U.S. patent application number 15/418986 was filed with the patent office on 2017-07-20 for phenyl substituted cycloalkylamines as monoamine reputake inhibitors.
This patent application is currently assigned to Sunovion Pharmaceuticals Inc.. The applicant listed for this patent is Sunovion Pharmaceuticals Inc.. Invention is credited to Una CAMPBELL, Sharon Rae ENGEL, Larry Wendell HARDY, Michael Charles HEWITT, Patrick KOCH, Jianguo MA, Scott Christopher MALCOLM, Seth RIBE, Rudy SCHREIBER, Liming SHAO, Kerry L. Spear, Mark A. VARNEY, Fengjiang WANG.
Application Number | 20170204050 15/418986 |
Document ID | / |
Family ID | 40094167 |
Filed Date | 2017-07-20 |
United States Patent
Application |
20170204050 |
Kind Code |
A1 |
SHAO; Liming ; et
al. |
July 20, 2017 |
PHENYL SUBSTITUTED CYCLOALKYLAMINES AS MONOAMINE REPUTAKE
INHIBITORS
Abstract
Phenyl-substituted cyclohexylamine derivatives and methods for
their synthesis and characterization are disclosed. Use of these
compounds to treat/prevent neurological disorders as well as
methods for their synthesis are set forth herein. Exemplary
compounds of the invention inhibit reuptake of endogenous
monoamines, such as dopamine, serotonin and norepinephrine (e.g.,
from the synaptic cleft) and modulate one or more monoamine
transporter. Pharmaceutical formulations incorporating compounds of
the invention are also provided.
Inventors: |
SHAO; Liming; (Lincoln,
MA) ; WANG; Fengjiang; (Northborough, MA) ;
MALCOLM; Scott Christopher; (Southborough, MA) ;
HEWITT; Michael Charles; (Somerville, MA) ; MA;
Jianguo; (Natick, MA) ; RIBE; Seth;
(Worcester, MA) ; VARNEY; Mark A.; (Laguna Nigel,
CA) ; CAMPBELL; Una; (Marlborough, MA) ;
ENGEL; Sharon Rae; (Hudson, MA) ; HARDY; Larry
Wendell; (Sturbridge, MA) ; KOCH; Patrick;
(Marlborough, MA) ; SCHREIBER; Rudy; (Watertown,
MA) ; Spear; Kerry L.; (Concord, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Pharmaceuticals Inc. |
Marlborough |
MA |
US |
|
|
Assignee: |
Sunovion Pharmaceuticals
Inc.
|
Family ID: |
40094167 |
Appl. No.: |
15/418986 |
Filed: |
January 30, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14149492 |
Jan 7, 2014 |
9586888 |
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15418986 |
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12131845 |
Jun 2, 2008 |
8669291 |
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14149492 |
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60941242 |
May 31, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/28 20180101;
C07C 217/52 20130101; C07C 2601/14 20170501; A61P 25/24 20180101;
A61K 31/135 20130101; C07B 2200/07 20130101; C07C 217/76 20130101;
C07C 215/42 20130101 |
International
Class: |
C07C 215/42 20060101
C07C215/42; C07C 217/76 20060101 C07C217/76 |
Claims
1. A compound having a structure which is a member selected from
the group consisting of: ##STR00034## wherein n is an integer
selected from the group consisting of 0 to 2; s is an integer
selected from the group consisting of 0 to 2; A is a member
selected from the group consisting of H, substituted or
unsubstituted alkyl, halogen and substituted or unsubstituted
haloalkyl; X is a member selected from the group consisting of H,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted haloalkyl and
OR.sup.5 wherein 'R.sup.5 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, acyl and
S(O).sub.2R.sup.5a, wherein R.sup.5a is a member selected from the
group consisting of substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl; Y and Z are members independently
selected from the group consisting of halogen, CF.sub.3, CN,
OR.sup.9, SR.sup.9, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocycloalkyl, NR.sup.10R.sup.11 and NO.sub.2.
wherein Y and Z, together with the atoms to which they are
attached, are optionally joined to form a 5- to 7-membered ring,
optionally including from 1 to 3 heteroatoms, 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, substituted or unsubstituted heterocylcoalkyl; and
R.sup.10 and R.sup.11 are members independently selected from the
group consisting of H, OR.sup.12, acyl, S(O).sub.2R.sup.13,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl, wherein R.sup.12 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.13 is a
member selected from the group consisting of substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein R.sup.10 and R.sup.11, together with the atoms to which
they are attached, are optionally joined to form a 3- to 7-membered
ring, optionally including from 1 to 3 heteroatoms; R.sup.1 and
R.sup.2 are members independently selected from the group
consisting of H, halogen, CN, CF.sub.3, OR.sup.6, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein R.sup.6 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.7, acyl,
S(O).sub.2R.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.7 is a member
selected front 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;
R.sup.8 is a member selected from the group consisting of
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,
R.sup.3 and R.sup.4, together with the atoms to which they are
attached, are optionally joined to form a 3- to 7-membered ring,
optionally including from 1 to 3 heteroatoms.
2. The compound of claim 1, wherein R.sup.3 and R.sup.4 are members
independently selected front the group consisting of substituted or
unsubstituted C.sub.1-C.sub.4 alkyl and substituted or
unsubstituted C.sub.1-C.sub.4 heteroalkyl.
3. The compound of claim 1, wherein R.sup.3 and R.sup.4 are members
independently selected from the group consisting of substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl and
substituted or unsubstituted cycloalkyl.
4. The compound of claim 1, having a structure which is a member
selected from the group consisting of: ##STR00035## wherein A is
H.
5. The compound of claim 4, having a structure which is a member
selected from the group consisting of: ##STR00036##
6. The compound of claim 4, wherein Y and X are members
independently selected from the group consisting of H, halogen, CN
and CF.sub.3.
7. The compound of claim 6, wherein Y and X are chloro.
8. The compound of claim 7, wherein s is 1.
9. The compound of claim 8, wherein n is 1.
10. The compound of claim 9, having a structure which is a member
selected from the group consisting of: ##STR00037## wherein R.sup.4
is a member selected from the group consisting of H and
CH.sub.3.
11. The compound of claim 4, having a structure which is a member
selected from the group consisting of: ##STR00038## wherein
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are each independently
selected from the group consisting of O, S, N(R.sup.b).sub.b, and
C(R.sup.b).sub.b(R.sup.c); a is an integer selected from the group
consisting of 0 to 2; b is an integer selected from the group
consisting of 0 to 1; R.sup.b and R.sup.c are members independently
selected from the group consisting of H, halogen, CF.sub.3, CN,
OR.sup.14, SR.sup.14, NR.sup.15R.sup.16,
NR.sup.15S(O).sub.2R.sup.14, NR.sup.15C(O)R.sup.14,
S(O).sub.2R.sup.14, acyl, C(O)OR.sup.14, C(O)NR.sup.15R.sup.16,
S(O).sub.2NR.sup.15R.sup.16, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl; each R.sup.14,
R.sup.15 and R.sup.16 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.14, R.sup.15 and R.sup.16, together with the atoms to which
they are attached, are optionally joined to form a 3- to 7-membered
ring, which optionally includes from 1 to 3 heteroatoms.
12. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable carrier, vehicle or diluent.
13. A method for treating or preventing a neurological disorder,
said method comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt or solvate thereof.
14. The method of claim 13, wherein said neurological disorder is a
member selected from the group consisting of substance abuse,
fibromyalgia, pain, sleep disorder, attention deficit disorder
(ADD), attention deficit hyperactivity disorder (ADHD), restless
leg syndrome, depression, schizophrenia, anxiety, obsessive
compulsive disorder, panic disorder, posttraumatic stress disorder,
premenstrual dysphoria, and neurodegenerative disease.
15. The method of claim 14, wherein said sleep disorder is sleep
apnea.
16. The method of claim 14, wherein said pain is neuropathic
pain.
17. A method for treating or preventing an eating disorder, said
method comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt or solvate thereof.
18. A method for treating or preventing obesity, said method
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt or solvate thereof.
19. A method of inhibiting reuptake of at least one monoamine from
a cell, said method comprising administering to a mammalian subject
a compound of claim 1, or a pharmaceutically acceptable salt or
solvate thereof.
20. The method of 19, wherein said monoamine is a member selected
from group consisting of serotonin, dopamine and
norepinephrine.
21. A method of modulating one or more monoamine transporter, said
method comprising administering to a mammalian subject a compound
of claim 1, or a pharmaceutically acceptable salt or solvate
thereof.
22. The method of claim 21, wherein said monoamine transporter is a
member selected from the group consisting of serotonin transporter
(SERT), dopamine transporter (DAT) aminorepinephrine (NET)
transporter.
23. The method of claim 14, wherein, said substance abuse is abuse
of a member selected from cocaine, nicotine or a combination
thereof.
24. The method of claim 14, wherein said neurodegenerative disease
is Parkinson's disease.
25. A compound having the formula: ##STR00039##
26. A pharmaceutical formulation comprising a compound according to
claim 25 in combination with a pharmaceutically acceptable
excipient.
27. A compound having the formula: ##STR00040##
28. A pharmaceutical formulation comprising a compound according to
claim 27 in combination with a pharmaceutically acceptable
excipient.
29. A compound having the formula: ##STR00041##
30. A pharmaceutical formulation comprising a compound according to
claim 29 in combination with a pharmaceutically acceptable
excipient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 60/941,242, filed on May 31, 2007, the disclosure
of which 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 neurological 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 time, 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). Dual reuptake inhibitors 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, neuropharmalogical 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 adregnergic 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] Scrotonin (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 metabolism (e.g., monoamine oxidase
inhibitors) or reuptake (e.g., tricyclic antidepressants or
selective serotonin reuptake inhibitors (SSRISs)).
[0012] There are more than twenty approved antidepressant drugs
available in the United States. The classical tricylic
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 not 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,
adregnergic, 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
pharmalogically 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 current drug therapy.
SUMMARY OF THE INVENTION
[0018] The present invention relates to novel cycloalkylamines and
salts thereof. It also relates to novel pharmaceutically
compositions, and their use in the treatment of disorders and
conditions. Exemplary indications, for the compounds of the
invention include neurological 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). The
compounds of the invention are also of use to treat or prevent
obesity or to treat substance abuse, dependency or addiction,
including but not limited to nicotine and cocaine abuse, dependency
or addiction.
[0019] Hence, in a first aspect the invention provides a compound
having the formula:
##STR00001##
wherein the index n is an integer selected from the group
consisting of 0 to 2; and s is an integer selected from the group
consisting of 0 to 2. A is a member selected from the group
consisting of H, substituted or unsubstituted alkyl, halogen and
substituted or unsubstituted haloalkyl. X is a member selected from
the group consisting of H, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted aryl, substituted or
unsubstituted haloalkyl and OR.sup.5, in which R.sup.5 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, acyl and S(O).sub.2R.sup.5a, in which R.sup.5a is a
member selected from the group consisting of substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteraryl and substituted or unsubstituted heterocycloalkyl.
[0020] Y and Z are members independently selected from the group
consisting of halogen, CF.sub.3, CN, OR.sup.9, SR.sup.9,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heterocycloalkyl, NR.sup.10R.sup.11 and NO.sub.2, R.sup.9
represents H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted heterocycloalkyl. The radicals R.sup.10 and R.sup.11
independently represent H, OR.sup.12, acyl, S(O).sub.2R.sup.13,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl or substituted or unsubstituted
heterocycloalkyl. R.sup.10 and R.sup.11, together with the nitrogen
to which they are attached, are optionally joined to form a 3- to
7-membered ring, optionally having from 1 to 3 heteroatoms in
addition to the nitrogen to which R.sup.10 and R.sup.11 are
joined.
[0021] The symbol R.sup.12 is a member selected from H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl or substituted or unsubstituted heterocycloalkyl.
R.sup.13 is a member selected from substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl.
[0022] Y and Z, together with the atoms to which they are attached,
are optionally joined to form a 5- to 7-membered ring, which can
optionally have from 1 to 3 heteroatoms therein. As will be
apparent to those of skill in the art, when Y and Z are joined into
a ring, the substituents (e.g., R.sup.9, R.sup.10 and R.sup.11) on
atoms incorporated into the ring will be present (e.g.,
incorporated into the cyclic structure of the ring) or absent as
necessary to satisfy the valence of the atom to which these
substituents are attached.
[0023] R.sup.1 and R.sup.2 are members independently selected from
H, halogen, CN, CF.sub.3, OR.sup.6, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl or
substituted or unsubstituted heterocycloalkyl. R.sup.6 is a member
selected from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycloalkyl.
[0024] R.sup.3 and R.sup.4 are members independently selected from
H, OR.sup.7, acyl S(O).sub.2R.sup.8, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl or
substituted or unsubstituted heterocycloalkyl. R.sup.7 is a member
selected from H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocylcoalkyl. R.sup.8 is a member selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocylcoalkyl.
[0025] Two or more of R.sup.1, R.sup.2, R.sup.3 and R.sup.4,
together with the atoms to which they are attached, are optionally
joined to form a 3- to 7-membered ring, which optionally includes
from 1 to 4, preferably from 1 to 3 heteroatoms.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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 an exemplary
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.
[0032] In a further aspect, the invention provides a method of
treating a neurological 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 an exemplary embodiment, the subject is a
human.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1(A-G) is a table of exemplary compounds of the
invention.
[0034] FIG. 2 is a graph showing effect of a compound 4 on baseline
locomotor activity in the reserpinized rat.
[0035] FIG. 3 is a graph showing effect of compound 4 on rotarod
performance in the reserpinized rat.
[0036] FIG. 4 is a graph showing effect of compound 4 on catalepsy
in the reserpinized rat.
[0037] FIG. 5 is a graph showing combined compound 4 and low does
L-DOPA rotarod performance as compared to high dose L-DOPA.
[0038] FIG. 6 is a graph showing the effect of combination of
L-DOPA and compound 4 in the 6-OHDA lesioned rat.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0039] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain, or cyclic hydrocarbon radical, or combination thereof, which
may be fully saturated, unsaturated, e.g., mono- or polyunsaturated
and can include di- and multivalent radicals. Alkyl radicals are
optionally designated as having a number of carbons with a stated
range--i.e., C.sub.1-C.sub.10 means a substituted or unsubstituted
alkyl moiety having from 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,
see-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl,
n-heptyl, n-octyl; cyclic alkyl, e.g., cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, fused ring species
including, e.g., fused cycloalkyl (e.g., decalin) and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds, e.g., "alkenyl" and "alkynyl". 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". Exemplary
substituents found on "substituted alkyl" moieties are set forth
below.
[0040] The term "alkylene" by itself or as part of another
substituent 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.
[0041] 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.
[0042] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, is a subgenus of
"alkyl" as set forth above, a straight or branched chain, or cyclic
alkyl radical, or combinations thereof, saturated or unsaturated
alkyl radical consisting of a number of carbon atoms (optionally
stated) and at least one heteroatom, preferably selected from B, O,
N, P, 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) B, O, N, P, Si and S may be at
any internal position of the heteroalkyl group or at the position
at which the heteroalkyl group is attached to the remainder of the
molecule, or at the antipodal terminus thereof. 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. Two or more 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 substituent means
a divalent radical derived from heteroalkyl, as exemplified, but
not limited by, --CH.sub.2--CH.sub.3--S--CH.sub.3--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'-- optionally represents both --C(O)OR' and
--OC(O)R'.
[0043] 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.
[0044] The terms "halo" or "halogen," by themselves or as part of
another substituent, 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.
[0045] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, substituent that can be a single ring or
multiple rings (preferably from 1 to 3 rings), which are fused
together or linked covalently. "Aryl" species include structures
that include aryl rings fused with cycloalkyl, heterocycloalkyl and
heteroaryl rings. The term "heteroaryl" is subgeneric to "aryl" and
refers to aryl groups that contain from one to four heteroatoms,
preferably selected from B, O, N, P, Si and S, 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-pyrzaolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,
4-oxazolyl, 2-phenly-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 substituents
described below.
[0046] For brevity, the term "aryl" when used to define a
substituent (e.g., aryloxy, arylthioxy, arylalkyl) optionally
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).
[0047] 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
substituents for each type of radical are provided below.
[0048] 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 substituents," 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 preferably 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 substituents, 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).
[0049] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are generically
referred to as "aryl group substituents." The substituents 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', --CNR'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.
[0050] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent 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 substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the formula
--A--(CH.sub.2).sub.5--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 substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent 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
substituent R, R', R'' and R''' are preferably independently
selected from hydrogen or substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl.
[0051] As used herein, the term "acyl" described a substituent
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 heterocylcloalkyl.
[0052] 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 (i.e., aryl
or heteroaryl) as well as saturated or unsaturated non aromatic
rings (i.e., cycloalkyl, heterocycloalkyl). Examples of "fused ring
systems" are naphthalenes, indoles, quinolines, chromenes, decalin
and the like.
[0053] As used herein, the term "heteroatom" includes oxygen (O),
nitrogen (N), sulfur (S), silicon (Si), boron (B), and phosphorus
(P).
[0054] The symbol "R" is a general abbreviation that represents an
"alkyl group substituent" or "aryl group substituent" (e.g., a
substituent 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).
[0055] 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 the pathway in the treated organism)
at a reasonable benefit/risk ratio applicable to any medical
treatment.
[0056] 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.
[0057] 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 into 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, polycaronates and/or polyanhydrides; and (22)
other non-toxic compatible substances employed in pharmaceutical
formulations.
[0058] 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, furmarate, 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.
[0059] The term "pharmaceutically acceptable salts" includes salts
of the active compounds which are prepared with relatively nontoxic
acids or bases, depending on the particular substituents 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.
[0060] 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.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] 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): wavy lines indicate
disavowal of any stereochemical implication which the bond it
represents could generate; solid and broken wedges 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.
[0065] 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."
[0066] 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.
[0067] 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 the 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.
[0068] The term "eating disorder" refers to abnormal compulsions to
avoid eating or uncontrollable impulses to consume abnormally large
amounts of food. These disorders affect not only the social
well-being, but also the physical well-being of sufferers. Examples
of eating disorders include anorexia nervosa, bulimia, and binge
eating.
[0069] The term "neurological disorder" refers to any condition of
the central or peripheral nervous system of a mammal. The term
"neurological disorder" includes a neurodegenerative diseases
(e.g., Alzheimer's disease, Parkinson's disease and amyotrophic
lateral sclerosis), neuropsychiatric diseases (e.g., schizophrenia
and anxieties, such as general anxiety disorder). Exemplary
neurological disorders include MLS (cerebellar ataxia),
Huntington's disease, Down syndrome, multi-infaret dementia, status
epilecticus, contusive injuries (e.g. spinal cord injury and head
injury), viral infection induced neurodegeneration, (e.g. AIDS,
encephalopathies), epilepsy, benign forgetfulness, closed head
injury, sleep disorders, depression (e.g., bipolar disorder),
dementias, movement disorders, psychoses, alcoholism,
post-traumatic stress disorder and the like. "Neurological
disorder" also includes any condition associated with the disorder.
For instance, a method of treating a neurodegnerative disorder
includes methods of treating loss of memory and/or loss of
cognition associated with a neurodegenerative disorder. An
exemplary method would also include treating or preventing loss of
neuronal function characteristic of neurodegenerative disorder.
"Neurological disorder" also includes any disease or condition that
is implicated, at least in part, in monamine (e.g., norepinephrine)
signaling pathways (e.g., cardiovascular disease).
[0070] "Pain" is an unpleasant sensory and emotional experience.
Pain classifications have been based on duration, etiology or
pathophysiology, mechanism, intensity, and symptoms. The term
"pain" as used herein 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 peripheral neuropathic pain (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.
[0071] "Somatic" pain, as described above, refers to a normal nerve
response to a noxious stimulus such as injury or illness, e.g.,
trauma, burn, infection, inflammation, or disease process such as
cancer, and includes both cutaneous pain (e.g., skin, muscle or
joint derived) and visceral pain (e.g., organ derived).
[0072] "Neuropathic pain" is a heterogeneous group of neurological
conditions that result from damage to the nervous system.
"Neuropathic" pain, as described above, refers to pain resulting
from injury to or dysfunctions of peripheral and/or central sensory
pathways, and from dysfunctions of the nervous system, where the
pain often occurs or persists without an obvious noxious input.
This includes pain related to peripheral neuropathies as well as
central neuropathic pain. Common, types of peripheral neuropathic
pain include diabetic neuropathy (also called diabetic peripheral
neuropathic pain, or DN, DPN, or DPNP), post-herpetic peuralgia
(PHN), and trigeminal neuralgia (TGN). Central neuropathic pain,
involving damage to the brain or spinal cord, can occur following
stroke, spinal cord injury, and as a result of multiple sclerosis.
Other types of pain that are meant to be included in the definition
of neuropathic pain include pain from neuropathic cancer pain,
HIV/AIDS induced pain, phantom limb pain, and complex regional pain
syndrome. In an exemplary embodiment, the compounds of the
invention are of use for treating neuropathic pain.
[0073] Common clinical features of neuropathic pain include sensory
loss, allodynia (non-noxious stimuli produce pain), hyperalgesia
and hyperpathia (delayed perception, summation, and painful
aftersensation). Pain is often a combination of nociceptive and
neuropathic types, for example, mechanical spinal pain and
radiculopathy or myelopathy.
[0074] "Acute pain", is the normal, predicted physiological
response to a noxious chemical, thermal or mechanical stimulus
typically associated with invasive procedures, trauma and disease.
It is generally time-limited, and may be viewed as an appropriate
response to a stimulus that threatens and/or produces tissue
injury. "Acute pain", as described above, refers to pain which is
marked by short duration or sudden onset.
[0075] "Chronic pain" occurs in a wide range of disorders, for
example, trauma, malignancies and chronic inflammatory diseases
such as rheumatoid arthritis. Chronic pain usually lasts more than
about six months. In addition, the intensity of chronic pain may be
disproportionate to the intensity of the noxious stimulus or
underlying process. "Chronic pain", as described above, refers to
pain associated with a chronic disorder, or pain that persists
beyond resolution of an underlying disorder or healing of an
injury, and that is often more intense than the underlying process
would predict. It may be subject to frequent recurrence.
[0076] "Inflammatory pain" is pain in response to tissue injury and
the resulting inflammatory process. Inflammatory pain is adaptive
in that it elicits physiologic responses that promote healing.
However, inflammation may also affect neuronal function.
Inflammatory mediators, including PGE.sub.2 induced by the COX2
enzyme, bradykinins, and other substances, bind to receptors on
pain-transmitting neurons and alter their function, increasing
their excitability and thus increasing pain sensation. Much chronic
pain has an inflammatory component. "Inflammatory pain", as
described above, refers to pain which is produced as a symptom or a
result of inflammation or an immune system disorder.
[0077] "Visceral pain", as described above, refers to pain which is
located in an internal organ.
[0078] "Mixed etiology" pain, as described above, refers to pain
that contains both inflammatory and neuropathic components.
[0079] "Dual mechanism" pain, as described above, refers to pain
that is amplified and maintained by both peripheral and central
sensitization.
[0080] "Causalgia", as described above, refers to a syndrome of
sustained burning, allodynia, and hyperpathia after a traumatic
nerve lesion, often combined with vasomotor and sudomotor
dysfunction and later trophic changes.
[0081] "Central" pain, as described above, refers to pain initiated
by a primary lesion or dysfunction in the central nervous
system.
[0082] "Hyperesthesia", as described above, refers to increased
sensitivity to stimulation, excluding the special senses.
[0083] "Hyperpathia", as described above, refers to a painful
syndrome characterized by an abnormally painful reaction to a
stimulus, especially a repetitive stimulus, as well as an increased
threshold. It may occur with allodynia, hyperesthesia,
hyperalgesia, or dysesthesia.
[0084] "Dysesthesia", as described above, refers to an unpleasant
abnormal sensation, whether spontaneous or evoked. Special cases of
dysesthesia include hyperalgesia and allodynia.
[0085] "Hyperalgesia", as described above, refers to an increased
response to a stimulus that is normally painful. It reflects
increased pain on suprathreshold stimulation.
[0086] "Allodynia", as described above, refers to pain due to a
stimulus that does not normally provoke pain.
[0087] The term "pain" includes pain resulting from dysfunction of
the nervous system: organic pain states that share clinical
features of neuropathic pain and possible common, pathophysiology
mechanisms, but are not initiated by an identifiable lesion in any
part of the nervous system.
[0088] The term "Diabetic Peripheral Neuropathic Pain" (DPNP, also
called diabetic neuropathy, DN or diabetic peripheral neuropathy)
refers to chronic pain caused by neuropathy associated with
diabetes mellitus. The classic presentation of DPNP is pain or
tingling in the feet that can be described not only as "burning" or
"shooting" but also as severe aching pain. Less commonly, patients
may describe the pain as itching, tearing, or like a toothache. The
pain may be accompanied by allodynia and hyperalgesia and an
absence of symptoms, such as numbness.
[0089] The term "Post-Herperic Neuralgia", also called
"Postherpetic Neuralgia" (PHN), is a painful condition affecting
nerve fibers and skin. It is a complication of shingles, a second
outbreak of the varicella roster virus (VZV), which initially
causes chickenpox.
[0090] The term "neuropathic cancer pain" refers to peripheral
neuropathic pain as a result of cancer, and can be caused directly
by infiltration or compression of a nerve by a tumor, or indirectly
by cancer treatments such as radiation therapy and chemotherapy
(chemotherapy-induced neuropathy).
[0091] The term "HIV/AIDS peripheral neuropathy" or "HIV/AIDS
related neuropathy" refers to peripheral neuropathy caused by
HIV/AIDS, such as acute or chronic inflammatory demyelinating
neuropathy (AIDP and CIDP, respectively), as well as peripheral
neuropathy resulting as a side effect of drugs used to treat
HIV/AIDS.
[0092] The term "Phantom Limb Pain" refers to pain appearing to
come from where an amputated limb used to be. Phantom limb pain can
also occur in limbs following paralysis (e.g., following spinal
cord injury). "Phantom Limb Pain" is usually chronic in nature.
[0093] The term "Trigeminal Neuralgia" (TN) refers to a disorder of
the fifth cranial (trigeminal) nerve that causes episodes of
intense, stabbing, electric-shock-like pain in the areas of the
face where the branches of the nerve are distributed (lips, eyes,
nose, scalp, forehead, upper jaw, and lower jaw). It is also known
as the "suicide disease".
[0094] The term "Complex Regional Pain Syndrome (CRPS)," formerly
known as Reflex Sympathetic Dystrophy (RSD), is a chronic pain
condition. The key symptom of CRPS is continuous, intense pain out
of proportion to the severity of the injury, which gets worse
rather than better over time. CRPS is divided into type 1, which
includes conditions caused by tissue injury other than peripheral
nerve, and type 2, in which the syndrome is provoked by major nerve
injury, and is sometimes called causalgia.
[0095] The term "Fibromyalgia" refers to a chronic condition
characterized by diffuse or specific muscle, joint, or bone pain,
along with fatigue and a range of other symptoms. Previously,
fibromyalgia was known by other names such as fibrositis, chronic
muscle pain syndrome, psychogenic rheumatism and tension
myalgias.
[0096] The term "convulsion" refers to a neurological disorder and
is used interchangeably with "seizure," although there are many
types of seizure, some of which have subtle or mild symptoms
instead of convulsions. Seizures of all types may be caused by
disorganized and sudden electrical activity in the brain.
Convulsions are a rapid and uncontrollable shaking. During
convulsions, the muscles contract and relax repeatedly.
[0097] 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
[0098] One strategy to develop effective therapies for neurological
disorders 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.
[0099] An advantage of exemplary compounds and compositions of the
present invention is their ability to increase availability of at
least two neurotransmitters (e.g., NE, 5-HT and DA) by inhibiting
their dual (re)uptake, e.g., 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.
[0100] 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.
[0101] Taken together, the preclinical data for compounds such as
DOV 21,947 indicate that dual or triple reuptake inhibitors hold
potential as novel treatments for depression in the clinic.
III. Compositions
A. Cycloalkyl Amines
[0102] In an exemplary embodiment, the invention provides a
compound having the formula:
##STR00002##
wherein the index n is an integer selected from the group
consisting of 0, 1 and 2; and s is an. integer selected from the
group consisting of 0, 1 and 2. A is a member selected from H,
substituted or unsubstituted alkyl, halogen and substituted or
unsubstituted haloalkyl. X is selected from H, halogen, substituted
or nonsubstituted alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted haloalkyl and OR.sup.5, in which
R.sup.5 is selected from H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl
and S(O).sub.2R.sup.5a, in which R.sup.5a is selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.
[0103] Y and Z independently represent H, halogen, CF.sub.3, CN,
OR.sup.9, SR.sup.9, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocycloalkyl, NR.sup.10R.sup.11 or NO.sub.2. Y
and Z, together with the atoms to which they are attached, are
optionally joined to form a 5- to 7-membered ring, which can
optionally have 1, 2 or 3 heteroatoms therein. R.sup.9 represents
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heterocycloalkyl. The radicals R.sup.10 and R.sup.11 independently
represent H, OR.sup.12, acyl, S(O).sub.2R.sup.13, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl or substituted or unsubstituted heterocycloalkyl.
R.sup.10 and R.sup.11, together with the nitrogen to which they are
attached, are optionally joined to form a 3-, 4-, 5- 6- or
7-membered ring, optionally having 1, 2 or 3 heteroatoms in
addition to the nitrogen to which R.sup.10 and R.sup.11 are joined.
The symbol R.sup.12 represents H, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl or
substituted or unsubstituted heterocycloalkyl. R.sup.13 is selected
from substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocycloalkyl.
[0104] R.sup.1 and R.sup.2 are independently H, halogen, CN,
CF.sub.3, OR6, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycloalkyl. R.sup.6 is selected from H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocycloalkyl.
[0105] R3 and R4 independently represent H, OR.sup.7, acyl,
S(O).sub.2R.sup.8, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycloalkyl. R.sup.7 is H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl or substituted or unsubstituted heterocycloalkyl.
R.sup.8 is a member selected from substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl.
[0106] Two or more of R.sup.1, R.sup.2, R.sup.3 and R.sup.4,
together with the atoms to which they are attached, are optionally
joined to form a 3-, 4-, 5-, 6- or 7-membered ring, which
optionally includes 1, 2, 3 or 4 heteroatoms.
[0107] Y and Z, together with the atoms to which they are attached,
are optionally joined to form a 5-, 6- or 7-membered ring, which
can optionally have 1, 2 or 3 heteroatoms therein. As will be
apparent to those of skill in the art, when Y and Z are joined into
a ring, the substituents (e.g., R.sup.9, R.sup.10 and R.sup.11) on
atoms incorporated into the ring will be present (e.g.,
incorporated into the cyclic structure of the ring) or absent as
necessary to satisfy the valence of the atom to which these
substituents are attached.
[0108] In an exemplary embodiment, Y and Z independently represent
halogen, CF.sub.3, CN, OR.sup.9, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted heterocycloalkyl, NR.sup.10R.sup.11
and NO.sub.2. Y and Z, together with the atoms to which they are
attached, are optionally joined to form a 6- or 7-membered ring,
which can optionally have 1, 2 or 3 heteroatoms therein.
[0109] In an exemplary embodiment, the compound of the invention
does not have a structure according to the following formula:
##STR00003## ##STR00004##
[0110] In another exemplary embodiment, the compound does not have
a structure according to the following formula:
##STR00005## ##STR00006##
[0111] In an exemplary embodiment, the compound has a structure
such that when either Y or Z is H, then R.sup.9 is other than a
member selected from H and substituted or unsubstituted alkyl. In
an exemplary embodiment, the compound has a structure such that
when either Y or Z is H, then R.sup.9 is other than a member
selected from H and unsubstituted alkyl. In an exemplary
embodiment, the compound has a structure such that when either Y or
Z is H, then R.sup.9 is other than a member selected from H, methyl
or ethyl.
[0112] In an exemplary embodiment, the compound has a structure
such that R.sup.5 is other than a member selected from H and
substituted or unsubstituted alkyl. In an exemplary embodiment, the
compound has a structure such that R.sup.5 is other than a member
selected from H and unsubstituted alkyl. In an exemplary
embodiment, the compound has a structure such that R.sup.5 is other
than a member selected from H, methyl and ethyl.
[0113] In various exemplary embodiments, the index s is 1. In an
exemplary embodiment, the index n is 1. In various embodiments,
both s and n are 1.
[0114] In an exemplary embodiment, Y and Z are independently
selected from H, halogen, CN and CF.sub.3. In various embodiments,
at least one of Y and Z is other than H. In exemplary embodiments,
both Y and Z are other than H.
[0115] In an exemplary embodiment, R.sup.3 and R.sup.4 are members
independently selected from substituted or unsubstituted
C.sub.1-C.sub.4 alkyl and substituted or unsubstituted
C.sub.1-C.sub.4 heteroalkyl. In an exemplary embodiment, R.sup.3
and R.sup.4 are members independently selected from the group
consisting of substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl and substituted or unsubstituted
cycloalkyl.
[0116] In various embodiments, the compounds of the invention have
a structure which is a member selected from the group consisting
of:
##STR00007##
[0117] In selected embodiments, the compounds of the invention have
a structure selected from Formulae II and IIa:
##STR00008##
Exemplary compounds according to Formulae II and IIa include:
##STR00009##
[0118] In an exemplary embodiment, Y and Z are members
independently selected from the group consisting of H, halogen, CN
and CF.sub.3. In an exemplary embodiment, Y and Z are halogen. In
an exemplary embodiment, Y and Z are chloro. In an exemplary
embodiment, s is 1. In an exemplary embodiment, n is 1. In an
exemplary embodiment, R.sup.5 and R.sup.2 are H. In an exemplary
embodiment, A is H. In another exemplary embodiment, R.sup.1 and
R.sup.2 are H, and A is H.
[0119] In selected embodiments, the compounds of the invention have
a structure selected from Formulae III and IIIa:
##STR00010##
[0120] Exemplary compounds according to Formulae III and IIIa
include:
##STR00011##
[0121] In an exemplary embodiment, Y and Z are members
independently selected from the group consisting of H, halogen, CN
and CF.sub.3. In an exemplary embodiment, Y and Z are halogen. In
an exemplary embodiment, Y and Z are chloro. In an exemplary
embodiment, s is 1. In an exemplary embodiment, n is 1. In an
exemplary embodiment, R.sup.1 and R.sup.2 are H. In an exemplary
embodiment, A is H. In another exemplary embodiment, R.sup.1 and
R.sup.2 are H, and A is H.
[0122] In an exemplary embodiment, the compound has a structure
according to Formula (IV):
##STR00012##
wherein Y and Z are independently selected halogens. In an
exemplary embodiment, the compounds have a structure according
to:
##STR00013##
[0123] In an exemplary embodiment, the compounds have a structure
according to:
##STR00014##
[0124] In another embodiment, Y is a member selected from F and Cl.
In another embodiment, Z is a member selected from F and Cl. In
another embodiment, Y is Cl and Z is Cl. In another embodiment, Y
is F and Z is Cl. In another embodiment, Y is Cl and Z is F.
[0125] In an exemplary embodiment, the compound has a structure
according to Formula (V):
##STR00015##
wherein Y and Z are independently selected halogens. In an
exemplary embodiment, the compounds have a structure according
to:
##STR00016##
[0126] In an exemplary embodiment, the compounds have a structure
according to:
##STR00017##
[0127] In another embodiment, Y is a member selected from F and Cl.
In another embodiment, Z is a member selected from F and Cl. In
another embodiment, Y is Cl and Z is Cl. In another embodiment Y is
F and Z Is Cl. In another embodiment, Y is Cl and Z is F.
[0128] An exemplary compound of the invention has the formula:
##STR00018##
in which R.sup.4 is either H or CH.sub.3.
[0129] In an exemplary embodiment, the compound has a structure
according to Formula (VI):
##STR00019##
[0130] In another exemplary embodiment, the compound having this
structure has at least one member selected from Y and Z which is a
halogen. In another exemplary embodiment, Y and Z are halogen. In
another embodiment, Y is a member selected from F and Cl. In
another embodiment, Z is a member selected from F and Cl. In
another embodiment, Y is Cl and Z is Cl. In another embodiment, Y
is F and Z is Cl. In another embodiment, Y is Cl and Z is F.
[0131] In an exemplary embodiment, the compound has a structure
according to Formula (VII):
##STR00020##
wherein Y and Z are not H and A is a member selected from
substituted or unsubstituted alkyl. In another exemplary
embodiment, the compound having this structure has at least one
member selected from Y and Z which is a halogen. In another
exemplary embodiment, Y and Z are halogen. In another embodiment, Y
is a member selected from F and Cl. In another embodiment, Z is a
member selected from F and Cl. In another embodiment, Y is Cl and Z
is Cl. In another embodiment, Y is F and Z is Cl. In another
embodiment, Y is Cl and Z is F. In an exemplary embodiment, A is
substituted or unsubstituted methyl. In an exemplary embodiment, A
is methyl.
[0132] In an exemplary embodiment, the compound has a structure
according to Formula (VIII):
##STR00021##
wherein Y and Z are not H and R.sup.3 and R.sup.4 are each
independently selected from H and substituted or unsubstituted
alkyl. In another exemplary embodiment, R.sup.3 and R.sup.4 are
each independently selected from H and substituted or unsubstituted
methyl. In another exemplary embodiment, R.sup.3 and R.sup.4 are
each independently selected from H and methyl. In another exemplary
embodiment, the compound having this structure has at least one
member selected from Y and Z which is a halogen. In another
exemplary embodiment, Y and Z are halogen. In another embodiment, Y
is a member selected from F and Cl. In another embodiment, Z is a
member selected from F and Cl. In another embodiment, Y is Cl and Z
is Cl. In another embodiment, Y is F and Z is Cl. In another
embodiment, Y is Cl and Z is F.
[0133] Exemplary compounds of the invention have a structure
according to the following formulae:
##STR00022##
in which A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are each
independently selected from O, S, N(R.sup.b).sub.b, and
C(R.sup.b).sub.b(R.sup.c). The index a is an integer selected from
0, 1 and 2. The index b is 0 or 1 as needed to satisfy the valence
requirements of the atom to which it is attached. R.sup.b and
R.sup.c are member independently selected from H, halogen,
CF.sub.3, CN, OR.sup.14, SR.sup.14, NR.sup.15R.sup.16,
NR.sup.15S(O).sub.2R.sup.14, NR.sup.15C(O)R.sup.14,
S(O).sub.2R.sup.14, acyl, C(O)OR.sup.14, C(O)NR.sup.15R.sup.16,
S(O).sub.2NR.sup.15R.sup.16, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocycloalkyl. Each R.sup.14,
R.sup.15 and R.sup.16 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.14, R.sup.15 and R.sup.16, together with the atoms to which
they are attached, are optionally joined to form a 3-, 4-, 5-, 6-
or 7-membered ring, which optionally includes 1, 2 or 3
heteroatoms.
[0134] In an exemplary embodiment, R.sup.b and R.sup.c 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).
[0135] In an exemplary embodiment, Y and Z are joined to form a
fused ring system having 5, 6 or 7 members and, optionally
including 1, 2 or 3 heteroatoms. Hence, in one embodiment, the
phenyl ring substituent has the structure:
##STR00023##
in which, ring L is substituted or unsubstituted, saturated or
unsaturated cycloalkyl or heterocycloalkyl, or it is substituted or
unsubstituted aryl or heteroaryl.
[0136] An exemplary fused ring structure is:
##STR00024##
in which A.sup.1, A.sup.2, A.sup.3 and A.sup.4 and a are described
herein.
[0137] 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, e.g., a primary or secondary amine.
B. Compositions Including Stereoisomers
[0138] 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 enantiomers, diastereomers, racemic
mixtures, enantiomerically enriched mixtures, and
diastereomerically enriched mixture. Additional asymmetric carbon
atoms may be present in a substituent such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in this invention.
[0139] 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).
[0140] 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.
[0141] 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".
[0142] For example, the term "enantiomeric excess" is well known in
the art and is defined as:
ee a = ( conc . of a - conc . of b conc . of a + conc . of b )
.times. 100 ##EQU00001##
[0143] 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 of 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.
[0144] 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 as 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
[0145] Compounds of the invention may be synthesized as pure cis
isomers or a racemic mixture, 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. Stereochemical 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.
[0146] Stereochemical-configurations are defined according to the
relative configuration of the amine-bearing side chain and the
substituent on the cycloalkyl ring. When more than one substituent
is present, the higher order (IUPAC) substituent is used for the
determination of stereochemical-configuration.
[0147] Compounds of the invention may be synthesized according to
the schemes set forth below. It is within the abilities of a person
skilled in the art to select appropriate alternative reagents
replacing the exemplary reagents shown in the schemes 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.
2. General Synthesis of Cycloalkylamines
[0148] In one embodiment, the compounds of the invention were
synthesized from the corresponding amino ketone a as shown in
Scheme 1, below.
##STR00025##
[0149] Dimethylaminomethyl cyclohexanone a was condensed with aryl
Grignard reagents b-d to give racemic amino alcohols. The racemic
products were purified by chiral chromatography on a
semi-preparative chiralpak AD column to give enantiomers 1, 24 and
28, and 2, 26 and 27. In addition to the values of R.sup.y and
R.sup.x disclosed in Scheme 1, R.sup.y and R.sup.x are members
independently selected from substituted or unsubstituted alkyl, Cl,
Br, F, NR.sup.10R.sup.11, OR.sup.9, SR.sup.9 and substituted or
unsubstituted aryl.
##STR00026##
[0150] Referring to Scheme 2, the parent primary amine for 2,
compound 9, was obtained via chiral HPLC separation of racemic
cis-2-(aminomethyl)-1-(3,4-dichlorphenyl)cyclohexanol into
consititutive isomers 8 (faster moving enantiomer) and 9 (slower
moving enantiomer). 9 was converted to 2 via reductive animation
with formic acid, formaldehyde and sodium cyanoborohydride. 2 was
also obtained as the slower moving enantiomer after chiral HPLC
separation of racemic
cis-1-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol;
reduction of 2 in a two step procedure with DEAD and acidic EtOH
provided mono-methyl derivative 4.
D. Pharmaceutical Compositions
[0151] In an exemplary aspect, the invention provides a
pharmaceutical composition including a compound described herein or
a pharmaceutically acceptable salt or solvate thereof, and at least
one pharmaceutically acceptable carrier. In various embodiments,
the compound is a cis isomer. In an exemplary embodiment, the
compound has a structure which is a member selected from Formulae
(I) to (IX).
[0152] 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.
[0153] 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.
[0154] 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.
[0155] Exemplary unit dosage formulations are those containing an
effective dose, or an appropriate fraction thereof, of the active
ingredient, or a pharmaceutically acceptable salt thereof. The
magnitude of a prophylactic or therapeutic dose typically varies
with the nature and severity of the condition to be treated and the
route of administration. The dose, and perhaps the dose frequency,
will also vary according to the age, body weight and response of
the individual patient. In general, the total daily dose (in single
or divided doses) ranges from about 1 mg per day to about 7000 mg
per day, preferably about 1 mg per day to about 100 mg per day, and
more preferably, from about 10 mg per day to about 100 mg per day,
and even more preferably from about 20 mg to about 100 mg, to about
80 mg or to about 60 mg. In some embodiments, the total daily dose
may range from about 50 mg to about 500 mg per day, and preferably,
about 100 mg to about 500 mg per day. It is further recommended
that children, patients over 65 years old, and those with impaired
renal or hepatic function, initially receive low doses and that the
dosage be titrated based on individual responses and/or blood
levels. It may be necessary to use dosages outside these ranges in
some cases, as will be apparent to those in the art. Further, it is
noted that the clinician or treating physician knows how and when
to interrupt, adjust or terminate therapy in conjunction with
individual patient's response.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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, sialic acid 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.
[0160] 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.
[0161] 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 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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; 3,398,123; 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,
hydroxypropylmethyl 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 th us 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] Suitable excipients (e.g., earners 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.
[0175] 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.
[0176] 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.
[0177] 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.
[0178] 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.
[0179] 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 intrastemal injection and
infusion.
[0180] 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.
[0181] 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.
[0182] 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, oral, 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. In an exemplary embodiment the
oral dose of a compound of the invention will range from about 10
mg to about 300 mg per day. In an exemplary embodiment, the oral
dose of a compound of the invention will range from about 20 mg to
about 250 mg per day. In an exemplary embodiment, the oral dose of
a compound of the invention will range from about 100 mg to about
300 mg per day. In an exemplary embodiment, the oral dose of a
compound of the invention will range from about 10 mg to about 100
mg per day. In an exemplary embodiment, the oral dose of a compound
of the invention will range from about 25 mg to about 50 mg per
day. In an exemplary embodiment, the oral dose of a compound of the
invention will range from about 50 mg to about 200 mg per day. Each
of the above-recited dosage ranges may be formulated as a unit
dosage formulation.
[0183] The terms "treatment" or "treating" is intended to encompass
therapy, 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. The compounds of the invention
can also be used to prevent a disease (prophylaxis).
[0184] 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.
[0185] 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.
[0186] In an exemplary embodiment, the subject exhibiting an
indication for which a compound of the invention is therapeutically
efficacious is not otherwise in need of treatment with a compound
of the invention or a compound falling within the structural genus
encompassing the compounds of the invention.
IV. Methods
A. Binding To Monoamine Transporter
[0187] In various aspects 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.
[0188] The invention further 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.
[0189] In an exemplary embodiment, inhibition of ligand binding is
shown using an ex vivo binding assay, such as those described
herein. 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
[0190] In various embodiments, 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, or a pharmaceutically acceptable salt or solvate
thereof. The subject can be a human. In an exemplary embodiment,
the monoamine transporter is dopamine transporter (DAT), serotonin
transporter (SERT) or norepinephrine transporter (NET). In various
exemplary embodiments, 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. In an exemplary embodiment, the
functional uptake assay utilizes an appropriate cell-line
expressing a desired monoamine transporter. In various exemplary
embodiments, 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. An exemplary 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
[0191] In various aspects, 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.
[0192] 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, labeled monoamine.
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 nM in a
functional monoamine uptake assay, such as those described herein
below.
D. Treatment of Neurological Disorders
[0193] In another aspect, the invention provides a method of
treating a neurological disorder by inhibiting the activity at
least one monoamine transporter. The method includes administering
to a subject in need thereof a therapeutically effective amount of
a composition or compound of the invention, or a pharmaceutically
acceptable salt or solvate thereof. 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.
[0194] Demonstration of compound activity can be performed in
various art-recognized animal models. For example, 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. 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.
[0195] In an various embodiments, the compounds of the invention
are active in at least one animal model, which can be used to
measure the activity of the compounds and estimate their efficacy
in treating a neuroligal disorder. For example, when the animal
model is for depression (e.g., mean immobility), 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 % more preferably between about 1.0% and about 50%, more
preferably between about 15% and about 50% in at least one animal
model, when compared to vehicle. In various embodiments, the
compounds of the invention produce a similar disparity in measured
endpoint between treated animals and animals administered
vehicle.
[0196] In various embodiments, 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, 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.
[0197] In various exemplary embodiments, the neurological 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, cyclothymic disorder, obesity and substance
abuse or dependency (e.g. cocaine addiction, nicotine addiction).
In an exemplary embodiment, the neurological 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.
[0198] Neurological 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.
[0199] Neuropathic pain includes without limitation post herpetic
(or post-shingles) neuralgia, reflex sypathetic 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).
[0200] 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.
[0201] In an exemplary embodiment, the neurological disorder is
obesity, and the therapeutically effective amount of compound to
supply to a patient is enough so that said patient feels
satiated.
[0202] In an exemplary embodiment, the compounds described herein
treat/prevent a central nervous disorder, without causing addiction
to said compounds.
[0203] The following examples are provided to illustrate the
exemplary features of the invention.
EXAMPLES
[0204] The following examples are provided to illustrate selected
embodiments of the invention and are not to be construed as
limiting its scope.
Example 1
1a. General Procedures
[0205] 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 ware recorded on a Varian 400 MHz spectrometer in
deutcrochloroform 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.
1b. Analytical HPLC
[0206] 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=H2O 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).
1c. Reverse Phase HPLC Purification
[0207] Reverse phase HPLC purification was performed on a Gilson
system using a Phenomenex 5.mu. C18 (5.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).
1d. GC-MS
[0208] Gas chromotography was performed on a Hewlett Packard 6890
Series GC System with an HPI 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.
1e. LCMS
[0209] 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 NH.sub.4Ac in 95% H.sub.2O, 5% MeOH, pH 6.0, Solvent
B=Solvent B: 0.1 M NH.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.
1f. Microwave (.mu.W) Recrystallization
[0210] 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 recrysallized in CH.sub.3CN.
Example 2
2a. Experimental Procedures and Characterization Data
##STR00027##
[0212] To a solution of ketone a (2.0 g, 13 mmol) in THF (20 mL) at
-78.degree. C. was added 3,4-dichlorophenylmagnisium bromide (0.5 M
in THF, 38 mL, 19 mmol). The reaction mixture was stirred for 30
min at -78.degree. C. before being warmed to 0.degree. C. over 30
min. A saturated solution of NH.sub.4Cl (30 mL) was added to the
reaction mixture to quench the reaction. The resulting product was
extracted with diethyl ether (2.times.100 mL). The combined
extracts were dried and concentrated. The residue was subjected to
silica gel column chromatography (ethyl
acetate/hexane/Et.sub.3N=1:10:0.1) to give the racemic mixture of 1
and 2 (3.5 g, 90%). The racemic mixture was separated by chiral AD
column (hexane/iPrOH/DEA=95/5/0.1 as eluent) to give pure 1 (Faster
moving enantiomer) and 2 (Slower moving enantiomer).
2a1. Data for 1/2
[0213] .sup.1H NMR (440 MHz, CD3OD) .delta.7.73; (d, J=1.6 Hz, 1H),
7.52; (d, J=8.4 Hz, 1H), 7.47; (dd, J=1.6, 8.4 Hz, 1H), 3.01; (dd,
J=13.2, 10.4 Hz, 1H), 2.76; (s, 3H), 2.65; (s, 3 H), 2.57; (dd,
J=2.0, 13.2 Hz, 1H), 2.28; (m, 2H), 1.9; (m, 2H), 1.70; (m, 2H),
1.6; (m, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) .delta.148.86,
132.32, 130.32, 127.49, 125.08, 74.11, 60.22, 45.03, 41.22, 40.29,
25.71, 24.64, 21.16; ESI MS m/z 302.1, 304.0.
2b. Dealkylation of Cycloalkylamines
##STR00028##
[0215] To a solution of 2 (0.8 g, 2,65 mmol) in toluene was added
DEAD (0.69 g, 0.63 mL, 3.96 mmol). The reaction mixture was heated
at 100.degree. C. for 4 h before being concentrated. The residue
was dissolved in 30 mL of EtOH and a saturated solution of
NH.sub.4Cl (30 mL) was added. The reaction mixture was stirred at
50 for 6 h before being concentrated, NaOH solution (2 M, 10 mL)
was added to the resulting mixture and the product was extracted
with diethyl ether (2.times.80 mL). The combined extracts were
dried and concentrated. The residue was purified by reserve phase
column chromatography (CH.sub.3CN/H.sub.2O=5/95 to 95/5) to give 4
(0.32 g, 42%).
2b1. Data for 4
[0216] .sup.1H NMR (400 MHz, CD3OD) .delta.7.60; (s, 1H), 7.37; (m,
2H), 2.57; (dd, J=2.0, 12.4 Hz, 1H), 2.28; (dd, J=2.8, 12.4 Hz,
1H), 2.23; (s, 3H), 1.88; (m, 2H), 1.78; (m, 2H), 1.62; (m, 1H),
1.56; (m, 2H), 1.40; (m, 1H); .sup.13C NMR (100 MHz, CD.sub.3OD)
.delta.150.86, 132.40, 130.21, 130.09, 127.56, 124.77, 77.03,
53.54, 43.95, 40.82, 36.81, 26.45, 26.05, 22.05; ESI MS m/z
288.1.
2c. Synthesis of Cyclohexylamines from Cyclohexanone
##STR00029##
[0218] To a solution of cyclohexanone (23.7 g, 25.0 mL, 0.242 mol)
in H.sub.2O (50 mL) was added HCHO (37%, 37.5 mL, 0.46 mol) and
K.sub.2CO.sub.3 (0.52 g, 3.76 mmol). The reaction mixture was
stirred for three hours at 60.degree. C. Then the product was
extracted with diethyl ether (2.times.300 mL). The combined
extracts were dried and concentrated. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane=1.7 to 1:2)
to give k (10.8 g, 35%).
[0219] To a solution of k (3.2 g, 25 mmol) in THF (60 mL) at
-20.degree. C. was added 3,4-dichlorophenylmagnisium bromide
solution (0.5 M, 100 mL, 50 mmol). The reaction mixture was stirred
for 30 min before being quenched by NH.sub.4Cl solution (20 mL).
The product was then extracted by diethyl ether (2.times.100 mL).
The combined extracts were dried and concentrated. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=1:7 to 1:2) to give m (2.1 g, 31%).
[0220] To a solution of m (1.6 g, 5.8 mmol) in THF (40 mL) at r.t.
was added PPh.sub.3 (1.8 g, 7.0 mmol), DEAD (1.2 g, 7.0 mmol) and
diphenylphosphorazidate (DPPA) (1.9 g, 7.0 mmol). The resulting
yellow solution was stirred overnight before being concentrated.
The residue was subjected to silica gel column chromatography
(hexane/ethyl acetate)=1:10 to 1:1 to give the desired product n
(1.32 g, 74%).
[0221] To a solution of n (1.00 g, 3.34 mmol) in THF (30 mL) was
added PPh.sub.3 (1.75 g, 6.68 mmol). The reaction mixture was
stirred for 24 h before H.sub.2O (10 mL was added. The resulting
mixture was stirred for another 2 days before being concentrated.
The residue was subjected to reverse phase column chromatography
(CH.sub.3CN/H.sub.2O=5/95 to 95/5) to give the desired product o
(0.75 g, 82%). The racemic mixture was separated by chiral AD
column with (ethanol/methanol/hexane/DEA=3/2/95/0.1) to give the
pure enantiomer 8 (Faster moving enantiomer) and 9 (Slower moving
enantiomer).
##STR00030##
2e1. Data for 8/9
[0222] .sup.1H NMR (400 MHz, CD3OD) .delta.7.73; (broad, 1H), 7.40;
(d, J=8.4 Hz, 1H), 7.30; (m, 2H), 2.69; (dd, J=2.0, 13.2 Hz, 1H),
2.56; (dd, J=2.8, 13.2 Hz, 1H), 2.20; (m, 2H), 1.80; (m, 2H), 2.28;
(m, 2H), 1.60; (m, 2H), 1.50 (m, 3H); .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta.150.75, 132.38, 130.19, 130.06, 127.64, 124.81,
77.28, 43.63, 43.45, 41.16, 26.38, 25.34, 22.06; ESI MS m/z 274.1,
276.0.
[0223] Compound 9 was converted to 2 via reductive amination with
formaldehyde.
##STR00031##
Example 3
3a. Experimental Procedures
##STR00032##
[0225] Experimental conditions utilized for these syntheses were
similarly to those employed in Examples 1 and 2.
##STR00033##
[0226] Experimental conditions utilized for these syntheses were
similar to those employed in Examples 1 and 2.
Example 4
4a. In Vitro Human 5-HT/NE/DA Reuptake Inhibition Data
[0227] Compounds 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 straiatum, respectively, and/or using recombinant human
transporters. Details of the assays are described in US
2007/0203111 A1, which is incorporated by reference. Results for
functional uptake assay for human reuptake transporters are shown
below.
TABLE-US-00001 Corporate ID 5-HT IC.sub.50 (nM) NE IC.sub.50 (nM)
DA IC.sub.50 (nM) 2 +++ * # 4 ++++ * # 9 ++++ *** # 1 + ** ## 8 +++
**** ## 5-HT IC50 NE IC50 DA IC50 1-2000 nM (+) 10-200 nM (*)
10-200 nM (#) 2001-7000 nM (++) 201-1000 nM (**) 201-1000 nM (##)
7001-10000 nM (+++) 1001-5000 nM (***) 1001-5000 nM (###) >10001
nM (++++) >5001 nM (****) 5001-10000 nM (####)
4b. In Vitro PK Data (Human Metabolic Stability, Inhibition of
CYP450 Enzymes, Inhibition of HERG Current)
TABLE-US-00002 [0228] CYP inhibition IC.sub.50 Corporate HLM
t.sub.1/2 HERG IC.sub.50 (microM) 5 isoforms (2D6, ID (min)
(microM) 2C9, 3A4, 2C19, 1a) 2 + ** ## 4 ++ * # 1 + -- -- HLM t1/2
HERG IC50 CYPI IC50 25-175 min (+) 1-15 .mu.M (*) >10 .mu.M (#)
176-325 min (++) 16-30 .mu.M (**) >20 .mu.M (##)
4c. Tail Suspension Test, Locomotor Activity Test and Forced Swim
Test
4c1. Mouse Tail Suspension Test
[0229] 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.
[0230] 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 twelved mice were tested in
each group. 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.
[0231] Data were analyzed by one way analysis of variance (ANOVA)
followed by pose-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).
4c2. Locomotor Activity
[0232] 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 movements of the
animals. Horizontal and vertical activity were measured.
[0233] Rats or mice were pretreated with vehicle or test compounds
and placed back in home cage, following which they were
individually placed in locomotor cages and activity was monitored
in 1-5 minute intervals for intervals up to 60 min.
[0234] 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).
4c3. Result Summary
[0235] Effects of compounds of the invention were evaluated in the
mouse trail suspension and locomotor activity test. Results showed
that all compounds tested 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.
[0236] Effects of compounds of the invention were also evaluated in
the rat forced swim and locomotor activity tests. All compound
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). Similar to the mouse tail suspension results, the rat
forced swim test also showed anti-depressant like activity for this
compound.
Mouse Tail Suspension and Locomotor Activity Results
TABLE-US-00003 [0237] Treatment Dose Mouse Tail Suspension (mg/kg,
Mean Immobility Mouse Locomotor Activity PO) Time .+-. S.E.M. Total
Distance Traveled .+-. S.E.M. 2 0 +++ *** 0.3 +++ ** 1 +++ ** 3 +
*** 2 0 ++++ ** 3 +++ ** 10 + **** 30 + * 4 1 ++++ ** 3 ++++ ** 10
+++ *** 30 + * Mouse Tail Suspension Mouse Locomotor Activity
100-160 (+) 100-500 (*) 161-170 (++) 501-700 (**) 171-190 (+++)
701-900 (***) >191 (++++) >901 (****)
[0238] After the TST, brain and plasma samples were collected from
4 representative mice from each treatment group for analysis of 2
and 4 exposure levels in these tissues. 2 exhibited a
does-dependent decrease in immobility in this test (see above).
Significant levels of the 4 metabolite were found in plasma and
brain levels subsequent to oral 2 administration.
4c4. Rat Forced Swim Test
[0239] 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.
[0240] 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.
[0241] Data were analyzed by one way analysis of variance (ANOVA)
followed by post-hoc comparisons where appropriated. 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.).
Rat Forced Swim and Locomotor Activity Results
TABLE-US-00004 [0242] Rat Locomotor Treatment Rat Forced Swim
Activity Dose (Means .+-. S.E.M.) Total Distance (mg/kg, PO)
Immobility Swimming Climbing Traveled .+-. S.E.M. 2 0 +++ * #
.smallcircle. 1 +++ * ## .smallcircle. 3 +++ * # .smallcircle. 10 +
** ### .smallcircle..smallcircle..smallcircle. Immobility Swimming
Climbing Total Distance Traveled 1-20 (+) 1-5 (*) 1-10 (#) 100-2500
(.smallcircle.) 21-40 (++) 6-9 (**) 11-20 (##) 2501-5000
(.smallcircle..smallcircle.) >41 (+++) >10 (***) >21 (###)
>5001 (.smallcircle..smallcircle..smallcircle.)
Example 5
5a. Ex Vivo Binding Assay
[0243] 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.
[0244] C57BL/6 mice (25-30 g) were dosed orally with either vehicle
or compound at 4 dose level. 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.
[0245] Frontal cortex from each hemisphere or striata was
homogenized individually in ice-cold assay buffer using a tight
fitting glass/Teflon homogenizer and used immediately in the
binding assay.
5b. [.sup.3H] Citalopram Binding to 5-HT Transporter (SERT) Sites
in Mouse Brain
[0246] Cortical membranes (400 .mu.L; equivalents 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.
5c. [.sup.3H] Nisoxetine Binding to Norepinephrine Transporter
(NET) Sites in Mouse Brain
[0247] Cortical membranes (400 .mu.L; equivalent to 6.0 mg wet
weight of tissue/tube) were incubated with 50 .mu.L of [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.
5d. [.sup.3H] WIN 35428 Binding to DA Transporter (DAT) Sites in
Mouse Brain
[0248] Striatal membranes (200 .mu.L; equivalent to 2 mg wet weight
of tissue/tube) were incubated with 25 .mu.L of [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.
[0249] 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).
5e. Data Analysis
[0250] 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%.
5f. Results Summary
[0251] Ex vivo SERT, NET and DAT binding/receptor occupancy data
were generated for 2.
Ex Vivo Biding Profile of 2 in Mice
TABLE-US-00005 [0252] Treatment Mean Specific Binding (dpm) .+-.
S.E.M. Dose, (Values in Brackets Denote % Transporter Occupancy)
(mg/kg PO) NET SERT DAT 2 0 1050 .+-. 34 3302 .+-. 111 43327 .+-.
4273 1 845 .+-. 44 (19)* 2926 .+-. 119 (11) 36886 .+-. 1873 (15) 3
583 .+-. 20 (44)* 3330 .+-. 176 (-1) 21744 .+-. 1050 (50)* 10 271
.+-. 12 (74)* 3104 .+-. 131 (6) 8941 .+-. 305 (79)* 30 115 .+-. 13
(89)* 3126 .+-. 204 (5) 4236 .+-. 538 (90)*
Example 6
Summary of Selected In Vitro Data for Test Compounds
TABLE-US-00006 [0253] 5-HT NE DA IC50 nM IC50 nM IC50 nM 1 + ** ##
2 + * # 4 ++++ * # 7 ++ ** # 8 +++ **** ## 9 ++++ *** # 10 ++ ** #
11 + ** # 12 A/B +++ **** ### 13 A/B n.t n.t. n.t. 14 A/B ++ ****
## 15 A/B ++ **** ## 16 A/B + **** # 17 A/B ++ **** ## 18 A/B +++
*** # 19 A/B n.t n.t. n.t. 20 A/B n.t n.t. n.t. 21 A/B + **** # 22
A/B n.t n.t. n.t. 23 A/B ++ **** ## 24 +++ **** #### 25 ++++ * # 26
+ *** #### 27 ++ * ## 5-HT IC50 NE IC50 DA IC50 1-2000 nM (+)
10-200 nM (*) 10-200 nM (#) 2001-7000 nM (++) 201-1000 nM (**)
201-1000 nM (##) 7001-10000 nM (+++) 1001-5000 nM (***) 1001-5000
nM (###) >10001 nM (++++) >5001 nM (****) 5001-10000 nM
(####) Human Liver Microsome = HLM; Rat Liver Microsome = RLM;
Mouse Liver Microsome = MLM.
Example 7
7a. Resperine Rat Model
[0254] The effects of compound 4 alone and in combination with
L-DOPA were evaluated in the resperine-treated rat Parkinson's
disease model. The method, which detects antiparkinson activity
(reveral of motor deficits and akinesia), follows that described by
Johnson et al. (Exp. Neurol. 191, 243-250, 2005). Eighteen hours
prior to behavioural testing, rats were lightly anaesthetized with
isoflurane and reserpine (3 mg/kg, sc) was injected along with
saline (50 ml/kg) to prevent dehydration.
7b. Behavioral Assessment
[0255] Accelerating Rotarod: Performance on an accelerating rotarod
was assessed using a 4-station rat rotarod (MedAssociates, USA).
The speed of rotation of the rotarod was increased from 3.5 to 35
rpm over 5 minutes and the time for which the animal remained on
the rod determined as the mean of three trials.
[0256] Catalepsy Test: Catalepsy was assessed by placing the rat's
forepaws on top of a horizontal wooden rod suspended 6 cm above the
bench surface. Time taken to remove both paws from the rod was
recorded, up to a maximum of 120 seconds. Three trials per animal
were conducted.
[0257] Open Field: Activity in an open field arena was assessed
using automated activity monitors (Linton Instrumentation, UK).
Rats were placed in the activity boxes and locomotor activity was
recorded over a 240 minute period.
[0258] Drug Administration: For the monotherapy experiment, the
effects of 5 different treatments were assessed: 1) vehicle
(sterile water, PO), 2) 3 mg/kg compound 4 (PO), 3) 10 mg/kg
compound 4 (PO), 4) 30 mg/kg compound 4 and 5) 80 mg/kg (IP) of the
positive reference substance, L-DOPA (80 mg/kg). In the combination
experiment, 5 different treatments were assessed: 1) compound 4
vehicle (PO)+L-DOPA vehicle (IP), 2) compound 4 (10 mg/kg,
PO)+L-DOPA vehicle (IP), 3) compound 4 vehicle (PO)+L-DOPA (30
mg/kg, IP), 4) compound 4 (10 mg/kg, PO)+L-DOPA (30 mg/kg, IP) and
5) compound 4 vehicle (PO)+L-DOPA (80 mg/kg, IP). Treatments were
given in a randomized fashion and each animal received all
treatment conditions. Compound 4 was administered 60 minutes prior
to behavioral assessment and L-DOPA was administered immediately
prior to behavioral testing.
[0259] Results showed that compound 4 (3-30 mg/kg, PO) alone
dose-dependently improved performance in a variety of behavioral
tests (baseline locomotor activity, FIG. 2, rotarod, FIG. 3, and
catalepsy, FIG. 4). Depending upon the behavioral test, effects of
compound 4 were similar or smaller than those observed with L-DOPA
(80 mg/kg). In the combination experiment, the combination of
compound 4 (10 mg/kg, PO) and low dose L-DOPA (30 mg/kg) showed
effects that were equal in magnitude and of longer duration than
those provided by a higher dose of L-DOPA does (80 mg/kg). FIG.
5.
[0260] The data suggest that compound 4 may have some
anti-parkinsonian actions as monotherapy although effects are not
as powerful as L-DOPA. The combination compound 4 and low does
L-DOPA experiments indicated anti-parkinsonian actions that were
equal in magnitude and of longer duration than those provided by a
higher L-DOPA dose. Compound, 4 could thus be described as "L-DOPA
sparing".
Example 8
8a. Rat Unilateral 6-hydroxydopamine (6-OHDA) Lesion Model
[0261] The effects of compound 4 alone and in combination with
L-DOPA were evaluated in the rodent 6-OHDA-lesioned rat Parkinson's
disease model. The method, which detects antiparkinson activity
(reveral of motor deficits and akinesia), follows that described by
Henry et al. (Exp Neurol, 151(2):334-42, 1998).
[0262] Animal Preparation: Prior to surgery, rats were administered
pargyline (5 mg/kg, ip) and desipramine (25 mg/kg ip) to optimize
subsequent 6-OHDA availability and increase specificity for
toxicity to dopaminergic neurons. Rats were then anesthetized with
isoflurane and placed in a stereotaxic frame. After exposure of
Bregma, a burr hole was drilled in the skull above the right median
forebrain bundle at co-ordinates: 2.8 mm posterior and 2 mm lateral
to Bregma (according to the atlas of Paxinos and Watson, 1986). A
28G Hamilton needle was then lowered 9 mm below the skull.
Injection of 6-OHDA (12.5 .mu.g in 2.5 .mu.l) was then made (1
.mu.l/min). The needle was then left in place for 4 minutes to
ensure complete absorption of the solution. After slow retraction
of the injection needle, the wound was closed and animals were
administered saline (50 ml/kg, sc), an analgesic (Ketonprofen, 0.5
mg/kg) and a broad spectrum antibiotic (enrofloxacin, 75 mg/kg).
Following surgery, animals were left untreated for 3 weeks to allow
the lesion to develop and stabilize prior to the start of
behavioral assessment.
8b. Behavioral Assessment
[0263] Paw Placing Test: The paw placing test assesses correct
placing of each forepaw in response to a sensory stimulus. Rats
were gently held by their torsos and each forepaw was restrained
between thumb and forefinger whilst allowing the opposite paw to
hang free. The rat was then held parallel to the edge of a table
with the free forelimb placed adjacent to the edge. The animal was
then moved towards the table and the vibrissae brushed against the
table edge to elicit a forelimb placing response from the free
limb. A total of ten trials were conducted in quick succession
before repeating the procedure for the other paw. The test was
quantified as the percentage of successful placing responses of the
limb contralateral to the side of the 6-OHDA lesion. Placement of
the limb ipsilateral to the side of the lesion was successful in
100% of cases in all animals.
[0264] Drug Administration: For the monotherapy experiment, the
effects of 5 different treatments were assessed: 1) vehicle
(sterile water, PO), 2) 3 mg/kg compound 4 (PO), 3) 10 mg/kg
compound 4 (PO), 4) 30 mg/kg compound 4 and 5) 6.5 mg/kg (IP) of
the positive reference substance, L-DOPA. In the combination
experiment, 5 different treatments were assessed: 1) compound 4
vehicle (PO)+L-DOPA vehicle (IP), 2) compound 4 (10 mg/kg,
PO)+L-DOPA vehicle (IP), 3) compound 4 vehicle (PO)+L-DOPA (2
mg/kg, IP), 4) compound 4 (10 mg/kg, PO)+L-DOPA (2 mg/kg, IP) and
5) compound 4 vehicle (PO)+L-DOPA (6.5 mg/kg, IP). Treatments were
given in a randomized fashion and each animal received each
treatment condition. Compound 4 was administered 60 minutes prior
to behavioral assessment and L-DOPA was administered immediately
prior to behavioral testing.
[0265] Results showed that compound 4 (3-30 mg/kg, PO) alone
produced little or no improvement in performance in the paw
placement task. The combination of compound 4 (10 mg/kg, PO) and
low does L-DOPA significantly increased paw placement performance
providing some evidence of synergy between actions of compound 4
and L-DOPA (FIG. 6).
[0266] 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 modification 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.
[0267] All patents, patent applications, and other publications
cited in this application are incorporated by reference herein in
their entirety for all purposes.
* * * * *