2-Aminomethyl-6-(4-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0929]
2-Aminomethyl-6-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0930]
2-Aminomethyl-6-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0931]
2-Aminomethyl-6-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0932]
2-Aminomethyl-6-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0933]
2-Aminomethyl-6-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0934]
2-Aminomethyl-6-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-hexanoic
acid;
[0935]
2-Aminomethyl-4-methyl-6-(2,3,4-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0936]
2-Aminomethyl-4-methyl-6-(2,3,5-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0937]
2-Aminomethyl-4-methyl-6-(2,3,6-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0938]
2-Aminomethyl-4-methyl-6-(2,4,6-tri-trifluoromethoxy-phenyl)-hexano-
ic acid;
[0939] 2-Aminomethyl-6-(2-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0940] 2-Aminomethyl-6-(3-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0941] 2-Aminomethyl-6-(4-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0942]
2-Aminomethyl-6-(2,3-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0943]
2-Aminomethyl-6-(2,4-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0944]
2-Aminomethyl-6-(2,5-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0945]
2-Aminomethyl-6-(2,6-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0946]
2-Aminomethyl-6-(3,4-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0947]
2-Aminomethyl-6-(3,5-di-trifluoromethoxy-phenyl)-4-ethyl-hexanoic
acid;
[0948]
2-Aminomethyl-4-ethyl-6-(2,3,4-tri-trifluoromethoxy-phenyl)-hexanoi-
c acid;
[0949]
2-Aminomethyl-4-ethyl-6-(2,3,5-tri-trifluoromethoxy-phenyl)-hexanoi-
c acid;
[0950]
2-Aminomethyl-4-ethyl-6-(2,3,6-tri-trifluoromethoxy-phenyl)-hexanoi-
c acid;
[0951]
2-Aminomethyl-4-ethyl-6-(2,4,6-tri-trifluoromethoxy-phenyl)-hexanoi-
c acid;
[0952]
2-Aminomethyl-7-(2-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0953]
2-Aminomethyl-7-(3-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0954]
2-Aminomethyl-7-(4-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0955]
2-Aminomethyl-7-(2,3-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0956]
2-Aminomethyl-7-(2,4-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0957]
2-Aminomethyl-7-(2,5-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0958]
2-Aminomethyl-7-(2,6-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0959]
2-Aminomethyl-7-(3,4-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0960]
2-Aminomethyl-7-(3,5-di-trifluoromethoxy-phenyl)-4-methyl-heptanoic
acid;
[0961]
2-Aminomethyl-4-methyl-7-(2,3,4-tri-trifluoromethoxy-phenyl)-heptan-
oic acid;
[0962]
2-Aminomethyl-4-methyl-7-(2,3,5-tri-trifluoromethoxy-phenyl)-heptan-
oic acid;
[0963]
2-Aminomethyl-4-methyl-7-(2,3,6-tri-trifluoromethoxy-phenyl)-heptan-
oic acid;
[0964]
2-Aminomethyl-4-methyl-7-(2,4,6-tri-trifluoromethoxy-phenyl)-heptan-
oic acid;
[0965]
2-Aminomethyl-7-(2-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0966]
2-Aminomethyl-7-(3-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0967]
2-Aminomethyl-7-(4-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0968]
2-Aminomethyl-7-(2,3-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0969]
2-Aminomethyl-7-(2,4-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0970]
2-Aminomethyl-7-(2,5-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0971]
2-Aminomethyl-7-(2,6-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0972]
2-Aminomethyl-7-(3,4-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0973]
2-Aminomethyl-7-(3,5-di-trifluoromethoxy-phenyl)-4-ethyl-heptanoic
acid;
[0974]
2-Aminomethyl-4-ethyl-7-(2,3,4-tri-trifluoromethoxy-phenyl)-heptano-
ic acid;
[0975]
2-Aminomethyl-4-ethyl-7-(2,3,5-tri-trifluoromethoxy-phenyl)-heptano-
ic acid;
[0976]
2-Aminomethyl-4-ethyl-7-(2,3,6-tri-trifluoromethoxy-phenyl)-heptano-
ic acid;
[0977]
2-Aminomethyl-4-ethyl-7-(2,4,6-tri-trifluoromethoxy-phenyl)-heptano-
ic acid;
[0978] 2-Aminomethyl-4-(2-ethoxy-phenyl)-pentanoic acid;
[0979] 2-Aminomethyl-4-(3-ethoxy-phenyl)-pentanoic acid;
[0980] 2-Aminomethyl-4-(4-ethoxy-phenyl)-pentanoic acid;
[0981] 2-Aminomethyl-4-(2,3-diethoxy-phenyl)-pentanoic acid;
[0982] 2-Aminomethyl-4-(2,4-diethoxy-phenyl)-pentanoic acid;
[0983] 2-Aminomethyl-4-(2,5-diethoxy-phenyl)-pentanoic acid;
[0984] 2-Aminomethyl-4-(2,6-diethoxy-phenyl)-pentanoic acid;
[0985] 2-Aminomethyl-4-(3,4-diethoxy-phenyl)-pentanoic acid;
[0986] 2-Aminomethyl-4-(3,5-diethoxy-phenyl)-pentanoic acid;
[0987] 2-Aminomethyl-4-(2,3,4-triethoxy-phenyl)-pentanoic acid;
[0988] 2-Aminomethyl-4-(2,3,5-triethoxy-phenyl)-pentanoic acid;
[0989] 2-Aminomethyl-4-(2,3,6-triethoxy-phenyl)-pentanoic acid;
[0990] 2-Aminomethyl-4-(2,4,6-triethoxy-phenyl)-pentanoic acid;
[0991] 2-Aminomethyl-4-(2-ethoxy-phenyl)-hexanoic acid;
[0992] 2-Aminomethyl-4-(3-ethoxy-phenyl)-hexanoic acid;
[0993] 2-Aminomethyl-4-(4-ethoxy-phenyl)-hexanoic acid;
[0994] 2-Aminomethyl-4-(2,3-diethoxy-phenyl)-hexanoic acid;
[0995] 2-Aminomethyl-4-(2,4-diethoxy-phenyl)-hexanoic acid;
[0996] 2-Aminomethyl-4-(2,5-diethoxy-phenyl)-hexanoic acid;
[0997] 2-Aminomethyl-4-(2,6-diethoxy-phenyl)-hexanoic acid;
[0998] 2-Aminomethyl-4-(3,4-diethoxy-phenyl)-hexanoic acid;
[0999] 2-Aminomethyl-4-(3,5-diethoxy-phenyl)-hexanoic acid;
[1000] 2-Aminomethyl-4-(2,3,4-triethoxy-phenyl)-hexanoic acid;
[1001] 2-Aminomethyl-4-(2,3,5-triethoxy-phenyl)-hexanoic acid;
[1002] 2-Aminomethyl-4-(2,3,6-triethoxy-phenyl)-hexanoic acid;
[1003] 2-Aminomethyl-4-(2,4,6-triethoxy-phenyl)-hexanoic acid;
[1004] 2-Aminomethyl-5-(2-ethoxy-phenyl)-4-methyl-pentanoic
acid;
[1005] 2-Aminomethyl-5-(3-ethoxy-phenyl)-4-methyl-pentanoic
acid;
[1006] 2-Aminomethyl-5-(4-ethoxy-phenyl)-4-methyl-pentanoic
acid;
[1007] 2-Aminomethyl-5-(2,3-diethoxy-phenyl)-4-methyl-pentanoic
acid;
[1008] 2-Aminomethyl-5-(2,4-diethoxy-phenyl)-4-methyl-pentanoic
acid;
[1009] 2-Aminomethyl-5-(2,5-diethoxy-phenyl)-4-methyl-pentanoic
acid;
[1010] 2-Aminomethyl-5-(2,6-diethoxy-phenyl)-4-methyl-pentanoic
acid;
[1011] 2-Aminomethyl-5-(3,4-diethoxy-phenyl)-4-methyl-pentanoic
acid;
[1012] 2-Aminomethyl-5-(3,5-diethoxy-phenyl)-4-methyl-pentanoic
acid;
[1013] 2-Aminomethyl-4-methyl-5-(2,3,4-triethoxy-phenyl)-pentanoic
acid;
[1014] 2-Aminomethyl-4-methyl-5-(2,3,5-triethoxy-phenyl)-pentanoic
acid;
[1015] 2-Aminomethyl-4-methyl-5-(2,3,6-triethoxy-phenyl)-pentanoic
acid;
[1016] 2-Aminomethyl-4-methyl-5-(2,4,6-triethoxy-phenyl)-pentanoic
acid;
[1017] 2-Aminomethyl-5-(2-ethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1018] 2-Aminomethyl-5-(3-ethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1019] 2-Aminomethyl-5-(4-ethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1020] 2-Aminomethyl-5-(2,3-diethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1021] 2-Aminomethyl-5-(2,4-diethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1022] 2-Aminomethyl-5-(2,5-diethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1023] 2-Aminomethyl-5-(2,6-diethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1024] 2-Aminomethyl-5-(3,4-diethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1025] 2-Aminomethyl-5-(3,5-diethoxy-phenyl)-4-ethyl-pentanoic
acid;
[1026] 2-Aminomethyl-4-ethyl-5-(2,3,4-triethoxy-phenyl)-pentanoic
acid;
[1027] 2-Aminomethyl-4-ethyl-5-(2,3,5-triethoxy-phenyl)-pentanoic
acid;
[1028] 2-Aminomethyl-4-ethyl-5-(2,3,6-triethoxy-phenyl)-pentanoic
acid;
[1029] 2-Aminomethyl-4-ethyl-5-(2,4,6-triethoxy-phenyl)-pentanoic
acid;
[1030]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetraethoxy-phenyl)-pentanoic
acid;
[1031]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetraethoxy-phenyl)-pentanoic
acid;
[1032]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetraethoxy-phenyl)-pentanoic
acid;
[1033] 2-Aminomethyl-4-ethyl-5-pentaethoxyphenyl-pentanoic
acid;
[1034] 2-Aminomethyl-5-(2-ethoxy-phenyl)-4-methyl-hexanoic
acid;
[1035] 2-Aminomethyl-5-(3-ethoxy-phenyl)-4-methyl-hexanoic
acid;
[1036] 2-Aminomethyl-5-(4-ethoxy-phenyl)-4-methyl-hexanoic
acid;
[1037] 2-Aminomethyl-5-(2,3-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1038] 2-Aminomethyl-5-(2,4-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1039] 2-Aminomethyl-5-(2,5-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1040] 2-Aminomethyl-5-(2,6-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1041] 2-Aminomethyl-5-(3,4-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1042] 2-Aminomethyl-5-(3,5-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1043] 2-Aminomethyl-4-methyl-5-(2,3,4-triethoxy-phenyl)-hexanoic
acid;
[1044] 2-Aminomethyl-4-methyl-5-(2,3,5-triethoxy-phenyl)-hexanoic
acid;
[1045] 2-Aminomethyl-4-methyl-5-(2,3,6-triethoxy-phenyl)-hexanoic
acid;
[1046] 2-Aminomethyl-4-methyl-5-(2,4,6-triethoxy-phenyl)-hexanoic
acid;
[1047] 2-Aminomethyl-6-(2-ethoxy-phenyl)-4-methyl-hexanoic
acid;
[1048] 2-Aminomethyl-6-(3-ethoxy-phenyl)-4-methyl-hexanoic
acid;
[1049] 2-Aminomethyl-6-(4-ethoxy-phenyl)-4-methyl-hexanoic
acid;
[1050] 2-Aminomethyl-6-(2,3-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1051] 2-Aminomethyl-6-(2,4-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1052] 2-Aminomethyl-6-(2,5-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1053] 2-Aminomethyl-6-(2,6-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1054] 2-Aminomethyl-6-(3,4-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1055] 2-Aminomethyl-6-(3,5-diethoxy-phenyl)-4-methyl-hexanoic
acid;
[1056] 2-Aminomethyl-4-methyl-6-(2,3,4-triethoxy-phenyl)-hexanoic
acid;
[1057] 2-Aminomethyl-4-methyl-6-(2,3,5-triethoxy-phenyl)-hexanoic
acid;
[1058] 2-Aminomethyl-4-methyl-6-(2,3,6-triethoxy-phenyl)-hexanoic
acid;
[1059] 2-Aminomethyl-4-methyl-6-(2,4,6-triethoxy-phenyl)-hexanoic
acid;
[1060] 2-Aminomethyl-6-(2-ethoxy-phenyl)-4-ethyl-hexanoic acid;
[1061] 2-Aminomethyl-6-(3-ethoxy-phenyl)-4-ethyl-hexanoic acid;
[1062] 2-Aminomethyl-6-(4-ethoxy-phenyl)-4-ethyl-hexanoic acid;
[1063] 2-Aminomethyl-6-(2,3-diethoxy-phenyl)-4-ethyl-hexanoic
acid;
[1064] 2-Aminomethyl-6-(2,4-diethoxy-phenyl)-4-ethyl-hexanoic
acid;
[1065] 2-Aminomethyl-6-(2,5-diethoxy-phenyl)-4-ethyl-hexanoic
acid;
[1066] 2-Aminomethyl-6-(2,6-diethoxy-phenyl)-4-ethyl-hexanoic
acid;
[1067] 2-Aminomethyl-6-(3,4-diethoxy-phenyl)-4-ethyl-hexanoic
acid;
[1068] 2-Aminomethyl-6-(3,5-diethoxy-phenyl)-4-ethyl-hexanoic
acid;
[1069] 2-Aminomethyl-4-ethyl-6-(2,3,4-triethoxy-phenyl)-hexanoic
acid;
[1070] 2-Aminomethyl-4-ethyl-6-(2,3,5-triethoxy-phenyl)-hexanoic
acid;
[1071] 2-Aminomethyl-4-ethyl-6-(2,3,6-triethoxy-phenyl)-hexanoic
acid;
[1072] 2-Aminomethyl-4-ethyl-6-(2,4,6-triethoxy-phenyl)-hexanoic
acid;
[1073] 2-Aminomethyl-7-(2-ethoxy-phenyl)-4-methyl-heptanoic
acid;
[1074] 2-Aminomethyl-7-(3-ethoxy-phenyl)-4-methyl-heptanoic
acid;
[1075] 2-Aminomethyl-7-(4-ethoxy-phenyl)-4-methyl-heptanoic
acid;
[1076] 2-Aminomethyl-7-(2,3-diethoxy-phenyl)-4-methyl-heptanoic
acid;
[1077] 2-Aminomethyl-7-(2,4-diethoxy-phenyl)-4-methyl-heptanoic
acid;
[1078] 2-Aminomethyl-7-(2,5-diethoxy-phenyl)-4-methyl-heptanoic
acid;
[1079] 2-Aminomethyl-7-(2,6-diethoxy-phenyl)-4-methyl-heptanoic
acid;
[1080] 2-Aminomethyl-7-(3,4-diethoxy-phenyl)-4-methyl-heptanoic
acid;
[1081] 2-Aminomethyl-7-(3,5-diethoxy-phenyl)-4-methyl-heptanoic
acid;
[1082] 2-Aminomethyl-4-methyl-7-(2,3,4-triethoxy-phenyl)-heptanoic
acid;
[1083] 2-Aminomethyl-4-methyl-7-(2,3,5-triethoxy-phenyl)-heptanoic
acid;
[1084] 2-Aminomethyl-4-methyl-7-(2,3,6-triethoxy-phenyl)-heptanoic
acid;
[1085] 2-Aminomethyl-4-methyl-7-(2,4,6-triethoxy-phenyl)-heptanoic
acid;
[1086] 2-Aminomethyl-7-(2-ethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1087] 2-Aminomethyl-7-(3-ethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1088] 2-Aminomethyl-7-(4-ethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1089] 2-Aminomethyl-7-(2,3-diethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1090] 2-Aminomethyl-7-(2,4-diethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1091] 2-Aminomethyl-7-(2,5-diethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1092] 2-Aminomethyl-7-(2,6-diethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1093] 2-Aminomethyl-7-(3,4-diethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1094] 2-Aminomethyl-7-(3,5-diethoxy-phenyl)-4-ethyl-heptanoic
acid;
[1095] 2-Aminomethyl-4-ethyl-7-(2,3,4-triethoxy-phenyl)-heptanoic
acid;
[1096] 2-Aminomethyl-4-ethyl-7-(2,3,5-triethoxy-phenyl)-heptanoic
acid;
[1097] 2-Aminomethyl-4-ethyl-7-(2,3,6-triethoxy-phenyl)-heptanoic
acid;
[1098] 2-Aminomethyl-4-ethyl-7-(2,4,6-triethoxy-phenyl)-heptanoic
acid;
[1099] 2-Aminomethyl-4-(2-methyl-phenyl)-pentanoic acid;
[1100] 2-Aminomethyl-4-(3-methyl-phenyl)-pentanoic acid;
[1101] 2-Aminomethyl-4-(4-methyl-phenyl)-pentanoic acid;
[1102] 2-Aminomethyl-4-(2,3-dimethyl-phenyl)-pentanoic acid;
[1103] 2-Aminomethyl-4-(2,4-dimethyl-phenyl)-pentanoic acid;
[1104] 2-Aminomethyl-4-(2,5-dimethyl-phenyl)-pentanoic acid;
[1105] 2-Aminomethyl-4-(2,6-dimethyl-phenyl)-pentanoic acid;
[1106] 2-Aminomethyl-4-(3,4-dimethyl-phenyl)-pentanoic acid;
[1107] 2-Aminomethyl-4-(3,5-dimethyl-phenyl)-pentanoic acid;
[1108] 2-Aminomethyl-4-(2,3,4-trimethyl-phenyl)-pentanoic acid;
[1109] 2-Aminomethyl-4-(2,3,5-trimethyl-phenyl)-pentanoic acid;
[1110] 2-Aminomethyl-4-(2,3,6-trimethyl-phenyl)-pentanoic acid;
[1111] 2-Aminomethyl-4-(2,4,6-trimethyl-phenyl)-pentanoic acid;
[1112] 2-Aminomethyl-4-(2-methyl-phenyl)-hexanoic acid;
[1113] 2-Aminomethyl-4-(3-methyl-phenyl)-hexanoic acid;
[1114] 2-Aminomethyl-4-(4-methyl-phenyl)-hexanoic acid;
[1115] 2-Aminomethyl-4-(2,3-dimethyl-phenyl)-hexanoic acid;
[1116] 2-Aminomethyl-4-(2,4-dimethyl-phenyl)-hexanoic acid;
[1117] 2-Aminomethyl-4-(2,5-dimethyl-phenyl)-hexanoic acid;
[1118] 2-Aminomethyl-4-(2,6-dimethyl-phenyl)-hexanoic acid;
[1119] 2-Aminomethyl-4-(3,4-dimethyl-phenyl)-hexanoic acid;
[1120] 2-Aminomethyl-4-(3,5-dimethyl-phenyl)-hexanoic acid;
[1121] 2-Aminomethyl-4-(2,3,4-trimethyl-phenyl)-hexanoic acid;
[1122] 2-Aminomethyl-4-(2,3,5-trimethyl-phenyl)-hexanoic acid;
[1123] 2-Aminomethyl-4-(2,3,6-trimethyl-phenyl)-hexanoic acid;
[1124] 2-Aminomethyl-4-(2,4,6-trimethyl-phenyl)-hexanoic acid;
[1125] 2-Aminomethyl-5-(2-methyl-phenyl)-4-methyl-pentanoic
acid;
[1126] 2-Aminomethyl-5-(3-methyl-phenyl)-4-methyl-pentanoic
acid;
[1127] 2-Aminomethyl-5-(4-methyl-phenyl)-4-methyl-pentanoic
acid;
[1128] 2-Aminomethyl-5-(2,3-dimethyl-phenyl)-4-methyl-pentanoic
acid;
[1129] 2-Aminomethyl-5-(2,4-dimethyl-phenyl)-4-methyl-pentanoic
acid;
[1130] 2-Aminomethyl-5-(2,5-dimethyl-phenyl)-4-methyl-pentanoic
acid;
[1131] 2-Aminomethyl-5-(2,6-dimethyl-phenyl)-4-methyl-pentanoic
acid;
[1132] 2-Aminomethyl-5-(3,4-dimethyl-phenyl)-4-methyl-pentanoic
acid;
[1133] 2-Aminomethyl-5-(3,5-dimethyl-phenyl)-4-methyl-pentanoic
acid;
[1134] 2-Aminomethyl-4-methyl-5-(2,3,4-trimethyl-phenyl)-pentanoic
acid;
[1135] 2-Aminomethyl-4-methyl-5-(2,3,5-trimethyl-phenyl)-pentanoic
acid;
[1136] 2-Aminomethyl-4-methyl-5-(2,3,6-trimethyl-phenyl)-pentanoic
acid;
[1137] 2-Aminomethyl-4-methyl-5-(2,4,6-trimethyl-phenyl)-pentanoic
acid;
[1138] 2-Aminomethyl-5-(2-methyl-phenyl)-4-ethyl-pentanoic
acid;
[1139] 2-Aminomethyl-5-(3-methyl-phenyl)-4-ethyl-pentanoic
acid;
[1140] 2-Aminomethyl-5-(4-methyl-phenyl)-4-ethyl-pentanoic
acid;
[1141] 2-Aminomethyl-5-(2,3-dimethyl-phenyl)-4-ethyl-pentanoic
acid;
[1142] 2-Aminomethyl-5-(2,4-dimethyl-phenyl)-4-ethyl-pentanoic
acid;
[1143] 2-Aminomethyl-5-(2,5-dimethyl-phenyl)-4-ethyl-pentanoic
acid;
[1144] 2-Aminomethyl-5-(2,6-dimethyl-phenyl)-4-ethyl-pentanoic
acid;
[1145] 2-Aminomethyl-5-(3,4-dimethyl-phenyl)-4-ethyl-pentanoic
acid;
[1146] 2-Aminomethyl-5-(3,5-dimethyl-phenyl)-4-ethyl-pentanoic
acid;
[1147] 2-Aminomethyl-4-ethyl-5-(2,3,4-trimethyl-phenyl)-pentanoic
acid;
[1148] 2-Aminomethyl-4-ethyl-5-(2,3,5-trimethyl-phenyl)-pentanoic
acid;
[1149] 2-Aminomethyl-4-ethyl-5-(2,3,6-trimethyl-phenyl)-pentanoic
acid;
[1150] 2-Aminomethyl-4-ethyl-5-(2,4,6-trimethyl-phenyl)-pentanoic
acid;
[1151]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetramethyl-phenyl)-pentanoic
acid;
[1152]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetramethyl-phenyl)-pentanoic
acid;
[1153]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetramethyl-phenyl)-pentanoic
acid;
[1154] 2-Aminomethyl-4-ethyl-5-pentamethylphenyl-pentanoic
acid;
[1155] 2-Aminomethyl-5-(2-methyl-phenyl)-4-methyl-hexanoic
acid;
[1156] 2-Aminomethyl-5-(3-methyl-phenyl)-4-methyl-hexanoic
acid;
[1157] 2-Aminomethyl-5-(4-methyl-phenyl)-4-methyl-hexanoic
acid;
[1158] 2-Aminomethyl-5-(2,3-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1159] 2-Aminomethyl-5-(2,4-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1160] 2-Aminomethyl-5-(2,5-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1161] 2-Aminomethyl-5-(2,6-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1162] 2-Aminomethyl-5-(3,4-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1163] 2-Aminomethyl-5-(3,5-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1164] 2-Aminomethyl-4-methyl-5-(2,3,4-trimethyl-phenyl)-hexanoic
acid;
[1165] 2-Aminomethyl-4-methyl-5-(2,3,5-trimethyl-phenyl)-hexanoic
acid;
[1166] 2-Aminomethyl-4-methyl-5-(2,3,6-trimethyl-phenyl)-hexanoic
acid;
[1167] 2-Aminomethyl-4-methyl-5-(2,4,6-trimethyl-phenyl)-hexanoic
acid;
[1168] 2-Aminomethyl-6-(2-methyl-phenyl)-4-methyl-hexanoic
acid;
[1169] 2-Aminomethyl-6-(3-methyl-phenyl)-4-methyl-hexanoic
acid;
[1170] 2-Aminomethyl-6-(4-methyl-phenyl)-4-methyl-hexanoic
acid;
[1171] 2-Aminomethyl-6-(2,3-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1172] 2-Aminomethyl-6-(2,4-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1173] 2-Aminomethyl-6-(2,5-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1174] 2-Aminomethyl-6-(2,6-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1175] 2-Aminomethyl-6-(3,4-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1176] 2-Aminomethyl-6-(3,5-dimethyl-phenyl)-4-methyl-hexanoic
acid;
[1177] 2-Aminomethyl-4-methyl-6-(2,3,4-trimethyl-phenyl)-hexanoic
acid;
[1178] 2-Aminomethyl-4-methyl-6-(2,3,5-trimethyl-phenyl)-hexanoic
acid;
[1179] 2-Aminomethyl-4-methyl-6-(2,3,6-trimethyl-phenyl)-hexanoic
acid;
[1180] 2-Aminomethyl-4-methyl-6-(2,4,6-trimethyl-phenyl)-hexanoic
acid;
[1181] 2-Aminomethyl-6-(2-methyl-phenyl)-4-ethyl-hexanoic acid;
[1182] 2-Aminomethyl-6-(3-methyl-phenyl)-4-ethyl-hexanoic acid;
[1183] 2-Aminomethyl-6-(4-methyl-phenyl)-4-ethyl-hexanoic acid;
[1184] 2-Aminomethyl-6-(2,3-dimethyl-phenyl)-4-ethyl-hexanoic
acid;
[1185] 2-Aminomethyl-6-(2,4-dimethyl-phenyl)-4-ethyl-hexanoic
acid;
[1186] 2-Aminomethyl-6-(2,5-dimethyl-phenyl)-4-ethyl-hexanoic
acid;
[1187] 2-Aminomethyl-6-(2,6-dimethyl-phenyl)-4-ethyl-hexanoic
acid;
[1188] 2-Aminomethyl-6-(3,4-dimethyl-phenyl)-4-ethyl-hexanoic
acid;
[1189] 2-Aminomethyl-6-(3,5-dimethyl-phenyl)-4-ethyl-hexanoic
acid;
[1190] 2-Aminomethyl-4-ethyl-6-(2,3,4-trimethyl-phenyl)-hexanoic
acid;
[1191] 2-Aminomethyl-4-ethyl-6-(2,3,5-trimethyl-phenyl)-hexanoic
acid;
[1192] 2-Aminomethyl-4-ethyl-6-(2,3,6-trimethyl-phenyl)-hexanoic
acid;
[1193] 2-Aminomethyl-4-ethyl-6-(2,4,6-trimethyl-phenyl)-hexanoic
acid;
[1194] 2-Aminomethyl-7-(2-methyl-phenyl)-4-methyl-heptanoic
acid;
[1195] 2-Aminomethyl-7-(3-methyl-phenyl)-4-methyl-heptanoic
acid;
[1196] 2-Aminomethyl-7-(4-methyl-phenyl)-4-methyl-heptanoic
acid;
[1197] 2-Aminomethyl-7-(2,3-dimethyl-phenyl)-4-methyl-heptanoic
acid;
[1198] 2-Aminomethyl-7-(2,4-dimethyl-phenyl)-4-methyl-heptanoic
acid;
[1199] 2-Aminomethyl-7-(2,5-dimethyl-phenyl)-4-methyl-heptanoic
acid;
[1200] 2-Aminomethyl-7-(2,6-dimethyl-phenyl)-4-methyl-heptanoic
acid;
[1201] 2-Aminomethyl-7-(3,4-dimethyl-phenyl)-4-methyl-heptanoic
acid;
[1202] 2-Aminomethyl-7-(3,5-dimethyl-phenyl)-4-methyl-heptanoic
acid;
[1203] 2-Aminomethyl-4-methyl-7-(2,3,4-trimethyl-phenyl)-heptanoic
acid;
[1204] 2-Aminomethyl-4-methyl-7-(2,3,5-trimethyl-phenyl)-heptanoic
acid;
[1205] 2-Aminomethyl-4-methyl-7-(2,3,6-trimethyl-phenyl)-heptanoic
acid;
[1206] 2-Aminomethyl-4-methyl-7-(2,4,6-trimethyl-phenyl)-heptanoic
acid;
[1207] 2-Aminomethyl-7-(2-methyl-phenyl)-4-ethyl-heptanoic
acid;
[1208] 2-Aminomethyl-7-(3-methyl-phenyl)-4-ethyl-heptanoic
acid;
[1209] 2-Aminomethyl-7-(4-methyl-phenyl)-4-ethyl-heptanoic
acid;
[1210] 2-Aminomethyl-7-(2,3-dimethyl-phenyl)-4-ethyl-heptanoic
acid;
[1211] 2-Aminomethyl-7-(2,4-dimethyl-phenyl)-4-ethyl-heptanoic
acid;
[1212] 2-Aminomethyl-7-(2,5-dimethyl-phenyl)-4-ethyl-heptanoic
acid;
[1213] 2-Aminomethyl-7-(2,6-dimethyl-phenyl)-4-ethyl-heptanoic
acid;
[1214] 2-Aminomethyl-7-(3,4-dimethyl-phenyl)-4-ethyl-heptanoic
acid;
[1215] 2-Aminomethyl-7-(3,5-dimethyl-phenyl)-4-ethyl-heptanoic
acid;
[1216] 2-Aminomethyl-4-ethyl-7-(2,3,4-trimethyl-phenyl)-heptanoic
acid;
[1217] 2-Aminomethyl-4-ethyl-7-(2,3,5-trimethyl-phenyl)-heptanoic
acid;
[1218] 2-Aminomethyl-4-ethyl-7-(2,3,6-trimethyl-phenyl)-heptanoic
acid;
[1219] 2-Aminomethyl-4-ethyl-7-(2,4,6-trimethyl-phenyl)-heptanoic
acid;
[1220] 2-Aminomethyl-4-(2-hydroxy-phenyl)-pentanoic acid;
[1221] 2-Aminomethyl-4-(3-hydroxy-phenyl)-pentanoic acid;
[1222] 2-Aminomethyl-4-(4-hydroxy-phenyl)-pentanoic acid;
[1223] 2-Aminomethyl-4-(2,3-dihydroxy-phenyl)-pentanoic acid;
[1224] 2-Aminomethyl-4-(2,4-dihydroxy-phenyl)-pentanoic acid;
[1225] 2-Aminomethyl-4-(2,5-dihydroxy-phenyl)-pentanoic acid;
[1226] 2-Aminomethyl-4-(2,6-dihydroxy-phenyl)-pentanoic acid;
[1227] 2-Aminomethyl-4-(3,4-dihydroxy-phenyl)-pentanoic acid;
[1228] 2-Aminomethyl-4-(3,5-dihydroxy-phenyl)-pentanoic acid;
[1229] 2-Aminomethyl-4-(2,3,4-trihydroxy-phenyl)-pentanoic
acid;
[1230] 2-Aminomethyl-4-(2,3,5-trihydroxy-phenyl)-pentanoic
acid;
[1231] 2-Aminomethyl-4-(2,3,6-trihydroxy-phenyl)-pentanoic
acid;
[1232] 2-Aminomethyl-4-(2,4,6-trihydroxy-phenyl)-pentanoic
acid;
[1233] 2-Aminomethyl-4-(2-hydroxy-phenyl)-hexanoic acid;
[1234] 2-Aminomethyl-4-(3-hydroxy-phenyl)-hexanoic acid;
[1235] 2-Aminomethyl-4-(4-hydroxy-phenyl)-hexanoic acid;
[1236] 2-Aminomethyl-4-(2,3-dihydroxy-phenyl)-hexanoic acid;
[1237] 2-Aminomethyl-4-(2,4-dihydroxy-phenyl)-hexanoic acid;
[1238] 2-Aminomethyl-4-(2,5-dihydroxy-phenyl)-hexanoic acid;
[1239] 2-Aminomethyl-4-(2,6-dihydroxy-phenyl)-hexanoic acid;
[1240] 2-Aminomethyl-4-(3,4-dihydroxy-phenyl)-hexanoic acid;
[1241] 2-Aminomethyl-4-(3,5-dihydroxy-phenyl)-hexanoic acid;
[1242] 2-Aminomethyl-4-(2,3,4-trihydroxy-phenyl)-hexanoic acid;
[1243] 2-Aminomethyl-4-(2,3,5-trihydroxy-phenyl)-hexanoic acid;
[1244] 2-Aminomethyl-4-(2,3,6-trihydroxy-phenyl)-hexanoic acid;
[1245] 2-Aminomethyl-4-(2,4,6-trihydroxy-phenyl)-hexanoic acid;
[1246] 2-Aminomethyl-5-(2-hydroxy-phenyl)-4-methyl-pentanoic
acid;
[1247] 2-Aminomethyl-5-(3-hydroxy-phenyl)-4-methyl-pentanoic
acid;
[1248] 2-Aminomethyl-5-(4-hydroxy-phenyl)-4-methyl-pentanoic
acid;
[1249] 2-Aminomethyl-5-(2,3-dihydroxy-phenyl)-4-methyl-pentanoic
acid;
[1250] 2-Aminomethyl-5-(2,4-dihydroxy-phenyl)-4-methyl-pentanoic
acid;
[1251] 2-Aminomethyl-5-(2,5-dihydroxy-phenyl)-4-methyl-pentanoic
acid;
[1252] 2-Aminomethyl-5-(2,6-dihydroxy-phenyl)-4-methyl-pentanoic
acid;
[1253] 2-Aminomethyl-5-(3,4-dihydroxy-phenyl)-4-methyl-pentanoic
acid;
[1254] 2-Aminomethyl-5-(3,5-dihydroxy-phenyl)-4-methyl-pentanoic
acid;
[1255] 2-Aminomethyl-4-methyl-5-(2,3,4-trihydroxy-phenyl)-pentanoic
acid;
[1256] 2-Aminomethyl-4-methyl-5-(2,3,5-trihydroxy-phenyl)-pentanoic
acid;
[1257] 2-Aminomethyl-4-methyl-5-(2,3,6-trihydroxy-phenyl)-pentanoic
acid;
[1258] 2-Aminomethyl-4-methyl-5-(2,4,6-trihydroxy-phenyl)-pentanoic
acid;
[1259] 2-Aminomethyl-5-(2-hydroxy-phenyl)-4-methyl-hexanoic
acid;
[1260] 2-Aminomethyl-5-(3-hydroxy-phenyl)-4-methyl-hexanoic
acid;
[1261] 2-Aminomethyl-5-(4-hydroxy-phenyl)-4-methyl-hexanoic
acid;
[1262] 2-Aminomethyl-5-(2,3-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1263] 2-Aminomethyl-5-(2,4-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1264] 2-Aminomethyl-5-(2,5-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1265] 2-Aminomethyl-5-(2,6-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1266] 2-Aminomethyl-5-(3,4-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1267] 2-Aminomethyl-5-(3,5-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1268] 2-Aminomethyl-4-methyl-5-(2,3,4-trihydroxy-phenyl)-hexanoic
acid;
[1269] 2-Aminomethyl-4-methyl-5-(2,3,5-trihydroxy-phenyl)-hexanoic
acid;
[1270] 2-Aminomethyl-4-methyl-5-(2,3,6-trihydroxy-phenyl)-hexanoic
acid;
[1271] 2-Aminomethyl-4-methyl-5-(2,4,6-trihydroxy-phenyl)-hexanoic
acid;
[1272] 2-Aminomethyl-6-(2-hydroxy-phenyl)-4-methyl-hexanoic
acid;
[1273] 2-Aminomethyl-6-(3-hydroxy-phenyl)-4-methyl-hexanoic
acid;
[1274] 2-Aminomethyl-6-(4-hydroxy-phenyl)-4-methyl-hexanoic
acid;
[1275] 2-Aminomethyl-6-(2,3-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1276] 2-Aminomethyl-6-(2,4-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1277] 2-Aminomethyl-6-(2,5-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1278] 2-Aminomethyl-6-(2,6-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1279] 2-Aminomethyl-6-(3,4-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1280] 2-Aminomethyl-6-(3,5-dihydroxy-phenyl)-4-methyl-hexanoic
acid;
[1281] 2-Aminomethyl-4-methyl-6-(2,3,4-trihydroxy-phenyl)-hexanoic
acid;
[1282] 2-Aminomethyl-4-methyl-6-(2,3,5-trihydroxy-phenyl)-hexanoic
acid;
[1283] 2-Aminomethyl-4-methyl-6-(2,3,6-trihydroxy-phenyl)-hexanoic
acid;
[1284] 2-Aminomethyl-4-methyl-6-(2,4,6-trihydroxy-phenyl)-hexanoic
acid;
[1285] 2-Aminomethyl-5-(2-hydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1286] 2-Aminomethyl-5-(3-hydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1287] 2-Aminomethyl-5-(4-hydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1288] 2-Aminomethyl-5-(2,3-dihydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1289] 2-Aminomethyl-5-(2,4-dihydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1290] 2-Aminomethyl-5-(2,5-dihydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1291] 2-Aminomethyl-5-(2,6-dihydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1292] 2-Aminomethyl-5-(3,4-dihydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1293] 2-Aminomethyl-5-(3,5-dihydroxy-phenyl)-4-ethyl-pentanoic
acid;
[1294] 2-Aminomethyl-4-ethyl-5-(2,3,4-trihydroxy-phenyl)-pentanoic
acid;
[1295] 2-Aminomethyl-4-ethyl-5-(2,3,5-trihydroxy-phenyl)-pentanoic
acid;
[1296] 2-Aminomethyl-4-ethyl-5-(2,3,6-trihydroxy-phenyl)-pentanoic
acid;
[1297] 2-Aminomethyl-4-ethyl-5-(2,4,6-trihydroxy-phenyl)-pentanoic
acid;
[1298]
2-Aminomethyl-4-ethyl-5-(2,3,4,5-tetrahydroxy-phenyl)-pentanoic
acid;
[1299]
2-Aminomethyl-4-ethyl-5-(2,3,4,6-tetrahydroxy-phenyl)-pentanoic
acid;
[1300]
2-Aminomethyl-4-ethyl-5-(2,3,5,6-tetrahydroxy-phenyl)-pentanoic
acid;
[1301] 2-Aminomethyl-4-ethyl-5-pentahydroxyphenyl-pentanoic
acid;
[1302] 2-Aminomethyl-6-(2-hydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1303] 2-Aminomethyl-6-(3-hydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1304] 2-Aminomethyl-6-(4-hydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1305] 2-Aminomethyl-6-(2,3-dihydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1306] 2-Aminomethyl-6-(2,4-dihydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1307] 2-Aminomethyl-6-(2,5-dihydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1308] 2-Aminomethyl-6-(2,6-dihydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1309] 2-Aminomethyl-6-(3,4-dihydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1310] 2-Aminomethyl-6-(3,5-dihydroxy-phenyl)-4-ethyl-hexanoic
acid;
[1311] 2-Aminomethyl-4-ethyl-6-(2,3,4-trihydroxy-phenyl)-hexanoic
acid;
[1312] 2-Aminomethyl-4-ethyl-6-(2,3,5-trihydroxy-phenyl)-hexanoic
acid;
[1313] 2-Aminomethyl-4-ethyl-6-(2,3,6-trihydroxy-phenyl)-hexanoic
acid;
[1314] 2-Aminomethyl-4-ethyl-6-(2,4,6-trihydroxy-phenyl)-hexanoic
acid;
[1315] 2-Aminomethyl-7-(2-hydroxy-phenyl)-4-methyl-heptanoic
acid;
[1316] 2-Aminomethyl-7-(3-hydroxy-phenyl)-4-methyl-heptanoic
acid;
[1317] 2-Aminomethyl-7-(4-hydroxy-phenyl)-4-methyl-heptanoic
acid;
[1318] 2-Aminomethyl-7-(2,3-dihydroxy-phenyl)-4-methyl-heptanoic
acid;
[1319] 2-Aminomethyl-7-(2,4-dihydroxy-phenyl)-4-methyl-heptanoic
acid;
[1320] 2-Aminomethyl-7-(2,5-dihydroxy-phenyl)-4-methyl-heptanoic
acid;
[1321] 2-Aminomethyl-7-(2,6-dihydroxy-phenyl)-4-methyl-heptanoic
acid;
[1322] 2-Aminomethyl-7-(3,4-dihydroxy-phenyl)-4-methyl-heptanoic
acid;
[1323] 2-Aminomethyl-7-(3,5-dihydroxy-phenyl)-4-methyl-heptanoic
acid;
[1324] 2-Aminomethyl-4-methyl-7-(2,3,4-trihydroxy-phenyl)-heptanoic
acid;
[1325] 2-Aminomethyl-4-methyl-7-(2,3,5-trihydroxy-phenyl)-heptanoic
acid;
[1326] 2-Aminomethyl-4-methyl-7-(2,3,6-trihydroxy-phenyl)-heptanoic
acid;
[1327] 2-Aminomethyl-4-methyl-7-(2,4,6-trihydroxy-phenyl)-heptanoic
acid;
[1328] 2-Aminomethyl-7-(2-hydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1329] 2-Aminomethyl-7-(3-hydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1330] 2-Aminomethyl-7-(4-hydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1331] 2-Aminomethyl-7-(2,3-dihydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1332] 2-Aminomethyl-7-(2,4-dihydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1333] 2-Aminomethyl-7-(2,5-dihydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1334] 2-Aminomethyl-7-(2,6-dihydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1335] 2-Aminomethyl-7-(3,4-dihydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1336] 2-Aminomethyl-7-(3,5-dihydroxy-phenyl)-4-ethyl-heptanoic
acid;
[1337] 2-Aminomethyl-4-ethyl-7-(2,3,4-trihydroxy-phenyl)-heptanoic
acid;
[1338] 2-Aminomethyl-4-ethyl-7-(2,3,5-trihydroxy-phenyl)-heptanoic
acid;
[1339] 2-Aminomethyl-4-ethyl-7-(2,3,6-trihydroxy-phenyl)-heptanoic
acid;
[1340] 2-Aminomethyl-4-ethyl-7-(2,4,6-trihydroxy-phenyl)-heptanoic
acid;
[1341]
2-Aminomethyl-4-ethyl-7-(2,3,4,5-tetrahydroxy-phenyl)-heptanoic
acid;
[1342]
2-Aminomethyl-4-ethyl-7-(2,3,4,6-tetrahydroxy-phenyl)-heptanoic
acid;
[1343]
2-Aminomethyl-4-ethyl-7-(2,3,5,6-tetrahydroxy-phenyl)-heptanoic
acid;
[1344] 2-Aminomethyl-4-ethyl-7-pentahydroxyphenyl-heptanoic
acid;
[1345] (2R,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic
acid;
[1346] (2S,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic
acid;
[1347]
(2R,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[1348]
(2S,4S)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[1349] (2R,4S)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic
acid;
[1350] (2S,4S)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic
acid;
[1351] (2S,4S)-2-Aminomethyl-4-(3,5-difluoro-benzyl)-hexanoic
acid;
[1352] (2S,4S)-2-Aminomethyl-4-(2-fluoro-benzyl)-hexanoic acid;
[1353]
(2S,4S)-2-Aminomethyl-5-(2,4-difluoro-phenyl)-4-methyl-pentanoic
acid;
[1354] (2S)-2-Aminomethyl-5-(2,4-difluoro-phenyl)-pentanoic
acid;
[1355] (2S,4S)-2-Aminomethyl-4-(2,6-difluoro-benzyl)-hexanoic
acid;
[1356] (2S,4S)-2-Aminomethyl-4-(4-fluoro-benzyl)-hexanoic acid;
[1357] (2S,4S)-2-Aminomethyl-4-(2,5-difluoro-benzyl)-hexanoic
acid;
[1358] (2S,4S)-2-Aminomethyl-4-(3-fluoro-benzyl)-hexanoic acid;
[1359] (2S,4S)-2-Aminomethyl-4-pentafluorophenylmethyl-hexanoic
acid;
[1360]
(2S,4R)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-ethyl-heptanoic
acid;
[1361] (2S,4S)-2-Aminomethyl-4-(4-trifluoromethyl-benzyl)-hexanoic
acid;
[1362] 2-Aminomethyl-4-(4-methoxy-2-methyl-benzyl)-hexanoic
acid;
[1363]
2-Aminomethyl-5-(4-methoxy-2-methyl-phenyl)-4-methyl-pentanoic
acid;
[1364] 2-Aminomethyl-4-(4-methoxy-3-methyl-benzyl)-hexanoic acid;
and
[1365]
2-Aminomethyl-5-(4-methoxy-3-methyl-phenyl)-4-methyl-pentanoic
acid.
[1366] Other compounds of formula V include the following
compounds, and their pharmaceutically acceptable salts:
[1367] 2-Aminomethyl-4-ethyl-5-methyl-hexanoic acid;
[1368] 2-Aminomethyl-4-ethyl-3-methyl-hexanoic acid;
[1369] 2-Aminomethyl-3,4-dimethyl-hexanoic acid;
[1370] 2-Aminomethyl-3-ethyl-4-methyl-hexanoic acid;
[1371] 2-Aminomethyl-4-ethyl-3-methyl-heptanoic acid;
[1372] 2-Aminomethyl-3,4-dimethyl-octanoic acid;
[1373] 2-Aminomethyl-3-methyl-pentanoic acid;
[1374] 2-Aminomethyl-3-methyl-hexanoic acid;
[1375] 2-Aminomethyl-3-methyl-heptanoic acid;
[1376] 2-Aminomethyl-3,4-dimethyl-pentanoic acid;
[1377] 2-Aminomethyl-3,5-dimethyl-hexanoic acid;
[1378] 2-Aminomethyl-3,6-dimethyl-heptanoic acid;
[1379] 2-Aminomethyl-3,5,5-trimethyl-hexanoic acid;
[1380] 2-Aminomethyl-3-cyclopropyl-butyric acid;
[1381] 2-Aminomethyl-3-cyclopentyl-butyric acid;
[1382] 2-Aminomethyl-3-cyclohexyl-butyric acid;
[1383] 2-Aminomethyl-4-cyclohexyl-3-methyl-butyric acid;
[1384] 2-Aminomethyl-5-cyclohexyl-3-methyl-pentanoic acid;
[1385] 2-Aminomethyl-3-methyl-4-(4-methyl-cyclohexyl)-butyric
acid;
[1386] 2-Aminomethyl-3-ethyl-pentanoic acid;
[1387] 2-Aminomethyl-3-ethyl-hexanoic acid;
[1388] 2-Aminomethyl-3-ethyl-heptanoic acid;
[1389] 2-Aminomethyl-3-ethyl-4-methyl-pentanoic acid;
[1390] 2-Aminomethyl-3-cyclohexylmethyl-pentanoic acid;
[1391] 2-Aminomethyl-5-(4-methoxy-cyclohexyl)-3-methyl-pentanoic
acid;
[1392] 2-Aminomethyl-5-(4-methoxy-phenyl)-3-methyl-pentanoic
acid;
[1393] 2-Aminomethyl-4-(2-methoxy-phenyl)-3-methyl-butyric
acid;
[1394] 2-Aminomethyl-4-(4-methoxy-phenyl)-3-methyl-butyric
acid;
[1395] 2-Aminomethyl-3-phenyl-butyric acid;
[1396] 2-Aminomethyl-3-methyl-4-phenyl-butyric acid;
[1397] 2-Aminomethyl-3-methyl-5-phenyl-pentanoic acid;
[1398] 2-Aminomethyl-3-methyl-4-(3-trifluoromethyl-phenyl)-butyric
acid;
[1399] 2-Aminomethyl-3-(4-ethyl-phenyl)-butyric acid;
[1400] 2-Aminomethyl-3-(2,5-dimethyl-phenyl)-butyric acid;
[1401] 2-Aminomethyl-3-methyl-4-p-tolyl-butyric acid;
[1402] 2-Aminomethyl-3-m-tolyl-butyric acid;
[1403] 2-Aminomethyl-3-benzyl-pentanoic acid; and
[1404] 2-Aminomethyl-4-(4-fluoro-phenyl)-3-methyl-butyric acid.
[1405] This invention also provides compounds of formula VI 6
[1406] and their pharmaceutically acceptable salts, wherein
R.sub.3, R.sub.4, and R.sub.5 are as defined above in formula I,
with the proviso that R.sub.3, R.sub.4, and R.sub.5 are not
simultaneously hydrogen atoms.
[1407] Specific compounds of formula VI include the following
compounds and their pharmaceutically acceptable salts:
[1408] 2-Aminomethyl-5-cyclopropyl-hexanoic acid;
[1409] 2-Aminomethyl-5-cyclobutyl-hexanoic acid;
[1410] 2-Aminomethyl-5-cyclopentyl-hexanoic acid;
[1411] 2-Aminomethyl-5-cyclohexyl-hexanoic acid;
[1412] 2-Aminomethyl-5-phenyl-hexanoic acid;
[1413] 2-Aminomethyl-5-(3-chloro-phenyl)-hexanoic acid;
[1414] 2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-hexanoic
acid;
[1415] 2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-hexanoic
acid;
[1416] 2-Aminomethyl-5-cyclopropyl-heptanoic acid;
[1417] 2-Aminomethyl-5-cyclobutyl-heptanoic acid;
[1418] 2-Aminomethyl-5-cyclopentyl-heptanoic acid;
[1419] 2-Aminomethyl-5-cyclohexyl-heptanoic acid;
[1420] 2-Aminomethyl-5-phenyl-heptanoic acid;
[1421] 2-Aminomethyl-5-(3-chloro-phenyl)-heptanoic acid;
[1422] 2-Aminomethyl-5-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1423] 2-Aminomethyl-5-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1424] 2-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
[1425] 2-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic
acid;
[1426] 2-Aminomethyl-5-methyl-6-(3-trifluoromethyl-phenyl)-hexanoic
acid;
[1427] 2-Aminomethyl-5-methyl-6-(4-trifluoromethyl-phenyl)-hexanoic
acid;
[1428] 2-Aminomethyl-5-cyclopropylmethyl-heptanoic acid;
[1429] 2-Aminomethyl-5-cyclobutylmethyl-heptanoic acid;
[1430] 2-Aminomethyl-5-cyclopentylmethyl-heptanoic acid;
[1431] 2-Aminomethyl-5-cyclohexylmethyl-heptanoic acid;
[1432] 2-Aminomethyl-5-benzyl-heptanoic acid;
[1433] 2-Aminomethyl-5-(3-chloro-benzyl)-heptanoic acid;
[1434] 2-Aminomethyl-5-(3-trifluoromethyl-benzyl)-heptanoic
acid;
[1435] 2-Aminomethyl-5-(4-trifluoromethyl-benzyl)-heptanoic
acid;
[1436] 2-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
[1437] 2-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic
acid;
[1438]
2-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1439]
2-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1440] 2-Aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid;
[1441] 2-Aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid;
[1442] 2-Aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid;
[1443] 2-Aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid;
[1444] 2-Aminomethyl-5-ethyl-7-phenyl-heptanoic acid;
[1445] 2-Aminomethyl-7-(3-chloro-phenyl)-5-ethyl-heptanoic
acid;
[1446] 2-Aminomethyl-5-ethyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1447] 2-Aminomethyl-5-ethyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1448] 2-Aminomethyl-5,5-dimethyl-heptanoic acid;
[1449] 2-Aminomethyl-5,5-dimethyl-octanoic acid; and
[1450] 2-Aminomethyl-5,5-dimethyl-nonanoic acid.
[1451] This invention also provides pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
formula I, II, III, IV, V or VI, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
[1452] This invention also provides a method of treating a disorder
or condition in a mammal, including a human, the 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, post herpetic
neuralgia, lower back pain, surgical pain, vascular headache,
chronic headache, sinus headache, inflammatory disorders (e.g.,
rheumatoid arthritis, osteoarthritis, disease modification of
osteoarthritis disease, psoriasis), diuresis, premenstrual
syndrome, premenstrual dysphoric disorder, tinnitus, and gastric
damage. The method comprises administering to a mammal in need of
such treatment a therapeutically effective amount of a compound of
formula I, II, III, IV, V or VI, or a pharmaceutically acceptable
salt thereof.
[1453] The present invention also provides a method of treating
neurodegenerative disorders termed acute brain injury. These
include but are not limited to stroke, head trauma, and asphyxia.
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.
[1454] Compounds of formula I, II, III, IV, V or VI, 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.
[1455] This invention also provides a method of treating a disorder
or condition in a mammal, including a human, the 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 Alzheimer's
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, neuroleptic 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. The method comprises administering
to a mammal in need of such treatment a therapeutically effective
amount of a compound of formula I, II, III, IV, V or VI, or a
pharmaceutically acceptable salt thereof.
[1456] This invention also provides for improving cognition in
mammals, including humans, having AD, PD, and fibromyalgia by
enhancing the amount and the quality of sleep. The method comprises
administering to a mammal in need of improved cognition a
therapeutically effective amount of a compound of formula I, II,
III, IV, V or VI, or a pharmaceutically acceptable salt
thereof.
[1457] This invention also provides a method of treating pain in a
mammal, including a human, the method comprising administering to a
mammal in need of such treatment a therapeutically effective amount
of a compound of formula I, II, III, IV, V or VI, or a
pharmaceutically acceptable salt thereof. 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 three to six months and
includes somatogenic pain and psychogenic pain. Other pain is
nociceptive.
[1458] Examples of the types of pain that can be treated with the
compounds of formula I, II, III, IV, V or VI, 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.
[1459] 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.
[1460] Psychogenic pain is that which occurs without an organic
origin such as low back pain, atypical facial pain, and chronic
headache.
[1461] Other types of pain include 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.
[1462] This invention also provides a method of treating
depression, which comprises administering to a mammal, including a
human, in need of such treatment a therapeutically effective amount
of a compound of formula I, II, III, IV, V or VI, or a
pharmaceutically acceptable salt thereof. 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
Diagnostic and Statistical Manual of Mental Disorders (4th ed.,
1994), which is referred to as the DSM-IV-R Manual, and is
published by the American Psychiatric Association.
[1463] This invention also provides a method of treating a disorder
or condition in a mammal, including a human, the 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, including
weight loss associated with anorexia, cancer, old age and/or
frailty, 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, social anxiety disorder, social phobia, fear of
flying, 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.
The method comprises administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of
formula I, II, III, IV, V or VI, or a pharmaceutically acceptable
salt thereof.
[1464] 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 involve
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, parasomnias, restless leg syndrome, jet lag, periodic
limb movement disorder, and altered sleep architecture.
[1465] This invention also provides a method of treating a disorder
or condition in a mammal, including a human, the 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, and sleep disorders associated
with shift work and irregular work hours). The method comprises
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of formula I, II,
III, IV, V or VI, or a pharmaceutically acceptable salt
thereof.
[1466] Compounds of formulas I, II, III, IV, V or VI contain at
least one stereogenic (chiral) center and therefore may exist in
different enantiomeric and diastereomeric forms. This invention
includes all stereoisomers, including optical isomers, of the
compounds of formula I, II, III, IV, V or VI. Samples of the
compounds may exist as racemic mixtures, as individual enantiomers
and diastereoisomers, and as mixtures thereof. The invention also
includes all pharmaceutical compositions and methods of treatment
defined above that contain or employ stereoisomers of the compounds
of formula I, II, III, IV, V or VI.
[1467] Compounds with one stereogenic center may exist as a racemic
(equimolar) mixture, as a non-equimolar mixture of isomers, and as
pure enantiomers having S- or R-stereoconfiguration. Compounds with
two stereogenic centers may exist as a racemic mixture, as a
non-equimolar mixture of isomers, and as pure enantiomers having
SS, RR, SR or RS stereoconfiguration. Compounds with three
stereogenic centers may exist as a racemic mixture, as a
non-equimolar mixture of isomers, and as pure enantiomers having
RRR, SSS, SRR, RSS, RSR, SRS, RRS or SSR stereoconfiguration.
Individual isomers may 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 racemic
mixtures of these compounds, in the treatment of various disorders
or conditions.
[1468] The present invention also includes isotopically labeled
compounds, which are identical to those recited in formula I, II,
III, IV, V, or VI 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 labeled 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 labeled compounds of formula I, II,
III, IV, V, or VI 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 labeled reagent for a
non-isotopically labeled reagent.
[1469] Unless otherwise indicated, this disclosure uses definitions
provided below. Some of the definitions and formulae may include a
"-" (dash) to indicate a bond between atoms or a point of
attachment to a named or unnamed atom or group of atoms. Other
definitions and formulae may include an "=" (equal sign) or
".ident."(identity sign) to indicate a double bond or a triple
bond, respectively. Certain formulae may also include an "*"
(asterisk) to indicate a stereogenic (chiral) center. Such formulae
may refer to the racemate or to individual enantiomers, which may
or may not be substantially pure.
[1470] The term "substituted" when used in connection with a
compound, substituent, or moiety, indicates that one or more
hydrogen atoms have been replaced with one or more non-hydrogen
atoms or groups, provided that valence requirements are met and
that a chemically stable compound results from the
substitution.
[1471] The term "alkyl" refers to straight chain and branched
saturated hydrocarbon groups, generally having a specified number
of carbon atoms; i.e., (C.sub.1-C.sub.6)alkyl refers to an alkyl
group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl
groups include, without limitation, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl,
pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl,
2,2,2-trimethyleth-1-yl, n-hexyl, 3-ethylbutyl, and the like.
[1472] The term "cycloalkyl" refers to saturated monocyclic and
bicyclic hydrocarbon rings, generally having a specified number of
carbon atoms that comprise the ring; i.e.,
(C.sub.3-C.sub.6)cycloalkyl refers to a cycloalkyl group having 3,
4, 5, or 6 carbon atoms as ring members. The cycloalkyl may be
attached to a parent group or to a substrate at any ring atom,
unless such attachment would violate valence requirements.
Likewise, the cycloalkyl groups may include one or more
non-hydrogen substituents unless such substitution would violate
valence requirements. Useful substituents include, without
limitation, alkyl, as defined above, and hydroxy, mercapto, nitro,
halogen, and amino.
[1473] Examples of monocyclic cycloalkyl groups include, without
limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
the like. Examples of bicyclic cycloalkyl groups include, without
limitation, bicyclo[1.1.0]butyl, bicyclo[1.1.1]pentyl,
bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl,
bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl,
bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,
bicyclo[4.1.1]octyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl,
bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.0]nonyl,
bicyclo[3.3.2]decyl, bicyclo[4.2.2]decyl, bicyclo[4.3.1]decyl,
bicyclo[4.4.0]decyl, bicyclo[3.3.3]undecyl, bicyclo[4.3.2]undecyl,
bicyclo[4.3.3]dodecyl, and the like.
[1474] The term "alkoxy" refers to alkyl-O--, where alkyl is
defined above. Examples of alkoxy groups include, without
limitation, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,
s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, and the like.
[1475] The term "treating" refers to 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.
[1476] The phrase "leaving group" refers to any group that leaves a
molecule during a fragmentation process, including substitution
reactions, elimination reactions, and addition-elimination
reactions. Leaving groups may be nucleofugal, in which the group
leaves with a pair of electrons that formerly served as the bond
between the leaving group and the molecule, or may be electrofugal,
in which the group leaves without the pair of electrons. The
ability of a nucleofugal leaving group to leave depends on its base
strength, with the strongest bases being the poorest leaving
groups. Common nucleofugal leaving groups include nitrogen (e.g.,
from diazonium salts), sulfonates (including tosylates, brosylates,
nosylates, and mesylates), triflates, nonaflates, tresylates,
halide ions, carboxylate anions, phenylate ions, and alkoxides.
Some stronger bases, such as NH.sub.2-- and OH-- can be made better
leaving groups by treatment with an acid. Common electrofugal
leaving groups include the proton, CO.sub.2, and metals.
[1477] The phrase "enantiomeric excess" or "ee" is a measure, for a
given sample, of the excess of one enantiomer over a racemic sample
of a chiral compound and is expressed as a percentage. Enantiomeric
excess is defined as 100.times.(er-1)/(er+1), where "er" is the
ratio of the more abundant enantiomer to the less abundant
enantiomer.
[1478] The phrase "diastereomeric excess" or "de" is a measure, for
a given sample, of the excess of one diastereomer over a sample
having equal amounts of diastereomers and is expressed as a
percentage. Diastereomeric excess is defined as
100.times.(dr-1)/(dr+1), where "dr" is the ratio of a more abundant
diastereomer to a less abundant diastereomer. The term does not
apply if more than two diastereomers are present in the sample.
[1479] The terms "stereoselective," "enantioselective," and
"diastereoselective," and variants thereof, refer to a given
reaction (e.g., hydrogenation) that yields more of one
stereoisomer, enantiomer, or diastereoisomer than another,
respectively.
[1480] The phrases "high level of enantioselectivity" and "high
level of diastereoselectivity" refer to a given reaction that
yields product with an ee or de, respectively, of at least about
80%.
[1481] The phrases "enantiomerically enriched" and
"diastereomerically enriched" refer, respectively, to a sample of a
compound that has more of one enantiomer or diastereomer than
another. The degree of enrichment is measured by, respectively, er
or ee, or by dr or er.
[1482] The phrases "substantially pure enantiomer" or
"substantially enantiopure" and "substantially pure diastereomer"
or "substantially diastereopure" refer, respectively, to a sample
of an enantiomer or diastereomer having an ee or de of about 90% or
greater.
[1483] The phrases "enantiomerically pure" or "enantiopure" and
"diastereomerically pure" or "diastereopure" refer, respectively,
to a sample of an enantiomer or diastereomer having an ee or de of
about 99% or greater.
[1484] The phrase "opposite enantiomer" refers to a molecule that
is a non-superimposable mirror image of a reference molecule, which
may be obtained by inverting all of the stereogenic centers of the
reference molecule. For example, if the reference molecule has S
absolute stereochemical configuration, then the opposite enantiomer
has R absolute stereochemical configuration. Likewise, if the
reference molecule has S,S absolute stereochemical configuration,
then the opposite enantiomer has R,R stereochemical configuration,
and so on.
[1485] The phrase "pharmaceutically acceptable salts, esters,
amides, and prodrugs" refers to acid or base addition salts,
esters, amides, zwitterionic forms, where possible, and prodrugs of
claimed and disclosed compounds, which are within the scope of
sound medical judgment, suitable for use in contact with the
tissues of patients without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use.
[1486] Because amino acids are amphoteric, pharmacologically
compatible salts can be salts of appropriate inorganic or organic
acids, for example, hydrochloric, sulfuric, 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.
[1487] 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.
[1488] 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.
[1489] 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, improved solubility, enhanced systemic stability (for
an increase in plasma half-life, for example), and the like. These
chemical modifications include, but are not limited to (1) ester or
amide derivatives which may be cleaved by, for example, esterases
or lipases; (2) peptides, which may be recognized by specific or
nonspecific proteinases; (3) derivatives that accumulate at a site
of action through membrane selection of a prodrug form or modified
prodrug form; and (4) any combination of (1) to (3). The ester or
amides prodrugs may be derived from the carboxylic acid moiety of
the parent drug molecule or from the carboxylic acid moiety or the
amine moiety of the parent drug molecule, respectively, by known
means. In addition, the peptide prodrug may be coupled to the
parent drug molecule via amide bond formation with the amine or
carboxylic acid moiety of the parent drug molecule using known
techniques.
[1490] 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.
[1491] 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.
[1492] Prodrugs of compounds of formula I, II, III, IV, V or VI are
included within the scope of this invention. For a discussion of
prodrugs and soft drugs, see E. Palomino, Drugs of the Future
15(4):361-68 (1990). See also, T. Higuchi and V. Stella, "Pro-drugs
as Novel Delivery Systems," ACS Symposium Series 14 (1975); E. B.
Roche (ed.), Bioreversible Carriers in Drug Design (1987); and H.
Bundgaar, Design of Prodrugs (1985).
[1493] 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
[1494] The compounds of this invention can be prepared as described
below. In the reaction schemes and discussion that follow,
structural formulas I, II, III, IV, V, or VI, 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 as defined above.
[1495] In some of the reaction schemes and examples below, certain
compounds can be prepared using protecting groups, which prevent
undesirable chemical reaction at otherwise reactive sites.
Protecting groups may also be used to enhance solubility or
otherwise modify physical properties of a compound. For a
discussion of protecting group strategies, a description of
materials and methods for installing and removing protecting
groups, and a compilation of useful protecting groups for common
functional groups, including amines, carboxylic acids, alcohols,
ketones, aldehydes, and the like, see T. W. Greene and P. G. Wuts,
Protecting Groups in Organic Chemistry (1999) and P. Kocienski,
Protective Groups (2000).
[1496] In addition, some of the schemes and examples below may omit
details of common reactions, including oxidations, reductions, and
so on, which are known to persons of ordinary skill in the art of
organic chemistry. The details of such reactions can be found in a
number of treatises, including Richard Larock, Comprehensive
Organic Transformations (1999), and the multi-volume series edited
by Michael B. Smith and others, Compendium of Organic Synthetic
Methods (1974-2003). Generally, starting materials and reagents may
be obtained from commercial sources.
[1497] Generally, the chemical transformations described throughout
the specification may be carried out using substantially
stoichiometric amounts of reactants, though certain reactions may
benefit from using an excess of one or more of the reactants.
Additionally, many of the reactions disclosed throughout the
specification may be carried out at about RT (room temperature,
20.degree. C. to 25.degree. C., inclusive), but some reactions may
use higher (e.g., reflux temperatures) or lower temperatures (e.g.,
-78.degree. C.), depending on reaction kinetics, yields,
selectivity, and the like. Furthermore, many of the chemical
transformations may employ one or more compatible solvents, which
depending on the nature of the reactants, may be polar protic
solvents, polar aprotic solvents, non-polar solvents, or some
combination. Although the choice of solvent or solvents may
influence the reaction rate and yield, such solvents are generally
considered to be inert (unreactive). Any references in the
disclosure to a concentration range, a temperature range, a pH
range, a catalyst loading range, and so on, whether expressly using
the word "range" or not, includes the indicated endpoints.
[1498] Diverse methods exist for the preparation of chiral and
racemic .beta.-amino acids. Such methods can be found in Eusebio
Juaristi (editor), Enantioselective Synthesis of .beta.-Amino Acids
(1997).
[1499] The methods described below are illustrative of methods that
can be utilized for the preparation of such compounds but are not
limiting in scope. 7
[1500] The use of chiral amine additions to
.alpha.,.beta.-unsaturated systems as a synthetic approach to
.alpha.-amino acids, as illustrated in Method A above, has been
described previously. See, e.g., S. G. Davies et al, J. Chem. Soc.
Chem. Commun. 1153 (1993); S. G. Davies, Synlett 117 (1994);
Ishikawa et al, Synlett 1291 (1998); and Hawkins, J. Org. Chem.
51:2820 (1985). Referring to Method A above, compounds of formula I
can be prepared from the corresponding compounds of formula 4,
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 (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.
[1501] Compounds of formula 4 can be prepared from the
corresponding compounds of formula 3 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 3 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 4. Preferably, the reaction is carried out using palladium
on carbon in ethanol under about 1 atmosphere of hydrogen.
[1502] Compounds of formula 3 can be prepared by treating the
corresponding compounds of formula 2 with an appropriate amine such
as (R)-(+)-N-benzyl-.alpha.-methylbenzylamine,
(S)-(-)-N-benzyl-.alpha.-meth- ylbenzylamine 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 2. 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.-meth- ylbenzylamine, after deprotonation
with n-butyl-lithium in tetrahydrofuran, at a temperature of about
-78.degree. C., according to method described by S. D. Bull et al.,
J. Chem. Soc., Perkin Trans. 1 22:2931-38 (2001). Preferably, this
reaction is carried out using either
(R)-(+)-N-benzyl-.alpha.-methylbenzylamine, or
(S)-(-)-N-benzyl-.alpha.-m- ethylbenzylamine, after deprotonation
with n-butyl-lithium in tetrahydrofuran, at a temperature of about
-78.degree. C., according to method described by S. D. Bull et al.,
J. Chem. Soc., Perkin Trans. 1 22:2931-38 (2001).
[1503] Compounds of formula 2 can be prepared from the
corresponding compounds of formula 1 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 1 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 formula 1
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 formula I may possess one or more stereogenic
centers. Using the above-described method, compounds with specific
stereochemical configurations can be prepared.
[1504] Compounds that can be made by this method include, but are
not limited to the following:
[1505] 3-Amino-4,5-dimethyl-hexanoic acid;
[1506] 3-Amino-4,5-dimethyl-heptanoic acid;
[1507] 3-Amino-4,5-dimethyl-octanoic acid;
[1508] 3-Amino-4,5-dimethyl-nonanoic acid;
[1509] 3-Amino-4-ethyl-5-methyl-heptanoic acid;
[1510] 3-Amino-4-ethyl-5-methyl-octanoic acid;
[1511] 3-Amino-4-ethyl-5-methyl-nonanoic acid;
[1512] 3-Amino-4-ethyl-5,6-dimethyl-heptanoic acid;
[1513] 3-Amino-4-ethyl-5,7-dimethyl-octanoic acid;
[1514] 3-Amino-4-ethyl-5,8-dimethyl-nonanoic acid;
[1515] (3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
[1516] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
[1517] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
[1518] (3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
[1519] (3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid;
[1520] 3-Amino-4,6-dimethyl-heptanoic acid;
[1521] 3-Amino-4,6-dimethyl-octanoic acid;
[1522] 3-Amino-4,6-dimethyl-nonanoic acid;
[1523] 3-Amino-4,6-dimethyl-decanoic acid;
[1524] 3-Amino-4,6,7-trimethyl-octanoic acid;
[1525] 3-Amino-4,6,8-trimethyl-nonanoic acid;
[1526] 3-Amino-4,6,9-trimethyl-decanoic acid;
[1527] 3-Amino-6-cyclopropyl-4-methyl-heptanoic acid;
[1528] 3-Amino-6-cyclobutyl-4-methyl-heptanoic acid;
[1529] 3-Amino-6-cyclopentyl-4-methyl-heptanoic acid;
[1530] 3-Amino-6-cyclohexyl-4-methyl-heptanoic acid;
[1531] 3-Amino-7-cyclopropyl-4,6-dimethyl-heptanoic acid;
[1532] 3-Amino-7-cyclobutyl-4,6-dimethyl-heptanoic acid;
[1533] 3-Amino-7-cyclopentyl-4,6-dimethyl-heptanoic acid;
[1534] 3-Amino-7-cyclohexyl-4,6-dimethyl-heptanoic acid;
[1535] 3-Amino-8-cyclopropyl-4,6-dimethyl-octanoic acid;
[1536] 3-Amino-8-cyclobutyl-4,6-dimethyl-octanoic acid;
[1537] 3-Amino-8-cyclopentyl-4,6-dimethyl-octanoic acid;
[1538] 3-Amino-8-cyclohexyl-4,6-dimethyl-octanoic acid;
[1539] 3-Amino-6-(3-chloro-phenyl)-4-methyl-heptanoic acid;
[1540] 3-Amino-6-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
[1541] 3-Amino-4-methyl-6-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1542] 3-Amino-4-methyl-6-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1543] 3-Amino-7-(3-chloro-phenyl)-4,6-dimethyl-heptanoic acid;
[1544] 3-Amino-7-(3,4-dichloro-phenyl)-4,6-dimethyl-heptanoic
acid;
[1545] 3-Amino-4,6-dimethyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1546] 3-Amino-4,6-dimethyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1547] 3-Amino-8-(3-chloro-phenyl)-4,6-dimethyl-octanoic acid;
[1548] 3-Amino-8-(3,4-dichloro-phenyl)-4,6-dimethyl-octanoic
acid;
[1549] 3-Amino-4,6-dimethyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid;
[1550] 3-Amino-4,6-dimethyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid;
[1551] 3-Amino-4-ethyl-6-methyl-octanoic acid;
[1552] 3-Amino-4-ethyl-6-methyl-nonanoic acid;
[1553] 3-Amino-4-ethyl-6-methyl-decanoic acid;
[1554] 3-Amino-4-ethyl-6,7-dimethyl-octanoic acid;
[1555] 3-Amino-4-ethyl-6,8-dimethyl-nonanoic acid;
[1556] 3-Amino-4-ethyl-6,9-dimethyl-decanoic acid;
[1557] 3-Amino-6-cyclopropyl-4-ethyl-heptanoic acid;
[1558] 3-Amino-6-cyclobutyl-4-ethyl-heptanoic acid;
[1559] 3-Amino-6-cyclopentyl-4-ethyl-heptanoic acid;
[1560] 3-Amino-6-cyclohexyl-4-ethyl-heptanoic acid;
[1561] 3-Amino-7-cyclopropyl-4-ethyl-6-methyl-heptanoic acid;
[1562] 3-Amino-7-cyclobutyl-4-ethyl-6-methyl-heptanoic acid;
[1563] 3-Amino-7-cyclopentyl-4-ethyl-6-methyl-heptanoic acid;
[1564] 3-Amino-7-cyclohexyl-4-ethyl-6-methyl-heptanoic acid;
[1565] 3-Amino-8-cyclopropyl-4-ethyl-6-methyl-octanoic acid;
[1566] 3-Amino-8-cyclobutyl-4-ethyl-6-methyl-octanoic acid;
[1567] 3-Amino-8-cyclopentyl-4-ethyl-6-methyl-octanoic acid;
[1568] 3-Amino-8-cyclohexyl-4-ethyl-6-methyl-octanoic acid;
[1569] 3-Amino-6-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
[1570] 3-Amino-6-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
[1571] 3-Amino-4-ethyl-6-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1572] 3-Amino-4-ethyl-6-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1573] 3-Amino-7-(3-chloro-phenyl)-4-ethyl-6-methyl-heptanoic
acid;
[1574] 3-Amino-7-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-heptanoic
acid;
[1575]
3-Amino-4-ethyl-6-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1576]
3-Amino-4-ethyl-6-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1577] 3-Amino-8-(3-chloro-phenyl)-4-ethyl-6-methyl-octanoic
acid;
[1578] 3-Amino-8-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-octanoic
acid;
[1579]
3-Amino-4-ethyl-6-methyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid; and
[1580]
3-Amino-4-ethyl-6-methyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid. 8
[1581] The diastereoselective alkylation of imides such as those of
formula 7 to afford chiral succinate analogs such as those of
formula 8 has been previously described as an approach to preparing
.beta.-amino acids. See, e.g., Evans et al, J. Org. Chem. 64:6411
(1999); Sibi and Deshpande, J. Chem. Soc. Perkin Trans 1 1461
(2000); and Arvanitis et al, J. Chem. Soc. Perkin Trans 1 521
(1998).
[1582] Compounds of formula 8 can be prepared from compounds of
formula 7 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.
[1583] Compounds of formula 9 can be prepared by hydrolyzing the
corresponding compounds of formula 8 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 P.-W.
Yuen et al., Bioorganic and Medicinal Chem. Lett. 4(6):823-26
(1994).
[1584] Treatment of the compound of formula 9 with
diphenylphosphorylazide (DPPA) followed by treatment with a
suitable alcohol such as t-butanol, benzyl alcohol or
p-methoxybenzyl alcohol, in a suitable solvent such as toluene,
benzene, MTBE, or THF, at a temperature from about 50.degree. C. to
about the reflux temperature of the reaction mixture yields the
corresponding compound of formula 10, wherein R.sub.7 is methyl,
ethyl, t-butyl, benzyl, or p-methoxybenzyl. R.sub.7 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.
[1585] Compounds of formula 10 can be converted into the desired
compounds of formula I 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
(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.
[1586] Compounds of formula 7 can be prepared by treating the
corresponding compounds of formula 5 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
formula 6. Examples of other oxazolidinones 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-oxazoli- dinone,
(S)-(+)-4-phenyl-2-oxazolidinone; (R)-(-)-4-phenyl-2-oxazolidinone-
; (R)-4-isopropyl-2-oxazolidinone; and
(4R,5S)-(+)-4-methyl-5-phenyl-2-oxa- zolidinone)) and lithium
chloride. Preferably, this reaction is carried out by treating an
acid of formula 5 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
formula 6 and lithium chloride at about room temperature according
to literature procedures. See G.-J. Ho and D. J. Mathre, J. Org.
Chem. 60:2271-73 (1995).
[1587] Alternatively, compounds of formula 7 can be prepared by
treating the corresponding compounds of formula 6 with an acid
chloride derived from treatment of the corresponding compound of
formula 5 with oxalyl chloride, in a solvent such as
dichloromethane, in the presence of dimethylformamide (DMF). Acids
of formula 5 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 stereogenic centers.
[1588] Alternatively, referring to Method C below, compounds of
formula 8 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 12, which can then be
subjected to a Curtius rearrangement (where R.sub.7 is defined as
above) to yield the corresponding compounds of formula 13. See
Arvanitis et al, J. Chem. Soc. Perkin Trans 1 521 (1998) for a
description of this approach. Further hydrolysis of the imide group
yields the corresponding compound of formula 14; hydrolysis of the
resulting carbamate group in formula 14 gives the desired
.beta.-amino acids of formula V.
[1589] Compounds of formula 13 may be converted to compounds of
formula 14 in a manner similar to the method for converting
compounds of formula 8 into compounds of formula 9 (Method B).
Furthermore, compounds of formula 14 may be converted to compounds
of formula II 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.7 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 stereogenic center in the
compounds of formula 8 and formula II, is utilized in Example 4
below. 9
[1590] Other alternative approaches to synthesizing
.alpha.-substituted .beta.-amino acids that can be utilized for
preparing the compounds of this invention. See, e.g., Juaristi et
al., Tetrahedron Asymm. 7(8):2233 (1996); Seebach et al., Eur. J.
Org. Chem. 335 (1999); Nagula et al., Org, Lett, 2:3527 (2000);
Arvanitis et al., J. Chem. Soc. Perkin Trans 1 521 (1998); and
Hintermann et al., Helv. Chim. Acta 81:2093 (1998), as shown in
Method D below. 10
[1591] The use of chiral sulfimines to afford .beta.-amino acids,
as illustrated in Method E below, has been described previously.
See, e.g., T. P. Tang and J. A. Ellman, J. Org. Chem. 64:12-13
(1999); Davis and McCoull, J. Org. Chem. 64:3396-97 (1999), and
Davis et al., J. Org. Chem. 64:1403-06 (1999). 11
[1592] The final step in the above scheme (R.sub.8=t-butyl or
p-tolyl, R.sub.9=a suitably derived ester such as methyl, ethyl or
t-butyl) is a hydrolysis of both the sulfonamide and ester groups
of a compound of formula 19 to give a compound of formula I. This
reaction is generally carried out using a strong acid such as
trifluoroacetic acid, 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 100.degree. C., preferably at about room temperature. The
reaction may be carried out by treating compounds of formula 19
with an acid such as TFA in a solvent such as methanol then
treating the product with TFA in a solvent such as dichloromethane
to give a compound of formula 1.
[1593] Compounds that can be made by this method include, but are
not limited to the following:
[1594] 3-Amino-4,5-dimethyl-hexanoic acid;
[1595] 3-Amino-4,5-dimethyl-heptanoic acid;
[1596] 3-Amino-4,5-dimethyl-octanoic acid;
[1597] 3-Amino-4,5-dimethyl-nonanoic acid;
[1598] 3-Amino-4-ethyl-5-methyl-heptanoic acid;
[1599] 3-Amino-4-ethyl-5-methyl-octanoic acid;
[1600] 3-Amino-4-ethyl-5-methyl-nonanoic acid;
[1601] 3-Amino-4-ethyl-5-methyl-decanoic acid;
[1602] 3-Amino-4-ethyl-5,6-dimethyl-heptanoic acid;
[1603] 3-Amino-4-ethyl-5,7-dimethyl-octanoic acid;
[1604] 3-Amino-4-ethyl-5,8-dimethyl-nonanoic acid;
[1605] 3-Amino-5-ethyl-4-methyl-octanoic acid;
[1606] 3-Amino-5-ethyl-4-methyl-nonanoic acid;
[1607] 3-Amino-4,5-diethyl-heptanoic acid;
[1608] 3-Amino-4,5-diethyl-octanoic acid;
[1609] 3-Amino-4,5-diethyl-nonanoic acid;
[1610] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[1611] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[1612] 3-Amino-4,5-diethyl-6-methyl-heptanoic acid;
[1613] 3-Amino-4,5-diethyl-7-methyl-octanoic acid;
[1614] 3-Amino-4,5-diethyl-8-methyl-nonanoic acid;
[1615] 3-Amino-4,5,6-trimethyl-heptanoic acid;
[1616] 3-Amino-4,5,7-trimethyl-octanoic acid;
[1617] 3-Amino-4,5,8-trimethyl-nonanoic acid;
[1618] 3-Amino-4-ethyl-5-methyl-hexanoic acid;
[1619] 3-Amino-5-ethyl-4-methyl-octanoic acid;
[1620] 3-Amino-5-ethyl-4-methyl-heptanoic acid;
[1621] 3-Amino-4-methyl-5-propyl-octanoic acid;
[1622] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[1623] 3-Amino-7-cyclopentyl-4,5-dimethyl-heptanoic acid;
[1624] 3-Amino-5-ethyl-4,6-dimethyl-heptanoic acid;
[1625] 3-Amino-5-ethyl-4,7-dimethyl-octanoic acid;
[1626] 3-Amino-5-ethyl-4,8-dimethyl-nonanoic acid;
[1627] (3R,4R)-3-Amino-4,5-dimethyl-hexanoic acid;
[1628] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid;
[1629] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid;
[1630] (3R,4R,5R)-3-Amino-4,5-dimethyl-nonanoic acid;
[1631] (3R,4R,5R)-3-Amino-4,5-dimethyl-decanoic acid;
[1632] 3-Amino-5-cyclopropyl-4-ethyl-hexanoic acid;
[1633] 3-Amino-6-cyclopropyl-4-ethyl-5-methyl-hexanoic acid;
[1634] 3-Amino-5-cyclobutyl-4-ethyl-hexanoic acid;
[1635] 3-Amino-6-cyclobutyl-4-ethyl-5-methyl-hexanoic acid;
[1636] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[1637] 3-Amino-6-cyclopentyl-4-ethyl-5-methyl-hexanoic acid;
[1638] 3-Amino-5-cyclohexyl-4-ethyl-hexanoic acid;
[1639] 3-Amino-6-cyclohexyl-4-ethyl-5-methyl-hexanoic acid;
[1640] 3-Amino-5-cyclopropyl-4-methyl-hexanoic acid;
[1641] 3-Amino-6-cyclopropyl-4,5-dimethyl-hexanoic acid;
[1642] 3-Amino-5-cyclobutyl-4-methyl-hexanoic acid;
[1643] 3-Amino-6-cyclobutyl-4,5-dimethyl-hexanoic acid;
[1644] 3-Amino-5-cyclopentyl-4-methyl-hexanoic acid;
[1645] 3-Amino-6-cyclopentyl-4,5-dimethyl-hexanoic acid;
[1646] 3-Amino-5-cyclohexyl-4-methyl-hexanoic acid;
[1647] 3-Amino-6-cyclohexyl-4,5-dimethyl-hexanoic acid;
[1648] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid;
[1649] 3-Amino-8-cyclohexyl-4,5-dimethyl-octanoic acid;
[1650] 3-Amino-4,6-dimethyl-heptanoic acid;
[1651] 3-Amino-4,6-dimethyl-octanoic acid;
[1652] 3-Amino-4,6-dimethyl-nonanoic acid;
[1653] 3-Amino-4,6-dimethyl-decanoic acid;
[1654] 3-Amino-4,6,7-trimethyl-octanoic acid;
[1655] 3-Amino-4,6,8-trimethyl-nonanoic acid;
[1656] 3-Amino-4,6,9-trimethyl-decanoic acid;
[1657] 3-Amino-6-cyclopropyl-4-methyl-heptanoic acid;
[1658] 3-Amino-6-cyclobutyl-4-methyl-heptanoic acid;
[1659] 3-Amino-6-cyclopentyl-4-methyl-heptanoic acid;
[1660] 3-Amino-6-cyclohexyl-4-methyl-heptanoic acid;
[1661] 3-Amino-7-cyclopropyl-4,6-dimethyl-heptanoic acid;
[1662] 3-Amino-7-cyclobutyl-4,6-dimethyl-heptanoic acid;
[1663] 3-Amino-7-cyclopentyl-4,6-dimethyl-heptanoic acid;
[1664] 3-Amino-7-cyclohexyl-4,6-dimethyl-heptanoic acid;
[1665] 3-Amino-8-cyclopropyl-4,6-dimethyl-octanoic acid;
[1666] 3-Amino-8-cyclobutyl-4,6-dimethyl-octanoic acid;
[1667] 3-Amino-8-cyclopentyl-4,6-dimethyl-octanoic acid;
[1668] 3-Amino-8-cyclohexyl-4,6-dimethyl-octanoic acid;
[1669] 3-Amino-6-(3-chloro-phenyl)-4-methyl-heptanoic acid;
[1670] 3-Amino-6-(3,4-dichloro-phenyl)-4-methyl-heptanoic acid;
[1671] 3-Amino-4-methyl-6-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1672] 3-Amino-4-methyl-6-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1673] 3-Amino-7-(3-chloro-phenyl)-4,6-dimethyl-heptanoic acid;
[1674] 3-Amino-7-(3,4-dichloro-phenyl)-4,6-dimethyl-heptanoic
acid;
[1675] 3-Amino-4,6-dimethyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1676] 3-Amino-4,6-dimethyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1677] 3-Amino-8-(3-chloro-phenyl)-4,6-dimethyl-octanoic acid;
[1678] 3-Amino-8-(3,4-dichloro-phenyl)-4,6-dimethyl-octanoic
acid;
[1679] 3-Amino-4,6-dimethyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid;
[1680] 3-Amino-4,6-dimethyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid;
[1681] 3-Amino-4-ethyl-6-methyl-octanoic acid;
[1682] 3-Amino-4-ethyl-6-methyl-nonanoic acid;
[1683] 3-Amino-4-ethyl-6-methyl-decanoic acid;
[1684] 3-Amino-4-ethyl-6,7-dimethyl-octanoic acid;
[1685] 3-Amino-4-ethyl-6,8-dimethyl-nonanoic acid;
[1686] 3-Amino-4-ethyl-6,9-dimethyl-decanoic acid;
[1687] 3-Amino-6-cyclopropyl-4-ethyl-heptanoic acid;
[1688] 3-Amino-6-cyclobutyl-4-ethyl-heptanoic acid;
[1689] 3-Amino-6-cyclopentyl-4-ethyl-heptanoic acid;
[1690] 3-Amino-6-cyclohexyl-4-ethyl-heptanoic acid;
[1691] 3-Amino-7-cyclopropyl-4-ethyl-6-methyl-heptanoic acid;
[1692] 3-Amino-7-cyclobutyl-4-ethyl-6-methyl-heptanoic acid;
[1693] 3-Amino-7-cyclopentyl-4-ethyl-6-methyl-heptanoic acid;
[1694] 3-Amino-7-cyclohexyl-4-ethyl-6-methyl-heptanoic acid;
[1695] 3-Amino-8-cyclopropyl-4-ethyl-6-methyl-octanoic acid;
[1696] 3-Amino-8-cyclobutyl-4-ethyl-6-methyl-octanoic acid;
[1697] 3-Amino-8-cyclopentyl-4-ethyl-6-methyl-octanoic acid;
[1698] 3-Amino-8-cyclohexyl-4-ethyl-6-methyl-octanoic acid;
[1699] 3-Amino-6-(3-chloro-phenyl)-4-ethyl-heptanoic acid;
[1700] 3-Amino-6-(3,4-dichloro-phenyl)-4-ethyl-heptanoic acid;
[1701] 3-Amino-4-ethyl-6-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1702] 3-Amino-4-ethyl-6-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1703] 3-Amino-7-(3-chloro-phenyl)-4-ethyl-6-methyl-heptanoic
acid;
[1704] 3-Amino-7-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-heptanoic
acid;
[1705]
3-Amino-4-ethyl-6-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic
acid;
[1706]
3-Amino-4-ethyl-6-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic
acid;
[1707] 3-Amino-8-(3-chloro-phenyl)-4-ethyl-6-methyl-octanoic
acid;
[1708] 3-Amino-8-(3,4-dichloro-phenyl)-4-ethyl-6-methyl-octanoic
acid;
[1709]
3-Amino-4-ethyl-6-methyl-8-(3-trifluoromethyl-phenyl)-octanoic
acid; and
[1710]
3-Amino-4-ethyl-6-methyl-8-(4-trifluoromethyl-phenyl)-octanoic
acid. 12
[1711] The synthesis of .beta.-amino acids of formula V via the
enantioselective alkylation of enantiopure
1-substituted-2-tert-butyl-3-m- ethylperhydropyrimidine-4-one 21,
as illustrated by Method F above, has been described previously.
See, e.g., E. Juaristi, et al., Tetrahedron: Asymmetry 7:2233
(1996) and references cited therein. Referring to Method F above,
compounds of formula 22 can be prepared from corresponding
compounds of formula 20 (HAL=Br, I, Cl or another suitable leaving
group), wherein R.sub.10 represents a phenyl or methoxy group,
preferably a methoxy group. The hydrolysis can be conducted under
acidic conditions in a sealed tube, at reflux, or in a microwave.
For instance, the method utilizing 6N HCl in a sealed tube heated
at 90-100.degree. C. for 8 hr is described by E. Juaristi et al.,
Tetrahedron: Asymmetry 7:2233 (1996). Other preferred methods
include heating a solution of compound 22 in a 1:1 mixture of
dioxane:6N HCl in a microwave for 1-3 hrs or at reflux for several
days to give a compound of formula V.
[1712] Compounds of formula 22 can be prepared from the
corresponding compounds of formula 20 by treating them with an
appropriate perhydropyrimidine-4-one of formula 21 after
deprotonation with an appropriate base such as lithium
diisopropylamide or lithium or sodium bis(trimethylsilyl)amide, in
a solvent such as ethyl ether, or, preferably, tetrahydrofuran
(THF), at a temperature from about -80.degree. C. to about
0.degree. C., and then adding the appropriate compound of formula
20. The stereochemistry of the C5 center arises from approach of
the electrophile from the opposite face of the enolate from the
sterically congested axial disposition of the tert-butyl group at
C2. Preferably, the compound 22 is prepared by the reaction of
electrophiles 20 with compounds of formula 21, which have been
deprotonated at -78.degree. C. with sodium bis(trimethylsilyl)amide
in THF, at -78.degree. C. to -10.degree. C. The synthesis of
enantiopure compound 21 (R.sub.10=Ph) from L-asparagine is
described by E. Juaristi et al., Tetrahedron: Asymmetry 7:2233
(1996). 13
[1713] In a like manner, Method G shows the synthesis of
.alpha.-substituted, .beta.-amino acids of formula V via the
enantioselective alkylation of enantiopure
3-amino-N-(2-hydroxy-1-methyl--
2-phenyl-ethyl)-N-methyl-propionamide (formula 24). See, G. Nagula
et al., Organic Letters 2:3527-29 (2000). The method includes
alkylation of compound 24 using an appropriate alkylating agent 20,
where HAL in formula 20 is Br, I, Cl or another suitable leaving
group. The enolate alkylation is carried out in a polar aprotic
solvent (THF) with excess LiCl at a temperature of about -5.degree.
C. to about 0.degree. C. using a hindered base (e.g., lithium
hexamethyldisilazide, lithium diisopropylamide, etc.) that is
sufficiently strong to deprotonate the .alpha.-carbon of formula
24. Hydrolysis of the resulting alkylated amide 25 gives the
desired .beta.-amino acid of formula V.
[1714] The compound of formula 24 is prepared through N-acylation
of a chiral auxiliary, (+)- or (-)-pseudoephedrine, using a mixed
anhydride. The mixed anhydride is obtained by reacting an
N-terminal protected, 3-amino-propionic acid (e.g.,
3-tert-butoxycarbonylamino-propionic acid 23) with trimethylacetyl
chloride in the presence of triethylamine in methylene chloride.
Following the coupling reaction, the protecting group is removed
via known methods (e.g., treatment of the resulting Boc-protected
amide with HCl and MeOH) to give the compound of formula 24. See A.
Myers et al., J. Am. Chem. Soc. 119:656-73 (1997).
[1715] Compounds of formula 20 shown in Method F and Method G 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 formula 20 may possess one or more stereogenic
centers. Using the above-described method, compounds with specific
stereochemical configurations can be prepared.
[1716] Method H shows a synthesis of .beta.-substituted,
.beta.-amino acids of formula IV and their salts, solvates, and
hydrates. The method employs a stereoselective hydrogenation of a
chiral eneamide (formula 38) to give a chiral amide ester (formula
39), which is subsequently hydrolyzed with a strong acid, such as
HCl and other mineral acids, to give a chiral amino acid salt
(formula 40). The acid addition salt (formula 40) may be treated
with an inorganic or organic base to give the zwifterionic form of
formula IV, if desired. Generally, the hydrolysis reaction is
carried out in water at reflux conditions, and the resulting salt
(formula 40) is recrystallized from a polar solvent, such as MeOH,
EtOH, IPA, and the like. In formula 38 through formula 40, R.sub.3
is as defined above in connection with formula IV; in formula 38
and formula 39, R.sub.13 and R.sub.15 are independently selected
from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, and
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.3)alkyl. As noted in the
examples, useful values of R.sub.13 and R.sub.15 include, without
limitation, ethyl and methyl, respectively.
[1717] The hydrogenation is carried out in the presence of a
catalyst and one or more polar solvents, such as MeOH, EtOH, IPA,
THF, EtOAc, and the like. Useful catalysts include, without
limitation, heterogeneous catalysts containing from about 0.1% to
about 20%, and more typically, from about 1% to about 5%, by
weight, of Pd, Pt, Rh, Ru, Ir, and combinations thereof, which are
supported on various materials, including Al.sub.2O.sub.3, C,
CaCO.sub.3, SrCO.sub.3, BaSO.sub.4, MgO, SiO.sub.2, TiO.sub.2,
ZrO.sub.2, and the like. Many of these metals, including Pd, may be
doped with an amine, sulfide, or a second metal, such as Pb, Cu, or
Zn. Useful catalysts thus include palladium catalysts such as
Pd/SrCO.sub.3, Pd/Al.sub.2O.sub.3, Pd/MgO, Pd/CaCO.sub.3,
Pd/BaSO.sub.4, and the like, containing from about 1% to about 5%
Pd, based on weight. The reaction may be carried out at a
temperature ranging from about 5.degree. C. to about 100.degree.
C., though as shown in the examples, good yields (e.g.,
.gtoreq.95%) and high stereoselectivity (e.g., .gtoreq.90%) may be
obtained for reactions carried out at room temperature. Generally,
the substrate-to-catalyst ratio may range from about 1:1 to about
1000:1, based on weight, and H.sub.2 pressure may range from about
atmospheric pressure, 0 psig, to about 1500 psig. More typically,
the substrate-to-catalyst ratios range from about 4:1 to about
20:1, and H.sub.2 pressures range from about 25 psig to about 100
psig.
[1718] As can be seen in Method H, the chiral eneamide (formula 38)
can be prepared from a chiral .beta.-keto ester (formula 33). The
.beta.-keto ester (formula 33) may be treated with ammonium acetate
in MeOH or EtOH to give a chiral enamine (formula 36), which is
subsequently acylated with an acyl halide (e.g., acid chloride of
formula 37), anhydride, etc., to give the chiral eneamide of
formula 38. To minimize epimerization of the .alpha.-carbon
adjacent to the keto moiety, the .beta.-keto ester (formula 33) may
be first treated with an alkoxy amine, silyloxy amine, etc.
(formula 34) in the presence of an acid catalyst (e.g., HCl), and
in the absence of water, to give an oxime (formula 35), which in
turn is hydrogenated in the presence of a catalyst, such as Ra--Ni,
to give the enamine (formula 36). Typically, the conversion of the
.beta.-keto ester (formula 33) to the oxime (formula 35) is carried
out at temperatures ranging from about 0.degree. C. to about RT,
and the subsequent hydrogenation of the oxime (formula 36) to the
enamine (formula 36) is carried out at RT. Substituents R.sub.3 and
R.sub.13 in formula 33-36, are as defined above in connection with
formula IV and formula 38, respectively. Similarly, R.sub.15 in
formula 37 is as defined above in connection with formula 38. In
formula 34, R.sub.14 is selected from (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, and silyl.
[1719] The .beta.-keto ester (formula 33) may be prepared from a
chiral acid (formula 30) using a variety of methods. For example,
the chiral acid (formula 30) may be reacted with carbonyl
diimidazole (CDI) to give an activated ester (an imidazolide),
which is subsequently reacted with an enolate to give the
.beta.-keto ester (formula 33). The enolate is prepared by
treatment of a malonate derivative (formula 31) with MgCl.sub.2,
Mg(OEt).sub.2, and so on. Alternatively, the chiral acid (formula
30) may be reacted with chloromethylene dimethyl-ammonium chloride
to give an activated acyl chloride, which is subsequently reacted
with the enolate, as prepared above, or with an enolate prepared by
treating a methyl ester (formula 32) with a hindered base. The
hindered base is sufficiently strong to deprotonate the methyl
group of formula 32 and includes lithium diisopropylamide (LDA),
lithium isopropylcyclohexylamide (LICA),
2,2,6,6-tetramethylpiperidine (LTMP), lithium hexamethyldisilazide
(LHMDS), and the like. In formula 30, R.sub.3 is as defined above
in connection with formula 6, and in formula 31 and formula 32,
R.sub.13 is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
and (C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.s- ub.3)alkyl. Useful
R.sub.13 substituents thus include ethyl.
[1720] As shown in Method H, the chiral acid (formula 30) may be
obtained by hydrolysis of a chiral imide (formula 29), which is
prepared by the stereoselective conjugate addition of an alkyl
(methyl) group to an .alpha.,.beta.-unsaturated imide (formula 28).
The conjugate addition is carried out by reacting a Grignard
reagent (e.g., CH.sub.3MgX, where X.dbd.Cl, Br, I, CH.sub.3Li,
etc.) with a suitable Cu(I) salt (e.g., copper bromide
dimethylsulfide complex, CuI, etc.) in a compatible solvent, such
as THF, diethylether, and the like, in the presence of a lithium
salt (LiCl, LiBr, etc.) to form an organocopper reagent. The
organocopper reagent is then reacted with the
.alpha.,.beta.-unsaturated imide of formula 28 to give the chiral
imide (formula 29). The conjugate addition may be quenched by
treating the reaction mixture with an acid (e.g., acetic acid) at
RT or below. The formation of the organocopper reagent and the
conjugate addition are typically carried out at temperatures
ranging from about -25.degree. C. to about 0.degree. C.
[1721] The .alpha.,.beta.-unsaturated imide (formula 28) may be
prepared from an .alpha.,.beta.-unsaturated acid (formula 26) and
appropriately substituted oxazolidinone (formula 27) using a
coupling agent, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
(EEDQ). Generally, the reaction may be carried out at temperatures
ranging from about RT to about 100.degree. C., but more typically,
the reaction may be carried out at temperatures ranging from about
40.degree. C. to about 75.degree. C. Alternatively, the coupling
reaction may be carried out using the methods described above to
prepare compound 7. In formula 26 through formula 29, R.sub.3 is as
defined above in connection with formula IV. In the chiral
auxiliary (formula 27), R.sub.11 and R.sub.12 are independently
hydrogen, (C.sub.1-C.sub.3)alkyl, phenyl, and benzyl, provided that
R.sub.11 and R.sub.12 are not both hydrogen. Useful R.sub.11 and
R.sub.12 thus include phenyl and hydrogen, respectively.
[1722] The enamine (formula 36) may optionally be converted to a
corresponding ester (formula 41) of the zwitterionic form (formula
IV) via the use of a chiral catalyst. The resulting ester may then
be converted to a salt (formula 40) via acid or base hydrolysis,
which may be treated with an appropriate acid or base to give the
zwitterionic compound (formula IV). Potentially useful chiral
catalysts include chiral phosphine (e.g., bisphosphine) or
phosphinite ligands bound to transition metals, such as ruthenium,
rhodium or iridium. Ru-, Rh- or Ir-phosphine, phosphinite or
phospino oxazoline complexes are optically active because they
possess a chiral phosphorus atom or a chiral group connected to a
phosphorus atom, or because in the case of BINAP and similar
atropisomeric ligands, they possess axial chirality. Chiral ligands
include, without limitation, Bis P*, (R,R)-DIOP, (R,R)-DIPAMP,
(R)-(S)-BPPFA, (S,S)-BPPM, (+)-CAMP, (S,S)-CHIRAPHOS, (R)-PROPHOS,
(R,R)-NORPHOS, (R)-BINAP, (R)-CYCPHOS, (R,R)-BDPP, (R,R)-DEGUPHOS,
(R,R)-Me-DUPHOS, (R,R)-Et-DUPHOS, (R,R)-i-Pr-DUPHOS, (R,R)-Me-BPE,
(R,R)-Et-BPE (R)-PNNP, (R)-BICHEP, (R,S,R,S)-Me-PENNPHOS,
(S,S)-BICP, (R,R)-Et-FerroTANE, (R,R)-t-butyl-miniPHOS,
(R)-Tol-BINAP, (R)-MOP, (R)-QUINAP, CARBOPHOS, (R)-(S)-JOSIPHOS,
(R)-PHANEPHOS, BIPHEP, (R)-Cl-MeO-BIPHEP, (R)-MeO-BIPHEP,
(R)-MonoPhos, BIFUP, (R)-SpirOP, (+)-TMBTP, (+)-tetraMeBITIANP,
(R,R,S,S) TANGPhos, (R)-PPh.sub.2-PhOx-Ph, (S,S) MandyPhos and
(R)-CnTunaPHOS, where n is an integer of 1 to 6.
[1723] Other chiral ligands include, without limitation,
(R)-(-)-1-[(S)-2-(di(3,5-bistrifluoromethylphenyl)phosphino)ferrocenyl]et-
hyldicyclohexyl-phosphine;
(R)-(-)-1-[(S)-2-(di(3,5-bis-trifluoromethylphe-
nyl)phosphino)ferrocen-yl]ethyldi(3,5-dimethylphenyl)phosphine;
(R)-(-)-1-[(S)-2-(di-t-butylphosphino)-ferro-cenyl]ethyldi(3,5-dimethylph-
enyl)phosphine;
(R)-(-)-1-[(S)-2-(dicyclo-hexylphosphino)ferrocenyl]ethyld-
i-t-butylphosphine;
(R)-(-)-1-[(S)-2-(dicyclo-hexylphosphino)ferrocenyl]et-
hyldicyclohexylphosphine;
(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocen-
yl]ethyldiphenylphosphine;
(R)-(-)-1-[(S)-2-(di(3,5-dimethyl-4-methoxyphen-
yl)phosphino)ferrocenyl]ethyldicyclohexyl-phosphine;
(R)-(-)-1-[(S)-2-(diphenylphos-phino)ferrocenyl]ethyldi-t-butylphos-phine-
;
(R)-N-[2-(N,N-dimethylamino)ethyl]-N-methyl-1-[(S)-1',2-bis(diphenyl-pho-
sphino)ferrocenyl]ethylamine; and
(R)-(+)-2-[2-(diphenylphosphino)-phenyl]-
-4-(1-methylethyl)-4,5-dihydrooxazole.
[1724] Useful ligands may also include stereoisomers (enantiomers
and diastereoisomers) of the chiral ligands described in the
preceding paragraphs, which may be obtained by inverting all or
some of the stereogenic centers of a given ligand or by inverting
the stereogenic axis of an atropoisomeric ligand. Thus, for
example, useful chiral ligands also include (S)-Cl-MeO-BIPHEP,
(S)-PHANEPHOS, (S,S)-Me-DUPHOS, (S,S)-Et-DUPHOS, (S)-BINAP,
(S)-Tol-BINAP, (R)-(R)-JOSIPHOS, (S)-(S)-JOSIPHOS, and so on.
[1725] Many of the chiral catalysts, catalyst precursors, or chiral
ligands may be obtained from commercial sources or may be prepared
using known methods. A catalyst precursor or pre-catalyst is a
compound or set of compounds, which are converted into the chiral
catalyst prior to use. Catalyst precursors typically comprise Ru,
Rh or Ir complexed with the phosphine ligand and either a diene
(e.g., norboradiene, COD, (2-methylallyl).sub.2, etc.) or a halide
(Cl or Br) or a diene and a halide, in the presence of a
counterion, X.sup.-, such as OTf.sup.-, PF6.sup.-, BF.sub.4.sup.-,
SbF.sub.6.sup.-, ClO.sub.4.sup.-, etc. Thus, for example, a
catalyst precursor comprised of the complex, [(bisphosphine
ligand)Rh(COD)].sup.+X.sup.- may be converted to a chiral catalyst
by hydrogenating the diene (COD) in MeOH to yield [(bisphosphine
ligand)Rh(MeOH).sub.2].sup.+X.sup.-. MeOH is subsequently displaced
by the enamine (formula 36), which undergoes enantioselective
hydrogenation to the desired chiral compound. Example chiral
catalysts or catalyst precursors include (+)-TMBTP-ruthenium(II)
chloride acetone complex; (S)-Cl-MeO-BIPHEP-ruthenium(II) chloride
Et.sub.3N complex; (S)-BINAP-ruthenium(II) Br.sub.2 complex;
(S)-tol-BINAP-ruthenium(II) Br.sub.2 complex; and
(1,5-cyclooctadiene)[(3R,4R)-3,4-bis(diphenylphosph-
ino)-1-methylpyrrolidine]rhodium tetrafluoroborate.
[1726] For a given chiral catalyst and prochiral substrate, the
molar ratio of the substrate and catalyst (s/c) may depend on,
among other things, H.sub.2 pressure, reaction temperature, and
solvent. Usually, the substrate-to-catalyst ratio exceeds about
10:1 or 20:1, and substrate-to-catalyst ratios of about 100:1 or
200:1 are common. Although the chiral catalyst may be recycled,
higher substrate-to-catalyst ratios are useful. For example,
substrate-to-catalyst ratios of about 1000:1, 10,000/1, and
20,000:1, or greater, would be useful. The asymmetric hydrogenation
is typically carried out at about RT or above, and under about 0.1
MPa (1 atm) or more of H.sub.2. The temperature of the reaction
mixture may range from about 20.degree. C. to about 80.degree. C.,
and the H.sub.2 pressure may range from about 0.1 MPa to about 5
Mpa or higher, but more typically, ranges from about 0.3 Mpa to
about 3 Mpa. The combination of temperature, H.sub.2 pressure, and
substrate-to-catalyst ratio is generally selected to provide
substantially complete conversion (i.e., about 95 wt %) of the
prochiral olefin within about 24 hours. With many of the chiral
catalysts, increasing the H.sub.2 pressure increases the
enantioselectivity.
[1727] A variety of organic solvents may be used in the asymmetric
hydrogenation, including protic solvents, such as MeOH, EtOH, and
IPA. Other useful solvents include aprotic polar solvents, such as
THF, MeCl.sub.2, and acetone, or aromatic solvents, such as
toluene, trifluorotoluene, and chlorobenzene. The enantioselective
hydrogenation may employ a single solvent, or may employ a mixture
of solvents, such as MeOH and THF. 14
[1728] 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.
[1729] 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.
[1730] The compounds of formula I, II, III, IV, V, and VI, and the
intermediates shown in the above reaction schemes can be isolated
and purified by conventional procedures, such as recrystallization
or chromatographic separation.
[1731] 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.
[1732] The radioligand binding assay using [.sup.3H]-gabapentin and
the .alpha.2.delta.-subunit derived from porcine brain tissue was
used. See Nicolas S. Gee et al., "The novel anticonvulsant drug,
gabapentin (Neurontin), binds to the .alpha.2 subunit of a calcium
channel," J. Biol. Chem. 271 (10):5768-76 (1996). Compounds of the
invention bind with nanomolar to micromolar affinity for the
.alpha.2.delta. protein. For example,
2-aminomethyl-5-ethyl-nonanoic acid binds with 75 nM affinity to
the .alpha.2.delta. protein; (S)-3-amino-5-ethyl-3-methyl-heptanoic
acid binds with 149 nM affinity to the .alpha.2.delta. protein; and
(3S,5R)-3-amino-3,5-dimethyl-heptanoic acid binds with 236 nM
affinity to the .alpha.2.delta. protein.
[1733] The in vivo activity of compounds of this invention can be
determined in animal models. For animal models related to
hyperalgesia, see, e.g., K. Sluka et al., "Unilateral intramuscular
injections of acidic saline produce a bilateral, long-lasting
hyperalgesia," Muscle Nerve 24:37-46 (2001); W. Dixon, "Efficient
analysis of experimental observations," Ann. Rev. Pharmacol.
Toxicol. 20:441-62 (1980); L. O. Randall and J. J. Selitto, "A
method for measurement of analgesic activity on inflamed tissue,"
Arch. Int. Pharmacodyn 4:409-19 (1957); K. Hargreaves et al., "A
new and sensitive method for measuring thermal nociception in
cutaneous hyperalgesia," Pain 32:77-88 (1988). Fir animal models
related to anxiety, see J. R. Vogel et al., "A simple and reliable
conflict procedure for testing anti-anxiety agents,"
Psychopharmacologia 21:1-7 (1971).
[1734] 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.
[1735] 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.
[1736] 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.
[1737] 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.
[1738] 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.
[1739] 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 formulas I to VI or a corresponding
pharmaceutically acceptable salt of such compound.
[1740] 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 that 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.
[1741] 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.
[1742] 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.
[1743] 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.
[1744] 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.
[1745] 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.
[1746] 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.
[1747] 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 that 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.
[1748] 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.
EXAMPLE 1
(4S,5R)-4-Methyl-3-pentanoyl-5-phenyl-oxazolidin-2-one
[1749] To a 0.degree. C. stirred solution of valeric acid (3.83 mL,
35.2 mmol) and Et.sub.3N (14.7 mL, 106 mmol) in dry THF (175 mL)
was added trimethylacetyl chloride (5.29 mL, 42.3 mmol) dropwise.
The mixture was stirred at 0.degree. C. for 1 hour and
(4S,5R)-(-)-4-methyl-5-phenyl-2-ox- azolidinone (7.50 g, 42.3 mmol)
was added followed by LiCl (1.79 g, 42.3 mmol). The reaction was
warmed to room temperature overnight with good stirring. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. Et.sub.2O (75 mL) was added to the residue, which
was washed with sat. NaHCO.sub.3 (3.times.40 mL), 1N HCl
(3.times.40 mL), and brine (2.times.40 mL). The organic phase was
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give a quantitative yield of crude product.
(4S,5R)-3-((S)-2-Ethyl-pentanoyl)-4-methyl-5-phenyl-oxazolidin-2-one
[1750] To a -78.degree. C. stirred solution of the
(4S,5R)-4-Methyl-3-pent- anoyl-5-phenyl-oxazolidin-2-one (9.20 g,
35.2 mmol) in dry THF (150 mL) was added NaHMDS (42.2 mL, 1.0 M in
THF) dropwise. After 1 hour, ethyl trifluoromethanesulfonate (5.93
mL, 45.7 mmol) was added dropwise and the reaction was stirred at
-78.degree. C. for an additional 2 hours. The reaction was warmed
to -30.degree. C. for 30 minutes and quenched with sat. NH.sub.4Cl.
The layers were separated and the aqueous layer was extracted with
EtOAc (3.times.40 mL). The organic extracts were combined and
washed with brine (2.times.40 mL). The organic phase was dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure to
yield 8.05 g of crude product.
(S)-2-Ethyl-pentan-1-ol
[1751] To a room temperature solution of the
(4S,5R)-3-((S)-2-ethyl-pentan-
oyl)-4-methyl-5-phenyl-oxazolidin-2-one (8.05 g, 27.8 mmol) in THF
(200 mL) was added a solution of NaBH.sub.4 (4.21 g, 111 mmol) in
H.sub.2O (90 mL). The reaction was allowed to stir overnight at
room temperature, was quenched with 2N HCl (75 mL) and the layers
were separated. The aqueous layer was extracted with EtOAc
(4.times.40 mL), and the organic extracts were combined and washed
with brine (2.times.30 mL). The organic phase was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
residue was triturated with n-hexanes (2.times.20 mL) to remove the
oxazolidinone side product. After filtering off the oxazolidinone,
the filtrate was concentrated under reduced pressure to yield 2.56
g of crude product.
Methanesulfonic Acid (S)-2-ethyl-pentyl Ester
[1752] To a -10.degree. C. stirred solution of
(S)-2-ethyl-pentan-1-ol (1.30 g, 11.2 mmol) in dry CH.sub.2Cl.sub.2
(35 mL) was added Et.sub.3N (2.33 mL, 16.8 mmol). The reaction was
stirred at this temperature for 15 minutes and methansulfonyl
chloride (0.952 mL, 12.3 mmol) was added. The reaction was allowed
to warm to room temperature overnight with good stirring. The
reaction was washed with 1N HCl (3.times.30 mL), sat. NaHCO.sub.3
(3.times.30 mL), and brine (2.times.30 mL). The organic phase was
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give a quantitative yield of crude product.
(S)-3-Iodomethyl-hexane
[1753] To a stirred solution of Methanesulfonic acid
(S)-2-ethyl-pentyl ester (2.18 g, 11.2 mmol) in acetone (35 mL) was
added NaI (3.36 g, 22.4 mmol) and the reaction was heated to reflux
overnight with good stirring. The reaction was allowed to cool to
room temperature and the mixture was filtered. The salts were
washed with acetone (3.times.15 mL) and H.sub.2O (60 mL) was added
to the filtrate. The aqueous phase was extracted with hexanes
(4.times.30 mL) and the organic extracts were combined and washed
with brine (2.times.30 mL). The organic phase was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
residue was purified by chromatography using hexanes (100%) to
yield 1.24 g (49%) of pure product.
(2S,5R)-2-tert-Butyl-5-((S)-2-ethyl-pentyl)-3-methyl-4-oxo-tetrahydro-pyri-
midine-1-carboxylic Acid Methyl Ester
[1754] To a -78.degree. C. stirred solution of
(S)-2-tert-butyl-3-methyl-4-
-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester (1.04 g,
4.57 mmol) in dry THF (15 mL) was added NaHMDS (5.03 mL, 1.0 M in
THF) dropwise. The reaction was stirred at -78.degree. C. for 1
hour and then a solution of (S)-3-Iodomethyl-hexane (1.24 g, 5.48
mmol) in dry THF (5 mL) was added dropwise. The reaction was
stirred at this temperature for 2 hours and than was placed in a
-10.degree. C. refrigerator overnight. The reaction was quenched
with sat. NH.sub.4Cl (20 mL) and was allowed to warm to room
temperature. The layers were separated and the aqueous layer was
extracted with EtOAc (3.times.15 mL). The organic extracts were
combined and washed with brine (2.times.15 mL). The organic phase
was dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The product was purified by chromatography using
hexanes/EtOAc (10->20%) to yield 0.185 g (12%) of pure product:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.9 (m, 6H), 1.3 (m,
5H), 1.4 (m, 3H), 1.7 (m, 1H), 2.5 (m, 1H), 2.9 (d, J=6.6 Hz, 2H).
MS: M+1 (328).
(2R,4S)-2-Aminomethyl-4-ethyl-heptanoic Acid
[1755] A stirred solution of
(2S,5R)-2-tert-butyl-5-((S)-2-ethyl-pentyl)-3-
-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester
(0.185 g, 0.567 mmol) in a 1:1 mixture of 6N HCl/dioxane (8 mL) was
heated at 105.degree. C. for 6 days. The reaction was cooled to
room temperature and concentrated under reduced pressure. The
product was dissolved in 1:1 MeOH/H.sub.2O and loaded onto an ion
exchange chromatography column (Varian SCX-Prepacked 10 g, 60 mL)
and eluted with 1:1 MeOH/H.sub.2O (95%)+NH.sub.4OH. The fractions
containing product were collected and concentrated under reduced
pressure to yield 0.06 g (57%) of product: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 0.9 (m, 6 H), 1.3 (m, 5H), 1.4 (m, 3H) 1.7
(m, 1H), 2.5 (m, 1H), 2.9 (d, J=6.6 Hz, 2H). MS: M+1 (188).
[1756] Using the above methodology the following compounds were
also made:
1 MS, Compound Name APCI.sup.+ .sup.1H NMR, 400MHz, .delta., PPM,
CD.sub.3OD (4R)-2-Aminomethyl-4- 188 (M + 1) 0.9(s, 6H), 1.3(m,
5H), 1.4(m, 3H), ethyl-heptanoic acid 1.7(s, 1H), 2.5(m, 1H),
2.9(d, J=6.1Hz, 2H) (2R,4S)-2- 202 0.9(d, J=6.6Hz, 6H), 0.9(d,
J=6.6Hz, Aminomethyl-4-7- (M + 1) 3H), 1.2(m, 4H), 1.2(m, 1H),
dimethyl-octanoic acid 1.4(m, 1H), 1.5(m, 2H), 1.7(m, 1H), 2.5(m,
1H), 2.9(d, 2H) (2S,4S)-2-Aminomethyl- 230 2.93(d, 2H), 2.47(5-line
4-ethyl-8- (M + 1) m, 1H), 1.72(m, 1H), 1.54(7-line m,
methylnonanoic acid 1H), 1.42-1.11(m, 10H), 0.85(d, 3H)
(2R/S,4S)-2- 257 2.93(d, 2H), 2.44(5-line m, 1H),
Aminomethyl-8-methyl- (M + 1) 1.72(m, 1H), 1.55(7-line m, 1H),
4-propyl-nonanoic acid 1.44(m, 1H), 1.40-1.10(m, 11H), 0.89(d, 3H)
(2S,4S)-2-Aminomethyl- 202 2.93(d, 2H), 2.43(m, 1H), 1.71(m,
4-ethyl-6-methyl-heptanoic acid. (M + 1) 1H), 1.63(m, 1H), 1.42(m,
1H), 1.36(m, 2H), 1.22(m, 1H), 1.06(m, 2H), 0.85(m, 9H) (2R,4S)-2-
202 2.89(d, 2H), 2.43(m, 1H), 1.62(m, Aminomethyl-4-ethyl-6- (M +
1) 2H), 1.44(m, 1H), 1.34(m, 1H), methyl-heptanoic acid 1.22(m,
2H), 1.12(m, 1H), 1.05(m, 1H), 0.80(m, 9H) (2R,4R)-2- 202.1 2.90(d,
2H), 2.43(m, 1H), 1.68(m, Aminomethyl-4-ethyl-6- (M + 1) 1H),
1.61(m, 1H), 1.42(m, 1H), methyl-heptanoic acid 1.32(m, 2H),
1.21(m, 1H), 1.11(m, 2H), 0.80(m, 9H) (2S,4R)-2- 202 2.94(d, 2H),
2.23(m, 1H), 1.62(m, Aminomethyl-4-ethyl-6- (M + 1) 2H), 1.44(m,
1H), 1.42(m, 1H), methyl-heptanoic acid 1.22(m, 2H), 1.13(m, 1H),
1.03(m, 1H), 0.85(m, 9H)
EXAMPLE 2
(R)-3-((R)-3-Methyl-hexanoyl)-4-phenyl-oxazolidin-2-one
[1757] To the copper (1) bromide dimethylsulfide complex (13.34 g,
64.87 mmol) in dry THF (150 mL) at -30.degree. C. under Nitrogen
was added a 2M ether solution of Propylmagnesiumchloride (64.87 mL,
129.7 mmol) and stirred for 20 minutes.
(R)-3-But-2-enoyl-4-phenyl-oxazolidin-2-one (15.0 g, 64.87 mmol) in
THF (60 mL) was added over a 15 minute period at -35.degree. C. and
let slowly warm up to room temperature over 4 hours. The mixture
was cooled to 0.degree. C. and quenched with saturated ammonium
chloride solution. The suspension was extracted into ether, washed
with 5% ammonium hydroxide solution and then with brine and dried
over MgSO.sub.4. The solution was concentrated under reduced
pressure to afford the titled compound (13.34 g; 100% yield) as a
white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) 8 ppm 0.8 (m, 6H)
1.2 (m, 3H) 1.6 (s, 1H) 2.0 (m, 1H) 2.7 (dd, J=16.1, 8.5 Hz, 1H)
3.0 (dd, J=15.9, 5.4 Hz, 1H) 4.3 (dd, J=8.9, 3.8 Hz, 1H) 4.7 (t,
J=8.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz,
1H) 7.3 (m, 5H). MS, m/z (relative intensity): 276 [M+1H,
100%].
(R)-3-((2R,3R)-2,3-Dimethyl-hexanoyl)-4-phenyl-oxazolidin-2-one
[1758] To a 1M THF solution of Sodium hexamethyldisylamide (16.2 g,
88.3 mmol) at -78.degree. C. was added via canular a 0.degree. C.
solution of (R)-3-((R)-3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one
(18.7 g, 67.9 mmol) in 70 mL dry THF. The resulting solution was
stirred at -78.degree. C. for 30 minutes. Methyl Iodide (48.2 g,
339.5 mmol) was added and stirring at -78.degree. C. was continued
for 4 hours. The reaction was quenched with saturated ammonium
chloride solution, extracted into CH.sub.2Cl.sub.2 and washed with
1M sodium Bisulfite. The solution was dried over MgSO.sub.4,
concentrated and chromatographed in 10% ethylacetate in hexane to
give the titled compound (11.1 g, 56.5% yield) as an oil. MS, m/z
(relative intensity): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
0.8 (t, J=7.0 Hz, 3H) 0.9 (d, J=6.6 Hz, 3H) 1.0 (d, J=6.8 Hz, 3H)
1.0 (d, J=8.5 Hz, 1H) 1.1 (m, 1H) 1.4 (m, 1H) 1.7 (m, 1H) 3.7 (m,
1H) 4.2 (dd, J=8.8, 3.4 Hz, 1H) 4.6 (t, J=8.7 Hz, 1H) 5.4 (dd,
J=8.7, 3.3 Hz, 1H) 7.2 (m, 2H) 7.3 (m, 3H). MS, m/z (relative
intensity):290 [M+1H, 100%].
(2R,3R)-2,3-Dimethyl-hexan-1-ol
[1759] A 1M THF solution of LAH (95.9 mL, 95.9 mmol) was added to
(R)-3-((2R,3R)-2,3-dimethyl-hexanoyl)-4-phenyl-oxazolidin-2-one in
THF (300 mL) under nitrogen at -78.degree. C. and stirred for 3
hours at that temperature. Water was added dropwise to quench the
excess LAH and the solution was poured into a mixture of ice and
ether. The mixture was extracted into ether, washed with water and
dried over MgSO.sub.4. The solution was concentrated followed by
the addition of excess hexane. The resulting white precipitate was
filtered and washed with haxane. The filtrate was concentrated to
afford the titled compound (5.05 g, 100% yield) as an oil: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.9 (m, 9H) 1.0 (d, J=6.8 Hz,
1H) 1.1 (m, 1H) 1.2 (m, 3H) 1.6 (m, 2H) 3.4 (m, 1H) 3.6 (m,
1H).
(2R,3R)-2,3-Dimethyl-hexanal
[1760] Pyridinium chlorochromate (27.35 g, 126.9 mmol) and neutral
alumina (96 g, 3.5 g per gram of pyridinium chlorochromate) in dry
dichloromethane (200 mL) was stirred under nitrogen for 0.25 hours.
(2R,3R)-2,3-Dimethyl-hexan-1-ol (5.0 g, 38.46 mmol) in
dichloromethane (60 mL) was added and the resulting dark slurry was
stirred at room temperature for 3 hours. The slurry was filtered
through a short pad of silica eluting with excess dichloromethane.
Evaporation of the solvent afforded the titled compound (4.1 g, 84%
yield) as an oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.8
(m, 3H) 0.9 (d, J=6.6 Hz, 3H) 1.0 (d, J=6.6 Hz, 3H) 1.2 (m, 4H) 1.8
(m, 1H) 2.2 (m, 1H) 9.6 (s, 1H).
4-Methyl-benzenesulfinic acid
((2R,3R)-2,3-dimethyl-hexylidene)-amide
[1761] Titanium(IV) ethoxide (5.16 g, 22.6 mmol) and
(S)-(+)-p-toluenesulfinamide(7.02 g, 45.2 mmol) were added to
(2R,3R)-2,3-dimethyl-hexanal (2.9 g, 22.6 mmol) in dry THF (30 mL).
The resulting mixture was stirred at room temperature for 18 hours
and poured into a brine solution (40 mL). The slurry was rapidly
stirred for 10 minutes and filtered. The filtrate was extracted
into ethyl acetate, washed with brine and dried over MgSO.sub.4.
The solvent was evaporated and the residue was filtered through a
silica plug, eluting with 50/50 solution of hexane/ethyl acetate to
afford the titled compound (3.1 g, 51.6% yield) as an oil: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.8 (m, 6H) 1.1 (m, 4H) 1.3
(m, 3H) 1.7 (m, 1H) 2.4 (s, 3H) 2.5 (m, 1H) 7.3 (d, J=8.3 Hz, 2H)
7.5 (d, J=8.1 Hz, 2H) 8.1 (d, J=5.4 Hz, 1H). MS, m/z (relative
intensity): 266 [M+1H, 100%].
(4R,5R)-4,5-Dimethyl-(R)-3-(toluene-4-sulfinylamino)-octanoic Acid
tert-butyl Ester
[1762] Butyl lithium (26.3 mL, 42.04 mmol) was added to a solution
of diisopropylamine (4.6 g, 45.6 mmol) in dry THF (40 mL) under
nitrogen at 0.degree. C. and stirred for 20 minutes. The solution
was cooled to -78.degree. C. followed by the addition of t-butyl
acetate (4.1 g, 35.0 mmol) and stirred at that temperature for 45
minutes. Chlorotitanium triisopropoxide (9.4 g, 36.2 mmol) was
added dropwise and stirring was continued for 30 minutes at
-78.degree. C. A -50.degree. C. solution of
4-methyl-benzenesulfinic acid
((2R,3R)-2,3-dimethyl-hexylidene)-amide (3.1 g, 11.7 mmol) in dry
THF (10 mL) was added to the reaction and the resulting mixture was
stirred at -78.degree. C. for 4 hours. The reaction was quenched
with a saturated solution of NaH.sub.2PO.sub.4 and extracted into
ethyl acetate. The solution was dried over MgSO.sub.4 and
concentrated. The resulting residue was chromatographed on silica,
eluting with 15% ethyl acetate in hexane to give the titled
compound (2.4 g, 53.9% yield) as white solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.9 (m, 6H) 1.0 (d, J=6.6 Hz, 3H) 1.1 (m,
1H) 1.3 (m, 2H) 1.4 (m, 9H) 1.5 (m, 2H) 2.4 (s, 3H) 2.6 (m, 2H) 3.8
(m, 1H) 4.4 (d, J=10.0 Hz, 1H) 7.3 (d, J=8.1 Hz, 2H) 7.6 (d, J=8.1
Hz, 2H). MS, m/z (relative intensity): 382 [M+1H, 100%], 326
[M+1H--C(CH.sub.3).sub.3, 50%].
(3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic Acid
[1763] To the solution of
(4R,5R)-4,5-dimethyl-(R)-3-(toluene-4-sulfinylam- ino)-octanoic
acid tert-butyl ester (1.8 g, 4.71 mmol) in dry Methanol (30 mL) at
0.degree. C. under nitrogen was added excess trifluoroacetic acid
(25 mL) and stirred for 2 hours at that temperature. The solution
was concentrated to dryness followed by the addition of dry
dichloromethane (20 mL) and trifluoroacetic acid (20 mL). The
resulting mixture was stirred for 2 hours under nitrogen and
concentrated to dryness. The residue was applied to BondElute SCX
ion exchange resin and eluted with water until the eluent was at
constant pH of 6.5. The resin was then eluted with a 1:1 solution
of methanol and with 10% ammonium hydroxide solution. The ammonium
hydroxide solution was evaporated and the residue was crystallized
with methanol-acetonitrile mixture to afford the titled compound
(0.717 g, 81.2% yield) as a white solid:
[1764] .sup.1H NMR (400 MHz, CD.sub.3OD-D) .delta. ppm 0.9 (m, 11
H) 1.1 (m, 2H) 1.3 (m, 1H) 1.4 (m, 1H) 1.6 (m, 1H) 1.7 (m, 2H) 2.3
(dd, J=16.6, 10.0 Hz, 1H) 2.5 (dd, J=16.7, 3.5 Hz, 1H) 3.3 (m, 1H).
MS, m/z (relative intensity): 188 [M+1H, 100%], 186 [M-1H,
100%].
EXAMPLE 3
(S)-4-Methyl-hexan-2-one (2)
[1765] The Grignard reagent made from (S)-1-bromo-2-methyl-butane
(10 g, 66.2 mmol) and Mg (1.77 g, 72.8 mmol) in Et.sub.2O (65 mL)
was added dropwise to a solution of acetic anhydride (8.1 g, 79.3
mmol) in Et.sub.2O (65 mL) at -78.degree. C. in 1 hour. Lots of
white solid precipitated. The reaction mixture was stirred at
-78.degree. C. for 1 hour. Then the temperature was allowed to
slowly rise to RT. The reaction was quenched with saturated
NH.sub.4Cl aqueous solution (150 mL). The ether phase was washed by
1 N NaOH (150 mL) and brine (150 mL). The ether phase was stripped
under reduce pressure at 0.degree. C. The residual oil was
dissolved in hexane (50 mL). The solution was dried by anhydrous
Na.sub.2SO.sub.4 and evaporated at 0.degree. C. under reduced
pressure to give (S)-4-methyl-hexan-2-one (5.7 g, 75% yield) as a
light orange oil: .sup.1H NMR (CDCl.sub.3) .delta. 2.26 (m, 2H),
2.08 (s, 3H), 1.86 (m, 1H), 1.21 (m, 2H), 0.83 (m, 6H); MS (APCl)
(M+1).sup.+115.0.
(S)-2-Methyl-propane-2-sulfinic Acid
((3S)-1,3-dimethyl-pentylidene)-amide
[1766] A mixture of (S)-4-methyl-hexan-2-one (1.6 g, 14 mmol),
(S)-2-methyl-propane-2-sulfinic acid amide (1.7 g, 14 mmol) and
titanium(IV) ethoxide (6.4 g, 28 mmol) in THF (30 mL) was refluxed
for 10 hours. Then the reaction mixture was poured into brine (150
mL). The mixture was filtered. The filtrate was extracted by EtOAc
(3.times.70 mL). The EtOAc phase was removed under reduce pressure
and the residue was purified by a silica gel column (Hexane/EtOAc
3:1) to give the titled compound (1.93 g, 63% yield) as a colorless
oil: .sup.1H NMR (CDCl.sub.3) .delta. 2.24 (m, 2H), 2.27 (s, 3H),
1.85 (m, 1H), 1.22 (m, 2H), 1.20(s, 9H), 0.85 (m, 6H); MS (APCl)
(M+1)+218.1.
(3S,5S)-3,5-Dimethyl-3-((S)-2-methyl-propane-2-sulfinylamino)-heptanoic
Acid Methyl Ester
[1767] To a solution of diisopropylamine (3.1 mL, 22.2 mmol) in THF
(40 mL) at -78.degree. C. was slowly added butyllithium (14.4 mL,
1.6 M, 23 mmol). The mixture was stirred at 0.degree. C. for 25
minutes and subsequently cooled down to -78.degree. C. Methyl
acetate (1.76 mL, 22.2 mmol) in THF (7 mL) was added. After
Stirring for 20 minutes, chlorotitaniumtriisopropoxide (11 mL, 46.2
mmol) in THF (10 mL) was added and the resulting mixture was
stirred at -78.degree. C. for 20 minutes.
(S)-2-Methyl-propane-2-sulfinic acid
((3S)-1,3-dimethyl-pentylidene)-amid- e (1.9 g, 8.9 mmol) in THF
(10 mL) was added. The mixture was stirred at -78.degree. C.
overnight. The reaction was quenched by NH.sub.4Cl solution (50
mL). The mixture was filtered. The filtrate was extracted by EtOAc
(3.times.70 mL). The EtOAc phase was reduced under reduce pressure
and the residue was purified by a silica gel column (Hexane/EtOAc
1:1) to give the titled compound (1.61 g, 62% yield) as a colorless
oil: .sup.1H NMR (CDCl.sub.3) .delta. 3.64 (s, 3H), 2.60 (m, 2H),
1.47 (m, 2H), 1.44 (m, 1H), 1.36(s, 3H), 1.27 (m, 2H), 1.19 (s,
9H), 0.90 (d, J=6.4 Hz, 3H), 0.81 (t, J=7.6 Hz, 3H); MS (APCl)
(M+1).sup.+292.2.
(3S,5S)-3-Amino-3,5-dimethyl-heptanoic Acid
[1768] A mixture of
(3S,5S)-3,5-dimethyl-3-((S)-2-methyl-propane-2-sulfiny-
lamino)-heptanoic acid methyl ester (0.4 g, 1.37 mmol) and
concentrated hydrochloric acid (7.6 mL) in acetone (10 mL) was
refluxed for 3 hours. The solvents were stripped under reduced
pressure. The residue was dissolved in water (10 mL) and extracted
by EtOAc (2.times.15 mL). The aqueous phase was evaporated to
dryness. The residue was dissolved in a mixture of water (10 mL)
and triethylamine (0.5 mL). The mixture was stirred at 40.degree.
C. for 20 minutes and then was evaporated to dryness. The residue
was washed thoroughly with acetonitrile, filtered, and dried under
vacuum to give the final product, (3S,5S)-3-amino-3,5-dim-
ethyl-heptanoic acid (0.182 g, 77% yield) as a white solid. m.p.
215-217.degree. C.: .sup.1H NMR (CDCl.sub.3) .delta. 4.85 (s, 3H),
2.38 (m, 2H), 1.75 (m, 1H), 1.39 (m, 4H), 1.35(s, 3H), 0.98 (d,
J=6.6 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H); MS (APCl) (M+1)+174.1.
[1769] Using the above methodology the following compounds were
also made.
2 MS, .sup.1H NMR, 400MHz, .delta., PPM, Compound Name APCI.sup.+
CD.sub.3OD (3R,5S)-3-Amino-3,5- 174 (M + 1) 4.84(s, 3H), 2.38(m,
2H), 1.58(m, dimethyl-heptanoic acid 1H), 1.37(m, 4H), 1.34(s, 3H),
0.98(d, J=6.3Hz, 3H), 0.91(t, J=7.4Hz, 3H) (3S,5R)-3-Amino-3,5- 174
(M + 1) 4.84(s, 3H), 2.38(m, 2H), 1.58(m, dimethyl-heptanoic 1H),
1.37(m, 4H), 1.34(s, 3H), acid 0.98(d, J=6.3Hz, 3H), 0.91(t,
J=7.4Hz, 3H) (3R)-3-Amino-3,5- 188 (M + 1) 4.84(s, 3H), 2.39(m,
2H)1.72(m, dimethyl-octanoic acid 1H)1.59(s, 3H)1.38(m, 6H)0.98(d,
J=6.1Hz, 3H), 0.91(m, 3H) (3R, 4R/S)-3-Amino-4- 160 (M + 1) 0.98(m,
6H)1.20(m, 1H)1.32(m, methyl-heptanoic acid 1H)1.43(m, 2H)1.78(m,
1H), 2.32(m, 1H)2.47(m, 1H)3.30(m, 1H) (3S,6R)-3-Amino-8- 256 (M +
1) 0.87(m, 2H)0.88(dd, J=15.86, cyclohexyl-6-methyl-octanoic acid
6.10Hz, 3H)1.20(m, 11H)1.39(m, 4H)1.69(m, 6H)2.53(dd, J=17.32,
8.05Hz, 1H)2.69(m, 1H) 3.44(ddd, J=14.70, 6.89, 4.76Hz, 1H)
EXAMPLE 4
[1770] (3R)-(3,7-Dimethyl-oct-6-enyl)-cyclohexane
[1771] A flask was charged with 100 mL of dry THF and cooled to
0.degree. C. To this flask was added 103 mL (205 mmol) of 2 M
cyclohexylmagnesium chloride in diethylether. Then 2.30 g (17 mmol)
copper (II) chloride was taken up in 60 mL of THF and added as a
slurry to the Grignard reagent. To this mixture was added 0.73 g
(17.1 mmol) lithium chloride, and the mixture was stirred at
0.degree. C. for 30 minutes. Then 13.5 mL (68.4 mmol) of
(S)-citronellyl bromide was added, and the mixture was stirred 2
hours at 0.degree. C. The reaction mixture was allowed to warm to
room temperature and stirred overnight. The reaction was quenched
by the addition of sat. aq. NH.sub.4Cl until bubbling ceased. The
THF was removed under reduced pressure. The residue was taken up in
water and extracted with diethyl ether. The combined ether layers
were dried over MgSO.sub.4. The drying agent was removed by
filtration. The solvent was removed under reduced pressure to yield
11.48 g (76% yield) of a clear oil. The crude long-chain alkyl was
not readily characterized, and was carried on without further
purification.
3-((R)-5-Cyclohexyl-3-methyl-pentyl)-2,2-dimethyl-oxirane
[1772] A flask was charged with 11.48 g (51.6 mmol) of crude
(3R)-(3,7-dimethyl-oct-6-enyl)-cyclohexane, 100 mL of
dichloromethane, and 9.33 g (111 mmol) of sodium bicarbonate. The
mixture was cooled in a 0.degree. C. bath. Slowly 11.6 mL (55.2
mmol) 32% peracetic acid was added. The mixture was stirred for 4
hours at 0.degree. C. Then 10% aqueous sodium sulfite was added
slowly until bubbling ceased. The layers were separated, and the
organic layer was washed twice with 10% aqueous sodium sulfite and
dried over magnesium sulfate. The drying agent was removed by
filtration, and the solvent was removed under reduced pressure. The
remaining residue was 10.65 g (87%) of a clear oil: .sup.1H NMR
(400 MHz, CDCl.sub.3) ppm 0.86 (m, 5H) 1.00 (d, J=6.59 Hz, 2H) 1.14
(m, 7H) 1.25 (s, 3H) 1.29 (s, 3H) 1.35 (m, 2H) 1.50 (m, 3H) 1.65
(m, 5H) 2.68 (td, J=6.16, 1.83 Hz, 1H). MS (APCl) m+1/z=239.
(R)-6-Cyclohexyl-4-methyl-hexanal
[1773] A flask was charged with 10.65 g (44.7 mmol) of
3-((R)-5-cyclohexyl-3-methyl-pentyl)-2,2-dimethyl-oxirane, 70 mL of
acetone, 12.3 g (53.6 mmol) of potassium periodate, 70 mL of water,
and 0.765 g (4 mmol) of tosic acid-monohydrate. The mixture was
stirred for 46 hours. The acetone was removed under reduced
pressure, and the mixture was diluted with water. The aqueous layer
was extracted with hexanes and dried with sodium sulfate. The
drying agent was filtered off and solvent was removed under reduced
pressure to get 7.12 g (81% yield) of a clear oil: .sup.1H NMR (400
MHz, CDCl.sub.3) ppm 0.87 (m, 5H) 1.13 (m, 3H) 1.25 (m, 5H) 1.66
(m, 8H) 2.40 (m, 2H) 9.75 (s, 1H). MS (APCl) m+1/z is
inconclusive.
(R)-6-Cyclohexyl-4-methyl-hexanoic Acid
[1774] A flask was charged with 7.12 g (36.3 mmol) of
(R)-6-cyclohexyl-4-methyl-hexanal, 40 mL of water, 20 mL of
acetone, 4 mL acetic acid, and 6.18 g (39.9 mmol) of potassium
permanganate. The mixture was stirred vigorously overnight. The
mixture was then treated with sat. aqueous sodium bisulfite until
the liquid became clear. The liquid was extracted with hexanes. The
combined hexane layers were washed with sat. aqueous sodium
bisulfite until the hexane layer was clear. The hexane phases were
dried with magnesium sulfate. The drying agent was filtered off and
the solvent was removed under reduced pressure, which yielded 4.17
g (54% yield) of a clear oil: .sup.1H NMR (400 MHz, CDCl.sub.3) ppm
0.89 (m, 5H), 1.13 (m, 3H) 1.25 (m, 5H) 1.66 (m, 8H) 2.40 (m, 2H).
MS (APCl) m+1/z=211.
(4R,5S)-3-((R)-6-Cyclohexyl-4-methyl-hexanoyl)-4-methyl-5-phenyl-oxazolidi-
n-2-one
[1775] A flask was charged with 4.17 g (19.6 mmol) of
(R)-6-cyclohexyl-4-methyl-hexanoic acid, 40 mL of THF, and 8.56 mL
(61.4 mmol) of triethylamine. The mixture was cooled in a 0.degree.
C. bath, and 2.41 mL (19.6 mmol) of pivaloyl chloride was added.
The mixture was stirred for 1 h at 0.degree. C. Then 2.79 g (16.4
mmol) of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.823 g
(19.6 mmol) of lithium chloride were added as solids. The mixture
was allowed to warm to room temperature and stirred overnight. The
resulting solids were filtered off. The solvent was stripped under
reduce pressure, and the residue was purified by column
chromatography (eluent: 4:1 hexanes/ethyl acetate) to give 6.09 g
(quant.) of a clear oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 0.89 (m, 8H) 1.16 (m, 6H) 1.68 (m, 9H) 2.87 (m, 1H) 2.99 (m,
1H) 4.76 (qd, J=6.83, 6.59 Hz, 1H) 5.66 (d, J=7.32 Hz, 1H) 7.30 (m,
2H) 7.40 (m, 3H). MS (APCl) m+1/z=372.
(5R,3S)-7-Cyclohexyl-5-methyl-3-((4R,5R)-4-methyl-2-oxo-5-phenyl-oxazolidi-
ne-3-carbonyl)-heptanoic Acid tert-butyl Ester
[1776] A dry flask was charged with 60 mL of THF, 2.87 mL (20.5
mmol) of diisopropyl amine, and the resulting solution was cooled
in a -78.degree. C. bath. To this solution was added 13.3 mL (19.7
mmol) of 1.48 M n-butyl lithium solution. The mixture was allowed
to warm to 0.degree. C. and was stirred for 30 minutes at this
temperature. The LDA solution was cooled again to -78.degree. C.,
and 6.10 g (16.4 mmol) of
(4R,5S)-3-((R)-6-cyclohexyl-4-methyl-hexanoyl)-4-methyl-5-phenyl-oxazolid-
in-2-one was added dropwise as a solution in 35 mL of THF. The
mixture was stirred for 45 minutes at -78.degree. C., and was then
allowed to warm slowly to -20.degree. C. over 2.5 hours. The
reaction mixture was quenched by the addition of sat. aq. ammonium
chloride. The solvent was removed under reduced pressure, and the
residue was partitioned between diethyl ether and water. The ether
layer was collected and washed successively with sat. aq. ammonium
chloride solution and sat. aq. sodium bicarbonate solution. The
ether layer was dried with magnesium sulfate. The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography (eluent 10:1 hexanes:ethyl acetate). This
gave 4.13 g (52% yield) of a white solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.88 (m, 8H) 1.14 (m, 8H) 1.39 (m, 12H)
1.67 (m, 6H) 2.41 (dd, J=16.47, 5.00 Hz, 1H) 2.70 (dd, J=16.47,
9.64 Hz, 1H) 4.31 (m, J=9.58, 7.29, 7.29, 5.12 Hz, 1H) 4.75 (qd,
J=6.75, 6.59 Hz, 1H) 5.64 (d, J=7.08 Hz, 1H) 7.31 (m, 2H) 7.38 (m,
3H). MS (APCl) m+1/z=430 (loss of t-Bu group).
(S)-2-((R)-4-Cyclohexyl-2-methyl-butyl)-succinic Acid 4-tert-butyl
Ester
[1777] A flask was charged with 4.13 g (8.50 mmol) of
(5R,3S)-7-cyclohexyl-5-methyl-3-((4R,5R)-4-methyl-2-oxo-5-phenyl-oxazolid-
ine-3-carbonyl)-heptanoic acid tert-butyl ester, 100 mL of THF, 25
mL of water, and the resulting mixture was cooled in a 0.degree. C.
bath. To this solution was added 0.57 g (13.6 mmol) of lithium
hydroxide monohydrate and 3.48 mL (34 mmol) of 30% hydrogen
peroxide. The mixture was stirred for 2.5 hours. The reaction was
quenched by the addition of 4.29 g (34 mmol) of sodium sulfite in
26 mL water. The mixture was allowed to warm to room temperature
and stirred overnight. The THF was removed under reduced pressure
and the remaining material was further diluted with water. The
water layer was made acidic by the slow addition of conc. HCl aq.
The aqueous layer was extracted with dichloromethane. The organic
layers were dried with magnesium sulfate. The resulting oil was
purified by column chromatography (eluent 3:1 hexanes:ethyl
acetate). This gave 2.19 g (79% yield) of a clear oil: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 0.88 (m, 5H) 1.17 (m, 10H) 1.43
(s, 10H) 1.68 (m, 7H) 2.35 (dd, J=16.35, 5.37 Hz, 1H) 2.60 (m, 1H)
2.87 (m, J=9.09, 9.09, 5.61, 5.49 Hz, 1H). MS (APCl) m+1/z is
inconclusive.
(3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic Acid Methyl
Ester
[1778] A flask was charged with 2.19 g (6.71 mmol) of
(S)-2-((R)-4-cyclohexyl-2-methyl-butyl)-succinic acid 4-tert-butyl
ester, 40 mL of toluene, 0.935 mL (6.71 mmol) of triethylamine, and
1.45 mL (6.71 mmol) of diphenylphosphorylazide. The mixture was
stirred for 15 minutes at room temperature and then heated to
110.degree. C. and stirred for 6 hours. The toluene was removed
under reduced pressure, and the residue was taken up in diethyl
ether. The ether layer was washed with 3M HCl aq., water, and
brine. The ether was removed under reduced pressure, and the crude
isocyanate was taken up in 3 M HCl aq. and heated at reflux for 8
hours. The water was removed under reduced pressure, and the
residue was triturated with ether. This provided 1.45 g of an
impure white solid. A portion of the white solid was dissolved in
methanol, and HCl gas was bubbled through for 15 minutes. The
acidic solution was stirred 2 hours. The methanol was removed under
reduced pressure, and the crude ester was purified by column
chromatography (4:1 dichloromethane: methanol). This gave 0.356 g
of the pure ester: .sup.1H NMR (400 MHz, CDCl.sub.3) 8 ppm 0.85 (m,
2H) 0.88 (d, J=8.00 Hz, 3H) 1.15 (m, 6H) 1.26 (m, 1H) 1.36 (ddd,
J=13.73, 9.21, 4.64 Hz, 1H) 1.51 (m, 1H) 1.65 (m, 7H) 2.28 (dd,
J=15.86, 8.78 Hz, 1H) 2.43 (dd, J=16.0, 4.00 Hz, 1H) 3.28 (m,
J=8.97, 8.97, 4.39, 4.27 Hz, 1H) 3.69 (s, 3H). MS (APCl)
m+1/z=256.
(3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic Acid
[1779] A flask was charged with 0.356 g of
(3S,5R)-3-amino-7-cyclohexyl-5-- methyl-heptanoic acid methyl ester
and 20 mL of 3 M HCl, and the mixture was heated at reflux
overnight. The mixture was cooled to room temperature and the
solvent was removed under reduced pressure. This provided 0.340 g
(88%) of a white solid HCl salt: .sup.1H NMR (400 MHz, CD.sub.3OD)
8 ppm 0.87 (s, 2H) 0.95 (d, J=6.34 Hz, 3H) 1.21 (m, 6H) 1.35 (m,
1H) 1.43 (ddd, J=13.85, 8.24, 5.98 Hz, 1H) 1.55 (ddd, J=12.81,
6.34, 6.22 Hz, 1H) 1.64 (dd, J=8.30, 5.37 Hz, 2H) 1.71 (m, 5H) 2.57
(dd, J=17.45, 7.44 Hz, 1H) 2.70 (m, 1H) 3.59 (m, J=7.72, 7.72,
5.73, 5.43 Hz, 1H). MS (APCl) m+1/z=242.
EXAMPLE 5
(4R,5S)-3-[3-(2,4-Difluoro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-
-2-one
[1780] A flask was charged with 29.5 g (158 mmol) of
3-(2,4-difluoro-phenyl)-propionic acid, 700 mL of THF, and 82.8 mL
of triethylamine. The mixture was cooled to 0.degree. C. and 23.4
mL of trimethyl acetyl chloride was added slowly. The mixture was
stirred cold for 1 hour. Then 8.06 g (190 mmol) of LiCl and 28.1 g
of (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one was added. The
mixture was allowed to warm room temperature and stirred overnight.
The solids were filtered off, and the solvent was removed under
reduced pressure. The residue was taken up in diethyl ether and
washed with sat. aq. ammonium chloride, sat. aq. sodium
bicarbonate, and the solvent was removed under reduced pressure.
The crude residue was purified by column chromatography (3:1
dichloromethane/hexanes eluent) to give 54 g (99% yield) of the
titled compound.
(4R,5S)-[(S)-2-(2,4-Difluoro-benzyl)-butyryl]-4-methyl-5-phenyl-oxazolidin-
-2-one
[1781] A flask was charged with 54 g (156 mmol) of
(4R,5S)-3-[3-(2,4-diflu-
oro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300
mL of dry THF, and the solution was cooled to -78.degree. C. To
this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and
the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of
ethyl triflate was added dropwise to the enolate solution, and the
reaction mixture was warmed to -40.degree. C. to -30.degree. C. and
stirred for 1.5 hours. The reaction mixture was quenched by the
addition of aqueous brine. The THF was removed under reduced
pressure and the residue was partitioned between EtOAc and water.
The organics were collected, and EtOAc was removed under reduced
pressure. The resulting crude oil was purified by column
chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an
impure oil that was used without further purification.
(S)-2-(2,4-Difluoro-benzyl)-butan-1-ol
[1782] A flask was charged with 29.5 g (.about.78.6 mmol) of
(4R,5S)-[(S)-2-(2,4-difluoro-benzyl)-butyryl]-4-methyl-5-phenyl-oxazolidi-
n-2-one and 200 mL of dry THF, and the solution was cooled to
0.degree. C. In a separate flask, 11.9 g (314 mmol) of sodium
borohydride was taken up in 70 mL of water and added dropwise over
15 minutes to the imide solution. The mixture was allowed to warm
to room temperature and stirred overnight. The reaction mixture was
quenched with conc. HCl until pH=3 (keeping the reaction mixture
temperature <20.degree. C.). THF was removed under reduced
pressure, and the residue was taken up in hexanes. The hexane layer
was washed with sat. aq. sodium bicarbonate. The hexane layer was
removed under reduced pressure, and the residue was purified by
column chromatography (9:1 Hexanes/EtOAc) which gave 7.2 g (46%
yield) of the titled compound as a clear oil.
(2S)-Methanesulfonic Acid 2-(2,4-difluoro-benzyl)-butyl Ester
[1783] A flask was charged with 7.2 g (36 mmol) of
(S)-2-(2,4-difluoro-ben- zyl)-butan-1-ol and 30 mL of
dichloromethane, and the solution was cooled to 0.degree. C. To
this solution was added 7.53 mL (54 mmol) of triethylamine, and the
mixture was stirred cold for 5 minutes. Then 3.1 mL (39.6 mmol) of
methane sulfonyl chloride was added dropwise. The reaction mixture
was stirred at room temperature for 16 hours. The dichloromethane
was removed under reduced pressure, and the residue was partitioned
between 1 N HCl aq. and diethyl ether. The ether layer was
collected and washed with sat. aq. sodium bicarbonate, water, and
brine. The ether layer was dried over sodium sulfate, filtered, and
the ether was removed under reduced pressure. This procedure gave
9.54 g (95% yield) of (2S)-methanesulfonic acid
2-(2,4-difluoro-benzyl)-butyl ester as an orange oil. This material
was used without further purification.
(S)-2,4-Difluoro-1-(2-iodomethyl-butyl)-benzene
[1784] A flask was charge with 9.54 g (34.3 mmol) of
(2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester, 10.3
g (68.6 mmol) of sodium iodide, and 60 mL of acetone. The solution
was heated at reflux for 30 hours. The acetone was removed under
reduced pressure. The residue was partitioned between water and
hexanes. The organic layer was collected and washed with sodium
bisulfite solution and brine. The hexane was removed under reduced
pressure, and the crude oil was purified by column chromatography
(hexanes eluent). This procedure gave 9.7 g (91% yield) of the
titled compound as a clear oil.
2-tert-Butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-p-
yrimidine-1-carboxylic Acid Methyl Ester
[1785] A flask was charged with 1.35 mL (9.64 mmol) of diisopropyl
amine and 15 mL of dry THF. The solution was cooled to -78.degree.
C. and 6.0 mL (9.64 mmol) of 1.6 M n-butyl lithium solution in
hexanes was added. The mixture was warmed to 0.degree. C. and
stirred for 30 minutes. The mixture was cooled again to -78.degree.
C. and 2.0 g (8.76 mmol) of
(2S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic
acid methyl ester was added as a solution in 10 mL of THF. This
mixture was warmed to 0.degree. C. and stirred for 1 hour. The
anion solution was cooled again to -78.degree. C. and 2.99 g (9.64
mmol) of (S)-2,4-difluoro-1-(2-iodomethyl-butyl)-benzene was added
as a solution in THF. The mixture was stirred at -78.degree. C. for
4 hours. The reaction mixture was warmed to -21.degree. C. and
stirred at that temperature for 5 days. The reaction mixture was
quenched with sat. aq. ammonium chloride solution. The crude
reaction mixture was extracted with diethyl ether. The ether was
removed under reduced pressure, and the crude residue was purified
by column chromatography (9:1 hexanes/EtOAc eluent) which gave 1.67
g (46% yield) of the titled compound as a white solid.
(2R,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic Acid
[1786] A flask was charged with 0.5 g (1.2 mmol) of
2-tert-butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro--
pyrimidine-1-carboxylic acid methyl ester, 20 mL of dioxane, and 20
mL of conc. HCl solution. The mixture was stirred and heated at
110.degree. C. for 4 days. The solvents were removed under reduced
pressure. The residue was taken up in 20 mL of water and 4 drops of
conc. HCl solution. The aqueous layer was washed with
dichloromethane. The aqueous layer was collected and the water was
removed under reduced pressure. The residue was treated with 2 mL
of triethylamine, and the excess triethylamine was removed under
reduced pressure. The remaining solid was purified by column
chromatography (1:8:27 NH.sub.4OH, MeOH, dichloromethane eluent).
The resulting white solid was washed with acetonitrile and dried
under vacuum. This gave 80 mg (24% yield) of the titled compound as
a white solid.
EXAMPLE 6
3-(2-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one
[1787] A flask was charged with 29.5 g (158 mmol) of
3-(2,4-difluoro-phenyl)-propionic acid, 700 mL of THF, and 82.8 mL
of triethylamine. The mixture was cooled to 0.degree. C. and 23.4
mL of trimethyl acetyl chloride was added slowly. The mixture was
stirred cold for 1 hour. Then 8.06 g (190 mmol) of LiCl and 28.1 g
of (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one was added. The
mixture was allowed to warm room temperature and stirred overnight.
The solids were filtered off, and the solvent was removed under
reduced pressure. The residue was taken up in diethyl ether and
washed with sat. aq. ammonium chloride, sat. aq. sodium
bicarbonate, and the solvent were removed under reduced pressure.
The crude residue was purified by column chromatography (3:1
dichloromethane/hexanes eluent) to give 54 g (99% yield) of the
titled compound.
(4R,5S)-[(S)-2-(2,4-Difluoro-benzyl)-butyryl]-4-methyl-5-phenyl-oxazolidin-
-2-one
[1788] A flask was charged with 54 g (156 mmol) of
(4R,5S)-3-[3-(2,4-diflu-
oro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300
mL of dry THF, and the solution was cooled to -78.degree. C. To
this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and
the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of
ethyl triflate was added dropwise to the enolate solution, and the
reaction mixture was warmed to -40.degree. C. to -30.degree. C. and
stirred for 1.5 hour. The reaction mixture was quenched by the
addition of aqueous brine. The THF was removed under reduced
pressure and the residue was partitioned between EtOAc and water.
The organics were collected, and EtOAc was removed under reduced
pressure. The resulting crude oil was purified by column
chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an
impure oil that was used without further purification.
(S)-2-(2,4-Difluoro-benzyl)-butan-1-ol
[1789] A flask was charged with 29.5 g (.about.78.6 mmol) of
(4R,5S)-[(S)-2-(2,4-difluoro-benzyl)-butyryl]-4-methyl-5-phenyl-oxazolidi-
n-2-one and 200 mL of dry THF, and the solution was cooled to
0.degree. C. In a separate flask, 11.9 g (314 mmol) of sodium
borohydride was taken up in 70 mL of water and added dropwise over
15 minutes to the imide solution. The mixture was allowed to warm
to room temperature and stirred overnight. The reaction mixture was
quenched with conc. HCl until pH=3 (keeping the reaction mixture
temperature <20.degree. C.). THF was removed under reduced
pressure, and the residue was taken up in hexanes. The hexane layer
was washed with sat. aq. sodium bicarbonate. The hexane layer was
removed under reduced pressure, and the residue was purified by
column chromatography (9:1 Hexanes/EtOAc) which gave 7.2 g (46%
yield) of the titled compound as a clear oil.
(2S)-Methanesulfonic Acid 2-(2,4-difluoro-benzyl)-butyl Ester
[1790] A flask was charged with 7.2 g (36 mmol) of
(S)-2-(2,4-difluoro-ben- zyl)-butan-1-ol and 30 mL of
dichloromethane, and the solution was cooled to 0.degree. C.
[1791] To this solution was added 7.53 mL (54 mmol) of
triethylamine, and the mixture was stirred cold for 5 minutes. Then
3.1 mL (39.6 mmol) of methane sulfonyl chloride was added dropwise.
The reaction mixture was stirred at room temperature for 16 hours.
The dichloromethane was removed under reduced pressure, and the
residue was partitioned between 1 N HCl aq. and diethyl ether. The
ether layer was collected and washed with sat. aq. sodium
bicarbonate, water, and brine. The ether layer was dried over
sodium sulfate, filtered, and the ether was removed under reduced
pressure. This procedure gave 9.54 g (95% yield) of the titled
compound as an orange oil. This material was used without further
purification.
(S)-2,4-Difluoro-1-(2-iodomethyl-butyl)-benzene
[1792] A flask was charge with 9.54 g (34.3 mmol) of
(2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester, 10.3
g (68.6 mmol) of sodium iodide, and 60 mL of acetone. The solution
was heated at reflux for 30 hours. The acetone was removed under
reduced pressure. The residue was partitioned between water and
hexanes. The organic layer was collected and washed with sodium
bisulfite solution and brine. The hexane was removed under reduced
pressure, and the crude oil was purified by column chromatography
(hexanes eluent). This procedure gave 9.7 g (91% yield) of the
titled compound as a clear oil.
2-tert-Butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-p-
yrimidine-1-carboxylic Acid Methyl Ester
[1793] A flask was charged with 1.35 mL (9.64 mmol) of diisopropyl
amine and 15 mL of dry THF. The solution was cooled to -78.degree.
C. and 6.0 mL (9.64 mmol) of 1.6 M n-butyl lithium solution in
hexanes was added. The mixture was warmed to 0.degree. C. and
stirred for 30 minutes. The mixture was cooled again to -78.degree.
C. and 2.0 g (8.76 mmol) of
(2S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic
acid methyl ester was added as a solution in 10 mL of THF. This
mixture was warmed to 0.degree. C. and stirred for 1 hour. The
anion solution was cooled again to -78.degree. C. and 2.99 g (9.64
mmol) of (S)-2,4-difluoro-1-(2-iodomethyl-butyl)-benzene was added
as a solution in THF. The mixture was stirred at -78.degree. C. for
4 hours. The reaction mixture was warmed to -21.degree. C. and
stirred at that temperature for 5 days. The reaction mixture was
quenched with sat. aq. ammonium chloride solution. The crude
reaction mixture was extracted with diethyl ether. The ether was
removed under reduced pressure, and the crude residue was purified
by column chromatography (9:1 hexanes/EtOAc eluent) which gave 1.67
g (46% yield) of the titled compound as a white solid.
(2R,4R)-2-Aminomethyl-4-(2,4-difluoro-benzyl)-hexanoic Acid
[1794] A flask was charged with 0.5 g (1.2 mmol) of
2-tert-butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro--
pyrimidine-1-carboxylic acid methyl ester, 20 mL dioxane, and 20 mL
of conc. HCl solution. The mixture was stirred and heated at
110.degree. C. for 4 days. The solvents were removed under reduced
pressure. The residue was taken up in 20 mL of water and 4 drops of
conc. HCl solution. The aqueous layer was washed with
dichloromethane. The aqueous layer was collected and the water was
removed under reduced pressure. The residue was treated with 2 mL
of triethylamine, and the excess triethylamine was removed under
reduced pressure. The remaining solid was purified by column
chromatography (1:8:27 NH.sub.4OH, MeOH, dichloromethane eluent).
The resulting white solid was washed with acetonitrile and dried
under vacuum. This gave 80 mg (24% yield) of the titled compound as
a white solid.
EXAMPLE 7
(S)-3-((E)-2-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one
[1795] A 20 L jacketed reactor was fitted with a reflux condenser
and a nitrogen inlet. To the flask was charged 1006 g (8.81 mol) of
(E)-2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of
(S)-(+)-4-phenyl-oxazolidin-2-one, 2179 g (8.81 mol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 81 g (1.915
mol) of lithium chloride, and 12.5 L of ethyl acetate (EtOAc). The
reaction was heated to 75.degree. C. for 20 hours and then cooled
to room temperature. The reaction solution was extracted 3.times.
with 4 L aliquots of 1N HCl and 1.times. with 4 L of 0.2N NaOH. The
20 L reactor was fitted with a distillation head. The organic layer
was distilled to remove, in succession: 6.5 L of EtOAc, after which
8 L of heptane was added back to the reactor; 4 L of EtOAc/heptane,
after which 4 L of heptane was added to the reactor; and 4 L of
EtOAc/heptane, after which 8 L of heptane was added to the reactor.
After an additional 2 L of EtOAc/heptane was removed by
distillation, the reaction mixture was cooled to an internal
temperature of 40.degree. C., and the reactor contents were charged
to a filter and filtered under 5 psig of nitrogen washing with 8 L
of heptane. The solids were dried under 5 psig of nitrogen
overnight to give 1772 g of the titled compound: .sup.1H-NMR (DMSO)
7.363-7.243 (m, 5H), 6.137-6.096 (m, 1H), 5.434-5.394 (m, 1H),
4.721-4.678 (t, 1H, J=8.578), 4.109-4.069 (m, 1H), 2.119-2.044 (m,
2H), 1.703-1.700 (d, 3H, J=1.364), 0.945-0.907 (t, 3H, J=7.603);
Anal Calc'd for C.sub.15H.sub.17N.sub.1O.sub.3: C, 69.48; H, 6.61;
N, 5.40. Found: C, 68.66; H, 6.60; N, 5.60; MS (Ion Mode: APCI)
m/z=260 [M+1].sup.+.
(4S,5R)-3-((E)-2-Methyl-pent-2-enoyl)-4,5-diphenyl-oxazolidin-2-one
[1796] To a solution of (E)-2-methyl-2-pentenoic acid (5.3 g, 47
mmol) in 250 mL of THF at 0.degree. C. was added 16.3 mL (117 mmol)
of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride
resulting in a thick suspension. The mixture was stirred for 1 hour
at 0.degree. C. at which time 2.0 g (47 mmol) of lithium chloride
was added in one portion, followed by 10 g (42 mmol) of
(4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was
maintained throughout the solid additions. The reaction mixture was
stirred for 1 hour at 0.degree. C., and for 1 hour at ambient
temperature, and was vacuum filtered through a coarse frit and
concentrated. The residue was partitioned between EtOAc/water, and
the organics were dried over MgSO.sub.4 and concentrated. To the
residue was added 200 mL of MTBE and the mixture was warmed
cautiously with swirling. The warm slurry was filtered to provide
13.0 g (83% yield) of the titled compound as a colorless solid:
.sup.1H NMR (CDCl.sub.3) .delta. 7.12 (m, 3H), 7.08 (m, 3H), 6.93
(m, 2H), 6.86 (m, 2H), 6.14 (m, 1H), 5.90 (d, J=7.8 Hz, 1H), 5.69
(d, J=7.8 Hz, 1H), 2.23 (pent, J=7.6 Hz, 2H), 1.92 (s, 3H), 1.07
(t, J=7.6 Hz, 3H). The titled acylated oxazolidinone may be used in
the next step instead of (S)-3-((E)-2-Methyl-pent-2-enoyl)-4-phen-
yl-oxazolidin-2-one.
(2R,3R,4S)-3-(2,3-Dimethyl-pentanoyl)-4-phenyl-oxazolidin-2-one
[1797] A 20 L jacketed reactor was fit with a gas inlet and a 2 L
dripping funnel. A nitrogen sweep was begun over the reactor and
maintained throughout the process. To the reactor was charged 392 g
(9.26 mol) of lithium chloride, 1332 g (6.479 mol) of copper
bromide dimethylsulfide complex and 11 L of tetrahydrofuran. The
reaction was stirred for 30 minutes at room temperature and then
cooled to -15.degree. C. To the reaction mixture was added 4.268 L
(12.80 mol) of 3.0M methyl magnesium chloride at a rate such that
the reaction temperature did not exceed -10.degree. C. Upon
completion of the addition, the cuprate solution was allowed to
stir at -5.degree. C. overnight. To the cuprate solution was added
500 g (3.09 mol) of
(S)-3-((E)-2-methyl-pent-2-enoyl)-4-phenyl-oxaz- olidin-2-one as a
solid. The reaction was stirred at -3.degree. C. for 2 hours. The
reaction solution was charged to a 22 L round bottom flask
containing 800 mL of acetic acid and 2 L of tetrahydrofuran at a
rate such that the temperature of the quench solution did not
exceed 25.degree. C. To the quenched solution was added 6 L water.
The resulting emulsion was filtered and the layers were separated.
The organic layer was extracted with 9 L of 4.8 M NH.sub.4OH
followed by 9 L of saturated NH.sub.4Cl. The organic layer was
clarified through a plug of magnesol. The organic layer was
concentrated to give 822 g of a crude solid. The crude solid was
recrystallized from 8 L of 20% H.sub.2O in MeOH, filtered and dried
in a vacuum oven to give 550 g of a white solid. The white solid
was recrystallized from 5 L of 20% H.sub.2O in MeOH, filtered and
dried in a vacuum oven to give 475 g of the titled compound:
.sup.1H-NMR (DMSO) 7.338-7.224 (m, 5H), 5.431-5.399 (q, 1H,
J=4.288), 4.696-4.652 (t, 1H, J=8.773), 4.120-4.087 (m, 1H),
3.622-3.556 (m, 1H), 1.648-1.584 (m, 1H), 1.047-0.968 (m, 1H),
0.900-0.883 (d, 3H, J=6.823), 0.738-0.721 (d, 3H, J=6.628),
0.693-0.656 (t, 3H, J=7.408); Anal Calc'd for
C.sub.16H.sub.21N.sub.1O.sub.3: C, 69.79; H, 7.69; N, 5.09. Found:
C, 69.81; H, 7.61; N, 5.07; MS (ion Mode: APCI) m/z=276
[M+1].sup.+.
(2R,3R)-2,3-Dimethyl-pentanoic Acid
[1798] A 20 L jacketed flask was fit with a gas inlet. A nitrogen
purge was begun over the reactor and maintained throughout the
process. To the flask was charged 450 g (1.634 mol) of
(2R,3R,4S)-3-(2,3-dimethyl-pentano- yl)-4-phenyl-oxazolidin-2-one
and 3.375 L tetrahydrofuran. The contents of the reactor were
stirred at 15.degree. C. In a separate 3 L round bottom flask,
placed in an ice bath, was charged 500 mL of water, 137 g (3.269
mol) of LiOH--H.sub.2O and 942 mL (9.81 mol) of 30% wt/wt
H.sub.2O.sub.2. The contents of the 3 L round bottom flask were
stirred for 3 minutes and then poured into the 20 L jacketed
reactor at a rate such that the temperature did not exceed
25.degree. C. The reaction was stirred at 15.degree. C. for 2 hours
and then raised to 25.degree. C. and stirred for an additional 2
hours. The jacket temperature of the reactor was set to -20.degree.
C. To the reaction was added 1.66 L of saturated NaHSO.sub.3 at a
rate such that the temperature of the reaction did not exceed
25.degree. C. The layers were separated. The aqueous layer was
extracted 2.times. with 1 L aliquots of MTBE. The organic phases
were combined and concentrated to give a solid/oil mixture. The
solid/oil mixture was slurried in 1.7 L of hexane. The slurry was
filtered and the collected solids were washed with 1.7 L of hexane.
The hexane filtrates were extracted 2.times. with 1.35 L aliquots
of 1N NaOH. The aqueous extracts were combined and extracted with
800 mL of dichloromethane. The aqueous layer was then acidified
with 240 mL of concentrated hydrochloric acid. The aqueous solution
was extracted 2.times. with 1 L aliquots of dichloromethane. The
organic extracts were combined, dried over MgSO.sub.4 and
concentrated to give 201 g of the titled compound: .sup.1H-NMR
(DMSO) 11.925 (bs, 1H), 2.204-2.135 (m, 1H), 1.556-1.490 (m, 1H),
1.382-1.300 (m, 1H), 1.111-1.000 (m, 1H), 0.952-0.934 (d, 3H,
J=7.018), 0.809-0.767 (m, 6H); Gas Chromatogram 9.308 minutes,
98.91% area; Anal Calc'd for C.sub.7H.sub.14O.sub.2: C, 64.58; H,
10.84; N, O. Found: C, 64.39; H, 10.77; N, 0.18; MS (Ion Mode:
APCI) m/z=131 [M+1]+.
(4R,5R)-4,5-Dimethyl-3-oxo-heptanoic acid ethyl ester
[1799] To a 1 L round bottom flask equipped with a nitrogen inlet
was charged 22 g (230 mmol) of magnesium chloride, 39 g (230 mmol)
of potassium ethyl malonate and 200 mL of dimethylformamide. The
contents of the flask were stirred at 50.degree. C. for 1 hour and
then cooled to 35.degree. C. In a separate 500 mL, nitrogen inerted
flask was added 200 mL of dimethylformamide, 28.6 g (177 mmol) of
carbonyl diimidazole and 20 g of (2R,3R)-2,3-dimethyl-pentanoic
acid was dripped in over 30 minutes. When the gas evolution had
ceased, the contents of the 500 mL flask were added to the 1 L
flask. The reaction was stirred for 2 days at 35.degree. C. The
reaction was cooled to room temperature and diluted with 800 mL of
1N HCl. The aqueous solution was extracted 3.times. with 1 L
aliquots of MTBE. The organic extracts were combined and extracted
with 200 mL of saturated NaHCO.sub.3. The organic layer was dried
over MgSO.sub.4 and concentrated to give 31.74 g of the titled
compound: .sup.1H-NMR (CDCl.sub.3) 4.180-4.120 (m, 2H), 3.454 (s,
2H), 2.522-2.453 (q, 1H, J=7.018), 1.738-1.673 (m, 1H), 1.418-1.328
(m, 1H), 1.270-1.217 (m, 3H), 1.113-1.010 (m, 4H), 0.889-0.815 (m,
5H); MS (Ion Mode: APCI) m/z=201 [M+1].sup.+.
(4R,5R)-3-Methoxyimino-4,5-dimethyl-heptanoic acid ethyl ester
[1800] (4R,5R)-4,5-Dimethyl-3-oxo-heptanoic acid ethyl ester (21.23
g, 106 mmol) was dissolved in 200 mL of EtOH and added to 10.6 g
(127 mmol) of methoxylamine-HCl and 10.6 g (127 mmol) of sodium
acetate solids. The slurry was stirred at room temperature for 48
hours. MTBE (200 mL) and 100 mL of water were added, and the
resulting phases were separated. The organic phase was washed with
100 mL of water and was evaporated to yield a two-phase mixture.
Hexanes (100 mL) were added and the phases were separated. The
aqueous phase was extracted with 50 mL of hexanes and the combined
organic phases were washed with 50 mL of water, dried over
magnesium sulfate, and evaporated to give 21.24 g (87.4% yield) of
the titled compound as a clear yellow oil: .sup.1H NMR (CDCl.sub.3,
399.77 MHz) .delta. 0.84-0.88 (m, 6H), 1.07 (d, J=7.1 Hz, 3H), 1.24
(t, J=7.1 Hz, 3H), 1.4-1.6 (m, 2H), 2.24 (m, 1H), 3.08 (d, J=15.8
Hz, 1H), 3.19 (d, J=15.8 Hz, 1H), 3.80 (s, 3H), 4.10-4.2 (m, 3H).
Low resolution mass spec: nominal m/e calc'd for
C.sub.12H.sub.23NO.sub.3 (M+H).sup.+: 230. Found: m/e 230.
(4R,5R)-3-Amino-4,5-dimethyl-hept-2-(Z)-enoic Acid Ethyl Ester
[1801] A solution of 21.1 g (92 mmol) of
(4R,5R)-3-methoxyimino-4,5-dimeth- yl-heptanoic acid ethyl ester in
Methanol (200 mL) was treated with Sponge nickel (10 g, Johnson
Matthey A7000). The resulting slurry was hydrogenated on a Parr
shaker type hydrogenator at 50 psig and room temperature for 20
hours. At this time an additional 10 g of the nickel catalyst was
added and hydrogenation was continued for a total of 42.0 hours.
The slurry was filtered, the solids were washed with fresh
methanol, and the combined filtrate was evaporated to give 17.75 g
(96.8% yield) of the titled compound as a colorless oil: .sup.1H
NMR (CDCl.sub.3, 399.77 MHz) .delta. 0.83-0.89 (m, 6H), 1.1 (d,
J=6.8 Hz, 3H), 1.25 (t, J=7.1 Hz, 2H), 1.35-1.6 (m, 4H), 1.85-1.93
(m, 1H), 4.1 (q, J=7.0 Hz, 2H), 4.5 (s, 1H). Low resolution mass
spec: nominal m/e calc'd for C.sub.11H.sub.21NO.sub.2 (M+H).sup.+:
200. Found: m/e 200.
(4R,5R)-3-Acetylamino-4,5-dimethyl-hept-2-(Z)-enoic Acid Ethyl
Ester
[1802] A solution of 15.84 g (79.84 mmol) of
(4R,5R)-3-amino-4,5-dimethyl-- hept-2-(Z)-enoic acid ethyl ester
and 6.89 g (7.04 mL, 87.82 mL) of pyridine was stirred in 200 mL of
methylene chloride and cooled to 0.degree. C. A solution of 6.85 g
(6.21 mL, 87.82 mL) of acetyl chloride in 20 mL of methylene
chloride was added dropwise over 1 hour. The solution was warmed to
room temperature and stirred for two hours. 1M hydrochloric acid
(100 mL) was added and the phases were separated. The organic phase
was washed with saturated aqueous NaHCO.sub.3 solution and dried
briefly over Na.sub.2SO.sub.4. The solvent was evaporated and then
the resulting oil was passed through a short column of silica (200
g silica, 230-400 mesh) with 8:1 (v/v) hexane/EtOAc. The
product-containing fractions were evaporated to give 13.75 g (71.7%
yield) of the titled compound as a clear, nearly colorless oil:
.sup.1H NMR (CDCl.sub.3, 399.77 MHz) .delta. 0.84 (t, J=7.1 Hz,
3H), 0.95 (d, J=6.8 Hz, 3H), 1.0 (d, J=7.0 Hz, 3H), 1.29 (t, J=7.2
Hz, 3H), 1.30-1.45 (m, 3H), 2.13 (s, 3H), 3.79-3.82 (m, 1H),
4.11-4.18 (m, 2H), 5.01 (s, 1H). Low resolution mass spec: nominal
m/e calc'd for C.sub.13H.sub.23NO.sub.3 (M+H).sup.+: 242. Found:
m/e 242.
(3R,4R,5R)-3-Acetylamino-4,5-dimethyl-heptanoic Acid Ethyl
Ester
[1803] A solution containing 13.75 g (57 mmol) of
(4R,5R)-3-acetylamino-4,- 5-dimethyl-hept-2-(Z)-enoic acid ethyl
ester in 200 mL of Methanol was treated with 5% Pd/Al.sub.2O.sub.3
(1.5 g, Johnson Matthey #2127, lot 13449). The resulting slurry was
hydrogenated on a Parr shaker type hydrogenator at 40 psig to 50
psig and room temperature for a total of 3.8 hours. The slurry was
filtered and the solids were washed with fresh methanol. The
combined filtrate was evaporated to give 13.63 g (98.6% yield) of
the titled compound as a colorless oil: .sup.1H NMR (CDCl.sub.3,
399.77 MHz) .delta. 0.82 (d, J=7.0 Hz, 3H), 0.86 (t, J=7.3 Hz, 3H),
0.90 (d, J=6.5 Hz, 3H), 0.98-1.1 (m, 2H), 1.25 (t, J=7.2 Hz, 2H),
1.3-1.6 (m, 2H), 1.96 (s, 3H), 2.48 (dd, J=16, 5.65 Hz, 1H), 2.53
(dd, J=16, 5.2 Hz, 1H), 4.08-4.19 (m, 2H), 4.27-4.34 (m, 1H), 5.86
(br d, J=8.9 Hz, 1H). Low resolution mass spec: nominal m/e calc'd
for C.sub.13H.sub.25NO.sub.3 (M+H).sup.+: 244. Found: m/e 244.
(3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic Acid hydrochloride
[1804] (3R,4R,5R)-3-Acetylamino-4,5-dimethyl-heptanoic acid ethyl
ester (13.63 g, 56.0 mmol) was heated under reflux with 200 mL of
1M hydrochloric acid for 72 hours. The solution was cooled and
extracted 2.times. with 50 mL aliquots of MTBE. The aqueous phase
was evaporated to a semisolid. Acetonitrile (4.times.100 mL) was
added and evaporated to give 10.75 g (89% yield) of the titled
compound as a white crystalline solid: .sup.1H NMR (CD.sub.3OD,
399.77 MHz) 0.87 (t, J=7.3 Hz, 3H), 0.94 (t, J=6.6 Hz, 6H),
1.02-1.15 (m, 1H), 1.37-1.53 (m, 2H), 1.58-1.68 (m, 1H), 2.64 (dd,
J=17.5, 7.4 Hz, 1H), 2.73 (dd, J+17.5, 4.8 Hz, 1H), 3.54-3.61 (m,
1H). Low resolution mass spec: nominal m/e calc'd for
C.sub.9H.sub.20ClNO.sub.2 (M+H).sup.+: 174. Found: m/e 174.
(3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic Acid
[1805] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid hydrochloride
(10.8 g, 51.5 mmol) was dissolved in 50 mL of Methanol. To this
solution was added triethylamine (5.2 g, 7.2 mL, 51.5 mmol). The
solution was stirred for 10 minutes and then evaporated to a
flocculent solid. Dichloromethane (376 mL) was added and the
resulting slurry was stirred at room temperature for 45 minutes.
Next, 188 mL of acetonitrile was added and the slurry was stirred
for 30 minutes and then filtered. The solids were washed with 20 mL
of 2:1 (v/v) dichloromethane-acetonitrile and dried on a nitrogen
press to give 7.64 g (85.6% yield) of the titled compound as a
white solid: .sup.1H NMR (CD.sub.3OD, 399.77 MHz) 0.88 (t, J=7.5
Hz, 3H), 0.91 (d, J=7.0 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.98-1.12
(m, 1H), 1.32-1.43 (m, 1H), 1.43-1.64 (m, 2H), 2.26 (dd, J=16.5,
9.9 Hz, 1H), 2.47 (dd, J=19.5, 3.7 Hz, 1H), 3.28-3.36 (m, 1H). Low
resolution mass spec: nominal m/e calc'd for
C.sub.9H.sub.19NO.sub.2 (M+H).sup.+: 174. Found: m/e 174.
(3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic Acid-1/6-succinic Acid
complex-1/6-hydrate, i.e.,
6-((3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic Acid): 1-(succinic
Acid): 1-(H.sub.2O)
[1806] (3R,4R,5R)-3-Amino-4,5-dimethyl-heptanoic acid (7.6 g, 44
mmol) and succinic acid (2.6 g, 22 mmol) were suspended in 20.2 mL
of water. The slurry was heated to 100.degree. C. to dissolve the
solids. Acetonitrile (253 mL) was added to the hot solution. The
mixture was stirred at 55.degree. C. for 1 hour, and then cooled
gradually to room temperature overnight. The resulting solids were
filtered, washed with 10 mL of acetonitrile, and dried on a
nitrogen press to give 6.21 g (72% yield) of the titled compound as
fluffy white crystals: .sup.1H NMR (CD.sub.3OD, 399.77 MHz) .sup.1H
NMR (CD.sub.3OD, 399.77 MHz) 0.88 (t, J=7.5 Hz, 3H), 0.91 (d, J=7.0
Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.98-1.12 (m, 1H), 1.32-1.43 (m,
1H), 1.43-1.64 (m, 2H), 2.26 (dd, J=16.5, 9.9 Hz, 1H), 2.47 (dd,
J=19.5, 3.7 Hz, 1H), 2.50 (s, 0.67H), 3.28-3.36 (m, 1H). Low
resolution mass spec: nominal m/e calc'd for
C.sub.9H.sub.19NO.sub.2 (M+H).sup.+: 174. Found: m/e 174. Anal.
calc'd for 6-((3S,4R,5R 3-amino-4,5-dimethyl-heptanoic acid):
1-(succinic acid):1-(H.sub.2O), C.sub.58H.sub.122N.sub.6O.sub.13:
C, 59.26; H, 10.46; N, 7.15. Found: C, 59.28; H, 10.58; N, 7.09. KF
calc'd for C.sub.58H.sub.122N.sub.6O.sub.13:- H.sub.20, 1.43 wt %.
Found: H.sub.20, 1.50 wt %.
EXAMPLE 8
(4S,5R)-4,5-Diphenyl-oxazolidin-2-one
[1807] To a 5 L round bottom flask equipped with an overhead
stirrer, thermocouple and distillation head, was charged 550 g
(2.579 mol) of (1R,2S)-diphenyl-2-aminoethanol, 457 g (3.868 mol,
1.5eq) of diethylcarbonate, 18 g (0.258 mol, 0.1 eq) of NaOEt in
100 mL of EtOH and 3.5 L of toluene. The reaction was heated until
an internal temperature of 90.degree. C. was reached and EtOH
distillation began. The reaction was refluxed until an internal
temperature of 110.degree. C. was reached (7 hours). For every 500
mL of solvent that was removed via the distillation head, 500 mL of
toluene was added back to the reaction. A total of about 1.6 L of
solvent was removed. The reaction was allowed to cool to room
temperature and then filtered on a 3 L coarse fritted funnel with 2
psig N.sub.2. Nitrogen was blown over the cake overnight to give
580 g (94% yield) of the titled compound: .sup.1H NMR (DMSO)
7.090-6.985 (m, 6H), 6.930-6.877 (m, 4H), 5.900 (d, 1H, J=8.301),
5.206 (d, 1H, J=8.301).
(4S,5R)-3-((E)-2-Methyl-hex-2-enoyl)-4,5-diphenyl-oxazolidin-2-one
[1808] (Alternative A)
[1809] A 20 L jacketed reactor was fitted with a reflux condenser.
To the reactor was charged 1100 g (4.597 mol) of
(4S,5R)-4,5-diphenyl-oxazolidin- -2-one, 884 g (6.896 mol)
(E)-2-methyl-2-pentenoic acid, 1705 g (6.896 mol) of EEDQ, 48 g
(1.149 mol) of LiCl and 16 L of EtOAc. The reaction mixture was
heated to 65.degree. C. and was held for 200 minutes. The reaction
mixture was cooled to room temperature and was extracted 3.times.
with 3.5 L aliquots of 1N HCl. The combined aqueous extracts were
filtered to give a white solid. The recovered white solid was added
back to the organic layer. The 20 L reactor was fitted with a
distillation head and the organic layer was distilled to remove in
succession: 13.5 L of EtOAc, after which 5 L of heptane was added
to the reactor; 5 L of EtOAc/heptane, after which 5 L of heptane
was added to the reactor; and 2.7 L of EtOAc/heptane, after which
2.7 L of heptane was added to the reactor. The contents of the
reactor were cooled to 25.degree. C. and the resulting mixture was
filtered under 5 psig nitrogen while washing with 4 L of heptane.
The wet cake was dried under nitrogen pressure overnight to give
1521 g of the titled compound: .sup.1H NMR (DMSO) 7.12-6.94 (m,
8H), 6.834 (dd, 2H, J=7.813, 1.709), 6.060 (d, 1H, J=8.057), 6.050
(td, 1H, J=7.447, 1.221), 5.795 (d, 1H, J=8.057), 2.119-2.064 (m,
2H), 1.778 (d, 3H, J=0.997), 1.394 (m, 2H), 0.874 (t, 3H, J=7.324);
Anal Calc'd for C.sub.22H.sub.23N.sub.1O.sub.3: C, 75.62; H, 6.63;
N, 4.01. Found: C, 75.26; H, 6.72; N, 3.95.
(4S,5R)-3-(2-(E)-Methyl-hex-2-enoyl)-4,5-diphenyl-oxazolidin-2-one
[1810] (Alternative B)
[1811] To a solution of (E)-2-methyl-2-hexenoic Acid (6.0 g, 47
mmol) in 250 mL of THF at 0.degree. C. was added 16.3 mL (117 mmol)
of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride
resulting in a thick suspension. The mixture was stirred for 1 hour
at 0.degree. C. at which time 2.0 g (47 mmol) of lithium chloride
was added in one portion, followed by 10.0 g (42 mmol) of
(4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was
maintained throughout the solid additions. The resulting mixture
was stirred for 1 hour at 0.degree. C., then for 1 hour at ambient
temperature, and was vacuum filtered through a coarse frit and
concentrated. The residue was partitioned between EtOAc/water, and
the organics were dried over MgSO.sub.4 and concentrated. To the
residue was added 100 mL of MTBE and the mixture warmed cautiously
with swirling. The warm slurry was filtered to provide 10.5 g (64%
yield) of the titled compound as a colorless solid: .sup.1H NMR
(CDCl.sub.3) .delta. 7.12 (m, 3H), 7.07 (m, 3H), 6.94 (m, 2H), 6.84
(m, 2H), 6.17 (m, 1H), 5.89 (d, J=7.8 Hz, 1H), 5.68 (d, J=7.8 Hz,
1H), 2.18 (m, 2H), 1.92 (s, 3H), 1.50 (m, 2H), 0.96 (t, J=7.6 Hz,
3H).
(4S,5R)-3-((2R,3R)-2,3-Dimethyl-hexanoyl)-4,5-diphenyl-oxazolidin-2-one
[1812] A 22 L 4-neck round bottom flask was equipped with an
addition funnel, mechanical stirrer, and nitrogen inlet. The system
was purged with nitrogen for 1 hour. THF (6 L) were charged to the
flask followed by 1236 g (6.01 mol) of CuBr.S(CH.sub.3).sub.2 and
364 g (8.59 mol) of LiCl. The reaction was stirred for 15 minutes
at ambient temperature. The solution was cooled to -35.degree. C.
and 3.96 L (11.88 mol) of a 3M solution of CH.sub.3MgCl in THF was
charged at a rate as to keep the internal temperature of the
reaction mixture below -25.degree. C. The reaction was stirred for
1 hour after the addition of CH.sub.3MgCl was complete.
(4S,5R)-3-((E)-2-Methyl-hex-2-enoyl)-4,5-diphenyl-oxazolidin-2--
one (1.00 Kg, 2.86 mol) was added as a solid in one portion and the
reaction was stirred at -30.degree. C. for 4 hours. The reaction
mixture was transferred over a 2 hour period into another 22 L
flask equipped with a mechanical stirrer, transfer line, vacuum
line, and containing 4 L of 1:1 acetic acid:THF solution cooled in
an ice-water bath. The quenched solution was stirred for 30 minutes
and then diluted with 4 L of 2M NH.sub.4OH in saturated aqueous
NH.sub.4Cl and 2 L of water. The biphasic mixture was stirred for
15 minutes and the phases separated. The organic phase was washed
4.times. with 4 L aliquots of the 2M NH.sub.4OH solution. No more
blue color was observed in the washes or the organic phase so the
organic phase was diluted with 8 L of water and the THF was
distilled off until the internal temperature of the distillation
pot reached 95.degree. C. The suspension was cooled to ambient
temperature and filtered. The solids were washed with 4 L of water
and suction dried to give 868.2 g of an off white solid. This
material was recrystallized from 2 L of 95:5 heptane:toluene with a
cooling rate of 5.degree. C. per hour to provide 317.25 g of the
titled compound as a white solid: .sup.1H NMR (CDCl.sub.3)
7.12-6.85 (m, 10H), 5.90 (d, 1H, J=8.06 Hz), 5.72 (d, 1H, J=7.81),
3.83-3.76 (m, 1H), 1.95-1.89 (m, 1H), 1.35-1.31 (m, 1H). 1.11 (d,
3H, J=6.84), 1.10-0.95 (m, 3H), 0.92 (d, 3H, J=6.59), 0.76 (t, 3H,
J=7.20) MS (APCl) M+1=366.2.
(2R,3R)-2,3-Dimethyl-hexanoic Acid
[1813] A 12 L, 4-necked round bottom flask, equipped with a
mechanical stirrer, 500 mL addition funnel, nitrogen inlet, and
thermometer, was charged with 4515 mL of THF and 330.0 g of
(4S,5R)-3-((2R,3R)-2,3-dimethy-
l-hexanoyl)-4,5-diphenyl-oxazolidin-2-one. The resulting liquid
mixture (all solids dissolved) was cooled to -5.degree. C. to
0.degree. C. using an acetone/ice bath. A solution of 60.6 g of
LiOH--H.sub.2O in 1800 mL of deionized water was cooled to
0.degree. C. to 5.degree. C. and was combined with 512 g of cold
30% (wt/wt) hydrogen peroxide in a 2 L Erlenmeyer flask. The
solution was kept cold using an ice/water bath. After the
oxazolidinone/THF solution in the 12 L reaction flask reached
-5.degree. C. to 0.degree. C., the addition funnel was charged with
approximately one quarter of the cold LiOH/water/H.sub.2O.sub.2
solution. While maintaining a nitrogen sweep to minimize oxygen
concentration in the reactor headspace, the
LiOH/water/H.sub.2O.sub.2 solution was added dropwise to the
vigorously stirred oxazolidinone/THF solution at such a rate as to
maintain the reaction temp at 0.degree. C. to 5.degree. C. The
addition funnel was recharged with approximately one quarter of the
cold LiOH/water/H.sub.2O.sub.2 solution as required until all of
the solution had been added to the reaction mixture (about 40
minutes for 0.45 mol scale). After the addition was completed, the
mixture was stirred at 0.degree. C. to 5.degree. C. for 5 hours,
during which the reaction mixture changed from a homogeneous
solution to white slurry. A solution of 341 g of Na.sub.2SO.sub.3
and 188 g of NaHSO.sub.3 in 2998 mL of deionized water (15 wt %)
was added dropwise to the reaction mixture over about a 1.5 hour
period (reaction was exothermic) via the addition funnel, while
maintaining the reaction temperature at 0.degree. C. to 10.degree.
C. Following the addition, the reaction mixture was stirred at
0.degree. C. to 1.degree. C. for 1 hour. The reaction mixture was
tested with potassium iodide-starch test paper to ensure the
absence of peroxides. The reaction mixture was charged with 2000 mL
of EtOAc and was stirred 5 minutes. The phases were separated and
the aqueous phase was extracted with 2000 mL of EtOAc. The combined
organic extract was washed with brine (2.times.1500 mL). The
colorless organic solution was concentrated under vacuum
(35.degree. C.-40.degree. C.) to a "wet," white solid. Heptane
(1000 mL) was added and the slurry was concentrated under vacuum
(35.degree. C.-40.degree. C.) to a wet, white solid. Heptane (5000
mL) was added and the slurry was maintained at 0.degree. C. to
5.degree. C. for 16 hours and then at -10.degree. C. to -5.degree.
C. for 1 hour. The cold slurry was filtered through a thin pad of
celite, and the filter cake was washed with 100 mL of -10.degree.
C. to -5.degree. C. heptane. The colorless filtrate was
concentrated under vacuum (40.degree. C.-45.degree. C.) to give 130
g of the titled compound as a pale yellow oil: .sup.1H NMR (400
MHz, CHLOROFORM-D) 0.89 (t, J=7.00 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H),
1.13 (d, J=7.0 Hz, 3H), 1.75-1.82 (m, 1H), 2.34-2.41 (m, 1H); GC
Chiral purity: 99.18% (with 0.82% diastereomer) (direct acid
method). Chemical purity: 100%. Anal. Calc'd for
C.sub.8H.sub.16O.sub.2: C, 66.63; H, 11.18. Found: C, 66.15; H,
11.41.
(4R,5R)-4,5-Dimethyl-3-oxo-octanoic Acid Ethyl Ester (Alternative
A)
[1814] A 5 L 3-neck round bottom flask, equipped with a reflux
condenser, mechanical stirrer, nitrogen inlet, and thermometer, was
charged with 1390 mL of dry THF and 389.3 g of potassium ethyl
malonate. MgCl.sub.2 (217.8 g) was added in three equal portions so
that the internal temperature was less than 50.degree. C. The
resulting grey slurry was heated to 55.degree. C. to 60.degree. C.
using a temperature controlled heating mantle. The mixture was
stirred at 55.degree. C. to 60.degree. C. for 5 hours. A 2 L 3-neck
round bottom flask, equipped with a 500 mL addition funnel,
mechanical stirrer, nitrogen inlet, and thermometer, was charged
with 680 mL of dry THF and 286.8 g of 1,1'-carbonyldiimidazole
(CDI). The addition funnel was charged portion-wise with a solution
of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry
THF. The entire dimethyl-hexanoic acid acid/THF solution was added
dropwise to the stirred CDI/THF suspension at such a rate so as to
control the evolution of CO.sub.2 and to maintain the reaction at a
temperature of 20.degree. C. to 25.degree. C. Following the
addition, the reaction mixture was stirred at 20.degree. C. to
25.degree. C. for 1 hour, during which the slurry became a pale
yellow solution. After the 5-hour reaction time, the
malonate/MgCl.sub.2 reaction mixture was cooled to 20.degree. C. to
25.degree. C. and the condenser was replaced with a 1 L addition
funnel. The addition funnel was charged portion-wise with the
dimethylhexanoic acid/CDI/THF reaction mixture. This entire
reaction mixture was added dropwise to the stirred
malonate/MgCl.sub.2/THF reaction mixture over about 10 minutes.
After the addition was completed, the reaction mixture was heated
to 35.degree. C. to 40.degree. C. Some effervescence was noted. The
reaction mixture was stirred at 35.degree. C. to 40.degree. C. for
16 hour. The reaction mixture was cooled to 20.degree. C. to
25.degree. C. A 12 L 3-neck round bottom flask, equipped with a
mechanical stirrer and thermometer, was charged with 3060 mL of 2N
aq. HCl. The reaction mixture (a grey suspension) was added
portion-wise to the aq. HCl solution while maintaining an internal
temperature of 20.degree. C.-25.degree. C. The reaction temperature
was moderated with an ice/water bath; the reaction mixture pH was
about 1. Following the addition, the reaction mixture was stirred
at 20.degree. C. to 25.degree. C. for 2 hours. The reaction mixture
was subsequently charged with 4000 mL of EtOAc and was stirred for
5 minutes. The phases were separated and the aqueous phase was
extracted with 2000 mL of EtOAc. The combined organic extract was
washed sequentially with: 1N aq. HCl (2.times.1 500 mL); 1000 mL of
water (incomplete phase separation); half saturated aq.
Na.sub.2CO.sub.3 (2.times.1500 mL); 1000 mL water; and brine
(2.times.1000 mL). (The aqueous base wash removed unreacted
malonate ester-acid.) The straw colored organic solution was
concentrated under vacuum (35.degree. C.-40.degree. C.) to give a
cloudy, pale yellow oil with some white solid present. The oil was
redissolved in 1500 mL of n-heptane and was filtered. The filtrate
was concentrated under vacuum (40.degree. C.-45.degree. C.) to give
327 g of the titled compound as a pale yellow oil: .sup.1H NMR (400
MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3H), 0.85 (d, J=6.8 Hz,
3H), 0.99 (d, J=7.1 Hz, 3H), 1.20 (t, J=7.3 Hz, 3H), 2.42-2.49 (m,
1H), 3.39 (s, 2H) 4.12 (q, J=7.16 Hz, 3H). GC Chemical purity:
96.24%.
(4R,5R)-4,5-Dimethyl-3-oxo-octanoic Acid Ethyl Ester (Alternative
B)
[1815] To a solution containing 2.0 g (13.9 mmol) of
(2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was
added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium
chloride. After stirring the resulting solution under nitrogen for
1.5 hours, the solvent was evaporated to give
(2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml,
52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5
mmol) in dry THF (20 mL) under nitrogen at 0.degree. C. and stirred
for 20 minutes. The solution was cooled to -78.degree. C. and 4.3 g
(48.5 mmol) of ethyl acetate was added. The solution was stirred at
that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl
chloride in dry THF (20 mL) was slowly added to the ethyl acetate
enolate at -78.degree. C. and the resulting reaction mixture was
allowed to warm to room temperature. The reaction mixture was
stirred at room temperature for 2.5 hours and was cooled to
0.degree. C. The reaction was quenched with a saturated solution of
ammonium chloride and extracted into ethyl acetate. The solution
was washed with brine, dried over MgSO.sub.4 and concentrated. The
resulting residue was filtered through a silica plug, eluting with
60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2%
yield) of the titled compound as an oil.
(4R,5R)-4,5-Dimethyl-3-oxo-octanoic Acid Ethyl Ester (Alternative
C)
[1816] To a solution containing 1.0 g (6.9 mmol) of
(2R,3R)-2,3-dimethyl-hexanoic acid in 10 mL of dichloromethane was
added 1.1 g of chloromethylene dimethyl-ammonium chloride (8.3
mmol). The resulting solution was stirred under nitrogen for 1.5
hours. The solvent was subsequently evaporated to give
(2R,3R)-2,3-dimethyl-hexanoyl chloride. To a solution containing
2.5 g (14.6 mmol) of potassium monoethyl malonate in 50 mL of
acetonitrile was added 1.7 g (17.3 mmol) of magnesium chloride and
1.2 g (11.4 mmol) of triethylamine. The resulting mixture was
stirred at room temperature for 2.5 hours. The reaction was cooled
to 0.degree. C. and a solution of the (2R,3R)-2,3-dimethyl-hexanoyl
chloride in acetonitrile (20 mL) was slowly added followed by the
addition of triethylamine (0.4.degree. g., 0.4 mmol). The reaction
was heated to 40.degree. C. and stirred at that temperature for 6
hours. The reaction mixture was cooled to 25.degree. C., quenched
with a saturated solution of ammonium chloride and extracted into
ethyl acetate. The solution was washed with brine, dried over
MgSO.sub.4 and concentrated. The resulting residue was filtered
through a silica plug, eluting with 60/40 solution of hexane/ethyl
acetate to afford 1.3 g (87.8% yield) of the titled compound as an
oil.
(4R,5R)-3-Methoxyamino-4,5-dimethyl-(Z)-oct-2-enoic Acid Ethyl
Ester
[1817] A 2 L 3-necked round bottom flask, equipped with magnetic
stirring and nitrogen inlet, was charged with 153.degree. g. (0.71
mol) of (4R,5R)-4,5-dimethyl-3-oxo-octanoic acid ethyl ester and
600 mL of anhydrous EtOH. The solution was cooled to 0.degree.
C.-5.degree. C. with an ice bath and 65.6 g (0.79 mol) of
methoxylamine hydrochloride was added, followed by 58.6 g (0.71
mol) of sodium acetate. This flask contents were slowly warmed to
room temperature (about 2 hours) and the reaction mixture was
stirred at room temperature for another 24 hours. The solvent
(EtOH) was removed under reduced pressure and the mixture was
charged with CH.sub.2Cl.sub.2 (2.times.300 mL), which was
subsequently removed. The mixture was cooled to RT, diluted with
CH.sub.2Cl.sub.2 (300 mL), stirred at room temperature for 0.5
hours, and filtered under 5 psig of nitrogen. The filter cake was
washed with CH.sub.2Cl.sub.2 (150 mL). The filtrate was
concentrated under vacuum (50.degree. C.) to give 172 g (99% yield)
of the titled compound as a light yellow oil: .sup.1H NMR (400 MHz,
CHLOROFORM-D) 0.87 (t, J=3.5 Hz, 5H), 0.89 (d, J=7.2 Hz, 3H), 1.08
(d, J=7.0 Hz, 3H), 1.24 (t, J=7.2 Hz, 4H), 1.3-1.55 (m, 2H), 2.25
(m, 1H), 3.15 (q, J=19.5 Hz, 2H) 3.81 (s, 3H), 4.14 (q, J=7.0 Hz,
2H).
(4R,5R)-3-Amino-4,5-dimethyl-(Z)-oct-2-enoic Acid Ethyl Ester
[1818] A reactor vessel charged with 171 g of
(4R,5R)-3-methoxyamino-4,5-d- imethyl-(Z)-oct-2-enoic acid ethyl
ester, 1600 mL of MeOH, and 65 g of Raney nickel (Ra--Ni) catalyst.
The methoxyamino ester was reacted with hydrogen at 50 psig to 55
psig. During the hydrogenation, additional Ra--Ni was added at
reaction times of 8 hours (20 g), 21 hours (20 g), and 37 hours (8
g). After the reaction was completed (51 hours), the Ra--Ni was
filtered off and the filtrate was concentrated under reduced
pressure to give 150 g (>99% yield) of the titled compound as an
oil: .sup.1H NMR (400 MHz, CHLOROFORM-D): 0.86 (t, J=4.5 Hz, 3H),
0.88 (d, J=4.9 Hz, 3H), 1.05-1.50 (m, 6H), 1.10 (d, J=7.0 Hz, 3H),
1.24 (t, J=7.2 Hz, 3H), 1.87 (m, 1H), 3.45 (s, 2H) 4.08 (q, J=7.0
Hz, 2H).
(4R,5R)-3-Acetylamino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl
ester
[1819] To a 1 L 3-necked round bottom flask equipped with an
overhead stirrer, thermocouple, addition funnel, and nitrogen
inlet, was charged 150 g (0.70 mol) of
(4R,5R)-3-amino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester and
50 mL of dry CH.sub.2Cl.sub.2. The reaction mixture was cooled to
-20.degree. C. To the mixture was added, successively, acetyl
chloride (60 mL, 0.84 mol) and pyridine (66.8.degree. g., 0.84 mol)
over 0.5-hour time intervals. After the additions, the mixture was
stirred at -20.degree. C. to 0.degree. C. for 2 hours and then
filtered to remove the pyridine.HCl salt. The filtrate was diluted
with 200 mL of CH.sub.2Cl.sub.2 and washed 2.times. with aliquots
of aq NH.sub.4Cl. The organic solution was treated with silica gel
(50 g), MgSO.sub.4 (20 g) and charcoal (20 g), and stirred at room
temperature for 0.5 hours. The solids were filtered off and the
filtrate was concentrated under reduced pressure to give 166.5 g
(93% yield) of the titled compound as an oil: .sup.1H NMR (400 MHz,
CHLOROFORM-D) 0.85 (t, J=7.4 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), 1.00
(d, J=7.0 Hz, 3H), 1.11 (m, 1H) 1.29 (t, J=5.8 Hz, 3H), 1.40-1.25
(m, 2H), 1.65 (m, 1H) 2.13 (s, 3H), 3.80 (m, 1H) 4.2-4.14 (m, 3H),
5.01 (s, 1H), 11.28 (s, 1H).
(3R,4R,5R)-3-Acetylamino-4,5-dimethyl-octanoic Acid Ethyl Ester
[1820] A reactor was charged with 166 g of
(4R,5R)-3-acetylamino-4,5-dimet- hyl-(Z)-oct-2-enoic acid ethyl
ester (substrate), 2650 mL of MeOH, and 36 g of Pd/SrCO.sub.3
(lot#D25N17) catalyst. The substrate was reacted with H.sub.2 at a
pressure of 50 psig to 51 psig of. During hydrogenation, additional
catalyst was added at a reaction time of 67 hours (10 g). After the
reaction was completed (90 hours), Pd/SrCO.sub.3 was filtered off
and the filtrate was concentrated under reduced pressure to give
167 g (>99% yield) of the titled compound as an oil: .sup.1H NMR
(400 MHz, CHLOROFORM-D): 0.82 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.2 Hz,
3H), 0.90 (d, J=6.6 Hz, 3H), 1.25 (t, J=7.3 Hz, 3H), 1.00-1.58 (m,
6H), 1.96 (s, 3H), 2.52 (q, J=5.2 Hz, 2H), 3.47 (s, 1H), 4.10-4.30
(m, 2H), 4.12 (t, J=7.1 Hz, 1H), 5.9(d, 1H).
(3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic Acid hydrochloride
[1821] Under nitrogen, 167 g of crude
(3R,4R,5R)-3-acetylamino-4,5-dimethy- l-octanoic acid ethyl ester
was diluted 1100 mL of 6N HCl, stirred at room temperature for 16
hours, and then heated to reflux for another 24 hours. The reaction
mixture was concentrated and recharged with 500 mL of isopropyl
alcohol (IPA), which was subsequently removed. Acetonitrile (500
mL) was added to the crude white HCl salt and the mixture stirred
at 20.degree. C. to 25.degree. C. for 1 hour. The resulting slurry
was filtered, and the solids isolated to give 97 g of the titled
compound (67% yield, 89.7% chemical purity; 90.7% chiral purity
with two major diastereomers, 6.8% and 1.5%): .sup.1H NMR
(CD.sub.3OD): .delta. 0.89t J=7.0 Hz, 3H), 0.94t, J=6.9 Hz, 6H),
1.65-1.0 (m, 4H), 2.61 (dd, J=7.6 Hz, 1H), 2.73 (dd, J=4.6 HZ, 1H),
3.27 (m, J=1.6 Hz, 2H), 3.56 (m, 1H), 4.82 (s, 3H).
(3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic Acid
[1822] (3R,4R,5R)-3-Amino-4,5-dimethyl-octanoic acid hydrochloride
(92 g, 0.41 mol) was dissolved in 250 mL to 260 mL of dry MeOH in a
2 L 3-necked round bottom flask. To this solution was added
Et.sub.3N (0.45 mol, 45.8 g) dropwise, which formed a white
precipitate. The resulting slurry was stirred at room temperature
for 15 minutes. The solvent was removed to dryness. The white solid
was dispersed in 1 L of CH.sub.2Cl.sub.2 (1 L) and stirred for 1
hour. CH.sub.3CN (0.6 L) was added, and the slurry was stirred for
another 0.5 hours. The slurry was filtered and the solids were
washed 2.times. with 50 mL aliquots of CH.sub.3CN, giving 71 g of
the titled compound as a white solid (92% yield; 98.8% chiral
purity; 99.7% chemical purity): .sup.1H NMR (400 MHz, CD.sub.3OD):
0.89 (t, J=7.2 Hz, 3H), 0.91 (d, J=5.1 Hz, 3H), 0.93 (d, J=6.6 Hz,
3H), 1.02-1.65 (m, 4H), 2.26 (dd, J=10.2 Hz, 1H), 2.50 (dd, J=3.7
Hz, 1H), 3.27 (m, J=1.6 Hz, 2H) 3.33-3.28 (m, 1H), 4.82 (s,
3H).
EXAMPLE 9
(3R,4R,5R)-3-Acetylamino-4,5-dimethyl-octanoic Acid Ethyl Ester
(Catalyst Screening)
[1823] Ten mL ampoules were each charged with 20 mg of
(4R,5R)-3-acetylamino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester
(substrate), 2 mL of MeOH, and approximately 10 mg of catalyst. The
ampoules were placed in a multi-reactor, purged with hydrogen, then
pressurized to 20 psig with hydrogen and shaken at room temperature
for 18 hours. For each ampoule following reaction, the solids were
removed by filtration and the filtrate was analyzed by chiral GC
(CHIRASIL-DEX CB, 140.degree. C. isothermal). The table below
provides conversion and ratio of
(3R,4R,5R)-3-acetylamino-4,5-dimethyl-octanoic acid ethyl ester
(desired diastereoisomer) to
(3S,4R,5R)-3-acetylamino-4,5-dimethyl-octano- ic acid ethyl ester
(undesired diastereoisomer) for various hydrogenation
catalysts.
3 Conv. RRR/ Entry Catalyst Source % SRR 1 5% Pd/BaSO.sub.4
JM/B21H25 100 17.9:1 2 5% Rh/Al2O.sub.3 Engelhard/SOC99179 100
9.1:1 3 1.5% Pt/C Engelhard/CH02216 59 7.5:1 4 3% Pd/C
EngelhardSoc02089 100 7.2:1 5 5% Rh/C Engelhard/JJH429 100 6.8:1 6
Raney Nickel AMC/A7000 24 5.6:1 7 Raney Nickel Grace/2800 0 N/A 8
Raney Cobalt AMC/A8B46 0 N/A 9 5% Pd/BaSO.sub.4 (THF) JM/B21H25 9
25.0:1 10 5% Pd/BaSO.sub.4 Degussa/CCI-1660 100 16.4:1 11 5%
Pd/BaSO.sub.4 (MeOH) JM/B21H25 97 10.8:1 12 Pd black Am Plat/no#
100 5.7:1 13 Lindlar's catalyst JM 0 N/A 14 5% Pd/SrCO.sub.3
JM/D25N17 66 52:1 15 5% Pd/Al2O.sub.3 JM/L02M05 100 49:1 16 1%
Pd/Al2O.sub.3 JM/K13M02 72 42:1 17 5% Pd/MgO PMC/12221 93 38:1 18
5% Pd/CaCO.sub.3 PMC/13159 >99 34:1 19 5% Pd/CaCO.sub.3
PMC/13261 89 33:1 20 5% Pd/BaSO.sub.4 PMC/13257 100 31:1 21 5%
Pd/Al.sub.2O.sub.3 PMC/13449 100 28:1 22 5% Pd/BaSO.sub.4 JM/B21H25
100 20:1 23 3% Pd/BaCO.sub.3 PMC/10313 100 17:1 24 5% Pd/CaCO.sub.3
PMC/12263 100 14:1 25 5% Pd/Al.sub.2O.sub.3 PMC/1205 100 12:1 26 5%
Pd/MgO PMC/12243 100 13:1 27 5% Pd/Al.sub.2O.sub.3 PMC/13079 100
12:1 28 PtO.sub.2 (Adam's Cat.) PMC/12585 8 5:1 29 5% Pd/CaSO.sub.4
JM/K06M18 0 N/A 30 5% Pd/MgO PMC/1221 94 47:1 31 5% Pd/SrCO.sub.3
JM/D25N17 100 43:1 32 PdO.sub.2 Am Plat 100 10:1 33 6% Pd/Deloxan
DEG/Pd369 100 10:1 34 20% Pd/C PMC/20770 100 9:1 35 5% Rh/SiO.sub.2
ENG/JJH100 100 7:1 36 3% Rh/Deloxan DEG/RG607 100 6:1 37 1% Pt on
JMJ27N37 0 N/A Polyethyleneimine/ SiO.sub.2
EXAMPLE 10
(3R,5R)-3-Acetylamino-4,5-dimethyl-heptanoic Acid Ethyl Ester
(Catalyst ing)
[1824] Ten mL ampoules were each charged with 20 mg of
(4R,5R)-3-amino-4,5-dimethyl-(Z)-hept-2-enoic acid ethyl ester
(substrate), 2 mL of MeOH, and approximately 10 mg of catalyst. The
ampoules were placed in a reactor, purged with hydrogen, then
pressurized to 20 psig with gen and shaken at room temperature for
18 hours. For each ampoule ing reaction, the solids were removed by
filtration and the filtrate was zed by chiral GC (CHIRASIL-DEX CB,
140.degree. C. isothermal). The table provides conversion and ratio
of (3R,4R,5R)-3-acetylamino-4,5-yl-heptanoic acid ethyl ester
(desired diastereoisomer) to
(3S,4R,5R)-ylamino-4,5-dimethyl-heptanoic acid ethyl ester
(undesired reoisomer) for various hydrogenation catalysts.
4 Entry Catalyst Source Conv. % RRR/SRR 1 5% Pd/SrCO.sub.3
JM/D25N17 100 41:1 2 3% Pd/BaCO.sub.3 PMC/10313 76 44:1 3 5%
Pd/BaSO.sub.4 100 13:1 4 5% Pd/BaSO.sub.4 >99 66:1 5 1% Pt on
JMJ27N37 0 N/A Polyethyleneimine/SiO.sub.2
[1825] It should be noted that, as used in this specification and
the appended claims, singular articles such as "a," "an," and
"the," may refer to a single object or to a plurality of objects
unless the context clearly indicates otherwise. Thus, for example,
reference to a composition containing "a compound" may include a
single compound or two or more compounds.
[1826] It is to be understood that the above description is
intended to be illustrative and not restrictive. Many embodiments
will be apparent to those of skill in the art upon reading the
above description. The scope of the invention should, therefore, be
determined not with reference to the above description, but should
instead be determined with reference to the appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *