U.S. patent application number 11/649927 was filed with the patent office on 2007-08-30 for cycloalkylamines as monoamine reuptake inhibitors.
This patent application is currently assigned to SEPRACOR INC.. Invention is credited to Larry R. Bush, John E. Campbell, Una Campbell, Sharon Rae Engel, Larry Wendell Hardy, Michael Charles Hewitt, Patrick Koch, Jianguo Ma, Scott Christopher Malcolm, Liming Shao, Mark A. Varney, Fengjiang Wang.
Application Number | 20070203111 11/649927 |
Document ID | / |
Family ID | 38256951 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070203111 |
Kind Code |
A1 |
Shao; Liming ; et
al. |
August 30, 2007 |
Cycloalkylamines as monoamine reuptake inhibitors
Abstract
The invention relates to novel cyclohexylamine derivatives and
their use in the treatment and/or prevention of central nervous
system (CNS) disorders, such as depression, anxiety, schizophrenia
and sleep disorder as well as methods for their synthesis. The
invention also relates to pharmaceutical compositions containing
the compounds of the invention, as well as methods of inhibiting
reuptake of endogenous monoamines, such as dopamine, serotonin and
norepinephrine from the synaptic cleft and methods of modulating
one or more monoamine transporter.
Inventors: |
Shao; Liming; (Lincoln,
MA) ; Wang; Fengjiang; (Northborough, MA) ;
Malcolm; Scott Christopher; (Southborough, MA) ;
Hewitt; Michael Charles; (Somerville, MA) ; Bush;
Larry R.; (Worcester, MA) ; Ma; Jianguo;
(Natick, MA) ; Varney; Mark A.; (Laguna Niguel,
CA) ; Campbell; Una; (Marlborough, MA) ;
Engel; Sharon Rae; (Hudson, MA) ; Hardy; Larry
Wendell; (Sturbridge, MA) ; Koch; Patrick;
(Marlborough, MA) ; Campbell; John E.; (Waban,
MA) |
Correspondence
Address: |
MORGAN, LEWIS & BOCKIUS LLP (SF)
2 PALO ALTO SQUARE
3000 El Camino Real, Suite 700
PALO ALTO
CA
94306
US
|
Assignee: |
SEPRACOR INC.
Marlborough
MA
|
Family ID: |
38256951 |
Appl. No.: |
11/649927 |
Filed: |
January 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60756550 |
Jan 6, 2006 |
|
|
|
Current U.S.
Class: |
514/183 ;
514/210.01; 514/212.01; 514/319; 514/408; 540/484; 546/205;
548/577; 548/950; 548/954 |
Current CPC
Class: |
C07C 215/44 20130101;
C07C 2602/08 20170501; A61P 25/14 20180101; C07C 211/40 20130101;
A61P 13/02 20180101; C07D 207/06 20130101; A61P 3/04 20180101; C07D
207/08 20130101; C07D 211/14 20130101; C07C 217/52 20130101; A61P
25/24 20180101; C07C 217/74 20130101; C07C 2601/10 20170501; C07D
265/14 20130101; C07C 211/17 20130101; A61P 21/02 20180101; A61P
25/20 20180101; C07C 2601/08 20170501; C07D 277/28 20130101; A61P
25/02 20180101; C07C 2601/16 20170501; A61P 25/28 20180101; A61P
43/00 20180101; C07C 323/32 20130101; A61P 21/00 20180101; C07D
317/72 20130101; C07D 491/056 20130101; A61P 25/16 20180101; C07C
215/42 20130101; C07C 211/29 20130101; C07C 2601/14 20170501; A61P
15/12 20180101; A61P 25/04 20180101; A61P 25/06 20180101; A61P
25/00 20180101; A61P 29/00 20180101; A61P 15/10 20180101; C07C
2601/02 20170501; C07D 307/52 20130101; A61P 15/00 20180101; A61P
15/02 20180101; C07D 211/16 20130101; C07D 333/20 20130101; C07D
295/06 20130101; A61P 11/16 20180101; A61P 25/18 20180101; C07D
319/06 20130101; A61P 25/22 20180101; C07D 317/58 20130101; A61P
25/08 20180101 |
Class at
Publication: |
514/183 ;
514/212.01; 514/319; 514/408; 548/577; 546/205; 540/484;
514/210.01; 548/950; 548/954 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/445 20060101 A61K031/445; A61K 31/40 20060101
A61K031/40; A61K 31/397 20060101 A61K031/397; A61K 31/396 20060101
A61K031/396; C07D 211/06 20060101 C07D211/06; C07D 203/04 20060101
C07D203/04; C07D 207/04 20060101 C07D207/04 |
Claims
1. A compound having a structure according to Formula (I):
##STR347## wherein n is an integer from 0 to 2; s is an integer
from 1 to 3; m is an integer from 0 to 12, with the proviso that
when n is 0, then m is not greater than 8; and when n is 1, then m
is not greater than 10; Ar is a member selected from the group
consisting of substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and a fused ring system; each X is a
member independently selected from the group consisting of H,
halogen, CN, CF.sub.3, OR.sup.5, SR.sup.5, acyl, C(O)OR.sup.5,
C(O)NR.sup.6R.sup.7, S(O).sub.2R.sup.5, S(O).sub.2NR.sup.6R.sup.7,
NR.sup.6R.sup.7, NR.sup.6S(O).sub.2R.sup.5, NR.sup.6C(O)R.sup.5,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl, wherein each R.sup.5, R.sup.6 and R.sup.7 is a
member independently selected from the group consisting of H, acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl, wherein two of R.sup.5, R.sup.6 and
R.sup.7, together with the atoms to which they are attached, are
optionally joined to form a 3- to 7-membered ring; each R.sup.1 and
R.sup.2 is a member independently selected from the group
consisting of H, halogen, CN, CF.sub.3, OR.sup.8, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein R.sup.8 is a member selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl; and R.sup.3 and R.sup.4 are members independently
selected from the group consisting of H, OR.sup.9, acyl,
C(O)OR.sup.9, S(O).sub.2R.sup.9, N.dbd.N, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl, with
the proviso that when one member of R.sup.3 and R.sup.4 is N.dbd.N,
then the other member is not present, wherein R.sup.9 is a member
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl;
wherein at least two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X,
together with the atoms to which they are attached, are optionally
joined to form a 3- to 7-membered ring; at least one of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is optionally joined with Ar to form a
5- to 7-membered ring; and any pharmaceutically acceptable salt,
solvate, enantiomer, diastereomer, racemic mixture,
enantiomerically enriched mixture, and enantiomerically pure form
thereof.
2. The compound according to claim 1, wherein said compound is
chiral.
3. The compound according to claim 1 having a Formula, which is a
member selected from the group consisting of Formula (II) and
Formula (III): ##STR348##
4. The compound according to claim 3, said compound having a
Formula, which is a member selected from the group consisting of:
##STR349## wherein X.sup.1 and X.sup.2 are members independently
selected from the group consisting of H, OR.sup.5, SR.sup.5,
halogen, CN, CF.sub.3, S(O).sub.2R.sup.5, NR.sup.6R.sup.7,
NR.sup.6S(O).sub.2R.sup.5, NR.sup.6C(O)R.sup.5, acyl, substituted
or unsubstituted C.sub.1-C.sub.4 alkyl and substituted or
unsubstituted C.sub.1-C.sub.4 heteroalkyl, wherein at least two of
R.sup.1, R.sup.3, R.sup.4, X.sup.1 and X.sup.2, together with the
atoms to which they are attached, are optionally joined to form a
3- to 7-membered ring.
5. The compound according to claim 4, wherein X.sup.1 and X.sup.2
are members independently selected from the group consisting of H,
methyl, ethyl, n-propyl, OH, OMe, Ot, F, Cl, CN, CH.sub.2OH,
CH.sub.2OMe, and CF.sub.3.
6. The compound according to claim 4, wherein R.sup.1 is H or
substituted or unsubstituted C.sub.1-C.sub.4 alkyl.
7. The compound according to claim 4, wherein R.sup.3 and R.sup.4
are members independently selected from the group consisting of
substituted or unsubstituted alkyl and substituted or unsubstituted
heteroalkyl.
8. The compound according to claim 3, wherein Ar is a member
selected from the group consisting of substituted or unsubstituted
phenyl and substituted or unsubstituted naphthyl.
9. The compound according to claim 8, wherein Ar has a structure,
which is a member selected from the group consisting of: ##STR350##
wherein Y, Z, Y.sup.1 and Z.sup.1 are members independently
selected from the group consisting of H, halogen, CF.sub.3, CN,
OR.sup.11, SR.sup.11, NR.sup.12R.sup.13,
NR.sup.12S(O).sub.2R.sup.11, NR.sup.12C(O)R.sup.11,
S(O).sub.2R.sup.11, acyl, C(O)OR.sup.11, C(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.12S(O).sub.2R.sup.11,
NR.sup.12C(O)R.sup.11, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heterocycloalkyl, wherein two of Y, Z,
Y1 and Z1, together with the atoms to which they are attached, are
optionally joined to form a 5- to 7-membered ring; and each
R.sup.11, R.sup.12 and R.sup.13 is a member independently selected
from the group consisting of H, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heterocycloalkyl, wherein two of
R.sup.11, R.sup.12 and R.sup.13, together with the atoms to which
they are attached, are optionally joined to form a 3- to 7-membered
ring.
10. The compound of claim 9, wherein Y, Z, Y.sup.1 and Z.sup.1 are
members independently selected from the group consisting of H,
CF.sub.3, OR.sup.11, SR.sup.11, OCF.sub.3, halogen and CN.
11. The compound of claim 9, wherein Ar has the structure:
##STR351##
12. A composition comprising a first stereoisomer and at least one
additional stereoisomer of a compound according to claim 1, wherein
said first stereoisomer is present in a diastereomeric excess of at
least 80% relative to said at least one additional
stereoisomer.
13. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
14. A method of inhibiting binding of a monoamine transporter
ligand to a monoamine transporter, said method comprising
contacting said monoamine transporter and a compound of claim
1.
15. A method of inhibiting the activity of at least one monoamine
transporter, said method comprising contacting said monoamine
transporter and a compound of claim 1.
16. The method of claim 14 or 15, wherein said monoamine
transporter is a member selected from the group consisting of
serotonin transporter (SERT), dopamine transporter (DAT),
norepinephrine transporter (NET) and combinations thereof.
17. The method of claim 15, wherein said compound inhibits the
activity of at least two different monoamine transporters.
18. A method of inhibiting uptake of at least one monoamine by a
cell, said method comprising contacting said cell and a compound of
claim 1.
19. The method of claim 18, wherein said monoamine is a member
selected from the group consisting of serotonin, dopamine,
norepinephrine and combinations thereof.
20. The method of claim 18, wherein said compound inhibits uptake
of at least two different monoamines.
21. The method of claim 18, wherein said cell is a neuronal
cell.
22. A method of treating depression by inhibiting the activity of
at least one monoamine transporter, said method comprising
administering to a mammalian subject a compound of claim 1.
23. The method of claim 22, wherein said mammalian subject is a
human.
24. The method of claim 22, wherein said compound inhibits said
activity of at least two different monoamine transporters.
25. A method of treating a central nervous system disorder, said
method comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1.
26. The method of claim 25, wherein said subject is a human.
27. The method of claim 25, wherein said central nervous system
disorder is a member selected from the group consisting of
depression, cognitive deficit, fibromyalgia, pain, sleep disorder,
attention deficit disorder (ADD), attention deficit hyperactivity
disorder (ADHD), restless leg syndrome, schizophrenia, anxiety,
obsessive compulsive disorder, posttraumatic stress disorder,
premenstrual dysphoria, and neurodegenerative disease.
28. The method according to claim 27, wherein said depression is a
member selected from the group consisting of major depressive
disorder (MDD), unipolar depression, bipolar disorder, seasonal
affective disorder (SAD) and dysthymia.
29. The method according to claim 27, wherein said
neurodegenerative disease is Parkinson's disease.
30. The method according to claim 27, wherein said sleep disorder
is sleep apnea.
31. The method according to claim 27, wherein said pain is
neuropathic pain.
32. A compound having a structure, which is a member selected from
the group consisting of: ##STR352## wherein n is an integer from 0
to 2; p is an integer from 0 to 2; m is an integer from 0 to 12,
with the proviso that when n is 0, then m is not greater than 8;
and when n is 1, then m is not greater than 10; Ar is a member
selected from the group consisting of substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl and a fused ring
system; each X is a member independently selected from the group
consisting of H, halogen, CN, CF.sub.3, OR.sup.5, SR.sup.5, acyl,
C(O)OR.sup.5, C(O)NR.sup.6R.sup.7, S(O).sub.2R.sup.5,
S(O).sub.2NR.sup.6R.sup.7, NR.sup.6R.sup.7,
NR.sup.6S(O).sub.2R.sup.5, NR.sup.6C(O)R.sup.5, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein each R.sup.5, R.sup.6 and R.sup.7 is a member independently
selected from the group consisting of H, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl, wherein two of R.sup.5, R.sup.6 and R.sup.7, together
with the atoms to which they are attached, are optionally joined to
form a 3- to 7-membered ring; each R.sup.1 and R.sup.2 is a member
independently selected from the group consisting of H, halogen, CN,
CF.sub.3, OR.sup.8, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl, wherein R.sup.8 is a member
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl; and
wherein at least two of R.sup.1, R.sup.2 and X, together with the
atoms to which they are attached, are optionally joined to form a
3- to 7-membered ring; at least one of R.sup.1 and R.sup.2 is
optionally joined with Ar to form a 5- to 7-membered ring; and any
salt form, solvate, enantiomer, diastereomer, racemic mixture,
enantiomerically enriched mixture, and enantiomerically pure form
thereof.
33. The compound of claim 32, wherein p is 0.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Patent Application No. 60/756,550 filed
Jan. 6, 2006, which application is incorporated herein by reference
in its entirety for all purposes.
FIELD OF THE INVENTION
[0002] The invention relates to compounds and compositions for the
treatment of central nervous system (CNS) disorders.
BACKGROUND OF THE INVENTION
[0003] Psychiatric disorders are pathological conditions of the
brain characterized by identifiable symptoms that result in
abnormalities in cognition, emotion, mood, or affect. These
disorders may vary in severity of symptoms, duration, and
functional impairment. Psychiatric disorders afflict millions of
people worldwide resulting in tremendous human suffering and
economic burden due to lost productivity and dependent care.
[0004] Over the past several decades, the use of pharmacological
agents to treat psychiatric disorders has greatly increased,
largely due to research advances in both neuroscience and molecular
biology. In addition, chemists have become increasingly
sophisticated at creating chemical compounds that are more
effective therapeutic agents with fewer side effects, targeted to
correct the biochemical alterations that accompany mental
disorders.
[0005] Yet, despite the many advances that have occurred, many
psychiatric diseases remain untreated or inadequately treated with
current pharmaceutical agents. In addition, many of the current
agents interact with molecular targets not involved with the
psychiatric disease. This indiscriminate binding can result in side
effects that can greatly influence the overall outcome of therapy.
In some cases the side effects are so severe that discontinuation
of therapy is required.
[0006] Depression is an affective disorder, the pathogenesis of
which cannot be explained by any single cause or theory. It is
characterized by a persistently low mood or diminished interests in
one's surroundings, accompanied by at least one of the following
symptoms: reduced energy and motivation, difficulty concentrating,
altered sleep and appetite, and at times, suicidal ideation
(American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, ed. 4. Washington, American Psychiatric
Association, 1994). Major depression is associated with high rates
of morbidity and mortality, with suicide rates of 10-25% (Kaplan H
I, Sadock B J (eds): Synopsis of Psychiatry. Baltimore, Williams
& Wilkins, 1998, p. 866). The compounds of the invention may
also be used to reduce fatigue commonly associated with depression
(see, for example, "Bupropion augmentation in the treatment of
chronic fatigue syndrome with coexistent major depression episode"
Schonfeldt-Lecuona et al., Pharmacopsychiatry 39(4):152-4, 2006;
"Dysthymia: clinical picture, extent of overlap with chronic
fatigue syndrome, neuropharmacological considerations, and new
therapeutic vistas" Brunello et al., J. Affect. Disord. 52
(1-3):275-90, 1999; "Chronic fatigue syndrome and seasonal
affective disorder: comorbidity, diagnostic overlap, and
implications for treatment" Terman et al., Am. J. Med. 105
(3A):115S-124S, 1998).
[0007] Depression is believed to result from dysfunction in the
noradrenergic or serotonergic systems, more specifically, from a
deficiency of certain neurotransmitters (NTs) at functionally
important adrenergic or serotonergic receptors.
[0008] Neurotransmitters produce their effects as a consequence of
interactions with specific receptors. Neurotransmitters, including
norepinephrine (NE) and/or serotonin (5-hydroxytryptamine, or
5-HT), are synthesized in brain neurons and stored in vesicles.
Upon a nerve impulse, NTs are released into the synaptic cleft,
where they interact with various postsynaptic receptors. Regional
deficiencies in the synaptic levels of 5-HT and/or NE are believed
to be involved in the etiology of depression, wakefulness, and
attention.
[0009] Norepinephrine is involved in regulating arousal, dreaming,
and moods. Norepinephrine can also contribute to the regulation of
blood pressure, by constricting blood vessels and increasing heart
rate.
[0010] Serotonin (5-HT) is implicated in the etiology or treatment
of various disorders. The most widely studied effects of 5-HT are
those on the CNS. The functions of 5-HT are numerous and include
control of appetite, sleep, memory and learning, temperature
regulation, mood, behavior (including sexual and hallucinogenic
behavior), cardiovascular function, smooth muscle contraction, and
endocrine regulation. Peripherally, 5-HT appears to play a major
role in platelet homeostasis and motility of the GI tract. The
actions of 5-HT are terminated by three major mechanisms:
diffusion; metabolism; and reuptake. The major mechanism by which
the action of 5-HT is terminated is by reuptake through presynaptic
membranes. After 5-HT acts on its various postsynaptic receptors,
it is removed from the synaptic cleft back into the nerve terminal
through an uptake mechanism involving a specific membrane
transporter in a manner similar to that of other biogenic amines.
Agents that selectively inhibit this uptake increase the
concentration of 5-HT at the postsynaptic receptors and have been
found to be useful in treating various psychiatric disorders,
particularly depression.
[0011] Approaches to the treatment of depression over the years
have involved the use of agents that increase the levels of NE and
5-HT, either by inhibiting their metabolism (e.g., monoamine
oxidase inhibitors) or reuptake (e.g., tricyclic antidepressants or
selective serotonin reuptake inhibitors (SSRIs)).
[0012] There are more than twenty approved antidepressant drugs
available in the United States. The classical tricyclic
antidepressants (TCAs) currently available block primarily the
uptake of NE and also, to varying degrees, the uptake of 5-HT,
depending on whether they are secondary or tertiary amines.
Tertiary amines such as imipramine and amitriptyline are more
selective inhibitors of the uptake of 5-HT than of catecholamines,
compared with secondary amines such as desipramine.
[0013] Selective serotonin reuptake inhibitors have been
investigated as potential antidepressants. Fluoxetine
(PROZAC.RTM.), sertraline (ZOLOFT.RTM.), and paroxetine
(PAXIL.RTM.) are three examples of SSRIs currently on the U.S.
market. These agents do not appear to possess greater efficacy than
the TCAs, nor do they generally possess a faster onset of action;
however, they do have the advantage of causing less side-effects.
Of these three SSRIs, paroxetine is the most potent inhibitor of
5-HT uptake, fluoxetine the least. Sertaline is the most selective
for 5-HT versus NE uptake, fluoxetine the least selective.
Fluoxetine and sertraline produce active metabolites, while
paroxetine is metabolized to inactive metabolites. The SSRIs, in
general, affect only the uptake of serotonin and display little or
no affinity for various receptor systems including muscarinic,
adrenergic, dopamine, and histamine receptors.
[0014] In addition to treating depression, several other potential
therapeutic applications for SSRIs have been investigated. They
include treatment of Alzheimer's disease, aggressive behavior,
premenstrual syndrome, diabetic neuropathy, chronic pain,
fibromyalgia, and alcohol abuse. For example, fluoxetine is
approved for the treatment of obsessive-compulsive disorder (OCD).
Of particular significance is the observation that 5-HT reduces
food consumption by increasing meal-induced satiety and reducing
hunger, without producing the behavioral effects of abuse liability
associated with amphetamine-like drugs. Thus, there is interest in
the use of SSRIs in the treatment of obesity.
[0015] Venlafaxine (EFFEXOR.RTM.) is a dual-reuptake antidepressant
that differs from the classical TCAs and the SSRIs chemically and
pharmacologically in that it acts as a potent inhibitor of both
5-HT and NE uptake. Neither venlafaxine nor its major metabolite
have a significant affinity for adrenergic alpha-1 receptors.
Venlafaxine possesses an efficacy equivalent to that of the TCAs,
and a benign side effect profile similar to those of the SSRIs.
[0016] Dopamine is hypothesized to play a major role in psychosis
and certain neurodegenerative diseases, such as Parkinson's
disease, where a deficiency in dopaminergic neurons is believed to
be the underlying pathology. Dopamine affects brain processes that
control movement, emotional response, and ability to experience
pleasure and pain. Regulation of DA plays a crucial role in our
mental and physical health. Certain drugs increase DA
concentrations by preventing DA reuptake, leaving more DA in the
synapse. An example is methylphenidate (RITALIN.RTM.), used
therapeutically to treat childhood hyperkinesias and symptoms of
schizophrenia. Dopamine abnormalities are believed to underlie some
of the core attentional abnormalities seen in acute
schizophrenics.
[0017] A therapeutic lag is associated with the use of these drugs.
Patients must take a drug for at least three (3) weeks before
achieving clinically meaningful symptom relief. Furthermore, a
significant number of patients do not respond to current therapies
at all. For example, it is currently estimated that up to thirty
percent (30%) of clinically diagnosed cases of depression are
resistant to all forms of drug therapy.
SUMMARY OF THE INVENTION
[0018] The present invention relates to novel cycloalkylamines and
salts thereof. It further relates to novel pharmaceutical
compositions, and their use in the treatment of CNS disorders such
as depression (e.g., major depressive disorder, bipolar disorder),
fibromyalgia, pain (e.g., neuropathic pain), sleep apnea, attention
deficit disorder (ADD), attention deficit hyperactivity disorder
(ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive
compulsive disorder, posttraumatic stress disorder, seasonal
affective disorder (SAD), premenstrual dysphoria as well as
neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's
disease).
[0019] Hence, in a first aspect the invention provides a compound
having a structure according to Formula (I): ##STR1##
[0020] In Formula (I), n is an integer from 0 to 2; s is an integer
from 1 to 3. The integer m is selected from 0 to 12. When n is 0, m
is preferably not greater than 8; when n is 1, m is preferably not
greater than 10. Ar is a member selected from the group consisting
of substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and a fused ring system.
[0021] Each X is an independently selected alkyl group
substitutent. In an exemplary embodiment, each X is a member
independently selected from the group consisting of H, halogen, CN,
CF.sub.3, OR.sup.5, SR.sup.5, acyl, C(O)OR.sup.5,
C(O)NR.sup.6R.sup.7, S(O).sub.2R.sup.5, S(O).sub.2NR.sup.6R.sup.7,
NR.sup.6R.sup.7, NR.sup.6S(O).sub.2R.sup.5, NR.sup.6C(O)R.sup.5,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl, wherein each R.sup.5, R.sup.6 and R.sup.7 is a
member independently selected from the group consisting of H, acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl, wherein two of R.sup.5, R.sup.6 and
R.sup.7, together with the atoms to which they are attached, are
optionally joined to form a 3- to 7-membered ring.
[0022] Each R.sup.1 and R.sup.2 is an independently selected alkyl
group substitutent. In an exemplary embodiment, each R.sup.1 and
R.sup.2 is a member independently selected from the group
consisting of H, halogen, CN, CF.sub.3, OR.sup.8, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein R.sup.8 is a member selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.
[0023] R.sup.3 and R.sup.4 are members independently selected from
the group consisting of H, OR.sup.9, acyl, C(O)OR.sup.9,
S(O).sub.2R.sup.9, .dbd.N.dbd.N, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl. When one member of
R.sup.3 and R.sup.4 is .dbd.N.dbd.N, the other member is preferably
not present. R.sup.9 is a member selected from the group consisting
of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl.
[0024] At least two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and any
of the substitutents X, together with the atoms to which they are
attached, are optionally joined to form a 3- to 7-membered
ring.
[0025] Any pharmaceutically acceptable salt, solvate, enantiomer,
diastereomer, racemic mixture, enantiomerically enriched mixture,
and enantiomerically pure form of the above described compounds
falls within the scope of the invention.
[0026] In a second aspect, the invention provides a pharmaceutical
composition including a compound of the invention or a
pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable carrier.
[0027] In a third aspect, the invention provides a method of
inhibiting binding of a monoamine transporter ligand to a monoamine
transporter, such as serotonin transporter, dopamine transporter
and norepinephrine transporter. The method includes contacting the
monoamine transporter and a compound of the invention. In an
exemplary embodiment the monoamine transporter ligand is a
monoamine, such as serotonin, dopamine and norepinephrine.
[0028] In a fourth aspect, the invention provides a method of
inhibiting the activity of at least one monoamine transporter, such
as serotonin transporter, dopamine transporter and norepinephrine
transporter. The method includes contacting the monoamine
transporter and a compound of the invention.
[0029] In another aspect, the invention provides a method of
inhibiting uptake of at least one monoamine, such as serotonin,
dopamine and norepinephrine, by a cell. The method includes
contacting the cell with a compound of the invention. In an
exemplary embodiment, the cell is a brain cell, such as a neuronal
cell or a glial cell.
[0030] In yet another aspect, the invention provides a method of
treating depression by inhibiting the activity at least one
monoamine transporter. The method includes administering to a
mammalian subject a compound of the invention. In a preferred
embodiment, the compound of the invention inhibits the activity of
at least two different monoamine transporters. In another preferred
embodiment, the mammalian subject is a human.
[0031] In a further aspect, the invention provides a method of
treating a central nervous system disorder. The method includes
administering to a subject in need thereof a therapeutically
effective amount of a compound of the invention or a
pharmaceutically acceptable salt or solvate thereof. In a preferred
embodiment, the subject is a human.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0032] The term "alkyl," by itself or as part of another
substitutent, means, unless otherwise stated, a straight or
branched chain, or cyclic hydrocarbon radical, or combination
thereof, which may be fully saturated, mono- or polyunsaturated and
can include di- and multivalent radicals, having the number of
carbon atoms designated (i.e. C.sub.1-C.sub.10 means one to ten
carbons). Examples of saturated hydrocarbon radicals include, but
are not limited to, groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds. Examples of unsaturated alkyl groups include, but are
not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The
term "alkyl," unless otherwise noted, is also meant to include
those derivatives of alkyl defined in more detail below, such as
"heteroalkyl." Alkyl groups that are limited to hydrocarbon groups
are termed "homoalkyl".
[0033] The term "alkylene" by itself or as part of another
substitutent means a divalent radical derived from an alkane, as
exemplified, but not limited, by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and further includes those
groups described below as "heteroalkylene." Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having eight or fewer
carbon atoms.
[0034] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
[0035] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or cyclic hydrocarbon radical, or combinations
thereof, consisting of the stated number of carbon atoms and at
least one heteroatom selected from the group consisting of O, N, Si
and S, and wherein the nitrogen and sulfur atoms may optionally be
oxidized and the nitrogen heteroatom may optionally be quaternized.
The heteroatom(s) O, N and S and Si may be placed at any interior
position of the heteroalkyl group or at the position at which the
alkyl group is attached to the remainder of the molecule. Examples
include, but are not limited to, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3. Similarly, the term
"heteroalkylene" by itself or as part of another substitutent means
a divalent radical derived from heteroalkyl, as exemplified, but
not limited by, --CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--CO.sub.2R'-- represents both --C(O)OR' and --OC(O)R'.
[0036] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1-1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0037] The terms "halo" or "halogen," by themselves or as part of
another substitutent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is mean to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0038] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, substitutent that can be a single ring
or multiple rings (preferably from 1 to 3 rings), which are fused
together or linked covalently. The term "heteroaryl" refers to aryl
groups (or rings) that contain from one to four heteroatoms
selected from N, O, S, Si and B, wherein the nitrogen and sulfur
atoms are optionally oxidized, and the nitrogen atom(s) are
optionally quaternized. A heteroaryl group can be attached to the
remainder of the molecule through a heteroatom. Non-limiting
examples of aryl and heteroaryl groups include phenyl, 1-naphthyl,
2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,
3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,
4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,
4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,
2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents for each of the above noted aryl and heteroaryl ring
systems are selected from the group of acceptable substitutents
described below.
[0039] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those radicals in which an aryl
group is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like) including those alkyl groups in which a
carbon atom (e.g., a methylene group) has been replaced by, for
example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, and the like).
[0040] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl" and "heteroaryl") are meant to include both substituted and
unsubstituted forms of the indicated radical. Preferred
substitutents for each type of radical are provided below.
[0041] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are
generically referred to as "alkyl group substitutents," and they
can be one or more of a variety of groups selected from, but not
limited to: substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocycloalkyl, --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', -halogen, --SiR'R''R''', --OC(O)R',
--C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'--C(O)NR''R''', --NR''C(O).sub.2R',
--NR--C(NR'R''R''').dbd.NR'''', --NR--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN
and --NO.sub.2 in a number ranging from zero to (2m'+1), where m'
is the total number of carbon atoms in such radical. R', R'', R'''
and R'''' each preferably independently refer to hydrogen,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, e.g., aryl substituted with 1-3 halogens,
substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or
arylalkyl groups. When a compound of the invention includes more
than one R group, for example, each of the R groups is
independently selected as are each R', R'', R''' and R'''' groups
when more than one of these groups is present. When R' and R'' are
attached to the same nitrogen atom, they can be combined with the
nitrogen atom to form a 5-, 6-, or 7-membered ring. For example,
--NR'R'' is meant to include, but not be limited to, 1-pyrrolidinyl
and 4-morpholinyl. From the above discussion of substitutents, one
of skill in the art will understand that the term "alkyl" is meant
to include groups including carbon atoms bound to groups other than
hydrogen groups, such as haloalkyl (e.g., --CF.sub.3 and
--CH.sub.2CF.sub.3) and acyl (e.g., --C(O)CH.sub.3, --C(O)CF.sub.3,
--C(O)CH.sub.2OCH.sub.3, and the like).
[0042] Similar to the substitutents described for the alkyl
radical, substitutents for the aryl and heteroaryl groups are
generically referred to as "aryl group substitutents." The
substitutents are selected from, for example: substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heterocycloalkyl, --OR',
.dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR--C(NR'R''R''').dbd.NR'''',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --CN and --NO.sub.2, --R',
--N.sub.3, --CH(Ph).sub.2, fluoro(C.sub.1-C.sub.4)alkoxy, and
fluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to the
total number of open valences on the aromatic ring system; and
where R', R'', R''' and R'''' are preferably independently selected
from hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl. When a compound of the
invention includes more than one R group, for example, each of the
R groups is independently selected as are each R', R'', R''' and
R'''' groups when more than one of these groups is present.
[0043] Two of the substitutents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substitutent of
the formula -T-C(O)--(CRR').sub.q--U--, wherein T and U are
independently --NR--, --O--, --CRR'-- or a single bond, and q is an
integer of from 0 to 3. Alternatively, two of the substitutents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substitutent of the formula -A-(CH.sub.2).sub.r-D-,
wherein A and D are independently --CRR'--, --O--, --NR--, --S--,
--S(O)--, --S(O).sub.2--, --S(O).sub.2NR'-- or a single bond, and r
is an integer of from 1 to 4. One of the single bonds of the new
ring so formed may optionally be replaced with a double bond.
Alternatively, two of the substitutents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substitutent of the formula
--(CRR').sub.s--X''--(CR''R''').sub.d--, where s and d are
independently integers of from 0 to 3, and X'' is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substitutents R, R', R'' and R''' are preferably independently
selected from hydrogen or substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl.
[0044] As used herein, the term "acyl" describes a substitutent
containing a carbonyl residue, C(O)R'. Exemplary species for R
include H, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, and
substituted or unsubstituted heterocycloalkyl.
[0045] As used herein, the term "fused ring system" means at least
two rings, wherein each ring has at least 2 atoms in common with
another ring. "Fused ring systems may include aromatic as well as
non aromatic rings. Examples of "fused ring systems" are
naphthalenes, indoles, quinolines, chromenes and the like.
[0046] As used herein, the term "heteroatom" includes oxygen (O),
nitrogen (N), sulfur (S), silicon (Si) and boron (B).
[0047] The symbol "R" is a general abbreviation that represents a
substitutent group that is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, and substituted or unsubstituted heterocycloalkyl
groups.
[0048] The phrase "therapeutically effective amount" as used herein
means that amount of a compound, or composition comprising a
compound of the present invention which is effective for producing
some desired therapeutic effect (e.g., by inhibiting uptake of a
monoamine from the synaptic cleft of a mammal, thereby modulating
the biological consequences of that pathway in the treated
organism) at a reasonable benefit/risk ratio applicable to any
medical treatment.
[0049] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk
ratio.
[0050] The phrase "pharmaceutically acceptable carrier" as used
herein means any pharmaceutically acceptable material, which may be
liquid or solid. Exemplary carriers include vehicles, diluents,
additives, liquid and solid fillers, excipients, solvents, solvent
encapsulating materials. Each carrier must be "acceptable" in the
sense of being compatible with the other ingredients of the
formulation and not injurious to the patient. Some examples of
materials which can serve as pharmaceutically-acceptable carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2)
starches, such as corn starch and potato starch; (3) cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt;
(6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
(10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,
such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as magnesium hydroxide and aluminum hydroxide; (15)
alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)
Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions;
(21) polyesters, polycarbonates and/or polyanhydrides; and (22)
other non-toxic compatible substances employed in pharmaceutical
formulations.
[0051] As set out above, certain embodiments of the present
compounds may contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming pharmaceutically
acceptable salts with pharmaceutically acceptable acids. The term
"pharmaceutically acceptable salts" in this respect, refers to the
relatively non-toxic, inorganic and organic acid addition salts of
compounds of the present invention. These salts can be prepared in
situ in the administration vehicle or the dosage form manufacturing
process, or by separately reacting a purified compound of the
invention in its free base form with a suitable organic or
inorganic acid, and isolating the salt thus formed during
subsequent purification. Representative salts include the
hydrobromide, hydrochloride, sulfate, sulfamate, bisulfate,
phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,
laurate, benzoate, lactate, tosylate, citrate, maleate, ascorbate,
palmitate, fumarate, succinate, tartrate, napthylate, mesylate,
hydroxymaleate, phenylacetate, glutamate, glucoheptonate,
salicyclate, sulfanilate, 2-acetoxybenzoate, methanesulfonate,
ethane disulfonate, oxalate, isothionate, lactobionate, and
laurylsulphonate salts and the like. See, for example, Berge et al.
(1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.
[0052] The term "pharmaceutically acceptable salts" includes salts
of the active compounds which are prepared with relatively nontoxic
acids or bases, depending on the particular substitutents found on
the compounds described herein. When compounds of the present
invention contain relatively acidic functionalities, base addition
salts can be obtained by contacting the neutral form of such
compounds with a sufficient amount of the desired base, either neat
or in a suitable inert solvent. Examples of pharmaceutically
acceptable base addition salts include sodium, potassium, calcium,
ammonium, organic amino, or magnesium salt, or a similar salt. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., Journal of Pharmaceutical Science, 66: 1-19
(1977)). Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0053] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar solvents,
but otherwise the salts are equivalent to the parent form of the
compound for the purposes of the present invention.
[0054] In addition to salt forms, the present invention provides
compounds, which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0055] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms. In general, all physical
forms are equivalent for the uses contemplated by the present
invention and are intended to be within the scope of the present
invention. "Compound or a pharmaceutically acceptable salt or
solvate of a compound" intends the inclusive meaning of "or", in
that a material that is both a salt and a solvate is
encompassed.
[0056] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers and individual isomers
are encompassed within the scope of the present invention.
Optically active (R)- and (S)-isomers may be prepared using chiral
synthons or chiral reagents, or resolved using conventional
techniques. When the compounds described herein contain olefinic
double bonds or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers. Likewise, all tautomeric forms are also
intended to be included.
[0057] The graphic representations of racemic, ambiscalemic and
scalemic or enantiomerically pure compounds used herein are taken
from Maehr, J. Chem. Ed., 62: 114-120 (1985): solid and broken
wedges are used to denote the absolute configuration of a chiral
element; wavy lines indicate disavowal of any stereochemical
implication which the bond it represents could generate; solid and
broken bold lines are geometric descriptors indicating the relative
configuration shown but not implying any absolute stereochemistry;
and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute
configuration.
[0058] The terms "enantiomeric excess" and "diastereomeric excess"
are used interchangeably herein. Compounds with a single
stereocenter are referred to as being present in "enantiomeric
excess," those with at least two stereocenters are referred to as
being present in "diastereomeric excess."
[0059] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. For example, the compounds
may be radiolabeled with radioactive isotopes, such as for example
tritium (.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C).
All isotopic variations of the compounds of the present invention,
whether radioactive or not, are intended to be encompassed within
the scope of the present invention.
[0060] The term "monoamine transporter ligand" refers to any
compound, which binds to a monoamine transporter. Ligands include
endogenous monoamines, which are the natural ligands for a given
monoamine transporter as well as drug molecules and other
compounds, such as synthetic molecules known to bind to a
particular monoamine transporter. In one example, the ligand
includes a radioisotope, such as tritium or is otherwise (e.g.,
fluorescently) labeled. It is within the abilities of a skilled
person to select an appropriate ligand for a given monoamine
transporter. For example, known ligands for the dopamine
transporter include dopamine and WIN35428, known ligands for the
serotonin transporter include 5-hydroxytryptamine (serotonin) and
citalopram, and ligands for the norepinephrine transporter include
norepinephrine and nisoxetine.
[0061] The term "central nervous system disorder" refers to any
abnormal condition of the central nervous system of a mammal.
Central nervous system disorder includes neurodegenerative diseases
such Alzheimer's disease and Parkinson's disease, neuropsychiatric
diseases (e.g. schizophrenia), anxieties, sleep disorders,
depression, dementias, movement disorders, psychoses, alcoholism,
post-traumatic stress disorder and the like. "Central nervous
system disorder" also includes any condition associated with the
disorder, such as loss of memory and/or loss of cognition. For
instance, a method of treating a neurodegenerative disease would
also include treating or preventing loss of neuronal function
characteristic of such disease. "Central nervous system disorder"
also includes any disease or condition that is implicated, at least
in part, in monoamine (e.g., norepinephrine) signaling pathways
(e.g., cardiovascular disease).
[0062] The term "pain" refers to all categories of pain, including
pain that is described in terms of stimulus or nerve response,
e.g., somatic pain (normal nerve response to a noxious stimulus)
and neuropathic pain (abnormal response of a injured or altered
sensory pathway, often without clear noxious input); pain that is
categorized temporally, e.g., chronic pain and acute pain; pain
that is categorized in terms of its severity, e.g., mild, moderate,
or severe; and pain that is a symptom or a result of a disease
state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain,
arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and
diabetic neuropathy (see, e.g., Harrison's Principles of Internal
Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams
et al., J. of Med. Chem. 42: 1481-1485 (1999), herein each
incorporated by reference in their entirety). "Pain" is also meant
to include mixed etiology pain, dual mechanism pain, allodynia,
causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia,
and hyperalgesia.
[0063] The term "depression" includes all forms of depression,
which include major depressive disorder (MDD), bipolar disorder,
seasonal affective disorder (SAD) and dysthymia. "Major depressive
disorder" is used herein interchangeably with "unipolar depression"
and "major depression. "Depression" also includes any condition
commonly associated with depression, such as all forms of fatigue
(e.g., chronic fatigue syndrome) and cognitive deficits.
II. Introduction
[0064] One strategy to develop effective therapies is the use of
broad spectrum antidepressants that simultaneously inhibit the
reuptake of more than one biogenic amine, such as serotonin (5-HT),
norepinephrine (NE) and dopamine (DA). The rationale for this
approach is based upon clinical and preclinical evidence showing
that deficiencies in dopaminergic function can be correlated with
anhedonia, which is a core symptom of depression. Baldessarini, R.
J., "Drugs and the Treatment of Psychiatric Disorders: Depression
and Mania, in Goodman and Gilman's The Pharmacological Basis of
Therapeutics 431-459 (9.sup.th ed 1996) Hardman et al. eds.
[0065] An advantage of the compounds and compositions of the
present invention is their ability to increase synaptic
availability of at least two neurotransmitters (e.g., NE, 5-HT and
DA) by inhibiting their (re)uptake from the synaptic cleft.
Skolnick and coworkers report on a body of preclinical evidence
suggesting that the therapeutic profile of an antidepressant
concurrently increasing the synaptic availability of DA, NE and
5-HT will differ from a compound inhibiting only NE and/or 5-HT.
Skolnick, P. et al., "Antidepressant-like actions of DOV-21,947: a
"triple" reuptake inhibitor," Eur. J. Pharm. 2003, 461, 103.
[0066] For example, Skolnick and coworkers have reported that a
compound, DOV 21,947
((+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane), inhibits
the reuptake of serotonin, norepinephrine, and dopamine in human
embryonic kidney (HEK293) cells expressing the corresponding human
recombinant transporters (IC.sub.50 values of 12, 23 and 96 nM,
respectively). Skolnick, P. et al., "Antidepressant-like actions of
DOV-21,947: a "triple" reuptake inhibitor," Eur. J. Pharm. 2003,
461, 99. In addition, DOV 21,947 reduces the duration of immobility
in the forced swim test (in rats) and also produces a
dose-dependent reduction in immobility in the tail suspension test.
Additional evidence can be found in preclinical data for new triple
reuptake inhibitors such as DOV 21,947 in, e.g., U.S. Pat. No.
6,372,919, wherein DOV 21,947 was disclosed as having a
significantly greater affinity for the norepinephrine and serotonin
uptake sites than the racemic compound,
(.+-.)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
[0067] Taken together, the preclinical data for compounds such as
DOV 21,947 indicate that dual or triple reuptake inhibitors may
hold potential as novel treatments for depression in the
clinic.
III. Compositions
A. Cycloalkyl Amines
[0068] In a first aspect, the invention provides a compound having
a structure according to Formula (I): ##STR2##
[0069] In Formula (I), n is an integer from 0 to 2. Hence, in one
embodiment, the invention provides cyclopentyl-, cyclohexyl- and
cycloheptylamines. The integer s is selected from 0 to 3,
preferably from 1 to 2. In a particularly preferred embodiment, s
is 1. The integer m is selected from 0 to 12. When n is 0, m is
preferably not greater than 8; when n is 1, m is preferably not
greater than 10. Ar is a member selected from the group consisting
of substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and a fused ring system.
[0070] Each X is a member independently selected from an alkyl
group substitutent. In an exemplary embodiment, each X is a member
independently selected from the group consisting of H, halogen, CN,
CF.sub.3, OR.sup.5, SR.sup.5, acyl, C(O)OR.sup.5,
C(O)NR.sup.6R.sup.7, S(O).sub.2R.sup.5, S(O).sub.2NR.sup.6R.sup.7,
NR.sup.6R.sup.7, NR.sup.6S(O).sub.2R.sup.5, NR.sup.6C(O)R.sup.5,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl. Each R.sup.5, R.sup.6 and R.sup.7 is a member
independently selected from the group consisting of H, acyl,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl and substituted or
unsubstituted heteroaryl, wherein two of R.sup.5, R.sup.6 and
R.sup.7, together with the atoms to which they are attached, are
optionally joined to form a 3- to 7-membered ring.
[0071] Each R.sup.1 and R.sup.2 is an independently selected alkyl
group substitutent. In an exemplary embodiment, each R.sup.1 and
R.sup.2 is a member independently selected from the group
consisting of H, halogen, CN, CF.sub.3, OR.sup.8, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein R.sup.8 is a member selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.
[0072] In one embodiment, R.sup.3 and R.sup.4 are members
independently selected from the group consisting of H, OR.sup.9,
acyl, C(O)OR.sup.9, S(O).sub.2R.sup.9, .dbd.N.dbd.N, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl. When
one member of R.sup.3 and R.sup.4 is .dbd.N.dbd.N, the other member
is preferably not present. R.sup.9 is a member selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl.
[0073] At least two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and any
substitutent X, together with the atoms to which they are attached,
are optionally joined to form a 3- to 7-membered ring. In an
exemplary embodiment, two substitutents X, together with the atoms
to which they are attached, are optionally joined to form a 3- to
7-membered ring. In another exemplary embodiment, R.sup.3 and
R.sup.4 are joined to form a ring, such as a morpholine,
N-methyl-piperazine and the like. In another exemplary embodiment,
R.sup.1 and R.sup.3 are joined to form a ring, such as a
pyrrolidine ring. In yet another exemplary embodiment, at least one
of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is optionally joined with
the Ar group or a substitutent on the Ar group to form a 5- to
7-membered ring. An exemplary structure, in which Ar-s substituted
phenyl and R.sup.3 is joined with Ar to form a 6-membered ring is
provided below: ##STR3## wherein Y and Z are as defined below.
[0074] In an especially preferred embodiment, the integer s in
Formula (I) is 1. Exemplary compounds according to this embodiment
have a Formula, which is a member selected from Formula (II) and
Formula (III): ##STR4##
[0075] In an exemplary embodiment, the cycloalkyl ring is mono- or
disubstituted at either the 2-, 3-, or 4-position. Exemplary
compounds according to this embodiment have a Formula, which is a
member selected from the group consisting of: ##STR5## wherein
X.sup.1 and X.sup.2 are alkyl group substitutents. In an exemplary
embodiment, X.sup.1 and X.sup.2 are each defined as the
substitutent X, above. In another exemplary embodiment, X.sup.1 and
X.sup.2 are members independently selected from the group
consisting of H, OR.sup.5, SR.sup.5, halogen, CN, CF.sub.3,
S(O).sub.2R.sup.5, NR.sup.6R.sup.7, NR.sup.6S(O).sub.2R.sup.5,
NR.sup.6C(O)R.sup.5, acyl, substituted or unsubstituted
C.sub.1-C.sub.4 alkyl and substituted or unsubstituted
C.sub.1-C.sub.4 heteroalkyl, wherein at least two of R.sup.1,
R.sup.3, R.sup.4, X.sup.1 and X.sup.2, together with the atoms to
which they are attached, are optionally joined to form a 3- to
7-membered ring.
[0076] In a preferred embodiment, X.sup.1 and X.sup.2 are members
independently selected from H, methyl, ethyl, propyl, OR.sup.5
(e.g., OH, OMe, OEt, OPh), CH.sub.2OR.sup.5 (e.g., CH.sub.2OH),
halogen substituted alkyl (e.g., CF.sub.3, CH.sub.2F), halogen
(e.g., F or Cl) and CN. In another preferred embodiment, R.sup.1 is
a member selected from H and substituted or unsubstituted
C.sub.1-C.sub.4 alkyl. In yet another preferred embodiment, R.sup.3
and R.sup.4 are members independently selected from H, substituted
or unsubstituted alkyl and substituted or unsubstituted
heteroalkyl, such as substituted or unsubstituted C.sub.1-C.sub.4
alkyl or substituted or unsubstituted C.sub.1-C.sub.4 heteroalkyl.
In one example, R.sup.3 and R.sup.4, together with the nitrogen
atom to which they are attached, are joined to form a 3- to
7-membered ring, such as a morpholine, piperidine, pyrrolidine or
N-alkyl-piperazine moiety.
[0077] In another embodiment, the compound of the invention
includes a cyclobutyl ring. An exemplary structure is provided
below in Formula (IV): ##STR6## wherein the integer q is selected
from 0 to 6. Aryl Group Substituent (Ar)
[0078] In one embodiment, Ar is a member selected from substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl and
a fused ring system. Preferably, Ar is a member selected from
substituted or unsubstituted phenyl and substituted or
unsubstituted naphthyl, including 1-naphthyl and 2-naphthyl
analogs. Hence, in one embodiment, Ar is a member selected from:
##STR7## wherein Y, Z, Y.sup.1 and Z.sup.1 are members
independently selected from aryl group substitutents. In an
exemplary embodiment, Y, Z, Y.sup.1 and Z.sup.1 are members
independently selected from H, halogen, CF.sub.3, CN, OR.sup.11,
SR.sup.11, NR.sup.12R.sup.13, NR.sup.12S(O).sub.2R.sup.11,
NR.sup.12C(O)R.sup.11, S(O).sub.2R.sup.11, acyl, C(O)OR.sup.11,
C(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl. Each
R.sup.11, R.sup.12 and R.sup.13 is a member independently selected
from the group consisting of H, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heterocycloalkyl, wherein two of
R.sup.11, R.sup.12 and R.sup.13, together with the atoms to which
they are attached, are optionally joined to form a 3- to 7-membered
ring.
[0079] Two of Y, Z, Y.sup.1 and Z.sup.1, together with the atoms to
which they are attached, are optionally joined to form a 5- to
7-membered ring, such as a dioxolyl ring. In another exemplary
embodiment, Y, Z, Y.sup.1 and Z.sup.1 are members independently
selected from the group consisting of H, halogen, CN, halogen
substituted C.sub.1-C.sub.4 alkyl (e.g., CF.sub.3) and
C.sub.1-C.sub.4 alkoxy (e.g., OMe, OEt, OCF.sub.3).
[0080] In yet another exemplary embodiment, Ar is a
3,4-disubstituted phenyl moiety and has the structure: ##STR8##
[0081] In a preferred embodiment, Y and Z, in the structure above,
are members independently selected from H, halogen, CN, CF.sub.3
and OR.sup.16 (e.g., OMe, OEt, OCF.sub.3). In a particular
preferred embodiment, Y and Z are both halogen. In an exemplary
embodiment, Ar in any of the structures above is
3,4-dichlorophenyl.
[0082] Exemplary compounds according to the above described
embodiments are provided below: ##STR9## ##STR10##
[0083] In an exemplary embodiment, in the structures above,
R.sup.1, R.sup.3 and R.sup.4 are independently selected from H and
C.sub.1 to C.sub.4 alkyl (e.g., methyl) and X.sup.1 and X.sup.2 are
independently selected from H, OH, OMe, methyl, ethyl, CH.sub.2OH,
halogen (e.g., Cl and F), CN and CF.sub.3.
[0084] The compounds of the invention include an amine moiety
(e.g., a primary, secondary or tertiary amino group) and as such
can be converted into a salt form by contacting the compound (e.g.,
the free base) with an acid. In an exemplary embodiment, the salt
form is generated to convert an otherwise oily or viscous compound
into a solid substance for easier handling. In another exemplary
embodiment, converting the free base of a compound of the invention
into a corresponding salt increases solubility of the compound in
aqueous media, which can effect biological characteristics, such as
bioavailability, pharmacokinetics and pharmacodynamics. Hence, any
salt forms, such as pharmaceutically acceptable salts, including
salts of inorganic acids (e.g., hydrochloride salts) or organic
acids, of the compounds of the invention are within the scope of
the current invention. Also within the scope of the invention are
any prodrugs of the compounds of the invention. For example,
R.sup.3 and R.sup.4 can be any group, which is cleavable in vivo to
result in an amine, such as a primary or secondary amine.
[0085] In another embodiment, the invention provides synthetic
precursors for the cycloalkylamines of the invention. For example,
a large subset of the currently provided amines can be synthesized
via the corresponding nitrile (e.g., by reduction) or the
corresponding aldehyde (e.g., by reductive amination). Thus, the
invention provides compounds having a structure selected from the
following Formulae: ##STR11## wherein p is an integer selected from
0 to 2. Ar, R.sup.1, R.sup.2, X and the integers m and n are as
defined above. In a preferred embodiment p is 0.
[0086] In another embodiment, the invention provides
cycloalkylamines, wherein the cycloalkyl ring includes one or more
double bonds. Exemplary compounds are shown below: ##STR12##
wherein the integer r is selected from 0 to 8 and t is selected
from 0 to 6. B. Compositions Including Stereoisomers
[0087] The compound of the invention can include one or more
stereocenter and may exist in particular geometric or
stereoisomeric forms. Compounds can be chiral, racemic or be
present in a composition including one or more stereoisomer. The
current invention encompasses any enantiomer, diastereomer, racemic
mixtures, enantiomerically enriched mixtures, and
diastereomerically enriched mixture as well as any enantiomerically
or diastereomerically (essentially) pure forms of the compounds of
the invention. The invention contemplates cis- and trans-isomers,
(-)- and (+)-enantiomers, (D)-isomers, (L)-isomers, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substitutent such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in this invention.
[0088] If, for instance, a particular enantiomer of a compound of
the present invention is desired, it may be prepared by asymmetric
synthesis, or by derivatization with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as an amino group, or an acidic functional group, such
as a carboxyl group, diastereomeric salts may be formed with an
appropriate optically active acid or base, followed by resolution
of the diastereomers thus formed by fractional crystallization or
chromatographic means known in the art, and subsequent recovery of
the pure enantiomers. In addition, separation of enantiomers and
diastereomers is frequently accomplished using chromatography
employing chiral, stationary phases, optionally in combination with
chemical derivatization (e.g., formation of carbamates from
amines).
[0089] As used herein, the term "enantiomerically enriched" or
"diastereomerically enriched" refers to a compound having an
enantiomeric excess (ee) or a diastereomeric excess (de) greater
than about 50%, preferably greater than about 70% and more
preferably greater than about 90%. In general, higher than about
90% enantiomeric or diastereomeric purity is particularly
preferred, e.g., those compositions with greater than about 95%,
greater than about 97% and greater than about 99% ee or de.
[0090] The terms "enantiomeric excess" and "diastereomeric excess"
are used interchangeably herein. Compounds with a single
stereocenter are referred to as being present in "enantiomeric
excess", those with at least two stereocenters are referred to as
being present in "diastereomeric excess".
[0091] For example, the term "enantiomeric excess" is well known in
the art and is defined as: ee a = ( conc . .times. of .times.
.times. a - conc . .times. of .times. .times. b conc . .times. of
.times. .times. a + conc . .times. of .times. .times. b ) .times.
100 ##EQU1##
[0092] The term "enantiomeric excess" is related to the older term
"optical purity" in that both are measures of the same phenomenon.
The value of ee will be a number from 0 to 100, zero being racemic
and 100 being enantiomerically pure. A compound which in the past
might have been called 98% optically pure is now more precisely
characterized by 96% ee. A 90% ee reflects the presence of 95% of
one enantiomer and 5% of the other(s) in the material in
question.
[0093] Hence, in one embodiment, the invention provides a
composition including a first stereoisomer and at least one
additional stereoisomer of a compound of the invention. The first
stereoisomer may be present in a diastereomeric or enantiomeric
excess of at least about 80%, preferably at least about 90% and
more preferably at least about 95%. In a particularly preferred
embodiment, the first stereoisomer is present in a diastereomeric
or enantiomeric excess of at least about 96%, at least about 97%,
at least about 98%, at least about 99% or at least about 99.5%.
Enantiomeric or diastereomeric excess may be determined relative to
exactly one other stereoisomer, or may be determined relative to
the sum of at least two other stereoisomers. In an exemplary
embodiment, enantiomeric or diastereomeric excess is determined
relative to all other detectable stereoisomers, which are present
in the mixture. Stereoisomers are detectable if a concentration of
such stereoisomer in the analyzed mixture can be determined using
common analytical methods, such as chiral HPLC.
C. Synthesis of the Compounds
1. General
[0094] Compounds of the invention may be synthesized as a racemic
mixture, a mixture of cis and trans isomers, or a mixture of two or
more diastereomers. Stereoisomers may be separated at an
appropriate synthetic stage, for example, by chiral column
chromatography, such as HPLC to give
enantiomerically/diastereomerically enriched or enantiomerically or
diastereomerically pure forms of the respective stereoisomers. Cis
and trans assignments may be made on the basis of NMR coupling
patterns optionally in conjunction with literature values. Absolute
configurations can be determined by synthesis from chiral precursor
of known configuration, or by X-ray crystallographic determination
using crystallized materials.
[0095] Numbering of the positions within the cycloalkyl ring
structure is based on the following Scheme: ##STR13##
[0096] Cis- and trans-configurations are defined according to the
relative configuration of the amine-bearing side chain and the
substitutent on the cyclalkyl ring. When more than one substitutent
is present, the higher order (IUPAC) substitutent is used for the
determination of cis- and trans-configuration. Examples are
Outlined Below
(a) 2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol
[0097] ##STR14##
(b) 3-(aminomethyl)-3-(3,4-dichlorophenyl)-1-methylcyclohexanol
[0098] ##STR15##
[0099] Compounds of the invention may be synthesized according to
Schemes 1 to 23, below. It is within the abilities of a person
skilled in the art to select appropriate alternative reagents
replacing the exemplary reagents shown in Schemes 1-23 in order to
synthesize a desired compound of the invention. It is also within
the abilities of a skilled artisan to omit or add synthetic steps
when necessary. As a non-limiting example, Ar in Schemes 1 to 23 is
selected from substituted or unsubstituted phenyl. In an exemplary
embodiment, Ar is 3,4-dichlorophenyl.
2. General Synthesis of Cycloalkylamines
[0100] In one embodiment, the compounds of the invention are
synthesized from the corresponding nitrile C as shown in Scheme 1,
below. ##STR16##
[0101] Synthesis of the nitrile C and the carboxylic acid
intermediate E can, for example, be accomplished as described by
Calderon et al., J. Med. Chem. 1994, 37, 2285, which is
incorporated herein by reference. In addition, the reduction of the
nitrile C to the corresponding primary amine D can be accomplished
by borane reduction, for example, as described by Nagarathnam et
al., J. Med. Chem. 1998, 41, 5320, which is also incorporated
herein by reference.
[0102] Referring to Scheme 1, alkylation of the acetonitrile A with
dibromoalkane B (e.g., with NaH in DMSO) gives the nitrile C, which
is subsequently converted to acid E (e.g., NaOH, 1,3-propanediol).
The dibromoalkane can optionally be substituted to afford a
substituted cycloalkane analog of the invention. The integer n may
be selected from 0 to 2, resulting in cyclopentyl, cyclohexyl and
cycloheptyl intermediates, respectively. Alternatively, substituted
or unsubstituted 1,3-dibromopropane may be used to prepare a
cyclobutyl analog of the invention.
[0103] Coupling of acid E with either a primary amine
(R.sup.4.dbd.H) or a secondary amine is performed using peptide
coupling reagents known in the art resulting in the corresponding
amide (not shown). In an exemplary embodiment the amide is formed
using EDCI and HOBt in DMF as the coupling reagents. In another
exemplary embodiment, the amide is formed using PyBOP in DMF as the
coupling reagent. Exemplary coupling procedures are described in
General Procedures G to G3.
[0104] Referring to Scheme 1, the amide is then reduced using a
reducing agent, such as borane. Exemplary borane reagents include
BH.sub.3.THF and borane.dimethylsulfide complexes. The resulting
amine may be converted to the corresponding salt form. For example,
treatment of the amine with HCl in Et.sub.2O affords the HCl salt,
which may be recrystallized to give the amine F as a solid.
[0105] Alternatively, the nitrile C can be reduced to the primary
amine D using a reducing agent, such as borane (e.g.,
BH.sub.3.THF). The amine may be converted to the corresponding salt
form. For example, treatment of the amine with HCl in Et.sub.2O
affords the HCl salt, which may be recrystallized to give a pure
solid. The primary amine may be converted to a secondary or
tertiary amine by alkylation of the amino group as described
below.
[0106] Alternatively, the carboxylic acid intermediate E can be
activated by formation of an acid chloride, which may then be
reacted with a primary or secondary amine to give the amide, as
outlined for an exemplary cyclopentylamine in Scheme 2, below.
##STR17##
[0107] In another approach, the nitrile C can be converted to the
corresponding aldehyde G using a reducing agent, such as DIBAL
(Scheme 3). The aldehyde can then be converted to an amine, for
example, through reductive amination. This synthetic route is
particularly useful for the preparation of secondary amines of the
invention (R.sup.4.dbd.H), as the amination of the aldehyde with a
secondary amine to form a tertiary amine may be sluggish.
##STR18##
3. Synthesis of Substituted Cyclopentyl Amines
[0108] Substituted cyclopentyl amines (n=0) can be synthesized
according to the route outlined in Scheme 4, below. The nitrile H
may be synthesized from dibromobutene and an appropriate aryl
acetonitrile and can be converted to the racemic cis and trans
hydroxylamines I and J via reduction of the nitrile and
hydroboration of the alkene with BH.sub.3/H.sub.2O.sub.2, NaOH.
Alternatively, reduction of H to the aldehyde K, followed by
reductive amination affords the ene-amine L. The double bond of L
may be used to introduce a substitutent (X) into the 5-membered
ring structure. ##STR19##
4. Synthesis of Secondary and Tertiary Amines
[0109] The synthesis of secondary amines from primary amines can,
for example, be accomplished using the method described by De Luca
et al., Synlett 2004, 2570, which is incorporated herein by
reference. The method is outlined in Scheme 5, below. The primary
amine is converted to the N-formylated intermediate M, which may be
reduced to the corresponding methyl amine. Typically, N-formylation
followed by borane reduction led to clean mono-methylated products.
##STR20##
[0110] Dialkylamine analogs of the invention can be synthesized
according to Scheme 6 below. In this method, a secondary amine is
reacted with formaldehyde and concentrated formic acid to form a
methylated tertiary amine. ##STR21##
[0111] In an exemplary embodiment, reaction of a methyl amine
analog (R.sup.3=Me) with a 1:1 mixture of concentrated formic acid
and 37% aqueous formaldehyde at 100.degree. C. for 1 h, typically
gives the dimethyl amine in good yield.
[0112] Another method useful for the synthesis of N,N-dimethyl and
N-methyl amines is shown in Scheme 7, below. Treatment of a primary
amine with diisopropylethylamine (DIEA) and methyl iodide (e.g., in
CH.sub.2Cl.sub.2) leads to the formation of both the N-methyl amine
and the N,N-dimethyl amine, which can be separated
chromatographically. Selectivity for either the mono- or
dimethylated product can be controlled by altering the ratio of
methyl iodide to the amine as well as the reaction time. For
example, mono-methylated analogs may be obtained selectively by
keeping the concentration of methyl iodide low and reaction times
short. ##STR22##
5. Synthesis of 2-Substituted Cycloalkylamines
[0113] In an exemplary embodiment, cycloalkylamines of the
invention are substituted at the 2-position. Such compounds may be
synthesized according to Scheme 8, below. ##STR23##
[0114] The method, outlined above for an exemplary 3,4-diphenyl
cyclohexylamine of the invention, is applicable to the synthesis of
2-substituted cycloalkylamines. Reaction of ethyl
2-oxocyclohexanecarboxylate N with an aryl-lead triacetate (e.g.,
3,4-dichlorophenyllead triacetate) affords the ethyl
1-aryl)-2-oxocyclohexanecarboxylate O. NaBH.sub.4 mediated
reduction of the keto-ester yields the alcohol P, which is
subsequently saponified to afford the acid Q as a mixture of
diastereomers. Amide coupling and reduction of the resulting amide
group affords the amine S. Chiral HPLC can be used to separate
enantiomers/diastereomers. The hydroxyl group of S may be
functionalized (e.g., alkylation) or replaced by another
substitutent (X), such as a halogen atom (e.g., Cl or F) to yield
compound T. Alternatively the hydroxyl group may be converted to a
leaving group, which can subsequently be replaced with a selected
nucleophile.
[0115] Corresponding dialkylamines of S or another hydroxyamine can
be prepared from the corresponding primary amine or mono-alkylated
analog (R.sup.4.dbd.H) when using an appropriate base, such as
DIEA. For example, synthesis of the N,N-dimethyl amino-alcohols is
prepared via alkylation of the N-methyl amines with methyl iodide
and DIEA in acetone, as shown in Scheme 9, below. ##STR24##
[0116] In another exemplary embodiment, the invention provides
compounds, which include a substituted alkyl-substitutent within in
the cycloalkyl ring structure. For example, hydroxymethyl analogs
may be synthesized according to Scheme 10 below. The hydroxyl group
may optionally be replaced with another substitutent, such as a
halogen atom. ##STR25##
[0117] Referring to Scheme 10, the cycloalkyl lactone U is
converted to the aryl derivative V. The lactone is then reacted
with a lithium salt of a selected amine (e.g., dimethylamine) to
give the amido-alcohol W, which is subsequently reduced to the
amine. For certain amides W (e.g., dichlorophenyl analogs) it may
be preferable to use LAH as the reducing agent instead of
borane.
6. Synthesis of 3-Substituted Cycloalkylamines
[0118] In another exemplary embodiment, the compounds of the
invention are substituted at the 3-position of the cycloalkyl ring.
Exemplary synthetic approaches for the preparation of such
compounds are outlined below. Referring to Scheme 11, treatment of
ketone X with an aryl Grignard reagent, followed by acidic
hydrolysis and Michael addition of the cyanide (e.g., following the
procedure described by Callis et al., J. Org. Chem. 1996, 61, 4634)
gives the cyano-ketone Y. Addition of an alkyl lithium reagent to
the carbonyl group affords the alcohol Z. In one example, this
addition is stereoselective and racemic cis Z is formed
selectively. The cyano group of the alcohol Z can be reduced with a
reducing agent, such as borane, and the resulting amine can be
N--BOC protected to give the racemic alcohol AA. Chiral
chromatography followed by removal of the BOC group (e.g., by TFA)
gives the enantiomeric cis amino-alcohols BB and CC. The amines can
then be converted to the corresponding alkyl amines (e.g., N-Me and
NMe.sub.2 derivatives) as described herein, above. ##STR26##
[0119] Alternatively, the ketone Y can be treated with sodium
borohydride to afford DD as a mixture of cis- and
trans-diastereomers (Scheme 12). In an exemplary embodiment, in
which Ar is 3,4-dichlorophenyl, the cis-diastereomer of DD was
formed primarily. Reduction of the nitrile and BOC protection of
the resulting amino group affords the amine EE. The stereoisomers
may be separated by chiral chromatography to give two pairs of
enantiomers derived from cis EE and trans EE. ##STR27##
[0120] In addition, the hydroxyl group of any of the above analogs
(e.g., compound DD) can be functionalized or replaced to generate
further 3-substituted cyclohexyl amine analogs. For example,
alkylation of the hydroxyl group of DD with methyl iodide gave the
methoxy nitrile FF as described in Scheme 13, below. Stereoisomers
of FF may be isolated through chiral chromatography. The nitrile is
further processed to generate an amine. For example, the nitrile
group is reduced (e.g., borane reduction) to afford the
corresponding amine, which may then be converted to the
corresponding alkylamine (e.g., methylamine or dimethylamine) as
described above. ##STR28##
[0121] In another exemplary embodiment, 3,3-difunctionalized
cycloalkylamine derivatives are synthesized from the ketonitrile Y
according to the procedure outlined in Scheme 14, below. For
example, the 3,3-difluoro-cyclohexylamine GG is synthesized by
treatment of the ketonitrile Y with diethylaminosulfur trifluoride
(DAST), followed by reduction of the nitrile group. Treatment of GG
with methyl iodide and Hunig's base leads to a separable mixture of
the corresponding N-methyl amine HH and N,N-dimethyl amine II. The
enantiomers of both HH and II can be resolved by chiral
chromatography. ##STR29##
7. Synthesis of 4-Substituted Cycloalkylamines
[0122] The invention further provides cycloalkylamines, in which
the 4-position of the cycloalkyl ring is derivatized. An exemplary
method for the synthesis of 4-substituted cycloalkyl amines was
adapted from a procedure described in WO 03/063797, which is
incorporated herein by reference in its entirety for all purposes.
The method is outlined in Scheme 15, below. ##STR30##
[0123] Referring to Scheme 15, above, the acetonitrile JJ is
condensed with methyl acrylate to give the di-ester KK, which is
cyclized via Dieckmann condensation to give the cyclic hydroxy
ester LL. Conversion of LL to the key intermediate MM can, for
example, be affected by heating the compound in the microwave to
about 160.degree. C. Addition of an alkyl nucleophile (such as MeLi
or EtLi) gives a mixture of the hydroxynitriles cis NN and trans
NN, which may be separated by silica gel column chromatography. In
an exemplary embodiment, in which Ar=3,4-dichlorophenyl and in
which propylmagnesium chloride is used as the nucleophile, only the
cis analog NN was obtained. Reduction of the nitrile group (e.g.,
borane) affords the corresponding amines cis OO and trans OO.
Subsequent alkylation of the amines as described herein give
corresponding alkyl amines, such as methyl- and dimethyl
amines.
[0124] Alternatively, the intermediate nitrile alcohol NN can be
reacted with an alkyl lithium reagent (such as MeLi/NaBH.sub.4) to
add an R.sup.1 group (e.g., a methyl group) before further
processing as shown in Scheme 16, below, to afford the racemic
amine PP. The enantiomers of PP can be separated by chiral
chromatography. ##STR31##
[0125] In another exemplary embodiment, the ketonitrile MM is
converted to chiral 4-hydroxy cyclohexylamines as shown in Scheme
17, below. Reduction of the carbonyl group (e.g., NaBH.sub.4),
followed by reduction of the nitrile group (e.g., borane) affords
the primary amine QQ, which typically has cis configuration.
Alternatively, the keto group of the ketonitrile MM is reduced
(e.g., NaBH.sub.4) and the stereocenter carrying the resulting
hydroxyl group is inverted under Mitsonobu conditions to afford the
hydroxynitrile RR, which is further processed to the corresponding
primary amine SS or to the respective alkyl amine as described
herein, above. ##STR32##
[0126] In an exemplary embodiment, the hydroxyl group of the
intermediate hydroxynitrile RR is replaced or functionalized before
further processing to the amine. For example, synthesis of
O-alkylated or O-arylated species is accomplished through
alkylation of the hydroxynitrile as shown in Scheme 18, below.
Alkylation with methyl iodide followed by borane reduction of the
nitrile provides the primary amine TT. A Mitsonobu protocol
utilizing an alcohol, such as phenol, followed by borane reduction
can be used to convert RR to the trans-analog UU, with inverted
stereochemistry at the 4-position. ##STR33##
[0127] In another exemplary embodiment, the intermediate hydroxyl
nitrile RR can be monofluorinated, for example, with morpholino
sulfurtrifluoride or DAST to give the 4-fluoro species W, which may
be obtained along with the elimination product WW (Scheme 19),
which can be separated chromatographically. Both, the 4-fluoro
nitrile VV and the alkene WW can be converted to the corresponding
primary amines or alkyl amine species as described herein, above.
The double bond can optionally be used to introduce a substitutent
in to the cycloalkyl ring (e.g., by hydroboration). ##STR34##
[0128] In yet another exemplary embodiment, the ketonitrile MM is
converted to a 4,4-disubstituted cycloalkylamine. For example,
synthesis of the 4,4-difluoro amine XX could be affected via the
action of morpholino sulfurtrifluoride or diethylamino trifluoride
(DAST), followed by reduction of the nitrile group (e.g., by
borane) as outlined in Scheme 19, below. The resulting primary
amine may be converted to the corresponding alkyl amines as
described herein. ##STR35##
[0129] The 4-position of the present cycloalkylamines can also be
derivatized via the formation of an intermediate epoxide, as shown
in Scheme 21, below. For example, epoxidation of the ketonitrile MM
using trimethylsulfonium iodide/KO.sup.tBu affords diastereomeric
epoxides, which may be separated by column chromatography. The
epoxide ring can be opened in a regioselective reaction with an
appropriate nucleophile, such as TBAF/HF to give the corresponding
hydroxyl derivative and subsequent reduction of the nitrile group
affords the primary amine, such as the fluoromethyl analog YY. The
primary amine is optionally converted to corresponding alkylamine
species as described herein. ##STR36##
[0130] In another embodiment, the invention provides
cycloalkylamines with an additional amino group substitutent in the
cycloalkyl ring structure. In one example, the amine substitutent
is located at the 4-position of the cycloalkyl ring. For instance,
the ketonitrile MM can be converted to a 4-amino-cyclohexylamine
using the exemplary synthetic conversions outlined in Scheme 22,
below. Protection of the keto group of MM (e.g., through formation
of a dioxolane), reduction of the nitrile group (e.g., with
borane), alkylation of the primary amine (e.g., methylation with
methyl iodide) and deprotection of the ketone functionality affords
the analog ZZ. Reductive amination of the keto group (e.g., using
methyl amine and sodium cyanoborohydride) affords a mixture of
diastereomers, which may be separated by preparative HPLC to give
the corresponding analogs cis- and trans AAA. ##STR37##
8. Introduction of R.sup.1 and/or R.sup.2
[0131] The invention further provides cycloalkylamines, in which
the amine-bearing side chain is substituted with substitutents
R.sup.1 and R.sup.2. In an exemplary embodiment, R.sup.1 is a short
alkyl group, such as C.sub.1- to C.sub.4-alkyl. Introduction of a
R.sup.1 group can, for example, be accomplished using the synthetic
procedure outlined in Scheme 23, below. ##STR38##
[0132] For example, addition of an alkyl lithium reagent to the
aryl nitrile C, followed by reduction of the resulting imine
affords the racemic primary amines BBB. The corresponding
enantiomeric primary amines may be obtained by chiral HPLC
chromatography.
9. Synthesis of Cycloalkylamines, in which R.sup.1 and R.sup.3 are
Joined in a Ring
[0133] The invention further provides cycloalkylamines, in which
the amine nitrogen is part of a ring. In an exemplary embodiment,
R.sup.1 and R.sup.3, together with the atoms to which they are
attached, are joined to form a 3- to 7-membered ring, such as a
substituted or unsubstituted pyrrolidine or piperidine ring. An
exemplary synthetic method for the preparation of pyrrolidine
analogs according to this embodiment is outlined in Scheme 24,
below. ##STR39##
[0134] For example, addition of an acetal Grignard reagent to an
aryl (e.g. 3,4-dichlorophenyl or 2-naphthyl) (R)-sulfinamine leads
to the corresponding sulfinamide CCC as mixtures of diastereomers.
Subsequent hydrolysis (e.g., 6M HCl in acetone) can be used to
remove both, the sulfinamine auxiliary and ketal side chain.
Intramolecular reductive amination (e.g., using polymer bound
sodium cyanoborohydride) affords the racemic pyrollidine DDD.
D. Pharmaceutical Compositions
[0135] In a second aspect, the invention provides a pharmaceutical
composition including a compound of the invention (e.g., a compound
of Formulae (I) to (IV)) or a pharmaceutically acceptable salt or
solvate thereof, and at least one pharmaceutically acceptable
carrier.
[0136] As described in detail below, the pharmaceutical
compositions of the present invention may be specially formulated
for administration in solid or liquid form, including those adapted
for oral administration, e.g., tablets, drenches (aqueous or
non-aqueous solutions or suspensions), parenteral administration
(including intravenous and intramuscular), or epidural injection
as, for example, a sterile solution or suspension, or sustained
release formulation. The pharmaceutical compositions of the present
invention may also be specifically formulated for administration
transdermally.
[0137] The pharmaceutical compositions of the invention may be
administered orally, parenterally, subcutaneously, transdermally,
nasally, or by anal suppository. The pharmaceutical compositions of
the invention may also be administered using controlled delivery
devices.
[0138] Formulations of the present invention include those suitable
for oral and parenteral administration, particularly intramuscular,
intravenous and subcutaneous administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will vary depending upon the host
being treated and the particular mode of administration. The amount
of active ingredient which can be combined with a carrier material
to produce a single dosage form will generally be that amount of
the compound which produces a therapeutic effect, without being
toxic to the patient. Generally, out of one hundred percent, this
amount will range from about 1 percent to about ninety-nine percent
of active ingredient.
[0139] In certain embodiments, a formulation of the present
invention comprises an excipient selected from the group consisting
of cyclodextrins, liposomes, micelle forming agents, e.g., bile
acids, and polymeric carriers, e.g., polyesters and polyanhydrides;
and a compound of the present invention. In certain embodiments, an
aforementioned formulation renders orally bioavailable a compound
of the present invention.
[0140] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0141] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, caplets, lozenges (using a flavored basis, usually sucrose
and acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia), each containing a predetermined
amount of a compound of the present invention as an active
ingredient. A compound of the present invention may also be
administered as a bolus, electuary or paste.
[0142] In solid dosage forms of the invention for oral
administration (capsules, tablets, caplets, pills, dragees,
powders, granules and the like), the active ingredient is mixed
with one or more pharmaceutically acceptable carriers, such as
sodium citrate or dicalcium phosphate, and/or any of the following:
(1) fillers or extenders, such as starches, lactose, sucrose,
glucose, mannitol, and/or silicic acid; (2) binders, such as, for
example, carboxymethylcellulose, alginates, gelatin, polyvinyl
pyrrolidone, sucrose and/or acacia; (3) humectants, such as
glycerol; (4) disintegrating agents, such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; (5) solution retarding agents,
such as paraffin; (6) absorption accelerators, such as quaternary
ammonium compounds; (7) wetting agents, such as, for example, cetyl
alcohol, glycerol monostearate, and non-ionic surfactants; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
a talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof; and (10)
coloring agents. In the case of capsules, tablets and pills, the
pharmaceutical compositions may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-shelled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0143] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0144] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be formulated for rapid release, e.g.,
freeze-dried. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0145] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0146] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0147] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0148] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
sugars, alcohols, antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0149] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0150] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms upon the subject
compounds may be ensured by the inclusion of various antibacterial
and antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In addition, prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0151] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0152] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue. Pharmaceutical compositions or unit
dosage forms of the present invention in the form of
prolonged-action tablets may comprise compressed tablets formulated
to release the drug substance in a manner to provide medication
over a period of time. There are a number of tablet types that
include delayed-action tablets in which the release of the drug
substance is prevented for an interval of time after administration
or until certain physiological conditions exist. Repeat action
tablets may be formed that periodically release a complete dose of
the drug substance to the gastrointestinal fluids. Also, extended
release tablets that continuously release increments of the
contained drug substance to the gastrointestinal fluids may be
formed.
[0153] Compounds of the invention can be also administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the compounds of this invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0154] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0155] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release other amounts of drug to maintain this level of
therapeutic or prophylactic effect over an extended period of time.
In order to maintain this constant level of drug in the body, the
drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0156] Compounds of the present invention may also be formulated as
transdermal, topical, and mucosal dosage forms, which forms
include, but are not limited to, ophthalmic solutions, sprays,
aerosols, creams, lotions, ointments, gels, solutions, emulsions,
suspensions, or other forms known to one of skill in the art. See,
e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia (1985). Transdermal dosage forms include "reservoir
type" or "matrix type" patches, which can be applied to the skin
and worn for a specific period of time to permit the penetration of
a desired amount of active ingredients.
[0157] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied.
[0158] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue.
[0159] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
[0160] When the compounds of the present invention are administered
as pharmaceuticals, to humans and animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99.5% of active ingredient in combination with a pharmaceutically
acceptable carrier.
[0161] The preparations of the present invention may be given
orally and parenterally. They are of course given in forms suitable
for each administration route. For example, they are administered
in tablets or capsule form, by injection, and by intravenous
administration. In one embodiment, oral administrations are
preferred.
[0162] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticulare, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0163] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion or metabolism of the particular compound being
employed, the duration of the treatment, other drugs, compounds
and/or materials used in combination with the particular compound
employed, the age, sex, weight, condition, general health and prior
medical history of the patient being treated, and like factors well
known in the medical arts.
[0164] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0165] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, intravenous, intracerebroventricular and subcutaneous
doses of the compounds of this invention for a patient will range
from about 0.005 mg per kilogram to about 5 mg per kilogram of body
weight per day.
[0166] The terms "treatment" or "treating" is intended to encompass
therapy, preventing (prophylaxis), preventing relapse, and
amelioration of acute symptoms. Note that "treating" refers to
either or both of the amelioration of symptoms and the resolution
of the underlying condition. In many of the conditions of the
invention, the administration of a compound or composition of the
invention may act not directly on the disease state, but rather on
some pernicious symptom, and the improvement of that symptom leads
to a general and desirable amelioration of the disease state
[0167] The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals such as
equines, cattle, swine and sheep, as well as poultry and pets in
general.
[0168] The compounds and pharmaceutical compositions of the
invention can be administered in conjunction with other
pharmaceutical agents, for instance antimicrobial agents, such as
penicillins, cephalosporins, aminoglycosides and glycopeptides.
Conjunctive therapy thus includes sequential, simultaneous and
separate administration of the active compound in a way that the
therapeutic effects of the first administered agent have not
entirely disappeared when the subsequent agent is administered.
IV. Methods
A. Binding To Monoamine Transporter
[0169] In another aspect the invention provides a method of binding
a compound of the invention to a monoamine transporter. The method
includes contacting the monoamine transporter and a compound of the
invention.
[0170] In yet another aspect, the invention provides a method of
inhibiting binding of a monoamine transporter ligand to a monoamine
transporter (such as serotonin transporter, dopamine transporter
and norepinephrine transporter). The method includes contacting the
monoamine transporter and a compound of the invention. In an
exemplary embodiment the monoamine transporter ligand is an
endogenous monoamine, such as serotonin, dopamine or
norepinephrine. In another exemplary embodiment, the ligand is a
drug molecule or another small molecule known to have binding
affinity to a monoamine transporter. In another exemplary
embodiment, the monoamine transporter ligand is a radioactively
labeled compound, known to bind to the monoamine transporter.
[0171] In an exemplary embodiment, inhibition of ligand binding is
shown using an ex vivo binding assay, such as those described
herein, below in Example 7. In an exemplary embodiment, the
compound of the invention inhibits mean binding by between about 1%
and about 100%, preferably by between about 10% and about 100%,
more preferably by between about 20% and about 90% when compared to
vehicle. Inhibition of mean binding is preferably dose
dependent.
B. Inhibition of Monoamine Transporter Activity
[0172] In yet another aspect, the invention provides a method of
modulating (e.g., inhibiting, augmenting) the activity of at least
one monoamine transporter, such as serotonin transporter, dopamine
transporter and norepinephrine transporter. The method includes
contacting the monoamine transporter and a compound of the
invention. In an exemplary embodiment, the monoamine transporter is
contacted with a compound of the invention by administering to a
subject a therapeutically effective amount of the compound of the
invention, e.g., a compound according to Formulae (I) to (V), or a
pharmaceutically acceptable salt or solvate thereof. In a preferred
embodiment, the subject is a human. In another exemplary
embodiment, the monoamine transporter is dopamine transporter
(DAT), serotonin transporter (SERT) or norepinephrine transporter
(NET). In another exemplary embodiment, the compound of the
invention inhibits the activity of at least two different monoamine
transporters. Inhibition of monoamine transporter activity may be
measured using assays known in the art. Exemplary assay formats
include in vitro functional uptake assays (Example 6). In an
exemplary embodiment, the functional uptake assay utilizes an
appropriate cell-line expressing a desired monoamine transporter.
In another exemplary embodiment, the functional uptake assay
utilizes synaptosomes isolated from brain tissue of an appropriate
organism. Alternatively, inhibition of monoamine transporter
activity may be assessed using receptor binding experiments known
in the art, e.g., utilizing appropriate membrane preparations.
Another assay involves treatment of a test subject (e.g., a rat)
with a compound of the invention as well as a reference compound,
followed by isolation of brain tissue and ex vivo analysis of
receptor occupancy, as described herein.
C. Inhibition of Monoamine Uptake
[0173] In yet another aspect, the invention provides a method of
inhibiting uptake of at least one monoamine (e.g., dopamine,
serotonin, norepinephrine) by a cell. The method includes
contacting the cell with a compound of the invention. In an
exemplary embodiment, the cell is a brain cell, such as a neuron or
a glial cell. In one example, inhibition of monoamine uptake occurs
in vivo. In an organism, neuronal uptake (also termed reuptake) of
a monoamine such as dopamine or serotonin occurs, for example, from
the synaptic cleft. Thus, in one embodiment, the neuronal cell is
in contact with a synaptic cleft of a mammal. In another exemplary
embodiment, inhibition of monoamine uptake occurs in vitro. In
those methods the cell, may be a brain cell, such as a neuronal
cell or a cell-type, which expresses a recombinant monoamine
transporter.
[0174] In one embodiment, the compound inhibits uptake of at least
two different monoamines. This can, for example, be shown by
performing various in vitro functional uptake assays utilizing a
cell-type, which simultaneously expresses multiple different
monoamine transporters (such as isolated synaptosomes), or may be
shown by using two different cell types, each expressing a
different monoamine transporter, such as a recombinant dopamine
transporter, together with an appropriate, labelled monoamine
(Example 6). Inhibition of monoamine uptake is demonstrated when
the inhibitor (e.g., a compound of the invention) has an IC.sub.50
of between about 0.1 nM and about 10 .mu.M, preferably between
about 1 nM and about 1 .mu.M, more preferably between about 1 nM
and about 500 nM, and even more preferably between about 1 nM and
about 100 mM in a functional monoamine uptake assay, such as those
described herein below.
D. Treatment of CNS Disorders
[0175] In another aspect, the invention provides a method of
treating depression by inhibiting the activity at least one
monoamine transporter. The method includes administering to a
mammalian subject a compound of the invention. In an exemplary
embodiment, the mammalian subject is a human. In another exemplary
embodiment, the compound of the invention inhibits the activity of
at least two different monoamine transporters. For example, the
compound of the invention inhibits the activity of at least two of
serotonin transporter, dopamine transporter and norepinephrine
transporter. Inhibition of monoamine transporter activity may be
shown by functional monoamine uptake assays as described herein
below (Example 6). Demonstration of anti-depressant activity of a
compound of the invention may be shown by utilizing an appropriate
animal model of depression, such as the Rat Forced Swim Test, the
Mouse Tail Suspension Test and Rat Locomotor Activity Analyses
(Example 8). The Rat Forced Swim Test is also suitable for the
analysis of compounds having activities against more than one
monoamine transporter (mixed monoamine transporter activity). For
example, an increase in swimming activity is indicative of
serotonin reuptake inhibition, while an increase in climbing
activity is indicative of norepinephrine reuptake inhibition. In a
preferred embodiment, the compounds of the invention are active in
at least one animal model, which can be used to measure
anti-depressant-like activities, for instance those assessing
immobility. In an exemplary embodiment, the compounds of the
invention are active when they inhibit mean immobility by between
about 5% and about 90%, preferably between about 10% and about 70%
and more preferably between about 10% and about 50% in at least one
animal model, when compared to vehicle.
[0176] In yet another aspect, the invention provides a method of
effecting an anti-depressant-like effect. The method includes
administering to a mammalian subject in need thereof a
therapeutically effective amount of a compound or composition of
the invention, e.g., a compound according to Formulae (I) to (IV),
or a pharmaceutically acceptable salt or solvate thereof.
Anti-depressant-like effects may be measured using an animal model
of disease, such as those described herein.
[0177] In a further aspect, the invention provides a method of
treating a central nervous system disorder. The method includes
administering to a subject in need thereof a therapeutically
effective amount of a composition or compound of the invention,
e.g., a compound according to Formulae (I) to (IV), or a
pharmaceutically acceptable salt or solvate thereof. In a preferred
embodiment, the subject is a human.
[0178] In another exemplary embodiment, the central nervous system
disorder is a member selected from the group consisting of
depression (e.g., major depressive disorder, bipolar disorder,
unipolar disorder, dysthymia and seasonal affective disorder),
cognitive deficits, fibromyalgia, pain (e.g., neuropathic pain),
sleep related disorders (e.g., sleep apnea, insomnia, narcolepsy,
cataplexy) including those sleep disorders, which are produced by
psychiatric conditions, chronic fatigue syndrome, attention deficit
disorder (ADD), attention deficit hyperactivity disorder (ADHD),
restless leg syndrome, schizophrenia, anxieties (e.g. general
anxiety disorder, social anxiety disorder, panic disorder),
obsessive compulsive disorder, posttraumatic stress disorder,
seasonal affective disorder (SAD), premenstrual dysphoria,
post-menopausal vasomotor symptoms (e.g., hot flashes, night
sweats), and neurodegenerative disease (e.g., Parkinson's disease,
Alzheimer's disease and amyotrophic lateral sclerosis), manic
conditions, dysthymic disorder, and cyclothymic disorder. In a
preferred embodiment, the CNS disorder is depression, such as major
depressive disorder. In an exemplary embodiment, the compounds of
the invention are useful to treat two conditions/disorders, which
are comorbid, such as cognitive deficit and depression.
[0179] Central nervous system disorder includes cerebral function
disorders, including without limitation, senile dementia,
Alzheimer's type dementia, cognition, memory loss, amnesia/amnestic
syndrome, epilepsy, disturbances of consciousness, coma, lowering
of attention, speech disorders, Lennox syndrome, autism, and
hyperkinetic syndrome.
[0180] Neuropathic pain includes without limitation post herpetic
(or post-shingles) neuralgia, reflex sympathetic
dystrophy/causalgia or nerve trauma, phantom limb pain, carpal
tunnel syndrome, and peripheral neuropathy (such as diabetic
neuropathy or neuropathy arising from chronic alcohol use).
[0181] Other exemplary diseases and conditions that may be treated
using the methods of the invention include obesity; migraine or
migraine headache; urinary incontinence, including without
limitation involuntary voiding of urine, dribbling or leakage of
urine, stress urinary incontinence (SUI), urge incontinence,
urinary exertional incontinence, reflex incontinence, passive
incontinence, and overflow incontinence; as well as sexual
dysfunction, in men or women, including without limitation sexual
dysfunction caused by psychological and/or physiological factors,
erectile dysfunction, premature ejaculation, vaginal dryness, lack
of sexual excitement, inability to obtain orgasm, and psycho-sexual
dysfunction, including without limitation, inhibited sexual desire,
inhibited sexual excitement, inhibited female orgasm, inhibited
male orgasm, functional dyspareunia, functional vaginismus, and
atypical psychosexual dysfunction.
EXAMPLES
1. General Procedures
[0182] In the examples, below, the following general experimental
procedures were used unless otherwise noted: All commercial
reagents were used without further purification. Anhydrous
reactions were performed in flame-dried glassware under N.sub.2.
NMR spectra were recorded on a Varian 400 MHz spectrometer in
deuterochloroform or methanol-d.sup.4 with trimethylsilane (TMS) as
an internal reference. Silica gel column chromatography was
performed using an ISCO Combiflash system with detection at 254 nm
or using ISCO normal phase silica gel cartridges.
Analytical HPLC
[0183] Analytical HPLC was performed on a Hewlett Packard Series
1100 pump connected to an Agilent Zorbax RX-C18 5 .mu.m,
4.6.times.250 mm column, with detection on a Hewlett Packard Series
1100 UV/Vis detector monitoring at 214 and 254 nm. Typical flow
rate=1 ml/min. Three different HPLC columns and various elution
protocols were used. For example, (1) Agilent Zorbax RX-C18 5
.mu.m, 4.6.times.250 mm column running a linear gradient. Solvent
A=H.sub.2O w/0.05% TFA, Solvent B=MeCN w/0.05% TFA. Time 0 min=5%
Solvent B, time 4 min=40% Solvent B, time 8 min=100% Solvent B, 12
min=5% Solvent B, 20 min=5% Solvent B; (2) Phenomenex 3.mu. C18
column running a 3 minute gradient of 5.fwdarw.100% B
(acetonitrile/0.1% formic acid) and solvent A (water/0.1% formic
acid); (3) Phenomenex 5.mu. C18 column running a 5 minute gradient
of 5.fwdarw.100% B where solvent B (acetonitrile/0.1% formic acid)
and solvent A (water/0.1% formic acid).
Reverse Phase HPLC Purification
[0184] Reverse phase HPLC purification was performed on a Gilson
system using a Phenomenex 5.mu. C18 (50.times.21.2 mm) column. The
standard separation method was: 10 minute gradient of
10.fwdarw.100% B (acetonitrile/0.1% formic acid) in solvent A
(water/0.1% formic acid). Crude samples were typically dissolved in
MeOH. Fractions were concentrated by Genovac (centrifugation at low
pressure).
GC-MS
[0185] Gas chromatography was performed on a Hewlett Packard 6890
Series GC System with an HP1 column (30 meters, 0.15.mu. film
thickness) coupled to a Hewlett Packard 5973 Series Mass Selective
Detector. The following linear temperature gradient was used:
100.degree. c. for 5 minutes, then 20.degree. C./min to 320.degree.
C. Hold @320.degree. C. for 10 minutes.
LCMS
[0186] LCMS was performed on an Agilent 1100 Series system
connected to a Micromass Platform LC. The following column and
gradient was used: Column: Luna C18(2), 3 um particle size
30.times.2.0 mm column dimension. Flow rate=0.5 mL/min, Solvent
A=0.1 M N.sub.4Ac in 95% H.sub.2O, 5% MeOH, pH 6.0, Solvent
B=Solvent B: 0.1 M N.sub.4Ac in MeOH. Linear gradient with 6
entries: Time 0 min=100% Solvent A, time 10 min=100% Solvent B,
time 12 min=100% Solvent B, time 12 min 10 sec=100% Solvent A, time
14 min=100% Solvent A, time 14 min 20 sec=100% Solvent A.
Microwave (.mu.W) Recrystallization
[0187] The crude salt (e.g., HCl salt) was loaded into a microwave
vessel with a stir bar. The recrystallization solvent was added and
the vessel was heated at the target temperature for a given time.
The vessel was cooled to 50.degree. C. in the reactor, was then
removed and allowed to slowly cool to RT. N,N-dimethyl amines were
typically recrystallized in EtOAc or EtOAc:CH.sub.3CN (2:1). N-Me
or primary amines were typically recrystallized in CH.sub.3CN.
Formylation-Reduction 1 (General Procedure A)
[0188] The amine free base was dissolved in CH.sub.2Cl.sub.2 at
approximately 0.4 M and concentrated formic acid (1.0 eq relative
to the amine), 1-chloro-3,5-dimethoxytriazine (1.1 eq), DMAP (0.03
eq) and N-methylmorpholine (1.1 eq) were added in this order. The
solution was heated in the .mu.W (60.degree. C., 10 min.) and
cooled to RT. The reaction was monitored by HPLC. When the starting
material was consumed, the crude reaction mixture was diluted with
CH.sub.2Cl.sub.2 (15 mL) and washed with aqueous HCl (twice),
saturated aqueous K.sub.2CO.sub.3 and brine. The crude product was
dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
N-formyl amide was dissolved in anhydrous THF at approximately 0.2
M and borane-THF (e.g., 1.0 M in THF, 3 eq) was added dropwise. The
clear solution was heated via .mu.W (150.degree. c., 30 min, FHT),
cooled to RT and quenched with 6M HCl (e.g., 10 mL). The solution
washed twice with Et.sub.2O (e.g., 20 mL). The aqueous phase was
adjusted to pH 12 with 3M NaOH and was then washed three times with
EtOAc (e.g., 20 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated.
Formylation-Reduction 2 (General Procedure B)
[0189] To acetic anhydride (1 eq relative to the amine) under
nitrogen at 0.degree. C. was added formic acid (3 eq) dropwise over
3 min. After stirring the reaction mixture for 1 h, a 0.1 M
solution of the amine (1 eq) in THF was added dropwise over 5 min.
The mixture was allowed to slowly warm, stirring at room
temperature for 3 d. The volatiles were removed in vacuo and the
residue was purified over silica gel. To a solution of the
formamide (1 eq) in THF (10 mL) under nitrogen was added
BH.sub.3.S(CH.sub.3).sub.2 (2 M in THF, 2 eq) dropwise over 5 min.
The mixture was stirred at room temperature for 20 hours. MeOH, and
2 N aqueous HCl were added and the mixture washed with diethyl
ether (50 mL). The pH was adjusted to 14 by addition of 2 N NaOH
and the mixture was extracted with diethyl ether (50 mL). The
combined organic phases were dried (sodium sulfate), filtered, and
concentrated. The crude N-methyl amine was purified by either
Gilson RP-HPLC or by transformation to the HCl salt and
recrystallization in the indicated solvent.
HCl Salt Formation
[0190] The crude amine was dissolved in Et.sub.2O (e.g., 3 mL) and
HCl (e.g., 3-5 mL, 2.0 M in Et.sub.2O). The solution was stirred
for 1 h and evaporated twice from CH.sub.2Cl.sub.2 (e.g., 20 mL).
The crude HCl salt was recrystallized in the indicated solvent,
filtered and dried in vacuo.
Eschweiler-Clarke N,N-Dimethylation (General Procedure C)
[0191] The amine free base (up to 100 mg) was suspended in 37%
aqueous formaldehyde (3 mL) and concentrated formic acid (3 mL) was
added. The yellowish solution was heated at 100.degree. c. for 1 h
and cooled to RT. The clear solution was poured into saturated
aqueous K.sub.2CO.sub.3 (20 mL) and washed with EtOAc (3.times.20
mL). The organic washes were combined, washed with brine
(1.times.10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude amine was dissolved in Et.sub.2O (3 mL) and
HCl (3-5 mL, 2.0 M in Et.sub.2O) was added. The solution was
stirred for 1 h and concentrated with CH.sub.2Cl.sub.2 (2.times.20
mL). The crude HCl salt was recrystallized in the indicated
solvent, filtered and dried in vacuo. Alternatively, the
dimethylamine could be purified on the reverse-phase HPLC system if
recrystallization was not unsuccessful.
Methylation Via Reductive Amination with Formaldehyde and
NaB(CN)H.sub.3 (General Procedure D)
[0192] To a stirred solution of the amine (approximately 0.05 M, 1
eq), 37% formaldehyde (10 eq), and acetic acid (1 drop) in
CH.sub.2Cl.sub.2 at room temperature was added NaBH(OAc).sub.3 (4
eq). The reaction mixture was stirred for 3 days. Saturated
NaHCO.sub.3 solution was then added and the mixture was extracted
with EtOAc. The combined organic layers were dried (sodium
sulfate), filtered, and concentrated. The crude amine was purified
by either Gilson RP-HPLC or by transformation to the HCl salt and
recrystallization. Borane Reduction of Amide or Nitrile (General
Procedure E) ##STR40##
[0193] To a solution of the nitrile in anhydrous THF (final
concentration: about 0.1M to about 0.2 M) was added dropwise
borane-THF (e.g., 1.0M in THF, 3 eq). The reaction mixture was
heated in the microwave (maximum temperature: 150.degree. C., about
1 min to about 40 min), cooled to room temperature and then
quenched with 6N HCl. The solution washed with EtOAc. The aqueous
phase was adjusted to pH 12 with 3N NaOH and extracted three times
with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated.
[0194] The crude amine was purified by column chromatography and/or
isolated as the HCl salt after precipitation from ether (e.g.,
Et.sub.2O) and HCl (e.g., 2.0 M in Et.sub.2O). The crude HCl salt
was optionally recrystallized from the indicated solvent.
Reduction of Nitrile with LiAlH.sub.4 (General Procedure E1)
[0195] To a 0.05 M solution of the nitrile (1 eq) in diethyl ether
was added LiAlH.sub.4 (5 eq). The reaction mixture was heated at
reflux for 30 min before NaOH solution was slowly added to quench
the reaction. The product was extracted with diethyl ether. The
combined extracts were dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was dissolved in MeOH and purified by
reverse phase HPLC.
JianguoMa Alkylation (General Procedure F)
[0196] The primary amine free base or HCl salt was
dissolved/suspended in anhydrous CH.sub.2Cl.sub.2 (volume to make
amine concentration=0.1 M) and neat anhydrous diisopropylethylamine
(3 eq) and methyl iodide (1-5 equiv. depending on desired outcome)
was added. The clear solution was stirred at RT for 1-5 h and
monitored by HPLC. Longer reaction times favor the formation of the
N,N-dimethyl amines; shorter reaction times favor formation of the
N-methyl amines. The reaction was checked by HPLC and quenched with
MeOH (5 mL) when the desired ratio of N-methyl:N,N-dimethyl amines
was reached. The reaction was concentrated under reduced pressure
and loaded directly onto a Biotage samplet. Purification by silica
gel column chromatography used hexane/0.1% DEA as the non-polar
phase and ethyl acetate as the polar phase. The following gradient
was employed: equilibration with hexane/0.1% DEA, 3 column volumes
(CV), linear 0-50% ethyl acetate over 7 CV, hold at 50% ethyl
acetate for 5.5 CV. Fractions were checked by HPLC and LCMS.
Product fractions eluted around fractions 7-15. Positive fractions
were concentrated and converted into HCl salts.
Amide Coupling (General Procedure G)
[0197] A solution of the respective carboxylic acid (approximately
0.1M, 1 eq), the respective amine (1-2 eq), N-methylmorpholine (1-2
eq) and PyBOP (1-2 eq) in anhydrous DMF was stirred at RT overnight
(The reaction mixture may optionally include DMAP). The reaction
mixture was poured into H.sub.2O (e.g., 20 mL) and washed three
times with Et.sub.2O (e.g., 3.times.20 mL). The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude product was purified by either silica gel column
chromatography, reverse phase HPLC or by transformation to the HCl
salt and recrystallization.
Alkyl Lithium Addition to Nitrile (General Procedure I)
[0198] To a solution of arylcyclohexanecarbonitrile (approximately
0.16 M, e.g., 12.8 g, 49.0 mmol) in anhydrous toluene at 0.degree.
C. was added dropwise a solution of methyllithium (1.6 M, 1.5 eq)
over 10 min. The ice bath was removed and the reaction mixture
stirred for 30 min. Methanol (65 eq) and sodium borohydride (6 eq)
were added portionwise. The mixture was stirred for 45 min and was
then carefully quenched with 6 N HCl. The mixture washed with ethyl
acetate. The pH of the aqueous layer was adjusted to 14 by addition
of 6 N NaOH and was then extracted with ethyl acetate. The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to give the crude racemic primary amine. The crude
amine was purified by either Gilson RP-HPLC or by transformation to
the HCl salt and recrystallization. Cycloalkyl Nitrile Synthesis
(General Procedure J) ##STR41##
[0199] To a 0.1 M suspension of sodium hydride (2.5 eq) in
anhydrous DMSO was added a 0.4 M solution of aryl acetonitrile (1
eq) in anhydrous DMSO dropwise over 35 min. The mixture was stirred
for 30 min and was then added to a 0.24 M solution of
1,5-dibromopentane (1.5 eq) in anhydrous DMSO dropwise over 20 min.
The mixture was stirred overnight at room temperature, poured into
water and extracted with chloroform or CH.sub.2Cl.sub.2. The
organic layers were combined, washed with water, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The resulting
residue was chromatographed on silica gel to give the
arylcyclohexanecarbonitrile.
Alkylation of Alcohol (General Procedure Y)
[0200] To a 0.2 M solution of the alcohol (1 eq) in THF was added
NaH (60% in mineral oil, 1.5 eq). The reaction mixture was stirred
for 20 min before alkyl halide (2 eq) was added. The reaction
mixture was stirred for 4 h and was then quenched with saturated
NH.sub.4Cl solution. The product was extracted with diethyl ether.
The combined organic layers were dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue was purified by silica gel column
chromatography (e.g., ethyl acetate/hexane) to give O-alkylated
product.
Lithio-amine Addition to Lactone (General Procedure AA)
[0201] To a cold solution of alkylamine (5 eq) at -78.degree. C.
was added n-Buli (3 eq) and the reaction mixture was stirred for
five minutes. A 0.3 M solution of the aryl lactone (1 eq) in
anhydrous THF was then added. The mixture was stirred at the low
temperature for one hour and at ambient temperature for an
additional hour. The reaction was then quenched with saturated
ammonium chloride and extracted with MTBE. The combined organic
layers were evaporated and the crude oil purified on silica gel to
give the amide.
Example 1
Synthesis of Cycloalkyl Amines
1.1. Synthesis of Cycloalkyl Nitriles
[0202] The following exemplary cycloalkylcarbonitriles were
prepared from the respective aryl nitriles according to General
Procedure J:
1-(biphenyl-4-yl)cyclohexanecarbonitrile
[0203] HPLC R.sub.t=11.29 min; GC-MS, SCOUT program 13.85 min,
M.sup.+261.
1-(thiophen-2-yl)cyclohexanecarbonitrile
[0204] HPLC R.sub.t=10.24 min; GC-MS, SCOUT program 8.42 min,
M.sup.+191.
1-(naphthalen-1-yl)cyclohexanecarbonitrile
[0205] HPLC R.sub.t=10.82 min; GC-MS 12.6 min, M.sup.+235.
1-(4-(trifluoromethoxy)phenyl)cyclohexanecarbonitrile
[0206] HPLC R.sub.t=10.76 min; GC-MS 8.59 min, M.sup.+269.
1.2. Synthesis of Primary Amines from Cycloalkyl Nitriles
[0207] The primary amines summarized in Table 1, below, were
prepared from the corresponding nitriles according to the indicated
General Procedures. Enantiomeric mixtures of selected primary
amines were separated by chiral chromatography using the indicated
chromatographic methods to give the fast moving enantiomer (E1) and
the slow moving enantiomer (E2), respectively. TABLE-US-00001 TABLE
1 ##STR42## Summary of Exemplary Primary Amines General Ar n
R.sup.1 Procedure (1-(3,4-dichlorophenyl)cyclobutyl)methanamine (1)
##STR43## 1 H E HPLC R.sub.t = 8.16 min; .sup.1H NMR(400 mHz,
MeOH-d.sup.4) 7.48(d, J=8.31Hz, 1H), 7.37(m, 1H), 7.14-7.10(m, 1H),
3.23(m, 2H), 2.44-2.34(m, 2H), 2.29-2.20(m,2H), 2.14-2.05(m, 1H),
1.93-1.86(m, 1H); LC-MS 6.91 min, (M + 1).sup.+ 230 @ 7.27 min.
(.+-.) 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanamine (2) ##STR44##
3 CH.sub.3 I Chiral HPLC (AD column; 98:2:0.1
hexanes:isopropanol:diethylamine, 280 nm) to give 2 E1 (R.sub.t = 8
min) and 2 E2 (R.sub.t = 10 min). HPLC R.sub.t = 8.77 min; .sup.1H
NMR(400 mHz, CD.sub.3OD) 7.52(d, J=8.8Hz, 1H), 7.48(d, J=2.2Hz,
1H), 7.26(dd, J=2.2, 8.8Hz, 1H), 3.21(1H, under solvent peak),
2.35(broad d, 13.2Hz, 1H), 2.24(broad d, 13.9Hz, 1H), 1.57-1.46(m,
5H), 1.24-1.11(m, 3H), 1.04(d, J=6.6Hz, 3H); LC-MS 8.13 min, (M +
1).sup.+ 272 @ 8.37 min (.+-.)
1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-methylbutan-1-amine (3)
##STR45## 3 iso-butyl I HPLC R.sub.t = 9.49 min; .sup.1H NMR(400
MHz, MeOH-d.sup.4) 7.4-7.38(m, 2H), 7.17-7.15(m, 1H), 2.58-2.55(m,
1H), 2.27-2.18(m, 2H), 1.64-1.44(m, 5H), 1.27-1.11(m, 7H), 0.83(d,
J=6.96, 3H), 0.78(d, J=6.96Hz, 3H), 0.69-0.62(m, 1H); LC-MS 9.81
min, (M + 1).sup.+ 314 @ 9.95 min.
(1-(3,4-dichlorophenyl)cycloheptyl)methanamine (4) 4 ##STR46## 4 H
E HPLC R.sub.t = 8.96 min; .sup.1H NMR(400 MHz, CDCl.sub.3)
7.51-7.48(m, 2H), 7.29(dd, J=2.2, 8.4Hz, 1H), 3.0(s, 2H),
2.12-2.07(m, 2H), 1.79-1.73(m, 2H), 1.66-1.38(m, 7H); LC-MS 8.61
min, (M + 1).sup.+ 272 @ 8.81 min (.+-.)
1-(1-(4-methoxyphenyl)cyclohexyl)ethanamine (5) ##STR47## 3
CH.sub.3 I HPLC R.sub.t = 8.07 min; LC-MS 5.57 min, (M + 1).sup.+
234 @ 5.98 min. (.+-.) 1-(1-(thiophen-2-yl)cyclohexyl)ethanamine
(6) ##STR48## 3 CH.sub.3 I HPLC R.sub.t = 7.81 min; LC-MS 4.90 min,
(M + 1).sup.+ 210 @ 5.78 min. (.+-.)
1-(1-(biphenyl-4-yl)cyclohexyl)ethanamine (7) ##STR49## 3 CH.sub.3
I HPLC R.sub.t = 9.07 min; LC-MS 7.47 min, (M + 1).sup.+ 280 @ 7.94
min. (1-(biphenyl-4-yl)cyclohexyl)methanamine (8) ##STR50## 3 H E
HPLC R.sub.t = 8.96 min; .sup.1H NMR(400 MHz, CD.sub.3OD) 7.64(d,
J=8.43Hz, 2H), 7.57(d, J=7.70Hz, 2H), 7.47(d, J=8.06Hz, 2H),
7.39-7.36(m, 2H), 7.27(t, J=7.33Hz, 1H), 3.01(s, 2H), 2.26-2.24(m,
2H), 1.64-1.52(m, 5H), 1.39-1.38(m, 3H); LC-MS 7.48 min, (M +
1).sup.+ 266 @ 7.86 min. (1-(thiophen-2-yl)cyclohexyl)methanamine
(9) ##STR51## 3 H E HPLC R.sub.t = 7.62 min; .sup.1H NMR(400 MHz,
CD.sub.3OD) 7.36(dd, J=1.1, 4.76Hz, 1H), 7.02-6.98(m, 2H), 2.98(s,
2H), 2.13-2.01(m, 2H), 1.98-1.35(m, 8H); LC-MS 4.55 min, (M +
1).sup.+ 196 @ 5.12 min.
(1-(4-(methylthio)phenyl)cyclohexyl)methanamine (10) ##STR52## 3 H
E HPLC R.sub.t = 8.30 min; .sup.1H NMR(400 MHz, CD.sub.3OD)
7.33-7.26(m, 4H), 2.96(s, 2H), 2.42(d, J=1.47Hz, 3H), 2.19-2.16(m,
2H), 1.60-1.49(m, 5H), 1.39-1.31(m, 3H); LC-MS 6.07 min, (M +
1).sup.+ 236 @ 6.45 min. (.+-.)
1-(1-(4-chlorophenyl)cyclohexyl)ethanamine (11) ##STR53## 3
CH.sub.3 I HPLC R.sub.t = 8.38 min; LC-MS 6.13 min, (M + 1).sup.+
238 @ 5.84 min. (1-(naphthalen-1-yl)cyclohexyl)methanamine (12)
##STR54## 3 H E HPLC R.sub.t = 8.49 min. .sup.1H NMR(400 MHz,
CD.sub.3OD) 8.39(d, J=8.43Hz, 1H), 7.90(d, J=7.70Hz, 1H), 7.82(d,
J=8.06Hz, 1H), 7.58(d, J=7.33Hz, 1H), 7.51-7.42(m, 3H), 3.64(bs,
2H), 2.56-2.51(m, 2H), 1.98-1.94(m, 2H), 1.62-1.50(m, 6H); LC-MS
7.40 min, (M + 1).sup.+ 240 @ 7.62 min. (.+-.)
1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (13) ##STR55## 3
CH.sub.3 I SFC w/AD column and 33% MeOH/0.1% DEA, 25.degree. C.
column temp., 10 ml/min total flow, 280 nm to give the fast moving
enantiomer 13 E1 (R.sub.t = 3.8 min) and the slow moving enantiomer
13 E2 (R.sub.t = 5 min). 13 E1 LC-MS (M + 1).sup.+ 254 @ 8.31 min
13 E2 LC-MS (M + 1).sup.+ 254 @ 8.33 min (.+-.)
1-(1-(4-chlorophenyl)cyclohexyl)-2-methylpropan-1-amine (14)
##STR56## 3 iso-propyl I HPLC R.sub.t = 8.89 min; LC-MS 8.67 min,
(M + 1).sup.+ 266 @ 8.85 min.
(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)methanamine (15)
##STR57## 3 H E HPLC R.sub.t = 8.63 min; .sup.1H NMR(400 MHz,
CD.sub.3OD) 7.50(d, J=9.16Hz, 2H), 7.28(d, J=8.80Hz, 2H), 3.02(s,
2H), 2.19(d, J=12.8Hz, 2H), 1.67-1.31(m, 8H); LC-MS 7.93 min, (M +
1).sup.+ 274 @ 8.18 min.
1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (16) ##STR58## 3
CH.sub.3 I SFC w/AS column and 30% MeOH/0.1% DEA, 280 nm. 16 E1:
HPLC R.sub.t = 2.23 min; LC-MS 7.56 min, (M + 1).sup.+ 254 @ 7.78
min 16 E2: LC-MS 7.59 min, (M + 1).sup.+ 254 @ 7.9 min.
1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-amine (17) ##STR59## 3
CH.sub.2CH.sub.3 I SFC w/AS column and 20% MeOH/0.1% DEA, 280 nm.
17 E1: HPLC R.sub.t = 1.58 min; .sup.1H NMR(400 MHz, CDCl.sub.3)
7.50(d, J=1.47Hz, 1H), 7.44(d, J=8.43Hz, 1H), 7.29-7.27(m, 1H),
3.01-2.97(m, 1H), 2.44(d, J=13.2Hz, 1H), 2.21(d, J=13.2Hz, 1H),
1.98-1.92(m, 1H), 1.79-1.25(m, 8H), 1.09-1.03(m, 4H); LC-MS 8.89
min, (M + 1).sup.+ 286 @ 9.01 min. 17 E2: LC-MS 8.89 min, (M +
1).sup.+ 288 @ 8.91 min. (.+-.)
1-(1-(4-chlorophenyl)cyclohexyl)propan-1-amine (18) ##STR60## 3
CH.sub.2CH.sub.3 I HPLC R.sub.t = 8.68 min; LC-MS 7.91 min, (M +
1).sup.+ 252 @ 8.04 min.
1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (19)
##STR61## 3 CH.sub.3 I Chiral HPLC with AD column and 100%
MeOH/0.1% DEA, 280 nm 19 E1: HPLC R.sub.t = 1.52 min; LC-MS (15
minute method) 8.18 min, (M + 1).sup.+ 288 @ 8.35 min. 19 E2: LC-MS
(15 minute method) 8.24 min, (M + 1).sup.+ 288 @ 8.27 min.
1-(1-(4-(furan-3-yl)phenyl)cyclohexyl)ethanamine (20) ##STR62## 3
CH.sub.3 I SFC w/AD column and 35% MeOH/10% IPA/0.1% DEA,
25.degree. C. column temp., 10 ml/min total flow, 280 nm to give
the fast moving enantiomer E1 and the slow moving enantiomer E2. 20
E1: .sup.1H NMR(400 MHz, CDCl.sub.3) 7.73(s, 1H), 7.48-7.46(m, 3H),
7.32(d, J=8.43Hz, 2H), 6.70(d, J=0.7Hz, 1H), 2.77-2.72(m, 1H),
2.37(d, J=13.2Hz, 1H), 2.30(d, J=13.2Hz, 1H), 1.58-1.42(m, 5H),
1.32-1.22(m, 3H), 0.87(d, J=6.60Hz, 3H); LC-MS 7.94 min, (M +
1).sup.+ 270 @ 8.06 min 20 E2: LC-MS 7.97 min, (M + 1).sup.+ 270 @
8.12 min 1-(1-(4-chlorophenyl)cyclohexyl)-3-methylbutan-1-amine
(21) ##STR63## 3 iso-butyl I SFC w/AS column and 15% IPA/0.1% DEA,
25.degree. C. column temp., 10 ml/min total flow, 280 nm to give
the fast moving enantiomer E1 and the slow moving enantiomer E2. 21
E1: HPLC R.sub.t = 9.26 min; .sup.1H NMR(400 MHz, CDCl.sub.3);
7.31-7.23(m, 4H), 2.57-2.54(m, 1H), 2.32-2.23(m, 2H), 1.65-1.43(m,
6H), 1.24-1.13(m, 4H), 0.93-0.78(m, 7H), 0.70-0.63(m, 1H); LC-MS
9.01 min, (M + 1).sup.+ 280 @ 9.19 min 21 E2: LC-MS 9.01 min, (M +
1).sup.+ 280 @ 9.19 min
1-(1-(4-(furan-2-yl)phenyl)cyclohexyl)ethanamine (22) ##STR64## 3
CH.sub.3 I SFC w/OD column and 12% MeOH/0.1% DEA, 40.degree. C.
column temp., 10 ml/min total flow, 280 nm to give the fast moving
enantiomer E1 and the slow moving enantiomer E2. 22 E1: HPLC
R.sub.t = 8.76 min; .sup.1H NMR(400 MHz, CDCl.sub.3) 7.66(d,
J=8.54Hz, 2H), 7.45(d, J=1.71Hz, 1H), 7.34(d, J=8.54Hz, 2H),
6.63(d, J=3.42Hz, 1H), 6.45(dd, J=1.71, 3.42Hz, 1H), 2.83(bs, 1H),
2.39(d, J=12.7Hz, 1H), 2.30(d, J=11.7Hz, 1H), 1.56-1.45(m, 5H),
1.26(bs, 3H), 0.90(d, J=6.35Hz, 3H); LC-MS 8.09 min, (M + 1).sup.+
270 @ 8.24 min. 22 E2: LC-MS 8.09 min, (M + 1).sup.+ 280 @ 8.24
min. (1-(3',5'-difluorobiphenyl-4-yl)cyclohexyl)methanamine (23)
##STR65## 3 H E HPLC R.sub.t = 9.24 min; .sup.1H NMR(400 mHz,
CD.sub.3OD) 7.68-7.64(m, 2H), 7.51(dd, J=1.95, 8.96, 2H),
7.26-7.19(m, 2H), 6.90-6.84(m, 1H), 3.03(s, 2H), 2.28-2.24(m, 2H),
1.67-1.36(m, 8H). (.+-.)
1-(1-(4-(thiazol-2-yl)phenyl)cyclohexyl)ethanamine (24) ##STR66## 3
CH.sub.3 I HPLC R.sub.t = 1.50 min; LC-MS (15 minute method) 7.51
min, (M + 1).sup.+ 287 @ 7.72 min; .sup.1H NMR(400 MHz, CDCl.sub.3)
7.95(d, J=8.43Hz, 2H), 7.85(d, J=3.30Hz, 1H), 7.44(d, J=8.43Hz,
2H), 7.32(d, J=3.30Hz, 1H), 3.13(d, J=6.23Hz, 1H), 2.50(d,
J=11.36Hz, 1H), 2.33(d, J=12.10Hz, 1H), 1.60-1.57(m, 2H),
1.33-1.20(m, 6H), 0.97-0.83(m, 3H). (.+-.)
1-(1-(3,4-dichlorophenyl)cyclohexyl)pentan-1-amine (25) ##STR67## 3
n-butyl I HPLC R.sub.t = 1.68 min; LC-MS (15 minute method) 9.92
min, (M + 1).sup.+ 316 @ 10.04 min; .sup.1H NMR(400 MHz,
CDCl.sub.3) 7.47-7.42(m, 2H), 7.26-7.23(m, 1H), 2.95(d, J=9.16Hz,
1H), 2.38(d, J=12.10Hz, 1H), 2.23(d, J=12.83Hz, 1H), 1.77-1.56(m,
5H), 1.45(s, 3H), 1.28-1.14(m, 6H), 0.78(t, J.sub.1=13.56Hz,
J.sub.2=6.60Hz, 3H). (.+-.)
1-(1-(3,4-dichlorophenyl)cyclohexyl)heptan-1-amine (26) ##STR68## 3
n-hexyl I HPLC R.sub.t = 1.78 min; LC-MS(15 minute method) 10.73
min, (M + 1).sup.+ 344 @ 10.8 min; .sup.1H NMR(400 MHz, CDCl.sub.3)
7.46-7.41(m, 2H), 7.26-7.21(m, 1H), 2.91(d, J=9.17Hz, 1H), 2.36(d,
J=12.46Hz, 1H), 2.23(d, J=13.20Hz, 1H), 1.73-1.44(m, 7H),
1.28-1.14(m, 11H), 0.82(t, J.sub.1=14.30Hz, J.sub.2=6.96Hz,
3H).
[0208] The following compounds were synthesized from the respective
cyclohexyl nitrile according to General Procedure E, and were
optionally converted to the respective HCl salt form: ##STR69##
(1-(3,4-dichlorophenyl)cyclohexyl)-methanamine hydrochloride
(27)
[0209] ##STR70##
[0210] The title compound was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarbonitrile (920 mg, 3.62 mmol).
The crude HCl salt was recrystallized from 1:5 CH.sub.3CN/IPA (10
mL) to give pure [1-(3,4-Dichloro-phenyl)-cyclohexyl]-methylamine
hydrochloride as an off-white solid. HPLC R.sub.t=8.66 min; .sup.1H
NMR (400 mHz, MeOH-d.sup.4) 7.55-7.51 (m, 2H), 7.35-7.31 (dd,
J=2.44, 8.55 Hz, 1H), 3.01 (s, 2H), 2.17-2.12 (m, 2H), 1.65-1.28
(m, 8H); LCMS 8.52 min, (M+1).sup.+258 @ 8.78 min.
(1-(3-chlorophenyl)cyclohexyl)methanamine hydrochloride (28)
[0211] ##STR71##
[0212] The title compound was synthesized from
1-(3-chlorophenyl)-cyclohexanecarbonitrile (320 mg, 1.46 mmol). The
crude HCl salt was recrystallized from CH.sub.3CN (7.5 mL) to give
pure (1-(3-chlorophenyl)cyclohexyl)-methanamine hydrochloride as
off-white needles/hay. HPLC R.sub.t=8.18 min; .sup.1H NMR (400 mHz,
MeOH-d.sup.4) 7.41-7.26 (m, 4H), 3.0 (s, 2H), 2.18-2.15 (m, 2H),
1.64-1.30 (m, 8H); LC-MS 7.72 min, (M+1).sup.+224 @ 8.0 min.
(1-(4-chlorophenyl)cyclohexyl)methanamine hydrochloride (29)
[0213] ##STR72##
[0214] The title compound was synthesized from
1-(4-chlorophenyl)-cyclohexanecarbonitrile. The crude HCl salt was
recrystallized from CH.sub.3CN (3 mL) to give pure
(1-(4-chlorophenyl)cyclohexyl)methanamine hydrochloride as
off-white needles/hay. HPLC R.sub.t=8.22 min; .sup.1H NMR (400 mHz,
MeOH-d.sup.4) 7.38 (s, 4H), 2.97 (s, 2H), 2.19-2.14 (m, 2H),
1.63-1.30 (m, 8H); LC-MS 7.83 min, (M+1).sup.+224 at 8.1 min.
(1-(3,4-difluorophenyl)cyclohexyl)methanamine hydrochloride
(30)
[0215] ##STR73##
[0216] The title compound was synthesized from
1-(3,4-difluorophenyl)-cyclohexanecarbonitrile. The crude HCl salt
was recrystallized from CH.sub.3CN (6 mL) to give pure
(1-(3,4-difluorophenyl)cyclohexyl)methanamine hydrochloride (38 mg,
17%) as off-white needles/hay HPLC R.sub.t=8.06 min; .sup.1H NMR
(400 mHz, MeOH-d.sup.4) 7.34-7.20 (m, 3H), 2.99 (m, 2H), 2.15-2.12
(m, 2H), 1.64-1.31 (m, 8H); LC-MS 7.01 min, (M+1).sup.+226 (7.16
min.
(1-phenylcyclohexyl)methaneamine hydrochloride (31)
[0217] ##STR74##
[0218] The title compound was synthesized from
1-phenylcyclohexane-carbonitrile. The crude HCl salt was
recrystallized from CH.sub.3CN to give pure
(1-phenylcyclohexyl)methaneamine hydrochloride as off-white
needles. HPLC R.sub.t=7.59 min; .sup.1H NMR (400 mHz, MeOH-d.sup.4)
7.40-7.36 (m, 4H), 7.27-7.25 (m, 1H), 2.98 (s, 2H), 2.22-2.20 (m,
2H), 1.62-1.32 (m, 8H); LC-MS 6.16 min, (M+1).sup.+190 @ 6.36
min.
(1-(3-chloro-4-fluorophenyl)cyclohexyl)-methanamine (32)
[0219] ##STR75##
[0220] The title compound was prepared from
1-(3-chloro-4-fluorophenyl)cyclohexanecarbonitrile. A solution of
the crude product in MTBE was basicified at 0.degree. C. with KOH,
extracted with MTBE and evaporated. The residue was diluted in DCM,
filtered through an aminopropyl column and evaporated to give the
primary amine (64.1 mg, 25%) as an oil. LCMS R.sub.t=7.62 min,
m/z=242 (M+1). .sup.1H NMR (CDCl.sub.3, .delta.) 7.34 (dd, J=2.4,
7.1 Hz, 1H), 7.19 (ddd, J=2.4, 4.6, 8.7 Hz, 1H), 7.11 (t, J=8.7 Hz,
1H), 2.68 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H), 0.79 (bs, 2H).
.sup.13C NMR (CDCl.sub.3, .delta., mult): 157.4(0), 154.9(0),
142.2(0), 129.5(0), 127.0(0), 126.9(1), 120.8(1), 120.6(1),
116.3(1), 116.1(1), 54.5(2), 43.3(0), 33.7(2), 26.5(2),
22.0(2).
(1-(naphthalen-2-yl)cyclohexyl)methanamine (33)
[0221] ##STR76##
[0222] The title compound was synthesized in 37% yield from
1-(naphthalen-2-yl)cyclohexane-carbonitrile. HPLC R.sub.t
(5-100-8)=8.44 min. LCMS R.sub.t=8.22 min, m/z=240 (M+1). .sup.1H
NMR (CDCl.sub.3, .delta.): 7.9-7.2 (m, 7H), 2.78 (s, 2H), 2.3 (m,
2H), 1.7-1.3 (m, 8H), 0.9 (bs, 2H). .sup.13C NMR (CDCl.sub.3,
.delta., mult): 133.4(0), 131.7(0), 128.0(1), 127.8(1), 127.3(1),
126.4(1), 125.8(1), 125.4(1), 125.2(1), 54.6(2), 43.7(0), 33.8(2),
26.7(2), 22.2(2).
(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (34)
[0223] ##STR77##
[0224] The title compound was prepared from
1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (127 mg, 0.50
mmol). The crude product was purified by silica gel column
chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 10%) to give
(1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine (62 mg, 48%)
as a clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.26-1.52 (m 4H),
1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.13-2.18 (m, 2H), 2.28 (s,
3H), 2.63 (s, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.3, 26.7, 34.8, 42.9, 54.4,
125.5, 125.6, 127.9, 129.9, 149.1. ESI MS m/z 258.
(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)methanamine (35)
[0225] ##STR78##
[0226] The title compound was prepared from
1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile (115 mg, 0.50
mmol). The crude product was purified by chromatography (SiO.sub.2,
MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 10%) to give (.+-.)
(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)methanamine (58 mg, 50%) as
a clear oil. .sup.1H NMR (CDCl.sub.3) 1.34-1.39 (m, 3H), 1.46-1.54
(m, 7H), 2.01-2.06 (m, 2H), 2.64 (s, 2H), 5.93 (s, 2H), 6.78 (s,
2H), 6.84 (s, 1H). .sup.13C NMR (CDCl.sub.3) 22.3, 26.9, 34.3,
43.5, 54.9, 101.1, 107.9, 108.2, 120.6, 138.7, 145.6, 148.2. ESI MS
m/z 234.
(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (36)
[0227] ##STR79##
[0228] The title compound was prepared from
1-(3-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (127 mg, 0.50
mmol). The crude product was purified by chromatography (SiO.sub.2,
MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 10%) to give (.+-.)
(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (26 mg, 20%)
as a clear oil. .sup.1H NMR (CDCl.sub.3): 1.26-1.41 (m, 5H),
1.50-1.63 (m, 5H), 2.12-2.16 (m, 2H), 2.73 (s, 2H), 7.47-7.49 (m,
2H), 7.52-7.55 (m, 1H), 7.58 (s, 1H). .sup.13C NMR (CDCl.sub.3)
22.3, 26.7, 33.8, 43.9, 54.6, 122.9, 124.1, 124.2, 129.1, 130.8,
130.9, 146.3. ESI MS m/z 257.
(1-(3-fluorophenyl)cyclohexyl)methanamine (37)
[0229] ##STR80##
[0230] The title compound was prepared from
1-(3-fluorophenyl)cyclohexanecarbonitrile (102 mg, 0.50 mmol). The
crude product was purified by chromatography (SiO.sub.2,
MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 10%) to give (.+-.)
(1-(3-fluorophenyl)cyclohexyl)methanamine (32 mg, 31%) as a clear
oil. .sup.1H NMR (CDCl.sub.3): 1.26-1.39 (m, 5H), 1.51-1.58 (m,
5H), 2.07-2.10 (m, 2H), 2.69 (s, 2H), 6.88-6.93 (m, 1H), 7.04 (d,
J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.27-7.34 (m, 1H). .sup.13C
NMR (CDCl.sub.3) 22.3, 26.8, 33.8, 43.9, 54.8, 112.7, 113.0, 114.5,
114.7, 123.0, 123.1, 129.9, 130.0, 162.3, 164.7. ESI MS m/z
208.
(1-(2,4-dichlorophenyl)cyclohexyl)methanamine (38)
[0231] ##STR81##
[0232] .sup.1H NMR (400 MHz, CD.sub.3Cl) .delta. 7.35 (d, J=2.4 Hz,
1H), 7.32 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.4, 8.4 Hz, 1H), 3.08 (s,
2H), 2.25 (m, 2H), 1.45 (m, 2H), 1.31 (m, 2H), 1.28-1.18 (m, 4H);
.sup.13C NMR (100 MHz, CD.sub.3Cl) .delta. 139.91, 134.39, 133.70,
132.89, 132.23 48.61, 45.83, 33.70, 26.77, 26.66, 22.56; ESI MS m/z
258.1.
(1-(6-fluoronaphthalen-2-yl)cyclohexyl)methanamine (39)
[0233] ##STR82##
[0234] The title compound was synthesized according to Scheme 25,
below. ##STR83##
[0235] To a solution of 6-fluoro-naphthalene-2-carboxylic acid (3.0
g, 15.8 mmol) was added BH.sub.3.THF (31.6 mL, 31.6 mmol). The
reaction mixture was stirred overnight before being concentrated.
To the residue was added diethyl ether (100 mL) and NaOH solution
(10 mL). The organic layer was separated, dried and concentrated.
The resultant residue was purified by silica gel column
chromatography (ethyl acetate/hexane 1:7) to afford
(6-fluoro-naphthalen-2-yl)-methanol (2.28 g, 82%).
[0236] To a solution of (6-fluoro-naphthalen-2-yl)-methanol (2.0 g,
11.3 mmol) in CH.sub.2Cl.sub.2 (30 mL) was added PBr.sub.3 (1.0 M
in CH.sub.2Cl.sub.2, 22.6 mmol). The reaction mixture was stirred
for 3 h at room temperature before being quenched by NH.sub.4Cl (30
mL). The organic layer was separated, dried and concentrated. The
resultant residue was purified by silica gel column chromatography
(ethyl acetate/hexane=1:10) to afford
2-bromomethyl-6-fluoro-naphthalene (2.23 g, 74%).
[0237] To a mixture of 2-bromomethyl-6-fluoro-naphthalene (1.5 g,
5.9 mmoL) in CH.sub.3CN (30 mL) was added KCN (1.16 g, 17.8 mmoL).
The reaction mixture was heated at reflux for 6 h before being
concentrated. To the residue was added diethyl ether (100 mL) and
H.sub.2O (15 mL). The organic layer was separated, dried and
concentrated. The resultant residue was purified by silica gel
column chromatography (ethyl acetate/hexane=1:10) to afford the
(6-fluoro-naphthalen-2-yl)-acetonitrile (0.88 g, 70%).
[0238] The title compound was synthesized from
(6-fluoro-naphthalen-2-yl)-acetonitrile (1.0 g, 5.48 mmoL)
according to General Procedure J to form the intermediate nitrile
(0.98 g, 71%), which was purified by silica gel column
chromatography (ethyl acetate/hexane 1:7), followed by General
Procedure E.
[0239] The crude product was dissolved in MeOH (4 mL) and subjected
to reverse phase column chromatography (CH.sub.3CN/H.sub.2O/0.1%
formic acid=5% to 100%) to give the title compound (0.53 g, 75%).
.sup.1H NMR (400 MHz, CD.sub.3Cl) .delta. 8.29 (m, 1H), 8.18 (m,
1H), 7.83 (m, 1H), 7.50 (dd, J=3.6, 6.8 Hz, 1H), 7.41 (dd, J=6.0
Hz, 8.8 Hz, 1H0, 7.06 (dd, J=8.8, 8.8 Hz, 1H), 3.37 (s, 2H), 2.34
(m, 2H), 1.89 (m, 2H), 1.58 (m, 2H), 1.45 (m, 2H); .sup.13C NMR
(100 MHz, CD.sub.3Cl) .delta. 168.08, 159.85, 157.34, 132.96,
132.93, 128.58, 128.50, 126.04, 125.69, 125.67, 125.63, 125.47,
125.35, 125.32, 122.44, 122.37, 108.63, 108.44, 47.62, 43.53,
35.59, 26.43, 22.47, 22.31; ESI MS m/z 258.1.
(1-(4-fluoronaphthalen-1-yl)cyclohexyl)methanamine (40)
[0240] ##STR84##
[0241] The title compound was synthesized from
4-fluoro-naphthalene-1-carboxylic acid (2.0 g, 10.3 mmol) according
to the synthetic procedures described above for the synthesis of 39
(Scheme 25). The crude product was dissolved in MeOH (4 mL) and
subjected to reverse phase column chromatography
(CH.sub.3CN/H.sub.2O/0.1% formic acid=5% to 100%) to give 40 (0.51
g). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.48(d, J=8.4 Hz,
1H), 8.20 (d, J=8.4 Hz, 1H), 7.6 (m, 3H), 7.21 (dd, J=8.4, 8.4 Hz,
1H), 3.67 (s, 2H), 2.52 (m, 2H), 2.04 (m, 2H), 1.68 (m, 2H), 1.50
(m, 4H); .sup.13C NMR (100 MHz, CD.sub.3OD), .delta. 160.04,
157.54, 133.03, 132.99, 131.91, 160.04, 157.54, 133.03, 132.99,
131.01, 128.74, 128.64, 126.64, 125.67, 125.65, 125.51, 125.24,
125.22, 121.80, 121.73, 108.33, 108.14, 47.00, 42.50, 35.12, 26.03,
21.89; ESI MS m/z 258.2.
1.3. Synthesis of Secondary and Tertiary Amines
[0242] Compounds in Table 2, below, were synthesized from the
indicated primary amine according to the indicated General
Procedure and were optionally converted to the corresponding HCl
salt form. TABLE-US-00002 TABLE 2 ##STR85## Summary of Exemplary
Secondary and Tertiary Amines Ar n R.sup.1 R.sup.3 R.sup.4 General
Procedure Prepared From
1-(1-(3,4-dichlorophenyl)cyclobutyl)-N,N-dimethylmethanamine (41)
##STR86## 1 H CH.sub.3 CH.sub.3 C 1 HPLC R.sub.t = 8.42 min;
.sup.1H NMR(400 mHz, MeOH-d.sup.4) 7.58-7.53(m, 2H), 7.34-7.31(m,
1H), 3.63(s, 2H), 2.65(s, 6H), 2.49-2.29(m, 4H), 2.07-1.87(m, 2H);
LC-MS 8.12 min, (M + 1).sup.+ 258 @ 8.1 min
1-(1-(3,4-dichlorophenyl)cyclobutyl)-N-methylmethanamine (42)
##STR87## 1 H H CH.sub.3 A 1 HPLC R.sub.t = 8.37 min; .sup.1H
NMR(400 mHz, MeOH-d.sup.4) 7.57(d, J=8.43Hz, 1H), 7.44(d, J=1.83Hz,
1H), 7.20(dd, J=2.2, 8.43Hz, 1H), 3.45(s, 2H), 2.65(s, 3H),
2.47-2.43(m, 2H), 2.37-2.31(m, 2H), 2.22-2.15(1H), 1.98-1.92(m,
1H); LC-MS 7.1 min, (M + 1).sup.+ 244 @ 7.28 min. (.+-.)
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylethanamine (43)
##STR88## 3 CH.sub.3 CH.sub.3 CH.sub.3 C 2 HPLC R.sub.t = 8.93 min;
.sup.1H NMR(400 mHz, CDCl.sub.3) 7.43(d, J=1.83Hz, 1H), 7.35(d,
J=8.8Hz, 1H), 7.22-7.19(m, 1H), 2.54(d, J=12.8Hz, 1H), 2.44-2.40(m,
1H), 2.09-2.05(d, J=13.9Hz, 1H), 1.95(s, 6H), 1.56-1.48(m, 5H),
1.25-1.11(m, 3H), 0.76(d, J=6.97Hz, 3H); LC-MS 10.2 min, (M +
1).sup.+ 300 @ 10.26 min.
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44 E1)
##STR89## 3 CH.sub.3 CH.sub.3 CH.sub.3 D 2 E1 HPLC R.sub.t = 9.02
min; .sup.1H NMR (400 MHz, CD.sub.3OD) 7.68(d, J=2.2Hz, 1H),
7.64-7.62(m, 1H), 7.45(dd, J=2.2, 8.43Hz, 1H), 3.56-3.52(m, 1H),
2.88(s, 3H), 2.71(d, J=12.8Hz, 1H), 2.36(d, J=13.2Hz, 1H), 2.19(s,
3H), 1.70-1.60(m, 5H), 1.38-1.25(m, 5H), 1.18-1.12(m, 1H); LC-MS
9.55 min, (M + 1).sup.+ 300 @ 9.84 min.
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (44 E2)
##STR90## 3 CH.sub.3 CH.sub.3 CH.sub.3 D 2 E2 LC-MS 9.47 min, (M +
1).sup.+ 300 @ 9.64 min. (.+-.)
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,3-dimethylbutan-1-amine (45)
##STR91## 3 iso-butyl H CH.sub.3 A 3 HPLC R.sub.t = 9.57 min;
.sup.1H NMR (400 MHz, CD.sub.3OD) 7.59(d, J=2.20Hz, 1H), 7.54(d,
J=8.80Hz, 1H), 7.35(dd, J=2.20, 8.43Hz, 1H), 3.01-2.98(m, 1H),
2.66(s, 3H), 2.39(m, 1H), 2.30(m, 1H), 1.97-1.46(m, 7H),
1.31-1.22(m, 3H), 1.12-1.06(m, 2H), 0.84(d, J=6.60Hz, 3H), 0.70(d,
J=6.60Hz, 3H); LC-MS 8.93 min, (M + 1).sup.+ 328 @ 9.18 min. (.+-.)
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N,3-trimethylbutan-1-amine
(46) ##STR92## 3 iso-butyl CH.sub.3 CH.sub.3 C 3 R.sub.t = 9.72
min; .sup.1H NMR(400 MHz, CD.sub.3OD) 8.05(bs, 1H), 7.48-7.46(m,
1H), 7.40(d, J=8.43Hz, 1H), 7.23(dd, J=1.83-8.43Hz, 1H), 2.62(dd,
J=3.67, 9.16Hz, 1H), 2.59-2.56(m, 1H), 2.30(s, 6H), 2.19-2.16(m,
1H), 1.61-1.11(m, 12H), 0.88-0.85(m, 6H); LC-MS 11.32 min, (M +
1).sup.+ 342 @ 11.7 min. (.+-.)
1-(1-(4-methoxyphenyl)cyclohexyl)-N-methylethanamine (47) ##STR93##
3 CH.sub.3 H CH.sub.3 A 5 HPLC R.sub.t = 8.22 min; .sup.1H NMR(400
MHz, CD.sub.3OD) 7.30-7.26(m, 2H), 6.97-6.94(m, 2H), 3.76(s, 3H),
3.09-3.04(m, 1H), 2.57(s, 3H), 2.50-2.47(m, 2H), 2.31-2.28(m, 2H),
1.59-1.45(m, 5H), 1.29-1.22(m, 3H), 1.09(d, J=6.60Hz, 3H); LC-MS
5.57 min, (M + 1).sup.+ 248 @ 6.07 min
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48 E1)
##STR94## 3 CH.sub.3 H CH.sub.3 A 2 E1 HPLC R.sub.t = 8.94 min;
.sup.1H NMR(400 MHz, CD.sub.3OD) 7.61-7.58(m, 2H), 7.36(dd, J=2.2,
8.43Hz, 1H), 3.20-3.16(m, 1H), 2.65(s, 3H), 2.51(d, J=12.5Hz, 1H),
2.34(d, J=10.6Hz, 1H), 1.69-1.55(m, 5H), 1.35-1.12(m, 6H); LC-MS
7.08 min, (M + 1).sup.+ 286 @ 7.46 min. [.alpha.].sub.D = -2.68(c =
0.41, MeOH).
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (48 E2)
##STR95## 3 CH.sub.3 H CH.sub.3 A 2 E2 LC-MS 7.03 min, (M +
1).sup.+ 286 @ 7.58 min.
1-(1-(biphenyl-4-yl)cyclohexyl)-N-methylmethanamine (49) ##STR96##
3 H H CH.sub.3 A 8 HPLC R.sub.t = 9.06 min; .sup.1H NMR(400 MHz,
CD.sub.3OD) 7.66(d, J=8.06Hz, 2H), 7.59(d, J=8.43Hz, 2H), 7.50(d,
J=8.06Hz, 2H), 7.40(d, J=7.70Hz, 2H), 7.31-7.29(m, 1H), 3.14(s,
2H), 2.54(s, 3H), 2.29-2.27(m, 2H), 1.69-1.52(m, 5H), 1.43-1.37(m,
3H); LC-MS 7.05 min, (M + 1).sup.+ 280 @ 7.52 min. (.+-.)
1-(1-(4-chlorophenyl)cyclohexyl)-N-methylethanamine (50) ##STR97##
3 CH.sub.3 H CH.sub.3 A 11 HPLC R.sub.t = 8.59 min; .sup.1H NMR(400
MHz, CD.sub.3OD) 7.43-7.34(m, 4H), 3.14-3.08(m, 1H), 2.59(d,
J=0.73Hz, 3H), 2.52-2.48(d, J=12.2Hz, 1H), 2.33-2.29(d, J=13.4Hz,
1H), 1.59-1.47(m, 5H), 1.31-1.13(m, 3H), 1.09(d, J=6.84Hz, 3H);
LC-MS 7.10 min, (M + 1).sup.+ 252 @ 7.32 min. (.+-.)
N-methyl-1-(1-(thiophen-2-yl)cyclohexyl)ethanamine (51) ##STR98## 3
CH.sub.3 H CH.sub.3 A 6 HPLC R.sub.t = 7.92 min; .sup.1H NMR(400
MHz, CD.sub.3OD) 7.42-7.40(m, 1H), 7.07-7.04(m, 1H), 7.01-6.99(m,
1H), 3.17-3.10(m, 1H), 2.61(s, 3H), 2.42-2.38(m, 1H); 2.14-2.10(m,
1H), 1.64-1.26(m, 8H), 1.19(d, J=6.59Hz, 3H); LC-MS 5.80 min, (M +
1).sup.+ 224 @ 6.19 min.
N,N-dimethyl-1-(1-(4-(methylthio)phenyl)cyclohexyl)methanamine (52)
##STR99## 3 H CH.sub.3 CH.sub.3 C 10 HPLC R.sub.t = 8.54 min;
.sup.1H NMR(400 MHz, CD.sub.3OD) 7.39(d, J=8.07Hz, 2H),
7.30-7.28(m, 2H), 3.34(s, 2H), 2.52(s, 6H), 2.43(s, 3H),
2.26-2.23(d, J=11.7Hz, 2H), 1.66-1.52(m, 5H), 1.38-1.37(m, 3H);
LC-MS 6.97 min, (M + 1).sup.+ 264 @ 7.16 min.
N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (53)
##STR100## 3 H CH.sub.3 CH.sub.3 F 12 HPLC R.sub.t = 8.96 min;
.sup.1H NMR(400 MHz, CD.sub.3OD) 8.00-7.86(m, 4H), 7.65(dd, J=2.2,
8.8Hz, 1H), 7.54-7.51(m, 2H), 3.52(s, 2H), 2.54(s, 6H),
2.46-2.44(d, J=8.43Hz, 2H), 1.84-1.50(m, 9H); LC-MS 8.28 min, (M +
1).sup.+ 268 @ 8.39 min. (.+-.)
1-(1-(4-chlorophenyl)cyclohexyl)-N,2-dimethylpropan-1-amine (54)
##STR101## 3 iso-propyl H CH.sub.3 F 14 HPLC R.sub.t = 9.09 min;
.sup.1H NMR(400 MHz, CD.sub.3OD) 7.40(s, 4H), 2.99(s, 1H), 2.67(s,
3H), 2.45-2.38(m, 2H), 2.17-2.14(m, 1H), 1.61-1.53(m, 5H),
1.31-1.16(m, 3H), 0.98(d, J=7.33Hz, 3H), 0.65(d, J=6.97Hz, 3H);
LC-MS 9.26 min, (M + 1).sup.+ 280 @ 9.29 min. (.+-.)
N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (55)
##STR102## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 13 HPLC R.sub.t = 9.04
min; .sup.1H NMR(400 MHz, CDCl.sub.3) 7.82-7.76(m, 4H),
7.58-7.56(m, 1H), 7.45-7.39(m, 2H), 2.78(d, J=12.5Hz, 1H),
2.53-2.48(m, 1H), 2.30(d, J=13.6Hz, 1H), 1.94-1.18(m, 8H), 0.76(d,
J=6.96Hz, 3H); LC-MS 8.04 min, (M + 1).sup.+ 282 @ 8.16 min.
N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56 E1)
##STR103## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 13 E1 HPLC R.sub.t = 9.12
min; .sup.1H NMR(400 MHz, CD.sub.3OD) 8.03(d, J=1.1Hz, 1H), 7.99(d,
J=8.80Hz, 1H), 7.96-7.93(m, 1H), 7.90-7.88(m, 1H), 7.65(dd, J=1.83,
8.80Hz, 1H), 7.56-7.51(m, 2H), 3.59(q, J=6.97, 13.9Hz, 1H),
2.95-2.92(m, 1H), 2.87(s, 3H), 2.59-2.56(m, 1H), 2.0(s, 3H),
1.76-1.19(m, 11H); LC-MS 7.37 min, (M + 1).sup.+ 282 @ 7.60 min.
N,N-dimethyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (56 E2)
##STR104## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 13 E2 LC-MS 8.42 min, (M
+ 1).sup.+ 282 @ 8.57 min.
N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)methanamine (57)
##STR105## 3 H H CH.sub.3 A 12 HPLC R.sub.t = 8.65 min; .sup.1H
NMR(400 MHz, CD.sub.3OD) 8.67(d, J=8.8Hz, 1H), 7.98(d, J=1.47Hz,
1H), 7.96(d, J=1.83Hz, 1H), 7.89(d, J=8.43Hz, 1H), 7.67-7.50(m,
3H), 3.80(bs, 2H), 2.63-2.58(s, 2H), 2.55(s, 3H), 2.05-2.01(bs,
2H), 1.69(bs, 2H), 1.55(bs, 3H); LC-MS 7.36 min, (M + 1).sup.+ 254
@ 7.50 min. N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine
(58 E1) ##STR106## 3 CH.sub.3 H CH.sub.3 A 13 E1 HPLC R.sub.t =
8.93 min; .sup.1H NMR(400 MHz, CD.sub.3OD) 7.98-7.87(m, 4H),
7.60-7.57(m, 1H), 7.55-7.50(m, 2H), 3.30(1H, hidden), 2.76-2.72(m,
1H), 2.64(s, 3H), 2.59-2.55(m, 1H), 1.69-1.60(m, 6H), 1.41-1.30(m,
3H), 1.21(d, J=6.96Hz, 3H); LC-MS 7.92 min, (M + 1).sup.+ 268 @
8.06 min. N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)ethanamine (58
E2) ##STR107## 3 CH.sub.3 H CH.sub.3 A 13 E2 LC-MS 7.88 min, (M +
1).sup.+ 268 @ 8.00 min.
N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59 E1)
##STR108## 3 CH.sub.3 H CH.sub.3 A 16 E1 HPLC R.sub.t = 1.56 min;
LC-MS (5 minute method) 2.75 min, (M + 1).sup.+ 268 @ 2.84 min.;
.sup.1H NMR(300 MHz, CD.sub.3OD) 8.43(s, 1H), 8.33(d, J=8.80Hz,
1H), 7.85(t, 1H), 7.78(d, J=8.07Hz, 1H), 7.56(d, J=7.70Hz, 1H),
7.45-7.38(m, 2H), 4.05(m, 1H), 2.52(bs, 5H), 1.82-1.78(m, 2H),
1.75-1.48(m, 4H), 1.32-1.06(m, 5H).
N-methyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (59 E2)
##STR109## 3 CH.sub.3 H CH.sub.3 A 16 E2 LC-MS (15 minute method)
7.19 min, (M + 1).sup.+ 268 @ 7.52 min.
N,N-dimethyl-1-(1-(naphthalen-1-yl)cylcohexyl)ethanamine (60 E1)
##STR110## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 16 E1 HPLC R.sub.t = 1.85
min; LC-MS (5 minute method) 2.63 min, (M + 1).sup.+ 282 @ 2.74
min. N,N-dimethyl-1-(1-(naphthalen-1-yl)cyclohexyl)ethanamine (60
E2) ##STR111## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 16 E2 LC-MS (15
minute method) 8.08 min, (M + 1).sup.+ 282 @ 8.14 min.
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylpropan-1-amine (61
E1) ##STR112## 3 ethyl CH.sub.3 CH.sub.3 F 17 HPLC R.sub.t = 1.61
min; LC-MS (15 minute method) 11.91 min, (M + 1).sup.+ 316 @ 12.08
min; .sup.1H NMR(300 mHz, CD.sub.3OD) 8.40(s, 1H), 7.43-7.37(m,
2H), 7.26-7.22(m, 1H), 2.62(d, J=12.46, 1H), 2.46-2.42(m, 1H),
2.33(s, 6H), 2.17(d, J=2.57,
1H), 1.63-1.46(m, 6H), 1.31-1.18(m, 3H), 1.13-1.04(m, 1H), 0.89(t,
3H).
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylpropan-1-amine (61
E2) ##STR113## 3 ethyl CH.sub.3 CH.sub.3 F 17 E2 LC-MS (15 minute
method) 11.90 min, (M + 1).sup.+ 316 @ 12.04 min.
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine (62 E1)
##STR114## 3 ethyl H CH.sub.3 A 17 E1 HPLC R.sub.t = 1.61 min;
LC-MS (15 minute method) 9.09 min, (M + 1).sup.+ 302 @ 9.21 min;
.sup.1H NMR(400 mHz, CDCl.sub.3) 7.47-7.42(m, 2H), 7.25(d,
J=7.70Hz, 1H), 2.54(s, 3H), 2.42-2.40(m, 1H), 2.33(d, J=13.20, 1H),
2.20(d, J=12.83, 1H), 1.76(t, J=11.73, 1H), 1.68-1.57(m, 5H),
1.36-1.14(m, 4H), 0.89(t, J=7.33Hz, 4H).
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylpropan-1-amine (62 E2)
##STR115## 3 ethyl H CH.sub.3 A 17 E2 LC-MS (15 minute method) 9.31
min, (M + 1).sup.+ 302 @ 9.36 min.
N,N-dimethyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine
(63 E1) ##STR116## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 19 E1 HPLC
R.sub.t = 1.58 min; LC-MS (15 minute method) 9.68 min, (M +
1).sup.+ 316 @ 9.90 min. .sup.1H NMR(400 MHz, CDCl.sub.3) 7.64(d,
J=8.80Hz, 2H), 7.39(d, J=8.43Hz, 2H), 4.85(s, 3H), 3.59-3.53(m,
1H), 3.34-3.30(m, 3H), 2.78(d, J=12.5Hz, 1H), 2.40(d, J=13.2Hz,
1H), 1.73-1.59(m, 5H), 1.40-1.34(m, 2H), 1.27-1.25(m, 3H),
1.16-1.15(m, 1H).
N,N-dimethyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine
(63 E2) ##STR117## 3 CH.sub.3 CH.sub.3 CH.sub.3 F 19 E2 LC-MS (15
minute method) 9.69 min, (M + 1).sup.+ 316 @ 9.88 min.
N-methyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (64
E1) ##STR118## 3 CH.sub.3 H CH.sub.3 A 19 E1 HPLC R.sub.t = 1.52
min; LC-MS (15 minute method) 7.82 min, (M + 1).sup.+ 302 @ 7.94
min.; .sup.1H NMR(400 MHz, CD.sub.3OD) 7.54(d, J=8.80Hz, 2H),
7.37(d, J=8.43Hz, 2H), 3.19-3.14(m, 1H), 2.64(s, 3H), 2.57(d,
J=11.73Hz, 1H), 2.39(d, J=12.83Hz, 1H), 1.69-1.57(m, 5H),
1.37-1.22(m, 3H), 1.14-1.13(d, J=6.6Hz, 3H).
N-methyl-1-(1-(4-(trifluoromethoxy)phenyl)cyclohexyl)ethanamine (64
E2) ##STR119## 3 CH.sub.3 H CH.sub.3 A 19 E2 LC-MS (15 minute
method) 7.91 min, (M + 1).sup.+ 302 @ 8.20 min.
[0243] The following compounds were synthesized from the
corresponding primary amine according to General Procedure F. The
crude product was purified by silica gel column chromatography to
give the respective mono- and di-methylated products.
1-(1-(2,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine (65)
[0244] ##STR120##
[0245] The title compound was synthesized from 38. .sup.1H NMR (400
MHz, CD.sub.3Cl) .delta. 7.35 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.4 Hz,
1H), 7.19 (dd, J=8.4, 2.4 Hz, 1H), 3.00 (s, 2H), 2.31 (s, 3H),
2.31-2.28 (m, 2H), 1.83 (m, 2H), 1.56 (m, 2H), 1.48-1.29 (m, 4H);
.sup.13C NMR (400 MHz, CD.sub.3Cl) .delta. 140.61, 134.31, 132.63,
132.53, 132.08, 126.99, 58.24, 44.40, 37.68, 34.44, 26.67, 22.58;
ESI MS m/z 272.07.
1-(1-(2,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine
(66)
[0246] ##STR121##
[0247] The title compound was synthesized from 38. .sup.1H NMR (400
MHz, CD.sub.3Cl) .delta. 7.42 (d, J=8.8 Hz, 1H), 7.32 (d, J=2.0 Hz,
1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 3.04 (s, 2H), 2.40 (m, 2H), 2.18
(s, 6H), 1.80 (m, 2H), 1.54 (m, 2H), 1.48-1.32 (m, 4H); .sup.13C
NMR (100 MHz, CD.sub.3Cl) .delta. 139.8, 134.27, 133.03, 132.99,
132.07, 127.29, 65.40, 47.26, 44.12, 34.37, 26.37, 22.34; ESI MS
m/z 286.1.
1-(1-(6-fluoronaphthalen-2-yl)cyclohexyl)-N-methylmethanamine
(67)
[0248] ##STR122##
[0249] The title compound was synthesized from 39. .sup.1H NMR (400
MHz, CD.sub.3Cl) .delta. 8.55 (m, 1H), 8.19 (m, 1H), 7.56-7.40 (m,
2H), 7.30 (m, 1H), 3.22 (s, 2H), 2.32 (m, 1H), 2.25 (s, 3H), 2.26
(m, 1H), 1.62 (m, 1H), 1.54-1.35 (m, 5H); .sup.13C NMR (400 MHz,
CD.sub.3Cl) 167.08, 159.65, 156.34, 132.86, 132.83, 127.56, 127.49,
126.06, 125.92, 125.85, 125.83, 125.72, 125.32, 125.29, 122.11,
122.03, 108.64, 108.45, 60.17, 44.42, 37.61, 36.73, 35.90, 26.89,
26.82, 22.68, 22.73; ESI MS m/z 272.1.
1-(1-(6-fluoronaphthalen-2-yl)cyclohexyl)-N,N-dimethylmethanamine
(68)
[0250] ##STR123##
[0251] The title compound was synthesized from 39. .sup.1H NMR (400
MHz, CD.sub.3Cl) .delta. 8.47 (m, 1H), 8.17 (m, 1H), 7.50-7.44 (m,
2H), 7.08 (dd, J=10.0, 8.4 Hz, 1H), 2.95 (m, 2H), 2.39 (m, 2H),
2.14 (m, 2H), 1.97 (s, 6H), 1.59 (m, 2H), 1.44(m, 2H); .sup.13CNMR
(100 MHz, CD.sub.3Cl) 167.07, 158.95, 158.31, 133.87, 132.73,
127.32, 127.23, 126.74, 126.72, 125.32, 125.00, 124.99, 121.96,
121.90, 108.61, 108.41, 68.39, 48.40, 45.03, 37.61, 36.62, 26.91,
22.74; ESI MS m/z 286.3.
1-(1-(4-fluoronaphthalen-1-yl)cyclohexyl)-N-methylmethanamine
(69)
[0252] ##STR124##
[0253] The title compound was synthesized from 40. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.5 (m, 1H) 8.19 (m, 1H), 7.5 (m, 3H),
7.10 (dd, J=8.4, 9.0 Hz, 1H), 3.22 (s, 2H), 2.31 (m, 2H), 2.25 (s,
3H), 2.04 (m, 2H), 1.61 (m, 2H), 1.44 (m, 4H); .sup.13C NMR (100
MHz, CD.sub.3OD) .delta. 159.26, 156.78, 136.59, 133.32, 133.29,
159.26, 156.78, 136.59, 133.32, 133.29, 127.56, 127.48, 125.85,
125.85, 125.31, 125.29, 122.11, 122.03, 108.64, 108.46, 60.13,
44.41, 37.59, 36.72, 29.94, 26.89, 26.82, 22.72; ESI MS m/z
272.2.
1-(1-(4-fluoronaphthalen-1-yl)cyclohexyl)-N,N-dimethylmethanamine
(70)
[0254] ##STR125##
[0255] The title compound was synthesized from 40. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.44 (m, 1H), 8.18 (m, 1H), 7.50 (m, 3H),
7.09 (dd, J=8.8, 8.8 Hz, 1H), 2.95 (s, 2H), 2.38 (m, 2H), 2.20 (m,
2H), 1.96 (s, 6H), 1.60 (m, 4H), 1.44 (m, 2H); .sup.13C NMR (100
MHz, CD.sub.3OD), .delta. 159.06, 156.57, 133.53, 127.22, 126.76,
126.73, 125.32, 125.00, 124.99, 121.96, 121.89, 108.00, 108.43,
68.40, 48.42, 45.03, 36.63, 29.94, 26.92, 22.74; ESI MS m/z
286.2.
1-(1-(3,4-dichlorophenyl)cyclohex-3-enyl)-N,N-dimethylmethanamine
(72)
[0256] The title compound was synthesized according to Scheme 26,
below. ##STR126##
[0257] (a) The primary amine 71 was synthesized from
1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile according to
General Procedures Q, U, and E1. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.45 (d, J=8.4 Hz, 1H), 7.39(s, 1H), 7.17 (d, J=8.4 Hz,
1H), 5.75 (m, 1H), 5.64 (m, 1H), 3.16 (d, J=12.8 Hz, 1H), 3.03 (d,
J=12.8 Hz, 1H), 2.5 (d, J=16.8 Hz, 1H), 2.23 (d, J=16.8 Hz, 1H),
2.06 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H), 1.74 (m, 1H); .sup.13C
NMR (100 MHz, CDCl.sub.3) .delta. 140.55, 133.33, 131.96, 131.33,
129.30, 127.53, 126.59, 123.44, 50.25, 39.35, 32.24, 30.58, 22.03;
ESI MS m/z 256.1.
[0258] The title compound was synthesized from 71 according to
General Procedure D. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.35
(broad, 1H), 7.41(s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4
Hz, 1H), 5.75 (m, 1H), 5.62 (m, 1H), 3.02 (s, 2H), 2.64 (d, J=15.6
Hz, 1H), 2.45 (d, J=18.8 Hz, 1H), 2.36 (s, 6H), 1.98 (m, 1H), 1.88
(m, 2H), 1.58 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3), .delta.
144.16, 138.66, 132.99, 131.14, 130.70, 129.04, 127.36, 126.53,
124.13, 69.27, 47.54, 46.45, 40.38, 33.04, 32.93, 21.99; ESI MS m/z
284.0.
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-ethylethanamine
(hydrochloride) (73)
[0259] ##STR127##
(a) Synthesis of
1-(3,4-dichlorophenyl)-N,N-diethylcyclohexane-carboxamide
[0260] The amide was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (232 mg, 0.85
mmol) and diethyl amine using General Procedure G and was isolated
in 13% yield as a white solid. HPLC R.sub.t=12.0 min; .sup.1H NMR
(400 mHz, CDCl.sub.3) 7.38-7.26 (m, 2H), 7.08 (dd, J=2.2, 8.4 Hz,
1H), 3.29 (bs, 2H), 2.84 (bs, 2H), 2.26 (d, J=12.1 Hz, 2H),
1.73-1.54 (m, 7H), 1.29-1.24 (m, 2H), 1.08 (bs, 3H), 0.82 (bs, 3H);
.sup.13C NMR (100 mHz, CDCl.sub.3) 172.9, 147.2, 133.0, 130.8,
130.4, 127.5, 125.2, 51.2, 42.0, 40.9, 37.3, 26.0, 23.7, 13.4,
12.4; GC-MS (SCOUT) 13.2 min, M.sup.+327.
(b) Synthesis of
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-ethylethanamine
(hydrochloride)
[0261] The title compound was synthesized from
1-(3,4-dichlorophenyl)-N,N-diethylcyclohexanecarboxamide (19 mg,
0.058 mmol) using General Procedure E followed by HCL salt
formation. The crude HCl salt was recrystallized from EtOAc (1.5
mL) to give pure
[1-(3,4-Dichloro-phenyl)-cyclohexylmethyl]-diethyl-amine
hydrochloride as an off-white solid. HPLC R.sub.t=9.07 min; .sup.1H
NMR (MeOH-d.sup.4) 7.65 (d, J=2.20 Hz, 1H), 7.55 (d, J=8.55 Hz,
1H), 7.43 (dd, J=2.2, 8.55 Hz, 1H), 3.24 (s, 2H), 2.90-2.83 (m,
4H), 2.30-2.25 (m, 2H), 1.68-1.53 (m, 5H), 1.35-1.24 (m, 3H), 1.10
(at, 6H); LCMS 10.8 min, (M+1).sup.+314 (11.0 min.
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine
(hydrochloride) (74)
[0262] ##STR128##
(a) Synthesis of 1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexane
carboxamide
[0263] The amide was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (182 mg, 0.67
mmol) and dimethyl amine using General Procedure G and isolated in
36% yield as a white solid. HPLC R.sub.t=11.27 min; .sup.1H NMR
(400 mHz, CDCl.sub.3) 7.36-7.34 (m, 2H), 7.06 (dd, J=2.2, 8.4 Hz,
1H), 2.71 (bs, 6H), 2.29 (d, J=12.1 Hz, 2H), 1.68-1.53 (m, 7H),
1.25-1.21 (m, 2H); .sup.13C NMR (100 mHz, CDCl.sub.3) 173.9, 146.9,
133.0, 130.9, 130.4, 127.4, 125.2, 51.0, 38.1, 36.7, 25.9, 23.6;
GC-MS (SCOUT) 12.8 min, M.sup.+299.
(b) Synthesis of
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N,N-dimethylmethanamine
(hydrochloride)
[0264] The title compound was synthesized from
1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexanecarboxamide (71 mg,
0.24 mmol) using General Procedure E followed by HCl salt
formation. The crude HCl salt was recrystallized from CH.sub.3CN (3
mL) to afford the product as an off-white solid. HPLC R.sub.t=8.70
min; .sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.72 (d, J=2.44 Hz, 1H),
7.63 (d, J=8.55 Hz, 1H), 7.49 (dd, J=2.44, 8.55 Hz, 1H), 3.47 (bs,
2H), 3.32 (s, 6H), 2.28-2.24 (bs, 2H), 1.81-1.39 (m, 8H); LCMS 9.79
min, (M+1).sup.+286 @ 10.0 min.
Synthesis of
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine
(hydrochloride) (75)
[0265] ##STR129##
(a) Synthesis of
1-(3,4-dichlorophenyl)-N-methylcyclohexane-carboxamide
[0266] The amide was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (218 mg, 0.80
mmol) and methyl amine using General Procedure G and was isolated
in 35% yield as a white solid. HPLC R.sub.t=10.3 min; .sup.1H NMR
(400 mHz, CDCl.sub.3) 7.47 (d, J=2.20 Hz, 1H), 7.41 (d, J=8.55 Hz,
1H), 7.24 (dd, J=2.44, 8.55 Hz, 1H), 2.71 (d, J=4.88 Hz, 3H),
2.29-2.21 (m, 2H), 1.93-1.85 (m, 2H), 1.61-1.38 (m, 6H); GC-MS
(SCOUT) 12.87 min, M.sup.+285.
(b) Synthesis of
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine
(hydrochloride)
[0267] The title compound was synthesized from
1-(3,4-dichlorophenyl)-N-methylcyclohexanecarboxamide (80 mg, 0.28
mmol) using General Procedure E followed by HCL salt formation. The
crude HCl salt was recrystallized from CH.sub.3CN (3 mL) to give
pure 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylmethanamine
hydrochloride as an off-white solid. HPLC R.sub.t=8.67 min; .sup.1H
NMR (400 mHz, CDCl.sub.3) 7.57-7.54 (m, 2H), 7.34 (dd, J=2.2, 8.43
Hz, 1H), 3.12 (s, 2H), 2.54 (s, 3H), 2.16-2.13 (m, 2H), 1.68-1.50
(m, 5H), 1.41-1.30 (m, 3H); LCMS 8.26 min, (M+1).sup.+272 @ 8.50
min.
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine
(hydrochloride) (76)
[0268] ##STR130##
(a)
1-(3,4-dichlorophenyl)-N-ethyl-N-methyl-cyclohexane-carboxamide
[0269] The amide was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (390 mg, 1.43
mmol) and ethylmethylamine using General Procedure G and was
isolated in 30% yield as a white solid. HPLC R.sub.t=11.66 min;
.sup.1H NMR (400 mHz, CDCl.sub.3) 7.40-7.30 (m, 2H), 7.10 (dd,
J=2.2, 8.4 Hz, 1H), 3.31 (bs, 2H), 2.59 (bs, 3H), 2.30 (d, J=12.5
Hz, 2H), 1.76-1.55 (m, 7H), 1.32-1.25 (m, 2H), 1.00 (bs, 3H);
.sup.13C NMR (100 mHz, CDCl.sub.3) 147.0, 132.9, 130.8, 130.3,
127.5, 125.2, 51.0, 44.5, 36.8, 25.9, 23.5; GC-MS (SCOUT) 13.01
min, M.sup.+313.
(b)
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine
[0270] The title compound was synthesized from
1-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclohexanecarboxamide (130
mg, 0.414 mmol) using General Procedure E followed by HCl salt
formation. The crude HCl salt was recrystallized from CH.sub.3CN (3
mL) to give pure
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine as
white crystals. HPLC R.sub.t=9.00 min; .sup.1H NMR (400 mHz,
MeOH-d.sup.4) 7.65 (d, J=2.2 Hz, 1H), 7.56 (d, J=8.43 Hz, 1H), 7.42
(dd, J=2.2, 8.43 Hz, 1H), 3.43-3.40 (m, 1H), 2.96-2.94 (m, 2H),
2.48 (s, 3H), 2.24 (m, 2H), 1.66-1.53 (m, 5H), 1.41-1.31 (m, 3H),
1.14 (t, 3H); LC-MS 10.07 min, (M+1).sup.+300 @ 10.3 min.
N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine
hydrochloride (77)
[0271] ##STR131##
(a) 1-(3,4-dichlorophenyl)-N-ethylcyclohexane-carboxamide
[0272] The amide was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (280 mg, 1.03
mmol) and ethylamine using General Procedure G and was isolated in
28% yield as a white solid. HPLC R.sub.t=10.61 min; .sup.1H NMR
(400 mHz, CDCl.sub.3) 7.44 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz,
1H), 7.21 (dd, J=2.2, 8.4 Hz, 1H), 5.4 (bs, 1H), 3.21-3.14 (m, 2H),
2.25-2.20 (m, 2H), 1.86-1.79 (m, 2H), 1.58-1.52 (m, 5H), 1.35-1.32
(m, 1H), 1.00 (at, 3H); .sup.13C NMR (100 mHz, CDCl.sub.3) 174.3,
144.8, 132.8, 130.9, 130.7, 128.7, 126.2, 50.5, 34.8, 34.7, 25.7,
23.0, 14.8; GC-MS (SCOUT) 12.9 min, M.sup.+299.
(b) N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine
(hydrochloride)
[0273] The title compound was synthesized from
1-(3,4-dichlorophenyl)-N-ethylcyclohexanecarboxamide (86 mg, 0.286
mmol) using General Procedure E followed by HCl salt formation. The
crude HCl salt was recrystallized from CH.sub.3CN (4.5 mL) to give
pure (.+-.) N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)ethanamine
hydrochloride as colorless crystals. HPLC R.sub.t=8.90 min; .sup.1H
NMR (400 mHz, McOH-d.sup.4) 7.57 (d, J=2.2 Hz, 1H), 7.54 (d, J=8.43
Hz, 1H), 7.34 (dd, J=2.2, 8.43 Hz, 1H), 3.11 (s, 3H), 2.94-2.88 (q,
2H), 2.18-2.15 (m, 2H), 1.68-1.58 (m, 5H), 1.51-1.30 (m, 3H), 1.17
(t, 3H); LC-MS 8.45 min, (M+1).sup.+286 @ 8.7 min.
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropanamine
hydrochloride (78)
[0274] ##STR132##
(a) Synthesis of
1-(3,4-dichlorophenyl)-N-cyclopropylcyclo-hexanecarboxamide
[0275] The tile compound was synthesized from
1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (372 mg, 1.37
mmol) and cyclopropylamine using General Procedure G and was
isolated in 25% yield as a white solid. HPLC R.sub.t=10.6 min;
.sup.1H NMR (400 mHz, CDCl.sub.3) 7.45 (d, J=2.2 Hz, 1H), 7.39 (d,
J=8.43 Hz, 1H), 7.23-7.21 (m, 1H), 5.49 (bs, 1H), 2.62-2.59 (m,
1H), 2.25-2.20 (m, 2H), 1.84-1.78 (m, 2H), 1.59-1.55 (m, 5H),
1.38-1.33 (m, 1H), 0.73-0.68 (m, 2H), 0.37-0.33 (m, 2H); .sup.13C
NMR (100 mHz, CDCl.sub.3) 176.0, 144.8, 133.0, 131.0, 130.8, 128.6,
126.2, 50.4, 34.9, 25.7, 23.1, 6.91; GC-MS (SCOUT) 13.5 min,
M.sup.+311.
(b) Synthesis of
N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-cyclopropanamine
hydrochloride
[0276] The title compound was synthesized from
1-(3,4-dichlorophenyl)-N-cyclopropylcyclohexane carboxamide (108
mg, 0.35 mmol) using General Procedure E followed by HCl formation.
The crude HCl salt was recrystallized from 3:1 EtOAc:CH.sub.3CN (4
mL) and 1:1 EtOAc:CH.sub.3CN (3 mL) to give pure
N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)cyclopropanamine
hydrochloride as white crystals. HPLC R.sub.t=9.02 min; .sup.1H NMR
(400 mHz, MeOH-d.sup.4) 7.57-7.52 (m, 2H), 7.35 (dd, J=1.83, 8.43
Hz, 1H), 3.29 (s, 2H), 2.56-2.54 (m, 1H), 2.16-2.13 (m, 2H),
1.67-1.30 (m, 8H), 0.78-0.74 (m, 4H); LC-MS 10.6 min,
(M+1).sup.+298 @ 10.8 min.
Synthesis of (1-(3-chlorophenyl)cyclohexyl)-N-methylmethanamine
hydrochloride (79)
[0277] ##STR133##
[0278] General Procedure H: A solution of
1-(3-chlorophenyl)cyclohexane-carbaldehyde (119 mg, 0.53 mmol),
methyl amine (291 .mu.L, 0.58 mmol, 2.0 M in THF) and sodium
cyanoborohydride (100 mg, 1.59 mmol) in 1:1
MeOH:Triethylorthoformate (4 mL) was shaken at RT overnight. The
solution was poured into saturated aqueous K.sub.2CO.sub.3 and
washed with EtOAc (2.times.20 mL). The combined organic washes were
dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
material was dissolved in Et.sub.2O and HCl (1.5 mL, 2.0 M in
Et.sub.2O) was added. The reaction was concentrated and the HCl
salt was recrystallized from CH.sub.3CN (4.5 mL) to give pure
(1-(3-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as
colorless crystals HPLC R.sub.t=8.25 min; .sup.1H NMR (400 mHz,
MeOH-d.sup.4) 7.43-7.28 (m, 4H), 3.12 (s, 2H), 2.54 (s, 3H),
2.19-2.16 (m, 2H), 1.67-1.30 (m, 8H); LC-MS 7.29 min,
(M+1).sup.+238 @ 7.50 min.
N-methyl(1-phenylcyclohexyl)methanamine (hydrochloride) (80)
[0279] ##STR134##
[0280] The title compound was synthesized from
1-phenylcyclohexane-carbaldehyde (126 mg, 0.67 mmol) and methyl
amine (370 .mu.L, 0.73 mmol, 2.0 M in THF) according to General
Procedure H, followed by HCl salt formation. The HCl salt was
recrystallized from CH.sub.3CN to give pure
N-methyl(1-phenylcyclohexyl)methanamine hydrochloride (8 mg, 6%) as
colorless crystals. HPLC R.sub.t=7.76 min; .sup.1H NMR (400 mHz,
MeOH-d.sup.4) 7.43-7.38 (m, 4H), 7.28-7.25 (m, 1H), 3.11 (s, 2H),
2.50 (s, 3H), 2.25-2.22 (m, 2H), 1.67-1.23 (m, 8H); LC-MS 6.37 min,
(M+1).sup.+204 @ 6.62 min.
(1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine
hydrochloride (81)
[0281] ##STR135##
[0282] The title compound was synthesized from
1-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (131 mg, 0.58 mmol)
and methyl amine (320 .mu.L, 0.64 mmol, 2.0 M in THF) according to
General Procedure H, followed by HCl salt formation. The HCl salt
was recrystallized from CH.sub.3CN to give pure
(1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine
hydrochloride as colorless crystals. HPLC R.sub.t=8.15 min; .sup.1H
NMR (400 mHz, MeOH-d.sup.4) 7.36-7.21 (m, 3H), 3.11 (s, 2H), 2.55
(d, J=3.67 Hz, 3H), 2.15-2.12 (m, 2H), 1.67-1.31 (m, 8H); LC-MS
7.04 min, (M+1).sup.+240 @ 7.19 min.
(1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine
hydrochloride (82)
[0283] ##STR136##
[0284] The title compound was synthesized from
1-(3-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (191 mg, 0.72
mmol) using General Procedure E, followed by HCl salt formation.
The crude HCl salt was recrystallized from 2:1 CH.sub.3CN:EtOAc
(4.5 mL) to give pure
(1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine
hydrochloride as an off-white solid (21 mg, 12%). HPLC R.sub.t=8.41
min; .sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.51-7.30 (m, 4H),
3.26-3.24 (m, 2H), 2.54 (s, 6H), 2.24-2.20 (m, 2H), 1.72-1.33 (m,
8H); LC-MS 8.16 min, (M+1).sup.+252 @ 8.27 min.
(1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine
hydrochloride (83)
[0285] ##STR137##
[0286] The title compound was synthesized from
1-(3,4-difluorophenyl)-N,N-dimethylcyclohexanecarboxamide (195 mg,
0.73 mmol) using General Procedure E (the amide was prepared from
the corresponding carboxylic acid according to General Procedure
G), followed by HCl salt formation. The crude HCl salt was
recrystallized from 1:1 CH.sub.3CN:EtOAc (3.0 mL) to give pure
(1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine
hydrochloride as an off-white solid (16 mg, 8%). HPLC R.sub.t=8.24
min; .sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.51-7.46 (m, 1H),
7.37-7.34 (m, 2H), 3.31-3.30 (m, 2H), 2.62 (s, 6H), 2.26-2.23 (m,
2H), 1.78-1.38 (m, 8H); LC-MS 7.69 min, (M+1).sup.+254 @ 7.91
min.
(1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride
(84)
[0287] ##STR138##
[0288] The title compound was synthesized from
1-(4-chlorophenyl)-N-methylcyclohexanecarboxamide (278 mg, 1.11
mmol) using General Procedure E, followed by HCl salt formation to
give pure (1-(4-chlorophenyl)cyclohexyl)-N-methylmethanamine
hydrochloride as an off-white solid (185 mg, 70%). HPLC
R.sub.t=8.38 min; .sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.39 (s, 4H),
3.10 (s, 2H), 2.52 (s, 3H), 2.19-2.16 (m, 2H), 1.65-1.49 (m, 6H),
1.37-1.30 (m, 4H); LC-MS 7.49 min, (M+1).sup.+238 (7.63 min.
(1-(4-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine (85)
[0289] ##STR139##
[0290] The title compound was prepared from
1-(4-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (241 mg, 0.91
mmol) according to General Procedure E. The crude product was
purified by preparative TLC with 10% MeOH/CH.sub.2Cl.sub.2
(R.sub.t=0.74) to give
(1-(4-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine free base
(11 mg, 5%) as a clear oil. HPLC R.sub.t=8.55 min; .sup.1H NMR (400
mHz, MeOH-d.sup.4) 7.30 (q, 4H), 2.30 (s, 2H), 2.09-2.06 (m, 2H),
1.97 (s, 6H), 1.60-1.25 (m, 10H); LC-MS 8.09 min, (M+1).sup.+252 @
8.15 min.
N,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride (86)
[0291] ##STR140##
[0292] The title compound was synthesized from
N,N-dimethyl-1-phenylcyclohexanecarboxamide (200 mg, 0.87 mmol)
using General Procedure E, followed by HCl salt formation. The
crude HCl salt was recrystallized from 2:1 EtOAc:CH.sub.3CN to give
N,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride as an
analytically pure off-white solid (8 mg, 4%). HPLC R.sub.t=8.55
min; .sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.30 (q, 4H), 2.30 (s,
2H), 2.09-2.06 (m, 2H), 1.97 (s, 6H), 1.60-1.25 (m, 10H); LC-MS
8.09 min, (M+1).sup.+252 @ 8.15 min. HPLC R.sub.t=8.03 min; .sup.1H
NMR (400 mHz, MeOH-d.sup.4) 7.48-7.39 (m, 4H), 7.29-7.28 (m, 1H),
3.34 (d, J=2.57 Hz, 2H), 2.46 (d, J=3.30 Hz, 6H), 2.29-2.26 (m,
2H), 1.67-1.39 (m, 8H); LC-MS 6.62 min, (M+1).sup.+218 (6.80
min.
(1-(3,4-dichlorophenyl)cyclopentyl)methanamine (87)
[0293] ##STR141##
[0294] General Procedure G1--Amidation with Oxalyl Chloride: To a
solution of 1-(3,4-dichlorophenyl)cyclopentanecarboxylic acid (200
mg, 0.7718 mmol) in DCM (1 mL) and DMF (1 mL) was added oxalyl
chloride (1.54 mL, IM in DCM) dropwise. After five minutes, the
volatiles were removed in vacuo and the residual oil was dissolved
in 2M ammonia (in ethanol). After five minutes, the solvent was
again removed, and the residual oil was partitioned between MTBE
and aqueous potassium bicarbonate. After drying (sodium sulfate),
the solvent was removed to give the crude amide.
[0295] The title compound was synthesized from the above amide
using General Procedure E. The crude product was purified by
reverse-phase preparative HPLC to give the primary amine (20 mg,
11% yield) as a pale-yellow oil. LCMS R.sub.t=7.92 min, m/z=244
(M+1). .sup.1H NMR (CDCl.sub.3, .delta.): 7.35 (m, 2H), 7.11 (dd,
J=2.2, 8.4 Hz, 1H), 2.72 (s, 2H), 2.0-1.6 (m, 8H), 1.1 (s, 2H).
.sup.13C NMR (CDCl.sub.3, .delta., mult): 147.9(0), 132.1(0),
129.9(0), 129.7(1), 129.3(1), 126.7(1), 51.7(2), 35.2(2),
23.4(2).
(1-(3,4-dichlorophenyl)cyclopentyl)-N-methylmethanamine (88)
[0296] ##STR142##
[0297] The title compound was synthesized from
1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and methyl amine
using General Procedure G1, followed by General Procedure E in 49%
yield. LCMS R.sub.t=11.16 min, m/z=258 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.4 (m, 2H), 7.17 (dd, J=2.2, 8.4 Hz, 1H),
2.65 (s, 2H), 2.34 (s, 3H), 2.1-1.6 (m, 8H). .sup.13C NMR
(CDCl.sub.3, .delta., mult): 148.3(0), 132.1(0), 129.9(1),
129.7(0), 129.1(1), 126.5(1), 62.1(2), 51.6(0), 37.3(3), 36.2(2),
23.5(2).
(1-(3,4-dichlorophenyl)cyclopentyl)-N,N-dimethylmethanamine
(89)
[0298] ##STR143##
[0299] The title compound was synthesized from
1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and dimethyl
amine using General Procedure G1, followed by General Procedure E
in 87% yield. LCMS R.sub.t=8.69 min, m/z=272 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.40 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.4 Hz,
1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 2.43 (s, 2H), 20.1 (s, 6H),
2.0-1.6 (m, 8H). .sup.13C NMR (CDCl.sub.3, .delta., mult):
149.2(0), 129.5(0), 129.2(1), 126.7(1), 131.6(1), 69.3(2), 52.1(0),
48.0(3), 36.0(2), 23.2(2).
1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine (90)
[0300] ##STR144##
(a) Synthesis of
1-(4-fluorophenyl)-N-methylcyclohexanecarboxamide
[0301] The title compound was synthesized from
1-(4-fluorophenyl)cyclohexane-carboxylic acid (222 mg, 1 mmol) and
methylamine (1 mL, 1M in THF, 1 eq) according to General Procedure
G. The crude product was purified by silica gel column
chromatography to give the amide (202.6 mg, 86%) as a white
solid.
(b) Synthesis of
1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine
[0302] The title compound was synthesized from the above amide (100
mg, 0.43 mmol) according to General Procedure E to give
1-(1-(4-fluorophenyl)cyclohexyl)-N-methylmethanamine (61.6 mg, 66%)
as a clear oil. LCMS R.sub.t=6.62 min, m/z=222 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.30 (dd, J=5.4, 8.9 Hz, 2H), 6.97 (t, J=8.8
Hz, 2H), 2.58 (s, 2H), 2.57 (s, 3H), 2.1 (m, 2H), 1.7-1.3 (m, 8H).
.sup.13CNMR(CDCl.sub.3, .delta., mult): 162.1(0), 159.7(0),
141.0(0), 128.5(1), 128.4(1), 115.1(1), 114.9(1), 64.6(2), 41.8(0),
37.3(3), 34.7(2), 26.6(2), 22.1(2).
(1-(4-fluorophenyl)cyclohexyl)methaneamine (91)
[0303] ##STR145##
[0304] The title compound was synthesized from
1-(4-fluorophenyl)-cyclohexane-carboxylic acid and ammonia using
General Procedure G, followed by General Procedure E in 99% yield
as a clear oil. LCMS R.sub.t=6.76 min, m/z=208 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.24 (ddd, J=3.2, 5.4, 12.2 Hz, 2H), 7.00
(t, J=8.8 Hz, 2H), 2.67 (s, 2H), 2.1 (m, 2H), 1.6-1.2 (m, 8H),
0.79(bs, 2H). .sup.13C NMR (CDCl.sub.3, .delta., mult): 162.1(0),
159.7(0), 140.3(0), 128.7(1), 128.6(1), 115.1(1), 114.9(1),
54.8(2), 43.2(0), 33.8(2), 26.6(2), 22.1(2).
(1-(4-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (92)
[0305] ##STR146##
[0306] The title compound was synthesized from
1-(4-fluorophenyl)cyclohexane-carboxylic acid and dimethyl amine
using General Procedure G, followed by General Procedure E in 9%
yield as a solid. LCMS R.sub.t=7.22 min, m/z=236 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.32 (dd, J=5.5, 8.9 Hz, 2H), 6.99 (t, J=8.8
Hz, 2H), 2.30 (s, 2H), 2.1 (m, 2H), 1.97, (s, 6H), 1.7-1.3 (m, 8H.
.sup.13C NMR (CDCl.sub.3, .delta., mult): 162.0(0), 159.6(0),
141.7(0), 128.8(1), 128.7(1), 114.7(1), 114.5(1), 72.9(2), 56.5(0),
48.4(3), 34.3(2), 26.6(2), 22.1(2).
N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine (93)
[0307] ##STR147##
[0308] The title compound was synthesized from
1-(naphthalen-2-yl)cyclohexane-carboxylic acid and methyl amine
using General Procedure G, followed by General Procedure E in 74%
yield as a clear oil. LCMS R.sub.t=7.66 min, m/z=254 (M+1). .sup.1H
NMR (CDCl.sub.3, .delta.): 7.82 (m, 4H), 7.54 (dd, J=1.8, 8.7 Hz,
1H), 7.45 (m, 2H), 2.69 (s, 2H), 2.3 (m, 2H), 2.25 (m, 3H), 1.8-1.3
(m, 8H). .sup.13CNMR(CDCl.sub.3, .delta., mult): 142.7(0),
133.4(0), 131.7(0), 128.0(1), 127.9(1), 127.2(1), 126.1(1),
125.7(1), 125.4(1), 125.0(1), 64.4(2), 42.4(0), 37.3(3), 34.7(2),
26.7(2), 22.3(2).
N,N-dimethyl(1-(naphthalen-2-yl)-cyclohexyl)methanamine (94)
[0309] ##STR148##
[0310] The title compound was synthesized from
1-(naphthalen-2-yl)cyclohexane-carboxylic acid and dimethyl amine
using General Procedure G, followed by General Procedure E and was
obtained in 11% yield as a clear oil. LCMS R.sub.t=6.47 min,
m/z=268 (M+1). .sup.1H NMR (CDCl.sub.3, .delta.): 7.80 (m, 4H),
7.55 (dd, J=1.7, 8.6 Hz, 1H), 7.45 (m, 2H), 2.2 (m, 2H), 1.97 (s,
6H), 1.8-1.3 (m, 8H). .sup.13C NMR(CDCl.sub.3, .delta., mult):
133.4, 131.6, 127.9, 127.4, 127.2, 126.2, 126.1, 125.8, 125.5,
125.1, 72.6, 56.6, 48.4, 34.3, 26.6, 22.3.
(1-(4-chloro-3-fluorophenyl)cyclohexyl)-N-methylmethanamine
(95)
[0311] ##STR149##
[0312] General Procedure H1--Reductive Amination: To a solution of
1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde (100 mg, 0.4154
mmol) in methylamine (2.1 mL, 2M in THF, 10 eq) was added acetic
acid (104 ul, 5% of volume), and methanol was added until the
solution became clear. The solution was stirred for two hours. To
the solution was added sodium borohydride (40 mg, 3 eq) and
stirring was continued for 30 minutes. The reaction was quenched
with aqueous potassium carbonate and extracted with MTBE. The
organic phase was separated and the solvent removed in vacuo. The
residue was redissolved in MTBE and extracted with 3M HCl. The
aqueous phase was separated, chilled in ice, and basicified with
KOH. The aqueous phase was then extracted with MTBE and the solvent
removed in vacuo. The residue was diluted in DCM, filtered through
aminopropyl cartridge. The solvent was again removed to give the
secondary amine (75.1 mg, 71%) as a clear oil. LCMS R.sub.t=7.39
min, m/z=256 (M+1). .sup.1H NMR (CDCl.sub.3, .delta.): 7.34 (t,
J=8.2 Hz, 1H), 7.15 (dd, J=2.2, 11.4 Hz, 1H), 7.09 (dd, J=1.9, 8.4
Hz, 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.0 (m, 2H), 1.7-1.3 (m, 8H).
.sup.13C NMR (CDCl.sub.3, .delta., mult): 159.4(0), 156.9(0),
147.2(0), 147.1(0), 130.2(1), 123.5(1), 123.5(1), 118.0(0),
117.8(0), 115.6(1), 115.4(1), 64.2(2), 42.3(0), 37.3(3), 34.5(2),
26.4(2), 22.1(2).
(1-(3-chloro-4-fluorophenyl)cyclohexyl)-N-methylmethanamine
(96)
[0313] ##STR150##
[0314] The title compound was synthesized from
1-(3-chloro-4-fluorophenyl)-cyclohexanecarbaldehyde and methyl
amine using General Procedure H1 and was obtained in 55% yield.
LCMS R.sub.t=7.73 min, m/z=256 (M+1). .sup.1H NMR (CDCl.sub.3,
.delta.): 7.37 (dd, J=2.4, 7.1 Hz, 1H), 7.22 (ddd, J=2.4, 4.6, 8.7
Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 2.58 (s, 2H), 2.29 (s, 3H), 2.0
(m, 2H), 1.7-1.2 (m, 8H). .sup.13C NMR (CDCl.sub.3, .delta., mult):
157.4(0), 154.9(0), 142.9(0), 129.2(1), 126.8(1), 126.7(1),
120.8(0), 120.6(0), 116.3(1), 116.1(1), 64.2(2), 42.1(0), 37.3(3),
34.6(2), 26.4(2), 22.1(2).
(1-(3-chloro-4-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine
(97)
[0315] ##STR151##
[0316] The title compound was synthesized from
1-(3-chloro-4-fluorophenyl)cyclohexanecarbaldehyde and dimethyl
amine using General Procedure H1 and was obtained in 88% yield as
an oily solid. The title compound was also synthesized from
1-(1-(3-chloro-4-fluorophenyl)-cyclohexyl)-N-methylmethanamine
according to General Procedure C.
[0317] LCMS R.sub.t=8.81 min, m/z=270 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.38 (dd, J=2.4, 7.2 Hz, 1H), 7.22 (ddd,
J=2.4, 4.6, 8.7 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 2.29 (s, 2H), 2.0
(m, 2H), 1.99 (s, 6H), 1.7-1.2 (m, 8H). .sup.13C NMR (CDCl.sub.3,
6, mult): 157.2(0), 154.7(0), 143.4(0), 129.6(1), 127.1(1),
127.1(1), 120.3(0), 120.1(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3),
43.0(0), 34.1(2), 26.4(2), 22.0(2).
(1-(4-chloro-3-fluorophenyl)cyclohexyl)-methanamine (98)
[0318] ##STR152##
[0319] The title compound was synthesized from
1-(4-chloro-3-fluorophenyl)-cyclohexanecarbonitrile using General
Procedure E and was obtained in 19% yield as a clear oil. HPLC
R.sub.t=8.28 min. LCMS R.sub.t=8.13 min, m/z=242 (M+1). HCl
salt-.sup.1H NMR (DMSO-d6, .delta.): 7.35 (t, J=8.1 Hz, 1H), 7.17
(d, J=11.3 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 2.82 (s, 2H), 2.1 (m,
2H), 1.7-1.1 (m, 8H). .sup.13C NMR (DMSO-d6, .delta., mult):
159.2(0), 156.7(0), 143.1(0), 143.0(0), 130.6(1), 124.1(1),
124.1(1), 118.5(0), 118.3(0), 116.2(1), 116.0(1), 50.2(2), 40.6(0),
33.3(2), 25.5(2), 21.4(2).
(1-(4-chloro-3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine
(99)
[0320] ##STR153##
[0321] The title compound was synthesized from
1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde and dimethyl
amine using General Procedure H1 and was obtained in 97% yield.
LCMS R.sub.t=9.07 min, m/z=270 (M+1). .sup.1H NMR (CDCl.sub.3,
.delta.): 7.31 (t, J=8.2 Hz, 1H), 7.17 (dd, J=2.1, 11.7 Hz, 1H),
7.09 (dd, J=1.8, 8.5 Hz, 1H), 2.30 (s, 2H), 2.0 (m, 2H), 1.99 (s,
3H), 1.7-1.3 (m, 8H). .sup.13C NMR (CDCl.sub.3, .delta., mult):
159.2(0), 156.7(0), 147.8(0), 129.7(1), 123.9(1), 123.8(1),
117.5(0), 117.3(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.3(0),
34.1(2), 26.4(2), 22.1(2).
N-methyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine
(100)
[0322] ##STR154##
(a) Preparation of
1-(4-(trifluoromethyl)phenyl)cyclohexanecarbonitrile
[0323] The title compound was synthesized from
2-(4-(trifluoromethyl)phenyl)-acetonitrile (4.11 g, 22.2 mmol) and
1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General
Procedure J and was obtained as a clear oil (4.98 g, 89%).
[0324] .sup.1H NMR (CDCl.sub.3) .delta. 1.23-1.39 (m, 1H),
1.76-1.92 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.63 (s, 4H). .sup.13C
NMR (CDCl.sub.3) .delta. 23.7, 25.0, 37.4, 44.7, 122.2, 126.0,
126.7, 130.2, 145.6, GC-MS m/z 253.
(b) Preparation of
1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde
[0325] ##STR155##
[0326] General Procedure M: To a solution of
1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbonitrile (4.80 g,
18.95 mmol) in toluene (60 ml) at -70.degree. C. was dropwise added
1 M DIBAL in hexane (38 ml, 38 mmol) over 30 min. The mixture was
stirred at -70.degree. C. for 30 min and for another 4 h at room
temperature, whereupon ethyl formate (3 ml) was added. The mixture
was stirred at room temperature for 1 hour and was then poured into
saturated NH.sub.4Cl solution (70 ml). After 30 min, 2 M aqueous
H.sub.2SO.sub.4 (100 ml) was added and the product was extracted
with hexanes (3.times.100 ml). The combined organic phases were
dried over MgSO.sub.4 and evaporated in vacuo. The residue was
purified by silica gel column chromatography (EtOAc/hexanes, EtOAc
from 0% to 25%) to give
1-(4-(trifluoromethyl)phenyl)-cyclohexanecarbaldehyde (3.0 g, 65%)
as clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.29-1.37 (m, 1H),
1.46-1.55 (m, 2H), 1.59-1.69 (m, 3H), 1.83-1.90 (m, 2H), 2.29-2.34
(m, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 9.40 (s,
1H). .sup.13C NMR (CDCl.sub.3) .delta. 22.9, 25.6, 31.5, 54.7,
125.9, 126.0, 127.8, 129.5, 144.2, 202.0.
(c) Preparation of
N-methyl(1-(4-(trifluoromethyl)phenyl)cyclohexyl)-methanamine
[0327] General Procedure H2--Reductive Amination: A mixture of
1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde (256 mg, 1.0
mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) in
1,2-dichloroethane was stirred at room temperature for 30 min and
was then treated with sodium triacetoxyborohydride (297 mg, 1.4
mmol). The reaction mixture was stirred at room temperature
overnight and was then quenched with aqueous saturated NaHCO.sub.3
solution (10 ml). The product was extracted with EtOAc (3.times.10
ml). The combined organic layers were dried over MgSO.sub.4 and
evaporated in vacuo. The residue was purified by silica gel column
chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 20%) to give
N-methyl-1-(1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine
(178 mg, 66%). .sup.1H NMR (CDCl.sub.3): .delta. 1.26-1.52 (m 4H),
1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.13-2.18 (m, 2H), 2.28 (s,
3H), 2.63 (s, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.3, 26.7, 34.7, 37.5, 42.9,
64.5, 125.4, 125.9, 127.6, 128.3, 150.2. ESI MS m/z 271.
N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine
(101)
[0328] ##STR156##
[0329] The title compound was prepared from
1-(4-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50
mmol) and dimethylamine (2.0 M in THF, 0.5 ml, 1.0 mmol) according
to General Procedure H2. The crude product was purified by silica
gel column chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to
15%) to give
N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine
(47 mg, 33%). .sup.1H NMR (CDCl.sub.3): .delta. 1.29-1.38 (m 3H),
1.48-1.57 (m, 3H), 1.62-1.68 (m, 2H), 1.97 (s, 6H), 2.13-2.18 (m,
2H), 2.35 (s, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.4, 26.7, 34.4, 37.5, 43.9,
48.6, 72.8, 123.3, 125.0, 125.1, 126.0, 127.6, 127.9, 128.3, 150.8.
ESI MS m/z 286.
1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine
(102)
[0330] ##STR157##
(a) Synthesis of
1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile
[0331] The title compound was prepared according to General
Procedure J to give
1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbonitrile (2.90 g, 57%)
as a white solid. .sup.1H NMR (CDCl.sub.3): .delta. 1.24-1.35 (m,
1H), 1.74-1.88 (m, 7H), 2.16 (d, J=11.2 Hz, 2H), 5.97 (s, 2H), 6.79
(d, J=8.0 Hz, 1H), 6.95-6.99 (m, 2H). .sup.13C NMR (CDCl.sub.3)
.delta. 23.7, 25.0, 37.5, 44.6, 122.5, 122.6, 124.9, 125.0, 129.5,
129.7, 142.8.
(b) Preparation of
1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde
[0332] ##STR158##
[0333] The title compound was prepared from the above nitrile
according to General Procedure M. The crude product was purified by
silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to
25%) to give 1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde
(1.65 g, 56%) as a white solid. .sup.1H NMR (CDCl.sub.3): .delta.
1.25-1.34 (m, 1H), 1.41-1.50 (m, 2H), 1.57-1.70 (m, 3H), 1.73-1.80
(m, 2H), 2.23-2.30 (m, 2H), 5.94 (s, 2H), 6.75-6.82 (m, 3H), 9.30
(s, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 23.0, 25.8, 31.7, 54.1,
101.4, 107.8, 108.7, 120.8, 133.7, 146.9, 148.5, 202.1.
(c)]-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine
[0334] The title compound was prepared from the above
1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0
mmol) and dimethylamine (2.0 M in THF, 1.0 ml, 2.0 mmol) according
to General Procedure H2. The crude product was purified by silica
gel column chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to
15%) to give
1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N,N-dimethylmethanamine
(47 mg, 33%) as clear oil. .sup.1H NMR (CDCl.sub.3): .delta.
1.31-1.41 (m 3H), 1.42-1.53 (m, 3H), 1.56-1.63 (m, 2H), 2.01 (s,
6H), 2.03-2.08 (m, 2H), 2.30 (s, 2H), 5.91 (s, 2H), 6.75 (d, J=8.0
Hz, 1H), 6.82 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.4, 26.8, 34.7, 37.5, 43.2,
48.2, 73.0, 100.9, 108.0, 108.2, 120.5, 140.3, 145.3, 147.8. ESI MS
m/z 262.
1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine
(103)
[0335] ##STR159##
[0336] The title compound was prepared from
1-(benzo[d][1,3]dioxol-5-yl)cyclohexanecarbaldehyde (232 mg, 1.0
mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) according to
General Procedure H2. The crude product was purified by silica gel
column chromatography (SiO.sub.2, MeOH/CH.sub.2Cl.sub.2, MeOH from
0% to 20%) to give
1-(1-(benzo[d][1,3]dioxol-5-yl)cyclohexyl)-N-methylmethanamine (218
mg, 88%). .sup.1H NMR (CDCl.sub.3): .delta. 1.26-1.52 (m 4H),
1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.03-2.12 (m, 2H), 2.28 (s,
3H), 2.60 (s, 2H), 5.90 (s, 2H), 6.75-6.86 (m, 2H), 6.90 (s, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.3, 26.7, 35.2, 37.4, 42.3,
64.8, 101.0, 107.6, 108.2, 120.3, 139.4, 145.6, 148.1. ESI MS m/z
248.
N-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine
(104)
[0337] ##STR160##
(a) Preparation of
1-(3-(trifluoromethyl)phenyl)cyclohexanecarbonitrile
[0338] The title compound was prepared from
2-(3-(trifluoromethyl)phenyl)acetonitrile (3.463 ml, 22.2 mmol) and
1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General
Procedure J to yield
1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.40 g, 90%)
as a clear oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.26-1.39 (m, 1H),
1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.51-7.60 (m, 3H), 7.73
(s, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 23.7, 25.0, 37.5, 44.6,
122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8, GC-MS m/z 253.
(b) Preparation of
1-(3-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde
[0339] ##STR161##
[0340] The title compound was prepared from the above
1-(3-(trifluoromethyl)phenyl)cyclohexane-carbonitrile (5.60 g, 22.1
mmol) according to General Procedure M. The crude product was
purified by silica gel column chromatography (EtOAc/hexanes, EtOAc
from 0% to 25%) to give
1-(3-(trifluoromethyl)phenyl)-cyclohexanecarbaldehyde (3.85 g, 68%)
as a clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.25-1.34 (m,
1H), 1.45-1.53 (m, 2H), 1.59-1.67 (m, 3H), 1.80-1.87 (m, 2H),
2.31-2.35 (m, 2H), 7.45-7.53 (m, 3H), 7.58 (s, 1H), 9.38 (s, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.8, 25.6, 31.5, 54.6, 123.9,
124.0, 124.3, 129.5, 130.9, 141.3, 148.5, 202.0.
(c) Synthesis of
N-methyl-1-(1-(3-(trifluoromethyl)phenyl)-cyclohexyl)methanamine
[0341] The title compound was prepared from
1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (116 mg, 0.5
mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to
General Procedure H2. The crude product was purified by silica gel
column chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 15%)
to give
N-methyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (50
mg, 45%). .sup.1H NMR (CDCl.sub.3): .delta. 1.28-1.52 (m 4H),
1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.29 (s,
3H), 2.66 (s, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.61 (s,
1H). .sup.13C NMR (CDCl.sub.3) .delta. 22.3, 26.7, 34.6, 37.4,
42.6, 64.2, 123.0, 123.9, 127.9, 129.1, 130.8, 131.1, 146.7. ESI MS
m/z 271.
N,N-dimethyl-1-(1-(3-(trifluoromethyl)-phenyl)cyclohexyl)-methanamine
(105)
[0342] ##STR162##
[0343] The title compound was prepared from
1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50
mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according
to General Procedure H2. The crude product was purified by silica
gel column chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to
15%) to give
N,N-dimethyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine
(74 mg, 52%) as a clear oil. .sup.1H NMR (CDCl.sub.3): .delta.
1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.63-1.70 (m, 2H), 1.97 (s,
6H), 2.11-2.15 (m, 2H), 2.34 (s, 2H), 7.41-7.43 (m, 2H), 7.56-7.59
(m, 1H), 7.63 (s, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 22.4,
26.7, 34.3, 43.9, 48.6, 72.7, 122.4, 124.3, 128.6, 126.0, 131.1,
147.6, 150.8. ESI MS m/z 286.
1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (106)
[0344] ##STR163##
(a) Preparation of 1-(3-fluorophenyl)cyclohexanecarbonitrile
[0345] The title compound was prepared from
2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and
1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General
Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile
(4.43 g, 97%) as a clear oil. .sup.1H NMR (CDCl.sub.3) .delta.
1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H),
6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H),
7.30-7.35 (m, 1H). .sup.13C NMR (CDCl3) .delta. 23.7, 25.0, 37.5,
44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.
(b) Preparation of 1-(3-fluorophenyl)cyclohexanecarbaldehyde
[0346] ##STR164##
[0347] The title compound was prepared from
1-(3-fluorophenyl)cyclohexanecarbonitrile (3.52 g, 17.32 mmol)
according to General Procedure M. The crude product was purified by
silica gel column chromatography (EtOAc/hexanes, EtOAc from 0% to
25%) to give 1-(3-fluorophenyl)cyclohexanecarbaldehyde (2.01 g,
56%) as a clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.29-1.37
(m, 1H), 1.44-1.53 (m, 2H), 1.58-1.67 (m, 3H), 1.79-1.85 (m, 2H),
2.26-2.31 (m, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09
(d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H), 9.36 (s, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 22.9, 25.7, 31.5, 54.5, 114.4, 123.0, 130.5,
142.8, 162.2, 164.7, 202.0.
(c) Synthesis of
1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine
[0348] The title compound was prepared from the above
1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.5 mmol) and
methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General
Procedure H2. The crude product was purified by silica gel column
chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 15%) to give
1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (50 mg, 45%).
.sup.1H NMR (CDCl.sub.3): 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H),
1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.28 (s, 3H), 2.61 (s, 2H),
7.45-7.48 (m, 2H), 6.87-6.92 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.16
(d, J=8.0 Hz, 1H), 7.27-7.32 (m, 1H). .sup.13C NMR (CDCl.sub.3)
.quadrature. 22.4, 26.8, 34.9, 37.5, 42.6, 64.6, 112.7, 112.9,
114.2, 114.4, 122.8, 129.9, 130.0, 162.2, 164.7. ESI MS m/z
222.
1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (107)
[0349] ##STR165##
[0350] The title compound was prepared from
1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.50 mmol) and
dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General
Procedure H2. The crude product was purified by column
chromatography (SiO.sub.2, MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to
15%) to give
1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (46 mg,
39%) as a clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.32-1.38 (m
3H), 1.49-1.56 (m, 3H), 1.59-1.66 (m, 2H), 1.99 (s, 6H), 2.05-2.09
(m, 2H), 2.33 (s, 2H), 6.83-6.88 (m, 1H), 7.08 (d, J=8.0 Hz, 1H),
7.14 (d, J=8.0 Hz, 1H), 7.23-7.29 (m, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 22.4, 26.8, 34.4, 43.6, 48.6, 72.9, 112.2,
112.4, 114.6, 114.8, 123.2, 129.4, 129.5, 162.0, 164.5. ESI MS m/z
236.
(.+-.) 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine
(108)
[0351] ##STR166##
(a) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol
[0352] ##STR167##
[0353] To a solution of
1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (440 mg, 1.71 mmol)
in anhydrous THF (17 mL) at 0.degree. C. was added slowly methyl
lithium (1.6 M in Et.sub.2O, 3.21 mL, 5.14 mmol). The solution was
allowed to warm to RT and was stirred for 16 h. It was then
quenched with MeOH (5 mL). The crude reaction mixture was poured
into 2M HCl (15 mL) and washed with EtOAc (3.times.20 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol.
HPLC R.sub.t=11.28 min; .sup.1H NMR (400 mHz, CDCl.sub.3) 7.44-7.41
(m, 2H), 7.20 (dd, J=2.2, 8.4 Hz, 1H), 3.63-3.58 (m, 1H), 2.39-2.35
(m, 1H), 2.14-2.10 (m, 1H), 1.67-1.48 (m, 5H), 1.31-1.16 (m, 3H),
0.92 (d, J=6.6 Hz, 3H).
(b) Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone
[0354] ##STR168##
[0355] To a solution of crude
1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol (494 mg, 1.81 mmol) in
CH.sub.2Cl.sub.2 (18 mL) was added Dess-Martin periodinane (997 mg,
2.35 mmol). The resulting suspension was stirred at RT for 2 h and
was then concentrated. The crude ketone was purified by silica gel
column chromatography with an EtOAc/hexane gradient (product
R.sub.f=0.6 in 10% EtOAc/hexanes) to give
1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (312 mg, 67%) as an
orange oil. HPLC R.sub.t=11.61 min; .sup.1H NMR (400 mHz,
CDCl.sub.3) 7.42-7.40 (m, 2H), 7.15 (dd, J=2.2, 8.4 Hz, 1H),
2.32-2.29 (m, 2H), 1.92 (s, 3H), 1.80-1.74 (m, 2H), 1.65-1.43 (m,
5H), 1.35-1.30 (m, 1H); .sup.13C NMR (100 mHz, CDCl.sub.3) 209.5,
143.3, 133.2, 131.3, 130.9, 128.9, 126.3, 56.2, 33.7, 25.8 (2
overlapping peaks), 23.2.
(c) Synthesis of
(.+-.)1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine
hydrochloride
[0356] A mixture of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone
(247 mg, 0.91 mmol) and methyl amine (455 .mu.L, 2.0 M in THF, 0.91
mmol) was stirred at RT for 2 min. Titanium (IV) isoproxide (336
.mu.L, 1.14 mmol) was then added. The viscous green/yellow solution
was stirred at RT for 3 h. NaBH.sub.3CN solution (640 .mu.L, 1.0 M
in MeOH, 0.64 mmol) was added and the cloudy solution was stirred
at RT for 16 h. The solution was quenched with saturated NaCl
solution (3 mL), filtered, and washed with MeOH (50 mL). 6M HCl (20
mL) was added and the aqueous phase washed with Et.sub.2O
(2.times.20 mL). The pH of the aqueous phase was adjusted to pH=12
with 3M NaOH and washed with EtOAc (3.times.30 mL). The combined
organic phases were dried (Na.sub.2SO.sub.4), filtered and
concentrated. To a solution of the crude amine in Et.sub.2O (3 mL)
was added HCl (3 mL, 2.0 M in Et.sub.2O). The crude HCl salt was
recrystallized from CH.sub.3CN (6 mL) at 110.degree. c. to give
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (8 mg) as
white crystals. HPLC R.sub.t=8.90 min; .sup.1H NMR (400 mHz,
CD.sub.3OD) 7.57-7.53 (m, 2H), 7.33-7.31 (m, 1H), 3.15-3.13 (m,
2H), 2.61 (s, 3H), 2.45 (broad d, J=11.73 Hz, 1H), 2.30 (broad d,
J=12.46, 1H), 1.59-1.51 (m, 5H), 1.31-1.08 (m, 6H); LC-MS 7.87 min,
(M+1).sup.+286 (8.10 min.
Synthesis of 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-one
(a) 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-ol
[0357] ##STR169##
[0358] 1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (519 mg, 2.01
mmol) was dissolved in anhydrous THF (17 mL) and cooled to
0.degree. C. Ethyl magnesium chloride (2.0 M in THF, 3.03 mL, 6.06
mmol) was added slowly. The solution was allowed to warm to RT and
stir for 16 h, then quenched with MeOH (5 mL). The crude reaction
mixture was poured into 2M HCl (15 mL) and washed with EtOAc
(3.times.20 mL). The combined organic washes were dried
(Na.sub.2SO.sub.4), filtered and concentrated to give the secondary
alcohol (443 mg, 77% for 2 steps) as a white solid. HPLC
R.sub.t=11.65 min; .sup.1H NMR (400 mHz, CDCl.sub.3) 7.43-7.41 (m,
2H), 7.19 (dd, J=2.2, 8.4 Hz, 1H), 3.27-3.23 (m, 1H), 2.37-2.33 (m,
1H), 2.17-2.14 (m, 1H), 1.57-1.46 (m, 6H), 1.29-1.17 (m, 4H),
0.90-0.77 (m, 4H); .sup.13C NMR (125 mHz, CDCl.sub.3) 143.0, 132.4,
130.9, 130.1, 130.0, 128.3, 81.7, 47.1, 32.6 (doublet), 26.7, 24.4,
22.2, 11.4.
(b) 1-(1-(3,4-dichlorophenyl)cyclohexyl)propan-1-one
[0359] ##STR170##
[0360] The crude ethyl alcohol product (577 mg, 2.01 mmol) was
dissolved in CH.sub.2Cl.sub.2 (20 mL) and Dess-Martin Periodinane
(1.1 g, 2.61 mmol) was added. The white opaque suspension was
stirred at RT for 2 h, then concentrated. The crude ketone was
purified by silica gel column chromatography with an EtOAc/hexane
gradient (R.sub.f=0.6 in 10% EtOAc/hexanes) to give the desired
ethyl ketone (443 mg, 77%) as a white solid. HPLC R.sub.t=12.0 min;
.sup.1H NMR (400 mHz, CDCl.sub.3) 7.44-7.38 (m, 2H), 7.11 (dd,
J=2.6, 8.4 Hz, 1H), 2.32-2.20 (m, 4H), 1.80-1.74 (m, 2H), 1.68-1.42
(m, 5H), 1.34-1.26 (m, 2H), 0.90 (t, 3H); .sup.13C NMR (125 mHz,
CDCl.sub.3) 212.1, 143.6, 133.1, 130.9, 130.8, 128.8, 126.3, 56.0,
33.7, 30.7, 25.8, 23.3, 8.49. This compound can be used to
synthesize compounds of the invention with R.sup.1=ethyl, e.g.,
through reductive amination. Exemplary compounds include:
##STR171##
1.4. Synthesis of 3,4-dichlorophenyl cyclohexylamines with Cyclic
Amine Substituents from Corresponding Carboxylic Acids
[0361] ##STR172##
[0362] Compounds in Table 3, below, were synthesized from the
corresponding carboxylic acids via the amide intermediate according
to General Procedure G and General Procedure E. TABLE-US-00003
TABLE 3 Summary of Exemplary Cyclic Amines
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)piperidine (109)
##STR173## HPLC R.sub.t = 9.20 min; .sup.1H NMR(400 MHz,
MeOH-d.sup.4) 7.65(s, 1H), 7.50(d, J=8.8Hz, 1H), 7.43-7.41(m, 1H),
3.22(t, J=1.47Hz, 1H), 3.05-2.99(m, 2H), 2.73-2.67(m, 2H),
2.22-2.18(m, 2H), 1.71-1.26(m, 14H); LC-MS 11.79 min, (M + 1).sup.+
326 @ 11.91 min.
4-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)morpholine (110)
##STR174## HPLC R.sub.t = 8.82 min; .sup.1H NMR(400 MHz,
MeOH-d.sup.4) 7.66(d, J=1.83Hz, 1H), 7.54(d, J=8.43Hz, 1H),
7.43(dd, J=2.2, 8.43Hz, 1H), 3.81-3.70(m, 4H), 3.46(s, 2H),
3.25-3.24(m, 2H), 3.07-3.04(m, 2H), 2.93-2.88(m, 2H), 2.24-2.20(m,
2H), 1.78-1.70(m, 2H), 1.61-1.31(m, 6H); LC-MS 11.09 min, (M +
1).sup.+ 328 @ 11.28 min.
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)pyrrolidine (111)
##STR175## HPLC R.sub.t = 9.12 min; .sup.1H NMR(400 MHz,
CDCl.sub.3) 7.43(d, J=2.20Hz, 1H), 7.35(d, J=8.43Hz, 1H),
7.22-7.20(m, 1H), 2.52(s, 2H), 2.23(s, 3H), 2.05-2.02(m, 2H),
1.65-1.48(m, 10H), 1.38-1.25(m, 3H); LC-MS 9.31 min, (M + 1).sup.+
312 @ 9.39 min.
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-4-methylpiperazine
(112) ##STR176## Prepared from Amide Intermediate 298 HPLC R.sub.t
= 9.47 min; .sup.1H NMR(400 MHz, MeOH-d.sup.4) 7.64(s, 1H), 7.49(d,
J=8.43Hz, 1H), 7.42(d, J=8.79Hz, 1H), 3.46(bs, 4H), 3.10(bs, 3H),
2.83(s, 3H), 2.26-2.22(m, 2H), 1.73-1.67(m, 2H), 1.57-1.28(m, 7H);
LC-MS 10.36 min, (M + 1).sup.+ 341 @ 10.51 min. (.+-.)
1-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)-2,3-di-
hydro-1H-inden-2-ol (113) ##STR177## HPLC R.sub.t = 9.44 min;
.sup.1H NMR(400 MHz, CDCl.sub.3) 7.49(d, J=2.2Hz, 1H), 7.42(d,
J=8.43Hz, 1H), 7.26-7.13(m, 4H), 6.91(d, J=6.97Hz, 1H),
4.35-4.32(m, 1H), 3.90(d, J=5.13Hz, 1H), 3.02-2.88(m, 3H), 2.79(d,
J=11.7Hz, 1H), 2.19-2.16(m, 1H), 2.07-2.04(m, 1H), 1.74-1.26(m,
9H); LC-MS 10.84 min, (M + 1).sup.+ 390 @ 10.99 min. (.+-.)
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-3-methylpiperidine
(114) ##STR178## HPLC R.sub.t = 9.46 min; .sup.1H NMR(400 MHz,
CD.sub.3OD) 7.69(dd, J=1.83, 14.66Hz, 1H), 7.54(d, J=8.43Hz, 1H),
7.49-7.44(m, 1H), 3.51-3.41(m, 1H), 3.26-3.25(d, J=1.47Hz, 1H),
3.06-2.90(m, 3H), 2.73-2.58(m, 1H), 2.43-2.37(m, 1H), 2.25(bs, 2H),
1.96-1.29(m, 11H), 1.08-0.96(m, 1H), 0.78(m, 3H); LC-MS 11.95 min,
(M + 1).sup.+ 340 @ 12.18 min. (.+-.)
1-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-2-methylpyrrolidine
(115) ##STR179## HPLC R.sub.t = 9.25 min; .sup.1H NMR(400 MHz,
CD.sub.3OD) 7.64(s, 1H), 7.55(dd, J=3.67, 8.43Hz, 1H), 7.42(d,
J=7.33Hz, 1H), 3.52(d, J=13.6Hz, 1H), 3.25(s, 2H), 3.00-2.98(m,
1H), 2.69-2.65(m, 1H), 2.37-2.34(m, 1H), 2.11(bs, 2H), 1.91-1.23(m,
14H); LC-MS 10.1 min, (M + 1).sup.+ 326 @ 10.1 min. (.+-.)
2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclopentanol
(116) ##STR180## HPLC R.sub.t = 8.86 min; .sup.1H NMR(400 MHz,
CD.sub.3OD) 7.58(d, J=2.57Hz, 1H), 7.53(d, J=8.43Hz, 1H),
7.39-7.36(m, 1H), 4.03-3.98(m, 1H), 3.40(d, J=13.2Hz, 1H),
3.17-3.10(m, 2H), 2.17-2.04(m, 3H), 1.95-1.89(m, 1H), 1.71-1.32(m,
12H); LC-MS 9.31 min, (M + 1).sup.+ 342 @ 9.42 min. (.+-.)
2-((1-(3,4-dichlorophenyl)cyclohexyl)methylamino)cyclohexanol (117)
##STR181## HPLC R.sub.t = 9.1 min; .sup.1H NMR(400 MHz, CD.sub.3OD)
7.60(d, J=2.20Hz, 1H), 7.60-7.52(m, 1H), 7.41-7.37(m, 1H),
3.48-3.43(m, 1H), 3.15-3.11(m, 1H), 2.75-2.69(m, 1H), 2.21-2.11(m,
2H), 1.98-1.15(m, 16H); LC-MS 9.50 min, (M + 1).sup.+ 356 @ 9.6
min.
Example 2
Synthesis of 2-Substituted Cycloalkylamines
2.1. Synthesis of 2-Hydroxy-Substituted Cycloalkylamines
[0363] The below described compound of the invention were
synthesized from the corresponding bromomethyl analogs according to
General Procedures O and P (outlined below). ##STR182##
cis-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (cis
121)
[0364] ##STR183## cis 121 E1 cis 121 E2
(a) Preparation of racemic
(cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)-cyclohexanol
[0365] General Procedure O: A mixture of
(cis)-2-(bromomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (148 mg,
0.438 mmol) and sodium azide (85 mg, 1.314 mmol), in DMF (2 ml) was
stirred at 70.degree. C. for 48 hours. The reaction mixture was
filtered and evaporated in vacuo. The residue was partitioned
between water (5 ml) and EtOAc (10 ml). The organic layer was
separated, washed with water (2.times.5 ml), dried over
Na.sub.2SO.sub.4, and evaporated to give
(cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (110 mg,
84%) as a clear oil.
[0366] The enantiomers of
(cis)-2-(azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol were
separated using preparative HPLC (ChiralPak OJ column;
hexanes:IPA=90:10; 8 ml/min; .lamda.=280 nm) to give cis 120 E1
(retention time=10.5 min) and cis 120 E2 (retention time=13.7 min).
The absolute configurations of the chiral centers were not
determined. .sup.1H NMR (CDCl.sub.3) .delta. 0.96-1.03 (m, 1H),
1.43-1.54 (m, 3H), 1.67-1.75 (m, 4H), 2.00 (brs, 1H), 2.08-2.14 (m,
1H), 3.43 (d, J=12.0 Hz, 1H), 3.65 (d, J=12.0 Hz, 1H), 4.04 (t,
J=6.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 2.4 Hz,
1H), 7.75 (s, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 21.4, 22.8,
30.2, 30.4, 47.4, 59.8, 74.0, 127.9, 130.6, 130.8, 131.2, 132.9,
142.7.
(b) Synthesis of
cis-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanols
[0367] General Procedure P: To a solution of cis 120 E1 (37 mg,
0.124 mmol) in EtOAc (2 ml) was added Pd/C (10%, 20 mg). A hydrogen
balloon was attached and the reaction mixture was stirred at room
temperature for 30 min. The mixture was filtered and evaporated.
The residue was purified by silica gel column chromatography
(MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 15%) to give the primary
amine cis 121 E1 (24 mg, 69%) as clear oil.
[0368] Cis 121 E2 was synthesized from cis 120 E2 (31 mg, 0.124
mmol) according to General Procedure P to give the primary amine
(21 mg, 72%) as a clear oil.
[0369] .sup.1H NMR (CDCl.sub.3) .delta.0.96-1.03 (m, 1H), 1.23-1.44
(m, 3H), 1.65-1.69 (m, 1H), 1.78-1.83 (m, 2H), 1.98-2.02 (m, 1H),
2.91 (d, J=13.6 Hz, 1H), 3.07 (d, J=13.6 Hz, 1H), 4.03 (dd, J=10.0
Hz, 3.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.71 (dd, J=12.0, 2.4 Hz,
1H), 7.96 (s, 1H). .sup.13C NMR (CD.sub.3Cl): .delta. 21.4, 24.6,
30.2, 35.2, 46.9, 56.3, 81.1, 129.3, 130.3, 130.4, 131.7, 132.6,
142.7. ESI MS m/z 274.
trans-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (trans
121)
[0370] ##STR184## trans 121 E1 trans 121 E2
(a) Preparation of racemic
(trans)-2-(Azidomethyl)-2-(3,4-dichlorophenyl)cyclohexanol
[0371] The title compound was prepared from
trans-2-(bromomethyl)-2-(3,4-dichlorophenyl)cyclohexanol (103 mg,
0.305 mmol) and sodium azide (59 mg, 1.314 mmol) according to
General Procedure O to give the azide (70 mg, 76%) as a clear oil.
The enantiomers were separated as described to give trans 120 E1
(retention time=11.7 min) and trans 120 E2 (retention time=14.2
min). .sup.1H NMR (CDCl.sub.3) .delta. 1.38-1.46 (m, 2H), 1.51-1.56
(m, 1H), 1.62-1.66 (m, 2H), 1.71-1.76 (m, 1H), 1.80-1.93 (m, 3H),
3.43 (d, J=12.4 Hz, 1H), 3.81 (d, J=12.4 Hz, 1H), 4.24 (t, J=4.0
Hz, 1H), 7.25-7.28 (m, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.51 (d, J=1.6
Hz, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 21.3, 21.6, 29.7, 29.8,
46.8, 57.6, 71.3, 126.7, 129.4, 130.4, 130.6, 132.9, 146.5.
(b) Synthesis of
trans-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclohexanol
[0372] Trans 121 E1 and trans 121 E2 were prepared from trans 120
E1 and trans 120 E2, respectively, according to General Procedure
P. The crude products were purified by chromatography (SiO.sub.2,
MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 15%) to give the primary
amines (about 15 mg each, 65%) as clear oils.
[0373] .sup.1H NMR (CDCl.sub.3) .delta. 1.28-1.50 (m, 4H),
1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 3.02 (d, J=12.4 Hz, 1H), 3.38
(d, J=12.4 Hz, 1H), 4.20 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40-7.47 (m,
2H), 7.69 (d, J=1.6 Hz, 1H). .sup.13C NMR (CDCl.sub.3) .delta.
21.5, 22.3, 29.9, 30.4, 44.8, 57.1, 71.5, 126.9, 129.6, 131.1,
131.4, 133.3, 142.9. ESI MS m/z 274.
2.2. Synthesis of 2-Methoxy-Cycloalkylamines
[0374] The following compounds were synthesized according to the
Scheme, below. ##STR185##
1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine
(124)
A. Synthesis of
cis-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine
(cis 124)
[0375] A solution of (.+-.) cis 122 [Boc-protected (.+-.)
cis-2-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclohexanol]
(0.88 g, 2.27 mmol) and NaH (100 mg, 2.50 mmol) in THF (30 ml) was
stirred at room temperature for 30 min. To the mixture was added
CH.sub.3I (1.41 ml, 22.7 mmol) and the reaction mixture was stirred
at room temperature for 24 hours. It was diluted with water (20 ml)
and extracted with CH.sub.2Cl.sub.2 (3.times.30 ml). The organic
layer washed with water (2.times.30 ml) and brine (30 ml), dried
over Na.sub.2SO.sub.4, and evaporated in vacuo. The residue was
purified by silica gel column chromatography
(MeOH/CH.sub.2Cl.sub.2, MeOH from 0% to 5%) to give (.+-.) cis
123.
[0376] To a solution of (.+-.) cis 123 in CH.sub.2Cl.sub.2 (5 ml)
was added dropwise TFA (5 ml) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 2 hours and the solvent was removed in
vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 (10 ml),
washed with saturated K.sub.2CO.sub.3 solution (5 ml), dried over
Na.sub.2SO.sub.4, and evaporated in vacuo. The residue was purified
by silica gel column chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH
from 0% to 15%) to give (.+-.) cis 124 (0.225 g, 33%) as clear oil.
.sup.1H NMR (CDCl.sub.3) .delta. 1.38-1.43 (m, 1H), 1.47-1.54 (m,
2H), 1.62-1.66 (m, 1H), 1.74-1.87 (m, 3H), 2.01-2.04 (m, 1H), 2.29
(s, 3H), 2.71 (d, J=14 Hz, 1H), 2.76 (d, J=14 Hz, 1H), 3.25 (s,
3H), 3.52 (dd, J=8.8, 3.2 HZ, 1H), 7.29-7.38 (m, 2H), 7.59 (s, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 21.9, 23.7, 25.0, 31.6, 48.7,
49.1, 56.7, 68.1, 83.3, 128.4, 129.5, 129.7, 131.1, 131.8, 145.8.
ESI MS m/z 302.
B. Synthesis of
trans-1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N-methylmethanamine
(trans 124)
[0377] The title compound was prepared from (.+-.) trans 122 (0.91
g, 2.34 mmol) according to the procedure described above for the
corresponding cis-isomer to give (.+-.) trans 124 (0.219 g, 30%) as
clear oil.
[0378] The enantiomers of (.+-.) trans 124 were separated using
preparative HPLC (ChiralPak OD column; hexanes:IPA:DEA=95:5:0.1; 8
ml/min; .lamda.=280 nm) to give trans 124 E1 (retention time=10
min) and trans 124 E2 (retention time=18 min). The absolute
configurations of the chiral centers were not determined. .sup.1H
NMR (CDCl.sub.3) .delta. 1.24-1.42 (m, 2H), 1.60-1.77 (m, 2H),
1.85-1.92 (m, 2H), 2.33 (s, 3H), 2.70 (d, J=13.6 Hz, 1H), 2.93 (d,
J=13.6 Hz, 1H), 3.33 (s, 3H), 3.64 (dd, J=7.6, 2.4 Hz, 1H), 7.25
(d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.47 (s, 1H). .sup.13C
NMR (CDCl.sub.3) .delta. 21.6, 21.8, 24.9, 30.6, 37.4, 46.8, 57.2,
58.5, 81.5, 127.2, 129.7, 130.2, 130.4, 132.7, 145.1. ESI MS m/z
302.
1-(1-(3,4-dichlorophenyl)-2-methoxycyclohexyl)-N,N-dimethylmethanamine
(125)
[0379] ##STR186##
[0380] The following compounds were prepared from the respective
monomethyl amine according to General Procedure F. The crude
products were purified by silica gel column chromatography
(dichloromethane/methanol, 0-5% MeOH) to give the desired dimethyl
amine.
[0381] (.+-.) cis 125 was prepared from (.+-.) cis 124 (54 mg, 83%,
clear oil). .sup.1H NMR (CDCl.sub.3) .delta. 1.35-1.42 (m, 2H),
1.47-1.54 (m, 2H), 1.62-1.66 (m, 1H), 1.74-1.87 (m, 2H), 2.01-2.04
(m, 1H), 2.12 (s, 6H), 2.31 (d, J=14 Hz, 1H), 2.65 (d, J=14 Hz,
1H), 3.31 (s, 3H), 3.52 (dd, J=8.8, 3.2 HZ, 1H), 7.32 (d, J=8.8 Hz,
1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.70 (s, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 21.9, 23.7, 25.0, 31.6, 48.7, 49.1, 56.7,
68.1, 83.3, 128.4, 129.5, 129.7, 131.1, 131.8, 145.8. ESI MS m/z
316.
[0382] Trans 125 E1 and trans 125 E2 were prepared from trans 124
E1 and trans 124 E2, respectively. 1H NMR (CDCl3) .delta. 1.24-1.39
(m, 3H), 1.42-1.60 (m, 2H), 1.77-1.88 (m, 2H), 1.91 (s, 6H), 2.25
(d, J=13.6 Hz, 1H), 2.71 (d, J=13.6 Hz, 1H), 3.36 (s, 3H), 3.76 (s,
1H), 7.25 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.49 (s, 1H).
13C NMR (CDCl3) .delta. 20.9, 21.5, 23.7, 28.8, 48.3, 56.5, 67.6,
79.4, 127.6, 129.8, 130.2, 130.4, 132.2, 145.6. ESI MS m/z 316.
2.3. Synthesis of 2-Aminomethyl-2-aryl-cyclohexanol Analogs via
Carboxylic Acids
[0383] ##STR187##
2.3.1. Preparation of Arylhydroxyacids (130a-130i)
[0384] The preparation of Arylhydroxyacids is outlined in Scheme
27, below. Commercial arylboronic acids 126 were converted to the
aryllead intermediates 127 using lead acetate and mercuric acetate.
Compounds 127 were used in situ to .alpha.-arylate
2-ethylcyclohexanonecarboxylate to provide ketoesters 128 as
racemic mixtures in 32-71% overall yield. Reduction of racemic
ketones 128 with sodium borohydride produced four isomeric
hydroxyester products, 129 (.+-.) cis and 129 (.+-.) trans in 29%
to quantitative yields. The pair of cis isomers were separated from
the pair of trans isomers to give the enantiomeric mixtures 129
(.+-.) cis and 129 (.+-.) trans using a Biotage chromatography
system (Sorbent Technologies, 800 g, 40-75 .mu.m SiO.sub.2,
heptane/ether). Each of 129 (.+-.) cis and 129 (.+-.) trans were
saponified with sodium hydroxide in methanol/water to provide the
hydroxyacids 130 (.+-.) cis and 130 (.+-.) trans, respectively, in
55% to quantitative yield after extraction. ##STR188##
2.3.2. General Procedure N: Synthesis of Aryl-Plumbanetriyl
Triacetate
[0385] A mixture of chloroform (e.g., 200 mL), lead (IV) acetate
(e.g., 58.1 g, 131 mmol, 1 eq), and mercuric acetate (2.09 g, 6.55
mmol, 0.05 eq) was warmed to 40.degree. C. The respective
arylboronic acid (e.g., 131 mmol) was added in portions over 15
minutes. The mixture was stirred at 40.degree. C. for one hour,
then cooled to room temperature and stirred overnight. This crude
mixture was used immediately in the next reaction step.
[0386] The following compounds were prepared from the corresponding
boronic acids 126 following the procedure outlined in General
Procedure N, above: [0387] (127a) (3,4-Dichlorophenyl)plumbanetriyl
triacetate [0388] (127b) (3,4-Methylenedioxy)plumbanetriyl
triacetate [0389] (127c) (4-Chlorophenyl)plumbanetriyl triacetate
[0390] (127d) (3-Chlorophenyl)plumbanetriyl triacetate [0391]
(127e) (4-Methoxyphenyl)plumbanetriyl triacetate [0392] (127f)
(4-Chloro-3-fluorophenyl)plumbanetriyl triacetate [0393] (127 g)
(4-Trifluoromethylphenyl)plumbanetriyl triacetate [0394] (127h)
(4-Trifluoromethoxyphenyl)plumbanetriyl triacetate [0395] (127i)
Naphthalen-2-ylplumbanetriyl triacetate
2.3.3 General Procedure Q: Synthesis of Esters (128a-128i)
[0396] To the crude reaction mixture of the respective lead
intermediate arylplumbanetriyl triacetate 2 was slowly added
pyridine (e.g., 31.8 mL, 393 mmol) and
ethyl-2-oxocyclohexanecarboxylate (e.g., 22.3 g, 131 mmol). The
reaction mixture was heated to 40.degree. C. and stirred for 72
hours and was then diluted with chloroform (e.g., 200 mL) and
poured into water (e.g., 300 mL). The phases were separated and the
organic layer washed with 2 N H.sub.2SO.sub.4 (2.times.200 mL),
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by silica gel flash chromatography using the indicated
solvent systems to give the alph-keto esters 3.
[0397] The following compounds were prepared from the corresponding
intermediate 127 following the procedure outlined in General
Procedure Q, above: [0398] (128a) (.+-.)
Ethyl-1-(3,4-Dichlorophenyl)-2-oxocyclohexane-carboxylate
(hexane/ethyl acetate, 100:0 to 90:10, 46%, white solid) [0399]
(128b) (.+-.)
Ethyl-1-(3,4-methylenedioxy)-2-oxocyclohexane-carboxylate
(hexane/ethyl acetate, 9:1, 45%, white solid) [0400] (128c) (.+-.)
Ethyl-1-(4-Chlorophenyl)-2-oxocyclohexanecarboxylate
(hexane/diethyl ether, 96.6 g, 68%, light yellow oil) [0401] (128d)
(.+-.) Ethyl-1-(3-chlorophenyl)-2-oxocyclohexane-carboxylate
(hexane/diethyl ether, 130 g, 71%, white solid) [0402] (128e)
(.+-.) Ethyl-1-(4-methoxyphenyl)-2-oxocyclohexane-carboxylate
(hexane/ethyl acetate, 100:0 to 90:10, 87.0 g, 63%, yellow
semi-solid) [0403] (128f) (.+-.)
Ethyl-1-(4-Chloro-3-fluorophenyl)-2-oxocyclohexane-carboxylate
(hexane/ethyl acetate, 100:0 to 95:5, 67.4 g, 52%, white solid).
[0404] (128 g) (.+-.)
Ethyl-1-(4-Trifluoromethylphenyl)-2-oxocyclohexanecarboxylate
(hexane/ethyl acetate, 100:0 to 90:10, 43.0 g, 34%, white solid).
[0405] (128h)
Ethyl-1-(4-trifluoromethoxy)-2-oxocyclohexanecarboxylate
(hexane/diethyl ether, 49.5 g, 61%, colorless oil) [0406] (128i)
(.+-.) Ethyl-1-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate
(hexane/ethyl acetate, 100:0 to 90:10, 79.8 g, 60%, yellow
semi-solid)
2.3.4. NaBH.sub.4 Reduction and Separation of Diastereomers
(Synthesis of 129a-129i)
[0407] General Procedure R: To a solution of the respective
ketoester 3 (e.g., 17.8 g, 56.5 mmol) in ethanol (e.g., 280 mL) at
0.degree. C. was added sodium borohydride (e.g., 2.56 g, 67.8 mmol)
portionwise. The mixture was stirred for 3 hours and was then
concentrated. The residue was dissolved in diethyl ether (e.g., 200
mL) and 2 N HCl (e.g., 125 mL) was then slowly added. The phases
were separated and the aqueous layer was extracted with diethyl
ether (e.g., 3.times.100 mL). The organic layers were combined and
washed with brine (e.g., 125 mL), dried over MgSO.sub.4, filtered,
and concentrated. The crude product was purified by silica gel
flash chromatography using hexane/ethyl acetate or hexane/ethyl
ether gradients to give a mixture of cis/trans diastereomers
(13-100 g, 59-96% yield).
[0408] Separation of the diastereomers was accomplished using a
Biotage chromatography system (Sorbent Technologies, 800 g, 40-75
.mu.m SiO.sub.2, heptane/ether, 80:20 isocratic), unless otherwise
indicated. Up to 20 g of crude product were separated per injection
to obtain the final products with 63-85% overall recovery.
Generally, the mixture of trans-enantiomers, (.+-.) trans 129,
eluted from the column first, followed by the mixture of
cis-enantiomers, (.+-.) cis 129.
[0409] The following compounds (cis- and trans-diastereomers each)
were prepared from the corresponding intermediate 128 following the
procedure outlined in General Procedure R, above. [0410] (cis 129a)
(.+-.) cis
ethyl-1-(3,4-dichlorophenyl)-2-hydroxycyclohexane-carboxylate
[0411] (trans 129a) (.+-.) trans
ethyl-1-(3,4-dichlorophenyl)-2-hydroxycyclohexane-carboxylate
[0412] (cis 129b) (.+-.) cis
ethyl-1-(3,4-methylenedioxy)-2-hydroxycyclohexanecarboxylate [0413]
(trans 129b) (.+-.) trans
ethyl-1-(3,4-methylenedioxy)-2-hydroxycyclohexanecarboxylate [0414]
(cis 129c) (.+-.) cis
ethyl-1-(4-chlorophenyl)-2-hydroxycyclohexane-carboxylate [0415]
(trans 129c) (.+-.) trans
ethyl-1-(4-chlorophenyl)-2-hydroxycyclohexanecarboxylate [0416]
(cis 129d) (.+-.) cis
ethyl-1-(3-chlorophenyl)-2-hydroxycyclohexane-carboxylate [0417]
(trans 4d) (.+-.) trans
ethyl-1-(3-chlorophenyl)-2-hydroxycyclohexane-carboxylate [0418]
Separation of the diastereomers was accomplished on a Symmetry C18
Column (50.times.250, 7.mu.; MeCN/water 55:45) [0419] (cis 129e)
(.+-.) cis
ethyl-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylate [0420]
(trans 129e) (.+-.) trans
ethyl-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylate [0421]
The mixture of cis/trans isomers was separated by reverse-phase
chromatography. [0422] (cis 129f) (.+-.) cis
ethyl-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexane-carboxylate
[0423] (trans 129f) (.+-.) trans
ethyl-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexane-carboxylate
[0424] (cis 129g) (.+-.) cis
ethyl-1-(4-trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylate
[0425] (trans 129g) (.+-.) trans
ethyl-1-(4-trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylate
[0426] (cis 129h) (.+-.) cis
ethyl-1-(4-trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylate
[0427] (trans 129h) (.+-.) trans
ethyl-1-(4-trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylate
[0428] (cis 129i) (.+-.) cis
ethyl-2-hydroxy-1-(naphthalen-2-yl)cyclohexane-carboxylate [0429]
(trans 129i) (.+-.) trans
ethyl-2-hydroxy-1-(naphthalen-2-yl)cyclohexane-carboxylate
2.3.5. Saponification (Synthesis of 130a-130i)
[0430] General Procedure S: To a solution of the respective (.+-.)
cis- or trans-hydroxy ester 129 (e.g., 3.90 g, 12.3 mmol) in water
(e.g., 12.0 mL) and methanol (e.g., 22.0 mL) at 0.degree. C. was
slowly added sodium hydroxide (e.g., 1.18 g, 29.5 mmol). The
mixture was stirred overnight and was then carefully acidified with
2 N HCl and extracted with ethyl acetate (3.times.50 mL). The
organic layers were combined, washed with brine (e.g., 40 mL),
dried over MgSO.sub.4, and filtered. The solvent was removed in
vacuo to give the respective carboxylic acid, either (.+-.) trans
130 or (.+-.) cis 130. Yields for this conversion were found to be
between 55% and quantitative.
[0431] The following compounds were prepared from the corresponding
intermediate 129 following the procedure outlined in General
Procedure S, above. [0432] (cis 130a) (.+-.)
cis-1-(3,4-Dichlorophenyl)-2-hydroxycyclohexane-carboxylic acid
[0433] (trans 130a) (.+-.)
trans-1-(3,4-Dichlorophenyl)-2-hydroxycyclohexanecarboxylic acid
[0434] (cis 130b) (.+-.)
cis-1-(3,4-Methylenedioxy)-2-hydroxycyclohexane-carboxylic acid
[0435] (trans 130b) (.+-.)
trans-1-(3,4-Methylenedioxy)-2-hydroxycyclohexane-carboxylic acid
[0436] (cis 130c) (.+-.)
cis-1-(4-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid [0437]
(trans 130c) (.+-.)
trans-1-(4-Chlorophenyl)-2-hydroxycyclohexanecarboxylic acid [0438]
(cis 130d) (.+-.)
cis-1-(3-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid [0439]
(trans 130d) (.+-.)
trans-1-(3-Chlorophenyl)-2-hydroxycyclohexane-carboxylic acid
[0440] (cis 130e) (.+-.)
cis-2-hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylic acid [0441]
(trans 130e) (.+-.)
trans-2-Hydroxy-1-(4-methoxyphenyl)cyclohexane-carboxylic acid
[0442] (cis 130f) (.+-.)
cis-1-(4-Chloro-3-fluorophenyl)-2-hydroxycyclohexanecarboxylic acid
[0443] (trans 130f) (.+-.)
trans-1-(4-chloro-3-fluorophenyl)-2-hydroxycyclohexanecarboxylic
acid [0444] (cis 130g) (.+-.)
cis-1-(4-Trifluoromethylphenyl)-2-hydroxycyclohexanecarboxylic acid
[0445] (trans 130g) (.+-.)
trans-1-(4-Trifluoromethylphenyl)-2-hydroxycyclohexane-carboxylic
Acid [0446] (cis 130h) (.+-.)
cis-1-(4-Trifluoromethoxyphenyl)-2-hydroxycyclohexanecarboxylic
acid [0447] (trans 130h) (.+-.)
trans-1-(4-Trifluoromethoxyphenyl)-2-hydroxycyclohexane-carboxylic
acid [0448] (cis 130i) (.+-.)
cis-2-Hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid [0449]
(trans 130i) (.+-.)
trans-2-Hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid
Preparation of 2-Phenylaminoalcohols (132a-132i)
[0450] PyBOP-mediated coupling of hydroxyacids (.+-.) cis 130 and
(.+-.) trans 130 with methylamine (e.g., General Procedure G) gave
hydroxyamides (.+-.) cis 131 and (.+-.) trans 131, respectively, in
39% to quantitative yield. Reduction of (.+-.) cis 131 and (.+-.)
trans 131 with borane.dimethylsulfide complex gave aminoalcohols
(.+-.) cis 132 and (.+-.) trans 132, respectively, in 39-95% yield.
The enantiomers of (.+-.) cis 132 and (.+-.) trans 132 were
separated using preparative chiral HPLC to give the fast moving
enantiomer E1 and the slow moving enantiomer E2 (Scheme 28). The
absolute configuration of the chiral centers was not determined.
##STR189##
2.3.6. General Procedure G2 (Amide Bond Formation)
[0451] A mixture of the respective carboxylic acid 130 (e.g., 3.56
g, 12.3 mmol), PyBOP (e.g., 7.04 g, 13.5 mmol), methylamine (e.g.,
2 M in THF, 37.0 mL, 74.0 mmol), and triethylamine (e.g., 1.24 g,
12.3 mmol) was stirred at room temperature overnight. The mixture
was acidified with 2 N HCl and was then extracted with ethyl
acetate (e.g., 3.times.60 mL). The organic layers were combined,
optionally washed with NaHCO.sub.3 solution, washed with brine
(e.g., 50 mL), dried over MgSO.sub.4, filtered, and concentrated.
The residue was purified by silica gel flash chromatography using
hexane/ethyl acetate or CH.sub.2Cl.sub.2/MeOH gradients and/or
optionally triturated with e.g., diethyl ether to give the
respective N-methyl amine 131.
2.3.7. General Procedure G3 (Amide Bond Formation)
[0452] A mixture of respective carboxylic acid 130 (e.g., 9.50 g,
37.3 mmol), PyBOP (e.g., 19.4 g, 37.3 mmol), methylamine (e.g., 2 M
in THF, 20.5 mL, 41.0 mmol), N-methylmorpholine (e.g., 4.50 mL,
41.0 mmol) and DMAP (e.g., 5.00 g, 41.0 mmol) was stirred in DMF
(e.g., 373 mL) at room temperature overnight. The mixture was
diluted with EtOAc (e.g., 3 L). The layers were separated and the
organic layer washed with 0.5 M HCl (e.g., 3.times.1 L), saturated
aqueous NaHCO.sub.3 (3.times.600 mL), saturated aqueous LiCl (600
mL), brine (600 mL), dried, filtered and concentrated. The residue
was purified by silica gel chromatography using hexane/ethyl
acetate or CH.sub.2Cl.sub.2/MeOH gradients to give the respective
N-methyl amine 131.
[0453] The following compounds were prepared from the corresponding
intermediate 130 using the procedures outlined in General Procedure
G2 or General Procedure G3, above, or slightly modified versions
thereof. [0454] (cis 131a) (.+-.)
cis-1-(3,4-Dichlorophenyl)-2-hydroxy-N-methylcyclohexane-carboxamide
[0455] (trans 131a) (.+-.)
trans-1-(3,4-Dichlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
[0456] (cis 131b) (.+-.)
cis-1-(3,4-Methylenedioxy)-2-hydroxy-N-methylcyclohexanecarboxamide
[0457] (trans 131b) (.+-.)
trans-1-(3,4-Methylenedioxy)-2-hydroxy-N-methylcyclohexanecarboxamide
[0458] (cis 131c) (.+-.)
cis-1-(4-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
[0459] (trans 131c) (.+-.)
trans-1-(4-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
[0460] (cis 131d) (.+-.)
cis-1-(3-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
[0461] (trans 131d) (.+-.)
trans-1-(3-Chlorophenyl)-2-hydroxy-N-methylcyclohexanecarboxamide
[0462] (cis 131e) (.+-.) cis
2-Hydroxy-1-(4-methoxyphenyl)-N-methylcyclohexanecarboxamide [0463]
(trans 131e) (.+-.) trans
2-Hydroxy-1-(4-methoxyphenyl)-N-methylcyclohexanecarboxamide [0464]
(cis 131f) (.+-.)
cis-1-(4-Chloro-3-fluorophenyl)-2-hydroxy-N-methylcyclohexane
carboxamide [0465] (trans 131f) (.+-.)
trans-1-(4-Chloro-3-fluorophenyl)-2-hydroxy-N-methylcyclohexane
Carboxamide [0466] (cis 131g) (.+-.)
cis-1-(4-Trifluoromethylphenyl)-2-hydroxy-N-methylcyclohexane
Carboxamide [0467] (trans 131g) (.+-.)
trans-1-(4-Trifluoromethylphenyl)-2-hydroxy-N-methylcyclohexane
Carboxamide [0468] (cis 131h) (.+-.)
cis-1-(4-Trifluoromethoxyphenyl)-2-hydroxy-N-methylcyclohexane
Carboxamide [0469] (trans 131h) (.+-.)
trans-1-(4-Trifluoromethoxyphenyl)-2-hydroxy-N-methylcyclohexane
Carboxamide
2.3.8. General Procedure T (Reduction of Amide 131 to Amine
132)
[0470] To a solution of the respective N-methylcarboxamide 131
(e.g., 2.70 g, 8.93 mmol) in tetrahydrofuran (90.0 mL) was slowly
added borane.dimethylsulfide (2 M in THF, 13.4 mL, 26.8 mmol). The
mixture was stirred 48 hours at reflux. After cooling, the mixture
was acidified by careful addition of 2 N HCl. The mixture was
concentrated in vacuo and the residue was washed with diethyl ether
(e.g., 60 mL). The phases were separated and the aqueous layer was
made basic through addition of 2 N NaOH and was then extracted with
ethyl acetate (e.g., 3.times.150 mL). The ethyl acetate layers were
combined, washed with brine (100 mL), dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by silica gel
flash chromatography using e.g., dichloromethane/methanol gradients
to give the respective amines (.+-.) cis 132 and (.+-.) trans
132.
[0471] The enantiomers for each of the amines (.+-.) cis 132 and
(.+-.) trans 132 were separated using preparative chiral HPLC.
Typical conditions are listed below:
1. ChiralPak AD; heptane:EtOH:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm.
2. Regis O1; hexanes:IPA:DEA=90:10:0.1; .mu.=25 ml/min; and
.lamda.=280 nm.
Absolute configurations of the chiral centers were not determined.
Compounds are identified by E1 for the fast moving enantiomer and
E2 for the slow moving enantiomer.
[0472] The following compounds were prepared from the corresponding
intermediate 131 using the procedures outlined in General Procedure
T or a slightly modified version thereof.
cis-2-(3,4-Dichlorophenyl)-2-((methylamino)methyl)cyclohexanol
(133)
[0473] ##STR190##
[0474] The enantiomeric mixture of (.+-.) cis 132a was separated
(ChiralPak AD column; heptane:EtOH:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 133 E1 (retention time=15.5 min) and 133 E2
(retention time=20.7 min). .sup.1H NMR (CDCl.sub.3) .delta.
0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H), 1.78-1.84
(m, 2H), 2.01-2.06 (m, 1H), 2.29 (s, 3H), 2.66 (d, J=13.6 Hz, 1H),
2.91 (d, J=13.6 Hz, 1H), 3.97 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.40 (d,
J=8.4 Hz, 1H), 7.71 (dd, J=12.0, 2.4 Hz, 1H), 7.96 (s, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 21.3, 24.9, 29.9, 35.9, 36.7,
46.2, 66.9, 81.4, 118.0, 129.2, 130.4, 131.6, 132.6, 142.7. ESI MS
m/z 289.
trans-2-(3,4-Dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol
(134)
[0475] ##STR191##
[0476] The enantiomeric mixture of (.+-.) trans 132a was separated
(ChiralPak AD column; heptane:EtOH:DEA=95:5:0.1; .mu.=25 ml/min;
and .lamda.=275 nm) to give 134 E1 (retention time=13.4 min) and
134 E2 (retention time=18.9 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 2.32 (s,
3H), 2.97 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.20 (dd,
J=10.0 Hz, 3.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.69 (d, J=1.6 Hz, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 21.9, 24.3, 32.4, 36.7, 37.5,
45.7, 57.1, 74.1, 126.7, 129.4, 130.4, 130.6, 132.9, 146.5. ESI MS
m/z 289.
cis-2-(4-chlorophenyl)-2-((methylamino)methyl)cyclohexanol
(135)
[0477] ##STR192##
[0478] The enantiomeric mixture (.+-.) cis 132c can be separated
(e.g., Regis O1 column; hexanes:IPA:DEA=90:10:0.1; .mu.=25 ml/min;
and .lamda.=280 nm) to give 135 E1 and 135 E2.
trans-2-(4-chlorophenyl)-2-((methylamino)methyl)-cyclohexanol
(136)
[0479] ##STR193##
[0480] The enantiomeric mixture (.+-.) trans 132c was separated
(Regis O1 column; hexanes:IPA:DEA=90:10:0.1; .mu.=25 ml/min; and
.lamda.=280 nm) to give 136 E1 (retention time=6.8 min) and 136 E2
(retention time=8.9 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.28-1.47 (m, 4H), 1.64-1.87 (m, 3H), 1.96-2.02 (m, 1H), 2.31 (s,
3H), 2.98 (d, J=12.4 Hz, 1H), 3.29 (d, J=12.4 Hz, 1H), 4.24 (dd,
J=10.0 Hz, 3.2 Hz, 1H), 7.30 (d, J=10.8 Hz, 2H), 7.58 (d, J=10.8
Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 21.9, 24.4, 32.4, 36.7,
37.5, 45.7, 57.1, 74.3, 128.6, 128.9, 132.1, 144.6. ESI MS m/z
254.
cis-2-(3-chlorophenyl)-2-((methylamino)methyl)cyclohexanol
(137)
[0481] ##STR194##
[0482] The enantiomeric mixture of (.+-.) cis 132d can be separated
(e.g., Regis O1 column; hexanes:IPA:DEA=90:10:0.1; .mu.=25 ml/min;
and .lamda.=280 nm) to give 137 E1 and 137 E2.
trans-2-(3-chlorophenyl)-2-((methylamino)methyl)cyclohexanol
(138)
[0483] ##STR195##
[0484] The enantiomeric mixture (.+-.) trans 132d was separated
(Regis O1 column; hexanes:IPA:DEA=90:10:0.1; .mu.=25 m/min; and
.lamda.=280 nm) to give 138 E1 (retention time=5.9 min) and 138 E2
(retention time=7.6 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.28-1.47 (m, 4H), 1.64-1.87 (m, 3H), 1.96-2.02 (m, 1H), 2.31 (s,
3H), 2.98 (d, J=12.4 Hz, 1H), 3.29 (d, J=12.4 Hz, 1H), 4.25 (dd,
J=10.0 Hz, 3.2 Hz, 1H), 7.18-7.22 (m, 1H), 7.29-7.32 (m, 1H),
7.48-7.52 (m, 1H), 7.60 (s, 1H). .sup.13C NMR (CDCl.sub.3) .delta.
22.1, 24.4, 32.5, 36.7, 37.5, 45.9, 57.2, 74.1, 125.3, 126.7,
127.4, 134.8, 148.3. ESI MS m/z 254.
cis-2-((methylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol
(139)
[0485] ##STR196##
[0486] The enantiomeric mixture (.+-.) cis 132e was separated
(Regis O1 column; hexanes:IPA:DEA=90:10:0.1; .mu.=25 ml/min; and
.lamda.=275 nm) to give 139 E1 (retention time=5.7 min) and 139 E2
(retention time=7.1 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.02-1.10 (m, 1H), 1.21-1.39 (m, 3H), 1.62-1.66 (m, 1H), 1.76-1.94
(m, 2H), 2.04-2.08 (m, 1H), 2.26 (s, 3H), 2.62 (d, J=12.4 Hz, 1H),
2.88 (d, J=12.4 Hz, 1H), 3.77 (s, 3H), 3.96 (dd, J=11.2 Hz, 4.0 Hz,
1H), 6.86 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 21.4, 25.0, 30.0, 35.8, 36.7, 46.2, 55.3,
67.1, 81.9, 113.8, 130.4, 133.7, 157.8. ESI MS m/z 250.
(.+-.)
trans-2-(4-Methoxyphenyl)-2-((methylamino)methyl)cyclohexanol
(140)
[0487] ##STR197##
[0488] The enantiomeric mixture (.+-.) trans 132e was separated
(ChiralPak AD column; hexanes:IPA:DEA=90:10:0.1; .mu.=25 ml/min;
and .lamda.=275 nm) to give 140 E1 (retention time=5.3 min) and 140
E2 (retention time=7.1 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.23-1.46 (m, 4H), 1.62-1.87 (m, 3H), 1.92-2.00 (m, 1H), 2.28 (s,
3H), 2.95 (d, J=12.4 Hz, 1H), 3.24 (d, J=12.4 Hz, 1H), 3.78 (s,
3H), 4.25 (dd, J=10.4 Hz, 3.2 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 7.48
(d, J=8.8 Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 22.1, 24.4,
32.5, 36.7, 37.7, 45.1, 55.4, 57.6, 74.4, 114.1, 128.0, 137.9,
157.9. ESI MS m/z 250.
cis-2-(4-Chloro-3-fluorophenyl)-2-((methylamino)methyl)cyclohexanol
(141)
[0489] ##STR198##
[0490] The enantiomeric mixture (.+-.) cis 132f was separated
(Regis O1 column; hexanes:IPA:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 141 E1 (retention time=7.2 min) and 141 E2
(retention time=10.8 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.28-1.50 (m, 4H), 1.64-1.86 (m, 3H), 1.98-2.02 (m, 1H), 2.32 (s,
3H), 2.97 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.19 (dd,
J=10.0 Hz, 3.2 Hz, 1H), 7.32-7.38 (m, 2H), 7.42-7.52 (m, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.0, 24.4, 32.5, 36.8, 37.7,
45.7, 57.1, 74.3, 115.7, 115.9, 118.6, 118.7, 123.6, 130.7, 147.5,
157.2, 159.7. ESI MS m/z 272.
trans-2-(4-chloro-3-fluorophenyl)-2-((methylamino)methyl)cyclohexanol
(142)
[0491] ##STR199##
[0492] The enantiomeric mixture (.+-.) trans 132f was separated
(Regis O1 column; hexanes:IPA:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 142 E1 (retention time=6.7 min) and 142 E2
(retention time=8.6 min). .sup.1H NMR (CDCl.sub.3) .delta.
0.96-1.03 (m, 1H), 1.23-1.44 (m, 3H), 1.65-1.69 (m, 1H), 1.78-1.84
(m, 2H), 2.01-2.06 (m, 1H), 2.29 (s, 3H), 2.66 (d, J=13.6 Hz, 1H),
2.91 (d, J=13.6 Hz, 1H), 3.97 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.34 (d,
J=8.4 Hz, 1H), 7.56 (dd, J=12.0, 2.4 Hz, 1H), 7.74(dd, J=12.0, 2.4
Hz, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 21.3, 24.9, 29.9, 35.9,
36.7, 46.8, 67.0, 81.5, 118.0, 118.3, 125.9, 126.0, 130.4, 143.4,
156.9, 159.3. ESI MS m/z 272.
cis-2-((methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol
(143)
[0493] ##STR200##
[0494] The enantiomeric mixture (.+-.) cis 132g was separated
(Regis O1 column; hexanes:IPA:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 143 E1 (retention time=8.2 min) and 143 E2
(retention time=11.8 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H), 1.61-1.70
(m, 1H), 1.79-1.85 (m, 1H), 1.93-1.99 (m, 2H), 2.03 (s, 6H),
2.67(d, J=13.6 Hz, 1H), 3.28 (d, J=13.6 Hz, 1H), 3.95 (dd, J=10.0
Hz, 3.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 1.2 Hz,
2H). .sup.13C NMR (CDCl.sub.3) .delta. 22.0, 24.4, 32.5, 36.8,
37.7, 46.0, 57.1, 74.2, 123.1, 125.6, 125.7, 125.9, 127.5, 128.5,
128.8, 150.3. ESI MS m/z 288.
trans-2-((Methylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol
(144)
[0495] ##STR201##
[0496] The enantiomeric mixture (.+-.) trans 132g was separated
(Regis O1 column; hexanes:IPA:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 144 E1 (retention time=7.9 min) and 144 E2
(retention time=11.2 min). .sup.1H NMR (CDCl.sub.3) .delta.
0.91-1.02 (m, 1H), 1.27-1.43 (m, 3H), 1.65-1.69 (m, 1H), 1.83-1.88
(m, 2H), 2.11-2.16 (m, 1H), 2.28 (s, 3H), 2.68 (d, J=13.6 Hz, 1H),
2.97 (d, J=13.6 Hz, 1H), 4.02 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.58 (d,
J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H). .sup.13C NMR (CDCl.sub.3)
.delta. 21.4, 24.9, 30.0, 36.0, 36.7, 47.1, 67.1, 81.6, 125.3,
125.4, 125.8, 128.3, 128.6, 129.9, 146.6. ESI MS m/z 288.
cis-2-((Methylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol
(145)
[0497] ##STR202##
[0498] The enantiomeric mixture (.+-.) cis 132h was separated
(Regis O1 column; hexanes:IPA:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 145 E1 (retention time=5.1 min) and 145 E2
(retention time=8.2 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.05-1.13 (m, 1H), 1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H), 1.30-1.48
(m, 4H), 1.68-1.88 (m, 3H), 1.99-2.03 (m, 1H), 2.32 (s, 3H), 3.02
(d, J=12.4 Hz, 1H), 3.31 (d, J=12.4 Hz, 1H), 4.27 (dd, J=10.4 Hz,
4.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H).
.sup.13C NMR (CDCl.sub.3) .delta. 21.3, 22.0, 24.5, 32.5, 36.7,
37.9, 45.5, 57.1, 74.3, 119.4, 120.8, 121.1, 122.0, 128.5, 131.0,
144.7, 147.6. ESI MS m/z 304.
trans-2-((Methylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol
(146)
[0499] ##STR203##
[0500] The enantiomeric mixture (.+-.) trans 132h was separated
(Regis O1 column; hexanes:IPA:DEA=95:5:0.1; .mu.=25 ml/min;
.lamda.=275 nm) to give 146 E1 (retention time=4.4 min) and 146 E2
(retention time=5.8 min). .sup.1H NMR (CDCl.sub.3) .delta.
0.96-1.04 (m, 1H), 1.25-1.42 (m, 3H), 1.65-1.69 (m, 1H), 1.81-1.88
(m, 2H), 2.07-2.16 (m, 1H), 2.29 (s, 3H), 2.68 (d, J=11.6 Hz, 1H),
2.95 (d, J=11.6 Hz, 1H), 4.00 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.18 (d,
J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H). .sup.13C NMR (CDCl.sub.3)
.delta. 21.3, 25.0, 30.0, 36.0, 36.7, 46.6, 67.1, 81.6, 119.4,
120.8, 122.0, 131.0, 140.7, 147.5. ESI MS m/z 304.
cis-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
(147)
[0501] ##STR204##
[0502] The enantiomeric mixture of (.+-.) cis 1321 was separated
(ChiralPak AD column; hexanes:IPA:DEA=90:10:0.1; .mu.=60 ml/min;
.lamda.=280 nm) to give 147 E1 (retention time=20.7 min) and 147 E2
(retention time=28.2 min). .sup.1H NMR (CDCl.sub.3) .delta.
0.96-1.03 (m, 1H), 1.22-1.41 (m, 3H), 1.60-1.65 (m, 1H), 1.84-1.92
(m, 1H), 2.01-2.12 (m, 1H), 2.22 (s, 3H), 2.66 (d, J=13.6 Hz, 1H),
3.01 (d, J=13.6 Hz, 1H), 4.05 (dd, J=10.0 Hz, 3.2 Hz, 1H),
7.19-7.24 (m, 2H), 7.71-7.87 (m, 4H), 8.49 (s, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 21.6, 25.1, 30.1, 35.9, 36.7, 47.1, 66.7,
81.9, 126.0, 126.1, 126.6, 127.5, 128.3, 128.5, 129.5, 132.1,
133.6, 139.3. ESI MS m/z 270.
trans-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
(148)
[0503] ##STR205##
[0504] The enantiomeric mixture (.+-.) trans 1321 was separated
(ChiralPak AD column; hexanes:IPA:DEA=90:10:0.1; .mu.=60 ml/min;
.lamda.=280 nm) to give 148 E1 (retention time=25.7 min) and 148 E2
(retention time=40.8 min). .sup.1H NMR (CDCl.sub.3) .delta.
1.28-1.50 (m, 4H), 1.71-1.86 (m, 2H), 1.95-2.06 (m, 2H), 2.25 (s,
3H), 3.06 (d, J=12.4 Hz, 1H), 3.30 (d, J=12.4 Hz, 1H), 4.45 (dd,
J=10.0 Hz, 3.2 Hz, 1H), 7.39-7.44(m, 2H), 7.60-7.63 (m, 1H),
7.76-7.85 (m, 3H), 8.14 (s, 1H). .sup.13C NMR (CDCl.sub.3) .delta.
22.1, 24.6, 32.7, 36.8, 37.7, 45.9, 57.1, 74.4, 124.8, 125.9,
126.2, 126.3, 127.5, 128.4, 128.5, 132.2, 133.8, 143.2. ESI MS m/z
270.
cis-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
(149)
[0505] ##STR206##
(a)
cis-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide
(300)
[0506] A mixture of (.+-.)
cis-2-hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid (9.74
g, 36.1 mmol), PyBOP (18.8 g, 36.1 mmol), methylamine (2 M in THF,
19.8 mL, 39.7 mmol), N-methylmorpholine (4.36 mL, 39.7 mmol) and
DMAP (4.84 g, 39.7 mmol) was stirred in DMF (361 mL) at room
temperature overnight. The mixture was diluted with EtOAc (1.5 L).
The layers were separated and the organic layer washed with 0.5 M
HCl (3.times.600 mL), saturated aqueous NaHCO.sub.3 (3.times.500
mL), brine (300 mL), dried and concentrated. The residue was
triturated with diethyl ether to give (.+-.)
cis-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide
(7.36 g, 72%) as a light yellow solid.
(b) cis-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
[0507] The title compound can be prepared from the above amide, for
example, according to General Procedure E.
(.+-.)
trans-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
(150)
[0508] ##STR207##
(a) (.+-.)
trans-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxam-
ide (301)
[0509] A mixture of (.+-.)
trans-2-hydroxy-1-(naphthalen-2-yl)cyclohexanecarboxylic acid (9.72
g, 36.0 mmol), PyBOP (18.7 g, 36.0 mmol), methylamine (2 M in THF,
19.8 mL, 39.6 mmol), N-methylmorpholine (4.35 mL, 39.6 mmol) and
DMAP (4.83 g, 39.6 mmol) was stirred in DMF (360 mL) at room
temperature overnight. The mixture was diluted with EtOAc (1.5 L).
The layers were separated and the organic layer washed with 1 M HCl
(3.times.600 mL), saturated aqueous NaHCO.sub.3 (3.times.500 mL),
brine (500 mL), dried and concentrated to give
(.+-.)-2-hydroxy-N-methyl-1-(naphthalen-2-yl)cyclohexanecarboxamide
(8.66 g, 85%) as a light yellow solid.
(b)
trans-2-((methylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
[0510] The title compound can be prepared from the above amide, for
example, according to General Procedure E.
2.4. Preparation of Tertiary Amines (151a to 151i)
[0511] Treatment of the respective methylamines 132 (Scheme 29)
with a methylating reagent, e.g., iodomethane and
N,N'-diisopropylethylamine (DIEA) in acetone or CH.sub.2Cl.sub.2
(modified General Procedure F) gave the dimethylamines cis 151 E1,
c is 151 E2, trans 151 E1, and trans 151 E2. ##STR208##
[0512] (Modified General Procedure F) To the solution of the
respective N-methylamine 132 (e.g., 86 mg. 0.285 mmol) and DIEA
(e.g., 0.164 ml, 0.942 mmol) in acetone (0.5 ml) was added
CH.sub.3I (e.g., 0.020 ml, 0.314 mmol). The mixture was stirred at
room temperature overnight and the solvent was then removed in
vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 (e.g., 10 ml),
washed with saturated K.sub.2CO.sub.3 solution (e.g., 5 ml), dried
over Na.sub.2SO.sub.4, and evaporated in vacuo. The crude product
was purified by silica gel flash chromatography using e.g.,
dichloromethane/methanol gradients to give the respective
dimethylamine 151 in 40 to 70% yield.
[0513] The following compounds were prepared from the corresponding
methylamine 133-148 using modified General Procedure F outlined
above, or slightly modified versions thereof.
cis-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol
(152)
[0514] ##STR209## 152 E1, 152 E2
[0515] The title compounds were prepared from 133 E1 and 133 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta.0.82-0.96 (m, 1H),
1.10-1.18 (m, 1H), 1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98
(m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 3.97
(dd, J=11.2, 4.8 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.73 (dd, J=8.4
Hz, 2.0 Hz, 1H). 7.98 (d, J=2 Hz, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 21.0, 25.1, 29.9, 37.2, 46.0, 47.8, 75.9, 80.8, 129.5,
130.0, 130.2, 131.9, 132.4, 143.7. ESI MS m/z 303.
trans-2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol
(153)
[0516] ##STR210## 153 E1, 153 E2
[0517] The title compounds were prepared from 134 E1 and 134 E,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.21-1.35 (m, 2H),
1.42-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.77-1.98 (m, 3H), 2.03 (s,
6H), 2.58 (d, J=14.0 Hz, 1H), 3.25 (d, J=14.0 Hz, 1H), 4.18 (dd,
J=9.6 Hz, 2.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8 Hz,
2.4 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H). .sup.13C NMR (CDCl.sub.3)
.delta.22.1, 24.1, 32.5, 36.9, 44.6, 44.7, 66.3, 74.8, 127.0,
129.6, 130.0, 130.3, 132.5, 148.2. ESI MS m/z 303.
trans-2-(4-chlorophenyl)-2-((dimethylamino)methyl)cyclohexanol
(154)
[0518] ##STR211## 154 E1, 154 E2
[0519] The title compounds were prepared from 136 E1 and 136 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.21-1.35 (m, 2H),
1.42-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.77-1.84 (m, 1H), 1.89-1.98
(m, 2H), 2.03 (s, 6H), 2.58 (d, J=14.0 Hz, 1H), 3.20 (d, J=14.0 Hz,
1H), 4.26 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.30 (d, J=10.8 Hz, 2H), 7.58
(d, J=10.8 Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 22.1, 24.1,
32.5, 36.7, 44.6, 47.7, 66.3, 74.8, 128.6, 128.8, 131.8, 146.0. ESI
MS m/z 268.
Cis-2-((dimethylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol
(155)
[0520] ##STR212## 155 E1, 155 E2
[0521] The title compounds were prepared from 139 E1 and 139 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta.0.92-1.00 (m, 1H),
1.07-1.12 (m, 1H), 1.25-1.36 (m, 2H), 1.61-1.66 (m, 1H), 1.80-2.03
(m, 9H), 2.59 (q, J=13.2 Hz, 2H), 3.95 (dd, J=11.6 Hz, 4.0 Hz, 1H),
6.82 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H). .sup.13C NMR
(CDCl.sub.3) .delta. 21.1, 25.3, 30.0, 37.1, 45.5, 47.7, 55.3,
76.0, 81.5, 113.6, 130.7, 134.6, 157.6. ESI MS m/z 264.
trans-2-((dimethylamino)methyl)-2-(4-methoxyphenyl)cyclohexanol
(156)
[0522] ##STR213## 156 E1, 156 E2
[0523] The title compounds were prepared from 140 E1 and 140 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.26-1.37 (m, 2H),
1.43-1.48 (m, 2H), 1.58-1.66 (m, 1H), 1.76-1.82 (m, 1H), 1.88-2.00
(m, 2H), 2.05 (s, 6H), 2.61 (d, J=14.0 Hz, 1H), 3.14 (d, J=14.0 Hz,
1H), 4.31 (dd, J=10.0 Hz, 3.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.49
(d, J=8.8 Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 22.2, 13.7,
32.4, 36.1, 44.0, 47.7, 55.4, 67.4, 74.9, 113.7, 128.2, 139.1,
157.7. ESI MS m/z 263.
Cis-2-(4-chloro-3-fluorophenyl)-2-((dimethylamino)methyl)cyclohexanol
(157)
[0524] ##STR214## 157 E1, 157 E2
[0525] The title compounds were prepared from 141 E1 and 141 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.21-1.35 (m, 2H),
1.42-1.48 (m, 2H), 1.56-1.66 (m, 1H), 1.77-1.98 (m, 3H), 2.03 (s,
6H), 2.56(d, J=14.0 Hz, 1H), 3.25 (d, J=14.0 Hz, 1H), 4.18 (dd,
J=9.6 Hz, 2.8 Hz, 1H), 7.32-7.35 (m, 2H), 7.43 (d, J=8.4 Hz, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 22.1, 24.1, 32.5, 36.9, 44.6,
44.7, 66.4, 74.9, 115.8, 116.1, 118.2, 118.4, 123.8, 130.3, 148.9,
157.0, 159.5. ESI MS m/z 286.
Trans-2-(4-chloro-3-fluorophenyl)-2-((dimethylamino)methyl)cyclohexanol
(158)
[0526] ##STR215## 158 E, 158 E2
[0527] The title compounds were synthesized from 142 E1 and 142 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 0.82-0.96 (m, 1H),
1.10-1.18 (m, 1H), 1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98
(m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 3.97
(dd, J=11.2, 4.8 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 7.55-7.58 (m,
1H). 7.75-7.79 (m, 1H). .sup.13C NMR (CDCl.sub.3) .delta. 21.0,
25.1, 29.9, 37.2, 46.1, 47.7, 75.9, 80.8, 118.3, 118.5, 126.3,
130.2, 144.4, 156.8, 159.3. ESI MS m/z 286.
cis-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol
(159)
[0528] ##STR216## 159 E1, 159 E2
[0529] The title compounds were prepared from 143 E1 and 143 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.05-1.13 (m, 1H),
1.26-1.36 (m, 2H), 1.45-1.52 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.85
(m, 1H), 1.93-1.99 (m, 2H), 2.03 (s, 6H), 2.67(d, J=13.6 Hz, 1H),
3.28 (d, J=13.6 Hz, 1H), 3.95 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.58 (d,
J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H). .sup.13C NMR (CDCl.sub.3)
.delta. 22.1, 24.0, 32.4, 36.8, 44.9, 66.4, 74.8, 123.2, 125.3,
125.4, 125.9, 127.7, 128.2, 128.5, 151.7. ESI MS m/z 302.
trans-2-((dimethylamino)methyl)-2-(4-(trifluoromethyl)phenyl)cyclohexanol
(160)
[0530] ##STR217## 160 E1, 160 E2
[0531] The title compounds were prepared from 144 E1 and 144 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 0.82-0.93 (m, 1H),
1.14-1.21 (m, 1H), 1.30-1.40 (m, 2H), 1.67-1.70 (m, 1H), 1.87-2.09
(m, 9H), 2.65-2.75 (m, 2H), 4.00-4.05 (m, 1H), 7.55 (d, J=8.4 Hz,
2H), 7.99 (d, J=8.4 Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta.
21.1, 25.2, 30.0, 37.4, 46.4, 47.6, 76.0, 81.0, 125.1, 125.2,
125.9, 128.0, 128.4, 130.2, 131.8, 147.6. ESI MS m/z 302.
cis-2-((dimethylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol
(161)
[0532] ##STR218## 161 E1, 161 E2
[0533] The title compounds were prepared from 145 E1 and 145 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.26-1.37 (m, 2H),
1.43-1.50 (m, 2H), 1.59-1.68 (m, 1H), 1.78-1.84 (m, 1H), 1.92-1.97
(m, 2H), 2.03 (s, 6H), 2.61 (d, J=14.0 Hz, 1H), 3.24 (d, J=14.0 Hz,
1H), 4.28 (dd, J=10.0 Hz, 3.2 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.63
(d, J=8.8 Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 22.2, 24.0,
32.4, 36.7, 44.4, 47.7, 66.7, 74.9, 119.5, 120.8, 122.0, 128.7,
131.2, 146.1, 147.4. ESI MS m/z 302.
trans-2-((dimethylamino)methyl)-2-(4-(trifluoromethoxy)phenyl)cyclohexanol
(162)
[0534] ##STR219## 162 E1, 162 E2
[0535] The title compounds were prepared from 146 E1 and 146 E2,
respectively. .sup.1H NMR(CDCl.sub.3) .delta.0.90-0.97 (m, 1H),
1.12-1.19 (m, 1H), 1.29-1.39 (m, 2H), 1.65-1.69 (m, 1H), 1.84-2.04
(m, 9H), 2.60 (d, J=14.0 Hz, 1H), 2.70 (d, J=14.0 Hz, 1H), 4.00
(dd, J=11.6 Hz, 4.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4
Hz, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 21.0, 25.2, 29.9, 37.3,
46.0, 47.7, 76.1, 81.1, 120.6, 122.0, 131.2, 141.7, 147.4. ESI MS
m/z 318.
Cis-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
(163)
[0536] ##STR220## 163 E1, 163 E2
[0537] The title compounds were synthesized from 147 E1 and 147 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta.0.82-0.96 (m, 1H),
1.10-1.18 (m, 1H), 1.28-1.39 (m, 2H), 1.64-1.70 (m, 1H), 1.83-1.98
(m, 9H), 2.60 (d, J=13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 4.05
(dd, J=11.2, 4.8 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.73 (dd, J=8.4
Hz, 2.0 Hz, 1H). 7.98 (d, J=2 Hz, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 21.0, 25.1, 29.9, 37.2, 46.0, 47.8, 75.9, 80.8, 126.0,
126.1, 126.6, 127.5, 128.3, 128.5, 129.5, 132.1, 133.6, 139.3. ESI
MS m/z 284.
trans-2-((dimethylamino)methyl)-2-(naphthalen-2-yl)cyclohexanol
(164)
[0538] ##STR221## 164 E1, 164 E2
[0539] The title compounds were prepared from 148 E1 and 148 E2,
respectively. .sup.1H NMR (CDCl.sub.3) .delta. 1.29-1.42 (m, 2H),
1.47-1.54 (m, 2H), 1.65-1.74 (m, 1H), 1.80-1.86 (m, 1H), 1.97-2.10
(m, 3H), 2.03 (s, 6H), 2.72 (d, J=14.0 Hz, 1H), 3.26 (d, J=14.0 Hz,
1H), 4.49 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.41-7.48 (m, 2H), 7.61 d,
J=8.8 Hz, 1H), 7.79-7.86 (m, 3H), 8.18 (s, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 22.3, 24.0, 32.5, 36.4, 44.8, 47.8, 66.6,
75.1, 125.5, 125.8, 126.0, 126.2, 127.5, 127.8, 128.5, 132.1,
133.8, 144.6. ESI MS m/z 284.
2.5. Preparation of
4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine
[0540] ##STR222##
[0541] A solution of the respective methylamine 132 (e.g., 26.5 mg,
0.0919 mmol) in formaldehyde (e.g., 37%, 2 ml) and formic acid
(e.g., 96%, 2 ml) was heated at 100.degree. C. for 2 hours. After
cooling to room temperature, the mixture was washed with hexanes
(e.g., 3.times.4 ml). The aqueous solution was then made basic with
5 N KOH solution to pH 12. The mixture was extracted with t-butyl
methylether (e.g., 3.times.5 ml) and the combined organic layers
were dried over Na.sub.2SO.sub.4, and the solvent was evaporated.
The residue was purified by reverse phase HPLC (C-18 column,
CH.sub.3CN/water, CH.sub.3CN from 5% to 100%) to give the
respective oxazine.
Cis-4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine
(165)
[0542] ##STR223## 165 E1 prepared from 133 E1 165 E2 prepared from
133 E2
[0543] .sup.1H NMR (CDCl.sub.3) .delta. 0.97-1.17 (m, 1H),
1.23-1.45 (m, 3H), 1.72-1.90 (m, 3H), 2.03 (s, 3H), 2.15 (d, J=12.8
Hz, 1H), 2.81 (d, J=12.4 Hz, 1H), 3.32-3.43 (m, 1H), 3.72 (d, J=7.8
Hz, 1H), 4.57 (d, J=7.8 Hz, 1H), 4.89-4.97 (m, 1H), 7.35 (d, J=7.8
Hz, 1H), 7.60-7.68 (m, 1H), 7.81 (s, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 21.2, 26.0, 27.8, 35.6, 41.0, 42.8, 69.1, 85.1, 88.7,
129.5, 129.9, 130.4, 131.8, 132.0, 144.6. ESI MS m/z 300.
Trans-4a-(3,4-dichlorophenyl)-3-methyloctahydro-2H-benzo[e][1,3]oxazine
(166)
[0544] ##STR224## 166 E1 prepared from 134 E1 166 E2 prepared from
134 E2
[0545] .sup.1H NMR (CDCl.sub.3) .delta. 1.25-1.41 (m, 2H),
1.48-1.79 (m, 4H), 1.88 (d, J=13.8 Hz, 1H), 1.98 (d, J=11.4 Hz,
1H), 2.13 (s, 3H), 2.58-2.68 (m, 2H), 3.62 (d, J=7.5 Hz, 1H), 4.00
(s, 1H), 4.55 (d, J=7.5 Hz, 1H), 7.20-7.27 (m, 1H), 7.39-7.46 (m,
2H). .sup.13C NMR (CDCl3) .delta. 20.3, 22.1, 27.0, 28.4, 40.4,
41.5, 68.5, 77.4, 87.8, 126.5, 129.3, 130.4, 130.7, 133.0, 144.7.
ESI MS m/z 300.
2.6. Synthesis of cis- and
trans-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclopentanol (167)
(a) Synthesis of
1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile
[0546] ##STR225##
[0547] To ice-cold DMSO (100 mL) was added 60% NaH (11.0 g, 2.3 eq)
in portions. The cooling bath was removed and the solution was
stirred at ambient temperature for ten minutes. A solution of
2-(3,4-dichlorophenyl)acetonitrile (2.0 g, 10.75 mmol) in DMSO (50
mL) was added. The brown solution was stirred for 15 minutes before
cis-1,4-dichlorobutene (1.0 mL, 0.9 eq) was added. The reaction
mixture was stirred overnight and was then poured into water. The
product was extracted with DCM. The organic layer washed with
brine, evaporated, diluted with 50% ethyl acetate in hexanes,
washed with water, and evaporated. The residual oil was separated
on silica to give the nitrile (966 mg, 43%) as a pale-brown oil.
GCMS R.sub.t=10.8 min m/z=237 (M+). .sup.1H NMR (CDCl.sub.3,
.delta.): 7.51 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28 (dd,
J=2.3, 8.5 Hz, 1H), 5.79 (s, 2H), 3.27 (d, J=14.7 Hz, 2H), 2.87 (d,
J=14.7 Hz, 2H). .sup.13C NMR(CDCl.sub.3, .delta.): 141.9, 133.2,
132.1, 131.0, 128.5, 127.6, 125.0, 124.0, 48.4.
(b) Synthesis of
3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclopentanol
[0548] A mixture of
1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile (119 mg, 0.500
mmol) and borane-THF (2 mL, 1M in THF, 2 eq) was heated at
65.degree. C. for 2 hours. The reaction was cautiously quenched
with ethanol (0.5 mL), sodium hydroxide (1 mL, 5M aqueous) and
stirred for two hours. It was then extracted with MTBE and
evaporated. The residue was purified by HPLC to give cis 167 and
trans 167.
[0549] cis 167: LCMS R.sub.t=4.7 min, m/z=260 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.39 (d, J=8.4 Hz, 1H), 7.37 (d, J=2.2 Hz,
1H), 7.13 (dd, J=2.2, 8.4 Hz, 1H), 4.48 (m, 1H), 3.21 (s, 1H), 2.68
(dd, J=13.0, 15.7 Hz, 2H), 2.32 (dd, J=6.4, 13.7 Hz, 1H), 2.2-1.8
(m, 4H), 1.7 (m, 1H), 1.2 (bs, 2H). .sup.13C NMR (CDCl.sub.3,
.delta.): 147.9, 132.2, 130.1, 129.2, 126.6, 72.9, 52.6, 51.9,
45.4, 34.3, 33.0.
[0550] trans 167: LCMS R.sub.t=5.7 min, m/z=260 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.37 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.3 Hz,
1H), 7.11 (dd, J=2.3, 8.4 Hz, 1H), 4.33 (m, 1H), 2.86 (d, J=13.0
Hz, 1H), 2.74 (d, J=13.0 Hz, 1H), 2.5 (bs, 3H), 2.25 (dd, J=6.0,
14.0 Hz, 1H), 2.2-1.7 (m, 5H). .sup.13C NMR (CDCl.sub.3, .delta.):
149.2, 132.2, 130.1, 129.9, 128.8, 126.1, 72.6, 52.7, 52.1, 46.7,
36.2, 32.8.
1-(1-(3,4-dichlorophenyl)cyclopent-3-enyl)-N-methylmethanamine
(168)
[0551] ##STR226##
(a) Synthesis of
1-(3,4-dichlorophenyl)cyclopent-3-enecarbaldehyde
[0552] To a -78.degree. C. solution of the nitrile (238 mg, 1 mmol)
in 5 mL toluene was added dibal (2 mL, 2 eq) dropwise. After 45
minutes, the cold solution was quenched with ethyl acetate (2 mL)
and stirred at ambient temperature for 30 minutes. The solution was
diluted with ethyl acetate and washed with 3M HCl, water, and
brine. The organic layer was dried with sodium sulfate, filtered
and evaporated. The crude product was purified by silica gel column
chromatography to give the aldehyde (161 mg, 67%) as a clear oil.
TLC R.sub.f(25% EA/Hex)=0.13. GCMS R.sub.t=7.7 min m/z=165 (M+).
.sup.1H NMR (CDCl.sub.3, .delta.): 5.89 (t, J=3.1 Hz, 2H), 3.09 (t,
J=2.8 Hz, 2H), 2.96 (s, 3H), 2.6 (m, 2H), 2.2 (m, 2H). .sup.13C NMR
(CDCl.sub.3, .delta.): 180.2, 127.7, 39.1, 24.9, 23.4.
(b) Synthesis of
1-(1-(3,4-dichlorophenyl)cyclopent-3-enyl)-N-methylmethanamine
(168)
[0553] To a solution of the aldehyde (100 mg, 0.4154 mmol) in
methylamine (2.1 mL, 2M in THF, 10 eq) was added acetic acid (104
ul, 5% of volume), and enough methanol to make a clear solution.
The solution was stirred for two hours. To this was added sodium
borohydride (40 mg, 3 eq) and stirring was continued for 30
minutes. The reaction was quenched with aqueous potassium carbonate
and extracted with MTBE. The organic phase was separated and the
solvent removed in vacuo. The residue was redissolved in MTBE and
extracted with 3M HCl. The aqueous phase was separated, chilled in
ice, and basicified with KOH. The aqueous phase was then extracted
with MTBE and the solvent removed in vacuo. The residue was diluted
in DCM, filtered through aminopropyl cartridge. The solvent was
again removed to give the title compound (75.1 mg, 71%) as a clear
oil. LCMS R.sub.t (SCM)=6.28 min; m/z=256 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.36 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.2 Hz,
1H), 7.10 (dd, J=2.2, 8.4 Hz, 1H), 5.73 (s, 2H), 5.67 (m, 6H), 2.31
(s, 3H). .sup.13C NMR (CDCl.sub.3, .delta., mult): 148.6(0),
132.2(0), 130.1(1), 129.8(0), 129.2(1), 129.1(1), 126.5(1),
63.1(2), 50.6(0), 43.2(2), 37.1(3).
2.7. Synthesis of 2-Hydroxymethyl Analogs
[0554] ##STR227## Synthesis of Aryl Lactones ##STR228##
[0555] General Procedure K: To a solution of lactone (5 mmol) and
Pd(dba).sub.2 (5 mol %) and toluene (6 mL) which was stirring under
nitrogen in a sealed vial, was added tri-t-butylphosphine (1 M in
toluene, 5 mol %), LiHMDS (1M in hexanes, 1.2 eq), and the aryl
bromide (1.5 eq). The solution was heated in the microwave for
fifteen minutes (max temp=140.degree. C.). After cooling, the
mixture was diluted with hexane, washed with 3M HCl, and
evaporated.
[0556] Alternatively, To a flame-dried 250 mL round bottom flask
was added Pd(dba).sub.2 (1 mol %) and toluene. The vessel was
purged with nitrogen and sealed before tri-t-butylphosphine (1M in
toluene, 1.1 mol %) was added via syringe followed by the aryl
bromide (51.27 mmol) as a solution in toluene (15 mL). LiHMDS (1 M
in hexanes, 1.3 eq) was added and the solution was stirred at
ambient temperature for 15 min. The lactone (1.3 eq) was added
dropwise as a solution in toluene (20 mL). The mixture was allowed
to stir at ambient temperature overnight (16 h) and then
partitioned between hexane and, in succession, 10% aqueous HCl, 10%
aqueous K.sub.2CO.sub.3, and brine. The volatile components were
removed in vacuo to give the crude arylated lactone.
(2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)-cyclohexyl)methanol
(169)
[0557] ##STR229## 169 E1, 169 E2
(a) Synthesis of racemic
7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one
[0558] The title compound was prepared in 30% yield according to
General Procedure K as a pale-yellow oil. GCMS R.sub.t (SCM)=13.0
min; m/z=284 (M+).
[0559] .sup.1H NMR (CDCl.sub.3, .delta.): 7.50 (d, J=2.3 Hz, 1H),
7.43 (d, J=8.5 Hz, 1H), 7.25 (dd, J=2.3, 8.5 Hz, 1H), 4.05 (dd,
J=4.9, 8.9 Hz, 1H), 3.94 (dd, J=2.4, 8.9 Hz, 1H), 2.8 (m, 1H), 2.2
(m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H). .sup.13C NMR (CDCl.sub.3,
.delta., mult): 177.7(0), 140.7(0), 133.0(0), 131.7(0), 130.7(1),
128.6(1), 125.9(1), 70.1(2), 51.7(1), 40.5(2), 34.0(2), 26.9(2),
23.0(2), 22.9(2).
(b)
(2-(3,4-dichlorophenyl)-2-((ethylamino)methyl)-cyclohexyl)methanol
[0560] The title compound was prepared from racemic
7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one and
ethylamine according to General Procedures AA, followed by General
Procedure E. The racemic aminol was separated using a chiral column
(Chiracel OD column; 95:5:0.1 hexanes:IPA:DEA, .lamda.=254 nm, 1
mL/min) to give the fast moving enantiomer 169 E1 (R.sub.t=7.5 min)
and the slow moving enantiomer 169 E2 (R.sub.t=9.7 min). LCMS
R.sub.t=7.88 min, m/z=316 (M+1). .sup.1H NMR (CDCl.sub.3, .delta.):
7.4 (m, 2H), 7.17 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.10 (d,
J=12.3 Hz, 1H), 2.71 (d, J=12.3 Hz, 1H), 2.6 (m, 2H), 2.3 (m, 1H),
1.9-1.3 (m, 8H), 1.04 (t, J=7.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3,
.delta., mult): 146.5(0), 133.1(0), 130.8(1), 130.0(0), 128.5(1),
125.7(1), 63.2(2), 53.6(br, 2), 45.4(0), 43.9(2), 41.9(1), 39.8(br,
2), 26.1(2), 24.8(2), 22.0(2), 14.5(3).
cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclohexyl)methanol
(170)
[0561] ##STR230## 170 E1, 170 E2
[0562] The title compound was prepared from racemic
7a-(3,4-dichlorophenyl)-hexahydroisobenzofuran-1(3H)-one and
methylamine according to General Procedures AA and E. The racemic
aminol was separated using a chiral column (Chiracel OD column;
95:5:0.1 hexanes:IPA:DEA, .lamda.=254 nm, 1 mL/min) to give the
fast moving enantiomer 170 E1 (R.sub.t=9.0 min) and the slow moving
enantiomer 170 E2 (R.sub.t, =11.5 min). LCMS R.sub.t=6.46 min,
m/z=302 (M+1). .sup.1H NMR (CDCl.sub.3, .delta.): 7.42-7.40 (m,
2H), 7.18 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.05 (d, J=12.3 Hz,
1H), 2.67 (d, J=12.3 Hz, 1H), 2.35 (s, 3H), 2.0-1.2 (m, 9H).
.sup.13C NMR (CDCl.sub.3, .delta., mult): 146.4(0), 133.0(0),
130.8(1), 130.0(0), 128.5(1), 125.7(1), 63.2(2), 62.5(2), 45.4(2),
42.4 (0), 41.8(1), 36.0(3), 26.1(2), 24.8(2), 22.0(2).
cis-(2-((dimethylamino)methyl)-2-phenylcyclohexyl)methanol
(171)
[0563] ##STR231## 171 E1, 171 E2
(a) Synthesis of 7a-Phenyl-hexahydro-isobenzofuran-1-one
[0564] ##STR232##
[0565] The title compound was prepared from
hexahydro-isobenzofuran-1-one (10 g, 1.3 eq) and phenyl bromide
(5.4 mL, 51.27 mmol) according to General Procedure K. It was
obtained as a clear oil (7.40 g, 67%). HPLC R.sub.t (5-100-8)=9.8
min. .sup.1H NMR (CDCl.sub.3, .delta.): 7.4-7.2 (m, 5H), 4.05 (dd,
1H), 3.90 (dd, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.8-1.3
(m, 6H). .sup.13C NMR (CDCl.sub.3, .delta., mult): 178.6 (0), 140.5
(0), 128.8 (1), 127.3 (1), 126.3 (1), 70.3 (2), 52.5 (0), 41.0 (1),
34.2 (2), 27.5 (2), 23.4 (2), 23.2 (2).
(b) Synthesis of 2-Hydroxymethyl-1-phenyl-cyclohexanecarboxylic
acid dimethylamide
[0566] ##STR233##
[0567] The amide was synthesized from the above lactone according
to General Procedure AA. The crude product was purified by silica
gel column chromatography to give a clear oil (239 mg, 100%).
.sup.1H NMR (CDCl.sub.3, .delta.): 7.4-7.0 (m, 5H), 5.4 (bs, 1H),
3.5-3.2 (m, 4H), 3.0 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H), 2.2 (m,
1H), 2.1 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.3 (m, 3H), 1.17 (t, 3H),
0.90 (t, 3H). .sup.13C NMR (CDCl.sub.3, .delta., mult): 175.5 (0),
142.9 (0), 128.7 (br), 126.8 (1), 63.1 (2), 57.3 (0), 53.3 (1),
43.1 (2), 41.1 (2), 35.2 (2), 26.7 (2), 26.6 (2), 23.4 (2), 13.0
(3), 12.1 (3).
(c) Synthesis of
cis-(2-((dimethylamino)methyl)-2-phenylcyclohexyl)methanol
[0568] The title compound was synthesized from the above amide
according to General Procedure E. The enantiomeric amines were
separated on a Chiracel OD semiprep column (95:5:0.05 Hex/IPA/DEA)
to give the fast-moving enantiomer 171 E1 (6.6 mg, 5.4%) and the
slow-moving enantiomer 171 E2 (6.0 mg, 4.9%). LCMS R.sub.t=5.84
min, m/z=248 (M+1). .sup.1H NMR (CDCl.sub.3, .delta.): 7.42 (d,
J=7.7 Hz, 2H), 7.31 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 3.95
(dd, J=6.6, 11.5 Hz, 1H), 3.83 (d, J=11.5 Hz, 1H), 2.96 (d, J=13.5
Hz, 1H), 2.6 (m, 1H), 2.53 (d, J=13.5 Hz, 1H), 1.99 (s, 6H),
1.9-1.1 (m, 8H). .sup.13CNMR (CDCl.sub.3, .delta.): 128.0, 127.0,
125.6, 64.2, 46.6, 45.3, 41.6, 26.8, 24.2, 22.1.
cis-(2-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexyl)methanol
(172)
[0569] ##STR234## 172 E, 172 E2
[0570] Powdered LAH (76 mg, 4 eq) was added to a solution of
1-(3,4-dichlorophenyl)-2-(hydroxymethyl)-N,N-dimethylcyclohexanecarboxami-
de (0.5 mmol) in THF (5 mL). After one hour at ambient temperature,
the reaction was quenched with aqueous ammonium chloride, washed
with MTBE, basicified with KOH, extracted with MTBE and evaporated
to give the crude amine (108 mg) as a yellow-black oil. The crude
oil was filtered (aminopropyl) and the enantiomers were separated
on a Chiracel OD column (98:2:0.1 Hex/IPA/DEA) to give the
fast-moving enantiomer 172 E1 (30.1 mg, 19%) and the slow-moving
enantiomer 172 E2 (26.6 mg, 17%). LCMS R.sub.t=8.33 min, m/z=316
(M+1). .sup.1H NMR (CDCl.sub.3, ): 7.50 (d, J=2.4 Hz, 1H), 7.38 (d,
J=8.6 Hz, 1H), 7.26 (dd, J=2.4, 8.6 Hz, 1H), 3.92 (dd, J=6.5, 11.6
Hz, 1H), 3.77 (dd, J=1.2, 11.7 Hz, 1H), 2.95 (d, J=13.7 Hz, 1H),
2.5 (m, 2H), 2.02 (s, 6H), 1.8-1.1 (m, 8H). .sup.13C NMR
(CDCl.sub.3, .delta., mult): 147.6, 132.2, 129.9, 129.6, 129.3,
126.6, 63.9, 46.8, 45.4, 41.8, 38.7, 29.7, 26.5, 23.9, 22.0.
cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)methanol
(173)
[0571] ##STR235## rac 173, 173 E1, 173 E2
(a) Synthesis of
cis-6a-(3,4-dichlorophenyl)hexahydro-1H-cyclopenta[c]furan-1-one
[0572] ##STR236##
[0573] The title compound was prepared from lactone (630 mg, 5
mmol) and dichlorophenylbromide (1.69 g, 1.5 eq) according to
General Procedure K. The crude product was separated by silica gel
column chromatography to give the lactone (578 mg, 44%) as a
pale-brown oil. TLC R.sub.f (25% EA/hex)=0.34. GC-MS R.sub.t=12.48
min, m/z=270 (M+). .sup.1H NMR (CDCl.sub.3, .delta.): 7.49 (d,
J=2.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.3, 8.4 Hz,
1H), 4.50 (dd, J=7.3, 9.6 Hz, 1H), 4.14 (dd, J=2.2, 9.6 Hz, 1H),
3.1 (m, 1H), 2.60 (ddd, J=3.0, 6.4, 12.5 Hz, 1H), 2.2-1.6 (m, 5H).
.sup.13C NMR (CDCl.sub.3, .delta., mult): 179.7(0), 140.6(0),
132.8(0), 131.5(0), 130.6(1), 128.3(1), 125.8(1), 72.7(2), 59.4(0),
46.2(1), 40.3(2), 34.4(2), 25.8(2).
(b) Synthesis of
cis-(2-(3,4-dichlorophenyl)-2-((methylamino)methyl)-cyclopentyl)methanol
[0574] The title compound was prepared from the above lactone and
methylamine according to General Procedures AA and E to give
racemic 173, which was separated by chiral HPLC (AD column;
2:3:95:0.1 MeOH:EtOH:Hex:DEA) to give the fast moving enantiomer
173 E1 (6.5 min) and the slow moving enantiomer 173 E2 (8.5 min).
LCMS (14 min) R.sub.t=5.98 min, m/z=288 (M+1). .sup.1H NMR
(CDCl.sub.3, .delta.): 7.6 (m, 1H), 7.4 (m, 2H), 6.8 (bs, 1H), 3.7
(m, 2H), 2.8 (m, 3H), 2.32 (s, 3H), 2.1-1.2 (m, 6H). .sup.13C NMR
(CDCl.sub.3, 6, mult): 147.3(0), 132.5(0), 130.2(1), 130.1(1),
129.3(0), 126.9(1), 63.7(2), 58.3(2), 52.9(0), 47.1(1), 41.6(2),
36.0(3), 28.6(2), 22.1(2).
2.8. Synthesis of 2-Methyl-Cycloalkylamines
(.+-.)-cis-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methanamine
hydrochloride (174)
[0575] ##STR237##
[0576] The title compound was synthesized from
1-(3,4-dichlorophenyl)-2-methylcyclohexanecarbonitrile (159 mg,
0.60 mmol) according to General Procedure E, followed by HCl salt
formation. The crude HCl salt was recrystallized from CH.sub.3CN
(1.5 mL) to give the title compound as white crystals. HPLC
R.sub.t=8.86 min; .sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.60-7.59 (m,
1H), 7.58-7.50 (m, 1H), 7.39-7.35 (m, 1H), 3.32-3.13 (m, 2H),
2.13-2.04 (m, 1H), 1.73-1.33 (m, 8H), 0.86 (d, J=6.96 Hz, 3H);
LC-MS 8.8 min, (M+1).sup.+272 @ 9.0 min.
(.+-.)
cis-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylmetha-
namine hydrochloride (175)
[0577] ##STR238##
[0578]
((+/-)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methanamin-
e free base (110 mg, 0.41 mmol), paraformaldehyde (ca. 100 mg),
polymer bound cyanoborohydride (762 mg, 2.13 mmol/g, 1.62 mmol) and
concentrated AcOH (1 mL) were suspended in 10 mL THF. The solution
was shaken overnight, then filtered and diluted with EtOAc. The
organic phase washed with 3M NaOH (2.times.20 mL) and brine (20
mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
material was dissolved in Et.sub.2O (3 mL) and HCl (ca. 1.5 mL, 2.0
M in Et.sub.2O) was added. A white ppt. formed immediately. The
crude HCl salt was recrystallized from EtOAc (1.5 mL) to give pure
((+/-)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N,N-dimethylmetha-
namine hydrochloride as white crystals. HPLC R.sub.t=9.1 min;
.sup.1H NMR (400 mHz, MeOH-d.sup.4) 7.73 (d, J=2.2 Hz, 1H), 7.56
(d, J=8.8 Hz, 1H), 7.51-7.48 (m, 1H), 3.58-3.54 (m, 1H), 3.42-3.39
(m, 1H), 2.64-2.52 (m, 6H), 2.20-2.18 (m, 2H), 1.83-1.76 (m, 1H),
1.63-1.42 (m, 6H), 1.01 (d, J=7.33 Hz, 3H); LC-MS 10.1 min,
(M+1).sup.+300 (10.3 min.
(.+-.)
cis-1-(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanami-
ne (176)
[0579] ##STR239##
[0580]
((+/-)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methanamin-
e free base (421 mg, 1.55 mmol) was dissolved in 3:1 THF:H.sub.2O
(8 mL) and K.sub.2CO.sub.3 (322 mg, 2.33 mmol) was added. The
solution was stirred for 2 minutes, then BOC.sub.2O (338 mg, 1.55
mmol) was added. After 2 h, the solution was poured into H.sub.2O
and the layers were separated. The organic layer washed with
H.sub.2O (1.times.20 mL) and brine (1.times.20 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. A portion of the
N--BOC amine (113 mg) was used directly in the next reaction. LAH
(34 mg, 0.9 mmol) was suspended in anhydrous THF (2 mL) and the
amine (113 mg, 0.30 mmol) in anhydrous THF (3 mL) was added
dropwise. The solution was heated in the MW (160.degree. C., 5 min,
FHT). The crude reaction was quenched with 6M HCl (10 mL). The
solution washed with EtOAc (2.times.20 mL) and the EtOAc washes
were discarded. After the pH of the aqueous phase was adjusted to
12 with 3M NaOH, it washed again with EtOAc (3.times.20 mL). The
combined "second" organic washes were dried (Na.sub.2SO.sub.4),
filtered and concentrated. The crude amine was purified by PTLC
with 10% MeOH/CH.sub.2Cl.sub.2 to give
((+/-)-(cis)-1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-N-methylmethanami-
ne as a clear oil. HPLC R.sub.t=8.91 min; .sup.1H NMR (400 mHz,
CDCl.sub.3) 7.48 (d, J=2.57 Hz, 1H), 7.39-7.36 (m, 1H), 7.25-7.23
(m, 1H), 2.71 (s, 2H), 2.38 (s, 3H), 2.11-2.03 (m, 1H), 1.85-1.73
(m, 2H), 1.70-1.60 (m, 1H), 1.53-1.33 (m, 5H), 0.83 (d, J=6.98 Hz,
3H); LC-MS 8.70 min, (M+1).sup.+286 @ 8.97 min.
(.+-.)
cis-N-((1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methyl)ethanamine
(177)
[0581] ##STR240##
[0582] t-Butyl
(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)-methylcarbamate (97 mg,
0.261 mmol) was dissolved in anhydrous DMF (3 mL) and NaH (60%
dispersion in mineral oil, 21 mg, 0.52 mmol) was added. The
solution was heated via MW (75.degree. C., 5 min), and cooled to
RT. Ethyl iodide (62 mL, 0.78 mmol) was added and the solution was
heated via MW (100.degree. C., 20 min). The yellow mixture was
poured into H.sub.2O (20 mL) and washed with Et.sub.2O (3.times.20
mL). The combined organic washes were dried (Na.sub.2SO.sub.4),
filtered and concentrated. Purification by silica gel column
chromatography with 0.fwdarw.10% EtOAc/hexanes gave tert-butyl
(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methylethylcarbamate (32
mg, 0.08 mmol) as a clear oil. tert-butyl
(1-(3,4-dichlorophenyl)-2-methylcyclohexyl)methylethylcarbamate (32
mg, 0.08 mmol) was dissolved in 1:1 CH.sub.2Cl.sub.2:TFA (3 mL) and
stirred for 2 h then concentrated. The crude amine was dissolved in
EtOAc (20 mL) and washed with 3M NaOH (2.times.20 mL) and brine (20
mL), then dried (Na.sub.2SO.sub.4), filtered and concentrated. The
crude amine was purified by PTLC with 10% MeOH/CH.sub.2Cl.sub.2 to
give the title compound as a clear oil. HPLC R.sub.t=9.17 min;
.sup.1H NMR (400 mHz, CDCl.sub.3) 7.51 (d, J=2.2 Hz, 1H), 7.37 (d,
J=8.43 Hz, 1H), 7.27-7.25 (m, 1H), 2.76 (d, J=1.47 Hz, 2H), 2.59
(q, 2H), 2.08-2.05 (m, 1H), 1.78-1.77 (m, 1H), 1.67-1.64 (m, 1H),
1.52-1.36 (m, 5H), 1.05 (at, 3H), 0.81 (d, J=6.97 Hz, 3H); LC-MS
8.94 min, (M+1).sup.+300 @ 9.17 min.
Example 3
Synthesis of 3-Substituted Cyclohexylamine Analogs
[0583] ##STR241##
3.1. Synthesis of
3-(aminomethyl)-3-(3,4-dichlorophenyl)-cyclohexanol analogs
[0584] ##STR242##
[0585] The synthesis of
3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol is outlined in
Scheme 30, below. Reaction of 3-ethoxy-2-cyclohexen-1-one 178 with
3,4-dichlorophenylmagnesium bromide in THF followed by quenching
the Grignard mixture with diluted H.sub.2SO.sub.4 gave
3-(3,4-dichlorophenyl)-2-cyclonexen-1-one 179. Addition of CN.sup.-
to the .alpha.,.beta.-unsaturated ketone by heating 179 with KCN in
the presence of NH.sub.4Cl in aqueous DMF afforded the cyano ketone
180 in 30% yield. The ketone was reduced to the alcohol 181 using
NaBH.sub.4 in ethanol at 0.degree. C. The major product was the cis
diastereomer and the minor product was the trans diastereomer. The
amine 182 was formed through reduction of the nitrile with
BH.sub.3.THF at room temperature overnight in 83% yield. Protection
of the amino group with Boc-anhydride afforded 183. The
diastereomers were then separated using reverse phase HPLC.
##STR243##
3.1.1. Preparation of Boc Protected Primary Amines 14
[0586] The primary amine 182 (mixture of cis and trans
diastereomers, 1.8 g, 6.57 mmol) was added to a 10% triethylamine
solution in MeOH (40 ml). To this mixture was added di-tert-butyl
dicarbonate (1.72 g, 7.88 mmol) with vigorous stirring. The mixture
was stirred at room temperature for 3 hours. The solvent was then
removed in vacuo. The residue was dissolved in EtOAc (70 ml),
washed with saturated K.sub.2CO.sub.3 solution (3.times.40 ml), 5%
HCl (2.times.40 ml), brine (40 ml), dried over Na.sub.2SO.sub.4,
and evaporated. The residue was purified by silica gel column
chromatography (MeOH/CH.sub.2Cl.sub.2, MeOH from 0 to 5%) to yield
183 (2.45 g, 97%) as a clear oil. The diastereomers of 183 were
separated (C-18 column, 50% acetonitrile, 50% water) to give the
cis isomer cis 183 (1.83 g) and the trans isomer trans 183 (0.45
g).
[0587] cis 183: .sup.1H NMR (CDCl.sub.3) .delta. 1.19-1.31 (m, 4H),
1.37 (s, 9H), 1.68-1.72 (m, 1H), 1.87-1.90 (m, 1H), 2.13 (d, J=12.8
Hz, 1H), 2.41 (d, J=12.8 Hz, 1H), 2.58 (brs, 1H), 3.09-3.22 (m,
2H), 3.54-3.66 (m, 1H), 4.72 (t, J=6.0 Hz, 1H), 7.18-7.21 (m, if
H), 7.40-7.49 (m, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 20.2,
28.5, 32.7, 35.8, 42.0, 44.8, 53.5, 66.8, 79.7, 126.7, 129.4,
130.6, 130.8, 133.0, 143.9, 156.3. ESI MS m/z 374.
[0588] trans 183: .sup.1H NMR (CDCl.sub.3) .delta. 1.21-1.38 (m,
4H), 1.39 (s, 9H), 1.60-1.66 (m, 1H), 1.87-1.90 (m, 1H), 1.98 (d,
J=10.8 Hz, 1H), 2.26 (d, J=10.8 Hz, 1H), 2.76 (brs, 1H), 3.30-3.45
(m, 2H), 398-4.08 (m, 1H), 7.06-7.18 (m, 1H), 7.39-7.43 (m, 2H).
.sup.13C NMR (CDCl.sub.3) .delta. 20.4, 28.5, 33.0, 35.1, 42.1,
43.1, 46.6, 67.1, 79.7, 125.6, 128.4, 130.5, 130.6, 132.8, 147.6,
156.2. ESI MS m/z 374.
3.1.2. Chiral HPLC Separation of Enantiomers
[0589] ##STR244##
[0590] The enantiomers of cis 183 were separated using a
preparative HPLC procedure (ChiralPak OD column; hexanes:IPA=90:10;
8 ml/min; .lamda.=280 nm) to give cis 183 E1 (retention time=10
min) and cis 183 E2 (retention time=18 min). The absolute
configuration of the chiral centers was not determined.
##STR245##
[0591] The enantiomers of trans 183 were separated using a
preparative HPLC procedure (ChiralPak OD column; hexanes:IPA=90:10;
8 ml/min; .lamda.=280 nm) to give trans 183 E1 (retention time=15
min) and trans 183 E2 (retention time=21 min). The absolute
configuration of the chiral centers was not determined.
3.1.3. Preparation of Primary Amines 182 (Removal of Boc-group)
[0592] General Procedure U: To the solution of the respective
Boc-protected primary amine 183 (e.g., 38 mg, 0.102 mmol) in
CH.sub.2Cl.sub.2 (e.g., 2 ml) was added TFA (e.g., 2 ml) at
0.degree. C. The mixture was stirred at 0.degree. C. for one hour
and the solvent was removed in vacuo. The residue was dissolved in
CH.sub.2Cl.sub.2 (10 ml), washed with saturated K.sub.2CO.sub.3
solution (2.times.3 ml), dried over Na.sub.2SO.sub.4, and then
filtered through an aminopropyl cartridge. The solvent was removed
to give the respective primary amine 182.
[0593] The following compounds were prepared following the
procedure outlined in General Procedure U, above.
Cis-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (184)
[0594] ##STR246## 184 E1, 184 E2
[0595] .sup.1H NMR (CDCl.sub.3): .delta.1.21-1.39 (m, 4H),
1.42-1.52 (m, 2H), 1.63-1.70 (m, 1H), 1.80-1.90 (m, 1H), 2.20 (d,
J=12.8 Hz, 1H), 2.43 (d, J=12.8 Hz, 1H), 2.62 (s, 2H), 3.51-3.60
(m, 1H), 7.16-7.20 (m, 1H), 7.40-7.49 (m, 2H). .sup.13C NMR
(CDCl.sub.3) .delta. 20.5, 32.8, 36.2, 42.5, 45.5, 57.0, 67.0,
126.9, 129.5, 130.7, 130.8, 133.0, 144.3. ESI MS m/z 274.
Trans-3-(aminomethyl)-3-(3,4-dichlorophenyl)cyclohexanol (185)
[0596] ##STR247## 185 E1, 185 E2
[0597] .sup.1H NMR (CDCl.sub.3): .delta. 1.21-1.30 (m, 4H),
1.42-1.58 (m, 3H), 1.77-1.82 (m, 1H), 2.00-2.05 (m, 2H), 2.34-2.40
(m, 1H), 2.85 (d, J=13.2 Hz, 1H), 2.90 (d, J=13.2 Hz, 1H),
3.85-3.93 (m, 1H), 7.18-7.20 (m, 1H), 7.40-7.43 (m, 2H). .sup.13C
NMR (CDCl.sub.3) .delta. 20.3, 32.6, 35.3, 42.2, 48.6, 67.4, 125.8,
128.6, 130.4, 132.7, 133.9, 147.9. ESI MS m/z 274.
3.1.4. Preparation of Secondary Amines 15
[0598] ##STR248##
[0599] General Procedure F1: A solution of acetic anhydride (e.g.,
0.118 ml, 1.254 mmol) and formic acid (e.g., 0.058 ml, 1.546 mmol)
in THF (e.g., 1.5 ml) was heated in a microwave at 100.degree. C.
for 5 min. After cooling to room temperature, a solution of the
respective primary amine 182 (e.g., 107 mg, 0.392 mmol) in THF
(e.g., 1.5 ml) was added. The mixture was heated in the microwave
at 100.degree. C. for 5 min. The solvent was then removed in vacuo.
The residue was dissolved in THF (e.g., 1.5 ml), and BH.sub.3.THF
(e.g., 1 ml, 1.0 mmol) was added. The mixture was heated in the
microwave at 60.degree. C. for 6 min. The reaction was then
quenched by the addition of MeOH (e.g., 2 ml) and 6N HCl (e.g., 1
ml). The solvent was removed in vacuo. To the residue was added 1 N
NaOH solution to pH 12. The aqueous solution was extracted with
CH.sub.2Cl.sub.2 (e.g., 3.times.10 ml). The combined organic phases
were dried over Na.sub.2SO.sub.4 and evaporated in vacuo. The
residue was purified by silica gel column chromatography
(MeOH/CH.sub.2Cl.sub.2, 0-10%) to give the respective secondary
amine 186.
[0600] The following compounds were prepared according to the
procedures outlined in General Procedure F1, above.
Cis-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol
(187)
[0601] ##STR249## 187 E1, 187 E2
[0602] .sup.1H NMR (CDCl.sub.3): .delta. 1.37-1.42 (m, 1H),
1.49-1.58 (m, 1H), 1.63-1.70 (m, 2H), 1.90-2.05 (m, 1H), 2.28 (d,
J=12.8 Hz, 1H), 2.46 (s, 3H), 2.85 (d, J=12.4 Hz, 1H), 3.38 (d,
J=12.4 Hz, 1H), 3.63-3.78 (m, 2H), 3.88-3.92 (m, 1H), 7.23 (d,
J=7.2 Hz, 1H), 7.40-7.49 (m, 2H). .sup.13C NMR (CDCl.sub.3) .delta.
20.3, 30.1, 33.7, 35.1, 45.5, 61.4, 62.9, 65.9, 126.3, 129.0,
131.2, 131.4, 133.3, 144.1. ESI MS m/z 288.
Trans-3-(3,4-dichlorophenyl)-3-((methylamino)methyl)cyclohexanol
(188)
[0603] ##STR250##
[0604] .sup.1H NMR (CDCl.sub.3): .delta. 1.15-1.26 (m, 1H),
1.36-1.44 (m, 2H), 1.52-1.63 (m, 1H), 1.76-1.82 (m, 1H), 2.03 (t,
J=13.2 Hz, 1H), 2.29 (s, 3H), 2.41-2.45 (m, 1H), 2.68 (d, J=12.0
Hz, 1H), 2.78 (d, J=12.0 Hz, 1H), 3.84-3.91 (m, 1H), 7.20 (dd,
J=8.4 Hz, 1.6 Hz, 1H), 7.38-7.44 (m, 2H). .sup.13C NMR (CDCl.sub.3)
.delta. 20.7, 33.9, 35.1, 37.4, 42.8, 42.9, 58.4, 67.0, 125.5,
128.3, 130.4, 130.5, 132.7, 148.5. ESI MS m/z 288.
188 E1, 188 E2
3.1.5. Preparation of Tertiary Amines 189
[0605] ##STR251##
[0606] General Procedure D1: A mixture of 37% formaldehyde (e.g.,
0.096 ml, 1.183 mmol) and 96% formic acid (e.g., 0.056 ml, 1.183
mmol) in water (e.g., 2 ml) was added to the respective primary
amine 182 (e.g., 130 mg, 0.473 mmol) at 0.degree. C. The mixture
was heated to 100.degree. C. overnight. The reaction mixture was
then washed with hexanes (e.g., 3.times.10 ml), and evaporated in
vacuo. The residue was purified by reverse phase HPLC (C-18 column,
CH.sub.3CN/water, CH.sub.3CN from 5% to 100%) to give the
respective tertiary amine 189.
[0607] The following compounds were prepared according to General
Procedure D1, above.
Cis-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol
(190)
[0608] ##STR252## 190 E1, 190 E2
[0609] .sup.1H NMR(CDCl.sub.3): .delta. 1.23-1.36 (m 2H), 1.46-1.53
(m, 1H), 1.59 (dd, J=12.8 Hz, 8 Hz, 1H), 1.68-1.73 (m, 1H),
1.81-1.85 (m, 1H), 2.05 (s, 6H), 2.07-2.10 (m, 1H), 2.27 (d, J=13.6
Hz, 1H), 2.37 (d, J=13.6 Hz, 1H), 2.43 (m, 1H), 2.63 (brs, 1H),
3.59-3.65 (m, 1H), 7.21 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.37 (d, J=8.4
Hz, 1H), 7.44 (d, J=2.0 Hz, 1H). .sup.13C NMR (CDCl.sub.3) .delta.
20.2, 33.7, 35.7, 42.2, 45.0, 48.4, 66.9, 73.5, 126.9, 129.4,
129.8, 130.3, 132.5, 146.2. ESI MS m/z 302.
Trans-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)cyclohexanol
(191)
[0610] ##STR253## 191 E1, 191 E2
[0611] .sup.1H NMR (CDCl.sub.3) .delta. 1.16-1.26 (m, 1H),
1.34-1.45 (m, 2H), 1.50-1.61 (m, 1H), 1.75-1.81 (m, 1H), 1.95 (s,
6H), 1.99-2.03 (m, 1H), 2.14 (brs, 1H), 2.40-2.47 (m, 2H), 2.55 (d,
J=13.6 Hz, 1H), 3.84-3.91 (m, 1H), 7.21 (dd, J=8.4 Hz, 2.0 Hz, 1H),
7.35 (d, J=8.4 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H). 13C NMR
(CDCl.sub.3) .delta. 20.6, 33.8, 35.1, 42.6, 43.0, 48.2, 66.3,
67.7, 125.8, 128.5, 129.8, 130.0, 132.2, 150.0. ESI MS m/z 302.
3.1.6. Synthesis of
cis-1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-methanamine
(192)
[0612] ##STR254##
[0613] To a solution of
1-(3,4-dichloro-phenyl)-3-methoxy-cyclohexanecarbonitrile (150 mg,
0.53 mmoL) in THF (5 mL) was added BH.sub.3.THF (1.0 M, 1.59 mL,
1.59 mmoL). The reaction mixture was stirred overnight before being
concentrated. The residue was dissolved in MeOH (3 mL) and
subjected to reverse phase column chromatography
(CH.sub.3CN/H.sub.2O/0.1% Formic acid=5% to 100%) to give the
desired product (109 mg, 72%).
3.2. Synthesis of 3-Disubstituted Aryl-Cyclohexylamines
Synthesis of
3-Aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol
(193)
[0614] ##STR255##
[0615] The title compound was synthesized from
1-(3,4-dichlorophenyl)-3-oxo-cyclohexanecarbonitrile (1.0 g, 3.7
mmol) according to General Procedure Y, followed by General
Procedure E (Scheme 31). The crude product was dissolved in MeOH (4
mL) and subjected to reverse phase column chromatography
(CH.sub.3CN/H.sub.2O/0.1% formic acid=5% to 100%) to give (.+-.)
3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.57
g, 81%). ##STR256## 193 E1, 193 E2
[0616] To a solution of
3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.5 g,
1.74 mmoL) in CH.sub.2Cl.sub.2 (15 mL) was added Et.sub.3N (528 mg,
727 mL, 5.22 mmol) and (BOC).sub.2O (567 mg, 2.60 mmol). The
reaction mixture was stirred for 2 h at room temperature before
being quenched by a saturated NH.sub.4Cl solution (10.0 mL). The
product was extracted with CH.sub.2Cl.sub.2 (2.times.15 mL). The
combined extracts were washed with saturated brine, dried and
concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane=1:5) to afford
(.+-.)tert-butyl
(1-(3,4-dichlorophenyl)-3-hydroxy-3-methylcyclohexyl)-methylcarbamate
(0.61 g, 90%). The enantiomers were separated (chiral AD column
with hexane/iso-propanol/DEA=95:5:0.1) to afford the fast moving
enantiomer E1 (0.22 g, retention time 4.085 min) and the slow
moving enantiomer E2 (0.32 g, retention time 6.051 min). To a
solution of the respective enantiomer E1 (200 mg, 0.52 mmol) or E2
(200 mg, 0.52 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added TFA (2.0
mL). The reaction mixtures were stirred for 0.5 h before being
concentrated. The mixtures were each purified by reverse phase
column chromatography (CH.sub.3CN/H.sub.2O) to give the amines 193
E1 and 193 E2 in each 80% yield. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.32 (broad, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.4
Hz, 1H), 7.37 (dd, J=2.0, 8.4 Hz, 1H), 3.55 (s, 2H), 2.15 (m, 2H)
1.88 (m, 1H), 1.74-1.58 (m, 4H), 1.40 (m, 1H), 1.21 (m, 3H);
.sup.13CNMR (100 MHz, CD.sub.3OD) .delta. 146.42, 132.75, 131.01,
130.83, 128.41, 125.97, 69.31, 46.48, 44.85, 40.15, 37.81, 32.81,
32.54, 30.91, 18.17; ESI MS m/z=288.4.
3.3. Synthesis of Chiral 3-Methoxy-Cyclohexylamines
[0617] ##STR257##
[0618] 1-(3,4-dichlorophenyl)-3-methoxycyclohexanecarbonitrile was
synthesized from
1-(3,4-dichloro-phenyl)-3-oxo-cyclohexanecarbonitrile (1.5 g, 5.61
mmoL) according to General Procedure W, followed by General
Procedure EE (Scheme 32). The crude product was purified by silica
gel column chromatography (ethyl acetate/hexane=1:7).
[0619] The cis enantiomers (170 mg) were separated (chiral OD
column; ethanol/methanol/hexane/DEA=1; 1:98:0.1) to give the fast
moving enantiomer E1 (67 mg) and the slow moving enantiomer E2 (81
mg).
[0620] E1 was converted to 192 and E2 (120 mg, 0.42 mmoL) was
converted to 194 according to General Procedure E. The crude
product was dissolved in MeOH (3 mL) and subjected to reverse phase
column chromatography (CH.sub.3CN/H.sub.2O/0.1% formic acid=5% to
100%) to give the desired product (90.4 mg, 75%). .sup.1H NMR (400
MHz, CD.sub.3Cl) .delta. 7.46 (m, 2H), 7.20 (m, 1H), 3.02 (s, 3H),
3.08 (m, 1H), 2.83 (s, 2H), 2.46 (m, 1H), 2.22 (m, 1H), 1.92 (m,
1H), 1.76 (m, 1H), 1.46 (m, 2H), 1.24 (m, 2H); .sup.13C NMR (100
MHz, CD.sub.3Cl) .delta. 141.71, 133.41, 131.46, 131.27, 129.67,
126.84, 75.30, 55.99, 51.80, 42.43, 39.20, 32.66, 31.31, 19.84; ESI
MS m/z 288.1. ##STR258## ##STR259##
[0621] Likewise, the methylated trans-enantiomers (100 mg) were
separated using a chiral OD column
(ethanol/methanol/hexane/DEA=1:1:98:0.1) to give trans E1 (43 mg)
and trans E2 (38 mg). Trans E2 (38 mg, 0.13 mmoL) was converted to
the respective amine according to General Procedure E. The crude
product was dissolved in MeOH (1 mL) and subjected to reverse phase
column chromatography (CH.sub.3CN/H.sub.2O/0.1% formic acid=5% to
100%) to give the desired product 195 E2 (31.2 mg, 82%). .sup.1H
NMR (400 MHz, CD.sub.3Cl) .delta. 7.47 (m, 2H), 7.22 (m, 1H), 3.04
(s, 3H), 3.10 (m, 1H), 2.85 (s, 2H), 2.49 (m, 1H), 2.20 (m, 1H),
1.94 (m, 1H), 1.74 (m, 1H), 1.49 (m, 2H), 1.26 (m, 2H); .sup.13C
NMR (100 MHz, CD.sub.3C1) .delta. 141.69, 133.52, 131.64, 131.09,
129.78, 127.01, 76.01, 56.109, 51.68, 42.56, 39.40, 32.77, 31.42,
20.01; ESI MS m/z 288.1.
3.4. Synthesis of Secondary and Tertiary Amines
[0622] Compounds in Table 4, below were prepared from the indicated
amine according to General Procedure F. TABLE-US-00004 TABLE 4
##STR260## R.sup.d R.sup.e R.sup.3 R.sup.4
cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-meth-
ylmethanamine (196) H OCH.sub.3 CH.sub.3 H The compound was
prepared from 194. The crude product was subjected to silica gel
column chromatography (Ethyl acetate/hexane/DEA = 1/4/0.1%) to give
196 (26.7 mg, 32%) and 197 (37.6 mg, 37%). .sup.1H NMR(400 MHz,
CD.sub.3Cl) .delta. 7.43(d, J=2.0Hz, 1H), 7.41(d, J=8.8Hz, 1H),
7.21(dd, J=2.0, 8.8Hz, 1H), 3.12(s, 3H), 3.07(m, 1H), 2.54(m, 1H),
2.55(s, 2H), 2.28(s, 3H), 2.26(m, 1H), 2.19(m, 1H), 1.70(m, 1H),
1.40(m, 2H), 1.22(m, 2H); .sup.13C NMR(100 MHz, CD.sub.3Cl) .delta.
144.77, 132.98, 130.68, 130.30, 129.44, 126.80, 75.83, 66.66,
55.89, 44.22, 40.19, 37.53, 33.81, 33.37, 20.43; ESI MS m/z 308.1.
cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-di-
methylmethanamine (197) H OCH.sub.3 CH.sub.3 CH.sub.3 The compound
was prepared from 194. The crude product was subjected to silica
gel column chromatography (Ethyl acetate/hexane/DEA = 1/4/0.1%) to
give 196 (26.7 mg, 32%) and 197 (37.6 mg, 37%). .sup.1H NMR(400
MHz, CD.sub.3Cl) .delta. 7.45(d, J=2.4Hz, 1H), 7.38(d, J=8.4Hz,
1H), 7.22(dd, J=2.4, 8.4Hz, 1H), 3.22(s, 3H), 3.06(m, 1H), 2.56(m,
1H), 2.28(s, 2H), 2.19(m, 1H), 2.02(s, 6H), 2.04-1.96(m, 1H),
1.68(m, 1H), 1.40(m, 1H), 1.20(m, 2H); .sup.13C NMR (100 MHz,
CD.sub.3Cl) .delta. 145.41, 132.53, 130.30, 129.84, 129.70, 127.10,
75.99, 74.35, 55.88, 48.76, 45.54, 39.82, 33.19, 32.32, 20.46; ESI
MS m/z 316.1. cis-3-(3,4-dichlorophenyl)-1-methyl-3-((meth-
ylamino)methyl)cyclohexanol (198) CH.sub.3 OH CH.sub.3 H The
compound was prepared from 193 E2. .sup.1HNMR(400 MHz, CD.sub.3OD)
.delta. 7.51(d, J=2.4Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.31(dd, J=2.4,
8.4Hz, 1H), 3.31(d, J=13.2Hz, 1H), 3.20(d, J=13.2Hz, 1H), 2.23(s,
3H), 2.00(m, 2H), 1.88(m, 1H), 1.75(m, 1H), 1.68(m, 1H), 1.60(m,
2H), 1.39(m, 1H), 1.05(s, 3H); .sup.13CNMR(100 mHz, CD.sub.3OD),
.delta. 146.32, 132.08, 130.19, 127.68, 128.37, 126.07, 69.45,
61.35, 46.74, 41.79, 38.58, 35.86, 32.74, 30.36, 18.97; ESI MS m/z
302.1. cis-3-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)-1-meth-
ylcyclohexanol (199) CH.sub.3 OH CH.sub.3 CH.sub.3 The compound was
prepared from 193 E2. .sup.1H NMR(400 MHz, CD.sub.3OD) .delta.
8.44(broad, 1H), 7.64(d, J=2.0Hz, 1H), 7.55(d, J=8.8Hz, 1H),
7.42(dd, J=2.0, 8.8Hz, 1H), 4.05(d, J=13.2Hz, 1H), 3.53(d,
J=13.2Hz, 1H) 2.558(s, 6H), 2.30(m, 1H), 2.15(m, 1H), 1.95(m, 1H),
1.80(d, J=14Hz, 1H), 1.68(m, 2H), 1.41(td, J=4.0, 13.2Hz, 2H),
1.33(s, 3H); .sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 148.30,
132.86, 130.99, 130.88, 128.21, 125.84, 69.03, 65.32, 44.56, 41.65,
39.83, 37.63, 36.48, 30.89, 18.36; ESI MS m/z 316.2.
cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N-meth-
ylmethanamine (200) H OCH.sub.3 CH.sub.3 H The compound was
prepared from 192. .sup.1H NMR(400 MHz, CD.sub.3Cl) .delta. 7.43(d,
J=2.0Hz, 1H), 7.41(d, J=8.8Hz, 1H), 7.21(dd, J=2.0, 8.8Hz, 1H),
3.12(s, 3H), 3.07(m, 1H), 2.54(m, 1H), 2.55(s, 2H), 2.28(s, 3H),
2.26(m, 1H), 2.19(m, 1H), 1.70(m, 1H), 1.40(m, 2H), 1.22(m, 2H);
.sup.13C NMR(100 MHz, CD.sub.3Cl) .delta. 144.77, 132.98, 130.68,
130.30, 129.44, 126.80, 75.83, 66.66, 55.89, 44.22, 40.19, 37.53,
33.81, 33.37, 20.43; ESI MS m/z 308.1.
cis-1-(1-(3,4-dichlorophenyl)-3-methoxycyclohexyl)-N,N-di-
methylmethanamine (201) H OCH.sub.3 CH.sub.3 CH.sub.3 The compound
was prepared from 192. .sup.1H NMR(400 MHz, CD.sub.3Cl) .delta.
7.45(d, J=2.4Hz, 1H), 7.38(d, J=8.4Hz, 1H), 7.22(dd, J=2.4, 8.4Hz,
1H), 3.22(s, 3H), 3.06(m, 1H), 2.56(m, 1H), 2.28(s, 2H), 2.19(m,
1H), 2.02(s, 6H), 2.04-1.96(m, 1H), 1.68(m, 1H), 1.40(m, 1H),
1.20(m, 2H); .sup.13C NMR(100 MHz, CD.sub.3Cl) .delta. 145.41,
132.53, 130.30, 129.84, 129.70, 127.10, 75.99, 74.35, 55.88, 48.76,
45.54, 39.82, 33.19, 32.32, 20.46; ESI MS m/z 316.1.
cis-3-(3,4-dichlorophenyl)-3-((methylamino)ethyl)cyclohexanol (202)
CH.sub.3 OH CH.sub.3 H The compound was prepared from 193 E1.
.sup.1HNMR(400 MHz, CD.sub.3OD) .delta. 7.51(d, J=2.4Hz, 1H),
7.45(d, J=8.4Hz, 1H), 7.31(dd, J=2.4, 8.4Hz, 1H), 3.31(d, J=13.2Hz,
1H), 3.20(d, J=13.2Hz, 1H), 2.23(s, 3H), 2.00(m, 2H), 1.88(m, 1H),
1.75(m, 1H), 1.68(m, 1H), 1.60(m, 2H), 1.39(m, 1H), 1.05(s, 3H);
.sup.13CNMR(100 mHz, CD.sub.3OD) .delta. 146.32, 132.08, 130.19,
127.68, 128.37, 126.07, 69.45, 61.35, 46.74, 41.79, 38.58, 35.86,
32.74, 30.36, 18.97; ESI MS m/z 302.1.
cis-3-(3,4-dichlorophenyl)-3-((di- methylamino)methyl)cyclohexanol
(203) CH.sub.3 OH CH.sub.3 CH.sub.3 The compound was prepared from
193 E1. .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 8.44(broad, 1H),
7.64(d, J=2.0Hz, 1H), 7.55(d, J=8.8Hz, 1H), 7.42(dd, J=2.0, 8.8Hz,
1H), 4.05(d, J=13.2Hz, 1H), 3.53(d, J=13.2Hz, 1H) 2.558(s, 6H),
2.30(m, 1H), 2.15(m, 1H), 1.95(m, 1H), 1.80(d, J=14Hz, 1H), 1.68(m,
2H), 1.41(td, J=4.0, 13.2Hz, 2H), 1.33(s, 3H); .sup.13C NMR(100
MHz, CD.sub.3OD) .delta. 148.30, 132.86, 130.99, 130.88, 128.21,
125.84, 69.03, 65.32, 44.56, 41.65, 39.83, 37.63, 36.48, 30.89,
18.36; ESI MS m/z 316.2.
(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-methanamine
(204)
[0623] ##STR261##
[0624] The title compound was synthesized from
1-(3,4-dichloro-phenyl)-3-oxo-cyclohexanecarbonitrile (0.60 g, 2.2
mmol) according to General Procedure CC, followed by General
Procedure E. The crude product was dissolved in MeOH (3 mL) and
subjected to reverse phase column chromatography
(CH.sub.3CN/H.sub.2O/0.1% Formic acid=5% to 100%) to give (86 mg,
72%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.64 (d, J=7.4 Hz,
1H), 7.57 (d, J=8.4 Hz, 1H), 7.39 (dd, J=2.4, 8.4 Hz, 1H), 3.23 (s,
2H), 2.4 (m, 2H), 2.52 (m, 2H), 1.95 (m, 2H), 1.80 (m, 2H);
.sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 142.17, 132.94, 131.58,
130.96, 129.06, 126.54, 123.11, 47.74, 41.65, 40.23, 32.98, 30.69,
18.21, 41.26; ESI MS m/z 294.0.
1-(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-N-methylmethanamine
(205)
205 E1, 205 E2
[0625] The title compound was synthesized from 204 according to
General Procedure F. The crude product was subjected to silica gel
column chromatography (ethyl acetate/hexane/DEA=1:4:0.1) to give
the mono-methylated analog (25 mg, 30%) and the N,N-dimethylated
analog (36 mg, 41%). The racemic mixture of the monomethylated
analog was purified by chiral column chromatography (OJ column;
Hexane/.sup.ipropanol/DEA=98/2/0.1) to give the fast moving
enantiomer 205 E1 (5.2 mg) and the slow moving enantiomer 205 E2
(6.3 mg). .sup.1H NMR (400 MHz, CD.sub.3Cl) .delta. 7.42 (d, J=2.4
Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.4, 8.8 Hz, 1H), 2.68
(s, 2H), 2.38-2.19 (m, 2H), 2.29 (s, 3H), 2.00-1.90 (m, 2H),
1.90-1.66 (m, 4H); .sup.13C NMR (100 MHz, CD.sub.3Cl) .delta.
132.78, 130.69, 130.45, 128.68, 126.09, 126.03, 123.69, 61.73,
45.5, 41.26, 37.41, 34.14, 32.05, 18.84; ESI MS m/z 308.1.
1-(1-(3,4-dichlorophenyl)-3,3-difluorocyclohexyl)-N,N-dimethylmethanamine
(206)
[0626] The racemic mixture of the dimethylated analog (Example
above) was purified by chiral column chromatography (OJ column;
hexane:.sup.ipropanol:DEA=98:2:0.1) to give the fast moving
enantiomer 206 E1 (5.2 mg) and the slow moving enantiomer 206 E2
(6.3 mg). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.41 (d, J=2.4
Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.4, 8.8 Hz, 1H), 2.36
(s, 2H), 2.36-2.24 (m, 1H), 2.07 (s, 6H), 1.94-1.80 (m, 4H),
1.74-1.64 (m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) .delta.
136.17, 132.27, 130.18, 129.99, 129.03, 126.47, 70.42, 48.52, 44.5,
40.26, 34.12, 31.58, 18.881; ESI MS m/z 332.1.
Example 4
Synthesis of 4-Substituted Cyclohexylamine Analogs
[0627] ##STR262##
4.1. Synthesis of Aryl Acetonitriles
[0628] ##STR263##
[0629] General Procedure V: To a 1.0 M solution of the carboxylic
acid (1 eq) in THF was added BH.sub.3/THF (3 eq). The reaction
mixture was stirred overnight before being concentrated. To the
residue was added diethyl ether and NaOH solution. The organic
layer was separated, dried (Na.sub.2SO.sub.4) and concentrated. The
residue was purified by silica gel column chromatography (ethyl
acetate/hexane) to afford the aryl alcohol.
[0630] To a 0.4 M solution of the aryl alcohol (1 eq) in
CH.sub.2Cl.sub.2 was added PBr.sub.3 (2 eq). The reaction mixture
was stirred for 3 h at room temperature before being quenched with
saturated aqueous NH.sub.4Cl. The organic layer was separated,
dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified
by silica gel column chromatography (ethyl acetate/hexane) to
afford the aryl alkyl bromide.
[0631] To a 0.2M solution of the aryl alkyl bromide (1 eq) in
CH.sub.3CN was added KCN (3 eq). The reaction mixture was heated to
reflux for 6 h before being concentrated. To the residue was added
diethyl ether and H.sub.2O. The organic layer was separated, dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to afford
the desired aryl acetonitrile.
4.2. Synthesis of 1-(aryl)-4-oxocyclohexanecarbonitriles
[0632] ##STR264##
[0633] Aryl-4-oxocyclohexanecarbonitriles were prepared according
to the Scheme, above, or procedures described in WO 00/25770 and WO
03/063797, the disclosures of which are incorporated herein by
reference for all purposes. Minor modifications of the described
procedures were used when appropriate. For example, 2.2 equivalents
of acrylate may be used in step 1, NaH (60% dispersion in mineral
oil) reduction was performed in refluxing toluene, and microwave
irradiation was used for reactions up to a multigram scale in the
final decarboxylation step. An exemplary synthesis of
1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile is outlined
below.
4.2.1. Synthesis of dimethyl
3-cyano-3-(naphthalen-2-yl)hexanedioate
[0634] ##STR265##
[0635] 2-naphthylacetonitrile (3.45 g, 20.6 mmol) and methyl
acrylate (9.7 ml, 107 mmol) were suspended in 2-methyl-2-propanol
(10 ml). Heat was applied to the reaction vessel until the solution
became clear. The mixture was cooled to room temperature, at which
time (Bu).sub.4NOH (6.9 mmol, 0.33 equiv.) was added as a solution
in 2-methyl-2-propanol:methanol (1:2). The combined reaction
mixture was heated to reflux for 4 h under vigorous stirring at
which time the reaction appeared complete by GC-MS. After allowing
the reaction to cool the mixture was partitioned between H.sub.2O
(75 ml) and EtOAc (50 ml). The aqueous layer was removed and washed
with EtOAc (2.times.50 ml). The combined organic phases were washed
with NaHCO.sub.3 (sat. aq.) and brine and dried over MgSO.sub.4.
After filtration the solvent was removed in vacuo. The crude
product was purified by flash column chromatography (25% EtOAc in
hexanes) to isolate the title compound as a light yellow oil (5.75
g, 82%).
4.2.2. Synthesis of methyl
5-cyano-2-hydroxy-5-(naphthalen-2-yl)cyclohex-1-enecarboxylate
[0636] ##STR266##
[0637] To a solution of the diester nitrile (2.3 g, 6.77 mmol) in
dry toluene (46 ml) was added NaH (60% suspension in mineral oil,
820 mg, 20.33 mmol). The reaction mixture was heated to reflux for
3 h at which time no starting material remained (GC-MS). The
reaction was cooled to room temperature and carefully quenched with
NH.sub.4Cl (aq., 100 ml) and extracted with EtOAc (3.times.50 ml).
The combined organics were washed with brine, dried over
MgSO.sub.4, filtered, and the solvent removed in vacuo. The
resulting oily product, suspended in mineral oil, washed with
hexanes to afford the desired product as a light yellow solid (1.4
g, 67% yield). The material was used in the following step without
further purification.
4.2.3. Synthesis of
1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile
[0638] ##STR267##
[0639] The above ketoester (0.75 g, 2.44 mmol) was dissolved in
DMSO (11 ml) and H.sub.2O (0.5 ml) and was sealed in a 20 ml
microwave reaction vial equipped with a magnetic stir bar. The
reaction mixture was heated to 160.degree. C. for 10 min in a
microwave reactor at which time complete conversion was observed by
HPLC. The reaction was diluted with EtOAc (50 ml) and washed with
10% LiCl (aq., 2.times.30 ml) followed by a brine wash. The organic
layer was removed, dried over MgSO.sub.4, filtered, and the solvent
was removed in vacuo. The product was further purified by flash
column chromatography (25% EtOAc in hexanes) to afford the desired
ketone (0.55 g, 90% yield) as a colorless oil, which solidified
upon standing.
4.3. Synthesis of 4-hydroxy-1-aryl-cyclohexanecarbonitrile
(NaBH.sub.4 Reduction)
[0640] ##STR268##
[0641] General Procedure W: To a solution of the ketonitrile (1 eq)
in dry methanol (about 0.1 M) at 0.degree. C. was added NaBH.sub.4
(4 eq) portionwise. The mixture was allowed to warm to 22.degree.
C. and was stirred at this temperature for about 2 h, or until
complete (e.g., HPLC). It was diluted with H.sub.2O and the aqueous
layer was extracted with Et.sub.2O. The combined organic layers
were washed with brine, dried over MgSO.sub.4 and filtered. The
solvent was removed in vacuo to afford the resulting alcohol,
typically as one diastereomer.
4.4. Synthesis of 4-hydroxy-1-aryl-cyclohexanecarbonitrile with
Inverse Stereochemistry at C-4 (Mitsunobu Reaction)
[0642] ##STR269##
[0643] General Procedure X: To a solution of PPh.sub.3 (1.2 eq) in
dry toluene (about 0.1 M) was added p-NO.sub.2-benzoic acid (1.2
eq) and the resulting suspension was cooled to -30.degree. C. To
the mixture was added a 2 M solution of the respective nitrile
alcohol (1 eq) in toluene (about) in one portion and a 1.0 M
solution of DEAD (1.2 eq) in toluene dropwise over 15 min. The
mixture was allowed to warm to 22.degree. C. and was stirred for 15
h, at which time the reaction was quenched with saturated aqueous
NaHCO.sub.3. The aqueous layer was extracted with EtOAc, the
combined organic layers were dried over MgSO.sub.4, filtered and
the solvent was removed in vacuo to afford the benzoate
intermediate, which was used without further purification (0.61 g,
74% yield).
[0644] To a solution of the crude benzoate (1 eq) in MeOH (about
0.1 M) was added a 1.0 M solution of NaOMe (95%, 1.11 eq) in THF
and the mixture was allowed to stir at 22.degree. C. for 4 h. The
solvent was removed in vacuo and the resulting residue was taken up
in H.sub.2O and extracted with EtOAc. The combined organics were
dried over MgSO.sub.4, filtered and the solvent was removed in
vacuo. The crude product was purified by silica gel column
chromatography (EtOAc in hexanes) to afford the desired nitrile
alcohol.
4.5. Synthesis of Tertiary Alcohols
[0645] ##STR270##
[0646] General Procedure Y: To a solution of the ketonitrile (1 eq)
in dry THF (about 0.4 M) at -78.degree. C. was added dropwise MeLi
(1.4 M in Et.sub.2O, 2 eq) so as to maintain an internal
temperature of <-60.degree. C. The reaction mixture was stirred
at -78.degree. C. for 3 h and the reaction was then quenched with
H.sub.2O (e.g., 1 ml). The reaction mixture was allowed to warm to
22.degree. C. and was then diluted with CH.sub.2Cl.sub.2. The
organic layer washed with aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4 and filtered and the solvent was removed in vacuo. The
crude product was purified by flash column chromatography (e.g.,
0-60% EtOAc in hexanes) to return starting material, fast moving
diastereomer as well as the slow moving diastereomer (major
product). Solvent removal afforded the desired products as white
solids.
4.6.Chlorination
[0647] ##STR271##
[0648] General Procedure Z: To a solution of the amino alcohol (1
eq) in MeOH containing 10% (v/v) NEt.sub.3 was added BOC.sub.2O (2
eq) and the resulting mixture was stirred at 22.degree. C. for 3 h,
at which time the solvent was removed in vacuo. Silica gel column
chromatography (e.g., EtOAc in hexanes) afforded the carbamate as a
clear oil.
[0649] To a solution of the purified carbamate (1 eq) in DMF (about
0.1 M) and CCl.sub.4 (1.5 eq) was added KF (3 eq) and PPh.sub.3 (2
eq) and the resulting mixture was stirred at 22.degree. C. for 3 h.
Saturated aqueous NaHCO.sub.3 was then added to quench the reaction
and the aqueous layer was extracted with EtOAc. The combined
organic phases were dried over Na.sub.2SO.sub.4, filtered and the
solvent was removed in vacuo to afford the halogenated mixture
e.g., as a 3:1 ratio of chlorinated to .alpha.-eliminated product
(66% conversion). Silica gel column chromatography (e.g., EtOAc in
hexanes) afforded the chlorinated carbamate.
[0650] The BOC group was removed and the HCl salt was prepared by
the addition of 4M HCl (Et.sub.2O) to the carbamate. After stirring
for 1 h, the HCl salt was filtered off.
4.7. Fluorination
[0651] ##STR272##
[0652] General Procedure BB: A 0.2 M solution of the nitrile
alcohol (1 eq) in CHCl.sub.3 was added drop-wise to a 0.1 M
solution of morpholino sulfurtrifluoride (4 eq) in CHCl.sub.3
(about 0.1 M) at -15.degree. C. over 5 min. The resulting mixture
was stirred between -30 and -15.degree. C. for 30 min, at which
time MeOH (5 eq) and saturated aqueous NaHCO.sub.3 were added. The
aqueous layer was extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered and the solvent removed in vacuo. Silica
gel column chromatography (e.g., EtOAc in hexanes) afforded
fluorinated and .alpha.-eliminated products e.g., in a 1:1
ratio.
4.8. Difluorination
[0653] ##STR273##
[0654] General Procedure CC: A 0.5 M solution of the ketonitrile (1
eq) in CHCl.sub.3 was added drop-wise to a 2 M solution of
morpholino sulfurtrifluoride (4 eq) in CHCl.sub.3 at -30.degree. C.
over 5 min. The resulting mixture was stirred between -30 and
0.degree. C. for 2 h, at which time MeOH and saturated aqueous
NaHCO.sub.3 were added. The aqueous layer was extracted with EtOAc,
dried over Na.sub.2SO.sub.4, filtered and the solvent was removed
in vacuo. Silica gel column chromatography (e.g., EtOAc in hexanes)
afforded difluorinated and .alpha.-eliminated products.
4.9. Synthesis of Fluoromethyl Analogs
[0655] ##STR274##
[0656] General Procedure DD: To a solution of the ketonitrile
(concentration about 0.3 M, 1 eq) and trimethylsulfonium iodide
(1.5 eq) in dry DMSO was added a solution of KOtBu (1.5 eq) in dry
DMSO (about 0.7 M). The mixture was stirred at 22.degree. C. for 5
h, at which time the reaction appeared complete by GC-MS. The
reaction mixture was diluted with brine, and extracted with EtOAc.
The combined organic layers were dried over MgSO.sub.4, filtered,
and the solvent was removed in vacuo. The crude product was
purified by silica gel chromatography (e.g., EtOAc in hexanes) to
afford two diastereomeric epoxides, termed the faster moving
diastereomer (FMD) and the slower moving diastereomer (SMD).
[0657] To a 1M solution of TBAF in THF (4 eq) in a clean glass
reaction flask was added HF (48% in H.sub.2O, 4 eq). The solvent
was removed in vacuo and the resulting mixture was added to a
mixture of the above epoxide (1 eq) and KHF.sub.2 (3 eq) in a
microwave reaction vial. The reagents were washed down the side of
the vial with heptane (minimal volume) and the reaction mixture was
heated in the microwave at 120.degree. C., for 15 min (FHT). After
the reaction mixture was cooled to 22.degree. C., the mixture was
diluted with H.sub.2O and saturated aqueous NaHCO.sub.3 and was
extracted with EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the solvent was removed in vacuo to
afford crude fluoromethylated nitrile, which was purified by silica
gel chromatography (EtOAc in hexanes) to afford the pure product as
a white solid (>20:1 regioselectivity).
4.10. Synthesis of Methylamine
[0658] General Procedure F2: To a 0.1 M solution of the amine (1
eq) in MeOH containing 10% (v/v) NEt.sub.3 was added BOC.sub.2O
(1.2 eq) and the resulting mixture was stirred at 22.degree. C. for
3 h, at which time the solvent was removed in vacuo. Silica gel
column chromatography (EtOAc in hexanes) afforded the
carbamate.
[0659] To a 0.1 M solution of the purified carbamate (1 eq) in THF
was added LAH (IM THF, 2 eq) and the resulting mixture was heated
to 65.degree. C. for 6 h. After the reaction was complete (HPLC),
6M HCl was added followed by saturated aqueous K.sub.2CO.sub.3. The
product was extracted with EtOAc. The combined organics were dried
over MgSO.sub.4, filtered and the solvent was removed in vacuo. The
crude mono-methylamine was purified by either Gilson RP-HPLC or by
transformation to the HCl salt and recrystallization.
4.11. Alkylation of Alcohol
[0660] General Procedure EE: To a 0.2 M solution of the alcohol (1
eq) in THF was added NaH (60% in mineral oil, 1.5 eq). The reaction
mixture was stirred for 20 min before alkyl halide (2 eq) was
added. It was stirred for 4 h before being quenched with saturated
NH.sub.4Cl solution. The product was then extracted with diethyl
ether. The combined organic layers were dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane) to give O-alkylated
product.
4.12. Preparation of Ketals
[0661] General Procedure FF: To a 0.1 M solution of the ketone (1
eq) in benzene was added ethylene glycol (3 eq) and TsOH--H.sub.2O
(0.4 eq). The reaction mixture was heated at reflux for 6 h before
being concentrated. The residue was dissolved in EtOAc, washed with
saturated aqueous NaHCO.sub.3, dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue was purified by silica gel column
chromatography (Ethyl acetate/hexane/DEA) to give the ketal.
4.13. Synthesis of 4-Substituted Cycloalkylamines
[0662] Compounds in Table 5, below, were synthesized from the
respective 1-(aryl)-4-oxocyclohexanecarbonitriles according to the
indicated General Procedures. TABLE-US-00005 TABLE 5 Summary of
4-Substituted Cycloalkylamines ##STR275## General Ar R.sup.b
R.sup.c Procedure 4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol
(207) ##STR276## H OH W, E HPLC R.sub.t = 7.54 min; LC-MS(5 minute
method) 2.24 min, (M + 1).sup.+ 256.0 @ 2.31 min; .sup.1H-NMR(400
MHz, CDCl.sub.3) 7.84-7.75(m, 4H), 7.51-7.43(m, 3H), 3.79(m, 1H),
2.88(brs, 2H), 2.10-1.97(m, 4H), 1.75-1.56(m, 4H).
4-(aminomethyl)-4-(naphthalen-2-yl)cyclohexanol (208) ##STR277## OH
H W, X, E HPLC R.sub.t = 6.83 min; LC-MS(15 minute method) 4.71
min, (M + 1).sup.+ 256.0 @ 4.73 min; .sup.1H-NMR(400 MHz,
CD.sub.3OD) 8.04-7.93(m, 4H), 7.69-7.49(m, 3H), 3.72(m, 1H),
3.13(s, 2H), 2.63(d, J=13.5Hz, 2H), 1.99-1.85(m, 2H), 1.80-1.68(m,
2H), 1.47-1.31(m, 2H).
4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (209)
##STR278## OH Me Y, E HPLC R.sub.t = 7.06 min; LC-MS(M + 1).sup.+
270.1; .sup.1H-NMR(400 MHz, CDCl.sub.3) 7.86-7.79(m, 4H), 7.58(brs,
2H), 7.43-7.35(m, 3H), 2.84(brs, 2H), 2.25 (m, 2H), 1.77(m, 2H),
1.58(m, 2H), 1.49(m, 2H), 1.28(s, 3H).
4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (210)
##STR279## Me OH Y, E HPLC R.sub.t = 1.39; LC-MS(15 minute method)
6.92 min, (M + 1).sup.+ 270.0 @ 6.88 min.
(4-chloro-1-(naphthalen-2-yl)cyclohexyl)methanamine (211)
##STR280## Cl H W, E, Z HPLC R.sub.t = 2.38 min; .sup.1H-NMR(400
MHz, CD.sub.3OD) 8.07-7.95(m, 4H), 7.65(dd, J=9.0, 1.5Hz, 1H),
7.61-7.51(m, 2H), 4.14(m, 1H), 3.18(s, 2H), 2.68(d, J=13.5Hz, 2H),
2.20(d, J=13.5Hz, 2H), 1.89-1.62(m, 4H). .sup.13C-NMR(100 MHz,
CD.sub.3OD) 134.0, 132.9, 129.5, 128.1, 127.4, 127.2, 126.4, 124.1,
58.6, 50.6, 40.4, 32.4, 32.1. LC-MS(15 minute method) 8.10 min,
(m/z) 274.0 @ 8.18 min.
(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (212)
##STR281## F H W, BB, E HPLC R.sub.t = 2.14 min; .sup.1H-NMR(400
MHz, CD.sub.3OD) 8.00-7.87(m, 4H), 7.63-7.51(m, 3H), 4.76(m, 0.5H),
4.61(m, 0.5H), 3.19(s, 2H), 2.52(m, 2H), 2.01-1.97(m, 2H),
1.82-1.76(m, 2H), 1.64-1.59(m, 2H). LC-MS(15 minute method) 7.30
min, (M + 1).sup.+ 258.1 @ 7.36 min
(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (213)
##STR282## H F W, X, BB, E HPLC R.sub.t = 1.48 min; .sup.1H-NMR(400
MHz, CDCl.sub.3) 7.87-7.62(m, 4H), 7.52-7.44(m, 3H), 4.75(m, 0.5H),
4.63(m, 0.5H), 2.79(s, 2H), 2.23(d, J=13.5Hz, 2H), 1.97-1.90(m,
4H), 1.70-1.52(m, 2H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 128.6,
128.1, 127.6, 126.6, 126.3, 126.0, 125.2, 90.6, 55.4, 28.1, 27.8,
27.6. LC-MS(M + 1)+ 258.1.
4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)cyclohexanol (214)
##STR283## H OH W, E HPLC R.sub.t = 1.18 min; LC-MS(15 minute
method) 4.51 min, (M + 1).sup.+ 250.0 @ 4.4.51 min; .sup.1H-NMR(400
MHz, CD.sub.3OD) 8.38(brs, 1H), 6.98(d, J=2.0Hz, 1H), 6.85(dd,
J=8.0, 2.0Hz, 1H), 6.82(d, J=8.0Hz, 1H), 5.95(s, 2H), 3.78(m, 1H),
3.03(s, 2H), 2.04-1.91(m, 4H), 1.71-1.58(m, 4H). .sup.13C-NMR(100
MHz, CD.sub.3OD) 120.3, 108.3, 107.1, 101.4, 66.2, 63.5, 40.0,
29.0.
4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)-1-methylcyclohexanol
(215) ##STR284## Me OH Y, E HPLC R.sub.t = 1.64 min;
.sup.1H-NMR(400 MHz, CD.sub.3OD) 8.37(brs, 1H), 6.97(s, 1H),
6.90(d, J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H), 5.97(s, 2H), 2.92(s,
2H), 2.13(d, J=13.5Hz, 2H), 1.89(t, J=13.0Hz, 2H), 1.56(d,
J=13.5Hz, 2H), 1.38(t, J=13.0Hz, 2H), 1.05(s, 3H). .sup.13C-NMR(100
MHz, CD.sub.3OD) 120.8, 108.4, 107.4, 101.5, 34.1, 29.7, 29.0,
28.8. LC-MS(M + 1).sup.+ 264.1.
4-(aminomethyl)-4-(benzo[d][1,3]dioxol-5-yl)-1-methylcyclohexanol
(216) ##STR285## OH Me Y, E HPLC R.sub.t = 2.03 min; LC-MS(15
minute method) 0.60 min, (M + 1).sup.+ 264.1 @ 0.70 min;
.sup.1H-NMR(400 MHz, CD.sub.3OD) 8.44(brs, 1H), 6.98(d, J=1.5Hz,
1H), 6.91(dd, J=8.5, 1.5Hz, 1H), 6.86(d, J=8.5Hz, 1H), 5.96(s, 2H),
3.11(s, 2H), 2.20-2.01(m, 2H), 1.77-1.71(m, 2H), 1.60-1.56(m, 4H),
1.27(s, 3H). .sup.13C-NMR(100 MHz, CD.sub.3OD) 168.1, 149.0, 147.0,
120.1, 108.3, 106.9, 101.4, 68.7, 39.7, 34.6, 30.0, 27.2.
4-(aminomethyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol
(217) ##STR286## CH.sub.2F OH DD, E HPLC R.sub.t = 1.84 min;
LC-MS(15 minute method) 6.65 min, (M + 1).sup.+ 288.2 @ 6.75 min;
.sup.1H-NMR(400 MHz, CD.sub.3OD) 7.99-7.87(m, 4H), 7.63(dd, J=9.0,
2H), 7.54-7.50(m, 2H), 4.04(s, 1H), 3.92(s, 1H), 3.09(s, 2H),
2.46(d, J=13.5Hz, 2H), 2.03(t, J=13.5Hz, 2H), 1.63(d, J=13.5Hz,
2H), 1.45(t, J=13.5Hz, 2H). .sup.13C-NMR(100 MHz, CD.sub.3OD)
136.1, 133.9, 132.8, 129.3, 128.0, 127.4, 127.3, 126.3, 124.3,
90.6, 88.9, 52.1, 41.0, 28.3, 28.2, 27.6.
4-(aminomethyl)-1-(fluoromethyl)-4-(naphthalen-2-yl)cyclohexanol
(218) ##STR287## OH CH.sub.2F DD, E HPLC R.sub.t = 1.19 min;
LC-MS(15 minute method) 4.91 min, (M + 1).sup.+ 288.1 @ 4.89 min;
.sup.1H-NMR(400 MHz, CD.sub.3OD) 7.97-7.86(m, 4H), 7.63(dd, J=9.0,
2.0Hz, 1H), 7.53-7.48(m, 2H), 4.38(s, 1H), 4.26(s, 1H), 3.35(s,
2H), 2.33(dt, J=13.5, 3.5Hz, 2H), 2.00(m, 2H), 1.81(dt, J=13.5,
3.5Hz, 2H), 1.65(m, 2H). .sup.13C-NMR(100 MHz, CD.sub.3OD) 133.9,
132.9, 129.1, 128.1, 127.3, 126.3, 126.2, 125.9, 123.7, 89.4, 87.7,
69.6, 45.9, 39.8, 28.5, 28.4.
4-(aminomethyl)-1-methyl-4-(4-(trifluoromethoxy)phenyl)-cyclohexanol
(219) ##STR288## Me OH Y, E HPLC R.sub.t = 1.45 min; LC-MS(15
minute method) 7.48 min, (M + 1).sup.+ 304.1 @ 7.60 min;
.sup.1H-NMR(400 MHz, CD.sub.3OD) 8.40(brs, 2H), 7.58(dd, J=9.0,
2.5Hz, 2H), 7.34(d, J=9.0Hz, 2H), 3.00(s, 2H), 2.20(d, J=13.5Hz,
2H), 1.96(t, J=13.5Hz, 2H), 1.59(d, J=14.0Hz, 2H), 1.31(t,
J=13.5Hz, 2H), 1.07(s, 3H). .sup.13C-NMR(100 MHz, CD.sub.3OD)
129.4, 121.5, 68.0, 51.9, 40.4, 34.0, 29.6, 28.5.
4-(aminomethyl)-4-(4-(trifluoromethoxy)phenyl)cyclohexanol (220)
##STR289## H OH W, E HPLC R.sub.t = 1.34 min; .sup.1H-NMR(400 MHz,
CDCl.sub.3) 8.44(brs, 1H), 7.60-7.56(m, 2H), 7.33(d, J=9.0Hz, 2H),
3.76(m, 1H), 3.15(s, 2H), 2.11-1.99(m, 4H), 1.64(m, 4H).
.sup.13C-NMR(100 MHz, CDCl.sub.3) 168.0, 148.4, 128.9, 121.4, 66.3,
49.0, 40.0, 29.0, 28.8. LC-MS(M + 1).sup.+ 290.2.
(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)methanamine (221)
##STR290## F F CC, E HPLC R.sub.t = 1.18 min; LC-MS(15 minute
method) 7.70 min, (M + 1).sup.+ 276.2 @ 7.76 min; .sup.1H-NMR(400
MHz, CD.sub.3OD) 8.39(brs, 2H), 8.01-7.88(m, 4H), 7.64(d, J=8.5Hz,
1H), 7.54-7.51(m, 2H), 3.18(s, 2H), 2.60(d, J=13.5Hz, 2H),
2.09-1.90(m, 4H), 1.89-1.71(m, 2H). .sup.13C-NMR(100 MHz,
CD.sub.3OD) 133.8, 132.9, 129.6, 128.1, 127.4, 127.0, 126.5, 126.4,
123.8, 50.0, 30.2, 30.0, 29.7, 29.6.
Synthesis of Secondary and Tertiary Amines
[0663] Compounds in Table 6, below, were synthesized from the
respective 1-(aryl)-4-oxocyclohexanecarbonitriles according to the
indicated General Procedures. TABLE-US-00006 TABLE 6 Summary of
Secondary and Tertiary Amines ##STR291## General Ar R.sup.1 R.sup.3
R.sup.4 R.sup.b R.sup.c Procedure
1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-yl)- cyclohexanol
(222) ##STR292## H H CH.sub.3 OH CH.sub.3 F2 Prepared from: 209
.sup.1H-NMR(400 MHz, CDCl.sub.3) 8.88(brs, 2H), 7.97-7.79(m, 4H),
7.54-7.46 (m, 3H), 3.12(m, 2H), 2.24(m, 2H), 2.23(t, J=5.0Hz, 3H),
2.04 (m, 2H), 1.71(m, 2H), 1.60(m, 2H), 1.35(s, 3H).
.sup.13C-NMR(100 MHz, CDCl.sub.3) 133.7, 132.6, 129.6, 128.6,
127.6, 127.0, 126.8, 126.7, 123.9, 70.1, 35.7, 35.1, 30.6. LC-MS(M
+ 1).sup.+ 284.1. 1-methyl-4-((methylamino)methyl)-4-(naphthalen-2-
yl)cyclohexanol (223) ##STR293## H H CH.sub.3 CH.sub.3 OH E, F2
.sup.1H-NMR(400 MHz, CDCl.sub.3) 9.24(brs, 2H), 7.94-7.83(m, 4H),
7.57(d, J=9.0Hz, 1H), 7.53-7.48(m, 2H), 3.03(s, 2H), 2.58(s, 3H),
2.59-2.43 (m, 4H), 1.68(d, J=13.5Hz, 2H), 1.46-1.39(m, 2H), 1.04(s,
3H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 137.8, 133.7, 132.5, 129.4,
128.4, 127.7, 127.0, 126.7, 126.6, 124.5, 69.1, 62.4, 41.6, 35.1,
34.9, 30.6, 28.2. LC- MS(M + 1).sup.+ 284.1.
4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2- yl)cyclohexanol
(224) ##STR294## H CH.sub.3 CH.sub.3 OH CH.sub.3 C Prepared from:
209 .sup.1H-NMR(400 MHz, CDCl.sub.3) 7.89-7.80(m, 4H), 7.60(dd,
J=8.5, 2.0 Hz, 1H), 7.52-7.45(m, 2H), 2.54(s, 2H), 2.35-2.21(m,
2H), 2.00(s, 6H), 1.99-1.85(m, 2H), 1.73-1.53(m, 4H), 1.35(s, 3H).
LC-MS (M + 1).sup.+ 298.0.
4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2- yl)cyclohexanol
(225) ##STR295## H CH.sub.3 CH.sub.3 CH.sub.3 OH C .sup.1H-NMR(400
MHz, CDCl.sub.3) 7.93(m, 4H), 7.68(dd, J=8.8, 2.0Hz, 1H), 7.52(m,
2H), 3.42(s, 2H), 2.50(s, 6H), 2.44(d, J=13.2Hz, 2H), 2.05(dt,
J=13.6, 3.2Hz, 2H), 1.63(d, J=13.2Hz, 2H), 1.41(dt, J=13.6, 3.2Hz,
2H), 1.05(s, 3H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 138.1, 135.3,
134.3, 130.9, 129.7, 129.3, 129.0, 128.2, 126.3, 73.4, 69.5, 47.6,
42.8, 35.6, 31.4, 30.9. LC-MS(M + 1).sup.+ 298.0.
4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (226)
##STR296## H H CH.sub.3 H OH F2 Prepared from: 207 .sup.1H-NMR(400
MHz, CD.sub.3OD) 7.99-7.87(m, 4H), 7.63(dd, J=8.5, 2.0 Hz, 1H),
7.54-7.52(m, 2H), 3.81(m, 1H), 3.32(s, 2H), 2.57(s, 3H), 2.18(m,
4H), 1.72(m, 4H). .sup.13C-NMR(100 MHz, CD.sub.3OD) 135.1, 134.1,
130.5, 129.3, 128.6, 127.8, 127.7, 127.6, 125.2, 67.5, 61.9, 35.4,
30.2, 30.1. LC-MS(M + 1).sup.+ 270.0.
4-((methylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (227)
##STR297## H H CH.sub.3 OH H F2 Prepared from: 208 .sup.1H-NMR(400
MHz, CDCl.sub.3) 7.92-7.82(m, 4H), 7.59-7.47(m, 3H), 3.77(m, 1H),
2.66(s, 2H), 2.61(d, J=13.5Hz, 2H), 2.29(s, 3H), 1.97-1.88 (m, 2H),
1.65(t, J=13.5Hz, 2H), 1.42-1.20(m, 4H). LC-MS (M + 1).sup.+ 270.1.
4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (228)
##STR298## H CH.sub.3 CH.sub.3 OH H F Prepared from: 208
.sup.1H-NMR(400 MHz, CD.sub.3OD) 8.11-7.89(m, 4H), 7.70(d, J=9.0Hz,
1H), 7.60-7.51(m, 2H), 3.72(m, 1H), 3.52(brs, 2H), 2.69(d,
J=13.0Hz, 2H), 2.57(s, 6H), 2.00-1.72(m, 4H), 1.50-1.32(m, 2H).
LC-MS (M + 1).sup.+ 284.1.
4-((dimethylamino)methyl)-4-(naphthalen-2-yl)cyclohexanol (229)
##STR299## H CH.sub.3 CH.sub.3 H OH C Prepared from: 207
.sup.1H-NMR(400 MHz, CD.sub.3OD) 7.90-7.77(m, 4H), 7.63(d, J=9.0Hz,
1H), 7.52-7.41(m, 2H), 3.73(m, 1H), 2.72(s, 2H), 2.25-2.12(m, 2H),
2.09-1.91(m, 2H), 1.95(s, 6H), 1.82-1.60(m, 4H). LC-MS(M + 1).sup.+
284.1. 1-(4-chloro-1-(naphthalen-2-yl)cyclohexyl)-N,N-
dimethylmethanamine (230) ##STR300## H CH.sub.3 CH.sub.3 Cl H C
Prepared from: 211 .sup.1H-NMR(400 MHz, CDCl.sub.3) 7.91-7.82(m,
4H), 7.55(dd, J=9.0, 1.5 Hz, 1H), 7.52-7.47(m, 2H), 4.06(m, 1H),
2.42(s, 2H), 2.18-2.01(m, 4H), 2.04(s, 6H), 1.83-1.71(m, 4H).
LC-MS(m/z) 302.3.
1-methyl-4-(1-(methylamino)ethyl)-4-(naphthalen-2- yl)cyclohexanol
(231) ##STR301## CH.sub.3 H CH.sub.3 CH.sub.3 OH I, F2 Prepared
from the corresponding nitrile. Enantiomers(E1, E2) separated by
SFC w/AD column and 30% MeOH/0.1% DEA, 280 nm. .sup.1H-NMR(400 MHz,
CD.sub.3OD) 7.93-7.84(m, 4H), 7.63(d, J=8.5Hz, 1H), 7.55-7.45(m,
2H), 2.59(q, J=7.0Hz, 1H), 2.44-2.22(m, 1H), 2.23(s, 3H),
2.18-2.03(m, 2H), 1.66-1.23(m, 5H), 1.04(d, J=7.0Hz, 3H), 1.01(s,
3H). LC-MS(M + 1).sup.+ 298.1.
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine
(232) ##STR302## H H CH.sub.3 F H F2 Prepared from: 212
.sup.1H-NMR(400 MHz, CDCl.sub.3) 7.87-7.81(m, 4H), 7.54-7.45(m,
3H), 4.74(m, 0.5H), 4.61(m, 0.5H), 2.70(s, 2H), 2.52(m, 2H),
2.25(s, 3H), 2.01-1.94(m, 2H), 1.76-1.56(m, 4H). .sup.13C-NMR(100
MHz, CDCl.sub.3) 133.7, 132.1, 128.8, 128.3, 127.6, 126.4, 126.3,
126.1, 124.7, 92.8, 91.1, 63.7, 42.0, 37.3, 31.2, 31.1, 28.7, 28.5.
LC-MS(M + 1).sup.+ 272.2.
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N- dimethylmethanamine
(233) ##STR303## H CH.sub.3 CH.sub.3 F H C Prepared from: 212
.sup.1H-NMR(400 MHz, CDCl.sub.3) 7.82(m, 4H), 7.54(dd, J=8.5,
2.0Hz, 1H), 7.45(m, 2H), 4.71(m, 0.5H), 4.58(m, 0.5H), 2.45(m, 2H),
2.42 (s, 2H), 2.00(s, 6H), 1.97(m, 2H), 1.77-1.57(m, 4H).
.sup.13C-NMR(100 MHz, CDCl.sub.3) 133.7, 132.0, 128.2, 128.1,
127.6, 126.3, 126.0, 125.7, 125.5, 93.4, 91.7, 72.2, 48.7, 30.9,
30.8, 28.8, 28.6. LC-MS(M + 1).sup.+ 286.4.
4-(1-(dimethylamino)ethyl)-1-methyl-4-(naphthalen-2-
yl)cyclohexanol (234) ##STR304## CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 OH I, C Prepared from the corresponding nitrile.
Enantiomers(E1, E2) separated by Chiral HPLC, AD column, 280 nm,
90/10/0.1 hexanes/isopropanol/diethylamine. .sup.1H-NMR(400 MHz,
CDCl.sub.3) 7.83-7.79(m, 4H), 7.61(m, 1H), 7.49-7.43 (m, 2H),
3.01(q, J=7.5Hz, 1H), 2.82(brd, J=13.0Hz, 1H), 2.62 (brs, 1H),
2.23(d, J=13.5Hz, 1H), 2.00(s, 6H), 2.00-1.85(m, 1H), 1.59-1.40(m,
4H), 1.30-1.21(m, 1H), 1.02(s, 3H), 0.84(d, J=7.0Hz, 3H).
.sup.13C-NMR(100 MHz, CDCl.sub.3) 133.5, 132.0, 128.3, 127.5,
127.3, 125.9, 125.7, 69.6, 44.0, 42.5, 35.5, 35.2, 31.2, 29.7,
28.6, 11.7, 7.6. LC-MS(M + 1).sup.+ 312.3.
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N- dimethylmethanamine
(235) ##STR305## H CH.sub.3 CH.sub.3 H F C Prepared from: 213
.sup.1H-NMR(400 MHz, CDCl.sub.3) 7.81(m, 4H), 7.55(d, J=8.0Hz, 1H),
7.45(m, 2H), 4.72(m, 0.5H), 4.60(m, 0.5H), 2.46(s, 2H), 2.22(d,
J=13.5Hz, 2H), 2.05-1.91(m, 4H), 1.96(s, 6H), 1.69-1.56(m, 2H).
.sup.13C- NMR(100 MHz, CDCl.sub.3) 133.6, 132.0, 128.2, 127.9,
127.6, 126.3, 126.0, 125.8, 125.7, 90.8, 89.1, 73.2, 48.7, 28.7,
27.8, 27.6. LC-MS (M + 1).sup.+ 286.2.
1-(4-fluoro-1-(naphthalen-2-yl)cyclohexyl)-N-methylmethanamine
(236) ##STR306## H H CH.sub.3 H F A Prepared from: 213
.sup.1H-NMR(400 MHz, CDCl.sub.3) 8.27(brs, 1H), 7.89-7.83(m, 4H),
7.53-7.49 (m, 3H), 4.73(m, 0.5H), 4.61(m, 0.5H), 2.84(s, 2H),
2.34(d, J=13.5Hz, 2H), 2.30(s, 3H), 2.08-1.96(m, 4H), 1.54(t,
J=13.0Hz, 2H). LC-MS(M + 1).sup.+ 272.2.
4-(benzo[d][1,3]dioxol-5-yl)-4-((methylamino)methyl)cyclohexanol
(237) ##STR307## H H CH.sub.3 H OH F2 Prepared from: 214
.sup.1H-NMR(400 MHz, CDCl.sub.3) 6.87(d, J=2.0Hz, 1H), 6.81(dd,
J=8.0, 2.0Hz, 1H), 6.76(d, J=8.0Hz, 1H), 5.94(s, 2H), 3.76(m, 1H),
2.65 (s, 2H), 2.29(s, 3H), 2.08-2.02(m, 2H), 1.82-1.70(m, 4H),
1.62-1.56 (m, 2H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 145.8, 119.8,
108.2, 107.3, 101.1, 68.7, 62.2, 41.4, 37.5, 30.8, 30.5. LC-MS(M +
1).sup.+ 264.1. 4-(benzo[d][1,3]dioxol-5-yl)-4-
((dimethylamino)methyl)cyclohexanol (238) ##STR308## H CH.sub.3
CH.sub.3 H OH F Prepared from: 214 .sup.1H-NMR(400 MHz, CD.sub.3OD)
6.88(s, 1H), 6.81(d, J=8.0Hz, 1H), 6.75(dd, J=8.0, 2.0Hz, 1H),
5.92(s, 2H), 3.78(m, 1H), 2.39(s, 2H), 2.04-1.99(m, 2H), 1.99(s,
6H), 1.78-1.67(m, 4H), 1.58(m, 2H). .sup.13C- NMR(100 MHz,
CD.sub.3OD) 120.1, 108.0, 107.8, 101.0, 70.7, 68.4, 48.5, 31.7,
30.3, 30.0. LC-MS(M + 1).sup.+ 278.2.
4-(benzo[d][1,3]dioxol-5-yl)-1-methyl-4-
((methylamino)methyl)cyclohexanol (239) ##STR309## H H CH.sub.3
CH.sub.3 OH F2 Prepared from: 215 .sup.1H-NMR(400 MHz, CD.sub.3OD)
8.45(brs, 1H), 6.98(s, 1H), 6.92(d, J=8.0Hz, 1H), 6.87(d, J=8.0Hz,
1H), 5.97(s, 2H), 3.03(s, 2H), 2.56(s, 3H), 2.14(d, J=13.5Hz, 2H),
1.91(t, J=13.0Hz, 2H), 1.55(d, J=13.5Hz, 2H), 1.34(t, J=13.0Hz,
2H), 1.07(s, 3H). .sup.13C-NMR(100 MHz, CD.sub.3OD) 168.2, 149.2,
147.2, 132.9, 120.9, 108.5, 108.4, 107.5, 101.5, 68.0, 62.4, 40.5,
34.1, 34.0, 29.8, 29.0, 28.8. LC-MS(M + 1).sup.+ 278.3.
4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)-1-
methylcyclohexanol (240) ##STR310## H CH.sub.3 CH.sub.3 CH.sub.3 OH
C Prepared from: 215 .sup.1H-NMR(400 MHz, CD.sub.3OD) 8.54(brs,
1H), 6.99(d, J=1.5Hz, 1H), 6.95(dd, J=8.5, 1.5Hz, 1H), 6.84(d,
J=8.5Hz, 1H), 5.96(s, 2H), 2.92(s, 2H), 2.34(s, 6H), 2.12(d,
13.0Hz, 2H), 1.89(t, J=13.5Hz, 2H), 1.53(d, J=13.0Hz, 2H), 1.37(d,
J=13.5Hz, 2H), 1.03(s, 3H). .sup.13C-NMR(100 MHz, CD.sub.3OD)
120.9, 108.2, 107.8, 101.4, 72.9, 68.2, 46.5, 34.1, 29.8, 29.5.
LC-MS(M + 1).sup.+ 292.2. 4-(benzo[d][1,3]dioxol-5-yl)-1-methyl-4-
((methylamino)methyl)cyclohexanol (241) ##STR311## H H CH.sub.3 OH
CH.sub.3 F
Prepared from: 216 .sup.1H-NMR(400 MHz, CD.sub.3OD) 8.39(brs, 1H),
7.00-6.86(m, 3H), 5.96 (s, 2H), 3.22(s, 2H), 2.58(s, 3H), 2.17(m,
2H), 1.78-1.74(m, 2H), 1.65-1.59(m, 4H), 1.27(s, 3H).
.sup.13C-NMR(100 MHz, CD.sub.3OD) 149.0, 147.2, 120.0, 108.4,
106.9, 101.5, 39.7, 34.5, 34.0, 30.3, 27.4. LC-MS (M + 1).sup.+
278.1. 4-(benzo[d][1,3]dioxol-5-yl)-4-((dimethylamino)methyl)-1-
methylcyclohexanol (242) ##STR312## H CH.sub.3 CH.sub.3 OH CH.sub.3
C Prepared from: 216 .sup.1H-NMR(400 MHz, CD.sub.3OD) 8.54(brs,
1H), 7.00(d, J=2.0Hz, 1H), 6.93(dd, J=8.5, 2.0Hz, 1H), 6.83(d,
J=8.5Hz, 1H), 5.94(s, 2H), 3.03(s, 2H), 2.33(s, 6H), 2.16(m, 2H),
1.73(m, 2H), 1.57(t, J=6.0Hz, 4H), 1.26(s, 3H). .sup.13C-NMR(100
MHz, CD.sub.3OD) 120.1, 108.1, 107.3, 101.3, 46.4, 34.8, 30.9.
LC-MS(M + 1).sup.+ 292.1.
1-(fluoromethyl)-4-((methylamino)methyl)-4-(naphthalen-2-
yl)cyclohexanol (243) ##STR313## H H CH.sub.3 CH.sub.2F OH A
Prepared from: 217 .sup.1H-NMR(400 MHz, CD.sub.3OD) 8.50(brs, 1H),
7.99-7.87(m, 4H), 7.63 (d, J=8.0Hz, 1H), 7.54-7.50(m, 2H), 4.03(s,
1H), 3.91(s, 1H), 3.19 (s, 2H), 2.54(s, 3H), 2.46(d, J=13.5Hz, 2H),
2.06(t, J=13.5Hz, 2H), 1.62(d, J=13.5Hz, 2H), 1.41(t, J=13.5Hz,
2H). .sup.13C-NMR(100 MHz, CD.sub.3OD) 136.0, 133.9, 132.9, 129.4,
128.0, 127.3, 127.3, 126.4, 124.2, 90.6, 88.9, 69.3, 62.4, 41.1,
34.1, 28.2, 28.1, 27.8. LC-MS (M + 1).sup.+ 302.3.
4-((dimethylamino)methyl)-1-(fluoromethyl)-4-(naphthalen-2-
yl)cyclohexanol (244) ##STR314## H CH.sub.3 CH.sub.3 CH.sub.2F OH F
Prepared from: 217 .sup.1H-NMR(400 MHz, CDCl.sub.3) 7.81(m, 4H),
7.55(dd, J=8.5, 1.5Hz, 1H), 7.47-7.44(m, 2H), 4.08(s, 1H), 3.96(s,
1H), 2.43(s, 2H), 2.34(d, J=13.5Hz, 2H), 2.01(dt, J=13.5, 3.0Hz,
2H), 1.98(s, 6H), 1.61(d, J=14.0Hz, 2H), 1.38(dt, J=13.5, 3.0Hz,
2H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 144.1, 133.7, 132.0, 128.2,
128.0, 127.6, 126.6, 126.0, 126.9, 125.7, 91.7, 90.0, 74.3, 48.8,
44.0, 29.2, 29.1, 28.4. LC-MS(M + 1).sup.+ 316.2.
1-(fluoromethyl)-4-((methylamino)methyl)-4-(naphthalen-2-
yl)cyclohexanol (245) ##STR315## H H CH.sub.3 OH CH.sub.2F A
Prepared from: 218 .sup.1H-NMR(400 MHz, CD.sub.3OD) 7.99-7.87(m,
4H), 7.64(dd, J=8.5, 2.0 Hz, 1H), 7.53-7.51(m, 2H), 4.39(s, 1H),
4.27(s, 1H), 3.46(s, 2H), 2.58(s, 3H), 2.37-2.29(m, 2H), 2.00(m,
2H), 1.86-1.79(m, 2H), 1.65 (m, 2H). .sup.13C-NMR(100 MHz,
CD.sub.3OD) 129.2, 128.1, 127.3, 126.4, 126.3, 125.8, 123.5, 34.1,
28.9, 28.4, 28.3. LC-MS(M + 1).sup.+ 302.3.
4-((dimethylamino)methyl)-1-(fluoromethyl)-4-(naphthalen-2-
yl)cyclohexanol (246) ##STR316## H CH.sub.3 CH.sub.3 OH CH.sub.2F F
Prepared from: 218 .sup.1H-NMR(400 MHz, CDCl.sub.3) 7.81(m, 4H),
7.54(dd, J=9.0, 1.5Hz, 1H), 7.47-7.42(m, 2H), 4.45(s, 1H), 4.33(s,
1H), 2.54(s, 2H), 2.25-2.20 (m, 2H), 1.96(s, 6H), 1.96-1.91(m, 2H),
1.78-1.63(m, 4H). .sup.13C- NMR(100 MHz, CDCl.sub.3) 133.7, 132.0,
128.3, 127.9, 127.5, 126.0, 125.7, 125.6, 125.3, 89.7, 88.0, 48.5,
29.8, 29.7. LC-MS(M + 1).sup.+ 316.4.
1-methyl-4-((methylamino)methyl)-4-(4-
(trifluoromethoxy)phenyl)cyclohexanol (247) ##STR317## H H CH.sub.3
CH.sub.3 OH F2 Prepared from: 219 .sup.1H-NMR(400 MHz, CD.sub.3OD)
8.34(brs, 2H), 7.58(d, J=8.5Hz, 2H), 7.36(d, J=8.5Hz, 2H), 3.10(s,
2H), 2.58(s, 3H), 2.20(d, J=13.0Hz, 2H), 1.98(dt, J=13.5, 3.0Hz,
2H), 1.58(d, J=13.5Hz, 2H), 1.29(dt, J=13.5, 3.0Hz, 2H), 1.05(s,
3H). .sup.13C-NMR(100 MHz, CD.sub.3OD) 129.4, 127.3, 121.6, 67.8,
62.2, 40.5, 34.1, 33.9, 29.7, 28.7. LC-MS (M + 1).sup.+ 318.2.
4-((dimethylamino)methyl)-1-methyl-4-(4-
(trifluoromethoxy)phenyl)cyclohexanol (248) ##STR318## H CH.sub.3
CH.sub.3 CH.sub.3 OH C Prepared from: 219 .sup.1H-NMR(400 MHz,
CDCl.sub.3) 7.39(d, 8.5Hz, 2H), 7.15(d, J=8.5Hz, 2H), 2.30(s, 2H),
2.09(d, J=13.5Hz, 2H), 1.97(s, 6H), 1.88(dt, J=13.5, 3.0Hz, 2H),
1.52(d, J=13.0Hz, 2H), 1.34(dt, J=13.5, 3.5Hz, 2H), 1.11(s, 3H).
.sup.13C-NMR(100 MHz, CDCl.sub.3) 129.0, 120.6, 48.7, 35.2, 29.4.
LC-MS(M + 1).sup.+ 332.3. 4-((methylamino)methyl)-4-(4-
(trifluoromethoxy)phenyl)cyclohexanol (249) ##STR319## H H CH.sub.3
H OH F2 Prepared from: 220 LC-MS(15 minute method) 6.57 min, (M +
1)+ 304.2 @ 6.75 min; 1H- NMR(400 MHz, CD.sub.3OD) 8.42(brs, 1H),
7.58(d, J=8.5Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 3.78-3.75(m, 1H),
3.24(s, 2H), 2.59(s, 6H), 2.09-2.01(m, 4H), 1.65-1.62(m, 4H).
13C-NMR(100 MHz, CD.sub.3OD), 167.9, 128.9, 121.5, 66.1, 59.5,
40.2, 34.1, 28.9. 4-((dimethylamino)methyl)-4-(4-
(trifluoromethoxy)phenyl)cyclohexanol (250) ##STR320## H CH.sub.3
CH.sub.3 H OH C Prepared from: 220 .sup.1H-NMR(400 MHz, CDCl.sub.3)
7.38(d, J=9.0Hz, 2H), 7.14(d, J=9.0Hz, 2H), 3.81-3.78(m, 1H),
2.42(s, 2H), 2.10-2.03(m, 2H), 1.96(s, 6H), 1.86-1.78(m, 2H),
1.70-1.57(m, 4H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 147.4, 128.5,
122.0, 120.6, 94.6, 70.6, 68.2, 48.5, 42.2, 30.3, 30.1, 29.6.
LC-MS(M + 1).sup.+ 318.3.
1-(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)-N- methylmethanamine
(251) ##STR321## H H CH.sub.3 F F F2 Prepared from: 221
.sup.1H-NMR(400 MHz, CDCl.sub.3) 7.89-7.79(m, 4H), 7.53-7.48(m,
3H), 2.70(s, 2H), 2.51(d, J=13.0Hz, 2H), 2.26(s, 3H), 2.05-1.91(m,
4H), 1.87-1.77(m, 2H). .sup.13C-NMR(100 MHz, CDCl.sub.3) 139.9,
133.6, 132.2, 128.9, 128.2, 127.6, 126.5, 126.3, 126.2, 124.6,
64.1, 42.0, 37.4, 31.0, 30.9, 30.8, 30.7, 30.5. LC-MS(M + 1).sup.+
290.3. 1-(4,4-difluoro-1-(naphthalen-2-yl)cyclohexyl)-N,N-
dimethylmethanamine (252) ##STR322## H CH.sub.3 CH.sub.3 F F F
Prepared from: 221 .sup.1H-NMR(400 MHz, CDCl.sub.3) 7.82(m, 4H),
7.53(d, J=8.5Hz, 1H), 7.47(m, 2H), 2.45(apd, J=10.0Hz, 2H), 1.97(s,
2H), 2.05-1.89(m, 4H), 1.97(s, 6H), 1.85-1.74(m, 2H).
.sup.13C-NMR(100 MHz, CDCl.sub.3) 128.3, 128.2, 127.6, 126.3,
126.2, 125.9, 125.3, 72.4, 48.6, 31.0, 30.7, 30.5, 30.4. LC-MS(M +
1).sup.+ 304.2.
3,4-Dichlorophenyl-Cyclohexylamine Analogs
[0664] TABLE-US-00007 TABLE 7 Summary of
3,4-Dichlorophenyl-Cyclohexylamine Analogs ##STR323## ##STR324##
##STR325## General R.sup.b R.sup.c R.sup.3 R.sup.4 Procedure
(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)methanamine (253) F H H
H W, BB, E .sup.1H NMR(400 MHz, CDCl.sub.3) .delta. 8.02(broad,
1H), 7.46(d, J=8.0Hz, 1H), 7.43(s, 1H), 7.19(d, J=8.0Hz, 1H),
4.62(m, 1H), 2.83(s, 2H), 2.26(m, 2H), 1.90(m, 2H), 1.58(m, 4H);
.sup.13C NMR(100 MHz, CDCl.sub.3), .delta. 141.52, 133.57, 131.80,
131.39, 129.57, 126.66, 91.08, 89.37, 49.49, 40.58, 30.02, 29.94,
27.92, 27.72; ESI MS m/z 276.
1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N,N-
dimethylmethanamine (254) F H CH.sub.3 CH.sub.3 W, BB, E, D
Prepared from 253 .sup.1H NMR(400 MHz, CDCl.sub.3) .delta.
8.31(broad, 1H), 7.47(d, J=2.4Hz, 1H), 7.44(d, J=8.4Hz, 1H),
7.26(dd, J=8.14, 2.4Hz, 1H), 4.62(m, 1H), 2.68 (s, 2H), 2.26(m,
2H), 2.22(s, 6H), 1.95(m, 2H), 1.70(t, J=13.6Hz, 1H), 1.57(m, 2H);
.sup.13C NMR(100 MHz, CDCl.sub.3) .delta. 166.24, 144.8, 133.23,
130.88, 129.44, 126.88, 91.90, 90.19, 70.43, 47.54, 41.98, 30.83,
30.74, 28.22, 28.02; ESI MS m/z 304.
(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (255) H
OCH.sub.3 H H W, EE, E .sup.1H NMR(400 MHz, CD.sub.3OD) .delta.
7.46(m, 2H), 7.22(d, J=7.6Hz, 1H), 6.69 (broad, 2H), 3.31(s, 3H),
2.80(s, 2H), 1.91(m, 4H), 1.72(m, 1H), 1.40 (m, 2H); .sup.13C
NMR(100 MHz, CDCl.sub.3) .delta. 142.92, 133.53, 131.78, 131.26,
129.46, 126.87, 75.16, 55.65, 50.76, 40.98, 28.54, 25.77; ESI MS
m/z 288. 1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N-
dimethylmethanamine (256) H OCH.sub.3 CH.sub.3 CH.sub.3 W, EE, E, D
Prepared from 255 .sup.1H NMR(400 MHz, CD.sub.3OD) 7.46(d, J=2.8Hz,
1H), 7.37(d, J=8.4Hz, 1H), 7.23(dd, J=2.0, 8.4Hz, 1H), 3.32(s, 3H),
3.23(m, 1H), 2.34(s, 2H), 1.87(s, 6H), 1.84(m, 2H), 1.78(m, 2H),
1.56(m, 2H), 1.48(m, 2H); .sup.13C NMR(100 MHz, CD.sub.3OD) 141.57,
133.26, 131.56, 131.34, 130.02, 128.66, 69.25, 50.70, 47.73, 40.57,
30.79, 30.31; ESI MS m/z 316.0.
(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)methanamine (257)
OCH.sub.3 H H H W, X, EE, E .sup.1H NMR(400 MHz, CD.sub.3OD)
.delta. 7.44(m, 2H), 7.20(d, J=7.6Hz, 1H), 6.68 (broad, 2H),
3.29(s, 3H), 2.82(s, 1H), 1.90(m, 4H), 1.73(m, 1H), 1.43 (m, 2H);
.sup.13C NMR(100 MHz, CDCl.sub.3), .delta. 141.92, 133.33, 131.38,
131.14, 129.75, 126.99, 75.06, 55.90, 50.95, 41.23, 28.43, 25.93;
ESI MS m/z 288. 1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N,N-
dimethylmethanamine (258) OCH.sub.3 H CH.sub.3 CH.sub.3 W, X, EE,
E, D Prepared from 257 .sup.1H NMR(400 MHz, CD.sub.3OD) 7.45(d,
J=2.4Hz, 1H), 7.36(d, J=8.8Hz, 1H), 7.21(dd, J=2.4, 8.8Hz, 1H),
3.33(s, 3H), 3.25(m, 1H), 2.37(s, 2H), 1.96(s, 6H), 1.91(m, 2H),
1.80(m, 2H), 1.66(m, 2H), 1.54(m, 2H); .sup.13C NMR(100 MHz,
CD.sub.3OD) 141.28, 133.16, 131.23, 131.24, 129.94, 127.56, 69.15,
50.80, 47.64, 40.48, 30.89, 30.26; ESI MS m/z 316.0.
1-(1-(3,4-dichlorophenyl)-4-methoxycyclohexyl)-N-methylmethanamine
(259) OCH.sub.3 H CH.sub.3 H W, X, EE, E, A Prepared from 257
.sup.1H NMR(400 MHz, CDCl.sub.3) .delta. 7.42(d, J=2.4Hz, 1H),
7.40(d, J=8.4Hz, 1H), 7.19(dd, J=2.4, 8.4Hz, 1H), 3.28(s, 3H),
3.25(m, 1H), 2.56(s, 2H), 2.32(m, 1H), 2.29(s, 3H), 1.88(m, 2H),
1.56(m, 1H), 1.24(m, 2H); .sup.13C NMR(100 MHz, CDCl.sub.3) .delta.
144.76, 132.95, 132.95, 130.64, 130.29, 129.59, 126.92, 78.96,
64.90, 55.79, 42.43, 37.48, 31.88, 29.93, 27.58; ESI MS m/z 302.1.
(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)methanamine (260) H F H
H W, X, BB, E .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 8.4(broad,
1H), 7.65(d, J=2.0Hz, 1H), 7.59(d, J=8.4Hz, 1H), 7.42(dd, J=2.0,
8.4Hz, 1H), 4.67(d, J=48.4Hz, 1H), 3.05(s, 2H), 2.18(m, 2H),
1.90(m, 4H), 1.51(m, 2H), 1.49(m, 2H); .sup.13C NMR(100 MHz,
CD.sub.3OD) .delta. 140.69, 133.19, 131.44, 131.24, 129.78, 127.43,
140.00, 88.69, 87.02, 50.75, 40.48, 27.37, 26.82, 26.61; ESI MS m/z
276.0. 1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N,N-
dimethylmethanamine (261) H F CH.sub.3 CH.sub.3 W, X, BB, E, D
Prepared from 260 .sup.1H NMR(400 MHz, CD.sub.3OD) 7.47(d, J=2.4Hz,
1H), 7.44(d, J=8.8Hz, 1H), 7.26(dd, J=2.4, 8.8Hz, 1H), 4.60(m, 1H),
2.69(s, 2H), 2.26(m, 2H), 2.22(s, 6H), 1.95(m, 2H), 1.70(m, 2H),
1.56(m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) 141.28, 133.22,
131.24, 130.87, 129.44, 126.88, 91.90, 90.20, 70.43, 47.54, 41.98,
30.83, 30.74, 28.22, 28.03; ESI MS m/z 274.0.
4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol (262) OH H H H
W, X, E .sup.1H NMR(400 MHz, CD.sub.3OD) 7.63(d, J=2.4Hz, 1H),
7.59(d, J=8.8Hz, 1H), 7.40(dd, J=2.4, 8.8Hz, 1H), 3.66(m, 1H),
3.02(s, 2H), 2.40(m, 2H), 1.86(m, 2H), 1.62(m, 2H), 1.24(m, 2H);
.sup.13C NMR(100 MHz, CD.sub.3OD) 141.28, 133.16, 131.23, 131.24,
129.94, 127.56, 69.15, 50.80, 47.64, 40.48, 30.89, 30.26; ESI MS
m/z 274.0.
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol (263)
OH H CH.sub.3 CH.sub.3 W, X, E, D Prepared from 262 .sup.1H NMR(400
MHz, CD.sub.3OD) 7.64(d, J=2.4Hz, 1H), 7.55(d, J=8.8Hz, 1H),
7.36(dd, J=2.4, 8.8Hz, 1H), 3.55(m, 1H), 3.01(s, 2H), 2.24(m, 2H),
2.23(s, 6H), 1.79(m, 2H), 1.67(m, 2H), 1.33(m, 2H); .sup.13C NMR
(100 MHz, CD.sub.3OD) 141.11, 133.06, 131.33, 131.31, 129.88,
127.76, 69.35, 51.82, 47.64, 45.78, 40.32, 30.77, 29.16; ESI MS m/z
302.0.
1-(1-(3,4-dichlorophenyl)-4-fluorocyclohexyl)-N-methylmethanamine
(264) F H CH.sub.3 H W, BB, E, A Prepared from 253 .sup.1H NMR(400
MHz, CDCl.sub.3) .delta. 7.46(d, J=2.0Hz, 1H), 7.44(d, J=8.4Hz,
1H), 7.23(dd, J=2.0, 8.4Hz, 1H), 4.47(d, J=48.8Hz, 1H), 2.71(s,
2H), 2.34(s, 3H), 2.28(m, 2H), 1.94(m, 2H), 1.59(m, 4H); .sup.13C
NMR(100 MHz, CDCl.sub.3), .delta. 144.46, 133.02, 130.69, 130.26,
129.47, 126.83, 90.63, 88.41, 64.91, 48.67, 42.24, 37.56, 29.97,
28.75, 28.92, 28.39, 27.71, 27.41; ESI MS m/z 290.0.
(1-(3,4-dichlorophenyl)-4-phenoxycyclohexyl)methanamine (265) OPh H
H H W, X, E .sup.1H NMR(400 MHz, CD.sub.3OD) 8.40(broad, 1H),
7.66(d, J=2.0Hz, 1H), 7.60(d, J=8.8Hz, 1H), 7.42(dd, J=2.0, 8.8Hz,
1H), 7.22(m, 2H), 6.84 (m, 3H), 4.43(m, 1H), 3.31(s, 2H), 2.40(m,
2H), 2.01(m, 2H), 1.75(m, 2H), 1.49(m, 2H); .sup.13C NMR(100 MHz,
CD.sub.3OD) 157.57, 141.57, 133.23, 131.37, 131.27, 129.69, 129.32,
127.32, 120.79, 115.94, 74.26, 49.93, 48.52, 48.44, 40.45, 30.31,
27.01; ESI MS m/z 336.1.
1-(1-(3,4-dichlorophenyl)-4-phenoxycyclohexyl)-N,N-
dimethylmethanamine (266) Oph H CH.sub.3 CH.sub.3 W, X, E, F
Prepared from 265 .sup.1H NMR(400 MHz, CD.sub.3OD) 7.46(d, J=2.0Hz,
1H), 7.40(d, J=8.4Hz, 1H), 7.24(m, 3H), 6.90(m, 1H), 6.84(m, 2H),
4.25(m, 1H), 2.36(s, 2H), 2.30(m, 2H), 2.08(s, 6H), 2.0(m, 2H),
1.70(m, 2H), 1.48(m, 2H); .sup.13C NMR(100 MHz, CD.sub.3OD) 157.57,
141.527, 133.10, 132.68, 130.45, 129.98, 129.67, 127.16, 120.92,
116.19, 75.87 72.52, 49.93, 48.56, 48.44, 40.45, 31.40, 27.82; ESI
MS m/z 378.0.
(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)methanamine (267) F
F H H CC, E .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 8.4(broad,
1H), 7.67(d, J=2.4Hz, 1H), 7.62(d, J=8.4Hz, 1H), 7.43(dd, J=8.4,
2.4Hz, 1H), 3.10(s, 2H), 2.40 (m, 2H), 2.20(m, 2H), 1.90(m, 2H),
1.70(m, 2H); .sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 133.43,
131.82, 137.41, 129.57, 127.20, 122.35, 49.58, 47.60, 40.18, 30.05,
29.76, 29.51, 29.45; ESI MS m/z 294.0.
1-(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)-N-
methylmethanamine (268) F F CH.sub.3 H CC, E, F Prepared from 267
to give 268 and 269, which were separated by silica gel column
chromatography(ethyl acetate/hexane/DEA = 1:4:0.1). .sup.1H NMR(400
MHz, CD.sub.3OD) .delta. 8.5(broad, 1H), 7.68(d, J=2.4Hz, 1H),
7.62(d, J=8.4Hz, 1H), 7.44(dd, J=8.4, 2.4Hz, 1H), 3.20(s, 2H),
2.58(s, 3H), 2.40(m, 2H), 2.05(m, 2H), 1.92(m, 2H), 1.70(m, 2H);
.sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 139.86, 133.53, 131.96,
131.30, 129.54, 127.16, 122.46, 59.57, 48.03, 40.24, 34.09, 29.94,
29.80, 29.70, 29.45; ESI MS m/z 307.9.
1-(1-(3,4-dichlorophenyl)-4,4-difluorocyclohexyl)-N,N-
dimethylmethanamine (269) F F CH.sub.3 CH.sub.3 CC, E, F Prepared
from 267 to give 268 and 269, which were separated by silica gel
column chromatography(ethyl acetate/hexane/DEA = 1:4:0.1) .sup.1H
NMR(400 MHz, CD.sub.3OD) .delta. 7.58(d, J=2.4Hz, 1H), 7.50(d,
J=8.4Hz, 1H), 7.37(dd, J=8.4, 2.4Hz, 1H), 2.43(s, 2H), 2.30(m, 2H),
2.01(s, 6H), 1.98(m, 2H), 1.82(m, 2H), 1.65(m, 2H); .sup.13C
NMR(100 MHz, CD.sub.3OD) .delta. 139.86, 133.53, 131.96, 131.30,
129.54, 127.16, 122.46, 59.57, 48.03, 40.24, 34.09, 30.41, 30.17,
29.90, 29.81; ESI MS m/z 322.0.
1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-N-
methylmethanamine (270) ##STR326## CH.sub.3 H FF, E, F 270 and 271
were separated by silica gel column chromatography(ethyl
acetate/hexane/DEA = 1:4:0.1). .sup.1H NMR(400 MHz, CD.sub.3Cl)
.delta. 7.42(d, J=2.4Hz, 1H), 7.38(d, J=8.8Hz, 1H), 7.19(dd, J=2.4,
8.8Hz, 1H), 3.90(m, 4H), 2.59(s, 2H), 2.27(s, 6H), 2.18(m, 2H),
1.82(m, 2H), 1.62(m, 2H), 1.46(m, 2H); .sup.13C NMR(100 MHz,
CD.sub.3Cl) .delta. 132.84, 130.54, 130.31, 129.39, 126.72, 109.02,
64.48, 64.47, 41.91, 37.57, 31.74, 31.35; ESI MS m/z 330.1.
1-(8-(3,4-dichlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)-N,N-
dimethylmethanamine (271) ##STR327## CH.sub.3 CH.sub.3 FF, E, F
.sup.1H NMR(400 MHz, CD.sub.3Cl) .delta. 7.44(d, J=2.4Hz, 1H),
7.36(d, J=8.8Hz, 1H), 7.21(dd, J=2.4, 8.8Hz, 1H), 3.91(m, 4H),
2.32(s, 2H), 2.13(m, 2H), 1.98(s, 3H), 1.80(m, 2H), 1.62(m, 2H),
1.42(m, 2H); .sup.13C NMR (100 MHz, CD.sub.3Cl) .delta. 145.35,
132.38, 130.14, 130.15, 129.62, 129.71, 127.11, 72.01, 64.48,
64.47, 48.58, 42.87, 31.35; ESI MS m/z 344.1.
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (272)
OH CH.sub.3 H H Y, E Stereoisomers(cis- and trans-) were separated
after methylation(General Procedure S) by silica gel column
chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent
transformations were performed using one stereoisomer,
respectively. .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 8.22(broad,
1H), 7.33(d, J=2.0Hz, 1H), 7.32(d, J=8.8Hz, 1H), 7.10(dd, J=8.8,
2.0Hz, 1H), 2.85(s, 2H), 1.92 (m, 2H), 1.51(m, 2H), 1.40(m, 4H),
1.10(s, 3H); .sup.13C NMR(100 MHz, CD.sub.3OD), .delta. 133.18,
131.29, 130.92, 129.00, 126.27, 68.63, 40.14, 34.52, 29.62, 28.171;
ESI MS m/z 288.2.
4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol
(273) OH CH.sub.3 CH.sub.3 H Y, E, F Prepared from 272 to give 273
and 274, which were separated by silica gel column
chromatography(ethyl acetate/hexane/DEA = 1:4:0.1). .sup.1H NMR(400
MHz, CD.sub.3OD) .delta. 7.44(d, J=2.0Hz, 1H), 7.39(d, J=8.8Hz,
1H), 7.21(dd, J=2.0, 8.8Hz, 1H), 2.65(s, 2H), 2.30(s, 3H), 2.04(m,
2H), 1.74(m, 2H), 1.62(m, 2H), 1.50(m, 2H), 1.28(s, 3H); .sup.13C
NMR (100 MHz, CD.sub.3OD) .delta. 132.79, 130.48, 130.25, 129.01,
126.29, 69.90, 60.98, 41.42, 37.57, 35.66, 30.60, 29.92, 29.17; ESI
MS m/z 302.2. 4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-
methylcyclohexanol (274) OH CH.sub.3 CH.sub.3 CH.sub.3 Y, E, F
Prepared from 272 to give 273 and 274 which were separated by
silica gel column chromatography(ethyl acetate/hexane/DEA =
1:4:0.1). .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 7.45(d, J=2.4Hz,
1H), 7.36(d, J=8.8Hz, 1H), 7.22(dd, J=2.4, 8.8Hz, 1H), 2.37(m, 2H),
2.20(m, 2H), 198(m,
6H), 1.76(m, 2H), 1.58(m, 2H), 1.48(m, 2H), 1.28(s, 3H); .sup.13C
NMR (100 MHz, CD.sub.3OD) .delta. 132.32, 130.07, 129.75, 129.38,
126.74, 70.25, 48.53, 35.94, 30.546, 28.49; ESI MS m/z 316.2.
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (275)
CH.sub.3 OH H H Y, E Stereoisomers(cis- and trans-) were separated
after methylation(General Procedure S) by silica gel column
chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent
transformations were performed using one stereoisomer,
respectively. .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 8.5(broad,
1H), 7.02(s, 1H), 7.57(d, J=8.8Hz, 1H), 7.40(d, J=8.8Hz, 1H),
2.98(s, 2H), 2.18(m, 2H), 1.94 (m, 2H), 1.58(m, 2H), 1.28(m, 2H),
1.07(s, 3H); .sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 140.93,
133.07, 131.19, 131.12, 129.92, 127.61, 67.90, 51.74, 40.64, 34.05,
29.66, 28.60, 28.37; ESI MS m/z 288.2.
4-(3,4-dichlorophenyl)-1-methyl-4-((methylamino)methyl)cyclohexanol
(276) CH.sub.3 OH CH.sub.3 H Y, E, F Prepared from 275(General
Procedure F) to give 276 and 277, which were separated by silica
gel column chromatography(ethyl acetate/hexane/ DEA = 1:4:0.1).
.sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 7.43(d, J=2.0Hz, 1H),
7.40(d, J=8.8Hz, 1H), 7.20(dd, J=8.8, 2.0Hz, 1H), 2.54(s, 2H),
2.27(s, 3H), 2.08(m, 2H), 1.90(m, 2H), 1.52(m, 2H), 1.30(m, 2H),
1.11(s, 3H); .sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 132.86,
130.56, 130.23, 129.63, 127.06, 69.68, 69.94, 42.40, 37.56, 35.16,
31.05, 29.82; ESI MS m/z = 302.2.
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-
methylcyclohexanol (277) CH.sub.3 OH CH.sub.3 CH.sub.3 Y, E, F
Prepared from 275(General Procedure F) to give 276 and 277, which
were separated by silica gel column chromatography(ethyl
acetate/hexane/ DEA = 1:4:0.1). .sup.1H NMR(400 MHz, CD.sub.3OD)
.delta. 7.44(d, J=2.4Hz, 1H), 7.36(d, J=8.8Hz, 1H), 7.21(dd, J=2.4,
8.8Hz, 1H), 7.21(dd, J=2.4, 8.8Hz, 1H), 2.28(s, 2H), 2.04(m, 2H),
1.99(s, 6H), 1.85(m, 2H), 1.51(m, 2H), 1.30(m, 2H), 1.09(s, 3H);
.sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 132.37, 130.14, 129.92,
129.73, 127.39, 73.73, 69.65, 48.72, 43.45, 35.15, 31.16, 29.32;
ESI MS m/z = 316.2.
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexanol (278) OH
ethyl H H Y, E Stereoisomers(cis- and trans-) were separated after
alkylation(General Procedure S) by silica gel column
chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent
transformations were performed using one stereoisomer,
respectively. .sup.1H NMR(400 MHz, CD.sub.3Cl) .delta. 7.40(d,
J=2.4Hz, 1H), 7.39(d, J=8.4Hz, 1H), 7.17(dd, J=2.4, 8.4Hz, 1H),
2.77(s, 2H), 2.12-1.94(m, 2H), 1.90-1.74(m, 2H), 1.72-1.64(m, 1H),
1.61-1.50(m, 3H), 1.48-1.38(m, 1H), 0.89(t, J=8.0Hz, 3H); .sup.13C
NMR(100 MHz, CD.sub.3Cl) .delta. 146.40, 132.79, 130.54, 130.35,
129.14, 126.38, 71.21, 49.55, 33.84, 32.94, 29.34, 7.51; ESI MS m/z
302.2.
4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol
(279) OH ethyl CH.sub.3 H Y, E, F Prepared from 278(General
Procedure F) to give 279 and 280, which were separated by silica
gel column chromatography(ethyl acetate/hexane/ DEA = 1:4:0.1).
.sup.1H NMR(400 MHz, CD.sub.3Cl) .delta. 7.64(d, J=2.4Hz, 1H),
7.58(d, J=8.4Hz, 1H), 7.41(dd, J=2.4, 8.4Hz, 1H), 3.30(s, 3H),
2.58(s, 2H), 2.16-2.09(m, 2H), 1.84-1.76(m, 2H), 1.68-1.50(m, 6H),
0.94(t, J=7.6Hz, 3H); .sup.13C NMR(100 MHz, CD.sub.3Cl) .delta.
133.02, 131.27, 131.08, 130.96, 128.96, 126.49, 69.96, 39.96,
34.20, 31.90, 29.45, 6.33; ESI MS m/z 316.1.
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexanol
(280) OH ethyl CH.sub.3 CH.sub.3 Y, E, F Prepared from 278(General
Procedure F) to give 279 and 280, which were separated by silica
gel column chromatography(ethyl acetate/hexane/ DEA = 1:4:0.1).
.sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 7.60(d, J=2.4Hz, 1H),
7.49(d, J=8.8Hz, 1H), 7.40(dd, J=2.4, 8.8Hz, 1H), 2.83(s, 2H),
2.16(s, 6H), 2.12-2.00 (m, 2H), 1.86-1.74(m, 2H), 1.64-1.46(m, 6H),
0.92(t, J=7.2Hz, 3H); .sup.13C NMR(100 MHz, CD.sub.3OD) 132.20,
130.26, 130.25, 129.94, 129.17, 126.84, 70.45, 46.79, 41.18, 32.33,
29.86, 6.40; ESI MS m/z 330.0.
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-ethylcyclohexanol (281)
ethyl OH H H Y, E Stereoisomers(cis- and trans-) were separated
after alkylation(General Procedure S) by silica gel column
chromatography(ethyl acetate/hexane = 1:15 to 1:7) and subsequent
transformations were performed using one stereoisomer,
respectively. .sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 7.63(d,
J=2.0Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.40(dt, J=2.0, 8.4Hz, 1H),
2.98(s, 2H), 2.18(d, J=13.2Hz, 2H), 1.90(dt, J=2.8, 13.6Hz, 2H),
1.36(d, J=13.2Hz, 2H), 1.32(q, J=7.6Hz, 2H), 1.21(td, J=2.8,
13.6Hz, 2H), 0.81(t, J=7.6Hz, 3H); .sup.13C NMR(100 MHz,
CD.sub.3OD) .delta. 140.68, 133.11, 131.27, 131.15, 129.95, 127.63,
69.95, 51.88, 40.89, 35.68, 31.72, 28.18; ESI MS m/z 284.1.
4-(3,4-dichlorophenyl)-1-ethyl-4-((methylamino)methyl)cyclohexanol
(282) ethyl OH CH.sub.3 H Y, E, F Prepared from 281(General
Procedure F) to give 282 and 283, which were separated by silica
gel column chromatography(ethyl acetate/hexane/ DEA = 1:4:0.1).
.sup.1H NMR(400 MHz, CD.sub.3Cl) .delta. 7.63(d, J=2.0Hz, 1H),
7.56(d, J=8.4Hz, 1H), 7.43(dd, J=2.0, 8.4Hz, 1H), 3.31(s, 3H),
2.56(s, 2H), 2.14-2.10(m, 2H), 1.82-1.78(m, 2H), 1.66-1.51(m, 6H),
0.93(t, J=7.6Hz, 3H); .sup.13C NMR(100 MHz, CD.sub.3Cl) .delta.
133.22, 131.37, 131.28, 131.02, 129.10, 126.51, 69.87, 39.93,
34.22, 32.40, 29.25; ESI MS m/z 316.1.
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-ethylcyclohexanol
(283) ethyl OH CH.sub.3 CH.sub.3 Y, E, F Prepared from 281(General
Procedure F) to give 282 and 283, which were separated by silica
gel column chromatography(ethyl acetate/hexane/ DEA = 1:4:0.1).
.sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 7.54(s, 1H), 7.45(d,
J=8.4Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 2.37(s, 2H), 2.09(d, J=13.6Hz,
1H), 1.98(s, 6H), 1.86(t, J=14.0Hz, 1H), 1.50(d, J=14.0Hz, 1H),
1.28(q, J=6.8Hz, 2H), 1.20(t, J=14.0Hz, 1H), 0.79(t, J=6.8Hz, 3H);
.sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 145.17, 131.92, 130.03,
129.99, 129.38, 127.79, 73.89, 70.62, 47.57, 43.26, 35.75, 32.09,
28.96; ESI MS m/z 332.1.
4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-propylcyclohexanol (284)
n- OH H H Y, E propyl .sup.1H NMR(400 MHz, CD.sub.3OD) .delta.
7.63(s, 1H), 7.56(d, J=8.0Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 3.30(s,
2H), 2.15(m, 2H), 1.84(m, 2H), 1.64(m, 2H), 1.54(m, 2H), 1.42(m,
2H), 0.95(t, J=6.8Hz, 3H); .sup.13C NMR(100 MHz, CD.sub.3OD)
.delta. 132.89, 131.13, 130.99, 129.09, 126.67, 70.03, 43.61,
39.76, 32.37, 29.48, 29.18, 16.04, 13.94; ESI MS m/z 316.4.
4-(3,4-dichlorophenyl)-4-((methylamino)methyl)-1-propylcyclohexanol
(285) n- OH CH.sub.3 H Y, E, F propyl Prepared from 284(General
Procedure F) to give 285 and 286, which were separated by silica
gel column chromatography(ethyl acetate/hexane/ DEA = 1:4:0.1).
.sup.1H NMR(400 MHz, CD.sub.3OD) .delta. 8.38(broad, 1H), 7.64(d,
J=2.0Hz, 1H), 7.62(d, J=8.8Hz, 1H), 7.41(dd, J=2.0, 8.8Hz, 1H),
3.34(s, 2H), 2.60(s, 3H), 2.16(m, 2H), 1.82(m, 2H), 1.64(m, 2H),
1.52(m, 2H), 1.42(m, 2H), 0.95(t, J=6.8Hz, 1H); .sup.13C NMR(100
MHz, CD.sub.3OD) .delta. 133.03, 131.33, 131.11, 130.99, 129.06,
126.57, 69.94, 39.87, 34.01, 32.33, 29.45, 29.14, 16.01, 15.96,
13.88; ESI MS m/z 330.2.
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-
propylcyclohexanol (286) n- OH CH.sub.3 CH.sub.3 Y, E, F propyl
Prepared from 284(General Procedure F) to give 285 and 286, which
were separated by silica gel column chromatography(ethyl
acetate/hexane/ DEA = 1:4:0.1). .sup.1H NMR(400 MHz, CD.sub.3OD)
.delta. 7.45(d, J=2.0Hz, 1H), 7.36(d, J=8.8Hz, 1H), 7.21(dd, J=2.0,
8.8Hz, 1H), 2.40(s, 2H), 2.02-1.94(m, 2H), 1.96 (s, 6H), 1.76(m,
2H), 1.60(m, 2H), 1.48(m, 2H), 1.40(m, 2H), 0.95(t, J=6.8Hz, 1H);
.sup.13C NMR(100 MHz, CD.sub.3OD) .delta. 132.25, 130.03, 129.69,
129.21, 126.58, 71.52, 48.46, 43.59, 33.27, 30.08, 16.44, 14.92;
ESI MS m/z 344.2.
cis-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol
(287)
[0665] ##STR328## 299 to 287
[0666] The title compound was prepared from
(1s,4s)-4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol 299 (63
mg, 0.230 mmol) according to General Procedure F2. The crude
product was purified by chromatography (SiO.sub.2,
MeOH/CH.sub.2Cl.sub.2, 0:100 to 10:90) to give
(1s,4s)-4-(3,4-dichlorophenyl)-4-((methylamino)methyl)cyclohexanol
(40 mg, 61%) as clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 1.57-1.72 (m 4H), 1.78-1.83 (m, 2H), 2.04-2.11 (m, 2H),
2.30 (s, 3H), 2.68 (s, 2H), 3.78-3.82 (m, 1H), 7.20 (dd, J=8.4, 2.4
Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.44 (s, 1H). ESI MS m/z 288.
(1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-cyclohexanol
(288)
[0667] ##STR329## 299 to 288
[0668] The title compound was prepared from
(1s,4s)-4-(aminomethyl)-4-(3,4-dichlorophenyl)cyclohexanol
(PharmaCore, 63 mg, 0.230 mmol) according to General Procedure F2.
The crude product was purified by reverse phase HPLC (C-18 column,
CH.sub.3CN/water, CH.sub.3CN from 5% to 100%) to give
(1s,4s)-4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)cyclohexanol
(50 mg, 75%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.57-1.68
(m 4H), 1.77-1.86 (m, 3H), 1.99 (s, 6H), 2.00-2.08 (m, 1H), 2.41
(s, 2H), 3.79-3.82 (m, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 7.36 (d,
J=8.4 Hz, 1H), 7.45 (s, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3):
.delta. 29.5, 30.2, 42.4, 48.6, 68.0, 70.4, 126.8, 129.4, 129.7,
130.1, 132.3, 147.1. ESI MS m/z 302.
4-(3,4-Dichloro-phenyl)-4-methylaminomethyl-cyclohexanone (289)
[0669] ##STR330##
[0670] To a solution of 270 (20 mg, 0.060 mmol) in acetone-H.sub.2O
(1:1, 1.5 mL) was added TsOH--H.sub.2O (12 mg, 0.060 mmol). The
reaction mixture was stirred overnight before being concentrated.
The residue was dissolved in MeOH (1 mL) and subjected to reverse
phase column chromatography (CH.sub.3CN:H.sub.2O:0.1% formic
acid=5% to 100%) to give
4-(3,4-dichloro-phenyl)-4-methylaminomethyl-cyclohexanone (8.5 mg,
50%). ESI MS m/z 286.1.
trans-4-(aminomethyl)-4-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclo-hexanam-
ine (290)
[0671] ##STR331##
[0672] To a solution of
1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile (600 mg, 2.22
mmol) in MeOH (10 mL) was added MeNH.sub.2.HCl (1.0 M in THF, 4.44
mL, 4.44 mmol), HCO.sub.2H (0.2 mL) and NaB(CN)H.sub.3 (420 mg,
6.66 mmol). The reaction mixture was stirred overnight before being
concentrated. The residue was dissolved in MeOH (2 mL) and
subjected to reverse phase column chromatography
(CH.sub.3CN/H.sub.2O/0.1% formic acid=5% to 100%) to give the
mixture of cis- and trans-isomers (446 mg, 71%), which were
separated (OD column, ethanol:methanol:hexane:DEA=3:2:95:0.1) to
give the cis-analog (88 mg) and the trans-analog (332 mg).
[0673] To a solution of the above trans-analog (200 mg, 0.71 mmol)
in CH.sub.2Cl.sub.2 (5 mL) was added pyridine (0.5 mL) and acetyl
chloride (80.3 mg, 72.2 .mu.L, 1.06 mmol). The reaction mixture was
stirred for 2 h before being quenched with saturated NH.sub.4Cl.
The product was extracted with CH.sub.2Cl.sub.2 (20 mL.times.2),
dried and concentrated. The residue was subjected to silica gel
column chromatography (ethyl acetate/hexane=1:10 to 1:1) to give
trans-1-(3,4-dichlorophenyl)-4-(ethyl(methyl)amino)cyclohexanecarbonitril-
e (202 mg, 88%).
[0674] The title compound was synthesized from the above nitrile
(150 mg, 0.46 mmol) according to General Procedure E. The crude
product was dissolved in MeOH (2 mL) and subjected to reverse phase
column chromatography (CH.sub.3CN:H.sub.2O:0.1 formic acid=5% to
100%) (77 mg, 76%). ESI MS m/z 315.2.
(.+-.)(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine (291)
[0675] ##STR332##
[0676] The unsaturated amine
(1-(naphthalen-2-yl)cyclohex-3-enecarbonitrile) was prepared
according to General Procedure BB and was formed together with the
monofluorinated intermediate in a 1:1 ratio.
[0677] To a 1M solution of LAH in THF (0.2 ml, 0.184 mmol), which
was diluted up to 1 ml with Et.sub.2O, was added a solution of
1-(naphthalen-2-yl)cyclohex-3-enecarbonitrile (0.043 g, 0.184 mmol)
in Et.sub.2O (2 ml) and the resulting mixture was stirred at
35.degree. C. for 16 h. The reaction was then quenched with
K.sub.2CO.sub.3 (sat. aq., 5 ml). It was extracted with EtOAc
(2.times.25 ml) and the combined organic phases were dried over
Na.sub.2SO.sub.4, decanted and the solvent was removed in vacuo to
give the product (0.042 g, 96%), which was pure by HPLC.
[0678] The corresponding HCl salt was prepared by the addition of
2M HCl (Et.sub.2O) to the free amine. After stirring for 1 h, the
white precipitate was filtered off to afford pure
(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine. LC-MS (m/z+)
238.1.
(.+-.) N-methyl-1-(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine
(292)
[0679] ##STR333##
[0680] The title compound was formed as a byproduct in the
reduction of the fluorinated carbamate. Preparative HPLC separation
(ChiralPak-AD column, 95:2.5:2.5:0.1 Hexanes:EtOH:MeOH:HNEt.sub.2)
afforded the crude product, which was converted to the
corresponding HCl salt by the addition of 2M HCl (Et.sub.2O) to the
free amine. After stirring for 1 h, the white precipitate was
filtered off to afford pure
N-methyl-1-(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine
hydrochloride salt (0.021 g). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 9.04 (brs, 1H), 8.67 (brs, 1H), 7.79-7.67 (m, 4H), 7.45 (m,
3H), 5.80 (d, J=8.0 Hz, 1H), 5.59 (d, J=7.5 Hz, 1H), 3.21 (brs,
1H), 3.12 (brs, 1H), 2.89 (m, 1H), 2.57 (m, 1H), 2.22-1.99 (m, 2H),
2.15 (s, 6H), 1.75 (m, 2H). .sup.13C-NMR (100 MHz, CDCl.sub.3)
.delta. 138.6, 133.5, 132.6, 129.1, 128.6, 127.7, 127.2, 126.9,
126.6, 126.5, 124.3, 59.7, 40.0, 35.6, 33.7, 31.4, 22.5. LC-MS
(m/z+) 252.1.
N,N-dimethyl(1-(naphthalen-2-yl)cyclohex-3-enyl)methanamine
(293)
[0681] ##STR334##
[0682] The title compound was prepared from 292 according to
General Procedure C (0.023 g, 49% yield). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.81-7.74 (m, 4H), 7.54 (dd, J=9.0, 2.0 Hz,
1H), 7.46-7.41 (m, 2H), 5.82 (m, 1H), 5.60 (apd, J=10.0 Hz, 1H),
2.70 (d, J=13.0 Hz, 1H), 2.63 (d, J=17.5 Hz, 1H), 2.53 (d, J=13.5
Hz, 1H), 2.43 (m, 1H), 2.02 (m, 2H), 1.98 (s, 6H), 1.72-1.70 (m,
2H). .sup.13C-NMR (100 MHz, CDCl.sub.3) .delta. 132.0, 128.3,
127.5, 127.2, 125.8, 125.8, 125.6, 125.5, 125.4, 70.8, 48.5, 34.4,
31.9, 22.9. LC-MS (m/z+) 266.1.
4',8-dimethyl-8,9-dihydro-7H-spiro[[1,3]dioxolo[4,5-h]isoquinoline-6,1'-cy-
clohexan]-4'-ol (diastereomer 1) (294)
[0683] ##STR335##
[0684] The title compound was isolated as a byproduct in the
Eschweiler-Clark alkylation (General Procedure C) of the amine 215.
The two products were separated by reverse phase preparative HPLC
(CH.sub.3CN: H.sub.2O) to afford the product as the formate salt:
.sup.1H-NMR (400 MHz, CHCl.sub.3) .delta. 8.42 (brs, 1H), 6.57 (s,
1H), 5.92 (s, 1H), 3.91 (s, 2H), 3.18 (s, 2H), 2.79 (s, 3H),
1.92-1.87 (m, 2H), 1.74-1.60 (m, 6H), 1.39 (s, 3H). LC-MS (m/z+)
290.3.
4',8-dimethyl-8,9-dihydro-7H-spiro[[1,3]dioxolo[4,5-h]isoquinoline-6,1'-cy-
clohexan]-4'-ol (diastereomer 2) (295)
[0685] ##STR336##
[0686] The title compound was isolated as a byproduct in the
Eschweiler-Clark alkylation (General Procedure C) of the amine 216.
The two products were separated by reverse phase preparative HPLC
(CH.sub.3CN:H.sub.2O). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
8.38 (brs, 1H), 7.02 (s, 1H), 6.59 (s, 1H), 5.93 (s, 2H), 4.07 (s,
2H), 3.34 (s, 2H), 2.91 (s, 3H), 2.23-2.19 (m, 2H), 1.65-1.53 (m,
6H), 1.26 (s, 3H). .sup.13C-NMR (100 MHz, CD.sub.3OD) .delta.
106.2, 101.6, 58.1, 56.5, 43.6, 33.7, 32.4, 30.1. LC-MS (M+1)
290.2.
2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidine (296)
[0687] ##STR337##
(a)
(R)--N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)-3-(1,3-dioxan-2-yl)propyl-
)-2-methylpropane-2-sulfinamide
[0688] ##STR338##
[0689] A flame dried flask under N.sub.2 was charged with anhydrous
Et.sub.2O (5 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M
in THF, 5.6 mL, 2.8 mmol) and cooled to -78.degree. C.
(R,E)-N-((1-(3,4-dichlorophenyl)cyclohexyl)methylene)-2-methylpropane-2-s-
ulfinamide (460 mg, 1.28 mmol) in anhydrous Et.sub.2O (3 mL) was
added dropwise and the solution was stirred at -78.degree. C. for 1
h, then allowed to warm to RT overnight. After 20 h sat'd aqueous
Na.sub.2SO.sub.4 solution (4 mL) was added and the suspension was
filtered, dried (Na.sub.2SO.sub.4), filtered and concentrated.
Purification on the Biotage with a 25M column and an ethyl
acetate/hexane (0.1% DEA) gradient (0.fwdarw.100% EtOAc over 3 CV,
hold at 100% EtOAc for 5 CV) gave the pure title compound (300 mg,
49%) as a clear oil. HPLC R.sub.t=2.62 min; .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.45-7.43 (m, 2H), 7.24-7.22 (d, J=8.43 Hz, 1H),
4.44-4.42 (m, 1H), 4.11-4.04 (m, 2H), 3.75-3.67 (m, 2H), 3.11-3.01
(m, 2H), 2.64 (d, J=12.8 Hz, 1H), 2.27 (d, J=13.9 Hz, 1H),
2.04-1.99 (m, 1H), 1.88-1.44 (m, 8H), 1.33-1.19 (m, 12H), 0.93-0.80
(m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 141.8, 132.7, 130.8,
130.4, 130.2, 128.4, 101.7, 66.8, 66.3, 57.1, 46.2, 34.3, 32.5,
26.1, 25.7 (d), 23.1, 22.2, 21.8; LC-MS 10.5 min, (M+1).sup.+476 @
10.6 min.
(b) 2-(1-(3,4-dichlorophenyl)cyclohexyl)pyrrolidine formate
[0690] The above sulfinamide (58 mg, 0.13 mmol) was dissolved in
wet acetone (3 mL) and 6 M HCl (1 mL) was added. The clear reaction
was stirred for 16 h, poured into 6 M HCl and washed with Et.sub.2O
(2.times.10 mL). The Et.sub.2O washes were discarded. The aqueous
phase was made basic (pH=10-11) with sat'd aqueous K.sub.2CO.sub.3,
at which point a white precipitate appeared. The basic aqueous
phase was washed with EtOAc (4.times.20 mL) and the EtOAc washes
were combined, dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude imine was dissolved in anhydrous THF (4 mL) in a product
vial and polymer bound cyanoborohydride (Argonaut, 2.43 mmol/g, 327
mg, 0.796 mmol) and glacial acetic acid (35 mL, 0.597 mmol) were
added. The slightly yellow clear solution was shaken at RT for 16 h
and filtered. The resin washed with CH.sub.2Cl.sub.2 and the
combined washes were concentrated. The crude amine was dissolved in
MeOH (3 mL) and purified on the Gilson with the standard method.
Fractions containing the major peak (Rt .about.3.4 min) were
concentrated on the Genevac and combined to give the title compound
as a formate salt (37 mg, 31%). HPLC R.sub.t=1.5 min; .sup.1H NMR
(400 MHz, CDCl.sub.3) 8.45 (s, 1H), 7.48 (d, J=1.83 Hz, 1H), 7.45
(d, J=8.43 Hz, 1H), 7.28-7.26 (m, 1H), 3.48-3.43 (m, 1H), 3.17-3.11
(m, 1H), 3.04-2.98 (m, 1H), 2.31 (d, J=12.8 Hz, 2H), 1.84-1.51 (m,
10H), 1.26-1.16 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 168.1,
141.2, 133.3, 131.2, 131.0, 130.5, 127.8, 69.4, 45.3, 43.7, 33.1,
31.0, 25.9 (d), 23.6, 21.8(d); LC-MS 8.35 min, (M+1).sup.+298@ 8.51
min.
2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidine (297)
[0691] ##STR339##
(a) Synthesis of
(R)--N-(3-(1,3-dioxan-2-yl)-1-(1-(naphthalen-2-yl)cyclohexyl)propyl)-2-me-
thylpropane-2-sulfinamide
[0692] ##STR340##
[0693] A flame dried flask under N.sub.2 was charged with anhydrous
Et.sub.2O (3 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M
in THF, 6.78 mL, 3.39 mmol) and cooled to -78.degree. C.
(R,E)-2-methyl-N-((1-(naphthalen-2-yl)cyclohexyl)methylene)propane-2-sulf-
inamide (524 mg, 1.54 mmol) in anhydrous Et.sub.2O (3 mL) was added
dropwise and the solution was stirred at -78.degree. C. for 1 h,
then allowed to warm to RT overnight. After 20 h sat'd aqueous
Na.sub.2SO.sub.4 solution (4 mL) was added and the suspension was
filtered, dried (Na.sub.2SO.sub.4), filtered and concentrated.
Purification on the Biotage with a 25M column and an ethyl
acetate/hexane (0.1% DEA) gradient (0.fwdarw.100% EtOAc over 3 CV,
hold at 100% EtOAc for 5 CV) gave the title compound (581 mg, 83%)
as a clear oil. HPLC (JPK method) R.sub.t=2.61 min; .sup.1H NMR
(400 MHz, CDCl.sub.3) 7.85-7.80 (m, 4H), 7.53 (d, J=8.8 Hz, 1H),
7.48-7.45 (m, 2H), 4.38 (t, J=5.13 Hz, 1H), 4.10-3.99 (m, 2H),
3.77-3.62 (m, 2H), 3.25 (d, J=8.8 Hz, 1H), 3.15-3.10 (m, 1H), 2.88
(d, J=12.1 Hz, 1H), 2.51 (d, J=11.7 Hz, 1H), 2.03-1.90 (m, 2H),
1.64-1.59 (m, 4H), 1.49-1.42 (m, 2H), 1.31-1.23 (m, 4H), 1.12 (s,
9H), 0.87-0.83 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 138.5,
133.6, 132.0, 128.2, 128.1, 127.5, 126.9, 126.2, 126.0, 102.1,
67.0, 66.7, 57.0, 46.4, 35.0, 34.8, 32.8, 26.2 (d), 25.9, 23.3,
22.6, 22.2; LC-MS 10.4 min, (M+1).sup.+458 @ 10.6 min.
(b) Synthesis of 2-(1-(naphthalen-2-yl)cyclohexyl)pyrrolidine
formate
[0694] The above sulfinamide (317 mg, 0.694 mmol) was dissolved in
wet acetone (12 mL) and 6 M HCl (4 mL) was added. The clear
reaction was stirred for 16 h, poured into 6 M HCl and washed with
Et.sub.2O (2.times.20 mL). The Et.sub.2O washes were discarded. The
aqueous phase was made basic (pH=10-11) with sat'd aqueous
K.sub.2CO.sub.3, at which point a white precipitate appeared. The
basic aqueous phase was washed with EtOAc (4.times.30 mL) and the
EtOAc washes were combined, dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude imine was dissolved in anhydrous THF (7 mL)
in a product vial and polymer bound cyanoborohydride (Argonaut,
2.43 mmol/g, 697 mg, 1.69 mmol) and glacial acetic acid (73 mL,
1.27 mmol) were added. The slightly yellow clear solution was
shaken at RT for 16 h and filtered. The resin washed with
CH.sub.2Cl.sub.2 and the combined washes were concentrated. The
crude amine was dissolved in MeOH (3 mL) and purified on the Gilson
with the standard method. Fractions containing the major peak
(Rt.about.3.4 min) were concentrated on the Genevac and combined to
give the title compound as the formate salt (96 mg, 49%). HPLC
R.sub.t=1.58 min; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.51 (s, 1H),
7.88-7.78 (m, 4H), 7.55-7.52 (dd, J=1.47, 8.80 Hz, 1H), 7.48-7.42
(m, 2H), 3.61-3.57 (m, 1H), 3.04-2.99 (m, 1H), 2.86-2.82 (m, 1H),
2.56-2.53 (m, 2H), 1.84-1.53 (m, 9H), 1.39-1.25 (m, 3H); .sup.13C
NMR (100 MHz, CDCl.sub.3) 168.3, 137.7, 133.6, 132.2, 128.7, 128.3,
127.8, 127.4, 126.3, 126.2, 125.5, 69.5, 45.2, 43.8, 33.4, 31.1,
26.0 (d), 23.6, 22.0 (d); LC-MS 8.14 min, (M+1).sup.+280 @ 8.23
min.
Example 5
Scaled-up Syntheses of 225, 93, 48 E1 and 277
5.1. Scaled-up Synthesis of
(1s,4s)-4-((dimethylamino)methyl)-1-methyl-4-(naphthalen-2-yl)cyclohexano-
l (225)
5.1.1. General
[0695] Reagents and solvents were used as received from commercial
suppliers. Proton and carbon nuclear magnetic resonance spectra
were obtained on a Bruker AC 300 spectrometer at 300 and 75 MHz,
respectively. High-pressure liquid chromatography was performed on
an Agilent 1100 series instrument. Gas chromatography-mass
spectroscopy was performed on a Hewlett-Packard G1800A GCD
System.
[0696] Compound 225 was prepared following the procedures outlined
in Scheme 33, below. ##STR341##
5.1.2. Preparation of dimethyl
4-cyano-4-(naphthalen-2-yl)heptanedioate
[0697] A 3-L, three-necked flask equipped with a temperature probe,
reflux condenser, addition funnel and overhead stirrer was charged
with 2-naphthylacetonitrile (300 g, 1.79 mol), methylacrylate (600
mL, 6.65 mol) and tert-butanol (900 mL). A solution of
tetrabutylammonium hydroxide (1 M; 75 mL, 75 mmol) in methanol was
added slowly through an addition funnel over a period of 30 min
(Note: Highly exothermic). The resulting clear solution was stirred
at 70.degree. C. for 2 h and assayed by TLC (3:7 EtOAc/Heptane;
stained using Hanessian solution) and GC. The reaction mixture was
cooled to room temperature before being concentrated under reduced
pressure. The residue was partitioned between 2 M HCl (1 L) and
MTBE (4 L). The phases were separated and the aqueous phase was
extracted with MTBE (500 mL). The combined organic phases were
washed with brine (1 L), dried over MgSO.sub.4, filtered and
concentrated under reduced pressure at 40-45.degree. C. to give a
residue which was passed through a bed of silica (1:4
EtOAc/Heptane) to yield the title compound [569 g, 93%, 100% (AUC)
by GC] as an off-white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz):
.delta. 7.75 (2 d merged, 2H), 7.45 (dd, 1H), 3.5 (s, 6H), 2.4-2.2
(m, 6H), 2.15-1.98 (m, 2H).
5.1.3. Preparation of methyl
5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate
[0698] A 12-L, three-neck flask equipped with a temperature probe,
reflux condenser, addition funnel and overhead stirrer was charged
with potassium tert-butoxide (365 g, 3.2 mol) and toluene (2.4 L).
A solution of dimethyl 4-cyano-4-(naphthalen-2-yl)heptanedioate
(500 g, 1.4 mol) in toluene (4 L) was added through an addition
funnel. The reaction mixture was heated to 90.degree. C. and
stirred for 1.5 h. The progress of the reaction was monitored by
TLC (3:7 EtOAc: Heptane). The reaction mixture was cooled to
20.degree. C. and quenched slowly with 2 M HCl (2 L) and extracted
with EtOAc (4 L). The phases were separated and the organic phase
washed with brine (2.times.1 L), dried over MgSO.sub.4, filtered
and concentrated under reduced pressure at 40-45.degree. C. to
yield compound 9 (546 g, 120%) as a yellow solid. It was taken into
the next step without further purification. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz): .delta. 8.1 (s, 1H), 8.0-7.9 (m, 4H), 7.7
(dd, 1H), 7.5 (m, 2H), 7.3 (dd, 1H), 7.2 (m, 1H), 3.7 (s, 3H), 3.4
(s, 1H), 3 (d, 1H), 2.9-2.6 (m, 2H), 2.5 (d, 1H), 2.8-2.5 (m, 2H),
2.48-2.3 (m, 6H).
5.1.4. Preparation of
1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile
[0699] A 12-L, four-neck flask equipped with a temperature probe,
reflux condenser and overhead stirrer was charged with methyl
5-cyano-5-(naphthalen-2-yl)-2-oxocyclohexanecarboxylate (600 g, 1.9
mol), brine (1 L) and DMSO (6 L). The mixture was heated to
135.degree. C. and stirred for 12 h. The progress of the reaction
was monitored by TLC (2:3 EtOAc/Heptane). After 12 h, the reaction
mixture was cooled to room temperature, diluted with water (6 L)
and extracted twice with MTBE (5 L, 3 L). The combined organic
phases were washed with brine (4.times.3 L), dried over MgSO.sub.4
and filtered. The filtrate was concentrated under reduced pressure
at 40-45.degree. C. to give a residue which was triturated with
heptane/MTBE (1:1, 2 L). The resulting slurry was stirred for 2 h,
filtered and dried under high vacuum for 12 h to yield the title
compound (301 g, 62%) as an off-white solid. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz): .delta. 8.1 (s, 1H), 8.0-7.9 (m, 4H), 7.8
(dd, 1H), 7.6 (m, 2H), 7.3 (dd, 1H), 7.2 (m, 1H), 3.1 (s, 1H), 2.8
(m, 2H), 2.2-2.6 (m, 8H), 1.2(s, 2H).
5.1.5. Preparation of
cis-4-hydroxy-4-methyl-1-(naphthalen-2-yl)cyclohexanecarbonitrile
[0700] A dried 5-L, three-neck flask equipped with a temperature
probe, addition funnel, nitrogen line and overhead stirrer was
charged with 1 M solution of MeLi in ether (800 mL, 1.23 mol) using
canula under anhydrous atmosphere. (Note: MeLi is highly flammable;
strictly anhydrous conditions are required.) The solution was
cooled to -70.degree. C. and added to a solution of
1-(naphthalen-2-yl)-4-oxocyclohexanecarbonitrile (160 g, 0.642 mol)
in anhydrous THF (1,600 mL) slowly over a period of 40 min
maintaining the temperature below -50.degree. C. The mixture was
stirred at -70.degree. C. for 1 h. Progress of the reaction was
monitored by TLC (2:3 EtOAc/Heptane) and GC. The reaction was
cautiously quenched with saturated ammonium chloride solution (700
mL) when the startin material was <15% by GC. The typical ratio
of starting material: (a): (b) by GC was 1:7:2. The desired
cis-nitrile (a) was a major and more polar compound by TLC. The
reaction mixture was gradually warmed to room temperature and
diluted with EtOAc (500 mL), DI water (200 mL), and the mixture was
stirred for 5 min. The phases were separated and the aqueous phase
was extracted with EtOAc (500 mL). The combined organic phases were
washed with brine (1 L), dried over MgSO.sub.4, filtered and
concentrated under reduced pressure at 40-45.degree. C. to afford a
residue which was purified by chromatography (10-40% EtOAc in
heptane). The pure fractions of most polar compound by TLC were
pooled and concentrated to yield the cis-nitrile (a) [88.5 g, 52%,
99% (AUC) by GC] as an off-white solid. .sup.1H NMR (DMSO-d.sub.6,
300 MHz): .delta. 8.1 (s, 1H), 8.0-7.8 (m, 3H), 7.75 (dd, 1H), 7.58
(2H, dd), 4.65 (s, 1H), 2.3-2.0 (m, 4H), 1.8 (dt, 2H), 1.68 (dd,
2H), 1.2 (s, 3H).
5.1.6. Preparation of
cis-4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol
[0701] A dried 5-L, three-neck flask equipped with a temperature
probe, addition funnel, nitrogen line and overhead stirrer was
charged with 1.0 M solution of BH.sub.3.THF (1.29 L, 1.29 mol)
using canula under anhydrous atmosphere. (Note: BH.sub.3.THF is
highly flammable; strictly anhydrous conditions are required.) The
solution was cooled to 10.degree. C. and added to a solution of
nitrile (a) (114 g, 0.429 mol) in anhydrous THF (1.2 L) slowly over
period of 30 min maintaining the temperature below 25.degree. C.
The mixture was stirred at room temperature for 16 h. The reaction
was cautiously quenched with 6 M HCl (250 mL) until pH 1-2. (Note:
Evolution of hydrogen gas; proper vent was needed). The reaction
mixture was concentrated under reduced pressure to give a residue
which was diluted with MTBE (600 mL) and water (300 mL). The
precipitated boron salts were filtered and the phases of filtrate
were separated. The aqueous phase was adjusted to pH 9-10 using 6 M
NaOH solution and extracted with dichloromethane (3.times.400 mL).
The combined organic phases were washed with brine (300 mL), dried
over MgSO.sub.4, filtered and concentrated under reduced pressure
at 40-45.degree. C. to yield the primary amine (92.1 g, 80%) as a
foamy solid which was taken into next step without further
purification. .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 7.95-7.8
(m, 4H), 7.6 (d, 1H), 7.5-7.4 (m, 2H), 2.7 (s, 2H), 2.3 (dd, 2H),
1.9 (dt, 2H), 1.6 (dd, 2H), 1.4 (dt, 2H), 1.05 (s, 3H).
5.1.7. Preparation of 225
[0702] A 3-L, three-neck flask equipped with a temperature probe,
nitrogen line, condenser, heating mantle and overhead stirrer was
charged with
cis-4-(aminomethyl)-1-methyl-4-(naphthalen-2-yl)cyclohexanol (92 g,
0.341 mol), 37% aqueous formaldehyde (300 mL), formic acid (46 mL)
and water (300 mL). The mixture was heated to 85.degree. C. and
stirred overnight. (Note: Gas evolution (CO.sub.2) was observed at
60.degree. C.) The reaction was monitored by TLC (9:1 DCM/MeOH).
After 16 h, the reaction mixture was cooled to room temperature,
diluted with water (400 mL) and washed with heptane (2.times.300
mL). The aqueous phase was adjusted to pH 2.0 using 6 M HCl and
washed with dichloromethane (2.times.100 mL). The aqueous phase was
adjusted to pH 9-10 using 6 M NaOH and extracted with
dichloromethane (3.times.400 mL). The combined organic phases were
washed with brine (500 mL), dried over MgSO.sub.4, filtered and
concentrated under reduced pressure at 40-45.degree. C. to yield
225 (71.1 g, 70.3%) as a off-white solid, which was taken into salt
formation step without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): .delta. 7.92-7.8 (m, 4H), 7.65 (d, 1H),
7.5-7.4 (m, 2H), 2.45 (s, 2H), 2.3 (dd, 2H), 1.99 (s and dd merged,
8H), 1.6 (dd, 2H), 1.5 (dt, 2H), 1.1 (s, 3H).
5.1.8. Preparation of 225 Hydrochloride
[0703] A 2-L, three-neck flask equipped with a temperature probe,
heating mantle, nitrogen line and overhead stirrer was charged with
225 (83 g, 0.28 mol), ethanol (300 mL) and heated to 50.degree. C.
until a clear solution was obtained. The solution was cooled to
room temperature and added to a solution of 2 M HCl in ether (150
mL) slowly over period of 10 min. The precipitated solids were
stirred for 1 h at room temperature and filtered. The cake washed
with mixture of MTBE/EtOH (2:1, 100 mL), dried overnight under high
vacuum to provide 225 hydrochloride [60.4 g, 66%, 97.7% (AUC) by
HPLC]. .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 8.1 (m, 4H), 7.7
(d, 1H), 7.6 (dd, 2H), 3.5 (s, 2H), 2.55 (s, 6H), 2.45 (dd, 2H),
2.1 (dt, 2H), 1.75 (dd, 2H), 1.5 (dt, 2H), 1.1 (s, 3H). .sup.13C
NMR (CD.sub.3OD, 300 MHz): .delta. 138.1, 135.3, 134.3, 130.8,
129.7, 129.2, 128.9, 128.1, 126.2, 73.3, 69.5, 47.5, 42.8, 35.6,
31.3, 30.89.
[0704] 5.2. Scaled-up Synthesis of
N-methyl-1-(1-(naphthalen-2-yl)cyclohexyl)methanamine (93)
##STR342##
[0705] The title compound was synthesized according to Scheme 34,
below. ##STR343##
5.2.1. Synthesis of 2-Naphthylacetonitrile
[0706] To a stirred solution of sodium cyanide (10.5 g, 0.214 mol)
in H.sub.2O (20 mL) was added a solution of
2-(bromomethyl)naphthalene (40.0 g, 0.181 mol) in EtOH (170 mL).
The resulting mixture was heated at reflux for 3 h, then
spin-evaporated in vacuo. The residue was partitioned between
H.sub.2O (175 mL) and CH.sub.2Cl.sub.2 (200 mL). The aqueous layer
was further extracted with CH.sub.2Cl.sub.2 (3.times.200 mL). The
combined organic layers were dried over MgSO.sub.4 (5 g) and
spin-evaporated in vacuo to a solid. The solid was dissolved in
refluxing EtOH (100 mL). The clarified solution was stored at
3.degree. C. for 16 h. Solids were collected by filtration and
dried to constant weight in vacuo to give 24.8 g (81.9%) of product
suitable for further transformation. A total of 257.2 g of material
was prepared in this fashion.
5.2.2. Synthesis of 1-(2-Naphthyl)cyclohexanecarbonitrile
[0707] To a stirred suspension of NaH (12.0 g, 0.3 mol) (60 wt %
oil dispersion) in DMSO (480 mL) was added a solution of 1 (20.0 g,
0.120 mol) in DMSO (120 mL) dropwise, in a thin stream. The
resulting mixture was stirred at 25.degree. C. for 1 h. The mixture
was cooled to 15.degree. C. and 1,5-dibromopentane (41.2 g, 0.179
mol) was added dropwise, while maintaining the temperature at
.ltoreq.22.degree. C. The resulting mixture was stirred at
25.degree. C. for 18 h. The mixture was cooled to 15.degree. C. and
quenched with sat. aq. NH.sub.4Cl (100 mL). The resulting mixture
was partitioned between H.sub.2O (1.2 L) and t-butyl methyl ether
(MTBE) (300 mL). The aqueous layer was further extracted with MTBE
(200 mL). The combined organic layers were washed with brine (200
mL), dried over MgSO.sub.4 (5 g) and spin-evaporated in vacuo to an
oil. The oil was chromatographed on a silica gel column (1.0 kg)
packed in, and eluted with hexanes-EtOAc (4:1) (8.0 L). Appropriate
fractions as determined by TLC were combined and spin-evaporated in
vacuo to an oil, which solidified when pumped down, giving 27.4 g
(97.0%) of purified product. A total of 240.2 g of product suitable
for further transformation was prepared in this fashion.
5.2.3. Synthesis of 1-(2-Naphthyl)cyclohexanecarboxaldehyde)
[0708] To a cold (-78.degree. C.), stirred mixture of 2 (140.9 g,
0.5988 mol) in toluene (1.85 L) was added diisobutylaluminum
hydride (DIBAL-H) (1.0 M in toluene) (1.273 L) dropwise, at such a
rate as to maintain the temperature at .ltoreq.-65'. The resulting
mixture was stirred at -78.degree. C. for 3 h. EtOAc (1.5 L) was
added, followed by the dropwise addition of aq. 1 M HCl (1.5 L).
The resulting mixture was filtered to remove gelatinous solids. The
biphasic filtrate was separated. The filter cake washed with EtOAc
(3.times.500 mL). The combined organic layer washed with brine (500
mL), dried over MgSO.sub.4 (20 g) and spin-evaporated in vacuo to
give 127.0 g (89.0%) of product suitable for further
transformation. A total of 197.7 g of product was prepared in a
similar fashion.
5.2.4. Synthesis of
N-methyl(1-(naphthalen-2-yl)cyclohexyl)-methanamine
[0709] To a stirred solution of 3 (127.0 g, 0.5329 mol) in 2.0 M
methylamine (in THF) (1.8 L, 3.6 mol) was added 20 drops of acetic
acid. The resulting mixture was stirred at 25.degree. C. for 3 h.
Potassium borohydride (64.2 g, 1.19 mol) was added, and stirring at
25.degree. C. was continued for 18 h. The mixture was quenched by
the careful addition of aq. 1 M HCl to pH .about.2. The resulting
biphasic mixture was separated. The organic layer was extracted
with aq. 1 M HCl (2.times.500 mL). The combined aqueous layers were
basified with 6 M NaOH to pH .about.10, and extracted with EtOAc
(3.times.1.0 L). The combined organic layers were washed with brine
(750 mL), dried over MgSO.sub.4 (20 g) and spin-evaporated in vacuo
to give 88.4 g (65.5%) of crude free-base as an oil. This material
was combined with 61.3 g of similar material and chromatographed on
a silica gel pad (1.5 kg) packed in and eluted with
CH.sub.2Cl.sub.2-MeOH (6:1) (12.2 L). Appropriate fractions as
determined by TLC were combined and spin-evaporated in vacuo to
give 141.0 g (94.2% recovery) of an oil. The oil was dissolved in
CH.sub.2Cl.sub.2 (500 mL). A solution of 1.0 M HCl (in Et.sub.2O)
(600 mL) was slowly added with stirring. The resulting suspension
was filtered. The solids were suspended in warm (38.degree. C.)
CH.sub.2Cl.sub.2 (500 mL), then re-collected by filtration and
dried to constant weight in vacuo at 25.degree. C. to give 91.1 g
of 93 HCl salt, mp; 228-230.degree. C. (dec., uncorrected).
5.3. Scaled-up Asymmetric Synthesis of 48 E1
[0710] The title compound was prepared via asymmetric synthesis
according to the synthetic route outlined in Scheme 35, below. The
absolute configuration of the chiral center .alpha. to the amine
was not determined. Rather, the final material was correlated via
chiral HPLC to an authentic sample of 48 E1 and 48 E2 and the
intermediates were assigned by analogy. ##STR344##
5.3.1. Synthesis of
1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone
[0711] A 2 L round bottom flask was charged with a magnetic stir
bar and 100.8 g (396.6 mmol) of
1-(3,4-dichloro-phenyl)-cyclohexanecarbonitrile and was flushed
with N.sub.2. The solid was then dissolved with 960 mL of dry
toluene and the mixture was cooled to -78.degree. C. The chilled
homogeneous solution was then treated with 300 mL of a 1.6 M
solution of MeLi (in Et.sub.2O). The resulting pale yellow solution
was allowed to slowly warm to r.t. and left to stir for 12 h. The
mixture was then chilled to -20.degree. C. and quenched with 2 N
HCl. The biphasic mixture was extracted with MTBE (2.times.). The
combined organic layers were washed sequentially with a saturated
solution of K.sub.2HCO.sub.3 and brine before drying over
Na.sub.2SO.sub.4. The dried mixture was filtered and all volatiles
were removed under reduced pressure to give 107.5 g (396.6 mmol) of
the title compound as a pale yellow oil in >90% purity (as
determined by reverse phase LCMS). This material was used in
subsequent steps without further purification: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.41-7.39 (m, 2H), 7.14 (d, 1H, J=8.4 Hz),
2.31-2.28 (m, 2H), 1.91 (s, 3H), 1.79-1.74 (m, 2H), 1.69-1.54 (m,
3H), 1.51-1.41 (m, 2H), 1.35-1.26 (m, 1H).
5.3.2. Synthesis of
N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)ethylidene)-2-methylpropane-2-sulf-
inamide
[0712] A mixture of 10.53 g (38.8 mmol) of
1-(1-(3,4-dichlorophenyl)cyclohexyl)-ethanone (7.02 g, 57.9 mmol)
of (R)-TBSA, 16.1 mL of Ti(OEt).sub.4 and 80 mL of anhydrous
toluene was heated to 110.degree. C. under an atmosphere of N.sub.2
for 2 days. The mixture was cooled to rt and poured into a
vigorously stirred solution of brine and the resulting biphasic
mixture was extracted with EtOAc. The combined organic layers were
dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The resulting residue was chromatographed on SiO.sub.2
using Hexanes/EtOAc (9:1) to afford 9.5 g (65%) of the title
compound: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.43-7.39 (m,
2H), 7.17 (dd, 1H, J=8.7, 2.4 Hz), 2.25-2.15 (m, 2H), 2.06 (s, 3H),
1.95-1.88 (m, 2H), 1.61-1.50 (m, 6H), 1.31 (s, 9H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 187.1, 144.2, 133.1, 131.2, 130.8,
129.3, 126.7, 57.1, 53.9, 34.5, 34.3, 26.0, 22.92, 22.89, 22.7,
19.7.
5.3.3. Synthesis of
N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)ethyl)-2-methylpropane-2-sulfinami-
de
[0713] 2-Methyl-propane-2-sulfinic acid
{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-amide: 56 g (149.6
mmol) of 2-Methyl-propane-2-sulfinic acid
{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethylidene}-amide was
dissolved in 1 L of THF. The solution was chilled to -20.degree. C.
and treated with 49 g (190 mmol) of Cp.sub.2ZrHCl. The mixture was
allowed to warm to rt and left to stir overnight before cooling
back to -20.degree. C. and quenching with a saturated solution of
NH.sub.4Cl. The mixture was warmed to rt extracted with EtOAc
(3.times.). The combined organic layers were washed with H.sub.2O,
brine and then dried over Na.sub.2SO.sub.4. All volatiles were then
removed under reduced pressure. The resulting mixture was suspended
in MTBE and filtered. All volatiles were again removed under
reduced pressure to give 54 g (96%) of the title compound as a
white solid in >90% chemical purity and was used without further
purification. The diastereomeric ratio was determined to be >98%
(reverse phase HPLC: Symmetry C18 column; solvent gradient using
H.sub.2O:ACN with 0.05% TFA): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.45-7.41 (m, 2H), 7.20 (dd, 1H, J=8.6, 2.3 Hz), 3.34-3.25
(m, 1H), 3.01 (d, 1H, J=6.9 Hz), 2.50-2.44 (m, 1H), 2.23-2.17 (m,
1H), 1.65-1.48 (m, 5H), 1.34-1.17 (m, 3H), 1.13 (s, 9H), 0.98 (d,
3H, J=6.6 Hz); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 141.9,
132.8, 131.1, 130.6, 130.4, 128.5, 60.6, 56.1, 46.5, 33.7, 33.0,
26.6, 22.8, 22.3, 22.1, 16.8.
5.3.4. Synthesis of
1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanamine
[0714] 54 g (143.5 mmol) of 2-Methyl-propane-2-sulfinic acid
{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-amide was dissolved
in 300 mL of MeOH, cooled to 0.degree. C. and 300 mL of a 4N HCl
solution (in dioxane) was added. After 3 h, the solution was
concentrated under reduced pressure. The resulting slurry was
suspended in 1.2 L of Et.sub.2O and left to stir over night at rt
before collecting the solid by filtration. The resulting pale
yellow solid washed with Et.sub.2O and dried. The solid was
dissolved in CH.sub.2Cl.sub.2 and washed with a 20%
K.sub.2HCO.sub.3. The organic layer was isolated, washed with brine
and concentrated under reduced pressure to yield 38 g (97%) of 2 E1
in >99% ee (ChiralPak AD, using heptane/EtOH/DEA 95:5:0.1 as the
eluent).
5.3.5. Synthesis of
N-(1-(1-(3,4-dichlorophenyl)cyclohexyl)-ethyl)formamide
[0715] N-{1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethyl}-formamide:
50 g (184.4 mmol) of
1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethylamine was dissolved in
1 L of ethylformate and left to stir under an N.sub.2 atmosphere
for 24 h before removing all volatiles under reduced pressure. The
resulting solid was filtered through a plug of SiO.sub.2 (using
CH.sub.2Cl.sub.21MeOH (20:1) as the eluent) to afford 51.32 g (93%)
of the title compound after the removal of all volatiles. This
material was used in the subsequent step without further
purification.
5.3.6. Synthesis of
1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine
hydrochloride (48 E1)
[0716] ##STR345##
[0717] To the refluxing solution of
N-{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-formamide (5.2 g,
17.32 mmol) in anhydrous THF (75 mL) was added slowly
BH.sub.3.SMe.sub.2 (2N solution in THF, 26 mL, 51.96 mmol). The
solution was stirred at 70.degree. C. for 20 mins then a
distillation head was installed. The solution was refluxed for 2 h,
during which SMe.sub.2 was distilled, and the solution was cooled
to R.T. and concentrated using a rotary evaporator. The pale yellow
residue was cooled to 0.degree. C. and added slowly to methanol (20
mL) to destroy the excess borane. The resulting clear solution was
added to 6N aqueous HCl (50 mL) and heated to reflux for 40
minutes, then cooled to room temperature. The solid that formed was
filtered and washed with water (2.times.50 mL), followed by
slurrying in ethyl ether (200 mL) and filtration to give 48 E1 as a
white solid. (4.04 g, 72.5%). Note: Same reaction was run on a 50 g
scale with 70% yield.
5.4. Scaled-up Synthesis of 277
5.4.1. General Experimental Details
[0718] Reagents and solvents were used as received from commercial
suppliers. Proton and carbon nuclear magnetic resonance spectra
were obtained on a Bruker AC 300 spectrometer at 300 and 75 MHz,
respectively. High-pressure liquid chromatography was performed on
an Agilent 1100 series instrument. Gas chromatography-mass
spectroscopy was performed on a Hewlett-Packard G1800A GCD System.
##STR346##
5.4.2. Synthesis of dimethyl
4-cyano-4-(3,4-dichlorophenyl)-heptanedioate
[0719] To a 2-L, three-neck flask equipped with a temperature
probe, reflux condenser, addition funnel and overhead stirrer was
charged with 3,4-dichlorophenylacetonitrile (100 g, 0.54 mol),
methylacrylate (139.56 g, 1.62 mol) and tert-butanol (475 mL). To
the mixture was added very slowly (highly exothermic) 1.0 M
solution of tetrabutylammonium hydroxide (11 mL, 0.011 mol) in
methanol. After the addition was complete, the temperature rose
from 21.1.degree. C. to 68.4.degree. C. The resulting clear
solution was stirred at 70.degree. C. for 2 h and assayed by TLC
(3:7 EtOAc/Heptane; stained using Hanessian solution) and GC. The
reaction mixture was cooled to room temperature before being
concentrated under reduced pressure. The residue was partitioned
between 2 M HCl (500 mL), brine (200 mL) and MTBE (1.5 L). The
phases were separated and the aqueous phase was extracted with MTBE
(250 mL). The combined organic phases were washed with brine (500
mL), dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under reduced pressure at 40-45.degree. C. to yield
the title compound [192.1 g, 99%, 100% (AUC) by GC] as an off-white
solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz): .delta. 7.75 (m, 2H),
7.45 (dd, 1H), 3.5 (s, 6H), 2.4-2.2 (m, 6H), 2.15-1.98 (m, 2H).
5.4.3. Synthesis of methyl
5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate
[0720] To a 12-L, three-neck flask equipped with a temperature
probe, reflux condenser, addition funnel and overhead stirrer was
charged with potassium tert-butoxide (266 g, 2.3 mol) and toluene
(1 L). A solution of dimethyl
4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (402 g, crude, 386 g
theoretical, 1.07 mol) in toluene (3 L) was added through an
addition funnel. The reaction mixture was heated to 90.degree. C.
and stirred for 1 h. The progress of the reaction was monitored by
TLC (4:6 EtOAc/Heptane; stained using Hanessian solution). After 1
h, the reaction mixture was cooled to 15.degree. C. and quenched
slowly with 2 M HCl (2.3 L). The phases were separated and the
aqueous phase was extracted with MTBE (1 L). The combined organic
phases were washed with brine (2.times.1 L), dried over MgSO.sub.4,
filtered and concentrated under reduced pressure at 40-45.degree.
C. to yield the title compound (424 g, >100%) as a yellow solid.
The crude was taken into next step without further purification.
.sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.8 (d, 1H), 7.7 (d,
1H), 7.6 (dd, 1H), 3.7 (s, 3H), 2.9 (d, 1H), 2.8-2.5 (m, 3H),
2.4-2.3 (m, 3H).
5.4.4. Synthesis of
1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile
[0721] To 12-L, four-neck flask equipped with a temperature probe,
reflux condenser and overhead stirrer was charged with methyl
5-cyano-5-(3,4-dichlorophenyl)-2-oxocyclohexanecarboxylate (424 g,
crude, 350 g theoretical, 1.07 mol), brine (500 mL) and DMSO (3.4
L). The mixture was heated to 135.degree. C. and stirred for 12 h.
The progress of the reaction was monitored by TLC (4:6
EtOAc/Heptane; stained using Hanessian solution). The reaction
mixture was cooled to room temperature and combined with the crude
mixture from a previous 145 g batch reaction, diluted with water (6
L), extracted with MTBE (6 L), and then EtOAc/MTBE (3:5, 8 L). The
organics were combined and washed with brine (4.times.2.5 L), dried
over MgSO.sub.4, filtered and concentrated under reduced pressure
at 40-45.degree. C. to afford a residue which was triturated with
heptane/MTBE (1:1, 1.2 L). The resulting slurry was stirred for 0.5
h, filtered and dried under high vacuum for 2 h to afford the title
compound [313 g, 77% over 2 steps, 100% (AUC) by GC] as an
off-white solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz): .delta. 7.9
(d, 1H), 7.75 (dd, 1H), 7.6 (dd, 1H), 2.8-2.5 (m, 2H), 2.48-2.3 (m,
6H).
5.4.5. Synthesis of
1-(3,4-dichlorophenyl)-4-hydroxy-4-methylcyclohexanecarbonitrile
[0722] To a dry 5-L, three-neck flask equipped with a temperature
probe, addition funnel, nitrogen line and overhead stirrer was
charged with 1.0 M solution of MeLi in ether (680 mL, 1.04 mol)
using canula under anhydrous atmosphere (Note: MeLi is highly
flammable; strictly anhydrous conditions are required). The
solution was cooled to -70.degree. C. and added a solution of
1-(3,4-dichlorophenyl)-4-oxocyclohexanecarbonitrile (198 g, 0.738
mol) in anhydrous THF (1,600 mL) slowly over a period of 45 min
while maintaining the temperature below -50.degree. C. The mixture
was stirred at -70.degree. C. for 1 h. The progress of the reaction
was monitored by TLC (2:3 EtOAc/heptane; stained using Hanessian
solution) and GC. The reaction was cautiously quenched with
saturated ammonium chloride solution (700 mL) when starting
material was <15% by GC. The typical ratio of starting material:
(a): (b) by GC was 3.1:70.5:26.4. The desired cis-nitrile (a) was a
major and more polar compound by TLC. The reaction mixture was
diluted with EtOAc (600 mL), DI water (300 mL), and stirred for 5
min. The phases were separated and the aqueous phase was extracted
with EtOAc (600 mL). The combined organic phases were washed with
brine (1 L), dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under reduced pressure at 40-45.degree. C. to yield a
residue which was purified by chromatography (10-40% EtOAc in
heptane). The pure fractions of most polar compounds by TLC were
pooled and concentrated to yield the cis nitrile (a) [114 g, 54.5%,
100% (AUC) by GC] as an off-white solid. .sup.1H NMR (DMSO-d.sub.6,
300 MHz): .delta. 7.85 (s, 1H), 7.7 (d, 1H), 7.55 (dd, 1H), 4.6 (s,
1H), 2.15-1.85 (m, 4H), 1.8 (dt, 2H), 1.6 (dd, 2H), 1.15 (s,
3H).
5.4.6. Synthesis of
cis-4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol
[0723] To a dry 5-L, three-neck flask equipped with a temperature
probe, addition funnel, nitrogen line and overhead stirrer was
charged with 1.0 M solution of BH.sub.3.THF (980 mL, 0.984 mol)
using canula under anhydrous atmosphere (Note: BH.sub.3.THF is
highly flammable; strictly anhydrous conditions are required). The
solution was cooled to 10-15.degree. C. and added to a solution of
the cis-nitrile (a) (114 g, 0.401 mol) in anhydrous THF (1,400 mL)
slowly over a period of 30 min while maintaining the temperature
below 25.degree. C. The mixture was stirred at room temperature
overnight. The reaction was cautiously quenched with 6 M HCl (300
mL) until pH 2-2.0. The reaction mixture was concentrated under
reduced pressure and the residue was taken into a 5-L flask
equipped with overhead stirrer and addition funnel. DI water (500
mL) was added into the flask and adjusted pH to 9-10 using 6 M NaOH
solution. The aqueous phase was extracted with dichloromethane
(3.times.500 mL). The combined organic phases were taken into
another 5-L flask and charged slowly with 6 M HCl (400 ml). The
precipitated HCl salt was filtered and the filtrate was taken into
a separating funnel. The aqueous phase was taken into a 5-L flask
and charged with water (2 L) and the HCl salt. The pH of the
mixture was adjusted to 9-10 using 6 M NaOH solution and extracted
with dichloromethane (2 L). The combined organic phases were washed
with brine (1 L), dried over MgSO.sub.4 and filtered. The filtrate
was concentrated under reduced pressure at 40.times.5.degree. C. to
yield the title compound (104 g, 90%) as a foamy solid which was
taken into next step without further purification. .sup.1H NMR
(CD.sub.3OD, 300 MHz): .delta. 7.45 (d and s merged, 2H), 7.25 (dd,
1H), 2.5 (s, 2H), 1.95 (dt, 2H), 1.7 (ddd, 2H), 1.45 (dt, 2H), 1.15
(ddd, 2H), 0.9 (s, 3H).
5.4.7. Synthesis of
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol
(277)
[0724] To a 3-L, three-neck flask equipped with a temperature
probe, nitrogen line and overhead stirrer was charged with
cis-4-(aminomethyl)-4-(3,4-dichlorophenyl)-1-methylcyclohexanol (99
g, 0.343 mol), 37% aqueous formaldehyde (80 mL), formic acid (80
mL) and cooled to 5-10.degree. C. Sodium cyanoborohydride (72 g,
1.14 mol) was added in portions and stirred for 1 h at room
temperature. The progress of the reaction was monitored by TLC
(9:1:0.1 DCM/MeOH/TEA). After 2 h, the reaction was not complete.
Additional 37% aqueous formaldehyde (3.2 mL), formic acid (3.2 mL),
and sodium cyanoborohydride (2.88 g, 4.58 mmol) was added. The
reaction was quenched with 6 M NaOH solution (100 mL) and
concentrated under reduced pressure to give a residue which was
diluted with dichloromethane (2 L), 6 M NaOH solution (500 mL), and
brine (500 mL). The phases were separated and the aqueous phase was
extracted with dichloromethane (1 L). The combined organic phases
were dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under reduced pressure at 40-45.degree. C. to yield
277 (104 g, 96%) as an off-white solid which was taken into salt
formation step without further purification. .sup.1H NMR
(CDCl.sub.3, 300 MHz): .delta. 7.45 (s, 1H), 7.4 (d, 1H), 7.2 (dd,
1H), 2.3 (s, 2H), 2.05 (dd, 1H), 2.0 (s, 6H), 1.9 (ddd, 2H), 1.55
(dd, 2H), 1.3 (m, 3H), 1.1 (s, 3H).
5.4.8. Preparation of
4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol
277 hydrochloride
[0725] To a 3-L, three-neck flask equipped with a temperature
probe, nitrogen line and overhead stirrer was charged with free
base of 277 (crude from previous reaction, 0.328 mol) and ethanol
(500 mL). The mixture was heated to 50.degree. C. until a clear
solution was obtained. The solution was cooled to room temperature
and added to a solution of 2 M HCl in ether (200 mL) slowly. After
5 min, precipitation of HCl salt was observed. The slurry was
stirred for 1 h at room temperature and filtered. The cake washed
with a mixture of MTBE/EtOH (2:1, 200 mL) and dried over night
under high vacuum to yield 277 hydrochloride [80.8 g, 70%, 98.0%
(AUC) by HPLC]. .sup.1H NMR (D.sub.2O, 300 MHz): .delta. 7.65 (d,
1H), 7.55 (d, 1H), 7.5 (dd, 1H), 3.5 (s, 2H), 2.5 (s, 6H), 2.15
(dd, 2H), 1.85 (dt, 2H), 1.5 (dd, 2H), 1.3 (dt, 2H), 0.05 (s,
3H).
Example 6
In Vitro Analyses (Monoamine Uptake Assays)
[0726] The compounds of the invention were tested for their
inhibition of functional uptake of serotonin (5-HT), norepinephrine
(NE), and dopamine (DA), in synaptosomes prepared from rat whole
brain, hypothalamus, or corpus striatum, respectively, and/or using
recombinant human transporters, as described herein, below.
Compounds were initially tested at 10 .mu.M in duplicate. Compounds
showing .gtoreq.50% inhibition of uptake were further tested at 10
different concentrations in duplicate in order to obtain full
inhibition curves. IC.sub.50 values (concentration inhibiting
control activity by 50%) were then determined by nonlinear
regression analysis of the inhibition curves. Results are
summarized in Table 8, below.
6.1. Serotonin Functional Uptake Assay for Rat Reuptake
Transporter
[0727] Quantification of 5-HT uptake was performed using
synaptosomes isolated in a 0.32M sucrose buffer from a male Wistar
rat cortex. The uptake of radiolabelled 5-HT by synaptosomes (100
.mu.g of proteins/point) was allowed by incubating them in a well
for 15 min at 37.degree. C. in presence of test compounds and
[.sup.3H]5-hydroxytryptamine (serotonin; 0.1 .mu.Ci/point).
[0728] Synaptosomes and [.sup.3H]serotonin were prepared in a Krebs
buffer pH 7.4 containing 25 mM NaHCO.sub.3, 11 mM glucose and 50
.mu.M ascorbic acid. This incubation buffer was oxygenated during 5
minutes before incubation. Basal control was incubated for 15
minutes at 4.degree. C. in order to avoid any uptake. Following
this incubation the uptake was stopped by filtration through a
unifilter 96-wells GFB Packard plate washed with Krebs buffer
containing 25 mM NaHCO.sub.3 in order to eliminate the free
[.sup.3H]serotonin. The radioactivity associated to the
synaptosomes retained on the unifilter corresponding to the uptake
was then measured with a microplate scintillation counter
(Topcount, Packard) using a scintillation fluid. Nonspecific
binding was measured in the presence of an excess of cold,
unlabeled ligand. Specific binding was obtained by subtracting
nonspecific binding from total binding.
[0729] The reference compound was imipramine tested at 10
concentrations ranging from 10.sup.-11 M to 10.sup.-5 M in order to
obtain an IC.sub.50 value. See, Perovics and Muller, Arzeim.
Forsch./Drug Res., 45:1145-1148 (1995).
6.2. Serotonin Functional Uptake Assay for Human Reuptake
Transporter
[0730] Inhibition of human serotonin reuptake transporter was
assayed using the recombinant human serotonin transporter expressed
in HEK-293 cells using a published method (Gu H et al., J. Biol.
Chem. 1994, 269 (10): 7124-7130). HEK-293 cells expressing human
serotonin transporter were plated before the assay. Test compound
and/or vehicle was preincubated with cells in modified HEPES buffer
pH 7.1 or pH 7.4 for 20 minutes at 18 to 25.degree. C. and 65 nM
[.sup.3H]serotonin was then added for an additional timed
incubation period (ten to thirty minutes). Cells with internalized
[.sup.3H]serotonin were washed and the amount of tritium taken into
cells is counted using a liquid scintillation counter to determine
[.sup.3H]serotonin uptake. Non-specific binding of tritium was
measured in a control reaction containing 10 .mu.M fluoxetine, and
was subtracted from the counts for assays to correct for
non-specific binding of tritium. Reduction of [.sup.3H]serotonin
uptake by 50 percent or more (.gtoreq.50%) relative to an
uninhibited control reaction indicates significant inhibitory
activity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001
.mu.M. The reference compound for the assay was fluoxetine, for
which the IC.sub.50 value of 7.1 nM was obtained in a typical
experiment.
6.3. Dopamine Functional Uptake Assay for Rat Reuptake
Transporter
[0731] Quantification of dopamine uptake was performed using
synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar
rat striatum. The uptake of radiolabelled dopamine by synaptosomes
(20 .mu.g of proteins/point) was allowed by incubating them for 15
minutes at 37.degree. C. in the presence of test compounds and
[.sup.3H]-dopamine (0.1 .mu.Ci/point). The experiment was performed
in a deep well.
[0732] Synaptosomes and [.sup.3H]-dopamine were prepared in a Krebs
buffer pH 7.4 containing 25 mM NaHCO.sub.3, 11 mM glucose and 50
.mu.M ascorbic acid. This incubation buffer was oxygenated for 5
minutes before incubation. Basal control was incubated for 15
minutes at 4.degree. C. in order to avoid any uptake. Following
this incubation, the uptake was stopped by filtration through a
unifilter 96-wells GFB Packard plate washed with Krebs buffer
containing 25 mM NaHCO.sub.3 in order to eliminate free
[.sup.3H]-dopamine. The radioactivity associated to the
synaptosomes retained onto the unifilter corresponding to the
uptake was then measured with a microplate scintillation counter
(Topcount, Packard) using a scintillation fluid.
[0733] The reference compound was GRB12909 tested at 8
concentrations ranging from 10.sup.-11 M to 10.sup.-6 M in order to
obtain an IC.sub.50 value. See, Jankowsky et al., J. Neurochem.
1986, 46:1272-1276).
6.4. Dopamine Functional Uptake Assay for Human Reuptake
Transporter
[0734] Inhibition of human dopamine reuptake transporter was
assayed using the recombinant human dopamine transporter expressed
in either CHO-K1 or HEK293 cells using a published method
(Pristupa, Z. B. et al., Mol. Pharmacol. 45: 125-135, 1994). Either
CHO-K1 or HEK293 cells expressing human recombinant dopamine
transporter were plated before the assay. Test compound and/or
vehicle was preincubated with cells in modified HEPES buffer pH 7.1
or pH 7.4 for 20 minutes at 18 to 25.degree. C. and 50 nM
[.sup.3H]dopamine was then added for an additional timed incubation
period (10 to 30 minutes). After washing the cells to remove
[.sup.3H]dopamine not internalized, the cells were lysed, and the
amount of tritium in the lysate was measured using a liquid
scintillation counter to determine [.sup.3H]dopamine uptake.
Non-specific binding of tritium was measured in a control reaction
containing 10 .mu.M nomifensine, and was subtracted from the counts
for assays to correct for non-specific binding of tritium.
Reduction of [.sup.3H]dopamine uptake by 50 percent or more
(.gtoreq.50%) relative to an uninhibited control reaction indicates
significant inhibitory activity. Compounds were screened at 10, 1,
0.1, 0.01 and 0.001 .mu.M. The reference compound for the assay was
nomifensine, for which the IC.sub.50 value of 11 nM was obtained in
a typical experiment.
6.5. Norepinephrine Functional Uptake Assay For Rat Reuptake
Transporter
[0735] Quantification of norepinephrine uptake was performed using
synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar
rat hypothalamus. The uptake of radiolabelled norepinephrine by
synaptosomes (100 .mu.g of proteins/point) was allowed by
incubating them for 20 minutes at 37.degree. C. in presence of test
compounds and [.sup.3H]-norepinephrine (0.1 .mu.Ci/point). The
experiment was performed in a deep well.
[0736] Synaptosomes and [.sup.3H]-norepinephrine were prepared in a
Krebs buffer pH 7.4 containing 25 mM NaHCO.sub.3, 11 mM glucose and
50 .mu.M ascorbic acid. This incubation buffer was oxygenated for 5
minutes before incubation. Basal control was incubated for 20
minutes at 4.degree. C. in order to avoid any uptake. Following
this incubation, the uptake was stopped by filtration through a
unifilter 96-wells GFB Packard plate washed with Krebs buffer
containing 25 mM NaHCO.sub.3 in order to eliminate the free
[.sup.3H]-norepinephrine. The radioactivity associated to the
synaptosomes retained onto the unifilter corresponding to the
uptake was then measured with a microplate scintillation counter
(Topcount, Packard) using a scintillation fluid.
[0737] The reference compound was protriptyline tested at 13
concentrations ranging from 10.sup.-11 M to 10.sup.-5 M in order to
obtain an IC.sub.50 value. See, Perovics and Muller, Arzeim.
Forsch./Drug Res., 45:1145-1148 (1995).
6.6. Norepinephrine Functional Uptake Assay for Human Reuptake
Transporter
[0738] Inhibition of human norepinephrine reuptake transporter was
assayed using the recombinant human norepinephrine transporter
expressed in either HEK293 or MDCK cells using a published method
(Galli A et al., J. Exp. Biol. 198: 2197-2212, 1995). The cells
were plated before the assay. Test compound and/or vehicle was
preincubated with cells in modified HEPES buffer pH 7.1 or pH 7.4
for 20 minutes at 18 to 25.degree. C. Following the preincubation,
25 nM [.sup.3H]norepinephrine was added for an additional timed
incubation period (10 to 20 minutes). After the cells were washed
to remove [.sup.3H]norepinephrine not internalized, the cells were
lysed, and the amount of tritium in the cell lysate was measured
using a liquid scintillation counter to determine
[.sup.3H]norepinephrine uptake. Non-specific binding of tritium was
measured in a control reaction containing 10 .mu.M imipramine (or
10 .mu.M nisoxetine), and was subtracted from the counts for assays
to correct for non-specific binding of tritium. Reduction of
[.sup.3H]norepinephrine uptake by 50 percent or more (.gtoreq.50%)
relative to an uninhibited control reaction indicates significant
inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01
and 0.001 .mu.M. The reference compounds for the assay were
desipramine and nisoxetine, for which IC.sub.50 values of 1.9 nM
and 5.3 nM respectively were obtained in typical experiments.
6.7. Results for Monoamine Uptake Assays
[0739] The results of the monoamine uptake assays are provided in
Table 8, below. TABLE-US-00008 TABLE 8 Summary of Results - In
vitro Monoamine Uptake Assays Rat Human IC.sub.50 Cmpd. IC.sub.50
(nM) (nM) No. hSERT hNET hDAT rSERT rNET rDAT 73 2240 6 1 710 15 6
74 19 4 1 30 6 10 27 201 273 150 500 150 95 75 169 85 21 110 20 58
76 156 9 1 77 158 19 4 170 E1 1030 189 1190 170 E2 673 26 427 78
651 36 2 172 E1 51 4 66 172 E2 89 127 762 174 246 2495 2781 175 55
15 125 176 533 612 775 177 3220 84 322 28 4560 1840 707 29 5240
1480 195 30 4520 >10,000 5870 31 >10,000 >10,000
>10,000 80 9170 >10,000 >10,000 79 768 270 884 101 96 529
268 102 195 586 420 100 1500 6630 3410 103 3540 5090 7740 81 2720
2190 3640 88 829 171 93 89 278 63 9 32 949 902 424 87 1470 334 139
82 55 9990 42 83 57 61 57 33 305 232 83 98 >10,000 782 419 105
1530 28 625 107 224 146 546 104 9490 516 5160 106 8330 816 1770 34
>10,000 6690 5320 35 >10,000 2970 4710 36 6550 1630
>10,000 37 >10,000 5760 >10,000 84 1870 326 395 85 102 51
26 96 688 137 170 97 31 10 11 95 480 160 324 91 >10,000 8550
1830 90 839 1850 3360 92 33 206 125 93 34 295 90 94 3 7 3 99 145 26
17 86 249 346 384 133 E1 969 217 355 133 E2 342 374 886 134 E1 260
179 598 134 E2 1260 132 149 173 1550 277 412 1 1290 175 103 41 898
22 82 165 E1 1580 183 66 165 E2 661 620 978 166 E1 176 310 245 166
E2 90 32 99 173 E1 1660 1350 388 173 E2 406 174 280 2 543 316 69
169 E2 332 22 87 169 E1 1100 242 778 152 E1 405 32 18 152 E2 77 157
585 153 E1 17 19 85 153 E2 64 135 25 42 935 280 761 cis 121
>10,000 2060 3390 E1 cis 121 3160 6580 >10,000 E2 trans 247
303 687 121 E1 trans 8150 392 665 121 E2 2 E1 406 167 180 2 E2 821
1040 770 108 65 36 85 43 15 7 64 3 331 888 <1 109 9674 114 12 4
637 2783 75 110 7932 790 2 111 8571 232 1.7 112 299 39 <1 298
>10,000 6730 76 184 E1 >10,000 2977 213 184 E2 >10,000
3385 789 187 E1 1896 1095 209 187 E2 376 928 17 116 2060 633 3 117
7903 405 33 115 >10,000 41 <1 114 >10,000 1813 16 113 2574
2217 285 185 E1 >10,000 >10,000 421 185 E2 >10,000
>10,000 121 190 E1 2962 442 24 190 E2 44 17 3 120 340 45 191 E1
2532 747 42 191 E2 426 74 2 45 5936 964 9 46 >10,000 >10,000
349 188 E1 4479 10000 426 188 E2 >10,000 5287 66 44 E1 12 10 36
14 2.2 150 cis 167 >10,000 >10,000 2217 trans 4912 1092 145
167 168 1465 732 108 253 906 949 37 254 294 19 <1 190 2.4 100 71
1298 1342 123 72 136 63 1.7 299 3873 2377 720 44 E2 239 570 219 210
44 1800 5 7115 5004 1522 287 1037 335 192 255 1421 2472 170 256 69
39 157 280 130 990 288 84 18 22 67 11 370 47 364 2894 5171 48 E2
149 441 297 230 74 550 48 E1 81 57 30 54 5.1 170 257 2075 6546 1999
259 5892 1179 665 6 >10,000 >10,000 1000 7 255 3987 527 260
2146 1772 306 261 30 62 7 262 >10,000 >10,000 4283 263 674
187 498 8 855 8733 996 9 >10,000 9987 >10,000 49 286 9217 739
10 1905 7446 2928 264 1052 194 17 11 7549 2811 532 265 109 3464
1454 266 168 2811 859 12 1517 5761 6043 1100 480 1900 57 1079 3177
1777 2200 740 2300 51 2948 >10,000 >10,000 50 1069 950 499
cis 124 6857 5934 5313 trans 2489 842 1475 124 E1 trans 227 288 187
124 E2 14 2953 257 46 267 1290 3256 147 268 704 241 27 269 787 36
<1 300 >10,000 7625 1733 301 >10,000 >10,000 8785 cis
125 684 399 871 trans 6 158 1408 125 E1 trans 32 783 1113 125 E2 52
44 1063 176 13 377 324 122 194 330 1832 2369 196 1445 732 911 197
227 67 450 192 >10,000 >10,000 1957 200 2051 3742 1100 201
261 518 88 204 2253 3457 296 205 E1 4208 999 800 205 E2 1714 326 12
cis 132i 708 5555 153 trans 28 353 140 132i 15 1398 >10,000
>10,000 206 E1 72 121 59 206 E2 306 7 <1 147 E1 94 5764 1391
18 370 1200 147 E2 2500 9706 1344 1700 1200 1500 148 E1 97 538 464
36 81 250 148 E2 229 1136 289 330 4900 680 53 <1 20 1 6.5 2.9
6.1 54 2387 857 85 55 <1 61 72 163 E1 43 2793 413 260 4200 1100
163 E2 139 2650 309 1900 3200 1500 164 E1 2 152 36 9.6 500 230 164
E2 13 194 40 45 720 140 195 E2 45 >10,000 5320 270 469 515 376
271 79 42 197 289 469 1467 282 290 992 >10,000 1388 17 657 119
29 16 1764 4034 4085 13 E1 187 528 66 18 3892 794 184 19 107 3177
2316 13 E2 60 779 108 56 E1 <1 21 28 2.9 2.3 24 56 E2 63 468 145
120 79 100 272 >10,000 9572 2601 273 830 474 528 274 809 321 251
275 1187 943 518 276 210 55 71 360 17 190 277 34 13 41 42 2.7 43 58
E1 6 23 63 9.5 3.6 22 58 E2 118 341 176 100 33 160 140 E1 2688
>10,000 8819 140 E2 >10,000 >10,000 5667 139 E1 >10,000
>10,000 >10,000 139 E2 >10,000 >10,000 >10,000 20 24
5847 275 20 E1 40 6439 369 20 E2 60 >10,000 437 21 2095 7192 43
207 142 3602 1025 209 1158 >10,000 4758 222 609 5347 2090 225 7
23 167 223 73 145 874 22 296 3727 141 155 E1 2986 >10,000
>10,000 155 E2 6281 >10,000 >10,000 136 E1 >10,000 6497
2871 136 E2 >10,000 >10,000 3375 138 E1 >10,000 1341 918
138 E2 6996 3946 2539 21 E1 9661 7606 234 21 E2 1235 6041 64 193 E2
957 >10,000 3163
193 E1 416 897 266 198 2324 >10,000 1940 202 868 1625 58 199
2188 2585 462 203 56 166 1.4 156 E1 76 >10,000 1310 156 E2 653
>10,000 3996 226 44 737 278 23 62 7678 682 22 E1 63 2624 136 22
E2 101 5566 112 208 1987 >10,000 7667 227 742 4103 5778 228 96
387 1565 229 11 33 40 224 69 665 993 154 E1 2170 3679 795 154 E2
439 981 888 16 E1 1755 1291 1286 16 E2 7296 1910 9248 211 55 1274
195 230 30 104 11 231 E1 1276 136 460 231 E2 63 19 83 291 185 784
72 212 91 948 75 213 283 2031 337 17 E1 355 66 71 17 E2 709 93 5 60
E1 184 86 748 60 E2 4632 3304 6740 61 E1 5947 1504 959 59 E2 4396
2197 3875 59 E1 1589 486 1754 61 E2 9442 1555 116 293 42 33 4 232
744 904 25 233 37 64 3 62 E1 3176 414 39 62 E2 4241 121 4 19 E1
1514 1901 696 19 E2 398 4027 735 234 E1 3382 820 346 234 E2 18 33
21 63 E2 2 1110 1818 64 E1 58 2797 >10,000 64 E2 32 2647 3640 63
E1 194 5946 6537 235 9 256 92 292 360 903 89 236 38 718 444 38 472
>10,000 9647 65 1618 3644 1936 66 221 587 355 278 5143
>10,000 3193 279 383 2477 1449 280 7 371 242 25 78 1029 90 26
740 2102 238 214 >10,000 10000 >10,000 237 7296 >10000
9129 238 1178 3533 5715 215 4192 >10000 6243 239 8661 7372 9451
240 1812 3694 9029 39 295 6644 2237 67 230 3149 1761 68 19 603 343
294 >10,000 >10,000 >10,000 281 256 788 384 282 296 289
186 283 20 41 37 216 >10,000 >10,000 >10,000 241
>10,000 >10,000 >10,000 242 7656 >10,000 >10,000 295
>10,000 >10,000 >10,000 217 47 1838 1975 243 26 293 851
244 14 59 334 24 364 6380 1370 141 E1 3687 2229 1252 141 E2 2771
10000 3665 142 E1 1898 >10,000 5247 142 E2 2315 >10,000 7852
218 480 >10,000 5587 245 538 10000 2274 246 43 984 282 40 753
7668 2324 69 930 2290 605 70 29 261 214 157 E1 1303 3725 575 157 E2
290 3446 849 158 E1 8439 7497 945 158 E2 2991 >10,000 5023 145
E1 75 10000 4726 145 E2 220 >10,000 6520 146 E1 4545 >10,000
>10,000 146 E2 2284 >10,000 >10,000 219 269 >10,000
>10,000 247 707 9690 10000 248 159 5689 7252 220 6150 10000
>10,000 249 405 >10,000 >10,000 250 47 1669 10000 284 7896
6662 2462 285 1139 4038 1897 286 46 182 198 162 E2 247 >10,000
>10,000 162 E1 495 >10,000 >10,000 161 E2 1.1 4395 4609
161 E1 9 8626 9950 221 61 5825 182 251 199 2131 107 252 11 108 6
252 12 134 5 143 E1 8611 >10,000 8787 143 E2 7172 >10,000
8630 144 E1 5626 >10,000 10000 144 E2 8748 >10,000 9858 159
E1 1255 >10,000 3801 159 E2 42 10000 2310 160 E1 7193 >10,000
9725 160 E2 5091 >10,000 >10,000 296 73 87 27 297 40 57
13
[0740] In Table 8, compound numbers correspond to those used in the
Examples above. In addition, the following abbreviations have been
used in Table I:SERT (serotonin transporter), NET (norepinephrine
transporter) and DAT (dopamine transporter).
[0741] The above results indicate that compounds of the invention
exhibit potent inhibition of neuronal uptake of NE, DA, and/or
5-HT, and compare favorably with potencies seen for various
existing therapeutic agents. For example, reported potencies
(IC.sub.50 or K.sub.i values) of approved and launched drugs
include: fluoxetine (PROZAC.RTM.), 7 nM for inhibition of human
5-HT reuptake transporter; methylphenidate (RITALIN.RTM.), 193 nM
and 38 nM for inhibition of human dopamine and norepinephrine
reuptake transporters, respectively (Eshleman et al., J. Pharmacol.
Exp. Ther. 1999, 289: 877-885); amitriptyline (ELAVIL.RTM.), 63 nM
and 67 nM for inhibition of the human norepinephrine and serotonin
reuptake transporters, respectively and venlafaxine (EFFEXOR.RTM.,
a so-called serotonin norepinephrine reuptake inhibitor (SNRI) 145
and 1420 nM, for inhibition of the human serotonin, and
norepinephrine reuptake transporters respectively (Vaishnavi et
al., Biol. Psychiatry. 2004, 55: 320-322). The multiple inhibition
of the neuronal uptake of NE, DA and/or 5-HT displayed by the
compounds of the invention provides the clinician with the ability
to more effectively treat CNS disorders, including without
limitation affective disorders, cerebral function disorders,
anxiety disorders, neuropathic pain, and migraine or migraine
headache, by elevating various monoamine levels in the brain
simultaneously and over the same dose-range without the need to
titrate separate drugs.
Example 7
Ex Vivo Binding Assays
[0742] Receptor occupancy of central noradrenaline (NA), 5-HT and
dopamine (DA) transporter sites following peripheral administration
of compounds was determined using [.sup.3H] nisoxetine, [.sup.3H]
citalopram and [.sup.3H] WIN 35428 binding, respectively. Liquid
scintillation counting was used to quantify the radioactivity.
7.1. Methods
[0743] C57BL/6 mice (25-30 g) were dosed orally with either vehicle
or compound at 4 dose levels. Mice were sacrificed 60 minutes after
treatment. Whole brains were removed and cortex and striata
dissected out before being frozen on dry ice. The brain tissue was
stored at -20.degree. C. until the day of the assay. The cortex
from each hemisphere was frozen separately. One was used to
determine occupancy of NA transporter sites and the other occupancy
of 5-HT transporter sites. Striatum was used to determine occupancy
of DA transporter sites.
7.2. Membrane Preparation
[0744] Frontal cortex from each hemisphere or striata was
homogenised individually in ice-cold assay buffer using a tight
fitting glass/Teflon homogeniser and used immediately in the
binding assay.
[.sup.3H] Citalopram Binding to 5-HT Transporter (SERT) Sites in
Mouse Brain
[0745] Cortical membranes (400 .mu.l; equivalent to 1.25 mg wet
weight of tissue/tube) were incubated with 50 .mu.l of [.sup.3H]
citalopram at a single concentration of 1.3 nM and either 50 .mu.l
of buffer (total binding) or 50 .mu.l of paroxetine (0.5 .mu.M;
non-specific binding) for 1 h at 27.degree. C. For each animal,
three tubes were used for the determination of total binding and
three tubes were used for the determination of non-specific
binding.
[.sup.3H] Nisoxetine Binding to Norepinephrine Transporter (NET)
Sites in Mouse Brain
[0746] Cortical membranes (400 .mu.l; equivalent to 6.0 mg wet
weight of tissue/tube) were incubated with 50 .mu.l of [.sup.3H]
nisoxetine at a single concentration of 0.6 nM and either 50 .mu.l
of buffer (total binding) or 50 .mu.l of mazindol (1 .mu.M;
non-specific binding) for 4 h at 4.degree. C. For each animal,
three tubes were used for the determination of total binding and
three tubes were used for the determination of non-specific
binding.
[.sup.3H] WIN 35428 Binding to DA Transporter (DAT) Sites in Mouse
Brain
[0747] Striatal membranes (200 .mu.l; equivalent to 2 mg wet weight
of tissue/tube) were incubated with 25 .mu.l of [.sup.3H] WIN 35428
at a single concentration of 24 nM and either 25 .mu.l of buffer
(total binding) or 25 .mu.l of GBR12935 (1 .mu.M; non-specific
binding) for 2 h at 4.degree. C. For each animal, two tubes were
used for the determination of total binding and two tubes for the
determination of non-specific binding.
[0748] Membrane bound radioactivity was recovered by filtration
under vacuum through Skatron 11731 filters, presoaked in 0.5% PEI,
using a Skatron cell harvester. Filters were rapidly washed with
ice-cold phosphate buffer and radioactivity (dpm) was determined by
liquid scintillation counting (1 ml Packard MV Gold
scintillator).
7.3. Data Analysis
[0749] A value for specific binding (dpm) was generated by the
subtraction of mean non-specific binding (dpm) from mean total
binding (dpm) for each animal. Data are presented as mean specific
binding (dpm) and as a percentage of the vehicle-treated control
taken as 100%.
7.4. Results Summary
[0750] Ex vivo SERT, NET and DAT binding/receptor occupancy data
were generated for selected compounds of the invention. Results are
summarized in Table 9, below. Results showed that the compounds
exhibited varying SERT, NET and DAT inhibition ratios.
TABLE-US-00009 TABLE 9 Ex Vivo Binding Profile in Mice. Treatment
Mean Specific Binding (dpm) .+-. S.E.M. Dose (Values in Brackets
Denote % Transporter Occupancy) (mg/kg, PO) NET SERT DAT 225 0 1570
.+-. 31 4639 .+-. 294 20453 .+-. 2500 1 1170 .+-. 68 (25)* 3842
.+-. 152 (17)* 19787 .+-. 3338 (3) 3 813 .+-. 64 (48)* 2118 .+-.
139 (54)* 21666 .+-. 3698 (-6) 10 393 .+-. 21 (75)* 904 .+-. 35
(81)* 18872 .+-. 2775 (8) 30 230 .+-. 33 (85)* 414 .+-. 37 (91)*
14618 .+-. 1209 (29) 48 E1 0 2405 .+-. 150 4345 .+-. 123 20378 .+-.
1315 1 2111 .+-. 119 (12) 4398 .+-. 39 (-1) 20656 .+-. 1531 (-1) 3
1911 .+-. 144 (21)* 3957 .+-. 224 (9) 18039 .+-. 1265 (11) 10 954
.+-. 115 (60)* 2796 .+-. 100 (36)* 9792 .+-. 977 (52)* 30 346 .+-.
55 (86)* 1003 .+-. 104 (77)* 3173 .+-. 541 (84)* 276 0 1541 .+-. 87
4269 .+-. 299 15011 .+-. 2450 1 1602 .+-. 51 (-4) 3743 .+-. 199
(12) 18155 .+-. 2275 (-21) 3 1631 .+-. 92 (-6) 3685 .+-. 292 (14)
16312 .+-. 2396 (-9) 10 1553 .+-. 27 (-1) 3092 .+-. 207 (28)* 15879
.+-. 2265 (-6) 30 1138 .+-. 59 (26)* 1558 .+-. 169 (64)* 10397 .+-.
931 (31) 58 E1 0 1763 .+-. 45 3410 .+-. 200 16873 .+-. 1162 1 1705
.+-. 71 (3) 3245 .+-. 107 (5) 15732 .+-. 1360 (7) 3 1748 .+-. 56
(1) 3021 .+-. 182 (11) 14938 .+-. 2613 (11) 10 1262 .+-. 79 (28)*
1799 .+-. 115 (47)* 17215 .+-. 2151 (-2) 30 502 .+-. 36 (71)* 469
.+-. 43 (86)* 12876 .+-. 2152 (24) 153 E2 0 1915 .+-. 57 3223 .+-.
109 20775 .+-. 1607 1 1804 .+-. 79 (6) 3271 .+-. 199 (-1) 22774
.+-. 916 (-10) 3 1726 .+-. 44 (10) 2968 .+-. 100 (8) 24159 .+-.
1313 (-16) 10 1734 .+-. 62 (9) 2327 .+-. 150 (28)* 22015 .+-. 1912
(-6) 30 1140 .+-. 53 (40)* 1359 .+-. 89 (58)* 16194 .+-. 1293 (22)
164 E1 0 1040 .+-. 76 3504 .+-. 223 21321 .+-. 1994 1 1122 .+-. 58
(-8) 2796 .+-. 133 (20)* 23574 .+-. 1313 (-11) 3 1046 .+-. 23 (-1)
2273 .+-. 74 (35)* 18002 .+-. 1516 (16) 10 903 .+-. 48 (13) 783
.+-. 61 (78)* 17727 .+-. 2871 (17) 30 610 .+-. 59 (41) 271 .+-. 50
(92)* 15630 .+-. 1085 (27) 56 E1 0 767 .+-. 34 3326 .+-. 78 43705
.+-. 2192 1 616 .+-. 50 (20)* 2625 .+-. 138 (19)* 41561 .+-. 1611
(5) 3 368 .+-. 17 (52)* 1346 .+-. 109 (58)* 42127 .+-. 2130 (4) 10
106 .+-. 20 (86)* 278 .+-. 42 (91)* 33478 .+-. 1779 (23)* 30 19
.+-. 2 (98)* 151 .+-. 60 (95)* 14637 .+-. 1567 (67)* 277 0 1007
.+-. 16 1423 .+-. 120 43023 .+-. 2628 1 950 .+-. 46 (6) 1508 .+-.
86 (-6) 35827 .+-. 2302 (17) 3 824 .+-. 30 (18)* 1491 .+-. 75 (-5)
34136 .+-. 4104 (21) 10 533 .+-. 25 (47)* 1416 .+-. 43 (0) 33230
.+-. 2807 (23) 30 294 .+-. 42 (71)* 1384 .+-. 101 (3) 31743 .+-.
4406 (26) *p < 0.05, vs. vehicle (0); One Way ANOVA
Example 8
In Vivo Analyses
8.1. Rat Forced Swim Test
[0751] The method, which detects antidepressant activity, followed
that described by Porsolt et al. (Eur. J. Pharmacol., 47, 379-391,
1978) and modified by Lucki et al. (Psychopharm., 121, 66-72,
1995). Rats forced to swim in a situation from which they cannot
escape rapidly become immobile. Antidepressants decrease the
duration of immobility. In addition, distinct patterns of active
behaviors are produced by antidepressants that selectively inhibit
norepinephrine (NE) and serotonin (5-HT) uptake in this test.
Selective NE reuptake inhibitors decrease immobility by increasing
climbing behaviors whereas selective 5-HT reuptake inhibitors
decrease immobility by increasing swimming behaviors.
[0752] Rats were individually placed in a cylinder (Height=40 cm;
Diameter=20 cm) containing 22 cm water (25.degree. C.) for 15
minutes on the first day of the experiment (Session 1) and were
then put back in the water 24 hours later for a 5 minute test
(Session 2). The sessions were videotaped and duration of
immobility as well as swimming and climbing behaviors during the 5
minute test were measured. Twelve rats were tested in each group.
The test was performed blind. Compounds were typically evaluated at
3 doses (1-30 mg/kg), administered orally 2 times: 24 hours and
30-60 minutes before the test (Session 2), and compared with a
vehicle control group. Desipramine (20 mg/kg i.p.), administered
under the same experimental conditions, was used as the positive
reference substance.
[0753] Data were analyzed by one way analysis of variance (ANOVA)
followed by post-hoc comparisons where appropriate. An effect will
be considered significant if p<0.05. Data are represented as the
mean and standard error to the mean (s.e.m).
8.2. Mouse Tail Suspension Test
[0754] The method, which detects antidepressant activity, follows
that described by Steru et al. (Psychopharmacology, 85, 367-370,
1985). Rodents, suspended by the tail, rapidly become immobile.
Antidepressants decrease the duration of immobility.
[0755] The behavior of the animal was recorded automatically for 5
minutes using a computerized device (Med-Associates Inc.) similar
to that developed by Steru et al. (Prog. Neuropsychopharmacol. Exp.
Psychiatry, 11, 659-671, 1987). Ten to twelve mice were tested in
each group. The test was performed blind. Compounds were typically
evaluated at 3 doses (1-30 mg/kg), administered orally one time:
30-60 minutes before the test, and compared with a vehicle control
group. Desipramine (100 mg/kg), administered under the same
experimental conditions, was used as the positive reference
substance.
[0756] Data were analyzed by one way analysis of variance (ANOVA)
followed by post-hoc comparisons where appropriate. An effect was
considered significant if p<0.05. Data are represented as the
mean and standard error to the mean (s.e.m).
8.3. Locomotor Activity
[0757] In order to ensure effects of the compounds on immobility
time were not related to a general stimulant effect on baseline
motor activity, locomotor activity was assessed using photocell
monitored cages (Med-Associates Inc.). Each test chamber was
equipped with infrared photocell beams to measure movement of the
animals. Horizontal and vertical activity were measured
[0758] Rats or mice were pretreated with vehicle or test compounds
and placed back in home cage, following which they will be
individually placed in locomotor cages and activity was monitored
in 5 minute intervals for up to 60 min.
[0759] Data were analyzed by one way analysis of variance (ANOVA)
followed by post-hoc comparisons where appropriate. An effect was
considered significant if p<0.05. Data are represented as the
mean and standard error to the mean (s.e.m).
8.4. Result Summary
[0760] Selected compounds of the invention were evaluated in the
mouse tail suspension and locomotor activity test (Table 10).
Results showed that all tested compounds exhibited an
antidepressant-like profile (i.e., significantly decreased
immobility time) with MED's in the range of 3-30 mg/kg, PO. At
doses active in the tail suspension test, no change or a decrease
in baseline motor activity was observed indicating that
antidepressant-like activity was not due to a general stimulant
effect.
[0761] Selected compounds of the invention were also evaluated in
the rat forced swim and locomotor activity tests (Table 11). All
tested compounds exhibited antidepressant-like effects with MED's
in the range of 10-30 mg/kg, PO. The decrease in immobility
produced by these compounds appeared to be due to increases in
swimming and climbing behaviors indicative of mixed transporter
activity (i.e., SNRI profiles). In conclusion, the tested compounds
of the invention exhibited an anti-depressant profile in at least
three animal models, the mouse tail suspension test and rat
locomotor activity test as well as the rat forced swim test.
TABLE-US-00010 TABLE 10 Mouse Tail Suspension and Locomotor
Activity Results Mouse Locomotor Mouse Tail Suspension Activity
Treatment Mean Immobility Total Distance Dose (mg/kg, PO) Time .+-.
S.E.M. Traveled .+-. S.E.M. 153 E2 0 200.1 .+-. 5.8 537.2 .+-. 67.2
3 195.4 .+-. 7.7 625.5 .+-. 88.8 10 170.2 .+-. 6.3* 519.5 .+-. 88.4
30 154.5 .+-. 8.4* 573.7 .+-. 63.6 44 E1 0 198.3 .+-. 7.6 660.0
.+-. 51.6 3 188.9 .+-. 7.3 576.5 .+-. 66.9 10 174.5 .+-. 8.1 721.1
.+-. 36.5 30 120.4 .+-. 9.0* 402.3 .+-. 71.0* 93 0 204.6 .+-. 5.6
494.0 .+-. 64.1 3 203.5 .+-. 8.0 644.0 .+-. 55.7 10 185.4 .+-. 7.9
606.9 .+-. 72.4 30 162.0 .+-. 8.1* 737.6 .+-. 89.5 48 E1 0 199.9
.+-. 6.7 647.7 .+-. 42.6 3 189.8 .+-. 7.2 622.5 .+-. 101.6 10 174.1
.+-. 5.8* 620.0 .+-. 79.4 30 134.5 .+-. 9.6* 468.6 .+-. 114.2 134
E2 0 200.0 .+-. 6.7 782.8 .+-. 94.2 3 191.4 .+-. 6.2 862.7 .+-.
100.4 10 170.8 .+-. 6.0* 671.6 .+-. 63.3 30 137.2 .+-. 7.2* 728.2
.+-. 107.7 75 0 194.2 .+-. 6.0 659.4 .+-. 63.1 3 187.8 .+-. 9.6
653.5 .+-. 48.4 10 177.7 .+-. 5.8 608.8 .+-. 83.4 30 143.5 .+-.
5.8* 655.3 .+-. 117.7 148 E1 0 207.6 .+-. 7.8 445.7 .+-. 71.5 3
193.7 .+-. 6.0 584.8 .+-. 65.7 10 189.3 .+-. 5.9 486.3 .+-. 74.3 30
174.5 .+-. 5.0* 559.6 .+-. 88.2 225 0 195.1 .+-. 4.1 735.2 .+-.
54.5 0.3 188.1 .+-. 8.0 519.5 .+-. 56.4* 1 186.5 .+-. 5.2 423.4
.+-. 62.3* 3 158.5 .+-. 4.9* 415.9 .+-. 61.6* 225 0 192.5 .+-. 6.3
336.6 .+-. 77.5 3 155.2 .+-. 6.0* 341.8 .+-. 78.3 10 137.8 .+-.
5.2* 234.2 .+-. 49.4 30 136.3 .+-. 2.5* 177.4 .+-. 47.8 164 E1 0
197.3 .+-. 7.0 509.4 .+-. 92.7 3 183.8 .+-. 6.5 377.8 .+-. 67.6 10
162.1 .+-. 4.6* 210.3 .+-. 40.4* 30 155.3 .+-. 7.8* 494.0 .+-. 84.9
56 E1 0 203.6 .+-. 4.5 439.6 .+-. 63.5 3 184.0 .+-. 4.8 410.2 .+-.
89.3 10 174.8 .+-. 6.1* 440.2 .+-. 62.6 30 141.9 .+-. 7.4* 252.2
.+-. 55.8 277 0 199.8 .+-. 6.1 378.9 .+-. 45.2 3 182.3 .+-. 8.1
418.8 .+-. 80.6 10 164.4 .+-. 6.8* 411.8 .+-. 87.8 30 147.1 .+-.
3.1* 327.7 .+-. 67.1 276 0 202.7 .+-. 6.3 565.9 .+-. 104.3 3 182.0
.+-. 4.2 625.9 .+-. 47.5 10 164.1 .+-. 5.7* 382.4 .+-. 63.4 30
160.2 .+-. 7.2* 607.8 .+-. 57.8 164 E2 0 184.6 .+-. 10.1 520.4 .+-.
103.8 3 181.8 .+-. 6.3 518.2 .+-. 106.1 10 179.1 .+-. 4.5 464.5
.+-. 86.2 30 141.8 .+-. 6.0* 669.9 .+-. 75.6 17 E1 0 197.3 .+-. 5.6
463.0 .+-. 73.4 3 184.7 .+-. 9.0 649.3 .+-. 78.4 10 182.6 .+-. 4.1
478.3 .+-. 88.5 30 150.9 .+-. 7.8* 428.3 .+-. 120.6 *p < 0.05,
vs. vehicle (0); One Way ANOVA
[0762] TABLE-US-00011 TABLE 11 Rat Forced Swim and Locomoter
Activity Results Rat Locomotor Treatment Activity Dose Total
Distance (mg/kg, Rat Forced Swim (Means .+-. S.E.M.) Traveled .+-.
PO) Immobility Swimming Climbing S.E.M. 48 E1 0 48.0 .+-. 2.1 4.8
.+-. 1.2 7.0 .+-. 1.5 1480.0 .+-. 67.4 3 49.6 .+-. 1.5 3.7 .+-. 1.0
7.1 .+-. 0.6 1869.9 .+-. 188.4 10 35.6 .+-. 3.5* 6.5 .+-. 1.6 17.9
.+-. 2.5* 1825.3 .+-. 109.3 30 26.9 .+-. 4.4* 9.7 .+-. 1.7* 20.6
.+-. 2.9* 1840.6 .+-. 56.6 153 0 50.8 .+-. 1.8 1.0 .+-. 0.3 8.2
.+-. 1.8 1685.1 .+-. 106.8 E2 3 49.9 .+-. 1.7 1.9 .+-. 0.8 8.8 .+-.
1.5 1577.8 .+-. 80.1 10 44.0 .+-. 2.1 4.3 .+-. 1.1* 11.7 .+-. 1.8
1994.2 .+-. 263.9 30 31.3 .+-. 6.7* 4.6 .+-. 1.3* 22.2 .+-. 5.2*
2033.7 .+-. 215.4 93 0 48.5 .+-. 1.4 3.7 .+-. 0.7 7.8 .+-. 1.1
1682.2 .+-. 66.8 3 44.5 .+-. 2.5 6.5 .+-. 1.6 9.0 .+-. 1.3 1802.6
.+-. 150.6 10 41.4 .+-. 2.8 6.9 .+-. 1.3 12.8 .+-. 2.2 1641.0 .+-.
144.5 30 25.8 .+-. 5.4* 12.0 .+-. 2.1* 22.2 .+-. 3.5* 2095.6 .+-.
147.2 277 0 46.5 .+-. 2.9 1.2 .+-. 0.6 12.1 .+-. 2.7 1586.0 .+-.
191.3 3 50.4 .+-. 1.1 0.8 .+-. 0.3 9.0 .+-. 1.2 1406.2 .+-. 84.9 10
42.5 .+-. 2.6 3.7 .+-. 0.9* 13.8 .+-. 2.3 1861.4 .+-. 187.8 30 14.6
.+-. 3.5* 6.1 .+-. 1.4* 35.6 .+-. 5.2* 2612.4 .+-. 210.8* 225 0
52.4 .+-. 1.8 0.8 .+-. 0.4 6.8 .+-. 1.8 1610.3 .+-. 101.1 3 50.8
.+-. 1.8 0.8 .+-. 0.3 8.4 .+-. 1.7 1783.4 .+-. 182.7 10 47.6 .+-.
3.0 1.2 .+-. 0.6 11.1 .+-. 2.7 1628.5 .+-. 159.2 30 33.4 .+-. 4.8*
1.1 .+-. 0.5 25.0 .+-. 4.6* 2182.8 .+-. 151.2* 56 E1 0 53.8 .+-.
0.6 0.4 .+-. 0.2 5.8 .+-. 0.7 1272.6 .+-. 113.2 3 52.2 .+-. 1.6 0.3
.+-. 0.2 7.1 .+-. 1.6 1227.9 .+-. 84.4 10 50.7 .+-. 1.0 0.8 .+-.
0.3 8.6 .+-. 0.9 1230.8 .+-. 64.8 30 40.4 .+-. 2.7* 1.0 .+-. 0.4
17.9 .+-. 2.4* 1359.8 .+-. 132.7 *p < 0.05, vs. vehicle (0); One
Way ANOVA
[0763] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the scope of the appended claims.
* * * * *