U.S. patent application number 14/110660 was filed with the patent office on 2014-02-13 for cyclopropyl derivatives and methods of use.
This patent application is currently assigned to WAKE FOREST UNIVERSITY HEALTH SCIENCES. The applicant listed for this patent is Spandan Chennamadhavuni, Steven R. Childrens, Huw M. Davies, Thomas J. Martin. Invention is credited to Spandan Chennamadhavuni, Steven R. Childrens, Huw M. Davies, Thomas J. Martin.
Application Number | 20140045936 14/110660 |
Document ID | / |
Family ID | 47042114 |
Filed Date | 2014-02-13 |
United States Patent
Application |
20140045936 |
Kind Code |
A1 |
Davies; Huw M. ; et
al. |
February 13, 2014 |
CYCLOPROPYL DERIVATIVES AND METHODS OF USE
Abstract
The disclosure relates to cyclopropyl derivatives and methods of
use. In some embodiments, the disclosure relates to methods of
managing medical disorders with pharmaceutical compositions
disclosed herein administered to subject in need thereof. In
certain embodiments, the disclosure relates to methods of managing
mental disorders, mood disorders, pain, and fibromyalgia and
related conditions with pharmaceutical compositions disclosed
herein.
Inventors: |
Davies; Huw M.; (Duluth,
GA) ; Chennamadhavuni; Spandan; (Natick, MA) ;
Martin; Thomas J.; (Walkertown, NC) ; Childrens;
Steven R.; (Winston-Salem, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Davies; Huw M.
Chennamadhavuni; Spandan
Martin; Thomas J.
Childrens; Steven R. |
Duluth
Natick
Walkertown
Winston-Salem |
GA
MA
NC
NC |
US
US
US
US |
|
|
Assignee: |
WAKE FOREST UNIVERSITY HEALTH
SCIENCES
Winston-Salem
NC
EMORY UNIVERSITY
Atlanta
GA
|
Family ID: |
47042114 |
Appl. No.: |
14/110660 |
Filed: |
April 13, 2012 |
PCT Filed: |
April 13, 2012 |
PCT NO: |
PCT/US12/33423 |
371 Date: |
October 8, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61477848 |
Apr 21, 2011 |
|
|
|
Current U.S.
Class: |
514/510 ;
514/531; 560/37; 560/42; 560/51 |
Current CPC
Class: |
C07C 67/313 20130101;
C07C 227/16 20130101; C07C 2601/02 20170501; A61P 25/04 20180101;
C07C 69/757 20130101; C07C 229/46 20130101; A61K 31/195 20130101;
C07C 227/04 20130101; A61K 45/06 20130101; A61K 31/216 20130101;
A61P 9/04 20180101; A61P 25/24 20180101; A61K 31/195 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/510 ; 560/51;
560/37; 560/42; 514/531 |
International
Class: |
C07C 69/757 20060101
C07C069/757; C07C 67/313 20060101 C07C067/313; C07C 227/04 20060101
C07C227/04; C07C 229/46 20060101 C07C229/46 |
Goverment Interests
ACKNOWLEDGEMENTS
[0002] This invention was made with government support under Grants
R01 DA023224 and R01 DA022599 awarded by the National Institutes of
Health. The government has certain rights in the invention.
Claims
1. A compound comprising formula I: ##STR00046## or salts thereof
wherein, A ring is a carbocyclyl, aryl, or heterocyclyl; n is 0, 1,
2, 3, 4, or 5; X and Y are the same or different O, S, NR.sup.4;
R.sup.1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.1
is optionally substituted with one or more, the same or different,
R.sup.5; R.sup.2 is hydrogen, alkyl, halogen, nitro, cyano,
hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy,
alkylthio, alkylamino, (alkyl).sub.2amino, alkylsulfinyl,
alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl,
wherein R.sup.2 is optionally substituted with one or more, the
same or different, R.sup.5; R.sup.3 is hydrogen, alkyl, halogen,
nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
alkoxy, alkylthio, alkylamino, (alkyl).sub.2amino, alkylsulfinyl,
alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl,
wherein R.sup.3 is optionally substituted with one or more, the
same or different, R.sup.5; R.sup.4 is hydrogen, alkyl, hydroxy,
amino, formyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.4
is optionally substituted with one or more, the same or different,
R.sup.5; R.sup.5 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.5
is optionally substituted with one or more, the same or different,
R.sup.6; and R.sup.6 is halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
2. A compound of formula I, wherein formula I is formula IA, IB,
IC, or ID wherein: formula IA is ##STR00047## formula IB is
##STR00048## formula IC is ##STR00049## and formula ID is
##STR00050##
3. A compound of claim 1, wherein the A ring is aryl.
4. A compound of claim 1, wherein X is oxygen.
5. A compound of claim 1, wherein Y is NR.sup.4.
5. A compound of claim 1, wherein R.sup.3 is hydrogen or
C.sub.1-4alkyl.
6. A compound of claim 1, wherein R.sup.2 is hydrogen or
C.sub.1-4alkyl.
7. A compound of claim 1, wherein R.sup.1 is a hydrogen, halogen,
or alkoxy.
8. A compound of claim 1 selected from: (1S,2S)-methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate,
(1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic
acid, (1S,2S)-methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxy-
lic acid, (1S,2S)-methyl
1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxyl-
ic acid, (1S,2S)-methyl
1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarbox-
ylic acid, (1S,2S)-methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1S,2S)-methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1S,2S)-methyl
1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1S,2S)-methyl
1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1S,2S)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1S,2S)-methyl
2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,
(1S,2S)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylic
acid, (1S,2S)-methyl
1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,
and
(1S,2S)-1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanec-
arboxylic acid, or salts thereof.
9. A compound of claim 1 selected from: (1S,2S)-methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate,
(1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic
acid, (1R,2R)-methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxy-
lic acid, (1R,2R)-methyl
1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxyl-
ic acid, (1R,2R)-methyl
1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarbox-
ylic acid, (1R,2R)-methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1R,2R)-methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1R,2R)-methyl
1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1R,2R)-methyl
1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
(1R,2R)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, (1R,2R)-methyl
2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,
(1R,2R)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylic
acid, (1R,2R)-methyl
1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,
and
(1R,2R)-1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanec-
arboxylic acid, or salts thereof.
10. A composition comprising a compound of claim 1 in greater than
60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.5% diastereomeric
excess.
11. An isolated composition of a compound of claim 1 in
substantially pure form.
12. A pharmaceutical composition comprising a compound of claim 1
or pharmaceutically acceptable salt or prodrug thereof.
13. A pharmaceutical composition of claim 12 further comprising a
second therapeutic agent.
14. A method of treating or preventing a medical disorder
comprising administering a pharmaceutical composition of claim 12
to a subject diagnosed with, exhibiting symptoms of, or at risk of
a medical disorder.
15. The method of claim 14, wherein the medical disorder is mental
disorder.
16. A method of managing neuropathic pain comprising administering
a pharmaceutical composition of claim 12 to a subject in need
thereof.
17. A method of treating fibromyalgia comprising administering a
pharmaceutical composition of claim 12 to a subject in need
thereof.
18. A process of producing a compound of formula I comprising
mixing a metal catalyst, a compound of formula II, formula II
##STR00051## and a compound of formula III, formula III
##STR00052## under conditions such that a compound of formula I is
formed.
19. The process of claim 18, wherein the metal catalyst is a chiral
catalyst.
20. The process of claim 18, wherein the metal catalyst is
Rh.sub.2(S-biTISP).sub.2, Rh.sub.2(S-DOSP).sub.4, or
Rh.sub.2(S-PTAD).sub.4.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/477,848 filed Apr. 21, 2011, hereby incorporated
by reference in its entirety.
FIELD
[0003] The disclosure relates to cyclopropyl derivatives and
methods of use. In some embodiments, the disclosure relates to
methods of managing medical disorders with pharmaceutical
compositions disclosed herein administered to subject in need
thereof. In certain embodiments, the disclosure relates to methods
of managing mental disorders, mood disorders, pain, fibromyalgia,
and related conditions with pharmaceutical compositions disclosed
herein.
BACKGROUND
[0004] Fibromyalgia is a medical disorder characterized by chronic
widespread pain and allodynia. Fibromyalgia is frequently comorbid
with psychiatric conditions such as depression, anxiety, and
stress-related disorders. Currently, there is no cure for
fibromyalgia. Medical therapies with anti-depressants have
demonstrated the ability to reduce symptoms. Milnacipran is a
cyclopropylamide and a selective norepinephrine and serotonin
reuptake inhibitor (SNRI) approved by the FDA for the management of
fibromyalgia. A significant percentage of patients discontinue
taking milnacipran due to adverse events such as nausea,
palpitations, depression, increased heart rate, constipation, and
headaches. Other adverse events reported when taking milnaciparan
include increases in heart rate and blood pressure, serotonin
syndrome, seizures, hepatotoxicity, hyponatremia, abnormal
bleeding, activation of mania and dysuria. Thus, there is a need to
identify improved therapies.
[0005] Bonnarud et al., J Med Chem, 1987, 30, 318-325 disclose
cyclopropane carbocylic acid derivatives. See also U.S. Pat. No.
4,567,288 and U.S. Published Application No. 2008/0051604. The
authors report uses as antidepressants and for the treatment of
pain. Certain cyclopropyl derivatives are also disclosed in Davies
& Denton, Chem. Soc. Rev., 2009, 38, 3061-3071; Pelphrey et
al., Chem. Sci., 2010, 1, 254-257, Davies et al., Tetrahedron
Letters, (1996) 37(24), 4133-4136, Denton & Davies, Organic
Letters, (2009) 11(4), 787-790. See also U.S. Pat. No.
7,385,064.
SUMMARY
[0006] This disclosure relates to cyclopropyl derivatives and
methods of use. In some embodiments, the disclosure relates to
methods of managing, treating, or preventing medical disorders with
pharmaceutical compositions disclosed herein administered in an
effective amount to subject in need thereof. In certain
embodiments, the disclosure relates to methods of managing mental
disorders, mood disorders, pain, and fibromyalgia and related
conditions with pharmaceutical compositions disclosed herein. In
certain embodiments, the disclosure relates to compounds comprising
the following formula I:
##STR00001##
and salts, prodrugs, or esters thereof wherein,
[0007] A ring is a carbocyclyl, aryl, or heterocyclyl;
[0008] n is 0, 1, 2, 3, 4, or 5;
[0009] X and Y are each the same or different O, S, NR.sup.4;
[0010] R.sup.1 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.1
is optionally substituted with one or more, the same or different,
R.sup.5;
[0011] R.sup.2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.2
is optionally substituted with one or more, the same or different,
R.sup.5;
[0012] R.sup.3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.3
is optionally substituted with one or more, the same or different,
R.sup.5;
[0013] R.sup.4 is hydrogen, alkyl, hydroxy, amino, formyl,
carbocyclyl, aryl, or heterocyclyl, wherein R.sup.4 is optionally
substituted with one or more, the same or different, R.sup.5;
[0014] R.sup.5 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.5
is optionally substituted with one or more, the same or different,
R.sup.6; and
[0015] R.sup.6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0016] In certain embodiments, the disclosure relates to a
composition comprising a compound disclosed herein in greater than
60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.5% diastereomeric
excess.
[0017] In certain embodiments, the disclosure relates to an
isolated composition of a compound disclosed herein in
substantially pure form.
[0018] In certain embodiments, the disclosure relates to a
pharmaceutical composition comprising a compound disclosed herein
or pharmaceutically acceptable salt or prodrug thereof.
[0019] In certain embodiments, the disclosure relates to a
pharmaceutical composition disclosed herein further comprising a
second therapeutic agent.
[0020] In certain embodiments, the disclosure relates to a method
of treating or preventing a mental or neurological disorder
comprising administering an effective amount of a pharmaceutical
composition disclosed herein to a subject diagnosed with,
exhibiting symptoms of, or at risk for a mental or neurological
disorder.
[0021] In certain embodiments, the disclosure relates to methods of
preparing compounds disclosed herein comprising mixing the starting
material and reagents under conditions such that the products are
formed.
BRIEF DESCRIPTION OF THE FIGURES
[0022] FIG. 1 shows a scheme illustrating the synthesis of racemic
cyclopropane amines.
[0023] FIG. 2 shows a scheme illustration synthesis of certain
diastereomers of cyclopropane amines.
[0024] FIG. 3 shows data on the anti-allodynic effects of SNRI
analogs and clonidine. All compounds were administered i.t. and paw
withdrawal threshold was determined before (baseline) and following
drug treatment (treatment) in a similar manner. Maximally effective
doses were given for clonidine (10 .mu.g), Milnacipran (30 .mu.g),
HD-286 (3 .mu.g) and HD-288 (3 .mu.g). N=8-10/group. *,
significantly different from clonidine, p.ltoreq.0.05.
[0025] FIG. 4 shows data on the effects of clonidine, milnacipran
and HD-288 on rotarod performance in SNL rats. Rats were trained to
walk on a rotarod apparatus during 5 minute trials on two
successive days. The rotarod was accelerated from 2 to 5 rpm over a
5 min period and the time until the rat fell from the rotarod was
recorded. Each trial was a maximum of 5 min in duration. Shown are
the mean.+-.SEM for time spent on the rotarod before (baseline) or
after (Treatment) drug administration (N=10-13 per group). *
significantly different from Baseline, p.ltoreq.0.05.
[0026] FIG. 5 shows illustrative schemes for preparing compounds
disclosed herein.
DETAILED DISCUSSION
[0027] The disclosure relates to cyclopropyl derivatives and
methods of use. In some embodiments, the disclosure relates to
methods of managing medical disorders with pharmaceutical
compositions disclosed herein administered to subject in need
thereof. In certain embodiments, the disclosure relates to methods
of managing mental disorders, mood disorders, pain, and
fibromyalgia and related conditions with pharmaceutical
compositions disclosed herein.
Compounds
[0028] In certain embodiments, the disclosure relates to compounds
comprising the following formula I:
##STR00002##
and salts, prodrugs, or esters thereof wherein,
[0029] A ring is a carbocyclyl, aryl, or heterocyclyl;
[0030] n is 0, 1, 2, 3, 4, or 5;
[0031] X and Y are each the same or different O, S, NR.sup.4;
[0032] R.sup.1 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.1
is optionally substituted with one or more, the same or different,
R.sup.5;
[0033] R.sup.2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.2
is optionally substituted with one or more, the same or different,
R.sup.5;
[0034] R.sup.3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.3
is optionally substituted with one or more, the same or different,
R.sup.5;
[0035] R.sup.4 is hydrogen, alkyl, hydroxy, amino, formyl,
carbocyclyl, aryl, or heterocyclyl, wherein R.sup.4 is optionally
substituted with one or more, the same or different, R.sup.5;
[0036] R.sup.5 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.5
is optionally substituted with one or more, the same or different,
R.sup.6; and
[0037] R.sup.6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0038] In certain embodiments, the A ring is aryl or
heteroaryl;
[0039] n is 0, 1, 2, or 3;
[0040] X is oxygen;
[0041] Y is NR.sup.4;
[0042] R.sup.1 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.1
is optionally substituted with one or more, the same or different,
R.sup.5;
[0043] R.sup.2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.2
is optionally substituted with one or more, the same or different,
R.sup.5;
[0044] R.sup.3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.3
is optionally substituted with one or more, the same or different,
R.sup.5;
[0045] R.sup.4 is hydrogen, alkyl, hydroxy, amino, formyl,
carbocyclyl, aryl, or heterocyclyl, wherein R.sup.4 is optionally
substituted with one or more, the same or different, R.sup.5;
[0046] R.sup.5 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.5
is optionally substituted with one or more, the same or different,
R.sup.6; and
[0047] R.sup.6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0048] In certain embodiments, the A ring is aryl or
heteroaryl;
[0049] n is 0, 1, 2, or 3;
[0050] X is oxygen;
[0051] Y is NR.sup.4 wherein R.sup.2 and R.sup.4 and the atoms to
which they are attached form a heterocyclyl optionally substituted
with one or more, the same or different R.sup.5;
[0052] R.sup.1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.1
is optionally substituted with one or more, the same or different,
R.sup.5;
[0053] R.sup.2 is hydrogen or alkyl;
[0054] R.sup.3 is hydrogen or alkyl;
[0055] R.sup.4 is hydrogen or alkyl;
[0056] R.sup.5 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.5
is optionally substituted with one or more, the same or different,
R.sup.6; and
[0057] R.sup.6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0058] In certain embodiments, the A ring is aryl;
[0059] n is 0, 1, 2, or 3;
[0060] X is oxygen;
[0061] Y is NH;
[0062] R.sup.1 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy,
amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.1
is optionally substituted with one or more, the same or different,
R.sup.5;
[0063] R.sup.2 is hydrogen or alkyl;
[0064] R.sup.3 is hydrogen or alkyl;
[0065] R.sup.5 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, or
N-methyl-N-ethylsulfamoyl.
[0066] In certain embodiments, the disclosure relates to a compound
of formula I, wherein formula I is formula IA, IB, IC, or ID
wherein:
formula IA is
##STR00003##
formula IB is
##STR00004##
formula IC is
##STR00005##
and formula ID is
##STR00006##
[0067] In certain embodiments, the A ring is aryl or
heteroaryl.
[0068] In certain embodiments, the A ring is aryl or heteroaryl and
X is oxygen or NR.sup.4.
[0069] In certain embodiments, the A ring is aryl or heteroaryl,
R.sup.3 is hydrogen or C.sub.1-4alkyl and X is oxygen or
NR.sup.4.
[0070] In certain embodiments, the A ring is aryl or heteroaryl,
R.sup.2 is hydrogen or C.sub.1-4alkyl, Y is NR.sup.4 or oxygen, and
X is oxygen or NR.sup.4.
[0071] In certain embodiments, the A ring is aryl or heteroaryl,
R.sup.1 is a hydrogen, halogen, or alkoxy, X is oxygen, Y is
NR.sup.4, and R.sup.2 is hydrogen or C.sub.1-4alkyl.
[0072] In certain embodiments, the A ring is aryl or heteroaryl, Y
is NR.sup.4 or oxygen, and X is oxygen or NR.sup.4.
[0073] In certain embodiments, the A ring is phenyl, napthyl or
biphenyl.
[0074] In certain embodiments, the A ring is phenyl, napthyl or
biphenyl and X is oxygen or NR.sup.4.
[0075] In certain embodiments, the A ring is phenyl, napthyl or
biphenyl, R.sup.3 is hydrogen or C.sub.1-4alkyl and X is oxygen or
NR.sup.4.
[0076] In certain embodiments, the A ring is phenyl, napthyl or
biphenyl, Y is NR.sup.4 or oxygen and X is oxygen or NR.sup.4.
[0077] In certain embodiments, the A ring is phenyl, napthyl or
biphenyl, R.sup.2 is hydrogen or C.sub.1-4alkyl, Y is NR.sup.4, and
X is oxygen.
[0078] In certain embodiments, the A ring is phenyl, napthyl or
biphenyl, R.sup.1 is a hydrogen, halogen, or alkoxy, X is oxygen,
and R.sup.2 is hydrogen or C.sub.1-4alkyl.
[0079] In certain embodiments, X is oxygen.
[0080] In certain embodiments, X is NR.sup.4, wherein R.sup.4 is
hydrogen or C.sub.1-4alkyl.
[0081] In certain embodiments, Y is NR.sup.4, wherein R.sup.4 is
hydrogen or C.sub.1-4alkyl.
[0082] In certain embodiments, R.sup.3 is hydrogen or
C.sub.1-4alkyl.
[0083] In certain embodiments, R.sup.3 is methyl or ethyl.
[0084] In certain embodiments, R.sup.2 is hydrogen or
C.sub.1-4alkyl.
[0085] In certain embodiments, R.sup.2 is methyl or ethyl.
[0086] In certain embodiments, R.sup.1 is a hydrogen, halogen, or
C.sub.1-4alkoxy.
[0087] In certain embodiments, R.sup.1 is methoxy or ethoxy.
[0088] In certain embodiments, n is 0, 1, 2, or 3;
[0089] In certain embodiments, n is 0, 1 or 2.
[0090] In certain embodiments, n is 1 or 2.
[0091] In certain embodiments, the disclosure relates to a compound
of formula IA, wherein the A ring is aryl. In certain embodiments,
the A ring is phenyl. In certain embodiments, the A ring is
napthyl. In certain embodiments, the A ring is biphenyl. In certain
embodiments, the A ring is aryl and X is oxygen or NR.sup.4. In
certain embodiments, the A ring is aryl, R.sup.3 is hydrogen or
C.sub.1-4alkyl and X is oxygen. In certain embodiments, the A ring
is aryl, Y is NR.sup.4 or oxygen, X is oxygen. In certain
embodiments, the A ring is aryl, R.sub.2 is hydrogen or
C.sub.1-4alkyl, Y is NR.sup.4, and X is oxygen. In certain
embodiments, the A ring is aryl, R.sup.1 is a hydrogen, halogen, or
alkoxy, X is oxygen, and R.sup.2 is hydrogen or C.sub.1-4alkyl. In
certain embodiment, R.sup.4 is C.sub.1-4alkyl.
[0092] In certain embodiments, the disclosure relates to a compound
of formula IB, wherein the A ring is aryl. In certain embodiments,
the A ring is phenyl. In certain embodiments, the A ring is
napthyl. In certain embodiments, the A ring is biphenyl. In certain
embodiments, the A ring is aryl and X is oxygen or NR.sup.4. In
certain embodiments, the A ring is aryl, R.sup.3 is hydrogen or
C.sub.1-4alkyl and X is oxygen. In certain embodiments, the A ring
is aryl, Y is NR.sup.4 or oxygen, and X is oxygen. In certain
embodiments, the A ring is aryl, R.sup.2 is hydrogen or
C.sub.1-4alkyl, Y is NR.sup.4, and X is oxygen. In certain
embodiments, the A ring is aryl, R.sup.1 is a hydrogen, halogen, or
alkoxy, X is oxygen, and R.sup.2 is hydrogen or C.sub.1-4alkyl. In
certain embodiment, R.sup.4 is C.sub.1-4alkyl.
[0093] In certain embodiments, the disclosure relates to
compositions comprising a compound of formula IA, in greater than
60%, 70%, 80%, 90%, 95%, or 98% diastereomeric excess wherein the A
ring is aryl, X is oxygen, Y is NR.sup.4, R.sup.3 is
C.sub.1-4alkyl, R.sup.2 is hydrogen or C.sub.1-4alkyl, R.sup.1 is a
hydrogen, halogen, or alkoxy, and n is 1 or 2. In certain
embodiments, the A ring is phenyl. In certain embodiments, A ring
is phenyl substituted with one or more halogens. In certain
embodiments substituted at the 3 and 4 position of the phenyl ring.
In certain embodiments, the A ring is napthyl. In certain
embodiments, the A ring is biphenyl. In certain embodiments,
R.sup.2 is C.sub.1-4alkyl. In certain embodiment, R.sup.4 is
C.sub.1-4alkyl.
[0094] In certain embodiments, the disclosure relates to a
composition comprising a compound of formula IB, in greater than
60%, 70%, 80%, 90%, 95%, or 98% diastereomeric excess wherein the A
ring is aryl, X is oxygen, Y is NR.sup.4, R.sup.3 is
C.sub.1-4alkyl, R.sup.2 is hydrogen or C.sub.1-4alkyl, R.sup.1 is a
hydrogen, halogen, or alkoxy, and n is 1 or 2. In certain
embodiment, R.sup.4 is C.sub.1-4alkyl.
[0095] In some embodiments, the disclosure relates to a compound
selected from: [0096] (1S,2S)-methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate, [0097]
(1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic
acid, [0098] (1S,2S)-methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0099]
(1S,2S)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropane-
carboxylic acid, [0100] (1S,2S)-methyl
1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0101]
(1S,2S)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanec-
arboxylic acid, [0102] (1S,2S)-methyl
1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0103]
(1S,2S)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropan-
ecarboxylic acid, [0104] (1S,2S)-methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0105]
(1S,2S)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, [0106] (1S,2S)-methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0107]
(1S,2S)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, [0108] (1S,2S)-methyl
1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0109]
(1S,2S)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecar-
boxylic acid, [0110] (1S,2S)-methyl
1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0111]
(1S,2S)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecar-
boxylic acid, [0112] (1S,2S)-methyl
2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,
[0113]
(1S,2S)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecar-
boxylic acid, [0114] (1S,2S)-methyl
1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,
and [0115]
(1S,2S)-1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarbo-
xylic acid, or salts thereof.
[0116] In certain embodiment the disclosure relates to a compound
selected from: [0117] (1R,2R)-methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate, [0118]
(1R,2R)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic
acid, [0119] (1R,2R)-methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0120]
(1R,2R)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropane-
carboxylic acid, [0121] (1R,2R)-methyl
1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0122]
(1R,2R)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanec-
arboxylic acid, [0123] (1R,2R)-methyl
1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0124]
(1R,2R)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropan-
ecarboxylic acid, [0125] (1R,2R)-methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0126]
(1R,2R)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, [0127] (1R,2R)-methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0128]
(1R,2R)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic
acid, [0129] (1R,2R)-methyl
1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0130]
(1R,2R)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecar-
boxylic acid, [0131] (1R,2R)-methyl
1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate,
[0132]
(1R,2R)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecar-
boxylic acid, [0133] (1R,2R)-methyl
2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate,
[0134]
(1R,2R)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecar-
boxylic acid, [0135] (1R,2R)-methyl
1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate,
and [0136]
(1R,2R)-1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarbo-
xylic acid, or salts thereof.
[0137] In certain embodiments, the disclosure relates to compounds
disclosed herein substituted with one or more substituents.
Compound Preparation
[0138] Methods for the preparation of certain cyclopropyl
derivatives are disclosed in Pelphrey et al., Chem. Sci., 2010, 1,
254-257, Davies et al., Tetrahedron Letters, (1996) 37(24),
4133-4136, Denton & Davies, Organic Letters, (2009) 11(4),
787-790, Davies & Denton, Chem. Soc. Rev., 2009, 38, 3061-3071.
See also U.S. Pat. No. 4,567,288, U.S. Pat. No. 7,385,064, and U.S.
Published Application No. 2008/0051604 all hereby incorporated by
reference.
[0139] In certain embodiments, the disclosure relates to a process
of producing a compound of formula I comprising mixing a metal
catalyst, a compound of formula II, formula II
##STR00007##
and a compound of formula III, formula III
##STR00008##
under conditions such that a compound of formula I is formed. In
certain embodiments a compound of formula IA, IB, IC, or IC is
formed. In certain embodiments, the metal catalyst is a chiral
catalyst such as Rh.sub.2(S-biTISP).sub.2, Rh.sub.2(S-DOSP).sub.4,
or Rh.sub.2(S-PTAD).sub.4.
Therapeutic Applications
[0140] In some embodiments, the disclosure relates to methods of
treating or preventing mental disorders with pharmaceutical
compositions disclosed herein administered to subject in need
thereof. Examples of mental disorders include, but are not limited
to, anxiety or mood disorders, depression, major depression
disorder; schizophrenia, paranoid, undifferentiates, residual,
catatonic or disorganized, subchronic or chronic with acute
exacerbation, in remission; delusional (paranoid) disorder; brief
reactive psychosis; schizophreniform disorder; schizoaffective
disorder; induced psychotic disorder; atypical psychosis;
personality disorders, paranoid, schizoid, schizotypal, antisocial;
and bipolar disorders, maniac, hypomaniac, dysthymic or cyclothymic
disorders; substance-induced major depression; and
substance-induced psychotic disorder. Also included are adjustment
disorders, eating disorders, sleep disorders, sexual identity
disorders, and impulse control disorders.
[0141] In anxiety disorders, anxiety interferes with normal
functioning. Representative classifications include specific
phobias, generalized anxiety disorder, social anxiety disorder,
panic disorder, agoraphobia, obsessive-compulsive disorder and
post-traumatic stress disorder.
[0142] Subjects with mood disorders typically report intense and
sustained sadness, melancholia or despair. Diagnosis can range from
depression, major depression or clinical depression (milder but
still prolonged depression can be diagnosed as dysthymia). Bipolar
disorder (also known as manic depression) involves abnormally
"high" or pressured mood states, known as mania or hypomania,
alternating with normal or depressed mood.
[0143] Representative psychotic disorders include schizophrenia,
and delusional disorder. Subjects with these disorders typically
exhibit patterns of disbelief and often language use and perception
can become disordered (e.g. delusions, thought disorder,
hallucinations). Schizoaffective disorder is a category used for
individuals showing aspects of both schizophrenia and affective
disorders. Schizotypy is a category used for individuals showing
some of the characteristics associated with schizophrenia but
without meeting cut-off criteria.
[0144] Personality may be considered disordered if judged to be
abnormally rigid and maladaptive. Representative personality
disorders include those sometimes classed as eccentric (e.g.
paranoid, schizoid and schizotypal personality disorders), to those
sometimes classed as dramatic or emotional (antisocial, borderline,
histrionic or narcissistic personality disorders) or those seen as
fear-related (avoidant, dependent, or obsessive-compulsive
personality disorders).
[0145] Eating disorders involve disproportionate concern in matters
of food and weight. Categories of disorder in this area include
anorexia nervosa, bulimia nervosa, exercise bulimia or binge eating
disorder.
[0146] Sleep disorders such as insomnia involve disruption to
normal sleep patterns, or a feeling of tiredness despite sleep
appearing normal.
[0147] Sexual and gender identity disorders may be diagnosed,
including dyspareunia, gender identity disorder and ego-dystonic
homosexuality. Various kinds of paraphilia are considered mental
disorders (sexual arousal to objects, situations, or individuals
that are considered abnormal or harmful to the person or
others).
[0148] Subjects with impulse control disorder are abnormally unable
to resist certain urges or impulses. Representative examples
include tic disorders such as Tourette's syndrome, and disorders
such as kleptomania or pyromania, and gambling addiction.
[0149] Subjects with dissociative identity disorder suffer
disturbances of their self-identity, memory and general awareness
of themselves and their surroundings. Representative examples
include depersonalization disorder or dissociative identity
disorder itself (which has also been called multiple personality
disorder, or "split personality), memory or cognitive disorders
include amnesia or various kinds of old age dementia.
[0150] Representative childhood disorders autism spectrum
disorders, oppositional defiant disorder and conduct disorder, and
attention deficit hyperactivity disorder (ADHD).
[0151] In some embodiments, the disclosure relates to the
management of neuropathic pain comprising administering a
pharmaceutical composition disclosed herein to a subject at risk
of, exhibiting symptoms or diagnosed with neuropathic pain.
Neuropathic pain refers to pain associated with abnormal sensations
sometimes called dysesthesias, which occur spontaneously and
allodynias. Neuropathic pain may have continuous and/or episodic
(paroxysmal) components. Common qualities of neuropathic pain
include burning or coldness, "pins and needles" sensations,
numbness and itching. Neuropathic pain may result from disorders of
the peripheral nervous system or the central nervous system (brain
and spinal cord). Thus, neuropathic pain may be divided into
peripheral neuropathic pain, central neuropathic pain, or mixed
(peripheral and central) neuropathic pain. Central neuropathic pain
is typically found in subjects with spinal cord injury, multiple
sclerosis, and strokes. Common causes of painful peripheral
neuropathies are herpes zoster infection, HIV-related neuropathies,
nutritional deficiencies, toxin exposures, remote manifestations of
malignancies, genetic, and immune mediated disorders or physical
trauma to a nerve trunk. Neuropathic pain is common in cancer as a
direct result of cancer on peripheral nerves (e.g., compression by
a tumor), or as a side effect of chemotherapy, radiation injury or
surgery.
[0152] In some embodiments, the disclosure relates to the
management of fibromyalgia comprising administering a
pharmaceutical composition disclosed herein to a subject at risk
of, exhibiting symptoms or diagnosed with fibromyalgia.
Fibromyalgia is a medical disorder characterized by chronic
widespread pain and a heightened and painful response to
pressure.
[0153] In some embodiments, the disclosure relates to the
management of pain from menstrual cramps comprising administering a
pharmaceutical composition disclosed herein to a woman.
Pharmaceutical Formulations
[0154] Pharmaceutical compositions disclosed herein may be in the
form of pharmaceutically acceptable salts, as generally described
below. Some preferred, but non-limiting examples of suitable
pharmaceutically acceptable organic and/or inorganic acids are
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
acetic acid and citric acid, as well as other pharmaceutically
acceptable acids known per se (for which reference is made to the
references referred to below).
[0155] When the compounds of the disclosure contain an acidic group
as well as a basic group, the compounds of the disclosure may also
form internal salts, and such compounds are within the scope of the
disclosure. When the compounds contain a hydrogen-donating
heteroatom (e.g. NH), this disclosure contemplates salts and/or
isomers formed by transfer of said hydrogen atom to a basic group
or atom within the molecule, such as in the case of an amino
acid.
[0156] Pharmaceutically acceptable salts of the compounds include
the acid addition and base salts thereof. Suitable acid addition
salts are formed from acids which form non-toxic salts. Examples
include the acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, cyclamate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, saccharate,
stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate
and xinofoate salts. Suitable base salts are formed from bases
which form non-toxic salts. Examples include the aluminium,
arginine, benzathine, calcium, choline, diethylamine, diolamine,
glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc salts. Hemisalts of acids and bases may also
be formed, for example, hemisulphate and hemicalcium salts. For a
review on suitable salts, see Handbook of Pharmaceutical Salts:
Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,
2002), incorporated herein by reference.
[0157] The compounds described herein may be administered in the
form of prodrugs. A prodrug can include a covalently bonded carrier
which releases the active parent drug when administered to a
mammalian subject. Prodrugs can be prepared by modifying functional
groups present in the compounds in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compounds. Prodrugs include, for example,
compounds wherein a hydroxyl group is bonded to any group that,
when administered to a mammalian subject, cleaves to form a free
hydroxyl group. Examples of prodrugs include, but are not limited
to, acetate, formate and benzoate derivatives of alcohol functional
groups in the compounds. Methods of structuring a compound as
prodrugs can be found in the book of Testa and Mayer, Hydrolysis in
Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs form
the active metabolite by transformation of the prodrug by
hydrolytic enzymes, the hydrolysis of amide, lactams, peptides,
carboxylic acid esters, epoxides or the cleavage of esters of
inorganic acids.
[0158] Pharmaceutical compositions for use in the present
disclosure typically comprise an effective amount of a compound and
a suitable pharmaceutical acceptable carrier. The preparations may
be prepared in a manner known per se, which usually involves mixing
the at least one compound according to the disclosure with the one
or more pharmaceutically acceptable carriers, and, if desired, in
combination with other pharmaceutical active compounds, when
necessary under aseptic conditions. Reference is again made to U.S.
Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No.
6,369,087, and U.S. Pat. No. 6,372,733 and the further references
mentioned above, as well as to the standard handbooks, such as the
latest edition of Remington's Pharmaceutical Sciences.
[0159] Generally, for pharmaceutical use, the compounds may be
formulated as a pharmaceutical preparation comprising at least one
compound and at least one pharmaceutically acceptable carrier,
diluent or excipient and/or adjuvant, and optionally one or more
further pharmaceutically active compounds.
[0160] The pharmaceutical preparations of the disclosure are
preferably in a unit dosage form, and may be suitably packaged, for
example in a box, blister, vial, bottle, sachet, ampoule or in any
other suitable single-dose or multi-dose holder or container (which
may be properly labeled); optionally with one or more leaflets
containing product information and/or instructions for use.
Generally, such unit dosages will contain between 1 and 1000 mg,
and usually between 5 and 500 mg, of the at least one compound of
the disclosure, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per
unit dosage.
[0161] The compounds can be administered by a variety of routes
including the oral, ocular, rectal, transdermal, subcutaneous,
intravenous, intramuscular, spinal, epidural, or intranasal routes,
depending mainly on the specific preparation used. The compound
will generally be administered in an "effective amount", by which
is meant any amount of a compound that, upon suitable
administration, is sufficient to achieve the desired therapeutic or
prophylactic effect in the subject to which it is administered.
Usually, depending on the condition to be prevented or treated and
the route of administration, such an effective amount will usually
be between 0.01 to 1000 mg per kilogram body weight of the patient
per day, more often between 0.1 and 500 mg, such as between 1 and
250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg,
per kilogram body weight of the patient per day, which may be
administered as a single daily dose, divided over one or more daily
doses. The amount(s) to be administered, the route of
administration and the further treatment regimen may be determined
by the treating clinician, depending on factors such as the age,
gender and general condition of the patient and the nature and
severity of the disease/symptoms to be treated. Reference is again
made to U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat.
No. 6,369,087, and U.S. Pat. No. 6,372,733 and the further
references mentioned above, as well as to the standard handbooks,
such as the latest edition of Remington's Pharmaceutical
Sciences.
[0162] For an oral administration form, the compound can be mixed
with suitable additives, such as excipients, stabilizers or inert
diluents, and brought by means of the customary methods into the
suitable administration forms, such as tablets, coated tablets,
hard capsules, aqueous, alcoholic, or oily solutions. Examples of
suitable inert carriers are gum arabic, magnesia, magnesium
carbonate, potassium phosphate, lactose, glucose, or starch, in
particular, corn starch. In this case, the preparation can be
carried out both as dry and as moist granules. Suitable oily
excipients or solvents are vegetable or animal oils, such as
sunflower oil or cod liver oil. Suitable solvents for aqueous or
alcoholic solutions are water, ethanol, sugar solutions, or
mixtures thereof. Polyethylene glycols and polypropylene glycols
are also useful as further auxiliaries for other administration
forms. As immediate release tablets, these compositions may contain
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and lactose and/or other excipients, binders, extenders,
disintegrants, diluents and lubricants known in the art.
[0163] When administered by nasal aerosol or inhalation, the
compositions may be prepared according to techniques well-known in
the art of pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other solubilizing or dispersing agents known
in the art. Suitable pharmaceutical formulations for administration
in the form of aerosols or sprays are, for example, solutions,
suspensions or emulsions of the compounds of the disclosure or
their physiologically tolerable salts in a pharmaceutically
acceptable solvent, such as ethanol or water, or a mixture of such
solvents. If required, the formulation can also additionally
contain other pharmaceutical auxiliaries such as surfactants,
emulsifiers and stabilizers as well as a propellant.
[0164] For subcutaneous, spinal, epidural, or intravenous
administration, the compounds, if desired with the substances
customary therefore such as solubilizers, emulsifiers or further
auxiliaries are brought into solution, suspension, or emulsion. The
compounds of formula I can also be lyophilized and the
lyophilizates obtained used, for example, for the production of
injection or infusion preparations. Suitable solvents are, for
example, water, physiological saline solution or alcohols, e.g.
ethanol, propanol, glycerol, sugar solutions such as glucose or
mannitol solutions, or mixtures of the various solvents mentioned.
The injectable solutions or suspensions may be formulated according
to known art, using suitable non-toxic, parenterally-acceptable
diluents or solvents, such as mannitol, 1,3-butanediol, water,
Ringer's solution or isotonic sodium chloride solution, or suitable
dispersing or wetting and suspending agents, such as sterile,
bland, fixed oils, including synthetic mono- or diglycerides, and
fatty acids, including oleic acid.
[0165] When rectally administered in the form of suppositories, the
formulations may be prepared by mixing the compounds of formula I
with a suitable non-irritating excipient, such as cocoa butter,
synthetic glyceride esters or polyethylene glycols, which are solid
at ordinary temperatures, but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0166] In certain embodiments, it is contemplated that these
compositions can be extended release formulations. Typical extended
release formations utilize an enteric coating. A barrier is applied
to oral medication that controls the location in the digestive
system where it is absorbed. Enteric coatings prevent release of
medication before it reaches the small intestine. Enteric coatings
may contain polymers of polysaccharides, such as maltodextrin,
xanthan, scleroglucan dextran, starch, alginates, pullulan,
hyaloronic acid, chitin, chitosan and the like; other natural
polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine;
sodium poly(acrylic acid); poly(hydroxyalkylmethacrylates) (for
example poly(hydroxyethylmethacrylate)); carboxypolymethylene (for
example Carbopol.TM.); carbomer; polyvinylpyrrolidone; gums, such
as guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum,
tamarind gum, gellan gum, gum tragacanth, agar, pectin, gluten and
the like; poly(vinyl alcohol); ethylene vinyl alcohol; polyethylene
glycol (PEG); and cellulose ethers, such as hydroxymethylcellulose
(HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),
methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose
(CEC), ethylhydroxyethylcellulose (EHEC),
carboxymethylhydroxyethylcellulose (CMHEC),
hydroxypropylmethyl-cellulose (HPMC), hydroxypropylethylcellulose
(HPEC) and sodium carboxymethylcellulose (Na CMC); as well as
copolymers and/or (simple) mixtures of any of the above polymers.
Certain of the above-mentioned polymers may further be crosslinked
by way of standard techniques.
[0167] The choice of polymer will be determined by the nature of
the active ingredient/drug that is employed in the composition of
the disclosure as well as the desired rate of release. In
particular, it will be appreciated by the skilled person, for
example in the case of HPMC, that a higher molecular weight will,
in general, provide a slower rate of release of drug from the
composition. Furthermore, in the case of HPMC, different degrees of
substitution of methoxyl groups and hydroxypropoxyl groups will
give rise to changes in the rate of release of drug from the
composition. In this respect, and as stated above, it may be
desirable to provide compositions of the disclosure in the form of
coatings in which the polymer carrier is provided by way of a blend
of two or more polymers of, for example, different molecular
weights in order to produce a particular required or desired
release profile.
Combination Therapies
[0168] With regard to mental disorders, compounds disclosed herein
may be administer in combinations with other psychiatric
medications, such as antidepressants, anxiolytics, anticonvulsants,
antipsychotics and stimulants such as anti-inflammatory agents.
[0169] Representative antidepressants include monoamine oxidase
inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic
antidepressants (TeCAs), selective serotonin reuptake inhibitors
(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and
others.
[0170] Representative selective and non-selective MAOIs include
benmoxin, hydralazine, iproclozide, iproniazid, isocarboxazid,
isoniazid, mebanazine, nialamide, octamoxin, phenelzine,
pheniprazine, phenoxypropazine, pivalylbenzhydrazine, procarbazine,
safrazine, caroxazone, echinopsidine, furazolidone, linezolid,
tranylcypromine, brofaromine, metralindole, minaprine, moclobemide,
pirlindole, toloxatone, lazabemide, pargyline, rasagiline,
selegiline, resveratrol, curcumin, catechin, desmethoxyyangonin,
epicatechin, hydroxytyrosol, and piperine.
[0171] Representative TCAs include amitriptyline,
amitriptylinoxide, butriptyline, clomipramine, demexiptiline,
desipramine, dibenzepin, dimetacrine dosulepin/dothiepin, doxepin,
imipramine, imipraminoxide, lofepramine, melitracen, metapramine,
nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine,
protriptyline, quinupramine, amineptine, iprindole, opipramol,
tianeptine, trimipramine. Representative TeCAs include, amoxapine,
maprotiline, mazindol, mianserin, mirtazapine, setiptiline,
ciclazindol, esmirtazapine, and oxaprotiline.
[0172] Representative SSRIs include citalopram, dapoxetine,
escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine,
sertraline, and zimelidine.
[0173] Representative SNRIs include venlafaxine, desvenlafaxine,
duloxetine, milnacipran, levomilnacipran, sibutramine, and
bicifadine.
[0174] Other representative anti-depressants include mianserin,
mirtazapine, atomoxetine, mazindol, reboxetine, viloxazine,
bupropion, tianeptine, and agomelatine.
[0175] Representative anxiolytics include alprazolam,
chlordiazepoxide, clonazepam, diazepam, lorazepam, buspirone,
tandospirone, gepirone, hydroxyzine, and pregabalin.
[0176] Representative anticonvulsants include lithium, valproic
acid, lamotrigine, carbamazepine, oxcarbazepine, and
gabapentin.
[0177] Representative antipsychotics include haloperidol,
droperidol, chlorpromazine, fluphenazine, perphenazine,
prochlorperazine, thioridazine, trifluoperazine, mesoridazine,
periciazine, promazine, triflupromazine, levomepromazine,
promethazine, pimozide, chlorprothixene, clopenthixol,
flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine,
risperidone, quetiapine, ziprasidone, amisulpride, asenapine,
paliperidone, iloperidone, zotepine, sertindole, aripiprazole,
bifeprunox, and cannabidiol.
[0178] Representative stimulants include caffeine nicotine,
amphetamine, methamphetamine, methylenedioxymethamphetamine,
troparil, lometopane, methylphenidate, bupropion atomoxetine,
reboxetine, modafinil, ampalex, carphedon, and yohimbine.
[0179] Suitable anti-inflammatory compounds include both steroidal
and non-steroidal structures. Suitable non-limiting examples of
steroidal anti-inflammatory compounds are corticosteroids such as
hydrocortisone, cortisol, hydroxyltriamcinolone, alpha-methyl
dexamethasone, dexamethasone-phosphate, beclomethasone
dipropionates, clobetasol valerate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclorolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylesters,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone, fludrocortisone,
difluorosone diacetate, fluocinolone, fluradrenolone acetonide,
medrysone, amcinafel, amcinafide, betamethasone and the balance of
its esters, chloroprednisone, chlorprednisone acetate,
clocortelone, clescinolone, dichlorisone, diflurprednate,
flucloronide, flunisolide, fluoromethalone, fluperolone,
fluprednisolone, hydrocortisone valerate, hydrocortisone
cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone,
prednisolone, prednisone, beclomethasone dipropionate,
triamcinolone. Mixtures of the above steroidal anti-inflammatory
compounds may also be used.
[0180] Non-limiting examples of non-steroidal anti-inflammatory
compounds include nabumetone, celecoxib, etodolac, nimesulide,
apasone, gold, oxicams, such as piroxicam, isoxicam, meloxicam,
tenoxicam, sudoxicam, the salicylates, such as aspirin, disalcid,
benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;
the acetic acid derivatives, such as diclofenac, fenclofenac,
indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,
zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,
felbinac, and ketorolac; the fenamates, such as mefenamic,
meclofenamic, flufenamic, niflumic, and tolfenamic acids; the
propionic acid derivatives, such as ibuprofen, naproxen,
benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,
indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen,
miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic;
and the pyrazoles, such as phenylbutazone, oxyphenbutazone,
feprazone, azapropazone, and trimethazone.
[0181] In other embodiments, the compounds are administered in
combination with medications that prevent indigestion or gastritis
such as H2 receptor antagonists (cimetidine, ranitidine,
famotidine, and nizatidine) or proton pump inhibitors such as
omeprazole, lansoprazole, dexlansoprazole, esomeprazole,
pantoprazole, and rabeprazole.
[0182] These compounds could be co-administered with analgesics to
treat acute or chronic pain conditions. Examples of such analgesics
would be opioid agonists (including morphine, codeine, methadone,
meperidine, etc.), .alpha..sub.2-adrenergic agonists (such as
clonidine), gabapentin, and cholinesterase inhibitors (such as
donepezil).
Terms
[0183] When describing the compounds for use in the disclosure, the
terms used are to be construed in accordance with the following
definitions, unless a context dictates otherwise.
[0184] A "chiral metal catalyst" refers to a catalytic metal
complex where the ligands have one or more chiral centers. Examples
include chiral 2-(2-aryl- or
2-alkyl-sulfonylamino)phenyl-4-phenyl-1,3-oxazolines as ligands for
copper-catalyzed enantioselective cyclopropanation reaction of
olefins described in Ichiyanagi et al, Tetrahedron, 1997, 53(28),
9599-9610 and Rh.sub.2(S-biTISP).sub.2, Rh.sub.2(S-DOSP).sub.4, or
Rh.sub.2(S-PTAD).sub.4 catalysts as disclosed in Denton &
Davis, Organic Letters, 2009, 11(4), 787-790, Davis et al.,
Tetrahedron Letters, 1996, 37(24) 4133-4136, and U.S. Pat. No.
7,385,064 hereby incorporated by reference. Chiral copper, rhodium,
and ruthenium catalysts are representative of those contemplated by
this disclosure. Typically, the chiral centers in the ligands
induce catalytic conversion in enantiomeric or diastereomeric
excess if present in the reaction product. Replacing the chiral
ligands with their enantiomers will typically invert the
stereochemistry of the reaction product.
[0185] As used herein, "alkyl" means a noncyclic straight chain or
branched, unsaturated or saturated hydrocarbon such as those
containing from 1 to 10 carbon atoms, while the term "lower alkyl"
or "C.sub.1-4alkyl" has the same meaning as alkyl but contains from
1 to 4 carbon atoms. The term "higher alkyl" has the same meaning
as alkyl but contains from 7 to 20 carbon atoms. Representative
saturated straight chain alkyls include methyl, ethyl, n-propyl,
n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the
like; while saturated branched alkyls include isopropyl, sec-butyl,
isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls
contain at least one double or triple bond between adjacent carbon
atoms (referred to as an "alkenyl" or "alkynyl", respectively).
Representative straight chain and branched alkenyls include
ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,
1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,
2,3-dimethyl-2-butenyl, and the like; while representative straight
chain and branched alkynyls include acetylenyl, propynyl,
1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,
and the like.
[0186] Non-aromatic mono or polycyclic alkyls are referred to
herein as "carbocycles" or "carbocyclyl" groups. Representative
saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and the like; while unsaturated carbocycles include
cyclopentenyl and cyclohexenyl, and the like.
[0187] "Heterocarbocycles" or heterocarbocyclyl" groups are
carbocycles which contain from 1 to 4 heteroatoms independently
selected from nitrogen, oxygen and sulfur which may be saturated or
unsaturated (but not aromatic), monocyclic or polycyclic, and
wherein the nitrogen and sulfur heteroatoms may be optionally
oxidized, and the nitrogen heteroatom may be optionally
quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl,
pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, and the like.
[0188] "Aryl" means an aromatic carbocyclic monocyclic or
polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems
may, but are not required to, contain one or more non-aromatic
rings, as long as one of the rings is aromatic.
[0189] As used herein, "heteroaryl" refers an aromatic
heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen,
oxygen and sulfur, and containing at least 1 carbon atom, including
both mono- and polycyclic ring systems. Polycyclic ring systems
may, but are not required to, contain one or more non-aromatic
rings, as long as one of the rings is aromatic. Representative
heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl,
pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl,
isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl,
imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,
isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that
the use of the term "heteroaryl" includes N-alkylated derivatives
such as a 1-methylimidazol-5-yl substituent.
[0190] As used herein, "heterocycle" or "heterocyclyl" refers to
mono- and polycyclic ring systems having 1 to 4 heteroatoms
selected from nitrogen, oxygen and sulfur, and containing at least
1 carbon atom. The mono- and polycyclic ring systems may be
aromatic, non-aromatic or mixtures of aromatic and non-aromatic
rings. Heterocycle includes heterocarbocycles, heteroaryls, and the
like.
[0191] "Alkylthio" refers to an alkyl group as defined above with
the indicated number of carbon atoms attached through a sulfur
bridge. An example of an alkylthio is methylthio, (i.e.,
--S--CH3).
[0192] "Alkoxy" refers to an alkyl group as defined above with the
indicated number of carbon atoms attached through an oxygen bridge.
Examples of alkoxy include, but are not limited to, methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
[0193] "Alkylamino" refers an alkyl group as defined above with the
indicated number of carbon atoms attached through an amino bridge.
An example of an alkylamino is methylamino, (i.e., --NH--CH3).
[0194] "Alkanoyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a carbonyl bride
(i.e., --(C.dbd.O)alkyl).
[0195] "Alkylsulfonyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a sulfonyl bridge
(i.e., --S(.dbd.O).sub.2alkyl) such as mesyl and the like, and
"Arylsulfonyl" refers to an aryl attached through a sulfonyl bridge
(i.e., --S(.dbd.O).sub.2aryl).
[0196] "Alkylsulfamoyl" refers to an alkyl as defined above with
the indicated number of carbon atoms attached through a sulfamoyl
bridge (i.e., --NHS(.dbd.O)2alkyl), and an "Arylsulfamoyl" refers
to an alkyl attached through a sulfamoyl bridge (i.e., (i.e.,
--NHS(.dbd.O)2aryl).
[0197] "Alkylsulfinyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a sulfinyl bridge
(i.e. --S(.dbd.O)alkyl).
[0198] The term "substituted" refers to a molecule wherein at least
one hydrogen atom is replaced with a substituent. When substituted,
one or more of the groups are "substituents." The molecule may be
multiply substituted. In the case of an oxo substituent (".dbd.O"),
two hydrogen atoms are replaced. Example substituents within this
context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano,
oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl,
heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, --NRaRb, --NR aC(.dbd.O)Rb, --NRaC(.dbd.O)NRaNRb,
--NRaC(.dbd.O)ORb, --NRaSO2Rb, --C(.dbd.O)Ra, --C(.dbd.O)ORa,
--C(.dbd.O)NRaRb, --OC(.dbd.O)NRaRb, --ORa, --SRa, --SORa,
--S(.dbd.O)2Ra, --OS(.dbd.O)2Ra and --S(.dbd.O)2ORa. Ra and Rb in
this context may be the same or different and independently
hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino,
alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl,
heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl.
[0199] The term "optionally substituted," as used herein, means
that substitution is optional and therefore it is possible for the
designated atom to be unsubstituted.
[0200] As used herein, "salts" refer to derivatives of the
disclosed compounds where the parent compound is modified making
acid or base salts thereof. Examples of salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines, alkylamines, or dialkylamines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like. In
preferred embodiment the salts are conventional nontoxic
pharmaceutically acceptable salts including the quaternary ammonium
salts of the parent compound formed, and non-toxic inorganic or
organic acids. Preferred salts include those derived from inorganic
acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric and the like; and the salts prepared from
organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like.
[0201] "Subject" refers any animal, preferably a human patient,
livestock, or domestic pet.
[0202] The term "prodrug" refers to an agent that is converted into
a biologically active form in vivo. Prodrugs are often useful
because, in some situations, they may be easier to administer than
the parent compound. They may, for instance, be bioavailable by
oral administration whereas the parent compound is not. The prodrug
may also have improved solubility in pharmaceutical compositions
over the parent drug. A prodrug may be converted into the parent
drug by various mechanisms, including enzymatic processes and
metabolic hydrolysis.
[0203] As used herein, the terms "prevent" and "preventing" include
the prevention of the recurrence, spread or onset. It is not
intended that the present disclosure be limited to complete
prevention. In some embodiments, the onset is delayed, or the
severity of the disease is reduced.
[0204] As used herein, the terms "treat" and "treating" are not
limited to the case where the subject (e.g. patient) is cured and
the disease is eradicated. Rather, embodiments, of the present
disclosure also contemplate treatment that merely reduces symptoms,
and/or delays disease progression.
[0205] A "mental disorder" or "mental illness" or "mental disease"
or "psychiatric or neuropsychiatric disease or illness or disorder"
refers to mood disorders (e.g., depression, mania, and bipolar
disorders), psychotic disorders (e.g., schizophrenia,
schizoaffective disorder, schizophreniform disorder, delusional
disorder, brief psychotic disorder, and shared psychotic disorder),
personality disorders, anxiety disorders (e.g.,
obsessive-compulsive disorder) as well as other mental disorders
such as substance-related disorders, childhood disorders, dementia,
autistic disorder, adjustment disorder, delirium, multi-infarct
dementia, and Tourette's disorder as described in Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, (DSM
IV).
EXPERIMENTAL
General Information
[0206] .sup.1H Nuclear Magnetic Resonance (NMR) spectra were
typically recorded on a Varian spectrometer at either 300, 400,
500, or 600 MHz, and .sup.13C NMR at either 75, 100, or 125 MHz
with the sample solvent being CDCl.sub.3. The following
abbreviations are used to explain multiplicities: s, singlet; d,
doublet; t, triplet; q, quartet; dd, doublet of doublet; m,
multiplet. Coupling constants were taken directly from the spectra
and are uncorrected. IR spectra were obtained using a Thermo
Scientific Nicolet iS10 FT-IR and reported in units of cm.sup.-1.
Melting points were measured on an electrothermal melting point
apparatus and are uncorrected. High Resolution Mass spectral (HRMS)
determinations (pos-APCI) were performed by the Instrument Center
of the Department of Chemistry, Emory University. Elemental
analysis was performed at Atlantic Microlabs Inc., Norcross Ga.
Optical rotations were measured at the sodium D line (589 nm) and
reported as follows: [.alpha.].sub.D.sup.25 concentration (c in
g/100 mL) and solvent. All rotations are measured at 25.0.degree.
C. Enantiomeric excess was determined by Varian Pro Star high
performance liquid chromatography (HPLC) using chiral analytical
columns (Chiralcel OD, Chiralcel OD-H, Chiralcel OJ, Chiralpak
AD-H, Chiralpak AS-H, Chiralpack AD-RH, (R,R)-Whelk, or
(S,S-Whelk)(UV detection at 254 or 273 nm). Chiral columns and
conditions are specified for individual compounds. Analytical TLC
was performed on 0.25 mm E. Merck silica gel (60F-254) plates using
UV light. Phosphomolybdic acid (PMA), KMnO.sub.4, Ninhydrin or
dinitrophenylhydrazine (DNP) was used as visualizing agent if
necessary.
[0207] Glassware was dried in an oven overnight prior to use.
Reactions were typically conducted under an atmosphere of argon.
Flash column chromatography was performed on Merck silica gel 60
(230-400 mesh). Hexanes, toluene, THF, DCM, Diethyl ether and
acetonitrile were dried by passage through activated alumina
columns in a solvent purification system prior to use. All other
reagents were purchased from Aldrich, Alfa Aesar, or Acros chemical
companies and used without additional purification unless noted.
Rhodium catalysts like Rh.sub.2(OAc).sub.4, Rh.sub.2(S-DOSP).sub.4,
Rh.sub.2(R-DOSP).sub.4, Rh.sub.2(S-PTAD).sub.4, were obtained from
lab sources and were used as is.
(E)-buta-1,3-dienylbenzene (1)
##STR00009##
[0209] Methyltriphenylphosphine bromide (178 g, 50 mmol) was added
to a flame dried 1 L flask and THF (500 mL) was added. The reaction
flask was cooled to 0.degree. C. and Potassium ter-butoxide (84 g,
75 mmol) and stirred for 5 hours at 0.degree. C.
(E)-3-phenylacrylaldehyde (66 g, 50 mmol) in THF (100 mL) was added
drop wise over 1 h, then stirred for 16 additional hours. The
reaction was poured into H.sub.2O (1 L) and extracted into pentane
(3.times.200 mL). The combined organic layers were washed with
brine, dried over MgSO.sub.4. Hexane was added to the reaction
flask. Triphenyl phosphine oxide precipitates out. The reaction
mixture was filtered through celite/silica gel and the solvent was
removed under reduced pressure. The crude material was purified
using Kughlerrohr distillation (85.degree. C.) to obtain product as
a colorless oil in 87% yield (56 g). .sup.1H NMR (500 MHz,
CDCl.sub.3): .delta.7.32 (m, 5H), 6.78 (dd, J=10.4 Hz, 1H), 6.54
(m, 2H), 5.34 (d, J=16.8 Hz, 1H), 5.17 (d, J=10.4 Hz, 1H).
Synthesis of Aryl Diazoacetates (2)
Methyl 2-diazo-2-phenyl acetate (2a)
##STR00010##
[0211] This was prepared according to a modified procedure provided
in Baum et al., Synth. Commun. 1987, 17, 1709-16 hereby
incorporated by reference. Methyl phenylacetate (4.5 g, 30 mmol)
and p-acetamidobenzene sulfonyl azide (p-ABSA) (7.93 g, 33 mmol)
were dissolved in acetonitrile (100 mL) and cooled to 0.degree. C.
in an ice bath. 1,8-Diazabicycloundec-7-ene (DBU) (5.48 mL, 36
mmol) was added in one portion and the reaction was stirred at
0.degree. C. for 1 hour, then 3 additional hours at room
temperature. The reaction was poured into saturated NH.sub.4Cl
solution (100 mL) and extracted into diethyl ether (2.times.100
mL). The combined ether layers were dried over MgSO.sub.4, filtered
and concentrated to obtain the crude product. The crude material
was purified by column chromatography (SiO.sub.2, 95:5 petroleum
ether/diethyl ether) to obtain 4.59 g (80% yield) of colored oil.
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta.3.84 (s, 3H), 7.46 (m,
5H).
Methyl 2-(4-bromophenyl)-2-diazoacetate (2b)
##STR00011##
[0213] In a flame dried round bottom flask, 2-(4-bromophenyl)acetic
acid (50 mmol, 1 eq.) was dissolved in MeOH (50 mL) and cooled to
0.degree. C. Acetyl chloride (60 mmol, 1.2 eq.) was added drop wise
at 0.degree. C. The resultant reaction mixture was stirred at rt
for overnight. The reaction mixture was poured in to a separation
funnel having ethyl ether and saturated NH.sub.4Cl solution.
Extracted twice; combined organic layers were washed with brine,
dried over MgSO.sub.4 and concentrated in vacuo. The crude methyl
acetate mixture was taken to next step without further
purification.
[0214] The resultant methyl acetate was dissolved in acetonitrile
and p-acetamidobenzene sulfonyl azide (p-ABSA) (60 mmol, 1.2 eq.)
was added. The reaction mixture was cooled to 0.degree. C. and
1,8-Diazabicycloundec-7-ene (DBU) (120 mmol, 2 eq.) was added drop
wise at 0.degree. C. The reaction mixture was stirred at rt for
overnight. Reaction mixture was quenched with saturated aqueous
NH.sub.4Cl solution, extracted twice with diethyl ether
(2.times.100 mL); combined organic layers were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using
9:1 hexane/Et.sub.2O as eluant to isolate 11.16 g (93% yield) of
yellow crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.87 (s, 3H) 7.36 (d, J=8.61 Hz, 2H) 7.50 (d, J=8.61 Hz, 2H).
Methyl 2-([1,1'-biphenyl]-4-yl)-2-diazoacetate (2c)
##STR00012##
[0216] In a flame dried round bottom flask,
2-([1,1'-biphenyl]-4-yl)acetic acid (50 mmol, 1 eq.) was dissolved
in MeOH (50 mL) and cooled to 0.degree. C. Acetyl chloride (60
mmol, 1.2 eq.) was added drop wise at 0.degree. C. The resultant
reaction mixture was stirred at rt for overnight. The reaction
mixture was poured in to a separation funnel having ethyl ether and
saturated NH.sub.4Cl solution. Extracted twice; combined organic
layers were washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. The crude methyl acetate mixture was taken
to next step without further purification.
[0217] The resultant methyl acetate was dissolved in acetonitrile
and p-acetamidobenzene sulfonyl azide (p-ABSA) (60 mmol, 1.2 eq.)
was added. The reaction mixture was cooled to 0.degree. C. and
1,8-Diazabicycloundec-7-ene (DBU) (120 mmol, 2 eq.) was added drop
wise at 0.degree. C. The reaction mixture was stirred at rt for
overnight. Reaction mixture was quenched with saturated aqueous
NH.sub.4Cl solution, extracted twice with diethyl ether
(2.times.100 mL); combined organic layers were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using
9:1 hexane/Et.sub.2O as eluant to isolate 9.6 g (80% yield) of
yellow crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.90 (s, 3H) 7.33-7.39 (m, 1H) 7.45 (t, J=7.63 Hz, 2H) 7.54-7.66
(m, 6H).
Methyl 2-diazo-2-(naphthalene-2-yl)acetate (2d)
##STR00013##
[0219] 2-(Naphthalen-2-yl)acetic acid (5.00 g, 24.8 mmol) was
dissolved in methanol (90 mL). Acetyl chloride (3.68 g, 46.8 mmol)
was then added and the reaction was stirred overnight. The reaction
was concentrated to obtain the crude acetate in 97% yield (5.25 g).
This compounds was used without further purification. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 3.70 (s, 3H), 3.75 (m, 2H), 7.40 (d,
J=8.5 Hz, 1H), 7.44 (m, 2H), 7.72 (s, 1H), 7.80 (m, 3H).
[0220] Methyl 2-(naphthalen-2-yl)acetate (5.00 g, 24.9 mmol) and
p-ABSA (7.49 g, 31.2 mmol) were dissolved in acetonitrile (35 mL)
and cooled to 0.degree. C. DBU (7.51 mL, 49.9 mmol) was added in
one portion and the reaction was stirred at 0.degree. C. for 1
hour, then 3 additional hours at room temperature. The reaction was
poured into saturated NH.sub.4Cl solution and extracted into
diethyl ether. The combined ether layers were dried over
MgSO.sub.4, filtered and concentrated to obtain the crude product.
The crude material was purified by column chromatography
(SiO.sub.2, 95:5 petroleum ether/diethyl ether) to obtain 4.59 g
(80% yield) of yellow crystalline solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.92 (s, 3H) 7.42-7.51 (m, 2H) 7.54 (dd,
J=8.80, 1.76 Hz, 1H) 7.81 (d, J=8.22 Hz, 2H) 7.86 (d, J=8.61 Hz,
1H) 8.02 (s, 1H).
Methyl 2-diazo-2-(3,4-dichlorophenyl)acetate (2e)
##STR00014##
[0222] 3,4-Dichlorophenylacetic acid (5.50 g, 26.8 mmol) was
dissolved in MeOH (100 mL). Acetyl chloride (4.21 g, 53.7 mmol) was
then added and the reaction was stirred overnight. The reaction was
concentrated to obtain the crude acetate in 93% yield (5.47 g).
This compound was used without further purification. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 3.61 (m, 2H), 3.79 (s, 3H), 7.14 (d,
2H, J=8.5 Hz), 7.42 (d, 2H, J=8.5 Hz).
[0223] Methyl 2-(3,4-dichlorophenyl)acetate (5.33 g, 24.3 mmol) and
p-ABSA (7.03 g, 30.4 mmol) were dissolved in acetonitrile (35 mL)
and cooled to 0.degree. C. DBU (7.40 mL, 48.7 mmol) was added in
one portion and the reaction was stirred at 0.degree. C. for 1
hour, then 3 additional hours at room temperature. The reaction was
poured into saturated NH.sub.4Cl solution and extracted into
diethyl ether. The combined ether layers were dried over
MgSO.sub.4, filtered and concentrated to obtain the crude product.
The crude material was purified by column chromatography
(SiO.sub.2, 95:5 petroleum ether/diethyl ether) to obtain 4.96 g
(83% yield) of yellow crystalline solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.88 (s, 3H) 7.29 (dd, J=8.61, 2.35 Hz, 1H)
7.43 (d, J=8.61 Hz, 1H) 7.64 (d, J=1.96 Hz, 1H).
Methyl 2-(2-chlorophenyl)-2-diazoacetate (2f)
##STR00015##
[0225] In a flame dried round bottom flask,
2-(2-chlorophenyl)acetic acid (55 mmol, 1 eq.) was dissolved in
MeOH (100 mL) and cooled to 0.degree. C. Acetyl chloride (66 mmol,
1.2 eq.) was added drop wise at 0.degree. C. The resultant reaction
mixture was stirred at rt for overnight. The reaction mixture was
poured in to a separation funnel having ethyl ether and saturated
NH.sub.4Cl solution. Extracted twice; combined organic layers were
washed with brine, dried over MgSO.sub.4 and concentrated in vacuo.
The crude methyl acetate mixture was taken to next step without
further purification.
[0226] The resultant methyl acetate was dissolved in acetonitrile
and p-acetamidobenzene sulfonyl azide (p-ABSA) (66 mmol, 1.2 eq.)
was added. The reaction mixture was cooled to 0.degree. C. and
1,8-Diazabicycloundec-7-ene (DBU) (110 mmol, 2 eq.) was added drop
wise at 0.degree. C. The reaction mixture was stirred at rt for
overnight. Reaction mixture was quenched with saturated aqueous
NH.sub.4Cl solution, extracted twice with diethyl ether
(2.times.100 mL); combined organic layers were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using
9:1 hexane/Et.sub.2O as eluant to isolate 10.16 g (87% yield) of
yellow crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.85 (s, 3H) 7.23-7.36 (m, 2H) 7.43 (d, J=7.43 Hz, 1H) 7.54 (d,
J=7.04 Hz, 1H).
Methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate (2 g)
##STR00016##
[0228] In a flame dried round bottom flask,
2-(3,4-dimethoxyphenyl)acetic acid (50 mmol, 1 eq.) was dissolved
in MeOH (100 mL) and cooled to 0.degree. C. Acetyl chloride (60
mmol, 1.2 eq.) was added drop wise at 0.degree. C. The resultant
reaction mixture was stirred at rt for overnight. The reaction
mixture was poured in to a separation funnel having ethyl ether and
saturated NH.sub.4Cl solution. Extracted twice; combined organic
layers were washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. The crude methyl acetate mixture was taken
to next step without further purification.
[0229] The resultant methyl acetate was dissolved in acetonitrile
and p-acetamidobenzene sulfonyl azide (p-ABSA) (60 mmol, 1.2 eq.)
was added. The reaction mixture was cooled to 0.degree. C. and
1,8-Diazabicycloundec-7-ene (DBU) (120 mmol, 2 eq.) was added drop
wise at 0.degree. C. The reaction mixture was stirred at rt for
overnight. Reaction mixture was quenched with saturated aqueous
NH.sub.4Cl solution, extracted twice with diethyl ether
(2.times.100 mL); combined organic layers were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using
9:1 hexane/Et.sub.2O as eluant to isolate 11.12 g (94% yield) of
yellow crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.86 (s, 3H) 3.88 (s, 3H) 3.90 (s, 3H) 6.87-6.90 (m, 1H) 7.19 (d,
J=1.17 Hz, 1H) 7.26 (s, 1H).
Synthesis of Styrylcyclopropanecarboxylates (3)
(E)-methyl 1-phenyl-2-styrylcyclopropanecarboxylate (3a)
##STR00017##
[0231] A solution of methyl 2-diazo-2-phenylacetate (176 mg, 1
mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump over
1 h to a solution of (E)-buta-1,3-dienylbenzene (390.2 mg, 3 mmol,
3 eq.) and Rh.sub.2(OAc).sub.4 (0.01 mmol, 0.1 eq.) in toluene (10
mL) at rt. The reaction mixture was stirred at rt for an additional
2 h, and then concentrated in vacuo. Crude reaction mixture was
purified by flash chromatography on silica gel using 9:1
hexane/EtOAc as eluant to isolate 163 mg (93% yield) of oily
liquid. .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 1.42 (m, 1H),
2.02 (m, 1H), 2.66 (m, 1H), 3.52 (s, 3H), 5.18 (dd, J=15.5 Hz, 10.0
Hz, 1H), 6.52 (d, J=15.5 Hz, 1H), 7.05 (m, 3H), 7.12 (m, 2H), 7.25
(m, 5H), .sup.13C NMR (300 MHz, CDCl.sub.3): .delta. 22.26
(CH.sub.2), 31.65 (CH), 35.47 (C), 52.12 (CH.sub.3), 125.6 (CH),
126.8 (CH), 127.0 (CH), 127.8 (CH), 128.1 (CH), 128.5 (CH), 131.0
(CH), 131.4 (CH), 135.6 (C), 136.8 (C), 173.7 (C), FTIR (neat):
1717, 1271, 1244, 1193, 1159, 960, 752, 694 cm.sup.-1. HRMS (EI)
m/z calcd for [C.sub.19H.sub.18O.sub.2Na.sub.1].sup.+ 301.1199.
Found: 301.1194.
(E)-methyl 1-(4-bromophenyl)-2-styrylcyclopropanecarboxylate
(3b)
##STR00018##
[0233] A solution of methyl 2-(4-bromophenyl)-2-diazoacetate (510
mg, 2 mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump
over 1 h to a solution of (E)-buta-1,3-dienylbenzene (781 mg, 6
mmol, 3 eq.) and Rh.sub.2(OAc).sub.4 (8 mg, 0.02 mmol, 0.1 eq.) in
toluene (10 mL) at rt. The reaction mixture was stirred at rt for
an additional 2 h, and then concentrated in vacuo. Crude reaction
mixture was purified by flash chromatography on silica gel using
9:1 hexane/EtOAc as eluant to isolate 671 mg (94% yield) of oily
liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40 (dd, J=6.41,
4.88 Hz, 1H) 2.04 (dd, J=8.85, 4.58 Hz, 1H) 2.62-2.73 (m, 1H) 3.59
(s, 3H) 5.17 (dd, J=15.87, 9.76 Hz, 1H) 6.55 (d, J=15.87 Hz, 1H)
7.03-7.27 (m, 7H) 7.41 (d, J=8.24 Hz, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3): .delta. 22.42, 31.83, 34.95, 52.42, 121.36, 125.75,
127.13, 127.98, 128.36, 131.11, 131.67, 133.20, 134.81, 136.72,
173.35; FTIR (Neat): 1716, 1488, 1270, 1242, 728 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.19H.sub.18O.sub.2.sup.79Br: 357.04847.
Found 357.04834; HRMS (neg-APCI) calcd for
C.sub.19H.sub.16O.sub.2.sup.79Br: 355.03391. Found 355.03397.
(E)-methyl 1-([1,1'-biphenyl]-4-yl)-2-styrylcyclopropanecarboxylate
(3c)
##STR00019##
[0235] A solution of methyl 2-([1,1'-biphenyl]-4-yl)-2-diazoacetate
(252 mg, 1 mmol, and 1 eq.) in toluene (10 mL) was added by syringe
pump over 1 h to a solution of (E)-buta-1,3-dienylbenzene (390.2
mg, 3 mmol, 3 eq.) and Rh.sub.2(OAc).sub.4 (4 mg, 0.01 mmol, 0.1
eq.) in toluene (10 mL) at rt. The reaction mixture was stirred at
rt for an additional 2 h, and then concentrated in vacuo. Crude
reaction mixture was purified by flash chromatography on silica gel
using 9:1 hexane/EtOAc as eluant to isolate 297 mg (84% yield) of
oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.51 (dd,
J=6.25, 4.73 Hz, 1H) 2.09 (dd, J=8.85, 4.58 Hz, 1H) 2.66-2.76 (m,
1H) 3.67 (s, 3H) 5.26 (dd, J=15.87, 9.76 Hz, 1H) 6.60 (d, J=15.87
Hz, 1H) 7.14 (t, J=7.78 Hz, 3H) 7.20 (d, J=7.02 Hz, 2H) 7.36 (d,
J=7.93 Hz, 3H) 7.44 (t, J=7.63 Hz, 2H) 7.56 (d, J=8.24 Hz, 2H) 7.62
(d, J=7.02 Hz, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3): .delta.
22.6, 32.1, 35.4, 52.6, 125.9, 126.7, 127.0, 127.1, 127.2, 128.4,
128.7, 128.8, 131.3, 132.0, 134.9, 137.1, 140.0, 140.7, 174.1; FTIR
(Neat): 1716, 1487, 1270, 1243, 753 cm.sup.-1; HRMS (pos-APCI)
calcd for C.sub.25H.sub.23O.sub.2: 355.16926. Found 355.16904.
(E)-methyl 1-(naphthalen-2-yl)-2-styrylcyclopropanecarboxylate
(3d)
##STR00020##
[0237] A solution of methyl 2-diazo-2-(naphthalen-2-yl)acetate (226
mg, 1 mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump
over 1 h to a solution of (E)-buta-1,3-dienylbenzene (390.2 mg, 3
mmol, 3 eq.) and Rh.sub.2(OAc).sub.4 (4 mg, 0.01 mmol, 0.1 eq.) in
toluene (10 mL) at rt. The reaction mixture was stirred at rt for
an additional 2 h, and then concentrated in vacuo. Crude reaction
mixture was purified by flash chromatography on silica gel using
9:1 hexane/EtOAc as eluant to isolate 295 mg (90% yield) of oily
liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.59 (dd, J=6.41,
4.58 Hz, 1H) 2.12 (dd, J=9.00, 4.42 Hz, 1H) 2.75 (td, J=9.31, 6.71
Hz, 1H) 3.58 (s, 3H) 5.20 (dd, J=15.87, 9.76 Hz, 1H) 6.60 (d,
J=15.56 Hz, 1H) 7.01-7.14 (m, 5H) 7.42 (dt, J=6.41, 3.20 Hz, 3H)
7.72-7.81 (m, 4H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 22.6,
32.1, 35.7, 52.4, 125.7, 125.9, 126.9, 127.4, 127.5, 127.7, 128.3,
128.5, 129.9, 129.9, 131.3, 132.5, 133.0, 133.5, 136.9, 174.0;
FT-IR (neat): 1715, 1434, 1270, 1244, 906, 728 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.23H.sub.21O.sub.2: 329.15361. Found:
329.15347.
(E)-methyl 1-(3,4-dichlorophenyl)-2-styrylcyclopropanecarboxylate
(3e)
##STR00021##
[0239] A solution of methyl 2-diazo-2-(3,4-dichlorophenyl)acetate
(490 mg, 2 mmol, and 1 eq.) in toluene (10 mL) was added by syringe
pump over 1 h to a solution of (E)-buta-1,3-dienylbenzene (781 mg,
6 mmol, 3 eq.) and Rh.sub.2(OAc).sub.4 (8 mg, 0.01 mmol, 0.1 eq.)
in toluene (10 mL) at rt. The reaction mixture was stirred at rt
for an additional 2 h, and then concentrated in vacuo. Crude
reaction mixture was purified by flash chromatography on silica gel
using 9:1 hexane/EtOAc as eluant to isolate 659 mg (95% yield) of
oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.42 (dd,
J=6.56, 4.73 Hz, 1H) 2.06 (dd, J=9.00, 4.73 Hz, 1H) 2.68 (td,
J=9.23, 6.86 Hz, 1H) 3.64 (s, 3H) 5.18 (dd, J=15.71, 9.61 Hz, 1H)
6.59 (d, J=15.87 Hz, 1H) 7.10-7.15 (m, 3H) 7.17 (d, J=7.02 Hz, 1H)
7.20-7.26 (m, 2H) 7.36 (d, J=8.24 Hz, 1H) 7.40 (d, J=1.83 Hz, 1H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 22.5, 32.0, 34.7, 52.6,
125.9, 127.3, 127.5, 128.4, 129.9, 131.2, 131.5, 132.0, 132.2,
133.3, 136.1, 136.7, 173.0; FT-IR (neat): 1717, 1473, 1272, 1241,
956, 753, 727 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.19H.sub.15O.sub.2.sup.35Cl.sub.2: 345.04546 Found:
345.04542.
(E)-methyl 1-(2-chlorophenyl)-2-styrylcyclopropanecarboxylate
(3f)
##STR00022##
[0241] A solution of methyl 2-(2-chlorophenyl)-2-diazoacetate (421
mg, 2 mmol, and 1 eq.) in toluene (10 mL) was added by syringe pump
over 1 h to a solution of (E)-buta-1,3-dienylbenzene (781 mg, 6
mmol, 3 eq.) and Rh.sub.2(OAc).sub.4 (8 mg, 0.01 mmol, 0.1 eq.) in
toluene (10 mL) at rt. The reaction mixture was stirred at rt for
an additional 2 h, and then concentrated in vacuo. Crude reaction
mixture was purified by flash chromatography on silica gel using
9:1 hexane/EtOAc as eluant to isolate 605 mg (97% yield) of oily
liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.49 (br. s., 1H)
1.92 (br. s., 1H) 2.89 (br. s., 1H) 3.57 (s, 3H) 5.30 (br. s., 1H)
6.52 (d, J=15.56 Hz, 1H) 7.03-7.20 (m, 7H) 7.27-7.33 (m, 2H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 22.2, 32.2, 35.1, 52.34,
125.71, 126.28, 126.94, 128.24, 128.65, 129.38, 136.95, 137.00,
172.95; FT-IR (neat): 1718, 1434, 1268, 1241, 953, 748 cm.sup.-1;
HRMS (pos-APCI) calcd for C.sub.19H.sub.18O.sub.2.sup.35Cl.sub.1:
313.09898 Found: 313.09897.
(E)-methyl 1-(3,4-dimethoxyphenyl)-2-styrylcyclopropanecarboxylate
(3 g)
##STR00023##
[0243] A solution of methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate
(472 mg, 2 mmol, and 1 eq.) in toluene (10 mL) was added by syringe
pump over 1 h to a solution of (E)-buta-1,3-dienylbenzene (781 mg,
6 mmol, 3 eq.) and Rh.sub.2(OAc).sub.4 (8 mg, 0.01 mmol, 0.1 eq.)
in toluene (10 mL) at rt. The reaction mixture was stirred at rt
for an additional 2 h, and then concentrated in vacuo. Crude
reaction mixture was purified by flash chromatography on silica gel
using 9:1 hexane/EtOAc as eluant to isolate 621 mg (92% yield) of
oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40-1.46
(m, 1H) 2.03 (dd, J=8.85, 4.27 Hz, 1H) 2.60-2.70 (m, 1H) 3.60 (s,
3H) 3.73 (s, 3H) 3.81 (s, 3H) 5.25 (dd, J=15.87, 9.76 Hz, 1H) 6.56
(d, J=15.87 Hz, 1H) 6.75-6.88 (m, 3H) 7.07-7.20 (m, 6H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 22.6, 31.6, 34.9, 52.0, 55.3,
55.3, 110.2, 114.5, 123.3, 125.4, 126.7, 127.9, 128.1, 128.7,
130.7, 136.7, 147.8, 147.9, 173.8 FT-IR (neat): 1715, 1516, 1246,
1226, 756, 727 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.21H.sub.23O.sub.4: 339.15909. Found: 339.15894.
Synthesis of Formyl Cyclopropanecarboxylates (4)
Methyl 2-formyl-1-phenylcyclopropanecarboxylate (4a)
##STR00024##
[0245] Ozone was bubbled through a solution of (E)-methyl
1-phenyl-2-styrylcyclopropanecarboxylate (835 mg, 3 mmol, 1 eq.) in
DCM (10 mL) at -78.degree. C. until the blue color of ozone
persists. The reaction mixture was warmed to rt and PPh.sub.3 was
added. The resultant mixture was stirred at rt for 2 h, and then
concentrated in vacuo. Purified by flash chromatography on silica
gel using 9:1 hexane/EtOAc as eluant to isolate 623 mg (86% yield)
of oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.03-2.08
(m, 1H) 2.10 (dd, J=8.54, 4.88 Hz, 1H) 2.71 (dd, J=8.54, 6.41 Hz,
1H) 3.62 (s, 3H) 7.25-7.34 (m, 5H) 8.53 (d, J=6.41 Hz, 1H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 19.1, 36.1, 37.2, 52.8,
128.0, 128.4, 130.8, 133.5, 171.8, 198.1; FT-IR (neat): 1706, 1249,
1155, 699 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.15H.sub.19O.sub.3: 247.13287 Found: 247.13284.
Methyl 1-(4-bromophenyl)-2-formylcyclopropanecarboxylate (4b)
##STR00025##
[0247] Ozone was bubbled through a solution of (E)-methyl
1-(4-bromophenyl)-2-styrylcyclopropanecarboxylate (535 mg, 1.5
mmol, 1 eq.) in DCM (10 mL) at -78.degree. C. until the blue color
of ozone persists. The reaction mixture was warmed to rt and
PPh.sub.3 was added. The resultant mixture was stirred at rt for 2
h, and then concentrated in vacuo. Purified by flash chromatography
on silica gel using 9:1 hexane/EtOAc as eluant to isolate 401 mg
(93% yield) of oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 2.01-2.08 (m, 1H) 2.12 (dd, J=8.70, 5.03 Hz, 1H) 2.77 (dt,
J=8.54, 6.25 Hz, 1H) 3.65 (s, 3H) 7.18 (d, J=8.54 Hz, 2H) 7.42-7.52
(m, 2H) 8.64 (d, J=6.10 Hz, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3):
.delta. 19.0, 35.9, 36.7, 52.8, 121.9, 128.1, 129.8, 131.4, 132.4,
133.3, 171.1, 197.5; FTIR (Neat): 1707, 1450, 1250, 1157, 713
cm.sup.-1; HRMS (pos-API) calcd for C.sub.21H.sub.10O.sub.4Br:
296.97679. Found 296.97673.
Methyl 1-([1,1'-biphenyl]-4-yl)-2-formylcyclopropanecarboxylate
(4c)
##STR00026##
[0249] Ozone was bubbled through a solution of (E)-methyl
1-([1,1'-biphenyl]-4-yl)-2-styrylcyclopropanecarboxylate (531 mg,
1.5 mmol, 1 eq.) in DCM (10 mL) at -78.degree. C. until the blue
color of ozone persists. The reaction mixture was warmed to rt and
PPh.sub.3 was added. The resultant mixture was stirred at rt for 2
h, and then concentrated in vacuo. Purified by flash chromatography
on silica gel using 9:1 hexane/EtOAc as eluant to isolate 355 mg
(83% yield) of oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 2.03-2.19 (m, 2H) 2.70-2.82 (m, 1H) 3.61 (s, 3H)
7.28-7.45 (m, 5H) 7.54 (dd, J=7.32, 6.10 Hz, 4H) .delta. 8.59 (d,
J=6.41 Hz, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 198.06,
171.7, 140.7, 140.0, 133.3, 132.4, 131.1, 129.8, 128.5, 128.2,
127.3, 127.0, 126.8, 52.7, 36.9, 36.1, 19.1; FTIR (Neat): 1707,
1487, 1249, 1155, 763 cm.sup.-1; HRMS (Pos-API) calcd for
C.sub.18H.sub.15O.sub.3: 279.10267. Found 279.10253.
Methyl 2-formyl-1-(naphthalen-2-yl)cyclopropanecarboxylates
(4d)
##STR00027##
[0251] Ozone was bubbled through a solution of (E)-methyl
1-(naphthalen-2-yl)-2-styrylcyclopropanecarboxylate (492 mg, 1.5
mmol, 1 eq.) in DCM (10 mL) at -78.degree. C. until the blue color
of ozone persists. The reaction mixture was warmed to rt and
PPh.sub.3 was added. The resultant mixture was stirred at rt for 2
h, and then concentrated in vacuo. Purified by flash chromatography
on silica gel using 9:1 hexane/EtOAc as eluant to isolate 202 mg
(53% yield) of oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 2.21 (d, J=7.63 Hz, 2H) 2.81 (q, J=7.22 Hz, 1H) 3.64 (s,
3H) 7.40 (dd, J=8.70, 1.07 Hz, 1H) 7.45-7.55 (m, 2H) 7.81 (d,
J=8.24 Hz, 4H) 8.56 (d, J=6.71 Hz, 1H) .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 19.2, 36.0, 36.6, 53.0, 130.2, 130.3, 132.3,
132.4, 132.7, 133.8, 134.9, 139.3, 141.0, 141.2, 170.94, 197.05;
FT-IR (neat): 1706, 1435, 1252, 1153, 733 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.16H.sub.13O.sub.3: 253.08702 Found:
253.08691.
Methyl 1-(3,4-dichlorophenyl)-2-formylcyclopropanecarboxylate
(4e)
##STR00028##
[0253] Ozone was bubbled through a solution of (E)-methyl
1-(3,4-dichlorophenyl)-2-styrylcyclopropanecarboxylate (520 mg, 1.5
mmol, 1 eq.) in DCM (10 mL) at -78.degree. C. until the blue color
of ozone persists. The reaction mixture was warmed to rt and
PPh.sub.3 was added. The resultant mixture was stirred at rt for 2
h, and then concentrated in vacuo. Purified by flash chromatography
on silica gel using 9:1 hexane/EtOAc as eluant to isolate 331 mg
(80% yield) of oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 2.03-2.08 (m, 1H) 2.13 (dd, J=8.70, 5.03 Hz, 1H) 2.80 (dt,
J=8.47, 6.14 Hz, 1H) 3.67 (s, 3H) 7.14 (dd, J=8.24, 1.83 Hz, 1H)
7.39-7.45 (m, 2H) 8.74 (d, J=5.80 Hz, 1H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 19.2, 36.0, 36.6, 53.0, 130.3, 130.3, 132.3,
132.4, 132.7, 133.8, 170.9, 197.0; FT-IR (neat): 1707, 1474, 1247,
1159, 726 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.12H.sub.9O.sub.3Cl.sub.2: 270.99342 Found: 270.99337.
Methyl 1-(2-chlorophenyl)-2-formylcyclopropanecarboxylate (4f)
##STR00029##
[0255] Ozone was bubbled through a solution of (E)-methyl
1-(2-chlorophenyl)-2-styrylcyclopropanecarboxylate (312 mg, 1 mmol,
1 eq.) in DCM (10 mL) at -78.degree. C. until the blue color of
ozone persists. The reaction mixture was warmed to rt and PPh.sub.3
was added. The resultant mixture was stirred at rt for 2 h, and
then concentrated in vacuo. Purified by flash chromatography on
silica gel using 9:1 hexane/EtOAc as eluant to isolate 166 mg (70%
yield) of oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.90-2.29 (m, 2H) 3.11 (br. s., 1H) 3.66 (s, 3H) 7.18-7.54 (m, 4H)
8.95 (br. s., 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 20.4,
36.1, 53.1, 127.0, 128.4, 129.5, 129.6, 130.1, 131.9, 133.6, 171.2,
196.2; FT-IR (neat): 1708, 1435, 1250, 1158, 727 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.12H.sub.10O.sub.3Cl: 237.03240 Found:
237.03194.
Synthesis of Methylamino Cyclopropanecarboxylates (5)
Methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate
(5a)
##STR00030##
[0257] In a 100 mL round bottom flask equipped with a magnetic stir
bar, methyl 2-formyl-1-phenylcyclopropanecarboxylate (612 mg, 3
mmol) was dissolved in methanol (50 mL) and flushed with argon.
This solution was treated with methylamine (2M in MeOH, 3 mL, 6
mmol) and Ti(O-iPr).sub.4 (2.4 mL, 6 mmol) and stirred at room
temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (170 mg, 4.5 mmol) was added and the reaction was
stirred for an additional 2 hours. The reaction was quenched with
H.sub.2O (1 mL) and filtered through a short path of celite and
rinsed with diethyl ether. The organic filtrate was diluted with
diethyl ether and washed with water, then brine, and dried over
MgSO.sub.4. The organic phase was then filtered and concentrated
under reduced pressure and the resulting residue was purified by
column chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give a colorless oil in 63% yield (416 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24 (dd, J=6.41, 4.58
Hz, 1H) 1.74 (dd, J=9.15, 4.27 Hz, 1H) 1.90-2.00 (m, 1H) 2.02-2.14
(m, 1H) 2.32 (s, 3H) 2.45 (dd, J=12.36, 5.95 Hz, 1H) 3.62 (s, 3H)
7.15-7.49 (m, 5H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 20.0,
27.7, 33.0, 36.1, 52.1, 127.0, 127.8, 130.85, 135.61, 174.35; FT-IR
(neat): 2949, 2843, 1715, 1434, 1251, 700 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.13H.sub.18O.sub.2N, 220.13321 Found:
220.13306.
Methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate
fumarate (5a salt)
##STR00031##
[0259] Methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate (471 mg,
2.1 mmol) was dissolved in isopropanol (20 mL) and then treated
with fumaric acid (249 mg, 2.1 mmol) and stirred for 30 minutes at
room temperature. The mixture was then concentrated under reduced
pressure and the residue was re-dissolved in 2:1:1
isopropanol/hexanes/ethyl acetate (10 mL) and refluxed for 2 hours.
The solution was cooled to room temperature and then to -20.degree.
C. using an acetone/ice bath. The resulting solid was filtered and
washed with cold acetone to give off-white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 1.47-1.58 (m, 1H) 1.78 (dd, J=8.54, 4.88
Hz, 1H) 1.95 (dd, J=12.51, 10.98 Hz, 1H) 2.12-2.24 (m, 1H) 2.59 (s,
3H) 3.23 (dd, J=12.81, 3.97 Hz, 1H) 3.58 (s, 3H) 6.67 (s, 2H)
7.26-7.38 (m, 5H); .sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 21.0,
23.5, 33.4, 33.4, 34.8, 51.1, 53.3, 129.1, 129.7, 132.3, 135.8,
136.3, 171.5, 175.0; FT-IR (neat): 3000, 1713, 1560, 1261, 1171,
702 cm.sup.-1; HRMS (pos-APCI) calcd for C.sub.13H.sub.18O.sub.2N,
220.13321. Found: 220.13298.
Methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
(5b)
##STR00032##
[0261] In a 100 mL round bottom flask equipped with a magnetic stir
bar, methyl 1-(4-bromophenyl)-2-formylcyclopropanecarboxylate (283
mg, 1 mmol) was dissolved in methanol (20 mL) and flushed with
argon. This solution was treated with methylamine (2M in MeOH, 0.5
mL, 2 mmol) and Ti(O-iPr).sub.4 (0.4 mL, 2 mmol) and stirred at
room temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (56 mg, 1.5 mmol) was added and the reaction was stirred
for an additional 2 hours. The reaction was quenched with H.sub.2O
(1 mL) and filtered through a short path of celite and rinsed with
diethyl ether. The organic filtrate was diluted with diethyl ether
and washed with water, then brine, and dried over MgSO.sub.4. The
organic phase was then filtered and concentrated under reduced
pressure and the resulting residue was purified by column
chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give colorless oil in 56% yield (166 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.19 (dd, J=6.56, 4.42
Hz, 1H) 1.24 (br. s., 1H) 1.75 (dd, J=8.85, 4.27 Hz, 1H) 1.92-2.00
(m, 1H) 2.01-2.12 (m, 1H) 2.32 (s, 3H) 2.42 (dd, J=12.20, 5.80 Hz,
1H) 3.60 (s, 3H) 7.19 (d, J=8.24 Hz, 2H) 7.44 (d, J=8.24 Hz, 2H);
.sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 20.1, 27.7, 32.5, 36.2,
52.0, 52.2, 121.1, 131.0, 132.5, 134.7, 173.8; FTIR (Neat): 1707,
1474, 1247, 1159, 726 cm.sup.-1; HRMS (Pos-APCI) calcd for
C.sub.12H.sub.9O.sub.3Cl.sub.2: 270.99342. Found 270.99337.
Methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
fumarate (5b salt)
##STR00033##
[0263] Methyl
1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
(298 mg, 1 mmol) was dissolved in isopropanol (20 mL) and then
treated with fumaric acid (116 mg, 1 mmol) and stirred for 30
minutes at room temperature. The mixture was then concentrated
under reduced pressure and the residue was re-dissolved in 2:1:1
isopropanol/hexanes/ethyl acetate (10 mL) and refluxed for 2 hours.
The solution was cooled to room temperature and then to -20.degree.
C. using an acetone/ice bath. The resulting solid was filtered and
washed with cold acetone to give off-white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 1.47-1.55 (m, 1H) 1.82 (dd, J=8.39, 4.73
Hz, 1H) 1.99 (dd, J=12.51, 10.98 Hz, 1H) 2.13-2.26 (m, 1H) 2.63 (s,
3H) 3.27 (dd, J=12.66, 3.81 Hz, 1H) 3.63 (s, 3H) 6.68 (s, 2H) 7.25
(d, J=8.24 Hz, 2H) 7.53 (d, J=8.24 Hz, 2H); .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 21.1, 23.6, 33.6, 34.3, 51.1, 53.4, 123.1,
132.8, 134.3, 135.1, 136.3, 171.5, 174.5; FT-IR (neat): 3027, 2954,
2768, 1720, 1262 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.13H.sub.17O.sub.2N, 298.04372 Found: 298.04364.
Methyl
1-([1,1'-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxy-
late hydrochloride (5c salt)
##STR00034##
[0265] In a 100 mL round bottom flask equipped with a magnetic stir
bar, methyl
1-([1,1'-biphenyl]-4-yl)-2-formylcyclopropanecarboxylate (280 mg, 1
mmol) was dissolved in methanol (20 mL) and flushed with argon.
This solution was treated with methylamine (2M in MeOH, 0.5 mL, 2
mmol) and Ti(O-iPr).sub.4 (0.4 mL, 2 mmol) and stirred at room
temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (56 mg, 1.5 mmol) was added and the reaction was stirred
for an additional 2 hours. The reaction was quenched with H.sub.2O
(1 mL) and filtered through a short path of celite and rinsed with
diethyl ether. The organic filtrate was diluted with diethyl ether
and washed with water, then brine, and dried over MgSO.sub.4. The
organic phase was then filtered and concentrated under reduced
pressure and the resulting residue was purified by column
chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give colorless oil in 78% yield (230 mg). The
product was dissolved in diethyl ether (15 mL), then treated with
hydrochloric acid in diethyl ether (2M in diethyl ether, 1 mL), and
the resulting white solid was filtered and washed with diethyl
ether to obtain white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.27 (dd, J=6.41, 4.58 Hz, 1H) 1.65 (br. s., 1H) 1.76 (dd,
J=8.70, 4.42 Hz, 1H) 1.95-2.04 (m, 1H) 2.05-2.13 (m, 1H) 2.31 (s,
3H) 2.48 (dd, J=12.20, 5.80 Hz, 1H) 3.60 (s, 3H) 7.29-7.37 (m, 3H)
7.38-7.45 (m, 2H) 7.56 (dd, J=16.78, 7.63 Hz, 4H); .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 20.1, 27.7, 32.7, 36.1, 52.0, 52.2, 126.6,
126.8, 127.0, 128.5, 131.2, 134.5, 139.8, 140.4, 174.3; FT-IR
(neat): 1716, 1487, 1434, 1250, 1010, 763 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.19H.sub.22O.sub.2N.sub.1: 296.16451
Found: 296.16429
Methyl
2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate
hydrochloride (5d salt)
##STR00035##
[0267] In a 100 mL round bottom flask equipped with a magnetic stir
bar, methyl 2-formyl-1-(naphthalen-2-yl)cyclopropanecarboxylate
(254 mg, 1 mmol) was dissolved in methanol (20 mL) and flushed with
argon. This solution was treated with methylamine (2M in MeOH, 0.5
mL, 2 mmol) and Ti(O-iPr).sub.4 (0.4 mL, 2 mmol) and stirred at
room temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (56 mg, 1.5 mmol) was added and the reaction was stirred
for an additional 2 hours. The reaction was quenched with H.sub.2O
(1 mL) and filtered through a short path of celite and rinsed with
diethyl ether. The organic filtrate was diluted with diethyl ether
and washed with water, then brine, and dried over MgSO.sub.4. The
organic phase was then filtered and concentrated under reduced
pressure and the resulting residue was purified by column
chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give colorless oil in 60% yield (161 mg). The
product was dissolved in diethyl ether (15 mL), then treated with
hydrochloric acid in diethyl ether (2M in diethyl ether, 1 mL), and
the resulting white solid was filtered and washed with diethyl
ether to obtain white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.28 (br. s., 1H) 1.37 (dd, J=6.56, 4.42 Hz, 1H) 1.81 (dd,
J=8.85, 4.27 Hz, 1H) 1.90-2.05 (m, 1H) 2.08-2.20 (m, 1H) 2.27 (s,
3H) 2.46 (dd, J=12.51, 6.10 Hz, 1H) 3.60 (s, 3H) 7.41-7.49 (m, 3H)
7.72 (s, 1H) 7.79 (d, J=8.54 Hz, 3H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 20.2, 28.0, 33.2, 36.2, 52.0, 52.2, 125.8,
125.9, 127.3, 127.4, 127.6, 129.1, 129.3, 132.4, 133.0, 133.3,
174.4; FT-IR (neat): 1715, 1433, 1255, 1165, 749 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.17H.sub.20O.sub.2N, 270.14886 Found:
270.14880.
Methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxyla-
te (5e)
##STR00036##
[0269] In a 100 mL round bottom flask equipped with a magnetic stir
bar, methyl 1-(3,4-dichlorophenyl)-2-formylcyclopropanecarboxylate
(819 mg, 3 mmol) was dissolved in methanol (50 mL) and flushed with
argon. This solution was treated with methylamine (2M in MeOH, 3
mL, 6 mmol) and Ti(O-iPr).sub.4 (2.4 mL, 6 mmol) and stirred at
room temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (170 mg, 4.5 mmol) was added and the reaction was
stirred for an additional 2 hours. The reaction was quenched with
H.sub.2O (1 mL) and filtered through a short path of celite and
rinsed with diethyl ether. The organic filtrate was diluted with
diethyl ether and washed with water, then brine, and dried over
MgSO.sub.4. The organic phase was then filtered and concentrated
under reduced pressure and the resulting residue was purified by
column chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give colorless oil in 57% yield (491 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.18 (dd, J=6.41, 4.58
Hz, 1H) 1.77 (dd, J=8.70, 4.42 Hz, 1H) 1.94-2.13 (m, 2H) 2.35 (s,
3H) 2.43 (dd, J=11.75, 5.34 Hz, 1H) 3.63 (s, 3H) 7.16 (dd, J=8.24,
1.83 Hz, 1H) 7.26 (s, 1H) 7.38-7.43 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 20.3, 28.0, 32.4, 36.3, 52.0, 52.4, 129.9,
130.5, 131.3, 131.9, 132.8, 136.1, 173.5; FT-IR (neat): 2950, 2843,
1718, 1474, 1247 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.13H.sub.16O.sub.2NCl.sub.2: 288.05526 Found: 288.05516.
Methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxyla-
te fumarate (5e salt)
##STR00037##
[0271] Methyl
1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
(288 mg, 1 mmol) was dissolved in isopropanol (20 mL) and then
treated with fumaric acid (116 mg, 1 mmol) and stirred for 30
minutes at room temperature. The mixture was then concentrated
under reduced pressure and the residue was re-dissolved in 2:1:1
isopropanol/hexanes/ethyl acetate (10 mL) and refluxed for 2 hours.
The solution was cooled to room temperature and then to -20.degree.
C. using an acetone/ice bath. The resulting solid was filtered and
washed with cold acetone to give off-white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 1.47-1.56 (m, 1H) 1.81 (dd, J=8.39, 5.03
Hz, 1H) 1.94-2.05 (m, 1H) 2.11-2.24 (m, 1H) 2.62 (s, 3H) 3.62 (s,
3H) 6.66 (s, 2H) 7.25 (dd, J=8.24, 1.83 Hz, 1H) 7.48-7.54 (m, 2H);
.sup.13C NMR (75 MHz, CD.sub.3OD) .delta. 21.2, 23.8, 33.5, 33.5,
34.0, 50.9, 53.5, 131.7, 132.3, 133.2, 133.5, 134.4, 136.3, 136.7,
171.5, 174.1; FT-IR (neat): 3022, 2771, 1719, 1270 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.13H.sub.16O.sub.2NCl.sub.2: 288.05526
Found: 288.05525.
Methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
(5f)
##STR00038##
[0273] In a 50 mL round bottom flask equipped with a magnetic stir
bar, methyl 1-(2-chlorophenyl)-2-formylcyclopropanecarboxylate (238
mg, 1 mmol) was dissolved in methanol (20 mL) and flushed with
argon. This solution was treated with methylamine (2M in MeOH, 0.5
mL, 2 mmol) and Ti(O-iPr).sub.4 (0.4 mL, 2 mmol) and stirred at
room temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (56 mg, 1.5 mmol) was added and the reaction was stirred
for an additional 2 hours. The reaction was quenched with H.sub.2O
(1 mL) and filtered through a short path of celite and rinsed with
diethyl ether. The organic filtrate was diluted with diethyl ether
and washed with water, then brine, and dried over MgSO.sub.4. The
organic phase was then filtered and concentrated under reduced
pressure and the resulting residue was purified by column
chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give colorless oil in 60% yield (152 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28 (br. s., 1H) 1.41
(br. s., 1H) 1.59-1.86 (m, 2H) 2.34 (s, 3H) 2.74 (dd, J=12.36, 5.03
Hz, 1H) 3.59 (s, 3H) 7.20-7.31 (m, 2H) 7.35-7.40 (m, 1H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 20.6, 27.0, 32.2, 35.9, 50.8,
52.1, 126.4, 128.4, 129.1, 131.5, 134.4, 136.4, 173.2; FT-IR
(neat): 2949, 1719, 1434, 1266, 1249, 728 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.13H.sub.16ClO2N, 254.09423 Found:
254.09419.
Methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
fumarate (5f salt)
##STR00039##
[0275] Methyl
1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate
(288 mg, 1 mmol) was dissolved in isopropanol (20 mL) and then
treated with fumaric acid (116 mg, 1 mmol) and stirred for 30
minutes at room temperature. The mixture was then concentrated
under reduced pressure and the residue was re-dissolved in 2:1:1
isopropanol/hexanes/ethyl acetate (10 mL) and refluxed for 2 hours.
The solution was cooled to room temperature and then to -20.degree.
C. using an acetone/ice bath. The resulting solid was filtered and
washed with cold acetone to give off-white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 1.56-1.77 (m, 2H) 1.90 (br. s., 1H) 2.43
(br. s., 1H) 2.61 (s, 3H) 3.43 (d, J=10.37 Hz, 1H) 3.60 (s, 3H)
6.66 (s, 2H) 7.30-7.39 (m, 3H) 7.41-7.47 (m, 1H); .sup.13C NMR (75
MHz, CD.sub.3OD) .delta. 33.44, 33.47, 53.45, 128.74, 130.82,
130.98, 133.85, 134.64, 136.35, 171.56, 174.09
Methyl
1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxyl-
ate hydrochloride (5 g salt)
##STR00040##
[0277] In a 50 mL round bottom flask equipped with a magnetic stir
bar, crude mixture of methyl
1-(3,4-dimethoxyphenyl)-2-formylcyclopropanecarboxylate (264 mg, 1
mmol) was dissolved in methanol (20 mL) and flushed with argon.
This solution was treated with methylamine (2M in MeOH, 0.5 mL, 2
mmol) and Ti(O-iPr).sub.4 (0.4 mL, 2 mmol) and stirred at room
temperature for 16 hours. After the allotted time had passed,
NaBH.sub.4 (56 mg, 1.5 mmol) was added and the reaction was stirred
for an additional 2 hours. The reaction was quenched with H.sub.2O
(1 mL) and filtered through a short path of celite and rinsed with
diethyl ether. The organic filtrate was diluted with diethyl ether
and washed with water, then brine, and dried over MgSO.sub.4. The
organic phase was then filtered and concentrated under reduced
pressure and the resulting residue was purified by column
chromatography (SiO.sub.2, Isolera, ethyl acetate:
triethylamine=9:1) to give colorless oil in 56% yield (156 mg) over
two steps. The product was dissolved in diethyl ether (15 mL), then
treated with hydrochloric acid in diethyl ether (2M in diethyl
ether, 1 mL), and the resulting white solid was filtered and washed
with diethyl ether to obtain white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.10 (t, J=5.03 Hz, 1H) 1.19 (br. s., 1H) 1.61
(dd, J=7.93, 3.97 Hz, 1H) 1.94 (d, J=7.93 Hz, 2H) 2.23 (s, 3H)
2.30-2.40 (m, 1H) 3.51 (s, 3H) 3.77 (d, J=1.83 Hz, 6H) 6.75 (d,
J=16.48 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 20.1,
27.7, 32.6, 36.1, 51.9, 51.9, 55.3, 55.5, 110.2, 113.9, 122.8,
127.9, 147.84, 148.0, 174.4; FT-IR (neat): 2950, 2837, 1715, 1516,
1249, 1226, 726 cm.sup.-1; HRMS (pos-APCI) calcd for
C.sub.15H.sub.22O.sub.4N, 280.15433 Found: 280.15430.
(1R,2S)-methyl 1-phenyl-2-((E)-styryl)cyclopropanecarboxylate
##STR00041##
[0279] A solution of methyl 2-diazo-2-phenylacetate (250 mg, 1
mmol, and 1 eq.) in hexane (5 mL) was added by syringe pump over 1
hr to a solution of (E)-buta-1,3-dienylbenzene (390.2 mg, 3 mmol, 3
eq.) and Rh.sub.2 (S-DOSP).sub.4 (18 mg, 0.01 mmol, 0.1 eq.) in
hexane (50 mL) at -45.degree. C. The reaction mixture was stirred
at -45.degree. C. for an additional 2 h, and then concentrated in
vacuo. Purified by flash chromatography on silica gel using 9:1
hexane/EtOAc as eluant to isolate colored oily liquid, 232 mg
(83%). >94% de and 96% ee. .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta.7.25 (m, 5H), 7.12 (m, 2H), 7.05 (m, 3H), 6.52 (d, J=15.5
Hz, 1H), 5.18 (dd, J=15.5 Hz, 10.0 Hz, 1H), 3.52 (s, 3H), 2.66 (m,
1H) 2.02 (m, 1H), 1.42 (m, 1H). .sup.13C NMR (300 MHz, CDCl.sub.3):
6173.7 (C), 136.8 (C), 135.6 (C), 131.4 (CH), 131.0 (CH), 128.5
(CH), 128.1 (CH), 127.8 (CH), 127.0 (CH), 126.8 (CH), 125.6 (CH),
52.12 (CH.sub.3), 35.47 (C), 31.65 (CH), 22.26 (CH.sub.2). IR
(CHCl.sub.3): 1717, 1271, 1244, 1193, 1159, 960, 752, 694
cm.sup.-1. HRMS (EI) m/z calcd for
[C.sub.19H.sub.18O.sub.2Na.sub.1].sup.+ 301.1199. Found: 301.1194.
[.alpha.].sup.20.sub.D=-181.degree. (10 mg/mL, MeOH). HPLC
analysis: 96% ee (Chiralcel SS-Whelk, 1% i-PrOH in hexane, 0.6
ml/min, .lamda.=254 nm, t.sub.R=24.3 min, minor; t.sub.R=33.5 min,
major).
(1S,2R)-methyl 1-phenyl-2-((E)-styryl)cyclopropanecarboxylate
##STR00042##
[0281] The enantiomer was made using Rh.sub.2(R-DOSP).sub.4 as
catalyst in the same reaction conditions as described above, to
obtain the 256 mg (92%). >94% de and 92% ee.
[.alpha.].sup.20.sub.D=181.degree. (10 mg/mL, MeOH). HPLC analysis:
96% ee (Chiralcel SS-Whelk, 1% i-PrOH in hexane, 0.6 ml/min,
.lamda.=254 nm, t.sub.R=24.3 min, major; t.sub.R=33.5 min,
minor).
(1R,2R)-methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate
##STR00043##
[0283] Ozone was bubbled through the solution of (E)-methyl
1-(phenyl)-2-styrylcyclopropanecarboxylate (556 mg, 2 mmol, 1 eq.)
in DCM at -78.degree. C. until blue color of ozone persists. The
reaction mixture was stirred at -78.degree. C. for an additional 2
h, and then PPh.sub.3 was added. The crude mixture was concentrated
in vacuo and dissolved in MeOH. Ti(O.sup.iPr).sub.4 and methylamine
were added at RT and stirred for 2 hours. NaBH.sub.4 was added in
portions at RT. Bubbles were observed. The reaction mixture is
quenched with H.sub.2O, filtered through celite and extracted into
EtOAc. The organic layer was dried over MgSO.sub.4 and concentrated
in vacuo to get crude mixture. The product was purified by flash
chromatography on silica gel using 9:1 EtOAc/Et.sub.3N as eluant to
isolate colorless oily liquid, 271 mg (62% over 2 steps). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 1.24 (dd, J=6.41, 4.58 Hz, 1H)
1.74 (dd, J=9.15, 4.27 Hz, 1H) 1.90-2.00 (m, 1H) 2.02-2.14 (m, 1H)
2.32 (s, 3H) 2.45 (dd, J=12.36, 5.95 Hz, 1H) 3.62 (s, 3H) 7.15-7.49
(m, 5H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 20.0, 27.7,
33.0, 36.1, 52.1, 127.0, 127.8, 130.85, 135.61, 174.35; FT-IR
(neat): 2949, 2843, 1715, 1434, 1251, 700 cm.sup.-1; HRMS
(pos-APCI) calcd for C.sub.13H.sub.18O.sub.2N, 220.13321 Found:
220.13306.
(1S,2S)-methyl
2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate
##STR00044##
[0285] The enantiomer was made using the same reaction conditions
as described above, to obtain product in 59% yield (258 mg) over 2
steps.
[0286] Modifying the procedures above with appropriate starting
materials provides desired products in disastereomeric excess. For
example, reductive amination described herein to make the N-methyl
derivatives may be extended to a series of amines to generate a
series of functionalized amines below. Other examples are
illustrated in FIG. 5.
##STR00045##
Transporter Binding Studies
[0287] Affinities of analogs at dopamine transport (DAT) sites are
determined by displacement of [.sup.125I]RTI-55 binding in
membranes from rat striatum. See Boja et al., Eur. J. Pharmacol.,
1991, 194, 133, hereby incorporated by reference. Frozen brains
from Sprague-Dawley rats are obtained commercially and striata are
dissected on ice. Tissue is homogenized in 10 vol of RTI-55 assay
buffer (0.32 M sucrose, 10 mM sodium phosphate buffer, pH 7.4) with
a Polytron, and centrifuged three times at 48,000 g for 10 min,
with fresh buffer resuspension for each centrifugation. Assay tubes
contain 0.5 mg (original wet weight) of membranes, 0.01 nM
[.sup.125I]RTI-55, and various concentrations of unlabeled drugs
dissolved in RTI-55 assay buffer in a final volume of 2 ml. Tubes
are incubated for 50 min at 25.degree. C., and the reaction is
terminated by rapid filtration with 3-5 ml of cold Tris buffer
through Whatman GF/B glass fiber filters pre-soaked in Tris buffer
containing 0.1% BSA for at least 1 h. Non-specific binding is
determined in the presence of 1 .mu.MWF-23.
[0288] Affinities of analogs at 5-HT transport (SERT) sites are
determined by displacement of [.sup.3H]citalopram binding in
membranes from rat frontal cortex. See D'Amato et al., J.
Pharmacol. Exp. Ther., 1987, 242, 364 hereby incorporated by
reference. Tissue is obtained from frozen rat brains as described
above, homogenized in vol of citalopram assay buffer (50 mM
Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4) with a Polytron, and
centrifuged two times at 48,000 g for 10 min, with fresh buffer
resuspension for each centrifugation. Assay tubes contain 50 mg
(original wet weight) of membranes, 0.4 nM [.sup.3H]citalopram, and
various concentrations of unlabeled drugs dissolved in citalopram
assay buffer in a final volume of 2 ml. Tubes are incubated for 60
min at 25.degree. C., and the reaction is terminated by rapid
filtration with 3.times.4 mL of cold Tris buffer through Whatman
GF/B glass fiber filters pre-soaked in Tris buffer containing 0.1%
BSA for at least 1 h. Non-specific binding is determined in the
presence of 10 M fluoxetine.
[0289] Binding of analogs at norepinephrine transporters (NET) was
determined by displacement of [.sup.3H]nisoxetine binding. See
Tejani-Butt, J. Pharmacol. Exp. Ther., 1991, 260, 427, hereby
incorporated by reference. Whole rat brains (minus cerebellum) are
homogenized in 30 vol of 120 mM NaCl, 5 mM KCl, 50 mM Tris-HCl, pH
7.4, and centrifuged at 48,000 g for 10 min. The membranes are
resuspended in nisoxetine assay buffer (300 mM NaCl, 5 mM KCl, 50
mM Tris-HCl, pH 7.4) and centrifuged again before final
resuspension in volumes of buffer. Assay tubes contain 7501 of
brain membranes, [.sup.3H]nisoxetine (0.7 nM) together with
unlabeled drugs dissolved in nisoxetine assay buffer to a final
volume of 1 ml. Tubes are incubated for 40 min at 25.degree. C.,
and the reaction is terminated by rapid filtration with 3.times.4
mL of cold Tris buffer through Whatman GF/B glass fiber filters
which have been pre-soaked in Tris buffer containing 0.1% BSA for
at least 1 h. Non-specific binding is determined in the presence of
1 .mu.M desipramine. In [.sup.3H]citalopram and [.sup.3H]nisoxetine
binding assays, radioactivity is determined by liquid scintillation
spectrophotometry (efficiency: 50%) after eluting filters overnight
in 5 mL of Ecolite scintillation fluid (ICN). IC.sub.50 values are
calculated from displacement curves using 7-10 concentrations of
unlabeled analogs. Because binding of tropanes at dopamine
transporter sites is generally regarded as multiphasic, potencies
in inhibiting [.sup.125I]RTI-55 binding are reported as IC.sub.50
values. For [.sup.3H]paroxetine and [.sup.3H]nisoxetine binding
assays, Ki values are calculated using the Cheng-Prusoff equation.
See Cheng & Prusoff, Biochem. Pharmacol., 1973, 22, 3099 hereby
incorporated by reference. In vitro data of cyclopropane amines is
provided in Table 1.
TABLE-US-00001 TABLE 1 Analog Ar Isomer Log-P NET SERT DAT HD-283
Milnacipran (S,R) 1.91 23.8 .+-. 1.7 35.1 .+-. 4.4 1970 .+-. 230
HD-284 C.sub.6H.sub.5 .+-. 1.65 152 .+-. 65 157 .+-. 4.8 1780 .+-.
87 HD-285 4-BrC.sub.6H.sub.4 .+-. 2.51 3.7 .+-. 1.4 210 .+-. 10
1460 .+-. 470 HD-286 4-PhC.sub.6H.sub.4 .+-. 3.54 315 .+-. 100 4.85
.+-. 1.0 189 .+-. 79 HD-287 2-naphthyl .+-. 2.82 3.49 .+-. 0.64
6.58 .+-. 0.71 177 .+-. 44 HD-288 3,4-diClC.sub.6H.sub.3 .+-. 2.95
0.80 .+-. 0.02 5.6 .+-. 0.39 107 .+-. 22 HD-289
3,4-di(OMe)C.sub.6H.sub.3 .+-. 1.31 8.62 .+-. 0.71 106 .+-. 21 1364
.+-. 198 HD-290 2-ClC.sub.6H.sub.4 .+-. 2.36 289 .+-. 24 329 .+-.
54 1840 .+-. 350 HD-324 4-BrC.sub.6H.sub.4 (S,S) 2.51 44.9 .+-. 1.0
946 .+-. 71 >10,000 HD-325 4-BrC.sub.6H.sub.4 (R,R) 2.51 2.49
.+-. 0.07 47.0 .+-. 2.9 333 .+-. 79 HD-326 3,4-diClC.sub.6H.sub.3
(S,S) 2.95 8.11 .+-. 0.80 40.5 .+-. 4.3 299 .+-. 97 HD-327
3,4-diClC.sub.6H.sub.3 (R,R) 2.95 0.31 .+-. 0.01 2.42 .+-. 0.31
23.8 .+-. 3.6 HD-328 3,4-diBrC.sub.6H.sub.3 (S,S) 3.17 4.57 .+-.
0.66 18.4 .+-. 2.5 87.9 .+-. 9.5 HD-329 3,4-diBrC.sub.6H.sub.3
(R,R) 3.17 0.62 .+-. 0.12 1.71 .+-. 0.05 35.2 .+-. 4.6 HD-330
2-naphthyl (S,S) 2.82 16.4 .+-. 0.52 27.0 .+-. 3.4 313 .+-. 55
HD-331 2-naphthyl (R,R) 2.82 10.4 .+-. 0.89 15.0 .+-. 2.8 320 .+-.
51 HD-332 4-PhC.sub.6H.sub.4 (S,S) 3.54 >10,000 79.8 .+-. 21 917
.+-. 62 HD-333 4-PhC.sub.6H.sub.4 (R,R) 3.54 86.6 .+-. 19 2.69 .+-.
0.62 86.7 .+-. 37
Analgesia Testing Methods:
Spinal Nerve Ligation
[0290] A 3 cm incision was made in the back using the iliac crests
as a midpoint. An incision was then made in the underlying muscle,
which was then separated by both sharp and blunt dissection to
expose the left transverse process of the fifth lumbar vertebra.
The transverse process was removed using bone microrongeurs, and
the fifth lumbar nerve was exteriorized from underneath the spinal
column using a small metal hook and ligated using 4.0 silk suture
with sufficient pressure to cause the nerve to bulge on each side
of the ligature. The sixth lumbar nerve was exteriorized from
underneath the iliac bone at the sciatic notch and ligated in a
similar manner. All muscle layers were sutured using 4.0 chromic
gut, the skin was sutured using 4.0 nylon suture.
Intrathecal Catheter Implantation
[0291] The animal is placed in a stereotaxic frame to immobilize
the head under pentobarbital anesthesia. The animal's body is
lifted and supported to render the spinal column straight and level
and the animal's head is placed downward such the top of the skull
forms a 90.degree. angle with the spinal column. A small incision
is placed at the back of the neck and the underlying musles are
blunt dissected to reveal the atlanto-occipital membrane. A small
incision is placed in the atlanto-occipital membrane through which
a 32 ga polyethylene catheter is inserted that is 8 cm in length.
The catheter is anchored to the neck muscles with 4.0 silk suture
and the exterior wounds are closed with 4.0 nylon suture.
Drug Administration
[0292] All compounds were dissolved in 0.9% (wt/vol) saline, pH 7.4
and administered through the intrathecal catheter in a volume of 5
.mu.l, followed by 15 .mu.l of 0.9% saline to flush the
catheter.
Determination of Mechanical Allodynia (Paw Withdrawal
Threshold)
[0293] Paw withdrawal threshold was determined before and at
selected time points following intrathecal drug administration
using calibrated von Frey filaments. The animals are placed in
elevated Plexiglas chambers with wire mesh floors and acclimated
for a minimum of 30 minutes. Beginning with a filament calibrated
to bend with a force of 2 g of pressure, the filament is applied to
the plantar surface of the left hindpaw with sufficient force to
bend slightly and left in place for 8 seconds or until the animal
withdraws it's paw from the filament. In the absence of a paw
withdrawal, the next highest calibrated filament is applied in a
similar manner. In the presence of a paw withdrawal, the next
lowest calibrated filament is applied. This up-down method
continues until 4 responses are recorded after an initial positive
response. The paw withdrawal threshold is calculated using Dixon
non-parametric statistics.
Anti-Allodynic Effects of Novel SNRI Analogs
[0294] The potency and efficacy of novel SNRI analogs in reversing
mechanical hypersensitivity were determined in the L5/L6 spinal
nerve ligation (SNL) model of neuropathic pain in rats. Compounds
were administered intrathecal (i.t.) and the effect on paw
withdrawal threshold was assessed at various time points following
treatment. The effects of HD-288 (NET selective), HD-283
(milnacipran, non-selective), and HD-286 (SERT selective) were
determined and compared to those of clonidine, a drug approved for
treatment of neuropathic pain in humans by spinal
administration.
[0295] HD-288 was potent following i.t. administration, producing
significant anti-allodynic effects with an A50 of 0.6.+-.0.3 .mu.g
and increasing the PWT from 2.9.+-.0.4 g to 24.9.+-.2.5 g at 3
.mu.g. Clonidine (10 .mu.g, i.t.) and HD-283 (milnacipran, 30
.mu.g, i.t.) reversed mechanical allodynia in SNL rats similar to
literature values. HD-286 produced an increase in PWT in SNL rats
over a similar dose range as HD-288 with significantly lower
efficacy, consistent with reports of the limited efficacy of SERT
inhibitors against neuropathic pain (FIG. 3). The maximum effect of
HD-288 was found to be significantly greater than clonidine.
Therefore, HD-288 appears to be efficacious in reversing a symptom
of neuropathic pain (mechanical allodynia) in nerve-injured rats
and is quite potent compared to medications approved for clinical
treatment of chronic pain (clonidine, milnacipran).
Effects of Novel SNRI Analogs on Sedation and/or Motor Coordination
in the Rotarod Assay
[0296] Rotarod performance was assessed to determine the relative
potency of novel SNRI analogs as well as clonidine for producing
sedation and/or motor impairment, two important dose-limiting side
effects of these compounds. Clonidine (10 .mu.g, i.t.) decreased
the time rats were able to stay on the rotarod by 35.+-.10% of
baseline values [F(1, 25)=12.3, p=0.002](FIG. 4). Administration of
the maximum dose of HD-288 (3 .mu.g, i.t.) had no significant
effect on rotarod performance [F(1, 19)=1.02, p=0.3]. Sedation is a
major dose-limiting side effect of clonidine and HD-288 appears to
produce greater anti-allodynic effects and less sedation than
clonidine in the rat.
* * * * *