U.S. patent application number 16/057701 was filed with the patent office on 2018-12-06 for methods of treating alpha adrenergic mediated conditions.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to Ken Chow, John E. Donello, Wenkui K. Fang, Michael E. Garst, Daniel W. Gil, Dario G. Gomez, Todd M. Heidelbaugh, Phong X. Nguyen, Santosh C. Sinha.
Application Number | 20180344692 16/057701 |
Document ID | / |
Family ID | 46317883 |
Filed Date | 2018-12-06 |
United States Patent
Application |
20180344692 |
Kind Code |
A1 |
Gil; Daniel W. ; et
al. |
December 6, 2018 |
METHODS OF TREATING ALPHA ADRENERGIC MEDIATED CONDITIONS
Abstract
Described herein are compounds for and methods of treating
conditions or diseases in a subject by administering to the subject
a pharmaceutical composition containing an effective amount of an
.alpha.-adrenergic modulator. The compounds and methods are also
useful for alleviating types of pain, acute, neuropathic and
chronic.
Inventors: |
Gil; Daniel W.; (Corona del
Mar, CA) ; Donello; John E.; (Dana Point, CA)
; Fang; Wenkui K.; (Irvine, CA) ; Nguyen; Phong
X.; (Placentia, CA) ; Chow; Ken; (Newport
Coast, CA) ; Heidelbaugh; Todd M.; (Fountain Valley,
CA) ; Gomez; Dario G.; (Laguna Niguel, CA) ;
Garst; Michael E.; (Newport Beach, CA) ; Sinha;
Santosh C.; (Ladera Ranch, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
|
|
Family ID: |
46317883 |
Appl. No.: |
16/057701 |
Filed: |
August 7, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15819838 |
Nov 21, 2017 |
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16057701 |
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15446650 |
Mar 1, 2017 |
9849113 |
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15819838 |
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14692042 |
Apr 21, 2015 |
9623006 |
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15446650 |
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13275029 |
Oct 17, 2011 |
9034910 |
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14692042 |
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12479129 |
Jun 5, 2009 |
8071636 |
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13275029 |
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61059837 |
Jun 9, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 233/48 20130101; A61P 25/00 20180101; A61K 31/40 20130101;
A61K 31/4168 20130101; C07D 233/50 20130101; A61K 31/4174 20130101;
A61K 9/0053 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating a condition or disease alleviated by
activation of .alpha.-adrenergic receptors in a mammal, the method
comprising administering to the mammal in need of such treatment a
pharmaceutically effective dose of
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine having the
following structure: ##STR00036## or a pharmaceutically acceptable
salt thereof.
2. The method of claim 1, wherein the condition or disease is
selected from the group consisting of hypertension, congestive
heart failure, asthma, depression, glaucoma, elevated intraocular
pressure, ischemic neuropathies, optic neuropathy, pain, visceral
pain, corneal pain, headache pain, migraine, cancer pain, back
pain, irritable bowel syndrome pain, muscle pain, pain associated
with diabetic neuropathy, the treatment of diabetic retinopathy,
other retinal degenerative conditions, stroke, cognitive deficits,
neuropsychiatric conditions, drug dependence, drug addiction,
withdrawal symptoms, obsessive compulsive disorder, obesity,
insulin resistance, stress related conditions, diarrhea, diuresis,
nasal congestions, spasticity, attention deficit disorder,
psychoses, anxiety, autoimmune disease, Crohn's disease, gastritis,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, and other neurodegenerative diseases.
3. The method of claim 1, wherein the dose is administered by an
oral route.
4. The method of claim 3, wherein the dose is orally administered
in the form of a tablet, liquid, capsule or powder.
5. The method of claim 1, wherein the dose is administered by a
transdermal, parenteral, subcutaneous, intranasal, intrathecal,
intramuscular, intravenous or intrarectal route.
6. The method of claim 1, wherein the mammal is a human.
7. A pharmaceutical composition comprising a compound having the
structure: ##STR00037## or a pharmaceutically acceptable salt or
imine tautomer thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/819,838, filed Nov. 21, 2017, which is a
continuation of U.S. patent application Ser. No. 15/446,650 filed
Mar. 1, 2017, now U.S. Pat. No. 9,849,113, issued Dec. 26, 2017,
which is a continuation of U.S. patent application Ser. No.
14/692,042 filed Apr. 21, 2015, now U.S. Pat. No. 9,623,006, issued
Apr. 18, 2017, which is a continuation of U.S. patent application
Ser. No. 13/275,029, filed Oct. 17, 2011, now U.S. Pat. No.
9,034,910, issued May 19, 2015, which is a continuation-in-part of
U.S. patent application Ser. No. 12/479,129, filed Jun. 5, 2009,
now U.S. Pat. No. 8,071,636, issued Dec. 6, 2011, and which claims
the benefit of U.S. Provisional Application No. 61/059,837 filed
Jun. 9, 2008, each of which are incorporated herein by reference in
their entireties and serve as the basis for a priority and/or
benefit claim for the present application.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of using compounds
as disclosed herein to treat pain.
BACKGROUND OF THE INVENTION
[0003] Clinical pain encompasses nociceptive and neuropathic pain.
Each type of pain is characterized by hypersensitivity at the site
of damage and in adjacent normal tissue. While nociceptive pain
usually is limited in duration and responds well to available
opioid therapy, neuropathic pain can persist long after the
initiating event has healed, as is evident, for example, in the
"ghost pain" that often follows amputation. Chronic pain syndromes
such as chronic neuropathic pain are triggered by any of a variety
of insults, including surgery, compression injury or trauma,
infectious agent, toxic drug, inflammatory disorder, or a metabolic
disease such as diabetes or ischemic.
[0004] Neuropathic pain is a unique kind of chronic pain that is
distinct from acute pain or inflammatory pain. Neuropathic pain, in
contrast to most types of pain, persists in the absence of any
detectable, on-going tissue injury process. It is common in
patients that experience nerve injury in conditions such as
diabetic neuropathy, postherpetic neuralgia and
chemotherapy-induced neuritis. A common feature is the occurrence
of allodynia, which is defined as the perception of normally
innocuous stimuli as being painful.
[0005] Unfortunately, chronic pain such as chronic neuropathic pain
generally is resistant to available drug therapy. Furthermore,
current therapies have serious side-effects such as cognitive
changes, sedation, nausea and, in the case of narcotic drugs,
addiction. Many patients suffering from neuropathic and other
chronic pain are elderly or have medical conditions that limit
their tolerance to the side-effects associated with available
analgesic therapy. The inadequacy of current therapy in relieving
neuropathic pain without producing intolerable side-effects often
is manifest in the depression and suicidal tendency of chronic pain
sufferers.
[0006] As alternatives to current analgesics, .alpha..sub.2
adrenergic agonists, which are devoid of respiratory depressant
effects and addictive potential are being developed. Such drugs are
useful analgesic agents when administered spinally. However,
undesirable pharmacological properties of .alpha.-adrenergic
agonists, specifically sedation and hypotension, limit the utility
of these drugs when administered orally or by other peripheral
routes. Thus, there is a need for effective analgesic agents that
can be administered by oral or other peripheral routes and that
lack undesirable side-effects such as sedation and hypotension. The
present invention satisfies this need and provides related
advantages as well.
[0007] Also provided herein are new therapies for chronic pain
sufferers, who, until now, have faced a lifetime of daily
medication to control their pain. Unfortunately, available
treatments for chronic neuropathic pain, such as tricyclic
antidepressants, anti-seizure drugs and local anesthetic
injections, only alleviate symptoms temporarily and to varying
degrees. No available treatment reverses the sensitized pain state
or cures pain such as neuropathic pain. Effective drugs that can be
administered, for example, once or several times a month and that
maintain analgesic activity for several weeks or months, are
presently not available. Thus, there is a need for novel methods of
providing long-term relief from chronic pain. The present invention
satisfies this need and also provides related advantages.
SUMMARY OF THE INVENTION
[0008] Described herein are compounds for and methods of treating
conditions or diseases in a subject by administering to the subject
a pharmaceutical composition containing an effective amount of an
.alpha.-adrenergic modulator. The compounds and methods are also
useful for alleviating types of pain, acute, neuropathic and
chronic.
[0009] Described herein is a method of treating a condition or
disease alleviated by activation of .alpha.-adrenergic receptors in
a mammal comprising: administering a compound having a
structure
##STR00001##
wherein R.sup.1 and R.sup.2 are each independently selected from
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, halogen,
NR'.sub.2, CN, CO.sub.2R', C(O)NR'R'', alcohol, C.sub.1-4
halogenated alkyl, C.sub.1-4 halogenated alkoxy, and substituted or
unsubstituted aryl or heteroaryl; R' is selected from hydrogen,
C.sub.1-4 alkyl and C.sub.1-4 halogenated alkyl, substituted or
unsubstituted aryl or heteroaryl; R'' is selected from hydrogen and
C.sub.1-4 alkyl, substituted or unsubstituted aryl or heteroaryl;
and wherein the compound activates at least one of the
.alpha.-adrenergic receptors.
[0010] Also described herein is a composition for treating a
condition or disease alleviated by activation of .alpha.-adrenergic
receptors in a mammal comprising: a compound having a structure
##STR00002##
wherein R.sup.1 and R.sup.2 are each independently selected from
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, halogen,
NR'.sub.2, CN, CO.sub.2R', C(O)NR'R'', alcohol, C.sub.1-4
halogenated alkyl, C.sub.1-4 halogenated alkoxy, and substituted or
unsubstituted aryl or heteroaryl; R' is selected from hydrogen,
C.sub.1-4 alkyl and C.sub.1-4 halogenated alkyl, substituted or
unsubstituted aryl or heteroaryl; R'' is selected from hydrogen and
C.sub.1-4 alkyl, substituted or unsubstituted aryl or heteroaryl;
and wherein the compound activates at least one of the
.alpha.-adrenergic receptors.
[0011] In one embodiment, the condition or disease is selected from
the group consisting of hypertension, congestive heart failure,
asthma, depression, glaucoma, elevated intraocular pressure,
ischemic neuropathies, optic neuropathy, pain, visceral pain,
corneal pain, headache pain, migraine, cancer pain, back pain,
irritable bowel syndrome pain, muscle pain, pain associated with
diabetic neuropathy, the treatment of diabetic retinopathy, other
retinal degenerative conditions, stroke, cognitive deficits,
neuropsychiatric conditions, drug dependence, drug addiction,
withdrawal symptoms, obsessive compulsive disorder, obesity,
insulin resistance, stress related conditions, diarrhea, diuresis,
nasal congestions, spasticity, attention deficit disorder,
psychoses, anxiety, autoimmune disease, Crohn's disease, gastritis,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, and other neurodegenerative diseases. In one embodiment,
the condition or disease is pain.
[0012] In another embodiment the condition or disease is selected
from the group consisting of postherpetic neuralgia (PHN),
post-traumatic neuropathy pain (PTN), complex regional pain
syndrome (CRPS) and drug-induced neuropathy.
[0013] In one embodiment, R.sup.1 and R.sup.2 are each
independently a halogen or halogenated alkyl. In another
embodiment, the compound is
N-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In another
embodiment, the compound is
N-(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In another
embodiment, the compound is
N-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine.
In another embodiment, the compound is
N-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(3-bromo-2-methoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In another
embodiment, the compound is
N-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In another
embodiment, the compound is
N-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine. In
another embodiment, the compound is
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine. In another
embodiment, the compound is
N-(2,3-dimethylbenzyl)-4,5-dihydro-1H-imidazol-2-amine. In another
embodiment, the compound is
N-(2-fluorobenzyl)-4,5-dihydro-1H-imidazol-2-amine.
[0014] In one embodiment, the compound is selected from the group
consisting of
N-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(3-bromo-2-methoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2,3-dimethylbenzyl)-4,5-dihydro-1H-imidazol-2-amine,
N-(2-fluorobenzyl)-4,5-dihydro-1H-imidazol-2-amine, and
combinations thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 depicts the peripheral analgesic effects of a single
oral dose of N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine
in Chung model rats at 30 .mu.g/kg, 100 .mu.g/kg or 300
.mu.g/kg.
[0016] FIG. 2 depicts sedative effects (total activity counts) 30
minutes post intraperitoneal injection of 1 mg/kg and 10 mg/kg
doses of
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine.
[0017] FIG. 3 shows compound
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine activity in
the Drug-Induced Neuropathic Pain Model 30 minutes after a single
intraperitoneal dose at concentrations of 10 .mu.g/kg, 30 .mu.g/kg
or 100 .mu.g/kg.
DEFINITION OF TERMS
[0018] Prodrug: A "prodrug" is a compound which is converted to a
therapeutically active compound after administration. While not
intending to limit the scope, conversion may occur by hydrolysis of
an ester group or some other biologically labile group. Prodrug
preparation is well known in the art. For example, "Prodrugs and
Drug Delivery Systems," which is a chapter in Richard B. Silverman,
Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier
Academic Press: Amsterdam, 2004, pp. 496-557, provides further
detail on the subject.
[0019] Halogen: As used herein, "halogen" is used to refer to a
substituent found in column VIIA of the periodic table of elements,
including fluorine, chlorine, bromine, and iodine.
[0020] Tautomer: As used herein, "tautomer" refers to the migration
of protons between adjacent single and double bonds. The
tautomerization process is reversible. Compounds described herein
can undergo the following tautomerization:
##STR00003##
DETAILED DESCRIPTION OF THE INVENTION
[0021] Described herein are N-(2 and/or 3-substituted
benzyl)-4,5-dihydro-1H-imidazol-2-amine compounds as subtype
selective .alpha..sub.2A and/or .alpha..sub.2C adrenergic
modulators having the general structure
##STR00004##
wherein R.sup.1 and R.sup.2 are each independently selected from
hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OH, halogen,
NR'.sub.2, CN, CO.sub.2R', C(O)NR'R'', alcohol, C.sub.1-4
halogenated alkyl, C.sub.1-4 halogenated alkoxy, and substituted or
unsubstituted aryl or heteroaryl; R' is selected from hydrogen,
C.sub.1-4 alkyl and C.sub.1-4 halogenated alkyl, substituted or
unsubstituted aryl or heteroaryl; and R'' is selected from hydrogen
and C.sub.1-4 alkyl, substituted or unsubstituted aryl or
heteroaryl.
[0022] In one embodiment, wherein R.sup.1 and R.sup.2 are each
independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.1-10
alkoxy, OH, halogen, NR'.sub.2, CN, CO.sub.2R', C(O)NR'R'',
alcohol, C.sub.1-10 halogenated alkyl, C.sub.1-10 halogenated
alkoxy, and substituted or unsubstituted aryl or heteroaryl; R' is
selected from hydrogen, C.sub.1-10 alkyl and C.sub.1-10 halogenated
alkyl, substituted or unsubstituted aryl or heteroaryl; and R'' is
selected from hydrogen and C.sub.1-10 alkyl, substituted or
unsubstituted aryl or heteroaryl.
[0023] R.sup.1 and R.sup.2 can each independently be a C.sub.1-10
alkyl, which includes C.sub.3-10 cycloalkyls and C.sub.3-10
branched alkyls. R.sup.1 and R.sup.2 can each also independently be
a substituted or unsubstituted aryl or heteroaryl which can include
aromatic, heteroaromatic, or multi-heteroaromatic groups. The
substituted or unsubstituted aryl or heteroaryl can be selected
from phenyl, pyridinyl, thienyl, furyl, naphthyl, quinolinyl,
indanyl or benzofuryl. Exemplary substituted or unsubstituted aryls
or heteroaryls include, but are not limited to, benzenes,
pyridines, thiophenes, furans, naphthalenes, quinolines, indans and
benzofurans. The aryl groups may be substituted with any common
organic fictional group. Such aryl groups may be bonded to Formula
1 at any available position on the aryl group.
[0024] An exemplary aryl group is a benzene (Formula 2):
##STR00005##
wherein at least one of R.sup.4-9 must be Formula 1 and wherein the
remaining R.sup.4-9 may be each independently substituted with a
common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, alkynyl, aryl,
halogen, hydroxyl, alkoxy, amino, cyano, nitro, thiol, or carboxy
group substituted with a C.sub.1-10 alkyl, C.sub.1-10 alkenyl,
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro, or
thiol group.
[0025] Another aryl group may be a pyridine as in Formula 3:
##STR00006##
wherein at least one of R.sup.4-8 must be Formula 1 and wherein the
remaining R.sup.4-8 may be each independently substituted with a
common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, alkynyl, aryl,
halogen, hydroxyl, alkoxy, amino, cyano, nitro, thiol, or carboxy
group substituted with a C.sub.1-10 alkyl, C.sub.1-10 alkenyl,
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro, or
thiol group.
[0026] Another aryl group may be a thiophene as in Formula 4:
##STR00007##
wherein at least one of R.sup.4-7 must be Formula 1 and wherein the
remaining R.sup.4-7 may be each independently substituted with a
common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, C.sub.1-10
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro,
thiol, or carboxy group substituted with a C.sub.1-10 alkyl,
C.sub.1-10 alkenyl, C.sub.1-10 alkynyl, aryl, halogen, hydroxyl,
alkoxy, amino, cyano, nitro, or thiol group.
[0027] Another aryl group may be a furan as in Formula 5:
##STR00008##
wherein at least one of R.sup.4-7 must be Formula 1 and wherein the
remaining R.sup.4-7 may be each independently substituted with a
common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, C.sub.1-10
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro,
thiol, or carboxy group substituted with a C.sub.1-10 alkyl,
C.sub.1-10 alkenyl, C.sub.1-10 alkynyl, aryl, halogen, hydroxyl,
alkoxy, amino, cyano, nitro, or thiol group.
[0028] Another aryl group may be a naphthalene as in Formula 6:
##STR00009##
wherein at least one of R.sup.4-11 must be Formula 1 and wherein
the remaining R.sup.4-11 may be each independently substituted with
a common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, C.sub.1-10
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro,
thiol, or carboxy group substituted with a C.sub.1-10 alkyl,
C.sub.1-10 alkenyl, C.sub.1-10 alkynyl, aryl, halogen, hydroxyl,
alkoxy, amino, cyano, nitro, or thiol group.
[0029] Another aryl group may be a quinoline as in Formula 7:
##STR00010##
wherein at least one of R.sup.4-1.degree. must be Formula 1 and
wherein the remaining R.sup.4-1.degree. may be each independently
substituted with a common organic functional group including, but
not limited to, hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl,
C.sub.1-10 alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano,
nitro, thiol, or carboxy group substituted with a C.sub.1-10 alkyl,
C.sub.1-10 alkenyl, C.sub.1-10 alkynyl, aryl, halogen, hydroxyl,
alkoxy, amino, cyano, nitro, or thiol group.
[0030] Another aryl group may be an indene as in Formula 8:
##STR00011##
wherein at least one of R.sup.4-13 must be Formula 1 and wherein
the remaining R.sup.4-13 may be each independently substituted with
a common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, C.sub.1-10
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro,
thiol, or carboxy group substituted with a C.sub.1-10 alkyl,
C.sub.1-10 alkenyl, C.sub.1-10 alkynyl, aryl, halogen, hydroxyl,
alkoxy, amino, cyano, nitro, or thiol group.
[0031] Another aryl group may be a benzofuran as in Formula 9:
##STR00012##
wherein at least one of R.sup.4-9 must be Formula 1 and wherein the
remaining R.sup.4-9 may be each independently substituted with a
common organic functional group including, but not limited to,
hydrogen, a C.sub.1-10 alkyl, C.sub.1-10 alkenyl, C.sub.1-10
alkynyl, aryl, halogen, hydroxyl, alkoxy, amino, cyano, nitro,
thiol, or carboxy group substituted with a C.sub.1-10 alkyl,
C.sub.1-10 alkenyl, C.sub.1-10 alkynyl, aryl, halogen, hydroxyl,
alkoxy, amino, cyano, nitro, or thiol group.
[0032] .alpha..sub.2 adrenergic receptors have been characterized
by molecular and pharmaceutical methods; the methods including
.alpha..sub.1A, .alpha..sub.1B, .alpha..sub.1D, .alpha..sub.2A,
.alpha..sub.2B and .alpha..sub.2C subtypes. Activation of these
.alpha.-receptors can evoke physiological responses. Adrenergic
modulators described herein activate one or both of the
.alpha..sub.2B and/or .alpha..sub.2C receptors and have useful
therapeutic actions.
[0033] The following structures are contemplated according to the
present description.
##STR00013## ##STR00014##
[0034] The compounds described herein may be useful for the
treatment of a wide range of conditions and diseases that are
alleviated by .alpha..sub.2B and/or .alpha..sub.2C activation
including, but not limited to, hypertension, congestive heart
failure, asthma, depression, glaucoma, elevated intraocular
pressure, ischemic neuropathies, optic neuropathy, pain, visceral
pain, corneal pain, headache pain, migraine, cancer pain, back
pain, irritable bowel syndrome pain, muscle pain, pain associated
with diabetic neuropathy, the treatment of diabetic retinopathy,
other retinal degenerative conditions, stroke, cognitive deficits,
neuropsychiatric conditions, drug dependence, drug addiction,
withdrawal symptoms, obsessive compulsive disorder, obesity,
insulin resistance, stress related conditions, diarrhea, diuresis,
nasal congestions, spasticity, attention deficit disorder,
psychoses, anxiety, autoimmune disease, Crohn's disease, gastritis,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, and other neurodegenerative diseases.
[0035] Applicants have discovered that these compounds activate or
modulate .alpha..sub.2B and .alpha..sub.2C receptors. Additionally,
these compounds act as a highly effective analgesic, particularly
in chronic pain models, with minimal undesirable side effects, such
as sedation and cardiovascular depression, commonly seen with
agonists of .alpha..sub.2B and .alpha..sub.2C receptors.
[0036] Such compounds may be administered at pharmaceutically
effective dosages. Such dosages are normally the minimum dose
necessary to achieve the desired therapeutic effect; in the
treatment of chronic pain, this amount would be roughly that
necessary to reduce the discomfort caused by the pain to tolerable
levels. Generally, such doses will be in the range 1-1000 mg/day;
more preferably in the range 10 to 500 mg/day. However, the actual
amount of the compound to be administered in any given case will be
determined by a physician taking into account the relevant
circumstances, such as the severity of the pain, the age and weight
of the patient, the patient's general physical condition, the cause
of the pain, and the route of administration.
[0037] The compounds may be useful in the treatment of pain in a
mammal, particularly a human being. Preferably, the patient will be
given the compound orally in any acceptable form, such as a tablet,
liquid, capsule, powder and the like. However, other routes may be
desirable or necessary, particularly if the patient suffers from
nausea. Such other routes may include, without limitation,
transdermal, parenteral, subcutaneous, intranasal, intrathecal,
intramuscular, intravenous, and intrarectal modes of delivery.
Additionally, the formulations may be designed to delay release of
the active compound over a given period of time, or to carefully
control the amount of drug released at a given time during the
course of therapy.
[0038] Another embodiment is drawn to therapeutic compositions
comprising the compounds of Formula 1, pharmaceutically acceptable
derivatives, salts, prodrugs and/or combinations of these compounds
and a pharmaceutically acceptable excipient. Such an excipient may
be a carrier or a diluent; this is usually mixed with the active
compound, or permitted to dilute or enclose the active compound. If
a diluent, the carrier may be solid, semi-solid, or liquid material
that acts as an excipient or vehicle for the active compound. The
formulations may also include wetting agents, emulsifying agents,
preserving agents, sweetening agents, and/or flavoring agents. If
used as in an ophthalmic or infusion format, the formulation will
usually contain one or more salt to influence the osmotic pressure
of the formulation.
[0039] Another embodiment is directed to methods for the treatment
of pain, particularly chronic pain, through the administration of a
compound of Formula 1, and pharmaceutically acceptable salts, and
derivatives thereof to a mammal in need thereof. As indicated
above, the compound will usually be formulated in a form consistent
with the desired mode of delivery.
[0040] Some embodiments provide methods that rely on administration
of one or more pharmaceutical compositions to a subject. As used
herein, the term "subject" means any animal capable of experiencing
pain, for example, a human or other mammal such as a primate,
horse, cow, dog or cat.
[0041] The methods described herein are used to treat acute,
neuropathic and chronic pain, and, as non-limiting examples, pain
which is neuropathic, visceral or inflammatory in origin. In
particular embodiments, the methods of the invention are used to
treat neuropathic pain; visceral pain; post-operative pain; pain
resulting from cancer or cancer treatment; and inflammatory
pain.
[0042] Both acute and chronic pain can be treated by the methods
described herein, and the term "pain" encompasses acute,
neuropathic and chronic pain. As used herein, the term "acute pain"
means immediate, generally high threshold, pain brought about by
injury such as a cut, crush, burn, or by chemical stimulation such
as that experienced upon exposure to capsaicin, the active
ingredient in chili peppers. The term "chronic pain," as used
herein, means pain other than acute pain and includes, without
limitation, neuropathic pain, visceral pain, inflammatory pain,
headache pain, muscle pain and referred pain. It is understood that
chronic pain is of relatively long duration, for example, several
years and can be continuous or intermittent.
[0043] Unless otherwise indicated, reference to a compound should
be construed broadly to include compounds, pharmaceutically
acceptable salts, prodrugs, tautomers, alternate solid forms,
non-covalent complexes, and combinations thereof, of a chemical
entity of a depicted structure or chemical name.
[0044] A pharmaceutically acceptable salt is any salt of the parent
compound that is suitable for administration to an animal or human.
A pharmaceutically acceptable salt also refers to any salt which
may form in vivo as a result of administration of an acid, another
salt, or a prodrug which is converted into an acid or salt. A salt
comprises one or more ionic forms of the compound, such as a
conjugate acid or base, associated with one or more corresponding
counter-ions. Salts can form from or incorporate one or more
deprotonated acidic groups (e.g. carboxylic acid/carboxylate), one
or more protonated basic groups (e.g. amine/ammonium), or both
(e.g. zwitterions).
[0045] A prodrug is a compound which is converted to a
therapeutically active compound after administration. For example,
conversion may occur by hydrolysis of an ester group or some other
biologically labile group. Prodrug preparation is well known in the
art. For example, "Prodrugs and Drug Delivery Systems," which is a
chapter in Richard B. Silverman, Organic Chemistry of Drug Design
and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004,
pp. 496-557, provides further detail on the subject.
[0046] Tautomers are isomers that are in rapid equilibrium with one
another. For example, tautomers may be related by transfer of a
proton, hydrogen atom, or hydride ion. Not intended to be limited
by the above described compounds, various tautomers of the above
compounds may be possible. For example, not intended as a
limitation, tautomers are possible between the 4,5-dihydrooxazole
and the adjacent nitrogen as shown below.
##STR00015##
[0047] Other tautomers are possible when the compound includes, for
example but not limited to, enol, keto, lactamin, amide, imidic
acid, amine, and imine groups. Tautomers will generally reach an
equilibrium state wherein the double bond is resonantly shared
between the two bond lengths.
[0048] Unless stereochemistry is explicitly and unambiguously
depicted, a structure is intended to include every possible
stereoisomer, both pure or in any possible mixture.
[0049] Alternate solid forms are different solid forms than those
that may result from practicing the procedures described herein.
For example, alternate solid forms may be polymorphs, different
kinds of amorphous solid forms, glasses, and the like.
[0050] Non-covalent complexes are complexes that may form between
the compound and one or more additional chemical species that do
not involve a covalent bonding interaction between the compound and
the additional chemical species. They may or may not have a
specific ratio between the compound and the additional chemical
species. Examples might include solvates, hydrates, charge transfer
complexes, and the like.
[0051] The following examples provide synthesis methods for forming
compounds described herein. One skilled in the art will appreciate
that these examples can enable a skilled artisan to synthesize the
compounds described herein.
Example 1
Generic Reaction 1
##STR00016##
[0053] In scheme A above, Formula 11 was either commercially
available or synthesized by different reductive amination methods
from Formula 10. One of those methods was published by David J. H.
et al (J. Org. Chem. 48: 289-294 (1983)). The key step was the
coupling for Formula 11 with imidazoline which had an appropriate
leaving group on the second position to give Formula 12. The
leaving group may be methylthiol (R.dbd.(O)COMe) or sulfuric acid
(R.dbd.H). There are also other known coupling procedures known by
those skilled in the art or by modifications of known procedures
known by those skilled in the art.
##STR00017##
[0054] In Scheme B, another method is depicted to synthesize
Formula 11 from substituted benzoic acid, substituted ester or
substituted benzyl alcohol, all of which are commercially
available. Formula 13 was converted to an ester which can be
reduced to Formula 14 with lithium aluminum hydride (LAH) or borane
as reagents. Conversion of the alcohol, Formula 14, to the azide,
Formula 15, may be accomplished by methods such as Mitsunobu
reaction with diphenylphosphoryl azide in one step, or converting
alcohol to a good leaving group which can be replaced with azide
anion. Denitrogenation of azide to amine was carried out with a
phosphine such as triphenyl phosphine. Subsequent basic hydrolysis
liberated the intermediate to amine.
[0055] The compounds described herein may also be synthesized by
other methods known by those skilled in the art.
Example 2
Synthesis of
N-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine
##STR00018##
[0057] To a 7.08 mmol solution of 2-chloro-3-fluorobenzaldehyde 1
(1.00 g, commercially available from 3B Medical Systems, Inc.) in
8.0 mL of tetrahydrofuran (THF) was added 8.50 mL of 1.0M lithium
bis(trimethylsilyl)-amide via syringe at 0.degree. C. The resulting
solution was stirred at 0.degree. C. for 3 hours. 8.50 mL of 1.0M
LAH was added via syringe. Three hours later, the reaction mixture
was carefully poured onto crushed ice. Ammonium chloride (aq) and
Rochelle's salt (aq) were added to this mixture. The aqueous layer
was extracted three times with 200 mL of chloroform/isopropanol
(3:1). The pooled organic layer was dried over magnesium sulfate.
The mixture was filtered, and the solvents were removed under
vacuum to give (2-chloro-3-fluorophenyl)methanamine 2. The weight
of the product was 0.92 g.
[0058] A mixture of 0.92 g of (2-chloro-3-fluorophenyl)methanamine
2 and 0.790 g of 4,5-dihydro-1H-imidazole-2-sulfonic acid
(commercially available from Astatech) in 10.0 mL of ethanol was
heated in a sealed tube to 90.degree. C. for 16 hours. Then, the
reaction mixture was cooled to room temperature. Next, the ethanol
was removed under vacuum. The remaining residue was basified with
aqueous sodium bicarbonate solution and the pH was adjusted to
about 10 with 2M sodium hydroxide. The aqueous layer was extracted
three times with 100 mL of chloroform/isopropanol (3:1). The pooled
organic layer was dried over magnesium sulfate and the mixture was
then filtered. Amino-modified silica gel was added to the filtrate
and the solvents were removed under vacuum. Purification by
chromatography on amino-modified silica gel (3.5% methanol in
dichloromethane) afforded 0.575 g of
N-(2-chloro-3-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine 3 as a
yellow solid.
[0059] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.32-7.21 (m,
2H), 7.15-7.09 (m, 1H), 4.42 (s, 2H), 3.48 (s, 4H).
[0060] The following compounds can also be prepared according to
Example 2.
##STR00019##
[0061]
N-(2-difluoromethoxy)-benzyl)-4,5-dihydro-1H-imidazol-2-amine:
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.43-7.32 (m, 2H),
7.24-7.16 (m, 2H), 6.90 (t, J=73.8 Hz, 1H), 4.43 (s, 2H), 3.62 (s,
4H).
##STR00020##
[0062] N-(2,3-dimethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine:
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.11-7.04 (m, 3H), 4.33
(s, 2H), 3.56 (s, 4H).
##STR00021##
[0063] N-(trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine:
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.76-7.65 (m, 2H),
7.58-7.50 (m, 2H), 4.61 (s, 2H), 3.74 (s, 4H).
##STR00022##
[0064] N-(trifluoromethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine:
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.51-7.48 (m, 1H),
7.39-7.28 (m, 3H), 4.45 (s, 2H), 3.60 (s, 4H).
##STR00023##
[0065] N-(2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine: .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.40 (t, J=7.5 Hz, 1H), 7.28 (q,
J=7.2 Hz, 1H), 7.11-7.03 (m, 2H), 4.41 (s, 2H), 3.56 (s, 4H).
##STR00024##
[0066]
N-(2-fluoro-3-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazol-2-ami-
ne: .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.66 (t, J=7.5 Hz,
1H), 7.57 (q, J=7.5 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 4.42 (s, 2H),
3.50 (s, 4H).
##STR00025##
[0067] N-(2,3-dimethoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine:
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.05-6.87 (m, 3H), 4.34
(s, 2H), 3.83 (s, 6H), 3.55 (s, 4H).
Example 3
Synthesis of
N-(3-bromo-2-methoxy-benzyl)-4,5-dihydro-1H-imidazol-2-amine
##STR00026##
[0069] 5.0 mL of sulfuric acid (H.sub.2SO.sub.4) was slowly added
to a solution of 5.0 g of 3-bromo-2-methoxy-benzoic acid 4 in 100
mL of methanol (MeOH). The resulting solution was heated to reflux
overnight. The solution was cooled to room temperature and quenched
with sodium bicarbonate to pH 7. The aqueous layer was extracted
several times with ethyl acetate. The combined organic extracts
were washed with brine and dried over sodium sulphate. The
resulting mixture was filtered. The solvents were evaporated under
reduced pressure to afford 5.3 g of 3-bromo-2-methoxy-benzoic acid
methyl ester 5.
[0070] 2.4 g of lithium borohydride (LiBH.sub.4) was added to a
solution of 5.3 g of 3-bromo-2-methoxy-benzoic acid methyl ester 5
in 200 mL of ether (Et.sub.2O) at 0.degree. C. After stirring for 5
minutes, 5 mL of methanol was added. The reaction mixture was
warmed to room temperature and kept there for 2.5 hours.
Thereafter, 2.4 g more of lithium borohydride was added. The
reaction mixture was quenched with aluminum chloride. After
standard aqueous work up, and silica gel column purification
(hexane/ethyl acetate 2:1), 4.0 g of
3-bromo-2-methoxy-phenyl-methanol 6 was obtained.
[0071] 6.00 g of diphenyl phosphorazidate and 4.1 g of
1,8-diazabicyclo[5.4.0] undec-7-ene were added to 4.0 g of
3-bromo-2-methoxy-phenyl-methanol 6 in 100 mL of toluene at
0.degree. C. The mixture was stirred at room temperature overnight.
The reaction mixture was quenched with aqueous ammonium chloride.
The aqueous layer was extracted with ethyl acetate/THF. The pooled
organic extracts were washed with brine and dried over magnesium
sulfate. The mixture was filtered. The solvents were removed under
vacuum. The residue was purified by chromatography on silica gel to
give 1-azidomethyl-3-bromo-2-methoxy-benzene 7.
[0072] 1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl
phosphine (Ph.sub.3P) were added to a solution of
1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10
mL of water. The mixture was stirred overnight at room temperature.
The mixture was quenched with aqueous concentrated hydrochloride.
After standard acid/base aqueous work up, 3.9 g of crude
3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps).
[0073] 10 mL of acetic acid (HOAc) was added to a solution of 3.9 g
of 3-bromo-2-methoxy-benzylamine 8 and 3.1 g of methyl
2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate in 100 mL of
methanol. The resulting solution was heated to a gentle reflux and
refluxed overnight. The solution was cooled to room temperature,
quenched with sodium hydroxide and extracted with ethyl acetate.
The combined organic extracts were washed with brine and dried over
magnesium sulfate. The mixture was then filtered. The solvents were
removed under vacuum. The remaining residue was purified by
chromatography on silica gel (10% saturated ammonia methanol in
dichloromethane) to give
(3-bromo-2-methoxy-benzyl-4,5-dihydro-1H-imidazol-2-yl)-amine
9.
[0074] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.51 (d, J=3 Hz,
1H), 7.25-7.29 (m, 1H), 6.80 (d, J=9 Hz, 1H), 4.46 (s, 2H), 3.84
(s, 4H), 3.63 (s, 3H).
[0075] The following compounds can also be prepared according to
Example 3.
##STR00027##
[0076] N-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-amine: .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.51-7.53 (m, 1H), 7.28-7.29 (m,
1H), 7.14-7.21 (m, 2H), 4.59 (s, 2H), 3.58 (s, 4H).
##STR00028##
[0077] N-(2-methyl-benzyl)-4,5-dihydro-1H-imidazol-2-amine: .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.08-7.12 (m, 4H), 4.45 (d, J=6
Hz, 2H), 3.54 (s, 4H), 2.28 (s, 3H).
##STR00029##
[0078]
N-(3-chloro-2-fluoro-benzyl)-4,5-dihydro-1H-imidazol-2-amine:
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.40-7.31 (m, 2H),
7.16-67.10 (m, 1H), 4.42 (s, 2H), 3.56 (s, 4H).
Example 4
Synthesis of
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine
##STR00030##
[0080] A mixture of 5.32 g of (2,3-dichlorophenyl)methanamine 10
and 4.56 g of 4,5-dihydro-1H-imidazole-2-sulfonic acid are mixed in
40.0 mL ethanol (EtOH) and heated in a sealed tube at 90.degree. C.
for 16 hours. Then, the reaction mixture was cooled to room
temperature. Next, the ethanol was removed under vacuum. The
remaining residue was basified with aqueous sodium bicarbonate
solution and the pH was adjusted to about 10 with 2M sodium
hydroxide. The aqueous layer was extracted three times with 400 mL
of chloroform/isopropanol (3:1). The pooled organic layer was dried
over magnesium sulfate and the mixture was then filtered. The
filtrate was added to amino-modified silica gel (4-5% methanol in
dichloromethane) and afforded 3.99 g of Compound 11 as a yellow
solid.
[0081] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.43 (dd, J=7.8,
1.8 Hz, 1H, 7.37-7.33 m, 1H), 7.26 (t, J=7.8 Hz, 1H), 4.43 (s, 2H),
3.51 (s, 4H).
Example 5
Biological Intrinsic Activity Data
[0082] Certain compounds described herein were tested for
.alpha.-adrenergic activity using the Receptor Selection and
Amplification Technology (RSAT) assay (Messier et al., 1995,
Pharmacol. Toxicol. 76, pp. 308-311). Cells expressing each of the
.alpha..sub.2 adrenergic receptors alone were incubated with the
various compounds and a receptor-mediated growth response was
measured. The compound's activity is expressed as its relative
efficacy compared to standard full agonist (see Table 1 below). The
compounds described herein activate .alpha..sub.2B and/or
.alpha..sub.2C receptors.
TABLE-US-00001 Compound .alpha..sub.1A .alpha..sub.2B
.alpha..sub.2C ##STR00031## 587 (1.01) 33 (1.11) 484 (0.60)
##STR00032## 345 (1.12) 50 (0.81) 471 (0.86) ##STR00033## 430
(0.79) 56 (0.92) 1594 (0.63) ##STR00034## nd 499 (0.73) nd
##STR00035## 282 (1.10) 14.0 (0.94) 46.8 (0.48) nd = not
determined
Example 6
Biological Intrinsic Activity Data
[0083] Various concentrations of
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine were
administered orally to Chung model rats. A model in accordance with
Kim and Chung 1992, Pain 150, pp 355-363 (Chung model), for chronic
pain (in particular peripheral neuropathy) involves the surgical
ligation of the L5 (and optionally the L6) spinal nerves on one
side in experimental animals. Rats recovering from the surgery gain
weight and display a level of general activity similar to that of
normal rats. However, these rats develop abnormalities of the foot,
wherein the hindpaw is moderately everted and the toes are held
together. More importantly, the hindpaw on the side affected by the
surgery appears to become sensitive to pain from low-threshold
mechanical stimuli, such as that producing a faint sensation of
touch in a human, within about 1 week following surgery. This
sensitivity to normally non-painful touch is called "tactile
allodynia" and lasts for at least two months. The response includes
lifting the affected hindpaw to escape from the stimulus, licking
the paw and holding it in the air for many seconds. None of these
responses is normally seen in the control group.
[0084] Rats are anesthetized before surgery. The surgical site is
shaved and prepared either with betadine or Novocain. Incision is
made from the thoracic vertebra XIII down toward the sacrum. Muscle
tissue is separated from the spinal vertebra (left side) at the
L4-S2 levels. The L6 vertebra is located and the transverse process
is carefully removed with a small rongeur to expose the L4-L6
spinal nerves. The L5 and L6 spinal nerves are isolated and tightly
ligated with 6-0 silk thread. The same procedure is done on the
right side as a control, except no ligation of the spinal nerves is
performed.
[0085] A complete hemostasis is confirmed, then the wounds are
sutured. A small amount of antibiotic ointment is applied to the
incised area, and the rat is transferred to the recovery plastic
cage under a regulated heat-temperature lamp. On the day of the
experiment, at least seven days after the surgery, typically six
rats per test group are administered the test drugs by
intraperitoneal (i.p.) injection or oral gavage. For i.p.
injection, the compounds are formulated in d H.sub.2O and given in
a volume of 1 ml/kg body weight using an 18-gauge, 3 inch gavage
needle that is slowly inserted through the esophagus into the
stomach.
[0086] Tactile allodynia is measured prior to and 30 minutes after
drug administration using von Frey hairs that are a series of fine
hairs with incremental differences in stiffness. Rats are placed in
a plastic cage with a wire mesh bottom and allowed to acclimate for
approximately 30 minutes. The von Frey hairs are applied
perpendicularly through the mesh to the mid-plantar region of the
rats' hindpaw with sufficient force to cause slight buckling and
held for 6-8 seconds. The applied force has been calculated to
range from 0.41 to 15.1 grams. If the paw is sharply withdrawn, it
is considered a positive response. A normal animal will not respond
to stimuli in this range, but a surgically ligated paw will be
withdrawn in response to a 1-2 gram hair. The 50% paw withdrawal
threshold is determined using the method of Dixon, W. J., Ann. Rev.
Pharmacol. Toxicol. 20:441-462 (1980) hereby incorporated by
reference. The post-drug threshold is compared to the pre-drug
threshold and the percent reversal of tactile sensitivity is
calculated based on a normal threshold of 15.1 grams.
[0087] Table 2 below shows the peak allodynia reversal at 30
.mu.g/kg, 100 .mu.g/kg or 300 .mu.g/kg doses.
TABLE-US-00002 TABLE 2 Peak Allodynia Reversal Dose (Oral, 30 min.)
300 .mu.g/kg 84% +/- 7.5% 100 .mu.g/kg 68% +/- 12.7% 30 .mu.g/kg
28% +/- 9.5%
[0088] As shown in Table 2, 30 .mu.g/kg oral dosage resulted in 28%
allodynia reversal. The analgesic effect was seen quickly, in about
30 minutes. FIG. 1 shows a peak percent allodynia reversal at 30
minutes followed by a steady decrease to baseline at about 120
minutes.
Example 7
In Vivo Activity Data
[0089] Data was acquired from wild type rats administered
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine
intraperitoneally (IP). Rats were split into groups of six and
administered 1 mg/kg or 10 mg/kg doses of
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine to assess
the sedative effects of the administration of the agent. As can be
seen in both FIG. 2 and Table 3, 10 mg/kg had a significant
sedative effect on the dosed rats.
TABLE-US-00003 TABLE 3 Dose Sedative Effect (IP) 1 mg/kg No
significant effect 10 mg/kg 23% sedating
Example 8
Dideoxycytidine (ddC) Model
[0090] The ddC Model in the rat is a relatively new model of
neuropathic pain discovered from clinical treatment of the AIDS
virus. Patients taking dideoxycytidine (ddC) for AIDS Highly Active
Antiretroviral Therapy (HAART) reported development of painful
neuropathies. The experimental animal model in the rat for
neuropathic pain by ddC injection manifests symptoms of human
patients with causalgia. It is considered predictive of clinical
activity against neuropathic pain (Joseph et al, 2004). Compound
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine was tested
in this ddC model of allodynic pain. The compound was administered
intraperitoneally to male ddC treated rats.
[0091] The animals are injected intraperitoneally (IP) with 25
mg/kg dideoxycytidine (ddC) using a sterile 30 gauge needle.
Approximately 3 weeks after the ddC injection a painful neuropathy
develops causing sensitivity to light touch on the animals'
extremities. This neuropathy can last for 2-3 months. The animals
show no spontaneous pain, only a heightened response to mechanical
stimuli (von Frey hair stimulation). The allodynia is quantitated
in the animals receiving ddC injections by stimulation with a
series of 8 Von Frey hairs on the mid planter area of the hind paws
in the up-down manner described by Dixon (Dixon, 1980).
[0092] Male Sprague-Dawley rats (Charles River, Wilmington, Mass.)
weighing approximately 150-300 grams were used for these studies.
All experimental animals received
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine or vehicle
in a single acute IP dose. In all studies, baseline measurements
were taken prior to drug administration and then at 15, 30, 60 and
120 minutes post acute IP dosing (vehicle or
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine). The %
allodynia reversal is calculated as: [(Postdrug threshold-Predrug
threshold)/(15-Predrug threshold)].times.100.
[0093] N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine was
dissolved in 42% DMSO (dimethyl sulfoxide; Sigma, St. Louis, Mo.)
at a concentration of 3 mg/ml. This stock solution was kept frozen
at -20.degree. C., was thawed on the day of the study and diluted
in dd-H.sub.2O to concentrations ranging from 0.01-0.1 mg/ml for IP
dosing (dosing volume=1 ml/kg). The vehicle is dd-H.sub.2O for
these studies.
[0094] Data were compiled and analyzed using Microsoft Excel and/or
Kaleidagraph. Data are expressed as mean.+-.standard error of the
mean. Comparisons between drug treated and vehicle groups were made
using a two-tailed, 2-sample, unpaired t-test. Comparisons between
baselines (pre-drug) and post-drug time points were made using a
two-tailed, 2-sample, paired t-test.
[0095] the ddC Model in male rats in a dose-related manner. A
maximal effect of 86% allodynia reversal was measured at 30 minutes
post 0.1 mg/kg IP
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine
administration. The minimal statistically significant efficacious
dose was 0.03 mg/kg, resulting in a 67% allodynia reversal (Table
4). The no-effect dose was 0.01 mg/kg.
[0096] N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine
alleviates the allodynia in
TABLE-US-00004 TABLE 4 Acute IP
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2- amine
Administration in the ddC Model of Neuropathic Pain. % Allodynia %
Allodynia % Allodynia % Allodynia Reversal: Reversal: Reversal:
Reversal: 15 min 30 min 60 min 120 min post post dose post dose
post dose dose 1 ml/kg vehicle 1.1 .+-. 1.6 0.7 .+-. 0.8 1.2 .+-.
1.3 1.5 .+-. 1.8 IP 0.01 mg/kg 1.8 .+-. 1.6 3.0 .+-. 1.7 1.5 .+-.
2.0 0.1 .+-. 1.3 200762 IP 0.03 mg/kg 34 .+-. 3.9** 67 .+-. 9.0**
20 .+-. 3.7** 2.0 .+-. 2.6 200762 IP 0.1 mg/kg 58 .+-. 9.1** 86
.+-. 6.3** 34 .+-. 2.5** 0.9 .+-. 1.2 200762 IP Data is expressed
as mean % MPE, which represents the % allodynia reversal, .+-.
standard error of the mean, n = 6 in all groups. Significance
values relative to vehicle: *p < 0.05; **p < 0.01.
N-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazol-2-amine alleviates
the allodynia in male ddC treated rats. The anti-allodynic effect
peaks at 0.1 mg/kg IP resulting in a 86% reduction of allodynia at
30 minutes post IP dose.
[0097] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained by the present invention.
At the very least, and not as an attempt to limit the application
of the doctrine of equivalents to the scope of the claims, each
numerical parameter should at least be construed in light of the
number of reported significant digits and by applying ordinary
rounding techniques. Notwithstanding that the numerical ranges and
parameters setting forth the broad scope of the invention are
approximations, the numerical values set forth in the specific
examples are reported as precisely as possible. Any numerical
value, however, inherently contains certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements.
[0098] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0099] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is deemed to contain the group
as modified thus fulfilling the written description of all Markush
groups used in the appended claims.
[0100] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects skilled
artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0101] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above-cited references and printed publications are individually
incorporated herein by reference in their entirety.
[0102] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *