U.S. patent application number 16/028257 was filed with the patent office on 2019-03-07 for novel 1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders.
The applicant listed for this patent is OTSUKA AMERICA PHARMACEUTICAL, INC.. Invention is credited to Anthony BASILE, Zhengming CHEN, Joseph W. EPSTEIN, Phil SKOLNICK.
Application Number | 20190070148 16/028257 |
Document ID | / |
Family ID | 37709141 |
Filed Date | 2019-03-07 |
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United States Patent
Application |
20190070148 |
Kind Code |
A1 |
SKOLNICK; Phil ; et
al. |
March 7, 2019 |
Novel 1-Aryl-3-Azabicyclo[3.1.0]Hexanes: Preparation And Use To
Treat Neuropsychiatric Disorders
Abstract
The invention provides novel, multiply-substituted
1-aryl-3-azabicyclo[3.1.0]hexanes, and related processes and
intermediates for preparing these compounds, as well as
compositions and methods employing these compounds for the
treatment and/or prevention of central nervous system (CNS)
disorders, including depression and anxiety.
Inventors: |
SKOLNICK; Phil; (Potomac,
MD) ; BASILE; Anthony; (Flourtown, PA) ; CHEN;
Zhengming; (Belle Meade, NJ) ; EPSTEIN; Joseph
W.; (Monroe, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA AMERICA PHARMACEUTICAL, INC. |
Rockville |
MD |
US |
|
|
Family ID: |
37709141 |
Appl. No.: |
16/028257 |
Filed: |
July 5, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15648424 |
Jul 12, 2017 |
10039746 |
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16028257 |
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14929361 |
Nov 1, 2015 |
9737506 |
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15648424 |
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14494512 |
Sep 23, 2014 |
9205074 |
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14929361 |
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13887367 |
May 5, 2013 |
8877798 |
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14494512 |
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13366219 |
Feb 3, 2012 |
8461196 |
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13887367 |
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13207199 |
Aug 10, 2011 |
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13366219 |
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12334432 |
Dec 12, 2008 |
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13207199 |
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11493431 |
Jul 25, 2006 |
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12334432 |
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60703364 |
Jul 27, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/32 20180101;
A61P 25/28 20180101; A61P 1/14 20180101; A61P 25/00 20180101; A61P
25/14 20180101; A61P 25/34 20180101; A61P 25/36 20180101; A61P
43/00 20180101; A61P 25/16 20180101; A61P 25/24 20180101; A61P
25/20 20180101; A61P 13/02 20180101; A61P 25/30 20180101; C07D
209/52 20130101; A61P 21/04 20180101; A61P 1/04 20180101; A61K
31/403 20130101; A61P 25/26 20180101; A61P 3/04 20180101; A61P
25/22 20180101; A61P 25/18 20180101; A61P 37/08 20180101; A61P 5/24
20180101; A61P 29/02 20180101 |
International
Class: |
A61K 31/403 20060101
A61K031/403; C07D 209/52 20060101 C07D209/52 |
Claims
1-93. (canceled)
94. A compound of the following formula II: ##STR00336## or a
pharmaceutically acceptable salt thereof, wherein: R.sub.1 and
R.sub.2 are independently selected from hydrogen, unsubstituted
C.sub.1-10 alkyl, C.sub.3-10 alkenyl and C.sub.3-10 alkynyl, and
substituted C.sub.1-10 alkyl, C.sub.3-10 alkenyl and C.sub.3-10
alkynyl wherein the substituent is one or more of hydroxy, cyano,
halogen, C.sub.1-6 alkoxy, aryl substituted C.sub.1-6 alkoxy,
aryloxy, aryloxy substituted with one or more halogens, C.sub.1-6
alkyl, C.sub.1-6 alkyl independently substituted with one or more
of cyano and halogen, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy;
R.sub.3 is selected from hydrogen, C.sub.1-6 alkoxycarbonyl,
C.sub.2-6 alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9 cycloalkanoyl,
aryl, heteroaryl, saturated heterocyclic, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, and substituted C.sub.1-6 alkyl, C.sub.2-10
alkenyl and C.sub.2-10 alkynyl wherein the substituent is one or
more of cyano, halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6
alkoxycarbonyl, C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6 alkanoyl,
C.sub.1-6 alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyloxy, C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl
and saturated heterocyclic; and R.sub.4 and R.sub.5 are
independently hydrogen or 1-4 substituents independently selected
from halogen, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy, C.sub.3-5
cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkoxy(C.sub.1-3)alkyl,
carboxy(C.sub.1-3)alkyl, C.sub.1-3 alkanoyl, halo(C.sub.1-3)alkoxy,
nitro, amino, C.sub.1-3 alkylamino, and
di(C.sub.1-3)alkylamino.
95. A compound of the following formula III: ##STR00337## or a
pharmaceutically acceptable salt thereof, wherein: R.sub.1 and
R.sub.2 are independently selected from hydrogen, unsubstituted
C.sub.1-10 alkyl, C.sub.3-10 alkenyl and C.sub.3-10 alkynyl, and
substituted C.sub.1-10 alkyl, C.sub.3-10 alkenyl and C.sub.3-10
alkynyl wherein the substituent is one or more of hydroxy, cyano,
halogen, C.sub.1-6 alkoxy, aryl substituted C.sub.1-6 alkoxy,
aryloxy, aryloxy substituted with one or more halogens, C.sub.1-6
alkyl, C.sub.1-6 alkyl independently substituted with one or more
of cyano and halogen, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy;
R.sub.3 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxycarbonyl, C.sub.2-6 alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9
cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, and substituted C.sub.1-6 alkyl,
C.sub.2-10 alkenyl and C.sub.2-10 alkynyl wherein the substituent
is one or more of cyano, halogen, hydroxy, C.sub.1-6 alkoxy,
C.sub.1-6 alkoxycarbonyl, C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6
alkanoyl, C.sub.1-6 alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyloxy, C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl
and saturated heterocyclic; and R.sub.4 and R.sub.5 are
independently hydrogen or 1-4 substituents independently selected
from halogen, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy, C.sub.3-5
cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkoxy(C.sub.1-3)alkyl,
carboxy(C.sub.1-3)alkyl, C.sub.1-3 alkanoyl, halo(C.sub.1-3)alkoxy,
nitro, amino, C.sub.1-3 alkylamino, and
di(C.sub.1-3)alkylamino.
96. The compound according to claim 95, wherein R.sub.4 and R.sub.5
are independently hydrogen or 1-4 substituents independently
selected from methyl, ethyl, propyl, fluoro, chloro,
trifluoromethyl, cyano, nitro, methoxy, ethoxy and
trifluoromethoxy.
97. The compound according to claim 96, wherein R.sub.1 and R.sub.2
are hydrogen, R.sub.3 is hydrogen, methyl, ethyl or isopropyl and
R.sub.4 and R.sub.5 are independently selected from hydrogen,
methyl, chloro, fluoro, propyl, methoxy and ethoxy.
98. The compound according to claim 97, wherein the compound is:
1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;
3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;
1-(1-fluoronaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane;
1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;
1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; or
3-methyl-1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; or
a pharmaceutically acceptable salt thereof.
99. The compound according to claim 98, wherein the compound is:
(1R,5 S)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;
(1S,5R)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;
(1R,5S)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; or
(1S,5R)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; or
a pharmaceutically acceptable salt thereof.
100. A pharmaceutical composition, wherein the pharmaceutical
composition comprises a compound or pharmaceutically acceptable
salt thereof according to claim 98 and a pharmaceutically
acceptable carrier or vehicle therefor.
101. A method for treating a central nervous system (CNS) disorder
in a mammalian subject in need thereof, wherein the method
comprises administering to the mammalian subject an effective
amount of a compound or pharmaceutically acceptable salt thereof
according to claim 98.
102. The method according to claim 101, wherein the CNS disorder is
depression.
103. The method according to claim 101, wherein the CNS disorder is
an anxiety disorder.
104. The method according to claim 101, wherein the CNS disorder is
attention deficit hyperactivity disorder (ADHD).
Description
REFERENCE TO RELATED APPLICATION
[0001] This application is related to and claims priority from U.S.
Provisional Application 60/703,364 filed on Jul. 27, 2005, the
disclosure of which is incorporated herein by reference in its
entirety.
TECHNICAL FIELD
[0002] The present invention relates to novel
1-aryl-3-azabicyclo[3.1.0]hexanes, intermediates and methods for
the production thereof, and their use for treating disorders of the
central nervous system (CNS), including neuropsychiatric
disorders.
BACKGROUND OF THE INVENTION
[0003] 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane has been
reported to inhibit reuptake of norepinephrine, serotonin and
dopamine--three biogenic amines that have been implicated in a wide
variety of neuropsychiatric disorders ranging from anxiety and
depression to eating disorders and drug addiction. One potential
use of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is as an
antidepressant. The ability of this compound to inhibit reuptake of
three biogenic amines closely linked to depression suggests a
possible use of the compound as a "broad spectrum antidepressant."
In this context, compounds having such activity may yield a more
rapid onset and/or higher efficacy of antidepressant activity than
currently available antidepressants, including agents that inhibit
single or dual reuptake of serotonin and/or norepinephrine
[Skolnick, P. et al., Eur. J. Pharmacol. 461: 99 (2003); Skolnick,
P. et al., Life Sci. 73: 3175-3179, (2003)].
[0004] In view of the limited availability and understanding of
currently-known "broad spectrum antidepressants," there remains a
compelling need in the art to identify additional drugs having
multiple reuptake inhibitory potential for inhibiting reuptake of
multiple biogenic amines linked to disorders of the central nervous
system (CNS), including neuropsychiatric disorders, such as
depression and anxiety.
SUMMARY OF EXEMPLARY EMBODIMENTS OF THE INVENTION
[0005] It is therefore an object of the present invention to
provide novel compounds having activity to inhibit reuptake of
multiple biogenic amines linked to CNS disorders, and to provide
related compositions, and methods for treating and managing CNS
disorders, including depression and anxiety.
[0006] It is a further object of the present invention to produce
and select novel 1-aryl-3-azabicyclo[3.1.0] hexanes as therapeutic
agents.
[0007] It is another object of the invention to provide new
synthetic methods and compositions useful for producing
1-aryl-3-azabicyclo[3.1.0] hexanes and related compounds.
[0008] It is an additional object of the invention to provide novel
1-aryl-3-azabicyclo[3.1.0] hexane compositions and methods useful
to treat or manage CNS disorders by modulating transport of one or
more biogenic amines, for example to simultaneously inhibit or
block reuptake of norepinephrine and/or serotonin and/or
dopamine.
[0009] The invention achieves these objects and satisfies
additional objects and advantages by providing novel
1-aryl-3-azabicyclo[3.1.0] hexanes that possess unexpected
activities for modulating biogenic amine transport.
[0010] In certain embodiments of the invention, novel
1-aryl-3-azabicyclo[3.1.0]hexanes are provided that have at least
two substituents on the aryl ring.
[0011] In other embodiments of the invention, novel
1-aryl-3-azabicyclo[3.1.0]hexanes are provided that are substituted
with a napthyl group on the nitrogen at the `3` position.
[0012] In exemplary embodiments, novel 1-aryl-3-azabicyclo[3.1.0]
hexanes of the invention are provided having the following formula
I:
##STR00001##
and enantiomers and pharmaceutically acceptable salts thereof,
wherein: Ar is a phenyl group substituted with two substituents
independently selected from halogen, C.sub.1-3 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy,
C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino; R.sub.1 and R.sub.2 are
independently selected from hydrogen, unsubstituted C.sub.1-10
alkyl, C.sub.3-10 alkenyl and C.sub.3-10 alkynyl, and substituted
C.sub.1-10 alkyl, C.sub.3-10 alkenyl and C.sub.3-10 alkynyl wherein
the substituent is one or more of hydroxy, cyano, halogen,
C.sub.1-6 alkoxy, aryl substituted C.sub.1-6 alkoxy, aryloxy,
aryloxy substituted with one or more halogens, C.sub.1-6 alkyl,
C.sub.1-6 alkyl independently substituted with one or more of cyano
and halogen, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; and
R.sub.3 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxycarbonyl, C.sub.2-6 alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9
cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, and substituted C.sub.1-6 alkyl,
C.sub.2-10 alkenyl and C.sub.2-10 alkynyl wherein the substituent
is one or more of cyano, halogen, hydroxy, C.sub.1-6 alkoxy,
C.sub.1-6 alkoxycarbonyl, C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6
alkanoyl, C.sub.1-6 alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyloxy, C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl
and saturated heterocyclic; with the proviso that when Ar is
3,4-dichlorophenyl, R.sub.3 cannot be hydrogen.
[0013] In further embodiments, the invention provides compounds of
the following formula II:
##STR00002##
and enantiomers and pharmaceutically acceptable salts thereof,
wherein: R.sub.1 and R.sub.2 are independently selected from
hydrogen, unsubstituted C.sub.1-10 alkyl, C.sub.3-10 alkenyl and
C.sub.3-10 alkynyl, and substituted C.sub.1-10 alkyl, C.sub.3-10
alkenyl and C.sub.3-10 alkynyl wherein the substituent is one or
more of hydroxy, cyano, halogen, C.sub.1-6 alkoxy, aryl substituted
C.sub.1-6 alkoxy, aryloxy, aryloxy substituted with one or more
halogens, C.sub.1-6 alkyl, C.sub.1-6 alkyl independently
substituted with one or more of cyano and halogen, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy; R.sub.3 is selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.2-6
alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9 cycloalkanoyl, aryl,
heteroaryl, saturated heterocyclic, C.sub.2-10 alkenyl, C.sub.2-10
alkynyl, and substituted C.sub.1-6 alkyl, C.sub.2-10 alkenyl and
C.sub.2-10 alkynyl wherein the substituent is one or more of cyano,
halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6; alkoxycarbonyl,
C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyloxy,
C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated
heterocyclic; and R.sub.4 and R.sub.5 are independently hydrogen or
1-4 substituents independently selected from halogen, C.sub.1-3
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl,
cyano, hydroxy, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino.
[0014] In additional embodiments, the invention provides compounds
of the following formula III:
##STR00003##
and enantiomers and pharmaceutically acceptable salts thereof,
wherein: R.sub.1 and R.sub.2 are independently selected from
hydrogen, unsubstituted C.sub.1-10 alkyl, C.sub.3-10 alkenyl and
C.sub.3-10 alkynyl, and substituted C.sub.1-10 alkyl, C.sub.3-10
alkenyl and C.sub.3-10 alkynyl wherein the substituent is one or
more of hydroxy, cyano, halogen, C.sub.1-6 alkoxy, aryl substituted
C.sub.1-6 alkoxy, aryloxy, aryloxy substituted with one or more
halogens, C.sub.1-6 alkyl, C.sub.1-6 alkyl independently
substituted with one or more of cyano and halogen, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy; R.sub.3 is selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.2-6
alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9 cycloalkanoyl, aryl,
heteroaryl, saturated heterocyclic, C.sub.2-10 alkenyl, C.sub.2-10
alkynyl, and substituted C.sub.1-6 alkyl, C.sub.2-10 alkenyl and
C.sub.2-10 alkynyl wherein the substituent is one or more of cyano,
halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl,
C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyloxy,
C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated
heterocyclic; and R.sub.4 and R.sub.5 are independently hydrogen or
1-4 substituents independently selected from halogen, C.sub.1-3
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl,
cyano, hydroxy, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino.
[0015] Useful 1-aryl-3-azabicyclo[3.1.0] hexanes of the invention
include the substituted 1-aryl-3-azabicyclo[3.1.0] hexanes
compounds described herein, as well as their active,
pharmaceutically acceptable salts, polymorphs, solvates, hydrates
and or prodrugs, or combinations thereof.
[0016] The invention also provides novel methods of making
1-aryl-3-azabicyclo[3.1.0] hexanes, including synthetic methods
that form novel intermediate compounds of the invention for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes. In related
embodiments, the invention provides novel processes for preparing
1-aryl-3-azabicyclo[3.1.0] hexanes, to yield novel compounds useful
in biologically active and/or therapeutic compositions.
[0017] In yet additional embodiments, the invention provides
pharmaceutical compositions and methods for treating disorders of
the central nervous system (CNS), including a wide array of serious
neurological or psychiatric conditions, in mammals that are
amenable to treatment using agents that inhibit or otherwise
modulate biogenic amine transport.
[0018] The foregoing objects and additional objects, features,
aspects and advantages of the present invention are further
exemplified and described in the following detailed
description.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION
[0019] The present invention fulfills these needs and satisfies
additional objects and advantages by providing novel
1-aryl-3-azabicyclo[3.1.0] hexanes as therapeutic agents to treat
and manage a wide variety of disorders of the central nervous
system (CNS), including neuropsychiatric disorders. CNS disorders
for treatment using the compositions and methods of the invention
are amenable to treatment, prophylaxis, and/or alleviation of the
disorder and/or associated symptom(s) by inhibiting reuptake of
multiple biogenic amines causally linked to the targeted CNS
disorder, wherein the biogenic amines targeted for reuptake
inhibition are selected from norepinephrine, and/or serotonin,
and/or dopamine. In exemplary embodiments, the novel compounds of
the invention are employed in effective compositions and methods
for treating a neuropsychiatric disorder, such as depression or
anxiety.
[0020] In one embodiment, the invention provides compounds of the
following formula I:
##STR00004##
and enantiomers and pharmaceutically acceptable salts thereof,
wherein: Ar is a phenyl group substituted with two substituents
independently selected from halogen, C.sub.1-3 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy,
C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino; R.sub.1 and R.sub.2 are
independently selected from hydrogen, unsubstituted C.sub.1-10
alkyl, C.sub.3-10 alkenyl and C.sub.3-10 alkynyl, and substituted
C.sub.1-10 alkyl, C.sub.3-10 alkenyl and C.sub.3-10 alkynyl wherein
the substituent is one or more of hydroxy, cyano, halogen,
C.sub.1-6 alkoxy, aryl substituted C.sub.1-6 alkoxy, aryloxy,
aryloxy substituted with one or more halogens, C.sub.1-6 alkyl,
C.sub.1-6 alkyl independently substituted with one or more of cyano
and halogen, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; and
R.sub.3 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxycarbonyl, C.sub.2-6 alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9
cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, and substituted C.sub.1-6 alkyl,
C.sub.2-10 alkenyl and C.sub.2-10 alkynyl wherein the substituent
is one or more of cyano, halogen, hydroxy, C.sub.1-6 alkoxy,
C.sub.1-6, alkoxycarbonyl, C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6
alkanoyl, C.sub.1-6 alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyloxy, C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl
and saturated heterocyclic; with the proviso that when Ar is
3,4-dichlorophenyl, R.sub.3 cannot be hydrogen.
[0021] In certain embodiments, Ar is a phenyl group substituted
with two substituents independently selected from methyl, ethyl,
fluoro, chloro, trifluoromethyl, cyano, nitro, and
trifluoromethoxy. In additional embodiments, R.sub.1 and R.sub.2
are hydrogen or methyl and R.sub.3 is hydrogen, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl or cyclopropyl.
[0022] In another embodiment, the invention provides compounds of
the following formula II:
##STR00005##
and enantiomers and pharmaceutically acceptable salts thereof,
wherein: R.sub.1 and R.sub.2 are independently selected from
hydrogen, unsubstituted C.sub.1-10 alkyl, C.sub.3-10 alkenyl and
C.sub.3-10 alkynyl, and substituted C.sub.1-10 alkyl, C.sub.3-10
alkenyl and C.sub.3-10 alkynyl wherein the substituent is one or
more of hydroxy, cyano, halogen, C.sub.1-6 alkoxy, aryl substituted
C.sub.1-6 alkoxy, aryloxy, aryloxy substituted with one or more
halogens, C.sub.1-6 alkyl, C.sub.1-6 alkyl independently
substituted with one or more of cyano and halogen, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy; R.sub.3 is selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.2-6
alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9 cycloalkanoyl, aryl,
heteroaryl, saturated heterocyclic, C.sub.2-10 alkenyl, C.sub.2-10
alkynyl, and substituted C.sub.1-6 alkyl, C.sub.2-10 alkenyl and
C.sub.2-10 alkynyl wherein the substituent is one or more of cyano,
halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl,
C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyloxy,
C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated
heterocyclic; and R.sub.4 and R.sub.5 are independently hydrogen or
1-4 substituents independently selected from halogen, C.sub.1-3
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl,
cyano, hydroxy, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino.
[0023] In certain embodiments, R.sub.4 and R.sub.5 are
independently hydrogen or 1-4 substituents independently selected
from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro,
methoxy, ethoxy and trifluoromethoxy. In additional embodiments,
R.sub.1 and R.sub.2 are hydrogen, R.sub.3 is hydrogen, methyl,
ethyl or isopropyl and R.sub.4 and R.sub.5 are independently
selected from hydrogen, methyl, chloro, fluoro, propyl, methoxy and
ethoxy.
[0024] In a further embodiment, the invention provides compounds of
the following formula III:
##STR00006##
and enantiomers and pharmaceutically acceptable salts thereof,
wherein: R.sub.1 and R.sub.2 are independently selected from
hydrogen, unsubstituted C.sub.1-10 alkyl, C.sub.3-10 alkenyl and
C.sub.3-10 alkynyl, and substituted C.sub.1-10 alkyl, C.sub.3-10
alkenyl and C.sub.3-10 alkynyl wherein the substituent is one or
more of hydroxy, cyano, halogen, C.sub.1-6 alkoxy, aryl substituted
C.sub.1-6 alkoxy, aryloxy, aryloxy substituted with one or more
halogens, C.sub.1-6 alkyl, C.sub.1-6 alkyl independently
substituted with one or more of cyano and halogen, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy; R.sub.3 is selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.2-6
alkanoyl, C.sub.3-8 cycloalkyl, C.sub.4-9 cycloalkanoyl, aryl,
heteroaryl, saturated heterocyclic, C.sub.2-10 alkenyl, C.sub.2-10
alkynyl, and substituted C.sub.1-6 alkyl, C.sub.2-10 alkenyl and
C.sub.2-10 alkynyl wherein the substituent is one or more of cyano,
halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl,
C.sub.2-6 alkyloxycarbonyloxy, C.sub.1-6 alkanoyl, C.sub.1-6
alkanoyloxy, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyloxy,
C.sub.4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated
heterocyclic; and R.sub.4 and R.sub.5 are independently hydrogen or
1-4 substituents independently selected from halogen, C.sub.1-3
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl,
cyano, hydroxy, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino.
[0025] In certain embodiments, R.sub.4 and R.sub.5 are
independently hydrogen or 1-4 substituents independently selected
from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro,
methoxy, ethoxy and trifluoromethoxy. In additional embodiments,
R.sub.1 and R.sub.2 are hydrogen, R.sub.3 is hydrogen, methyl,
ethyl or isopropyl and R.sub.4 and R.sub.5 are independently
selected from hydrogen, methyl, chloro, fluoro, propyl, methoxy and
ethoxy.
[0026] Within exemplary embodiments, the invention provides an
assemblage of novel 1-aryl-3-azabicyclo[3.1.0]hexanes having
multiple substitutions on the aryl ring. Novel, multiply
aryl-substituted, 1-aryl-3-azabicyclo[3.1.0]hexanes of the
invention include the following, exemplary compounds, which have
been made and characterized as illustrative embodiments of the
invention (Table 1).
TABLE-US-00001 TABLE 1 Exemplary 1-aryl-3-azabicyclo[3.1.0]hexanes
having multiple substitutions on the aryl ring ##STR00007##
1-(2,4-difluorophenyl)-3-methyl-3- 3-aza-bicyclo[3.1.0]hexane
##STR00008## 3-ethyl-1-(2,4-difluorophenyl)-
3-aza-bicyclo[3.1.0]hexane ##STR00009##
1-(2,4-difluorophenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane
##STR00010## 1-(3,4-difluorophenyl)-3- aza-bicyclo[3.1.0]hexane
##STR00011## 1-(3,4-difluorophenyl)-3-methyl-
3-aza-bicyclo[3.1.0]hexane ##STR00012##
1-(3,4-difluorophenyl)-3-ethyl- 3-aza-bicyclo[3.1.0]hexane
##STR00013## (1R,5S)-3-ethyl-1-(3,4-difluorophenyl)-
3-aza-bicyclo[3.1.0]hexane ##STR00014##
(1S,5R)-3-ethyl-1-(3,4-difluorophenyl)- 3-aza-bicyclo[3.1.0]hexane
##STR00015## 1-(3,4-difluorophenyl)-3-isopropyl-
3-aza-bicyclo[3.1.0]hexane ##STR00016##
1-(3-chloro-4-fluorophenyl)- 3-aza-bicyclo[3.1.0]hexane
##STR00017## (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-
aza-bicyclo[3.1.0]hexane ##STR00018##
(1S,5R)-1-(3-chloro-4-fluorophenyl)-3- aza-bicyclo[3.1.0]hexane
##STR00019## 1-(3-chloro-4-fluorophenyl)-3-methyl-3-
aza-bicyclo[3.1.0]hexane ##STR00020##
(1R,5S)-1-(3-chloro-4-fluorophenyl)-3-
methyl-3-aza-bicyclo[3.1.0]hexane ##STR00021##
(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-
methyl-3-aza-bicyclo[3.1.0]hexane ##STR00022##
1-(3-chloro-4-fluorophenyl)-3-ethyl-3- aza-bicyclo[3.1.0]hexane
##STR00023## (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-
ethyl-3-aza-bicyclo[3.1.0]hexane ##STR00024##
(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-
ethyl-3-aza-bicyclo[3.1.0]hexane ##STR00025##
1-(3-chloro-4-fluorophenyl)-3-isopropyl-3- aza-bicyclo[3.1.0]hexane
##STR00026## (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-
isopropyl-3-aza-bicyclo[3.1.0]hexane ##STR00027##
(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-
isopropyl-3-aza-bicyclo[3.1.0]hexane ##STR00028##
(1R,5S)-1-(4-chloro-3-fluorophenyl)-3- aza-bicyclo[3.1.0]hexane
##STR00029## (1S,5R)-1-(4-chloro-3-fluorophenyl)-3-
aza-bicyclo[3.1.0]hexane ##STR00030##
(1R,5S)-1-(4-chloro-3-fluorophenyl)-3-
methyl-3-aza-bicyclo[3.1.0]hexane ##STR00031##
(1S,5R)-(4-chloro-3-fluorophenyl)-3-
methyl-3-aza-bicyclo[3.1.0]hexane ##STR00032##
1-(2,4-dichlorophenyl)-3-methyl-3-aza- bicyclo[3.1.0]hexane
##STR00033## 1-(2,4-dichlorophenyl)-3-ethyl-3-aza-
bicyclo[3.1.0]hexane ##STR00034##
1-(2,4-dichlorophenyl)-3-isopropyl-3- aza-bicyclo[3.1.0]hexane
##STR00035## 1-(4-fluoro-3-methylphenyl)-3-aza-
bicyclo[3.1.0]hexane ##STR00036##
1-(4-fluoro-3-methylphenyl)-3-methyl-3-aza- bicyclo[3.1.0]hexane
##STR00037## 3-ethyl-1-(4-fluorbicyclo-3-methylphenyl)-3-
aza-bicyclo[3.1.0]hexane ##STR00038##
1-(4-fluoro-3-methylphenyl)-3-isopropyl- aza-bicyclo[3.1.0]hexane
##STR00039## 1-(3-fluoro-4-methylphenyl)-3-aza-
bicyclo[3.1.0]hexane ##STR00040##
(1R,5S)-1-(3-fluoro-4-methylphenyl)-3- aza-bicyclo[3.1.0]hexane
##STR00041## (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-
aza-bicyclo[3.1.0]hexane ##STR00042##
1-(3-fluoro-4-methylphenyl)-3-methyl-3- aza-bicyclo[3.1.0]hexane
##STR00043## (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-
methyl-3-aza-bicyclo[3.1.0]hexane ##STR00044##
(1S,5R)-1-(3-fluoro-4-methylphenyl)-3-
methyl-3-aza-bicyclo[3.1.0]hexane ##STR00045##
1-(3-fluoro-4-methylphenyl)-3-ethyl-3-aza- bicyclo[3.1.0]hexane
##STR00046## 1-(3-fluoro-4-methylphenyl)-3-
isopropyl-3-aza-bicyclo[3.1.0]hexane ##STR00047##
1-(3-fluoro-4-methoxyphenyl)-3-aza- bicyclo[3.1.0]hexane
##STR00048## 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-
3-aza-bicyclo[3.1.0]hexane ##STR00049##
(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-
3-aza-bicyclo[3.1.0]hexane ##STR00050##
(1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-
aza-bicyclo[3.1.0]hexane ##STR00051##
(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-
3-methyl-3-aza-bicyclo[3.1.0]hexane ##STR00052##
(1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-
3-methyl-3-aza-bicyclo[3.1.0]hexane ##STR00053##
1-(3-chloro-4-nitrophenyl)-3-methyl-3- aza-bicyclo[3.1.0]hexane
##STR00054## 1-(naphthalen-1-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00055## (1R,5S)-1-(naphthalen-1-yl)-3-aza-
aza-bicyclo[3.1.0]hexane
##STR00056## (1S,5R)-1-(naphthalen-1-yl)-3- bicyclo[3.1.0]hexane
##STR00057## 3-methyl-1-(naphthalen-1-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00058##
(1R,5S)-3-methyl-1-(naphthalen-1-yl)-3- aza-bicyclo[3.1.0]hexane
##STR00059## (1S,5R)-3-methyl-1-(naphthalen-1-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00060##
1-(1-fluoronaphthalen-4-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00061## 1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza-
bicyclo[3.1.0]hexane ##STR00062##
1-(1-methylnaphthalen-4-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00063## 3-methyl-1-(1-methylnaphthalen-4-yl)-3-
aza-bicyclo[3.1.0]hexane ##STR00064## 1-(naphthalen-2-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00065##
(1R,5S)-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00066## (1S,5R)-1-(naphthalen-2-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00067##
3-methyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00068## (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-
aza-bicyclo[3.1.0]hexane ##STR00069##
(1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00070## 3-ethyl-1-(naphthalen-2-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00071##
3-isopropyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane
##STR00072## (1R,5S)-3-isoixopyl-1-(naphthalen-2-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00073##
(1S,5R)-3-isopropyl-1-(naphthalen-2-yl)- 3-aza-bicyclo[3.1.0]hexane
##STR00074## 1-(2-methoxynaphthalen-6-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00075##
1-(2-methoxynaphthalen-6-yl)-3-methyl-3- 3-aza-bicyclo[3.1.0]hexane
##STR00076## 1-(2-ethoxynaphthalen-6-yl)-3-aza-
bicyclo[3.1.0]hexane ##STR00077##
1-(2-ethoxynaphthalen-6-yl)-3-methyl-3- aza-bicyclo[3.1.0]hexane
##STR00078## Cis-1-(3,4-dichlorophenyl)-2-methyl-3-
aza-bicyclo[3.1.0]hexane ##STR00079##
Cis-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza- bicyclo[3.1.0]hexane
##STR00080## Trans-1-(3,4-dichlorophenyl)-2-methyl-3-aza-
bicyclo[3.1.0]hexane ##STR00081##
Trans-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-
aza-bicyclo[3.1.0]hexane ##STR00082##
Cis-1-(3,4-dichlorophenyl)-4-methyl-3-aza- bicyclo[3.1.0]hexane
##STR00083## Trans-1-(3,4-dichlorophenyl)-4-methyl-
3-aza-bicyclo[3.1.0]hexane ##STR00084##
Trans-1-(34-dichlorophenyl)-3,4-
dimethyl-3-aza-bicyclo[3.1.0]hexane
[0027] It will be understood that the exemplary, multiply
aryl-substituted compounds identified in Table 1 are illustrative,
and that the subject modifications comprising multiple aryl
substitutions can be varied to comprise other substituents, can
include yet additional substituents (e.g., three or more
substitutions on the aryl ring), combined with one another, or
additionally combined with one or more substitutions on the
azabicyclo[3.1.0] hexane ring, to yield yet additional compounds
within the invention for treating CNS disorders (including a range
of neuropsychiatric disorders, such as depression and anxiety). For
example, the invention provides an illustrative assemblage of novel
1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexanes having multiple
substitutions, (e.g., as illustrated by multiple chloro
substitutions) on the aryl ring, combined with a substitution on
the nitrogen (alternatively, an "aza substitution") at the `3`
position. Novel 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanes
of the invention having a substitution on the nitrogen at the `3`
position of the invention include the following, exemplary
compounds, which have been made and characterized as illustrative
embodiments of the invention (Table 2). The subject compounds are
depicted as hydrochloride salts, whereas it will be understood that
the invention encompasses all forms of the compounds as described
herein, including free base forms, and all pharmaceutically
acceptable salts, polymorphs, solvates, hydrates, and prodrugs
thereof:
TABLE-US-00002 TABLE 2 Exemplary 1-aryl-3-azabicyclo[3.1.0]hexanes
having multiple substitutions on the aryl ring combined with an aza
substitution ##STR00085## (1R,5S)-1-(3,4-dichlorophenyl)-3-methyl-
3-aza-bicyclo[3.1.0]hexane ##STR00086##
(1S,5R)-1-(3,4-dichlorophenyl)-3-methyl- 3-aza-bicyclo[3.1.0]hexane
##STR00087## (1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-
aza-bicyclo[3.1.0]hexane ##STR00088##
(1S,5R)-1-(3,4-dichlorophenyl)-3-ethyl-3- aza-bicyclo[3.1.0]hexane
##STR00089## 1-(3,4-dichlorophenyl)-3-propyl-3-
aza-bicyclo[3.1.0]hexane ##STR00090##
(1R,5S)-1-(3,4-dichlorophenyl)-3-propyl- 3-aza-bicyclo[3.1.0]hexane
##STR00091## (1S,5R)-1-(3,4-dichlorophenyl)-3-propyl-
3-aza-bicyclo[3.1.0]hexane ##STR00092##
1-(3,4-dichlorophenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane
##STR00093## (1R5S)-1-(3,4-dichlorophenyl)-3-isopropyl-
3-aza-bicyclo[3.1.0]hexane ##STR00094##
(1S,5R)-1-(3,4-dichlorophenyl)-3-isopropyl-
3-aza-bicyclo[3.1.0]hexane ##STR00095##
1-(3,4-dichlorophenyl)-3-cyclopropyl- 3-aza-bicyclo[3.1.0]hexane
##STR00096## (1R,5S)-1-(3,4-dichlorophenyl)-3-cyclopropyl-
3-aza-bicyclo[3.1.0]hexane ##STR00097##
(1S,5R)-1-(3,4-dichlorcphenyl)-3-cyclopropyl-
3-aza-bicyclo[3.1.0]hexane ##STR00098##
3-butyl-1-(3,4-dichlorophenyl)- 3-aza-bicyclo[3.1.0]hexane
##STR00099## (1R,5S)-3-butyl-1-(3,4-dichlorophenyl)-3-
aza-bicyclo[3.1.0]hexane ##STR00100##
(1S,5R)-3-butyl-1-(3,4-dichlorophenyl)-3- aza-bicyclo[3.1.0]hexane
##STR00101## 1-(3,4-dichlorophenyl)-3-isobutyl-
aza-bicyclo[3.1.0]hexane ##STR00102##
(1R,5S)-1-(3,4-dichlorophenyl)-3-isobutyl-3-
3-aza-bicyclo[3.1.0]hexane ##STR00103##
(1S,5R)-1-(3,4-dichlorophenyl)-3-isobutyl-3-
3-aza-bicyclo[3.1.0]hexane ##STR00104##
3-tert-butyl-1-(3,4-dichlorophenyl)- 3-aza-bicyclo[3.1.0]hexane
##STR00105## (1R,5S)-3-tert-butyl-1-(3,4-dichlorophenyl)-
3-aza-bicyclo[3.1.0]hexane ##STR00106##
(1S,5R)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-
aza-bicyclo[3.1.0]hexane
[0028] Within related aspects of the invention, enantiomeric forms
of the novel compounds described herein, having chiral symmetric
structure, are provided, which provide yet additional drug
candidates for treating CNS disorders. In certain embodiments, the
invention provides enantiomers, diastereomers, and other
stereoisomeric forms of the disclosed compounds, including racemic
and resolved forms and mixtures thereof. The individual enantiomers
may be separated according to methods that are well known to those
of ordinary skill in the art. In certain embodiments, the
enantiomers, diastereomers and other stereoisomeric forms of the
disclosed compounds are substantially free of the corresponding
enantiomers, diastereomers and stereoisomers. In other embodiments,
the enantiomers, diastereomers and other stereoisomeric forms of
the disclosed compounds contain no more than about 10%, about 5%,
about 2% or about 1% of the corresponding enantiomers,
diastereomers and stereoisomers. When the compounds described
herein contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended to
include both E and Z geometric isomers. All tautomers are intended
to be encompassed by the present invention as well.
[0029] As noted above, the compounds of the present invention can
be prepared as both acid addition salts formed from an acid and the
basic nitrogen group of 1-aryl-3-azabicyclo[3.1.0] hexanes and base
salts. As further noted below, the methods of the present invention
can be used to prepare compounds as both acid addition salts formed
from an acid and the basic nitrogen group of
1-aryl-3-azabicyclo[3.1.0] hexanes and base salts. Suitable acid
addition salts are formed from acids which form non-toxic salts and
include, for example, hydrochloride, hydrobromide, hydroiodide,
sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen
phosphate salts. Other examples of pharmaceutically acceptable
addition salts include inorganic and organic acid addition salts.
Additional pharmaceutically acceptable salts include, but are not
limited to, metal salts such as sodium salt, potassium salt, cesium
salt and the like; alkaline earth metals such as calcium salt,
magnesium salt and the like; organic amine salts such as
triethylamine salt, pyridine salt, picoline salt, ethanolamine
salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt and the like; organic acid salts
such as acetate, citrate, lactate, succinate, tartrate, maleate,
fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,
oxalate, formate and the like; sulfonates such as methanesulfonate,
benzenesulfonate, p-toluenesulfonate and the like; and amino acid
salts such as arginate, asparginate, glutamate, tartrate, gluconate
and the like. Suitable base salts are formed from bases which form
non-toxic salts and include, for example, aluminum, calcium,
lithium, magnesium, potassium, sodium, zinc and diethanolamine
salts.
[0030] In other detailed embodiments, the invention provides
prodrugs of the disclosed compounds. Prodrugs are considered to be
any covalently bonded carriers which release the active parent drug
in vivo. Examples of prodrugs include esters or amides of a
compound of the present invention with hydroxyalkyl or aminoalkyl
as a substituent. These may be prepared by reacting such compounds
with anhydrides such as succinic anhydride.
[0031] The invention disclosed herein will also be understood to
encompass in vivo metabolic products of the disclosed compounds.
Such products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising contacting a compound of this invention with a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products typically are identified by preparing a
radiolabelled compound of the invention, administering it
parenterally in a detectable dose to an animal such as rat, mouse,
guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur and isolating its conversion products from the
urine, blood or other biological samples.
[0032] The invention disclosed herein will also be understood to
encompass the disclosed compounds isotopically-labelled by having
one or more atoms replaced by an atom having a different atomic
mass or mass number. Examples of isotopes that can be incorporated
into the disclosed compounds include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, fluorine and chlorine, such as
.sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl,
respectively.
[0033] The compounds of the instant invention may be prepared using
methods known to those skilled in the art, and in other embodiments
by employing novel synthetic schemes as provided herein, which,
along with the exemplified intermediate compounds, also fall within
the scope of the invention. Accordingly, the present invention also
provides novel methods and compositions for producing the compounds
of the present invention as well as other
1-aryl-3-azabicyclo[3.1.0] hexanes.
[0034] In certain embodiments, the present invention provides
methods for making a 1-aryl-3-azabicyclo[3.1.0] hexane of the
following formula IV,
##STR00107##
wherein Ar is a phenyl group substituted with two substituents
independently selected from halogen, C.sub.1-3 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy,
C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino, an unsubstituted napthyl
group or a napthyl group having 1-4 substituents independently
selected from halogen, C.sub.1-3 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy, C.sub.3-5
cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkoxy(C.sub.1-3)alkyl,
carboxy(C.sub.1-3)alkyl, C.sub.1-3 alkanoyl, halo(C.sub.1-3)alkoxy,
nitro, amino, C.sub.1-3 alkylamino, and di(C.sub.1-3)alkylamino,
and enantiomers and diastereomers thereof, comprising the steps of:
[0035] (a) reacting a compound of the following formula (i),
##STR00108##
[0035] wherein Ar is defined as above, with epichlohydrin or an
enantiomer thereof, to produce a compound of the following formula
(ii),
##STR00109##
or an enantiomer or diastereomer thereof; [0036] (b) reducing the
compound of formula (ii) to produce a compound of the following
formula (iii),
##STR00110##
[0036] or an enantiomer or diastereomer thereof; [0037] (c) causing
cyclization of the compound of formula (iii) to produce the
1-aryl-3-azabicyclo[3.1.0] hexane, or an enantiomer or diastereomer
thereof.
[0038] In other embodiments, the present invention provides methods
for making a 1-aryl-3-azabicyclo[3.1.0] hexane of the following
formula IV,
##STR00111##
wherein Ar is a phenyl group substituted with two substituents
independently selected from halogen, C.sub.1-3 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy,
C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino, an unsubstituted napthyl
group or a napthyl group having 1-4 substituents independently
selected from halogen, C.sub.1-3 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy, C.sub.3-5
cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkoxy(C.sub.1-3)alkyl,
carboxy(C.sub.1-3)alkyl, C.sub.1-3 alkanoyl, halo(C.sub.1-3)alkoxy,
nitro, amino, C.sub.1-3 alkylamino, and di(C.sub.1-3)alkylamino,
and enantiomers and diastereomers thereof, comprising the steps of:
[0039] (a) reacting a compound of the following formula (i),
##STR00112##
[0039] wherein Ar is defined as above, with epichlohydrin to
produce a compound of the following formula (ii),
##STR00113## [0040] (b) reducing the compound of formula (ii) to
produce a compound of the following formula (iii),
[0040] ##STR00114## [0041] (c) reacting the compound of formula
(iii) with (Boc).sub.2O to produce a compound of the following
formula (iv),
[0041] ##STR00115## [0042] (d) causing cyclization of the compound
of formula (iv to produce a compound of the following formula
(v),
[0042] ##STR00116## [0043] (e) deprotecting the compound of formula
(v) to produce a compound of the following formula (vi),
##STR00117##
[0043] and [0044] (f) reducing the compound of formula (vi) to
produce the 1-aryl-3-azabicyclo[3.1.0] hexane.
[0045] In additional embodiments, the present invention provides
methods of making a 1-aryl-3-azabicyclo[3.1.0] hexane of the
following formula V,
##STR00118##
wherein Ar is a phenyl group substituted with two substituents
independently selected from halogen, C.sub.1-3 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy,
C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino, an unsubstituted napthyl
group or a napthyl group having 1-4 substituents independently
selected from halogen, C.sub.1-3 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano, hydroxy, C.sub.3-5
cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkoxy(C.sub.1-3)alkyl,
carboxy(C.sub.1-3)alkyl, C.sub.1-3 alkanoyl, halo(C.sub.1-3)alkoxy,
nitro, amino, C.sub.1-3 alkylamino, and di(C.sub.1-3)alkylamino,
and R is hydrogen, methyl, ethyl, isopropyl or a nitrogen
protecting group, and enantiomers and diastereomers thereof,
comprising the steps of: [0046] (a) reacting a compound of the
following formula (vii),
##STR00119##
[0046] wherein R is as defined above, with
##STR00120##
wherein Ar is as defined above, to produce a compound of the
following formula (viii),
##STR00121## [0047] (b) causing cyclopropanation of the compound of
formula (viii) to produce a compound of the following formula
(ix),
##STR00122##
[0047] and [0048] (c) reducing the compound of formula (ix) to
produce the 1-aryl-3-azabicyclo[3.1.0] hexane.
[0049] In practicing the methods of the present for methods for
making 1-aryl-3-azabicyclo[3.1.0]hexanes, various reagents may be
utilized for the different reaction steps. In general, suitable
reagents for the various reaction steps may be selected by one of
ordinary skill in the art based on the present disclosure.
[0050] Suitable reducing agents and methodologies include, for
example, lithium aluminum hydride (LAH), sodium aluminum hydride
(SAH), NaBH.sub.4 with ZnCl.sub.2 and catalytic hydrogenation.
[0051] Suitable nitrogen protecting groups include, for example,
benzyl, allyl, tert-butyl and 3,4-dimethoxy-benzyl groups. In
general, nitrogen protecting groups are well known to those skilled
in the art, see for example, "Nitrogen Protecting Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7;
"Nitrogen Protecting Groups in Organic Chemistry", Plenum Press,
New York, N.Y., 1973, Chapter 2; T. W. Green and P. G. M. Wuts in
"Protective Groups in Organic Chemistry", 3rd edition, John Wiley
& Sons, New York, N.Y., 1999.
[0052] When the nitrogen protecting group is no longer needed, it
may be removed by methods well known in the art. For example,
benzyl or 3,4-dimethoxy-benzyl groups may be removed by catalytic
hydrogenation. In general, methods of removing nitrogen protecting
groups are well known to those skilled in the art, see for example,
"Nitrogen Protecting Groups in Organic Synthesis", John Wiley and
Sons, New York, N.Y., 1981, Chapter 7; "Nitrogen Protecting Groups
in Organic Chemistry", Plenum Press, New York, N.Y., 1973, Chapter
2; T. W. Green and P. G. M. Wuts in "Protective Groups in Organic
Chemistry", 3rd edition, John Wiley & Sons, Inc. New York,
N.Y., 1999.
[0053] Suitable reagents for causing cyclization include, for
example, SOCl.sub.2, POCl.sub.3, oxalyl chloride, phosphorous
tribromide, triphenylphosphorous dibromide and oxalyl bromide.
[0054] Exemplary synthetic methods, starting materials, and
intermediates useful in various aspects of the invention for
producing novel compounds of the present invention are described in
the examples.
[0055] For the purposes of describing the invention, including the
novel compounds and synthetic methods disclosed herein, the
following terms and definitions are provided by way of example.
[0056] The term "halogen" as used herein refers to bromine,
chlorine, fluorine or iodine. In one embodiment, the halogen is
chlorine. In another embodiment, the halogen is bromine.
[0057] The term "hydroxy" as used herein refers to --OH or
--O--.
[0058] The term "alkyl" as used herein refers to straight- or
branched-chain aliphatic groups containing 1-20 carbon atoms,
preferably 1-7 carbon atoms and most preferably 1-4 carbon atoms.
This definition applies as well to the alkyl portion of alkoxy,
alkanoyl and aralkyl groups. In one embodiment, the alkyl is a
methyl group.
[0059] The term "alkoxy" includes substituted and unsubstituted
alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen
atom. In one embodiment, the alkoxy group contains 1 to 4 carbon
atoms. Embodiments of alkoxy groups include, but are not limited
to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy
groups. Embodiments of substituted alkoxy groups include
halogenated alkoxy groups. In a further embodiment, the alkoxy
groups can be substituted with groups such as alkenyl, alkynyl,
halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkylamino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
Exemplary halogen substituted alkoxy groups include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, and trichloromethoxy.
[0060] The term "nitro", as used herein alone or in combination,
refers to a --NO.sub.2 group.
[0061] The term "amino" as used herein refers to the group --NRR',
where R and R' may independently be hydrogen, alkyl, aryl, alkoxy,
or heteroaryl. The term "aminoalkyl" as used herein represents a
more detailed selection as compared to "amino" and refers to the
group --NRR', where R and R' may independently be hydrogen or
(C.sub.1-C.sub.4)alkyl.
[0062] The term "trifluoromethyl" as used herein refers to
--CF.sub.3.
[0063] The term "trifluoromethoxy" as used herein refers to
--OCF.sub.3.
[0064] The term "cycloalkyl" as used herein refers to a saturated
cyclic hydrocarbon ring system containing from 3 to 7 carbon atoms
that may be optionally substituted. Exemplary embodiments include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl. In certain embodiments, the cycloalkyl group is
cyclopropyl. In another embodiment, the (cycloalkyl)alkyl groups
contain from 3 to 7 carbon atoms in the cyclic portion and 1 to 4
carbon atoms in the alkyl portion. In certain embodiments, the
(cycloalkyl)alkyl group is cyclopropylmethyl. The alkyl groups are
optionally substituted with from one to three substituents selected
from the group consisting of halogen, hydroxy and amino.
[0065] The terms "alkanoyl" and "alkanoyloxy" as used herein refer,
respectively, to --C(O)-alkyl groups and --O--C(O)-alkyl groups,
each optionally containing 2-5 carbon atoms. Specific embodiments
of alkanoyl and alkanoyloxy groups are acetyl and acetoxy,
respectively.
[0066] The term "aryl" as used herein refers to monocyclic or
bicyclic aromatic hydrocarbon groups having from 6 to 12 carbon
atoms in the ring portion, for example, phenyl, naphthyl, biphenyl
and diphenyl groups, each of which may be substituted with, for
example, one to four substituents such as alkyl, substituted alkyl
as defined above, halogen, trifluoromethyl, trifluoromethoxy,
hydroxy, alkoxy, cycloalkyloxy, alkanoyl, alkanoyloxy, amino,
alkylamino, dialkylamino, nitro, cyano, carboxy, carboxyalkyl,
carbamyl, carbamoyl and aryloxy. Specific embodiments of aryl
groups in accordance with the present invention include phenyl,
substituted phenyl, naphthyl, biphenyl, and diphenyl.
[0067] The term "aroyl," as used alone or in combination herein,
refers to an aryl radical derived from an aromatic carboxylic acid,
such as optionally substituted benzoic or naphthoic acids.
[0068] The term "aralkyl" as used herein refers to an aryl group
bonded to the 4-pyridinyl ring through an alkyl group, preferably
one containing 1-4 carbon atoms. A preferred aralkyl group is
benzyl.
[0069] The term "nitrile" or "cyano" as used herein refers to the
group --CN.
[0070] The term "dialkylamino" refers to an amino group having two
attached alkyl groups that can be the same or different.
[0071] The term "alkenyl" refers to a straight or branched alkenyl
group of 2 to 10 carbon atoms having 1 to 3 double bonds. Preferred
embodiments include ethenyl, 1-propenyl, 2-propenyl,
1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl,
3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl,
1-octenyl, 2-octenyl, 1,3-octadienyl, 2-nonenyl, 1,3-nonadienyl,
2-decenyl, etc.
[0072] The term "alkynyl" as used herein refers to a straight or
branched alkynyl group of 2 to 10 carbon atoms having 1 to 3 triple
bonds. Exemplary alkynyls include, but are not limited to, ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 4-pentynyl, 1-octynyl, 6-methyl-1-heptynyl,
and 2-decynyl.
[0073] The term "hydroxyalkyl" alone or in combination, refers to
an alkyl group as previously defined, wherein one or several
hydrogen atoms, preferably one hydrogen atom has been replaced by a
hydroxyl group. Examples include hydroxymethyl, hydroxyethyl and
2-hydroxyethyl.
[0074] The term "aminoalkyl" as used herein refers to the group
--NRR', where R and R' may independently be hydrogen or
(C.sub.1-C.sub.4)alkyl.
[0075] The term "alkylaminoalkyl" refers to an alkylamino group
linked via an alkyl group (i.e., a group having the general
structure -alkyl-NH-alkyl or -alkyl-N(alkyl)(alkyl)). Such groups
include, but are not limited to, mono- and di-(C.sub.1-C.sub.8
alkyl)aminoC.sub.1-C.sub.8 alkyl, in which each alkyl may be the
same or different.
[0076] The term "dialkylaminoalkyl" refers to alkylamino groups
attached to an alkyl group. Examples include, but are not limited
to, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl,
N,N-dimethylaminopropyl, and the like. The term dialkylaminoalkyl
also includes groups where the bridging alkyl moiety is optionally
substituted.
[0077] The term "haloalkyl" refers to an alkyl group substituted
with one or more halo groups, for example chloromethyl,
2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl,
8-chlorononyl and the like.
[0078] The term "carboxyalkyl" as used herein refers to the
substituent --R'--COOH wherein R' is alkylene; and carbalkoxyalkyl
refers to --R'--COOR wherein R' and R are alkylene and alkyl
respectively. In certain embodiments, alkyl refers to a saturated
straight- or branched-chain hydrocarbyl radical of 1-6 carbon atoms
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,
n-pentyl, 2-methylpentyl, n-hexyl, and so forth. Alkylene is the
same as alkyl except that the group is divalent.
[0079] The term "alkoxyalkyl" refers to an alkylene group
substituted with an alkoxy group. For example, methoxyethyl
[CH.sub.3OCH.sub.2CH.sub.2--] and ethoxymethyl
(CH.sub.3CH.sub.2OCH.sub.2--] are both C.sub.3 alkoxyalkyl
groups.
[0080] The term "carboxy", as used herein, represents a group of
the formula --COOH.
[0081] The term "alkanoylamino" refers to alkyl, alkenyl or alkynyl
groups containing the group --C(O)-- followed by --N(H)--, for
example acetylamino, propanoylamino and butanoylamino and the
like.
[0082] The term "carbonylamino" refers to the group
--NR--CO--CH.sub.2--R', where R and R' may be independently
selected from hydrogen or (C.sub.1-C.sub.4)alkyl.
[0083] The term "carbamoyl" as used herein refers to
--O--C(O)NH.sub.2.
[0084] The term "carbamyl" as used herein refers to a functional
group in which a nitrogen atom is directly bonded to a carbonyl,
i.e., as in --NRC(.dbd.O)R' or --C(.dbd.O)NRR', wherein R and R'
can be hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkoxy, cycloalkyl, aryl, heterocyclo, or heteroaryl.
[0085] The term "heterocyclo" refers to an optionally substituted,
unsaturated, partially saturated, or fully saturated, aromatic or
nonaromatic cyclic group that is a 4 to 7 membered monocyclic, or 7
to 11 membered bicyclic ring system that has at least one
heteroatom in at least one carbon atom-containing ring. The
substituents on the heterocyclo rings may be selected from those
given above for the aryl groups. Each ring of the heterocyclo group
containing a heteroatom may have 1, 2 or 3 heteroatoms selected
from nitrogen atoms, oxygen atoms and sulfur atoms. Plural
heteroatoms in a given heterocyclo ring may be the same or
different. The heterocyclo group may be attached to the 4-pyridinyl
ring at any heteroatom or carbon atom. In one embodiment, two R
groups form a fused ring with the carbons at position 2 and 3 of
the pyridinyl ring, there is formed a 7-quinolin-4-yl moiety.
[0086] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms in space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0087] The term "chiral center" refers to a carbon atom to which
four different groups are attached.
[0088] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposable on its mirror image and hence optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its mirror image rotates the plane of
polarized light in the opposite direction.
[0089] The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
[0090] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule.
[0091] In additional embodiments, the invention provides
pharmaceutical compositions and methods for treating CNS disorders,
including but not limited to neuropsychiatric conditions, such as
depression and anxiety. Suitable forms of the compounds of the
invention for use in biologically active compositions and methods
of the invention include the compounds exemplified herein, as well
as their pharmaceutically acceptable salts, polymorphs, solvates,
hydrates, and prodrugs.
[0092] Within related embodiments, the invention provides methods
for treating CNS disorders responsive to the inhibition of biogenic
amine transporters, in particular, one or more, or any combination
of, the norepinephrine, serotonin and dopamine transporters, in
mammalian subjects. In more detailed embodiments, the invention
provides methods for using the novel compounds disclosed herein for
treating CNS disorders, including a range of neuropsychiatric
disorders, such as depression and anxiety. In various embodiments,
the compositions and methods are formulated, and administered,
effectively as anti-depressants, or as anxiolytic agents.
[0093] In accordance with the invention, compounds disclosed
herein, optionally formulated with additional ingredients in a
pharmaceutically acceptable composition, are administered to
mammalian subjects, for example a human patient, to treat or
prevent one or more symptom(s) of a CNS disorder alleviated by
inhibiting dopamine reuptake, and/or norepinephrine reuptake,
and/or serotonin reuptake. In certain embodiments, "treatment" or
"treating" refers to amelioration of one or more symptom(s) of a
CNS disorder, whereby the symptom(s) is/are alleviated by
inhibiting dopamine and/or norepinephrine and/or serotonin
reuptake. In other embodiments, "treatment" or "treating" refers to
an amelioration of at least one measurable physical parameter
associated with a CNS disorder. In yet another embodiment,
"treatment" or "treating" refers to inhibiting or reducing the
progression or severity of a CNS disorder (or one or more
symptom(s) thereof) alleviated by inhibiting dopamine and/or
norepinephrine and/or serotonin reuptake, e.g., as discerned based
on physical, physiological, and/or psychological parameters. In
additional embodiments, "treatment" or "treating" refers to
delaying the onset of a CNS disorder (or one or more symptom(s)
thereof) alleviated by inhibiting dopamine and/or norepinephrine
and/or serotonin reuptake.
[0094] In certain embodiments, a compound of the present invention
or a pharmaceutically acceptable salt thereof is administered to a
mammalian subject, for example a human patient, as a preventative
or prophylactic treatment against a CNS disorder (or one or more
symptom(s) thereof) alleviated by inhibiting dopamine and/or
norepinephrine and/or serotonin reuptake. As used herein,
"prevention", "preventing", and prophylaxis refers to a reduction
in the risk or likelihood that the subject will acquire a CNS
disorder or one or more symptom(s) thereof, which risk or
likelihood is reduced in the subject by inhibiting dopamine and/or
norepinephrine and/or serotonin reuptake. Alternatively, prevention
and prophylaxis may correlate with a reduced risk of recurrence of
the CNS disorder or symptom(s) thereof in the subject once the
subject has been cured, restored to a normal state, or placed in
remission from the subject CNS disorder. In related embodiments, a
compound or pharmaceutical composition of the invention is
administered as a preventative measure to the subject. Exemplary
subjects amenable to prophylactic treatment in this context may
have a genetic predisposition to a CNS disorder amenable to
treatment by inhibiting dopamine, and/or serotonin, and/or
norepinephrine reuptake, such as a family history of a biochemical
imbalance in the brain, or a non-genetic predisposition to a
disorder alleviated by inhibiting dopamine and/or norepinephrine
and/or serotonin reuptake.
[0095] A compound of the present invention and pharmaceutically
acceptable salts thereof are useful for treating or preventing
endogenous disorders alleviated by inhibiting dopamine and/or
norepinephrine and/or serotonin reuptake. Such disorders include,
but are not limited to, attention-deficit disorder, depression,
anxiety, obesity, Parkinson's disease, tic disorders, and addictive
disorders.
[0096] Disorders alleviated by inhibiting dopamine and/or
norepinephrine and/or serotonin reuptake are not limited to the
specific disorders described herein, and the compositions and
methods of the invention will be understood or readily ascertained
to provide effective treatment agents for treating and/or
preventing a wide range of additional CNS disorders and associated
symptoms. For example, the compounds of the invention will provide
promising candidates for treatment and/or prevention of attention
deficit hyperactivity disorder and related symptoms, as well as
forms and symptoms of alcohol abuse, drug abuse, obsessive
compulsive behaviors, learning disorders, reading problems,
gambling addiction, manic symptoms, phobias, panic attacks,
opposition defiant behavior, conduct disorder, academic problems in
school, smoking, abnormal sexual behaviors, schizoid behaviors,
somatization, depression, sleep disorders, general anxiety,
stuttering, and tics disorders (see for example, U.S. Pat. No.
6,132,724). These and other symptoms, regardless of the underlying
CNS disorder, are each prospective therapeutic targets for the
novel compositions and methods of the invention that mediate
therapeutic benefits by inhibiting dopamine and/or norepinephrine
and/or serotonin reuptake. Additional CNS disorders contemplated
for treatment employing the compositions and methods of the
invention are described, for example, in the Quick Reference to the
Diagnostic Criteria From DSM-IV (Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition), The American Psychiatric
Association, Washington, D.C., 1994. These target disorders for
treatment and/or prevention according to the invention, include,
but are not limited to, Attention-Deficit/Hyperactivity Disorder,
Predominately Inattentive Type; Attention-Deficit/Hyperactivity
Disorder, Predominately Hyperactivity-Impulsive Type;
Attention-Deficit/Hyperactivity Disorder, Combined Type;
Attention-Deficit/Hyperactivity Disorder not otherwise specified
(NOS); Conduct Disorder; Oppositional Defiant Disorder; and
Disruptive Behavior Disorder not otherwise specified (NOS).
[0097] Depressive disorders amenable for treatment and/or
prevention according to the invention include, but are not limited
to, Major Depressive Disorder, Recurrent; Dysthymic Disorder;
Depressive Disorder not otherwise specified (NOS); and Major
Depressive Disorder, Single Episode.
[0098] Addictive disorders amenable for treatment and/or prevention
employing the methods and compositions of the invention include,
but are not limited to, eating disorders, impulse control
disorders, alcohol-related disorders, nicotine-related disorders,
amphetamine-related disorders, cannabis-related disorders,
cocaine-related disorders, hallucinogen use disorders,
inhalant-related disorders, and opioid-related disorders, all of
which are further sub-classified as listed below.
[0099] Eating disorders include, but are not limited to, Bulimia
Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; and Eating
Disorder not otherwise specified (NOS).
[0100] Impulse control disorders include, but are not limited to,
Intermittent Explosive Disorder, Kleptomania, Pyromania,
Pathological Gambling, Trichotillomania, and Impulse Control
Disorder not otherwise specified (NOS).
[0101] Alcohol-related disorders include, but are not limited to,
Alcohol-Induced Psychotic Disorder, with delusions; Alcohol Abuse;
Alcohol Intoxication; Alcohol Withdrawal; Alcohol Intoxication
Delirium; Alcohol Withdrawal Delirium; Alcohol-Induced Persisting
Dementia; Alcohol-Induced Persisting Amnestic Disorder; Alcohol
Dependence; Alcohol-Induced Psychotic Disorder, with
hallucinations; Alcohol-Induced Mood Disorder; Alcohol-Induced
Anxiety Disorder; Alcohol-Induced Sexual Dysfunction;
Alcohol-Induced Sleep Disorders; Alcohol-Related Disorders not
otherwise specified (NOS); Alcohol Intoxication; and Alcohol
Withdrawal.
[0102] Nicotine-related disorders include, but are not limited to,
Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related
Disorder not otherwise specified (NOS).
[0103] Amphetamine-related disorders include, but are not limited
to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine
Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication
Delirium, Amphetamine-Induced Psychotic Disorder with delusions,
Amphetamine-Induced Psychotic Disorders with hallucinations,
Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety
Disorder, Amphetamine-Induced Sexual Dysfunction,
Amphetamine-Induced Sleep Disorder, Amphetamine Related Disorder
not otherwise specified (NOS), Amphetamine Intoxication, and
Amphetamine Withdrawal.
[0104] Cannabis-related disorders include, but are not limited to,
Cannabis Dependence; Cannabis Abuse; Cannabis Intoxication;
Cannabis Intoxication Delirium; Cannabis-Induced Psychotic
Disorder, with delusions; Cannabis-Induced Psychotic Disorder with
hallucinations; Cannabis-Induced Anxiety Disorder; Cannabis Related
Disorder not otherwise specified (NOS); and Cannabis
Intoxication.
[0105] Cocaine-related disorders include, but are not limited to,
Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine
Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced
Psychotic Disorder with delusions, Cocaine-Induced Psychotic
Disorders with hallucinations, Cocaine-Induced Mood Disorder,
Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual
Dysfunction, Cocaine-Induced Sleep Disorder, Cocaine Related
Disorder not, otherwise specified (NOS), Cocaine Intoxication, and
Cocaine Withdrawal.
[0106] Hallucinogen-use disorders include, but are not limited to,
Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen
Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication
Delirium, Hallucinogen-Induced Psychotic Disorder with delusions,
Hallucinogen-Induced Psychotic Disorders with hallucinations,
Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety
Disorder, Hallucinogen-Induced Sexual Dysfunction,
Hallucinogen-Induced Sleep Disorder, Hallucinogen Related Disorder
not otherwise specified (NOS), Hallucinogen Intoxication, and
Hallucinogen Persisting Perception Disorder (Flashbacks).
[0107] Inhalant-related disorders include, but are not limited to,
Inhalant Dependence; Inhalant Abuse; Inhalant Intoxication;
Inhalant Intoxication Delirium; Inhalant-Induced Psychotic
Disorder, with delusions; Inhalant-Induced Psychotic Disorder with
hallucinations; Inhalant-Induced Anxiety Disorder; Inhalant Related
Disorder not otherwise specified (NOS); and Inhalant
Intoxication.
[0108] Opioid-related disorders include, but are not limited to,
Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid
Intoxication Delirium, Opioid-Induced Psychotic Disorder with
delusions, Opioid-Induced Psychotic Disorder with hallucinations,
Opioid-Induced Anxiety Disorder, Opioid Related Disorder not
otherwise specified (NOS), Opioid Intoxication, and Opioid
Withdrawal.
[0109] Tic disorders include, but are not limited to, Tourette's
Disorder, Chronic Motor or Vocal Tic Disorder, Transient Tic
Disorder, Tic Disorder not otherwise specified (NOS), Stuttering,
Autistic Disorder, and Somatization Disorder.
[0110] By virtue of their multiple reuptake inhibitory activity,
the novel compounds of the present invention are thus useful in a
wide range of veterinary and human medical applications, in
particular for treating and/or preventing a wide array of CNS
disorders and/or associated symptom(s) alleviated by inhibiting
dopamine and/or norepinephrine and/or serotonin reuptake.
[0111] Within additional aspects of the invention, combinatorial
formulations and coordinate administration methods are provided
which employ an effective amount of a compound of the invention (or
a pharmaceutically effective enantiomer, salt, solvate, hydrate,
polymorph, or prodrug thereof), and one or more additional active
agent(s) that is/are combinatorially formulated or coordinately
administered with the compound of the invention-yielding a
combinatorial formulation or coordinate administration method that
is effective to modulate, alleviate, treat or prevent a targeted
CNS disorder, or one or more symptom(s) thereof, in a mammalian
subject. Exemplary combinatorial formulations and coordinate
treatment methods in this context a therapeutic compound of the
invention in combination with one or more additional or adjunctive
treatment agents or methods for treating the targeted CNS disorder
or symptom(s), for example one or more antidepressant or anxiolytic
agent(s) and/or therapeutic method(s).
[0112] In related embodiments of the invention, the compounds
disclosed herein can be used in combination therapy with at least
one other therapeutic agent or method. In this context, compounds
of the invention can be administered concurrently or sequentially
with administration of a second therapeutic agent, for example a
second agent that acts to treat or prevent the same, or different,
CNS disorder or symptom(s) for which the compound of the invention
is administered. The compound of the invention and the second
therapeutic agent can be combined in a single composition or
adminstered in different compositions. The second therapeutic agent
may also be effective for treating and/or preventing a CNS disorder
or associated symptom(s) by inhibiting dopamine and/or
norepinephrine and/or serotonin reuptake. The coordinate
administration may be done simultaneously or sequentially in either
order, and there may be a time period while only one or both (or
all) active therapeutic agents, individually and/or collectively,
exert their biological activities and therapeutic effects. A
distinguishing aspect of all such coordinate treatment methods is
that the compound of the invention exerts at least some detectable
therapeutic activity toward alleviating or preventing the targeted
CNS disorder or symptom(s), as described herein, and/or elicit a
favorable clinical response, which may or may not be in conjunction
with a secondary clinical response provided by the secondary
therapeutic agent. Often, the coordinate administration of a
compound of the invention with a secondary therapeutic agent as
contemplated herein will yield an enhanced therapeutic response
beyond the therapeutic response elicited by either or both the
compound of the invention and/or secondary therapeutic agent
alone.
[0113] As many of the CNS disorders and symptoms treatable or
preventable using compounds of the present invention are chronic,
in one embodiment combination therapy involves alternating between
administering a compound of the present invention and a second
therapeutic agent (i.e., alternating therapy regimens between the
two drugs, e.g., at one week, one month, three month, six month, or
one year intervals). Alternating drug regimens in this context will
often reduce or even eliminate adverse side effects, such as
toxicity, that may attend long-term administration of one or both
drugs alone.
[0114] In certain embodiments of combinatorial formulations and
coordinate treatment methods of the invention, the secondary
therapeutic is a norepinephrine reuptake inhibitor. Examples of
norepinephrine reuptake inhibitors useful in this context include
tertiary amine tricyclics such as amitriptyline, clomipramine,
doxepin, imipramine, (+)-trimipramine, and secondary amine
tricyclics including amoxapine, atomoxetine, desipramine,
maprotiline, nortriptyline, and protriptyline.
[0115] In certain embodiments of combinatorial formulations and
coordinate treatment methods of the invention, the secondary
therapeutic is a serotonin reuptake inhibitor. Examples of other
serotonin reuptake inhibitors useful in this context include
citalopram, fluoxetine, fluvoxamine, (-)-paroxetine, sertraline,
and venlafaxine.
[0116] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-attention-deficit-disorder treatment
agent. Examples of useful anti-attention-deficit-disorder agents
for use in these embodiments include, but are not limited to,
methylphenidate; dextroamphetamine; tricyclic antidepressants, such
as imipramine, desipramine, and nortriptyline; and
psychostimulants, such as pemoline and deanol.
[0117] In additional embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-addictive-disorder agent. Examples of
useful anti-addictive-disorder agents include, but are not limited
to, tricyclic antidepressants; glutamate antagonists, such as
ketamine HCl, dextromethorphan, dextrorphan tartrate and
dizocilpine (MK801); degrading enzymes, such as anesthetics and
aspartate antagonists; GABA agonists, such as baclofen and muscimol
HBr; reuptake blockers; degrading enzyme blockers; glutamate
agonists, such as D-cycloserine, carboxyphenylglycine, L-glutamic
acid, and cis-piperidine-2,3-dicarboxylic acid; aspartate agonists;
GABA antagonists such as gabazine (SR-95531), saclofen,
bicuculline, picrotoxin, and (+) apomorphine HCl; and dopamine
antagonists, such as spiperone HCl, haloperidol, and (-)
sulpiride.
[0118] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-alcohol agent. Examples of useful
anti-alcohol agents include, but are not limited to, disulfiram and
naltrexone.
[0119] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-nicotine agent. Examples of useful
anti-nicotine agents include, but are not limited to,
clonidine.
[0120] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-opiate agent. Examples of useful
anti-opiate agents include, but are not limited to, methadone,
clonidine, lofexidine, levomethadyl acetate HCl, naltrexone, and
buprenorphine.
[0121] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is anti-cocaine agent. Examples of useful
anti-cocaine agents include, but are not limited to, desipramine,
amantadine, fluoxidine, and buprenorphine.
[0122] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-lysergic acid diethylamide
("anti-LSD") agent. Examples of useful anti-LSD agents include, but
are not limited to, diazepam.
[0123] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-phencyclidine ("anti-PCP") agent.
Examples of useful anti-PCP agents include, but are not limited to,
haloperidol.
[0124] In other embodiments of combinatorial formulations and
coordinate treatment methods provided herein, the secondary
therapeutic agent is an appetite suppressant. Examples of useful
appetite suppressants include, but are not limited to,
fenfluramine, phenylpropanolamine, and mazindol.
[0125] In yet additional embodiments of combinatorial formulations
and coordinate treatment methods provided herein, the secondary
therapeutic agent is an anti-Parkinson's-disease agent. Examples of
useful anti-Parkinson's-disease agents include, but are not limited
to dopamine precursors, such as levodopa, L-phenylalanine, and
L-tyrosine; neuroprotective agents; dopamine agonists; dopamine
reuptake inhibitors; anticholinergics such as amantadine and
memantine; and 1,3,5-trisubstituted adamantanes, such as
1-amino-3,5-dimethyl-adamantane (See, U.S. Pat. No. 4,122,193).
[0126] Mammalian subjects amenable for treatment according to the
methods of the invention include, but are not limited to, human and
other mammalian subjects suffering from a CNS disorder that is
amenable to treatment or beneficial intervention using an active
agent capable of inhibiting reuptake of norepinephrine, serotonin,
and/or dopamine by interfering with the CNS conditions that are
subject to treatment according to the methods and compositions of
the invention include depression, as well as a variety of other
neuropsychiatric conditions and disorders. Other disorders for
which the compounds of the present invention may be useful include
irritable bowel syndrome; inflammatory bowel disease; bulimia;
anorexia; obesity and related eating disorders; urinary tract
disorders, such as stress urinary incontinence; addictive disorders
(including addiction to nicotine, stimulants, alcohol, and
opiates); degenerative diseases, including Alzheimers disease,
amyotrophic lateral sclerosis, and Parkinson's disease; and pyretic
conditions (including fevers, and post- and peri-menopausal hot
flashes). For each of the foregoing disorders, combinatorial
formulations and coordinate treatment methods are provided within
the scope of the invention comprising compounds of the invention
coordinately administered or combinatorially formulated with a
second therapeutic agent or method known for treating the subject
disorder, and/or one or more symptom(s) associated therewith.
[0127] Subjects are effectively treated prophylactically and/or
therapeutically by administering to the subject an effective amount
of a compound of the invention, which is effective to treat,
alleviate, prevent or eliminate a targeted CNS disorder in the
subject, and/or one or more symptom(s) associated therewith, for
example depression.
[0128] Administration of an effective amount of a compound of the
present invention to a mammalian subject presenting with one or
more of the foregoing CNS disorders and/or symptom(s) will
detectably decrease, eliminate, or prevent the targeted CNS
disorder and/or associated symptom(s). In certain embodiments,
administration of a compound of the present invention to a suitable
test subject will yield a reduction in the targeted CNS disorder,
or one or more targeted symptom(s) associated therewith, such as
depression, by at least 10%, 20%, 30%, 50% or greater, up to a
75-90%, or 95% or greater, reduction in the one or more target
symptom(s), compared to placebo-treated or other suitable control
subjects. Comparable levels of efficacy are contemplated for the
entire range of CNS disorders described herein, including all
contemplated neurological and psychiatric disorders, as well as all
other CNS conditions and symptoms identified herein for treatment
or prevention using the compositions and methods of the
invention.
[0129] The active compounds of the invention may be optionally
formulated with a pharmaceutically acceptable carrier and/or
various excipients, vehicles, stabilizers, buffers, preservatives,
etc. An "effective amount," "therapeutic amount," "therapeutically
effective amount," or "effective dose" is an effective amount or
dose of an active compound as described herein sufficient to elicit
a desired pharmacological or therapeutic effect in a mammalian
subject--typically resulting in a measurable reduction in an
occurrence, frequency, or severity of one or more symptom(s)
associated with or caused by a CNS disorder, including a
neurological or psychological disease, condition, or disorder in
the subject. In certain embodiments, when a compound of the
invention is administered to treat a CNS disorder, for example
depression, an effective amount of the compound will be an amount
sufficient in vivo to delay or eliminate onset of symptoms of the
targeted condition or disorder. Therapeutic efficacy can
alternatively be demonstrated by a decrease in the frequency or
severity of symptoms associated with the treated condition or
disorder, or by altering the nature, recurrence, or duration of
symptoms associated with the treated condition or disorder.
Therapeutically effective amounts, and dosage regimens, of the
compositions of the invention, including pharmaceutically effective
salts, solvates, hydrates, polymorphs or prodrugs thereof, will be
readily determinable by those of ordinary skill in the art, often
based on routine clinical or patient-specific factors.
[0130] Suitable routes of administration for a compound of the
present invention include, but are not limited to, oral, buccal,
nasal, aerosol, topical, transdermal, mucosal, injectable, slow
release, controlled release, iontophoresis, sonophoresis, and other
conventional delivery routes, devices and methods. Injectable
delivery methods are also contemplated, including but not limited
to, intravenous, intramuscular, intraperitoneal, intraspinal,
intrathecal, intracerebroventricular, intraarterial, and
subcutaneous injection.
[0131] Suitable effective unit dosage amounts of
1-aryl-3-azabicyclo[3.1.0] hexanes of the present invention for
mammalian subjects may range from about 1 to 1200 mg, 50 to 1000
mg, 75 to 900 mg, 100 to 800 mg, or 150 to 600 mg. In certain
embodiments, the effective unit dosage will be selected within
narrower ranges of, for example, 10 to 25 mg, 30 to 50 mg, 75 to
100 mg, 100 to 150 mg, 150 to 250 mg or 250 to 500 mg. These and
other effective unit dosage amounts may be administered in a single
dose, or in the form of multiple daily, weekly or monthly doses,
for example in a dosing regimen comprising from 1 to 5, or 2-3,
doses administered per day, per week, or per month. In exemplary
embodiments, dosages of 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100
to 200 (anticipated dosage strength) mg, or 250 to 500 mg, are
administered one, two, three, or four times per day. In more
detailed embodiments, dosages of 50-75 mg, 100-150 mg, 150-200 mg,
250-400 mg, or 400-600 mg are administered once, twice daily or
three times daily. In alternate embodiments, dosages are calculated
based on body weight, and may be administered, for example, in
amounts from about 0.5 mg/kg to about 30 mg/kg per day, 1 mg/kg to
about 15 mg/kg per day, 1 mg/kg to about 10 mg/kg per day, 2 mg/kg
to about 20 mg/kg per day, 2 mg/kg to about 10 mg/kg per day or 3
mg/kg to about 15 mg/kg per day.
[0132] The amount, timing and mode of delivery of compositions of
the invention comprising an effective amount of a compound of the
present invention will be routinely adjusted on an individual
basis, depending on such factors as weight, age, gender, and
condition of the individual, the acuteness of the targeted CNS
disorder and/or related symptoms, whether the administration is
prophylactic or therapeutic, and on the basis of other factors
known to effect drug delivery, absorption, pharmacokinetics,
including half-life, and efficacy. An effective dose or multi-dose
treatment regimen for the compounds of the invention will
ordinarily be selected to approximate a minimal dosing regimen that
is necessary and sufficient to substantially prevent or alleviate
one or more symptom(s) of a neurological or psychiatric condition
in the subject, as described herein. Thus, following administration
of a compound of the present invention, test subjects will exhibit
a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95%
or greater, reduction, in one or more symptoms associated with a
targeted CNS disorder, including any targeted neuropsychiatric
disorder, such as depression, compared to placebo-treated or other
suitable control subjects.
[0133] Within additional aspects of the invention, combinatorial
formulations and coordinate administration methods are provided
which employ an effective amount of a compound of the present
invention--yielding an effective formulation or method to alleviate
or prevent one or more symptom(s) of a CNS disorder in a mammalian
subject.
[0134] Pharmaceutical dosage forms of a compound of the present
invention may optionally include excipients recognized in the art
of pharmaceutical compounding as being suitable for the preparation
of dosage units as discussed above. Such excipients include,
without intended limitation, binders, fillers, lubricants,
emulsifiers, suspending agents, sweeteners, flavorings,
preservatives, buffers, wetting agents, disintegrants, effervescent
agents and other conventional excipients and additives.
[0135] The compositions of the invention for treating CNS
disorders, including depression, can thus include any one or
combination of the following: a pharmaceutically acceptable carrier
or excipient; other medicinal agent(s); pharmaceutical agent(s);
adjuvants; buffers; preservatives; diluents; and various other
pharmaceutical additives and agents known to those skilled in the
art. These additional formulation additives and agents will often
be biologically inactive and can be administered to patients
without causing deleterious side effects or interactions with the
active agent.
[0136] If desired, a compound of the present invention can be
administered in a controlled release form by use of a slow release
carrier, such as a hydrophilic, slow release polymer. Exemplary
controlled release agents in this context include, but are not
limited to, hydroxypropyl methyl cellulose, having a viscosity in
the range of about 100 cps to about 100,000 cps.
[0137] A compound of the present invention will often be formulated
and administered in an oral dosage form, optionally in combination
with a carrier or other additive(s). Suitable carriers common to
pharmaceutical formulation technology include, but are not limited
to, microcrystalline cellulose, lactose, sucrose, fructose, glucose
dextrose, or other sugars, di-basic calcium phosphate, calcium
sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin,
mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugar
alcohols, dry starch, dextrin, maltodextrin or other
polysaccharides, inositol, or mixtures thereof. Exemplary unit oral
dosage forms for use in this invention include tablets, which may
be prepared by any conventional method of preparing pharmaceutical
oral unit dosage forms can be utilized in preparing oral unit
dosage forms. Oral unit dosage forms, such as tablets, may contain
one or more conventional additional formulation ingredients,
including, but are not limited to, release modifying agents,
glidants, compression aides, disintegrants, lubricants, binders,
flavors, flavor enhancers, sweeteners and/or preservatives.
Suitable lubricants include stearic acid, magnesium stearate, talc,
calcium stearate, hydrogenated vegetable oils, sodium benzoate,
leucine carbowax, magnesium lauryl sulfate, colloidal silicon
dioxide and glyceryl monostearate. Suitable glidants include
colloidal silica, fumed silicon dioxide, silica, talc, fumed
silica, gypsum and glyceryl monostearate. Substances which may be
used for coating include hydroxypropyl cellulose, titanium oxide,
talc, sweeteners and colorants. The aforementioned effervescent
agents and disintegrants are useful in the formulation of rapidly
disintegrating tablets known to those skilled in the art. These
typically disintegrate in the mouth in less than one minute, and
preferably in less than thirty seconds. By effervescent agent is
meant a couple, typically an organic acid and a carbonate or
bicarbonate. Such rapidly acting dosage forms would be useful, for
example, in the prevention or treatment of acute attacks of panic
disorder.
[0138] The compounds and compositions of the invention can be
prepared and administered in any of a variety of inhalation or
nasal delivery forms known in the art. Devices capable of
depositing aerosolized formulations of a compound of the present
invention in the sinus cavity or pulmonary alveoli of a patient
include metered dose inhalers, nebulizers, dry powder generators,
sprayers, and the like. Pulmonary delivery to the lungs for rapid
transit across the alveolar epithelium into the blood stream may be
particularly useful in treating impending episodes of seizures or
panic disorder. Methods and compositions suitable for pulmonary
delivery of drugs for systemic effect are well known in the art.
Suitable formulations, wherein the carrier is a liquid, for
administration, as for example, a nasal spray or as nasal drops,
may include aqueous or oily solutions of a compound of the present
invention, and any additional active or inactive ingredient(s).
[0139] Intranasal delivery permits the passage of active compounds
of the invention into the blood stream directly after administering
an effective amount of the compound to the nose, without requiring
the product to be deposited in the lung. In addition, intranasal
delivery can achieve direct, or enhanced, delivery of the active
compound to the CNS. In these and other embodiments, intranasal
administration of the compounds of the invention may be
advantageous for treating a variety of CNS disorders, including
depression, by providing for rapid absorption and CNS delivery.
[0140] For intranasal and pulmonary administration, a liquid
aerosol formulation will often contain an active compound of the
invention combined with a dispersing agent and/or a physiologically
acceptable diluent. Alternative, dry powder aerosol formulations
may contain a finely divided solid form of the subject compound and
a dispersing agent allowing for the ready dispersal of the dry
powder particles. With either liquid or dry powder aerosol
formulations, the formulation must be aerosolized into small,
liquid or solid particles in order to ensure that the aerosolized
dose reaches the mucous membranes of the nasal passages or the
lung. The term "aerosol particle" is used herein to describe a
liquid or solid particle suitable of a sufficiently small particle
diameter, e.g., in a range of from about 2-5 microns, for nasal or
pulmonary distribution to targeted mucous or alveolar membranes.
Other considerations include the construction of the delivery
device, additional components in the formulation, and particle
characteristics. These aspects of nasal or pulmonary administration
of drugs are well known in the art, and manipulation of
formulations, aerosolization means, and construction of delivery
devices, is within the level of ordinary skill in the art.
[0141] Yet additional compositions and methods of the invention are
provided for topical administration of a compound of the present
invention for treating CNS disorders, including depression. Topical
compositions may comprise a compound of the present invention and
any other active or inactive component(s) incorporated in a
dermatological or mucosal acceptable carrier, including in the form
of aerosol sprays, powders, dermal patches, sticks, granules,
creams, pastes, gels, lotions, syrups, ointments, impregnated
sponges, cotton applicators, or as a solution or suspension in an
aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or
water-in-oil liquid emulsion. These topical compositions may
comprise a compound of the present invention dissolved or dispersed
in a portion of a water or other solvent or liquid to be
incorporated in the topical composition or delivery device. It can
be readily appreciated that the transdermal route of administration
may be enhanced by the use of a dermal penetration enhancer known
to those skilled in the art. Formulations suitable for such dosage
forms incorporate excipients commonly utilized therein,
particularly means, e.g. structure or matrix, for sustaining the
absorption of the drug over an extended period of time, for example
24 hours. A once-daily transdermal patch is particularly useful for
a patient suffering from generalized anxiety disorder.
[0142] Yet additional formulations of a compound of the present
invention are provided for parenteral administration, including
aqueous and non-aqueous sterile injection solutions which may
optionally contain anti-oxidants, buffers, bacteriostats and/or
solutes which render the formulation isotonic with the blood of the
mammalian subject; aqueous and non-aqueous sterile suspensions
which may include suspending agents and/or thickening agents;
dispersions; and emulsions. The formulations may be presented in
unit-dose or multi-dose containers. Pharmaceutically acceptable
formulations and ingredients will typically be sterile or readily
sterilizable, biologically inert, and easily administered.
Parenteral preparations typically contain buffering agents and
preservatives, and may be lyophilized for reconstitution at the
time of administration.
[0143] Parental formulations may also include polymers for extended
release following parenteral administration. Such polymeric
materials are well known to those of ordinary skill in the
pharmaceutical compounding arts. Extemporaneous injection
solutions, emulsions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily
dose or unit, daily sub-dose, as described herein above, or an
appropriate fraction thereof, of the active ingredient(s).
[0144] In more detailed embodiments, a compound of the present
invention may be: encapsulated for delivery in microcapsules,
microparticles, or microspheres, prepared, for example, by
coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin-microcapsules and
poly(methylmethacylate) microcapsules, respectively, in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions.
[0145] The invention also provides pharmaceutical packs or kits
comprising one or more containers holding a compound of the present
invention, or any composition comprising a compound of the present
invention as described herein, including pharmaceutically
acceptable salts and other forms of a compound of the present
invention, in a pharmaceutically acceptable, stable form.
Optionally packaged with these packs and kits can be a notice,
e.g., in a form prescribed by a governmental agency regulating
pharmaceuticals or biological products, reflecting approval by the
agency of the manufacture, use and/or sale of the product contained
in the pack or kit for human administration (optionally specifying
one or more approved treatment indications as described
herein).
[0146] The following examples illustrate certain embodiments of the
present invention, and are not to be construed as limiting the
present disclosure.
Example I
Synthetic Methods for Preparing Substituted
1-aryl-3-azabicyclo[3.1.0]hexanes
[0147] Although many of the novel 1-aryl-3-azabicyclo[3.1.0]
hexanes of the invention may be prepared according to methods known
to those skilled in the art, they may also be generated, for
example, according to the exemplary reaction schemes set forth
below. While these novel schemes employ various intermediates and
starting materials, it is to be understood that the illustrated
processes are also applicable to compounds having alternative
structure, substituent patterns, or stereochemistry depicted in
these schemes.
[0148] With regard to the following synthetic schemes, and as
otherwise used herein unless specified differently, Ar is a phenyl
group substituted with two substituents independently selected from
halogen, C.sub.1-3 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
halo(C.sub.1-3)alkyl, cyano, hydroxy, C.sub.3-5 cycloalkyl,
C.sub.1-3 alkoxy, C.sub.1-3 alkoxy(C.sub.1-3)alkyl,
carboxy(C.sub.1-3)alkyl, C.sub.1-3 alkanoyl, halo(C.sub.1-3)alkoxy,
nitro, amino, C.sub.1-3 alkylamino, and di(C.sub.1-3)alkylamino, an
unsubstituted napthyl group or a napthyl group having 1-4
substituents independently selected from halogen, C.sub.1-3 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, halo(C.sub.1-3)alkyl, cyano,
hydroxy, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxy(C.sub.1-3)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, halo(C.sub.1-3)alkoxy, nitro, amino, C.sub.1-3
alkylamino, and di(C.sub.1-3)alkylamino, and R and R.sub.1 are
selected from, for example, hydrogen, C.sub.1-6 alkyl,
halo(C.sub.1-6)alkyl, C.sub.3-9 cycloalkyl, C.sub.1-5
alkoxy(C.sub.1-6)alkyl, carboxy(C.sub.1-3)alkyl, C.sub.1-3
alkanoyl, carbamate, halo(C.sub.1-3)alkoxy(C.sub.1-6)alkyl,
C.sub.1-3 alkylamino(C.sub.1-6)alkyl, and
di(C.sub.1-3)alkylamino(C.sub.1-6)alkyl, cyano(C.sub.1-6)alkyl,
methyl, ethyl, trifluoromethyl, trifluoroethyl and
2-methoxyethyl.
[0149] Reaction Scheme 1 below generally sets forth an exemplary
process for preparing 1-aryl-3-azabicyclo[3.1.0] hexane analogs
from the corresponding 2-bromo-2-arylacetate or
2-chloro-2-arylacetate. The bromo or chloro acetate react with
acrylonitrile to provide the methyl
2-cyano-1-arylcyclopropanecarboxylate, which is then reduced to the
amino alcohol by reducing agents such as lithium aluminum hydride
(LAH) or sodium aluminum hydride (SAH) or NaBH.sub.4 with
ZnCl.sub.2. Cyclization of the amino alcohol with SOCl.sub.2 or
POCl.sub.3 will provide the 1-aryl-3-azabicyclo[3.1.0]hexane. The
cyclization of substituted 4-aminobutan-1-ol by SOCl.sub.2 or
POCl.sub.3 into the pyrrolidine ring system was reported by
Armarego et al., J. Chem. Soc. [Section C: Organic] 19:3222-9,
(1971), and in Szalecki et al., patent publication PL 120095 B2,
CAN 99:158251. Oxalyl chloride, phosphorous tribromide,
triphenylphosphorous dibromide and oxalyl bromide may be used for
the same purpose. The methyl 2-bromo-2-arylacetate or methyl
2-chloro-2-arylacetate may be synthesized from substituted
benzoylaldehyde or methyl-2-arylacetate as shown in Reaction Scheme
1A.
##STR00123##
##STR00124##
[0150] Reaction Scheme 2 below illustrates another exemplary
process for transforming methyl
2-cyano-1-arylcyclopropanecarboxylate to a desired compound or
intermediate of the invention. Hydrolysis of the cyano ester
provides the potassium salt which can then be converted into the
cyano acid. Reduction and cyclization of the
2-cyano-1-arylcyclopropanecarboxylic acid with LAH or
LiAlH(OMe).sub.3 according to the procedure outlined in Tetrahedron
45:3683 (1989), will generate 1-aryl-3-azabicyclo[3.1.0]hexane. In
addition, the cyano-1-arylcyclopropanecarboxylic acid can be
hydrogenated and cyclized into an amide, which is then reduced to
1-aryl-3-azabicyclo[3.1.0]hexane.
##STR00125##
[0151] Reaction Scheme 3 below discloses an alternative exemplary
process for converting the methyl
2-cyano-1-arylcyclopropanecarboxylate to a desired compound or
intermediate of the invention. The methyl
2-cyano-1-arylcyclopropanecarboxylate is reduced and cyclized into
1-aryl-3-aza-bicyclo[3.1.0]hexan-2-one, which is then reduced to
1-aryl-3-azabicyclo[3.1.0]hexane [Marazzo, A. et al., Arkivoc
5:156-169, (2004)].
##STR00126##
[0152] Reaction Scheme 4 below provides another exemplary process
to prepare 1-aryl-3-azabicyclo[3.1.0] hexane analogs. Reaction of
2-arylacetonitrile with (.+-.)-epichlorohydrin gives approximately
a 65% yield of 2-(hydroxymethyl)-1-arylcyclopropanecarbonitrile
(85% cis) with the trans isomer as one of the by-products [Cabadio
et al., Fr. Bollettino Chimico Farmaceutico 117:331-42 (1978);
Mouzin et al., Synthesis 4:304-305 (1978)]. The methyl
2-cyano-1-arylcyclopropanecarboxylate can then be reduced into the
amino alcohol by a reducing agent such as LAH, SAH or NaBH.sub.4
with ZnCl.sub.2 or by catalytic hydrogenation. Cyclization of the
amino alcohol with SOCl.sub.2 or POCl.sub.3 provides the
1-aryl-3-azabicyclo[3.1.0]hexane. The cyclization of substituted
4-aminobutan-1-ol by SOCl.sub.2 or POCl.sub.3 into the pyrrolidine
ring system has been reported previously [Armarego et al., J. Chem.
Soc. [Section C: Organic] 19:3222-9 (1971); patent publication PL
120095 B2, CAN 99:158251).
##STR00127##
[0153] Reaction Scheme 5 provides an exemplary process for
synthesizing the (1R,5S)-(+)-1-aryl-3-azabicyclo[3.1.0]hexanes.
Using (S)-(+)-epichlorohydrin as a starting material in the same
process described in Scheme 4 will ensure a final product with 1-R
chirality [Cabadio, S. et al., Fr. Bollettino Chimico Farmaceutico
117:331-42 (1978)].
##STR00128##
[0154] Reaction Scheme 6 provides an exemplary process to prepare
the (1S,5R)-(-)-1-aryl-3-azabicyclo[3.1.0]hexanes. Using
(R)-(-)-epichlorohydrin as a starting material in the same process
described in Scheme 4 will ensure a final product with 1-S
chirality [Cabadio, S. et al., Fr. Bollettino Chimico Farmaceutico
117:331-42 (1978)]
##STR00129##
[0155] Reaction Scheme 7 provides an alternative exemplary process
for transforming the
2-(hydroxymethyl)-1-arylcyclopropanecarbonitrile to a desired
compound or intermediate of the invention via an oxidation and
cyclization reaction. Utilizing chiral starting materials
(+)-epichlorohydrin or (-)-epichlorohydrin will lead to the
corresponding (+)- or (-)-enantiomers and corresponding chiral
analogs through the same reaction sequences.
##STR00130##
[0156] Reaction Scheme 8 provides an exemplary process for
transforming the epichlorohydrin to a desired compound or
intermediate of the invention via a replacement and cyclization
reaction. The reaction of methyl 2-arylacetate with epichlorohydrin
gives methyl 2-(hydroxymethyl)-1-arylcyclopropanecarboxylate with
the desired cis isomer as the major product. The alcohol is
converted into an OR.sub.3 group such as --O-mesylate, --O--
tosylate, --O-nosylate, --O-brosylate,
--O-trifluoromethanesulfonate. Then OR.sub.3 is replaced by a
primary amine NH.sub.2R.sub.4, where R.sub.4 is a nitrogen
protection group such as a 3,4-dimethoxy-benzyl group or other
known protection group. Nitrogen protecting groups are well known
to those skilled in the art, see for example, "Nitrogen Protecting
Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y.,
1981, Chapter 7; "Nitrogen Protecting Groups in Organic Chemistry",
Plenum Press, New York, N.Y., 1973, Chapter 2; T. W. Green and P.
G. M. Wuts in "Protective Groups in Organic Chemistry", 3rd
edition, John Wiley & Sons, Inc. New York, N.Y., 1999. When the
nitrogen protecting group is no longer needed, it may be removed by
methods well known in the art. This replacement reaction is
followed by a cyclization reaction which provides the amide, which
is then reduced into an amine by a reducing agent such as LAH.
Finally the protection group is removed to yield the
1-aryl-3-azabicyclo[3.1.0]hexane analogs. Utilizing chiral
(S)-(+)-epichlorohydrin as a starting material leads to the
(1R,5S)-(+)-1-aryl-3-azabicyclo[3.1.0]hexane analogs with the same
reaction sequence. Similarly, the (R)-(-)-epichlorohydrin will lead
to the (1S,5R)-(-)-1-aryl-3-azabicyclo[3.1.0]hexane analogs.
##STR00131##
[0157] Reaction Scheme 9 provides an exemplary process for
transforming the diol to a desired compound or intermediate of the
invention. Reduction of the diester provides the diol which is then
converted into an OR.sub.3 group such as --O-mesylate, --O--
tosylate, --O-nosylate, --O-brosylate,
--O-trifluoromethanesulfonate. Then OR.sub.3 is replaced by a
primary amine NH.sub.2R.sub.6, where R.sub.6 is a nitrogen
protection group such as a 3,4-dimethoxy-benzyl group or other
protection groups known in the art (e.g., allyl amine, tert-butyl
amine). When the nitrogen protecting group is no longer needed, it
may be removed by methods known to those skilled in the art.
##STR00132##
[0158] Reaction Scheme 10 provides an exemplary process for
resolving the racemic 1-aryl-3-aza-bicyclo[3.1.0]hexane to
enantiomers. The resolution of amines through tartaric salts is
generally known to those skilled in the art. For example, using
O,O-Dibenzoyl-2R,3R-Tartaric Acid (made by acylating L(+)-tartaric
acid with benzoyl chloride) in dichloroethane/methanol/water,
racemic methamphetamine can be resolved in 80-95% yield, with an
optical purity of 85-98% [Synthetic Communications 29:4315-4319
(1999)].
##STR00133##
[0159] Reaction Scheme 11 provides an exemplary process for the
preparation of 3-alkyl-1-aryl-3-azabicyclo[3.1.0]hexane analogs.
These alkylation or reductive amination reaction reagents and
conditions are generally well known to those skilled in the
art.
##STR00134##
[0160] Enantiomers of compounds within the present invention can be
prepared as shown in Reaction Scheme 12 by separation through a
chiral chromatography.
##STR00135##
[0161] Alternatively, enantiomers of the compounds of the present
invention can be prepared as shown in Reaction Scheme 13 using
alkylation reaction conditions exemplified in scheme 11.
##STR00136##
[0162] Reaction Scheme 14 provides an exemplary process for
preparing some N-methyl 1-aryl-3-aza-bicyclo[3.1.0]hexane analogs.
The common intermediate N-methyl bromomaleide is synthesized in one
batch followed by Suzuki couplings with the various substituted
aryl boronic acids. Cyclopropanations are then carried out to
produce the imides, which are then reduced by borane to provide the
desired compounds.
##STR00137##
[0163] Reaction Scheme 15 provides an additional methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00138##
[0164] Reaction Scheme 16 provides an additional methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00139## ##STR00140##
[0165] Reaction Scheme 17 provides an additional methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00141##
[0166] Reaction Scheme 18 provides an additional methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes. Utilizing chiral
starting materials (+)-epichlorohydrin or (-)-epichlorohydrin will
lead to the corresponding chiral analogs through the same reaction
sequences.
##STR00142##
[0167] Reaction Scheme 19 provides an additional methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00143##
[0168] Reaction Scheme 20 provides an additional methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00144##
[0169] Reaction Scheme 21 provides an additional methodology for
producing 3- and/or 4-substituted 1-aryl-3-azabicyclo[3.1.0]
hexanes.
##STR00145##
[0170] Reaction Scheme 22 provides an additional methodology for
producing 3- and/or 4-substituted 1-aryl-3-azabicyclo[3.1.0]
hexanes.
##STR00146##
[0171] Reaction Scheme 23 provides an additional methodology for
producing 3- and/or 2-substituted 1-aryl-3-azabicyclo[3.1.0]
hexanes.
##STR00147##
[0172] Reaction Scheme 24 provides an additional methodology for
producing 2- and/or 3-substituted 1-aryl-3-azabicyclo[3.1.0]
hexanes.
##STR00148##
[0173] Reaction Scheme 25 provides an additional generic
methodology for producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00149##
[0174] Reaction Scheme 26 provides another generic methodology for
producing 1-aryl-3-azabicyclo[3.1.0] hexanes.
##STR00150##
Example II
Preparation of
aza-substituted-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane
Hydrochloride Compounds and Enantiomers Thereof
A. Synthesis of
1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00151##
[0176] To a stirred solution of
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride
(30.0 g, 132 mmol) in 37% aqueous formaldehyde (25.8 mL) was added
formic acid (32.4 mL). The resulting solution was stirred at
90.degree. C. for 6 h. The reaction was then diluted with water
(100 mL) and 2N aqueous sodium hydroxide added until the pH was
greater than 9. The resulting mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.200 mL) and the combined organic extracts
were washed with brine (200 mL), dried (MgSO.sub.4) and
concentrated under vacuum to provide the title compound (25.0 g,
79% yield) as an orange oil: LC (ELS)/MS: >99%, m/z 242.1
[C.sub.12H.sub.13C.sub.12N+H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 0.94 (dd, 1H, J=5.3 Hz, J=7.9 Hz), 1.73 (t,
1H, J=4.7 Hz), 1.80 (m, 1H), 2.55 (s, 3H), 2.78 (d, 2H, J=9.2 Hz),
3.35 (d, 1H, J=9.6 Hz), 3.54 (d, 1H, J=9.3 Hz), 6.99 (dd, 1H, J=2.1
Hz, J=8.3 Hz), 7.24 (d, 1H, J=2.1 Hz), 7.35 (d, 1H, J=8.3 Hz).
B. Synthesis of
1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane
##STR00152##
[0178] A stirred solution of
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride
(19.3 g, 72.9 mmol) in CH.sub.2Cl.sub.2 (100 mL) was rendered basic
with 2N NaOH (100 mL). The resulting mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.100 mL) and the combined extracts dried,
filtered and concentrated under reduced pressure. The residue was
dissolved in acetonitrile (200 mL) and bromoethane (15.9 g, 146
mmol) added at room temperature. The mixture was stirred for 4 h
during which time a white precipitate formed. After this time the
reaction was concentrated under reduced pressure then treated with
2N NaOH (200 mL). Subsequent extraction with CH.sub.2Cl.sub.2
(3.times.100 mL) drying the combined extracts (MgSO.sub.4),
filtration and concentration under reduced pressure afforded a
crude residue. This residue was purified by passing through a
silica gel plug, eluting with ether, to yield the title compound
(12.4 g, 66%) as a clear, viscous oil. This material was then used
directly for either chiral separation or hydrochloride salt
formation as provided in Example II, Section D hereinbelow.
C. Synthesis of
1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane
##STR00153##
[0180] To a stirred solution of
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride
(10.0 g, 43.8 mmol) in DMF (20 mL) was added 2-iodoethane (9.67 g,
56.9 mmol) and DIPEA (7.35 g, 56.9 mmol). The resulting solution
was stirred at ambient temperature for 6 h. After this time, the
solvent was removed under vacuum and the residue was dissolved in
CH.sub.2Cl.sub.2 (50 mL). The organic layer was washed with water
(2.times.50 mL), 2N sodium hydroxide (50 mL) and brine (50 mL). The
organics were dried (Na.sub.2SO.sub.4) and concentrated under
vacuum. Three reactions were run in parallel and then combined for
purification via column chromatography (silica gel, EtOAc) to
provide the title compound (17.3 g, 49% yield) as a yellow oil: LC
(ELS)/MS: 91%, m/z 271.6 [C.sub.14H.sub.17Cl.sub.2N+H].sup.+;
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.75 (dd, 1H, J=4.2 Hz,
J=8.1 Hz), 1.05 (dd, 6H, J=4.7 Hz, J=6.3 Hz), 1.44 (t, 1H, J=4.2
Hz), 1.67 (td, 1H, J=3.9 Hz, J=8.0 Hz), 2.50 (m, 3H), 3.11 (d, 1H,
J=8.6 Hz), 3.31 (d, 1H, J=8.4 Hz), 6.96 (dd, 1H, J=2.1 Hz, J=8.3
Hz), 7.22 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=8.3 Hz).
D. Chiral Separation Conditions and Hydrochloride Salt
Formation
[0181] The 3 racemic mixtures synthesized above in Sections A, B
and C of this Example II were subjected to chiral chromatography
using the following conditions:
[0182] 1: Chiralcel OD column, 4.6 mm.times.250 mm; 99:1
heptanes/i-propanol with 0.1% DEA added; 100 mL/min; 275 nm; 50
mg/mL loading. Peak A eluted at 13 minutes and peak B eluted at
14.5 minutes.
[0183] 2: Chiralcel OD column, 4.6 mm.times.250 mm; 90:10
heptanes/ethanol with 0.1% TFA added; 100 mL/min; 275 nm; 50 mg/mL
loading. Peak A eluted at 9 minutes and peak B eluted at 27
minutes.
[0184] 3: Chiralcel OD column, 4.6 mm.times.250 mm; 93:7
heptanes/ethanol with 0.1% TFA added; 100 mL/min; 275 nm; 50 mg/mL
loading. Peak A eluted at 12 minutes and peak B eluted at 19
minutes.
[0185] The appropriate fractions were collected and concentrated
under reduced pressure. The resulting, residue was dissolved in
CH.sub.2Cl.sub.2, washed with 2N sodium hydroxide, dried
(Na.sub.2SO.sub.4) and the solvent removed under vacuum to yield
the corresponding freebase.
[0186] To a stirred solution of the appropriate freebase in
CH.sub.2Cl.sub.2 (1 g/mL) was added 2 M HCl in ether (2 eq.). The
mixture was stirred at ambient temperature for 16 h. The solvent
was then removed under reduced pressure and the resulting salt was
slurried in ether and collected on a glass frit. Subsequent washing
with ether and drying under vacuum provided the desired
hydrochloride salt set forth below.
(1)
(1S,5R)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00154##
[0188] 7.72 g (88%), white solid: LC (ELS)/MS: 98.8%, m/z 242
[C.sub.12H.sub.13Cl.sub.2N].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.21 (t, 1H, J=7.8 Hz), 2.04 (td, 1H, J=4.3
Hz, J=8.6 Hz), 2.32 (dd, 1H, J=4.8 Hz, J=6.9 Hz), 2.92 (d, 3H,
J=4.5 Hz), 3.30 (m, 2H), 3.94 (dd, 1H, J=5.1 Hz, J=11.0 Hz), 4.11
(dd, 1H, J=5.2 Hz, J=10.9 Hz), 7.03 (dd, 1H, J=2.2 Hz, J=8.3 Hz),
7.29 (d, 1H, J=2.2 Hz), 7.42 (d, 1H, J=8.3 Hz); .sup.13C NMR (75
MHz, CDCl.sub.3): .delta. 136.11, 131.6, 130.3, 129.6, 127.6,
124.5, 58.5, 55.2, 39.3, 28.5, 22.0, 14.5; [.alpha.].sup.25.sub.D
-65.8.degree. (c 1.00, methanol); Anal. Calcd. for
C.sub.12H.sub.14Cl.sub.3N: C, 51.73; H, 5.06; N, 5.03. Found: C,
51.68; H, 5.14; N, 4.92.
(2)
(1R,5S)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00155##
[0190] 7.74 g (88%), white solid: LC (ELS)/MS: 99.3%, m/z 242
[C.sub.12H.sub.13Cl.sub.2N].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.21 (t, 1H, J=7.8 Hz), 2.04 (td, 1H, J=4.3
Hz, J-=8.6 Hz), 2.33 (m, 1H), 2.91 (m, 3H), 3.27 (m, 2H), 3.94 (dd,
1H, J=5.2 Hz, J=11.0 Hz), 4.12 (dd, 1H, J=5.2 Hz, J=10.9 Hz), 7.02
(dd, 1H, J=2.2 Hz, J=8.3 Hz), 7.27 (m, 1H), 7.42 (d, 1H, J=8.3 Hz);
.sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 138.6, 133.4, 132.2,
131.4, 129.6, 127.0, 60.3, 57.4, 41.6, 31.1, 23.9, 16.7;
[.alpha.].sup.25+67.0.degree. (c 1.00, methanol); Anal. Calcd. for
C.sub.12H.sub.14Cl.sub.3N: C, 51.73; H, 5.06; N, 5.03. Found: C,
51.78; H, 4.96; N, 4.97.
(3)
(1S,5R)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00156##
[0192] 2.31 g (45%), white solid: LC (ELS)/MS: >99%, m/z 256
[C.sub.1-3H.sub.15Cl.sub.2N+H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.19 (t, 1H, J=7.7 Hz), 1.52 (t, 3H, J=7.1
Hz), 2.03 (td, 1H, J=4.1 Hz, J=8.3 Hz), 2.39 (dd, 1H, J=4.7 Hz,
J=6.7 Hz), 3.23 (m, 4H), 3.93 (dd, 1H, J=5.2 Hz, J=10.8 Hz), 4.12
(dd, 1H, J=5.3 Hz, J=10.8 Hz), 7.02 (dd, 1H, J=2.0 Hz, J=8.3 Hz),
7.27 (m, 1H), 7.42 (d, 1H, J=8.3 Hz); .sup.13C NMR (75 MHz,
CDCl.sub.3): .delta. 136.8, 131.3, 130.1, 129.6, 127.7, 125.0,
56.4, 53.4, 49.9, 28.7, 21.5, 15.0, 9.4; [.alpha.].sup.25.sub.D
-62.7.degree. (c 1.096, methanol); Anal. Calcd. for
C.sub.1-3H.sub.16Cl.sub.3N: C, 53.36; H, 5.51; N, 4.79. Found: C,
52.78; H, 5.24; N, 4.71.
(4)
(1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00157##
[0194] 3.64 g (56%), white solid: LC (ELS)/MS: 97%, m/z 256
[C.sub.13H.sub.15Cl.sub.2N+H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.18 (t, 1H, J=7.3 Hz), 1.52 (t, 3H, J=7.2
Hz), 2.02 (m, 1H), 2.38 (m, 1H), 3.21 (m, 4H), 3.92 (d, 1H, J=10.9
Hz), 4.11 (d, 1H, J=10.8 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.27 (m, 1H),
7.42 (d, 1H, J=8.3 Hz); .sup.13C NMR (75 MHz, CDCl.sub.3): .delta.
137.5, 131.7, 130.1, 129.8, 128.2, 125.6, 57.2, 54.0, 50.5, 29.4,
22.2, 15.8, 9.8; [.alpha.].sup.25.sub.D+69.2.degree. (c 1.1,
methanol); Anal. Calcd. for C.sub.1-3H.sub.16Cl.sub.3N: C, 53.36;
H, 5.51; N, 4.79. Found: C, 52.71; H, 5.23; N, 4.65.
(5) (1
S,5R)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00158##
[0196] 5.61 g, white solid: LC (ELS)/MS: >99%, m/z 270
[C.sub.14H.sub.17Cl.sub.2N+H].sup.+; 1H NMR (300 MHz, CDCl.sub.3):
.delta. 1.15 (t, 1H, J=7.7 Hz), 1.55 (d, 6H, J=6.5 Hz), 2.02 (td,
1H, J=4.4 Hz, J=8.7 Hz), 2.50 (dd, 1H, J=4.8 Hz, J=6.7 Hz), 3.28
(m, 3H), 3.89 (dd, 1H, J=5.5 Hz, J=11.0 Hz), 4.08 (dd, 1H, J=5.5
Hz, J=10.9 Hz), 7.03 (dd, 1H, J=2.2 Hz, J=8.3 Hz), 7.27 (d, 1H,
J=3.0 Hz), 7.42 (d, 1H, J=8.3 Hz); .sup.13C NMR (75 MHz,
CDCl.sub.3): .delta. 136.9, 131.7, 130.1, 129.6, 127.7, 125.3,
58.6, 55.1, 52.2, 28.8, 21.7, 17.1, 14.9; [.alpha.].sup.25.sub.D
-74.1.degree. (c 1.00, methanol); Anal. Calcd. for
C.sub.14H.sub.18Cl.sub.3N: C, 54.83; H, 5.92; N, 4.57. Found: C,
54.50; H, 5.85; N, 4.42.
(6)
(1R,5S)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00159##
[0198] 5.20 g, white solid: LC (ELS)/MS: >99%, m/z 270
[C.sub.14H.sub.17Cl.sub.2N+H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.15 (t, 1H, J=7.7 Hz), 1.55 (d, 6H, J=6.5
Hz), 2.01 (td, 1H, J=4.4 Hz, J=8.7 Hz), 2.50 (dd, 1H, J=4.8 Hz,
J=6.7 Hz), 3.26 (ddd, 1H, J=7.0 Hz, J=14.6 Hz, J=28.8 Hz), 3.90
(dd, 1H, J=5.5 Hz, J=11.0 Hz), 4.08 (dd, 1H, J=5.5 Hz, J=10.9 Hz),
7.02 (dd, 1H, J=2.2 Hz, J=8.3 Hz), 7.27 (d, 1H, J=2.4 Hz), 7.42 (d,
1H, J=8.3 Hz); .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 137.0,
131.2, 129.9, 128.5, 127.3, 124.0, 58.0, 55.0, 50.7, 29.1, 20.9,
17.4, 14.2; [.alpha.].sup.25.sub.D+76.8.degree. (c 1.00, methanol);
Anal. Calcd. For C.sub.14H.sub.18Cl.sub.3N: C, 54.83; H, 5.92; N,
4.57. Found: C, 54.69; H, 5.82; N, 4.44.
Example III
Preparation of
1-(3,4-ichlorophenyl)-3-propyl-3-azabicyclo[3.1.0]hexane
Hydrochloride Using Reaction Scheme 19
##STR00160##
[0200] To a 3-necked flask under nitrogen was added
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (30 g)
and anhydrous DMF (220 mL). The mixture was then cooled to between
0 and 10.degree. C. using an ice/salt/water bath. At this point
sodium hydride (4.68 g) was added portionwise over approximately 1
h. Significant gas evolution was noted on addition of the sodium
hydride. On completion of the addition the reaction was allowed to
stir for 30 mins at room temperature before the addition of
bromopropane (17 mL). The reaction was then allowed to stir
overnight at room temperature. TLC of the reaction mixture revealed
no starting material. The reaction was quenched by adding the
reaction mixture dropwise to cold water (<10.degree. C.). This
led to the formation of a slurry; the solid was dissolved on
addition of ethyl acetate (500 mL). The organics were separated and
aqueous re-extracted with ethyl acetate (1 L). The organics were
again separated and washed with water (2.times.500 mL) and brine
(2.times.500 mL), leading to the formation of an emulsion. The
emulsion was separated after the addition of more water (500 mL)
and ethyl acetate (500 mL). The organics were then separated, dried
over magnesium sulphate, filtered and concentrated in vacuo to give
a brown oil (36.8 g). A sample was sent for 1H NMR (GMCP408A) and
this showed the crude product (36.8 g, 94% yield, purity >90%).
This was used directly in the reduction stage.
[0201] To a 3-necked flask under nitrogen was added the imide (36.8
g) in THF (300 mL). The mixture was cooled to 0.degree. C. and 1M
BH.sub.3 in THF was added dropwise. On completion of the addition
the reaction was heated to reflux for 4 h. TLC of the reaction
mixture showed that no starting material remained. The reaction
mixture was cooled to 0.degree. C. and quenched with 6N HCl (470
mL). The quenched mixture was then concentrated in vacuo to a
volume of approximately 300 mL. The mixture was again cooled to
0.degree. C. and made basic with 750 mL of 5M NaOH solution. The
mixture was then extracted with DCM (2.times.1 L). The organics
were then dried, filtered and concentrated in vacuo. The material
was subjected to column chromatography (98% DCM: 2% methanol: 0.1%
ammonia). However this led to the isolation of only mixed
fractions. An alternative solvent system using 20% ethyl acetate:
80% hexane was employed. Three sets of fractions were obtained.
Samples of each set of fractions were analysed via .sup.1H NMR and
showed that two sets of fractions (designated A and C) contained
mostly product with small amounts of impurities present. The third
set of fractions (designated B) was shown to contain only a small
amount of product with significant other impurities present. The A
and C sets of fractions were combined (7.7 g) and dissolved in
diethyl ether (8 mL) before being cooled to 0.degree. C. At this
point 1M HCl in ether (143 mL) was added carefully to the mixture
to form the salt. The slurry was stirred for 30 mins at 0.degree.
C. before being filtered. The salt was then dried in the oven
overnight at ambient temperature. This gave the product as a white
solid (6.08 g, 18.2%). .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta.
11.28 (1H, brs, NH.sup.+), 7.62-7.59 (2H, m, ArH), 7.28-7.25 (1H,
m, ArH), 3.97-3.90 (1H, m, NCH.sub.2), 3.63-3.44 (3H, m,
NCH.sub.2), 3.09-3.01 (2H, m, NCH.sub.2), 2.21-2.16 (1H, m, CH),
1.88 (1H, t, J=5.4 Hz, CH.sub.2), 1.77-1.69 (2H, m,
CH.sub.2CH.sub.3), 1.11 (1H, obs t, J=7.3 Hz, CH.sub.2), 0.87 (3H,
obs t, J=7.3 Hz, CH.sub.3); .sup.13C NMR (75 MHz,
.delta.-CDCl.sub.3) .delta. 140.5, 131.1, 130.4, 129.1, 128.9,
127.1, 56.5, 55.8, 54.5, 29.3, 23.4, 18.2, 15.9, 10.8; MS (m/z) 270
(MH.sup.+, 100).
Example IV
Preparation of
(1R,5S)-1-(3,4-dichlorophenyl)-3-propyl-3-azabicyclo[3.1.0]hexane
Hydrochloride Using Reaction Scheme 13
##STR00161##
[0203] To a stirred solution of
(1R,5S)-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane
hydrochloride (10 g) in anhydrous DMF (70 mL) under nitrogen was
added DIPEA (8.48 mL, 1.3 eq). The reaction was allowed to stir for
30 mins before the addition of propyl bromide (6.15 mL). The
reaction was stirred at room temperature for 2 h. TLC of the
reaction revealed a mixture of starting material and product.
Therefore the reaction was continued with a further addition of 0.7
eq of DIPEA, heated to 40.degree. C. and allowed to stir for 4 h.
The reaction was then allowed to stand overnight at room
temperature. TLC of the reaction revealed mainly product with a
small amount of starting material and baseline material present.
The reaction mixture was then concentrated in vacuo under reduced
pressure to remove the DMF. This gave a liquid, which solidified on
standing (pink solid). This was taken up in DCM (150 mL) and washed
with water (100 mL). The organics were then separated, dried over
magnesium sulphate, filtered and concentrated in vacuo. Once again
a pink solid was obtained. This material was purified via column
chromatography eluted using 98% DCM: 2% methanol: 0.1% ammonia.
This gave pure compound (15.3 g) as a solid (15% DMF present). The
solid was slurried in ethyl acetate (150 mL) and mixed with
saturated aqueous NaHCO.sub.3 solution (75 mL). The solid dissolved
on addition of the base. The organics were separated and washed
with water (2.times.200 mL) before drying over magnesium sulphate,
filtering and concentrating in vacuo to give an oil (8.8 g). The
oil was taken up in diethyl ether (9 mL) before being cooled to
0.degree. C. At this point 1M HCl in ether (163 mL) was added
carefully to the mixture to form the salt. The slurry was stirred
for 30 mins at 0.degree. C. before being filtered. The salt was
then dried in the oven overnight at ambient temperature. This gave
the product as a white solid (7.73 g, 66.7%). .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta. 11.19 (1H, brs, NH.sup.+), 7.62-7.57 (2H, m,
ArH), 7.29-7.25 (1H, m, ArH), 3.95-3.90 (1H, dd, J=11.1, 4.5 Hz,
NCH.sub.2), 3.64-3.59 (1H, dd, J=11.1, 4.5 Hz, NCH.sub.2),
3.55-3.41 (2H, m, NCH.sub.2), 3.07-3.04 (2H, m, NCH.sub.2),
2.21-2.16 (1H, m, CH), 1.88 (1H, t, J=5.4 Hz, CH.sub.2), 1.77-1.69
(2H, m, CH.sub.2CH.sub.3), 1.11 (1H, obs t, J=7.3 Hz, CH.sub.2),
0.87 (3H, obs t, J=7.3 Hz, CH.sub.3); .sup.13C NMR (75 MHz,
.delta.-CDCl.sub.3) .delta. 140.5, 131.1, 130.4, 129.1, 128.9,
127.1, 56.5, 55.8, 54.5, 29.3, 23.4, 18.2, 15.9, 10.8; MS (m/z) 270
(MH.sup.+, 100).
Example V
Preparation of
(1S,5R)-1-(3,4-Dichlorophenyl)-3-propyl-3-azabicyclo[3.1.0]hexane
Hydrochloride Using Reaction Scheme 13
##STR00162##
[0205] To a stirred solution of
(1S,5R)-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane
hydrochloride (10 g) in anhydrous DMF (70 mL) under nitrogen was
added DIPEA (8.48 mL, 1.3 eq). The reaction was allowed to stir for
30 mins before the addition of propyl bromide (6.15 mL). The
reaction was stirred at room temperature for 2 h. TLC of the
reaction revealed a mixture of starting material and product.
Therefore the reaction was continued with a further addition of 0.7
eq of DIPEA, heated to 40.degree. C. and allowed to stir for 4 h.
The reaction was then allowed to stand overnight at room
temperature. TLC of the reaction revealed mainly product with a
small amount of starting material and baseline material present.
The reaction mixture was then concentrated in vacuo under reduced
pressure to remove the DMF. This gave a liquid, which solidified on
standing (pink solid). This was taken up in DCM (150 mL) and washed
with water (100 mL). The organics were then separated, dried over
magnesium sulphate, filtered and concentrated in vacuo. Once again
a pink solid was obtained. This material was purified via column
chromatography eluted using 98% DCM: 2% methanol: 0.1% ammonia.
This gave pure compound (15.9 g) as a solid (15% DMF present). The
solid was slurried in ethyl acetate (150 mL) and mixed with
saturated aqueous NaHCO.sub.3 solution (75 mL). The solid dissolved
on addition of the base. The organics were separated and washed
with water (2.times.200 mL) before drying over magnesium sulphate,
filtering and concentrating in vacuo to give an oil (8.9 g). The
oil was taken up in diethyl ether (9 mL) before being cooled to
0.degree. C. At this point 1M HCl in ether (165 mL) was added
carefully to the mixture to form the salt. The slurry was stirred
for 30 mins at 0.degree. C. before being filtered. The salt was
then dried in the oven overnight at ambient temperature. This gave
the product as a white solid (8.61 g, 75%). .sup.1H NMR (300 MHz,
d.sub.6-DMSO) .delta. 11.20 (1H, brs, NH.sup.+), 7.62-7.57 (2H, m,
ArH), 7.29-7.25 (1H, m, ArH), 3.94-3.90 (1H, dd, J=11.1, 4.5 Hz,
NCH.sub.2), 3.64-3.59 (1H, dd, J=11.1, 4.5 Hz, NCH.sub.2),
3.55-3.41 (2H, m, NCH.sub.2), 3.07-3.04 (2H, m, NCH.sub.2),
2.21-2.16 (1H, m, CH), 1.89 (1H, obs t, J=5.4 Hz, CH.sub.2),
1.80-1.67 (2H, m, CH.sub.2CH.sub.3), 1.11 (1H, obs t, J=7.3 Hz,
CH.sub.2), 0.87 (3H, t, J=7.3 Hz, CH.sub.3); .sup.13C NMR (75 MHz,
.delta.-CDCl.sub.3) .delta. 140.5, 131.1, 130.4, 129.1, 128.9,
127.1, 56.5, 55.8, 54.5, 29.3, 23.4, 18.3, 15.9, 10.9; MS (m/z) 270
(MH.sup.+, 100).
Example VI
Preparation of
3-Butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane
Hydrochloride Using Reaction Scheme 19
##STR00163##
[0207] To a stirred solution of
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (15.8
g) in DMF (63 ml) was added sodium hydride (60 wt. % in oil; 2.5 g)
with the temperature kept below 20.degree. C. The suspension was
then stirred at room temperature for 20 mins before 1-bromobutane
(9.9 ml) was added. The solution was then stirred at room
temperature for 24 h when TLC (20% ethyl acetate in hexanes)
indicated complete reaction. The solution was quenched into water
(500 ml), extracted with ether (2.times.250 ml) and the extracts
washed with water (2.times.250 ml), saturated brine (2.times.250
ml), dried (MgSO.sub.4) and evaporated, yielding 15.6 g (81%)
imide.
[0208] The imide above (15.6 g) was dissolved in THF (310 ml) and a
solution of borane in THF (1M; 225 ml) was added with the
temperature kept below 5.degree. C. The solution was then heated to
reflux for 4 h when TLC (20% ethyl acetate in hexane) indicated
complete reaction. The solution was cooled to 0.degree. C. and
quenched by the addition of dilute HCl (6M; 200 ml) with the
temperature kept below 10.degree. C. The solution was then
extracted with ether (2.times.200 ml), the aqueous made basic with
sodium hydroxide (5M; 480 ml), extracted with ether (3.times.150
ml), the extracts combined, dried (MgSO.sub.4) and evaporated, to
give a crude oil with a yield of 3.2 g.
[0209] The oil was added to HCl in ether (2M; 20 ml), stored
overnight at -20.degree. C. and the resultant solid filtered off
and washed with ether (2.times.10 ml). TLC (20% ethyl acetate in
hexanes) indicated two components so the solid was dissolved in
water (50 ml) made basic with solid K.sub.2CO.sub.3 to pH 10 and
extracted with ether (3.times.100 ml). The extracts were dried
(MgSO.sub.4) and evaporated. The product was then purified by
chromatography [SiO.sub.2 (22.7 g): (25% EtOAc in hexanes)] to give
the required material as a yellow oil, 0.7 g (5%); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.16-7.06 (m, 4H, ArH), 3.97 (t, 1H, J=6.3
Hz, NCH.sub.2), 3.78 (s, 3H, NCH.sub.2), 2.34 (s, 3H, ArCH.sub.3),
1.87 (m, 1H, CHCH.sub.2), 1.19 (t, 1H, J=5.5 Hz, CHCH.sub.2), 0.87
(m, 1H, CHCH.sub.2); MS (m/z) 188 (MH.sup.+, 100).
Example VII
Preparation of
3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane
Using Reaction Scheme 20
A. Synthesis of
1-(3,4-Dichlorophenyl)-3-oxa-bicyclo[3.1.0]hexane-2,4-dione
##STR00164##
[0211] To a stirred solution of the
1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylic acid (28.3 g)
in acetyl chloride (142 ml) was heated to reflux for 3 h, cooled to
room temperature and evaporated. The oil was dissolved in toluene
(100 ml) and evaporated to dryness. This was then repeated twice
before triturating the semi-solid in hexane (100 ml). The solid was
filtered off, washed with hexane and pulled dry under a nitrogen
atmosphere to give a brown solid, yield=26.7 g (101%); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.52-7.46 (m, 2H, ArH), 7.27-7.24 (m,
1H, ArH), 3.35-3.30 (m, 1H, CH), 2.13-2.10 (m, 1H, CH), 1.97-1.95
(m, 1H, CH).
B. Synthesis of
2-(tert-Butylcarbamoyl)-2-(3,4-dichlorophenyl)-cyclopropane-1-carboxylic
Acid
##STR00165##
[0213] To a stirred solution of the anhydride prepared as described
in Example VII, Section A above (26.7 g) in THE (365 ml) was added
tert-butylamine (23 ml) with the temperature kept below 20.degree.
C. The suspension was then stirred at room temperature for 1 h when
TLC (50% ethyl acetate in hexane) indicated complete reaction. The
solvent was evaporated off and the resultant sticky mass used crude
in the next reaction.
C. Synthesis of
3-tert-Butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione
##STR00166##
[0215] A stirred suspension of the amide prepared as described in
Example: VII, Section B above and sodium acetate (4.3 g) in acetic
anhydride (145 ml) was heated to reflux for 4 h where TLC (50%
ethyl acetate in hexanes) indicated complete reaction so the
solvent was evaporated off and the oil absorbed onto silica (49.7
g). The product was then purified by chromatography [SiO.sub.2
(503.7 g): (10% EtOAc in hexanes)] to give the required material as
a yellow oil, in a yield of 23.7 g (73%); 1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.52-7.46 (m, 2H, ArH), 7.23-7.20 (m, 1H, ArH),
2.64-2.60 (m, 1H, CH), 1.72-1.66 (m, 2H, CH), 1.52 (s, 9H,
Bu.sup.t).
D. Synthesis of
3-tert-Butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2-one
##STR00167##
[0217] To a stirred solution of the imide prepared as described in
Example VII, Section C above (23.7 g) in THF (395 ml) at 5.degree.
C. was added a solution of borane in THE (1M; 304 ml) with the
temperature kept below 5.degree. C. The solution was then heated to
reflux for 2 h when TLC (20% ethyl acetate in hexane) indicated
complete reaction. The solution was cooled to 0.degree. C. and
quenched by the addition of dilute HCl (6M; 400 ml) with the
temperature kept below 10.degree. C. The THF was evaporated off and
the white solid filtered off and dried at 45.degree. C. in vacuo
overnight, yielding 17.0 g (75%) of the desired product. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.71 (d, 1H, J=2.4 Hz, ArH), 7.57
(d, 1H, J=8.4 Hz, ArH), 7.36 (dd, 1H, J=8.4 Hz, J=2.4 Hz, ArH),
4.86 (br s, 2H, CH.sub.2), 3.69-3.63 (m, 1H, CH), 3.46-3.43 (m, 1H,
CH), 2.37-2.31 (m, 1H, CH), 1.45-1.42 (m, 1H, CH), 1.32 (s, 9H,
Bu.sup.t); MS (m/z) 299 (MH.sup.+, 100).
E. Synthesis of
3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]-hexane
Maleate Salt
##STR00168##
[0219] To a stirred solution of the amide prepared as described in
Example VII, Section D above (15.1 g) in THF (270 ml) was added a
solution of borane in THF (1M; 203 ml) at 20.degree. C. The
solution was then heated to reflux for 16 h when TLC (20% ethyl
acetate in hexane) indicated incomplete reaction so the solution
was cooled to room temperature and a further portion of borane in
THF (1M; 130 ml) was added at 20.degree. C. The solution was then
again heated to reflux and held for 24 h. TLC indicated
approximately 50% reaction so the solution was cooled to 0.degree.
C. and quenched by the addition of dilute HCl (6M; 400 ml) with the
temperature kept below 10.degree. C. The THF was evaporated off,
the white solid filtered off, and the aqueous extracted with ethyl
acetate (3.times.250 ml). The aqueous was made basic with NaOH (5M;
500 ml) and the product extracted into ether (3.times.200 ml),
dried (MgSO.sub.4) and evaporated to give a colourless oil, in a
yield of 5.9 g (41%).
[0220] The crude amine was added to a solution of maleic acid (2.3
g) in methanol (11.5 ml) and stored at -20.degree. C. overnight.
The solid was filtered off, washed with methanol (2.5 ml) and dried
at 45.degree. C. in vacuo overnight, yielding the title compound
(1.1 g, 5%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.31-7.19
(m, 2H, ArH), 6.95-6.91 (m, 1H, ArH), 3.28 (d, 1H, J=8.4 Hz, CH),
3.10 (d, 1H, J=8.4 Hz, CH), 2.48-2.40 (m, 4H, CH), 1.68-1.62 (m,
1H, CH), 1.47-1.33 (m, 5H, CH), 0.92-0.87 (m, 3H, CH.sub.3),
0.77-0.74 (m, 1H, CH); MS (m/z) 284 (M.sup.+, 100).
Example VIII
Preparation of 1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane
Hydrochlorides Using Reaction Scheme 14
A. Synthesis of 3-Bromo-1-methyl-1H-pyrrole-2,5-dione
##STR00169##
[0222] Pursuant to steps a and b of Reaction Scheme 14, a solution
of bromomaleic anhydride (52.8 g, 0.298 mol) in diethyl ether (250
mL) was cooled to 5.degree. C. A 2 M solution of methylamine in THF
(298 mL, 0.596 mol, 2 eq.) was added dropwise over 1 hour and the
reaction stirred for a further 30 minutes, maintaining the
temperature below 10.degree. C. The resulting precipitate was
filtered, washed with diethyl ether (2.times.100 mL) and air-dried
for 30 minutes, then suspended in acetic anhydride (368 mL) and
sodium acetate (12.2 g, 0.149 mol, 0.5 eq.) added. The reaction was
heated to 60.degree. C. for 2 hours and solvent was then removed in
vacuo. The residue was taken up in DCM (500 mL) and washed with
saturated sodium bicarbonate solution (2.times.500 mL) and water
(2.times.300 mL). Organics were dried over MgSO.sub.4 (89 g),
filtered and reduced in vacuo. The resulting oil was azeotroped
with toluene (4.times.100 mL) to give N-methyl bromomaleimide as a
beige solid. Yield=41.4 g (73%); .sup.1H NMR (300 MHz, CDCl.sub.3)
b 6.95 (1H, s, CH), 3.07 (3H, s, NCH.sub.3).
B. General Synthetic procedure for preparation of
3-Aryl-1-methyl-pyrrole-2,5-diones
[0223] Pursuant to step c of Reaction Scheme 14, the following
provides a general procedure for synthesis of
3-aryl-1-methyl-pyrrole-2,5-diones. N-Methyl bromomaleimide (20 mL
of a 0.5 M solution in 1,4-dioxane, 1.96 g net, 10 mmol), aryl
boronic acid (11 mmol, 1.1 eq.), cesium fluoride (3.4 g, 22 mmol,
2.2 eq.) and [1,1'-bis-(diphenylphosphino)ferrocene]palladium (II)
chloride (0.4 g, 0.5 mmol, 5 mol %) were stirred at 40.degree. C.
for between 1 and 6 hours. Reactions were filtered, solids washed
with 1,4-dioxane (5 mL) and solvents removed in vacuo (two of the
solids required an extra wash with dichloromethane at this stage).
Residues were taken up in DCM (5 mL) then purified either by
passing through a flash silica chromatography cartridge (20 g
silica) or by column chromatography (30 g silica, eluted with 4:1
hexane:ethyl acetate then 2:1 hexane:ethyl acetate). Solvents were
removed in vacuo to give the required crude products as solids. The
compounds shown below (NMR data also listed below) were prepared
using the foregoing general procedure:
(1) 3-(3,4-Difluorophenyl)-1-methyl-pyrrole-2,5-dione
##STR00170##
[0225] Yield=1.4 g (61%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.88-7.81 (1H, m, ArH), 7.72-7.68 (1H, in, ArH), 7.29-7.20 (1H, m,
ArH), 6.71 (1H, s, CH), 3.07, (3H, s, NCH.sub.3); MS (m/z) 224
[MH.sup.+].
(2) 3-(3-Fluoro-4-methylphenyl)-1-methyl-pyrrole-2,5-dione
##STR00171##
[0227] Yield=1.2 g (53%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.65-7.59 (2H, m, ArH), 7.28-7.21 (1H, obs t, J=8.1 Hz, ArH), 6.69
(1H, s, CH), 3.06 (3H, s, NCH.sub.3), 2.32-2.31 (3H, d, J=2.3 Hz,
ArCH.sub.3); MS (m/z) 220 [MH.sup.+].
(3) 3-(4-Fluoro-3-methylphenyl)-1-methyl-pyrrole-2,5-dione
##STR00172##
[0229] Yield=1.4 g (62%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.80-7.76 (2H, m, ArH), 7.12-7.06 (1H, obs t, J=8.9 Hz, ArH), 6.67
(1H, s, CH), 3.08 (3H, s, NCH.sub.3), 2.33 (3H, d, J=1.8 Hz,
ArCH.sub.3); MS (m/z) 220 [MH.sup.+].
(4) 3-(2,4-Difluorophenyl)-1-methyl-pyrrole-2,5-dione
##STR00173##
[0231] Yield=1.8 g (78%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.39-8.31 (1H, m, ArH), 7.02-6.89 (3H, m, 2.times.ArH, CH), 3.08
(3H, s, NCH.sub.3); MS (m/z) 236 [MH.sup.+].
(5) 3-(2,4-Dichlorophenyl)-1-methyl-pyrrole-2,5-dione
##STR00174##
[0233] Yield=2.0 g (76%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.70-7.67 (1H, (d, J=8.4 Hz, ArH), 7.52 (1H, d, J=1.9 Hz, ArH),
7.37-7.33 (1H, m, ArH), 7.02 (1H, s. CH), 3.09 (3H, s, NCH.sub.3);
MS (m/z) 256 [MH.sup.+].
(6) 3-(2-methoxynaphthalen-6-yl)-1-methyl-pyrrole-2,5-dione
##STR00175##
[0235] Yield=1.30 g, (65%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.62 (br s, 1H), 7.83 (m, 1H), 7.76 (m, 2H), 7.18 (m, 1H),
7.12 (m, 1H), 6.75 (s, 1H), 3.94 (s, 3H), 3.09 (s, 3H).
(7) 3-(2-ethoxynaphthalen-6-yl)-1-methyl-pyrrole-2,5-dione
##STR00176##
[0237] Yield=1.02 g, (48%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.62 (m, 1H), 7.83 (m, 1H), 7.75 (m, 2H), 7.18 (m, 1H),
7.11 (m, 1H), 6.76 (s, 1H), 4.17 (q, 2H, J=7 Hz), 3.10 (s, 3H),
1.49 (t, 3H, J=7 Hz); MS (M+1) 282.1.
C. General Synthetic Procedure for Preparation of
1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-diones
[0238] Pursuant to step d of Reaction Scheme 14,
trimethylsulphoxonium chloride (1.2 eq.) and sodium hydride (60%
dispersion in mineral oil, 1.2 eq.) were suspended in THF (50 vol)
and heated at reflux (66.degree. C.) for 2 hours. The reactions
were cooled to 50.degree. C. and a solution of
1-methyl-3-(aryl)pyrrole-2,5-dione (1 eq.) in THF (10 mL) was added
in one portion. The reactions were heated at 50.degree. C. for
between 2 and 4 hours and then at 65.degree. C. for a further 2
hours if required (as judged by disappearance of starting material
by TLC), and then cooled to room temperature. Reactions were
quenched by the addition of IMS (5 mL) and the solvents removed in
vacuo. The residues were taken up in DCM (35 mL) and washed with
water (3.times.35 mL). Combined aqueous washes were back-extracted
with DCM (15 mL), organic portions combined and solvent removed in
vacuo. The reactions were purified by column chromatography (30 g
silica, eluting with increasingly polar fractions of ethyl acetate
in hexane) and solvents removed in vacuo to give the
3-methyl-1-(aryl)-3-aza-bicyclo[3.1.0]hexane-2,4-diones as crude
solids. The compounds shown below (NMR data also listed below) were
prepared using the foregoing general procedure:
(1)
1-(3,4-Difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-dione
##STR00177##
[0240] Yield=0.6 g (40%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.32-7.26 (1H, m, ArH), 7.20-7.07 (2H, m, ArH), 2.92 (3H, s,
NCH.sub.3), 2.75-2.71 (1H, dd, J=8.1 Hz, 3.7 Hz, CH), 1.87-1.85
(1H, obs t, J=4.2 Hz, CH.sub.2), 1.81-1.77 (1H, dd, J=8.1 Hz, 4.8
Hz, CH.sub.2); MS (m/z) 238 [MH.sup.+].
(2)
1-(3-Fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-di-
one
##STR00178##
[0242] Yield=0.2 g (16%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.19-7.14 (1H, t, J=7.8 Hz, ArH), 7.10-7.02 (2H, m, ArH), 2.91 (3H,
s, NCH.sub.3), 2.71-2.67 (1H, dd, J=8.1 Hz, 4.0 Hz, CH), 2.25 (3H,
d, J=1.9 Hz, ArCH.sub.3), 1.87-1.78 (2H, m, CH.sub.2); MS (m/z) 234
[MH.sup.+].
(3)
1-(4-Fluoro-3-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-di-
one
##STR00179##
[0244] Yield=0.5 g (33%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.25-7.21 (1H, m, ArH), 7.19-7.14 (1H, m, ArH), 7.02-6.96 (1H, t,
J=9.0 Hz), 2.92 (3H, s, NCH.sub.3), 2.69-2.65 (1H, dd, J=7.8 Hz,
4.1 Hz, CH), 2.27-2.26 (3H, d, J=2.2 Hz, ArCH.sub.3), 1.84-1.77
(2H, m, CH.sub.2); MS (m/z) 234 [MH.sup.+].
(4)
1-(2,4-Difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-dione
##STR00180##
[0246] Yield=0.7 g (36%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.35-7.20 (1H, m, ArH), 6.94-6.79 (2H, m, ArH), 2.92 (3H, s,
NCH.sub.3), 2.65-2.61 (1H, dd, J=7.7 Hz, 4.1 Hz, CH), 1.89-1.83
(2H, m, CH.sub.2); MS (m/z) 238 [MH.sup.+].
(5)
1-(2,4-Dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-dione
##STR00181##
[0248] Yield=1.0 g (47%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.45-7.44 (1H, s, ArH), 7.29-7.28 (2H, m, ArH), 2.94 (3H, s,
NCH.sub.3), 2.62-2.58 (1H, dd, J=7.7 Hz, 4.8 Hz, CH), 1.95-1.91
(2H, m, CH.sub.2); MS (m/z) 270 [MH.sup.+].
(6)
1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-d-
ione
##STR00182##
[0250] Yield=580 mg, (41%)); MS (M+1) 282.1. .sup.1H NMR
(CDCl.sub.3) .delta. 7.79 (m, 1H), 7.69-7.76 (m, 2H), 7.44 (m, 1H),
7.16 (m, 1H), 7.12 (m, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.78 (m,
1H), 1.87-1.97 (m, 2H).
(7)
1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-di-
one
##STR00183##
[0252] Yield=360 mg, (39%)); .sup.1H NMR (CDCl.sub.3) .delta. 7.78
(m, 1H), 7.71 (m, 2H), 7.43 (m, 1H), 7.16 (m, 1H), 7.11 (m, 1H),
4.15 (q, 2H, J=7 Hz), 2.95 (s, 3H), 2.78 (m, 1H), 1.91 (m, 2H); MS
(M+1) 296.1.
D. General Synthetic Procedure for Preparation of
1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane Hydrochlorides
[0253] Pursuant to steps e and f of Reaction Scheme 14, borane (1 M
complex in THF, 5 eq.) was cooled to <0.degree. C. and a
solution of 3-methyl-1-(aryl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione
(1 eq.) in THF (10 vol.) added dropwise, maintaining the
temperature <0.degree. C. The reactions were warmed to room
temperature for 15 minutes then heated to reflux (67 CC) for 2
hours. The reactions were cooled to <0.degree. C. and quenched
with the dropwise addition of 6 M HCl (5 vol., temperature
maintained <0.degree. C.). Solvents were removed in vacuo and
the resulting white residues made basic with the addition of 5 M
NaOH (25 mL) and extracted with DCM (2.times.20 mL). The organics
were washed with water (3.times.30 mL) then concentrated in vacuo
to .about.1 mL volume. The resulting oils were purified by column
chromatography (15 g silica, eluting with DCM then 5% MeOH in DCM)
to give the crude free bases. Samples were dissolved in diethyl
ether (1 mL) and 1 M HCl in ether (10 mL) was added. The resulting
white precipitates were stored at <20.degree. C. for 16 hours
then centrifuged. Ether was decanted and the solids washed with a
further three portions of ether (material isolated by
centrifugation and ether decanted after each wash). Materials were
dried in vacuo at 30.degree. C. to give the required products as
white solids. The compounds shown below (NMR data also listed
below) were prepared using the general procedures described
above:
(1) 1-(3,4-Difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00184##
[0255] Free Base:
[0256] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.07-6.95 (1H, m,
ArH), 6.92-6.79 (2H, m, ArH), 3.23-3.20 (1H, d, J=8.8 Hz,
CH.sub.2), 3.04-3.01 (1H, d, J=8.8 Hz, CH.sub.2), 2.48-2.42 (2H, m,
CH.sub.2), 2.32 (3H, s, NCH.sub.3), 1.62-1.58 (1H, m, CH),
1.39-1.38 (1H, m, CH.sub.2) 0.74-0.70 (1H, dd, J=8.1 Hz, 4.4 Hz,
CH.sub.2).
[0257] Hydrochloride Salt:
[0258] Yield=175 mg (28%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 12.16 (1H, br-s, N+H), 7.26-6.95 (3H, m, ArH), 3.95 (1H,
br-s, CH.sub.2), 3.80 (1H, br-s, CH.sub.2), 3.53 (1H, br-s,
CH.sub.2), 3.42 (1H, br-s, CH.sub.2), 2.92 (3H, s, NCH.sub.3), 2.10
(1H, br-s, CH.sub.2), 1.95 (1H, br-s, CH), 113 (1H, br-s,
CH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.67,
151.03, 148.51, 147.90, 134.70, 123.77, 123.64, 117.64, 117.42,
116.88, 116.65, 60.10, 56.96, 41.12, 30.63, 23.26, 15.29; MS (m/z)
210 [MH.sup.+]; LC purity 96.3%.
(2)
1-(3-Fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00185##
[0260] Free Base:
[0261] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.13-7.03 (2H, m,
ArH), 6.80-6.75 (1H, m, ArH), 3.28-3.25 (1H, d, J=8.9 Hz,
CH.sub.2), 3.08-3.05 (1H, d, J=8.8 Hz, CH.sub.2), 2.55-2.52 (1H, d,
J=8.5 Hz, CH.sub.2), 2.47-2.43 (1H, dd, J=8.8 Hz, 3.3 Hz, CH.sub.2)
2.36 (3H, s, NCH.sub.3), 2.22 (314, s, ArCH.sub.3), 1.67-1.62 (1H,
m, CH), 1.43-1.39 (1H, m, CH.sub.2) 0.79-0.75 (1H, dd, J=8.1 Hz,
4.4 Hz, CH.sub.2).
[0262] Hydrochloride Salt:
[0263] Yield=66 mg (30%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
12.12 (1H, br-s, N+H), 7.07-7.02 (1H, t, J=7.9 Hz, ArH), 6.87-6.80
(2H, m, ArH), 3.94-3.91 (1H, d, J=9.2 Hz, CH.sub.2), 3.78-3.75 (1H,
d, J=8.8 Hz, CH.sub.2), 3.44-3.39 (1H, m, CH.sub.2), 3.36-3.34 (1H,
m, CH.sub.2), 2.88 (3H, s, NCH.sub.3), 2.14 (3H, s, ArCH.sub.3),
2.07-2.04 (1H, m, CH.sub.2), 1.91-1.88 (1H, m, CH), 1.10-1.05 (1H,
obs t, J=7.6 Hz, CH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 162.68, 159.43, 137.39, 137.29, 131.69, 131.61, 124.01,
123.79, 122.44, 122.40, 113.92, 113.63, 59.88, 56.85, 40.75, 30.71,
23.17, 15.48, 13.91; MS (m/z) 206 [MH.sup.+]; LC purity 93.1%.
(3)
1-(4-Fluoro-3-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00186##
[0265] Free Base:
[0266] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.97-6.94 (1H, m,
ArH), 6.93-6.88 (2H, m, ArH), 3.28-3.25 (1H, d, J=8.4 Hz,
CH.sub.2), 3.08-3.05 (1H, d, J=8.5 Hz, CH.sub.2), 2.52-2.45 (2H, m,
CH.sub.2), 2.35 (3H, s, NCH.sub.3), 2.24 (3H, s, ArCH.sub.3),
1.64-1.59 (1H, m, CH), 1.38-1.35 (1H, obs t, J=4.3 Hz, CH.sub.2)
0.76-0.72 (1H, dd, J=8.1 Hz, 4.4 Hz, CH.sub.2).
[0267] Hydrochloride Salt:
[0268] Yield=134 mg (26%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 12.21 (1H, br-s, N+H), 6.99-6.93 (2H, m, ArH), 6.90-6.84
(1H, t, J=8.8 Hz, ArH), 3.98-3.93 (1H, dd, J=10.6 Hz, 5.1 Hz,
CH.sub.2), 3.83-3.78 (1H, dd, J=10.8 Hz, 4.9 Hz, CH.sub.2),
3.41-3.34 (1H, m, CH.sub.2), 3.27-3.21 (1H, obs t, J=9.4 Hz
CH.sub.2), 2.87-2.85 (3H, d, J=4.5 Hz, NCH.sub.3), 2.18 (3H, s,
ArCH.sub.3) 2.07-2.03 (1H, m, CH.sub.2), 1.92-1.87 (1H, m, CH).
1.09-1.04 (1H, obs t, J=7.5 Hz, CH.sub.2); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 162.00, 158.75, 133.04, 132.99, 130.45, 130.37,
126.18, 126.08, 125.33, 125.09, 115.32, 115.02, 60.37, 56.99,
40.85, 30.71, 22.73, 15.25, 14.28; MS (m/z) 206 [MH.sup.+]; LC
purity 98.6%.
(4) 1-(2,4-Difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00187##
[0270] Free Base:
[0271] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.18-7.13 (1H, m,
ArH), 6.78-6.68 (2H, m, ArH), 3.20-3.16 (1H, dd, J=8.5 Hz, 1.4 Hz,
CH.sub.2), 3.08-3.05 (1H, d, J=8.5 Hz, CH.sub.2), 2.55-2.51 (1H,
dd, J=8.8 Hz, 3.3 Hz, CH.sub.2), 2.40-2.37 (1H, d, J=8.4 Hz,
CH.sub.2), 2.32 (3H, s, NCH.sub.3), 1.65-1.60 (1H, m, CH),
1.35-1.32 (1H, obs t, J=4.3 Hz, CH.sub.2) 0.72-0.68 (1H, dd, J:=8.1
Hz, 4.4 Hz, CH.sub.2).
[0272] Hydrochloride Salt:
[0273] Yield=136 mg (19%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 12.20 (1H, br-s, N+H), 7.22-7.17 (1H, m, ArH), 6.89-6.75
(2H, m, ArH), 3.94-3.85 (2H, m, CH.sub.2), 3.37-3.35 (1H, d, J=8.1
Hz, CH.sub.2), 3.17-3.14 (1H, d, J=10.6 Hz, CH.sub.2), 2.85 (3H, s,
NCH.sub.3), 2.13 (1H, br-s, CH.sub.2), 1.92-1.87 (1H, m, CH),
1.18-1.13 (1H, obs t, J=7.9 Hz, CH.sub.2); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 164.29, 164.13, 163.75, 163.59, 160.97, 160.81,
160.45, 160.29, 131.91, 131.85, 120.51, 120.27, 111.84, 111.50,
104.47, 104.13, 103.79, 59.76, 56.90, 41.03, 26.69, 22.42, 13.37;
MS (m/z) 210 [MH.sup.+]; LC purity 95.1%.
(5) 1-(2,4-Dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00188##
[0275] Free Base:
[0276] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.37-7.16 (3H, m,
ArH), 3.16-3.13 (1H, d, J=8.8 Hz, CH.sub.2), 3.11-3.08 (1H, d,
J=8.8 Hz, CH.sub.2), 2.70-2.66 (1H, dd, J=8.8 Hz, 3.7 Hz,
CH.sub.2), 2.45-2.43 (1H, d, J=8.5 Hz, CH.sub.2), 2.35 (3H, s,
NCH.sub.3), 1.66-1.61 (1H, m, CH), 1.41-1.38 (1H, obs t, J=4.4 Hz,
CH.sub.2) 0.74-0.70 (1H, dd, J=8.1 Hz, 4.4 Hz, CH.sub.2).
(6)
1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00189##
[0278] Free Base:
[0279] Yield=276 mg, (61%) as a white solid. MS(M+1) 254.2. .sup.1H
NMR (CDCl.sub.3) .delta. 7.62-7.68 (m, 2H), 7.54 (m, 1H), 7.22 (m,
1H), 7.08-7.14 (m, 2H), 3.90 (s, 3H), 3.42 (m, 1H), 3.15 (m, 1H),
2.70 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H), 1.77 (m, 1H), 1.48 (m,
1H), 0.91 (m, 1H).
[0280] Hydrochloride Salt:
[0281] Yield=155 mg, (77%) as a white solid. MS (M+1) 254.2.
.sup.1H NMR (CDCl3) .delta..quadrature. 12.56 (br s, 1H),
.quadrature. 7.67 (m, 2H), 7.55 (m, 1H), 7.21 (m, 1H), 7.14 (m,
1H), 7.08 (m, 1H), 4.14 (m, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 3.34
(m, 2H), 2.90 (d, 2H, J=5 Hz). 2.24 (m, 1H), 2.06 (m, 1H), 1.26 (m,
1H). .sup.13C NMR (CDCl.sub.3) .delta. 158.18, 133.92, 132.89,
129.22, 128.87, 127.83, 126.15, 125.43, 119.81, 105.85, 60.76,
57.52, 55.55, 41.45, 31.77, 23.23, 16.11.
(7)
1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00190##
[0283] Free Base:
[0284] Yield=192 mg, (65%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 7.64 (m, 2H), 7.54 (m, 1H), 7.21 (m, 1H),
7.07-7.15 (m, 2H), 4.13 (q, 2H, J=7 Hz), 3.41 (m, 1H), 3.15 (m,
1H), 2.69 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H), 1.77 (m, 1H), 1.48
(m, 1H), 1.47 (t, 3H, J=7 Hz), 0.91 (m, 1H); MS (M+1) 268.2.
[0285] Hydrochloride Salt:
[0286] Yield=172 mg, (81%) as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta..quadrature. 12.50 (br s, 1H), 7.66 (m, 2H),
7.54 (m, 1H), 7.20 (m, 1H), 7.14 (m, 1H), 7.07 (m, 1H), 4.14 (m,
1H), 4.10 (t, 2H, J=7 Hz), 3.93 (m, 1H), 3.34 (m, 2H), 2.90 (d, 3H,
J=5 Hz), 2.22 (m, 1H), 2.06 (m, 1H), 1.45 (t, 3H, J=7 Hz), 1.26 (m,
1H). 13C NMR (CDCl.sub.3) .delta. 157.50, 133.96, 132.76, 129.17,
128.81, 127.79, 126.14, 125.37, 120.09, 106.61, 63.75, 60.77,
57.54, 41.46, 31.77, 23.21, 16.09, 14.98; MS (M+1) 268.2.
Example IX
Preparation of 1-Aryl-3-ethyl-3-aza-bicyclo[3.1.0]hexane
Hydrochlorides Using Reaction Scheme 15
A. Synthesis of 3-Bromo-1-ethylmaleimide
##STR00191##
[0288] A cooled (5.degree. C.) solution of N-ethylmaleimide (20 g,
0.16 mole) in carbon tetrachloride (20 mL) under nitrogen was
treated dropwise over 45 min with bromine (23 g, 0.14 mole) at a
rate to keep pot temp <10.degree. C. The mixture was stirred at
5.degree. C. for 2 hours. Dichloromethane (20 mL) was added to the
reaction and N.sub.2 was bubbled through the reaction for 15 min to
remove excess bromine. The reaction was blown dry with a steady
stream of N.sub.2 and then brought up in ethanol. Anhydrous sodium
acetate (12.3 g, 0.15 mole) was added and the reaction was refluxed
for 4 hours. The mixture was concentrated in vacuo and the residue
taken up in methylene chloride (300 mL), filtered and concentrated
in vacuo to yield an orange oil. Pure 3-bromo-1-ethylmaleimide was
obtained from recrystallization in chloroform to yield a yellowish
solid (26 g, 82%). NO MS (M+1) peak observed. .sup.1H NMR
(CDCl.sub.3) .delta. 1.20 (t, J=7.22 Hz, 3H), 3.62 (q, J=7.22 Hz,
2H), 6.85 (s, 1H).
B. Synthesis of
1-(3,4-Difluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00192##
[0290] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(1.0 g, 5 mmol) and 3,4-difluorophenylboronic acid (850 mg, 5.4
mmol) in dioxane (15 mL) under nitrogen was degassed with a stream
of nitrogen for 10 min, treated with cesium fluoride (1.6 g, 10.8
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol),
then stirred at room temperature for 1 h and at 40.degree. C. for
45 min. The mixture was then cooled and diluted with methylene
chloride (50 mL). The mixture was filtered through Celite.RTM.
(rinse filter cake with methylene chloride) and the brown filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride and filtered through a column of silica gel (eluted with
methylene chloride) to afford a pale yellow solid, which was
triturated from cold petroleum ethers to afford arylmaleimide
intermediate (973 mg, 84%) as a pale yellow solid.
[0291] A stirred suspension of sodium hydride oil dispersion (60%,
160 mg, 4.0 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.58 g,
4.5 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (937 mg, 4.0 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (429 mg, 42%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.09-1.16 (m, 3H) 1.21-1.31
(m, 1H) 1.73-1.87 (m, 2H) 2.72 (dd, J=8.00, 3.90 Hz, 1H) 3.40-3.53
(m, 2H) 7.05-7.22 (m, 2H) 7.26-7.34 (m, 1H).
[0292] A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (429 mg, 1.7 mmol) in anhydrous
THF (10 mL). The solution was stirred at room temperature for 15
min, refluxed for 4 h, cooled on an ice bath, and carefully treated
dropwise with 6N HCl (10 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (25 mL) and ether (50 mL). The organic
layer was separated and the aqueous extracted with ether (50 mL).
The combined organic solution was washed with water (25 mL), dried
(Mg.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL),
then stirred at room temperature for 16 h and at 55.degree. C. for
4 h. The solution was concentrated in vacuo and the residue
triturated from ether to afford
1-(3,4-difluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (105 mg, 21%) as a white solid. MS (M+1) 224. .sup.1H
NMR (CDCl.sub.3) .delta. 1.08-1.19 (m, J=6.64, 6.64 Hz, 1H) 1.49
(t, 3H) 1.71-1.86 (m, 1H) 1.90-2.03 (m, 1H) 2.30 (dd, 1H) 3.00-3.42
(m, 4H) 3.89 (dd, 1H) 4.06 (dd, 1H) 6.69-7.20 (m, 3H). .sup.13C NMR
(CDCl.sub.3) .delta..quadrature. 10.99, 16.31, 22.96, 30.42, 51.17,
55.07, 58.31, 116.85, 117.75, 123.82, 135.79, 148.65, 149.29,
150.63, 151.28.
C. Synthesis of
i-(3-Chloro-4-fluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00193##
[0294] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(1.09 g, 5 mmol) and 3-chloro-4-fluorophenylboronic acid (945 mg,
5.4 mmol) in dioxane (15 mL) under nitrogen was degassed with a
stream of nitrogen for 10 min, treated with cesium fluoride (1.6 g,
10.8 mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3
mmol), then stirred at room temperature for 1 h and at 40.degree.
C. for 45 min. The mixture was then cooled and diluted with
methylene chloride (50 mL). The mixture was filtered through
Celite.RTM. (rinse filter cake with methylene chloride) and the
brown filtrate concentrated in vacuo. The residue was dissolved in
methylene chloride and filtered through a column of silica gel
(eluted with methylene chloride) to afford a pale yellow solid,
which was triturated from cold petroleum ethers to afford
arylmaleimide intermediate (1.0 g, 83%) as a pale yellow solid.
[0295] A stirred suspension of sodium hydride oil dispersion (60%,
160 mg, 3.95 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.56 g,
4.3 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (1.0 g, 3.95 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (567 mg, 54%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.09-1.16 (m, 3H) 1.21-1.31
(m, 1H) 1.73-1.87 (m, 2H) 2.72 (dd, J=8.00, 3.90 Hz, 1H) 3.40-3.53
(m, 2H) 7.05-7.22 (m, 2H) 7.26-7.34 (m, 1H).
[0296] A stirred ice-cooled solution of 1.0N borane/THF (10.5 mL,
10.5 mmol) under nitrogen was treated dropwise with a solution of
the above bicyclic diimide intermediate (560 mg, 2.1 mmol) in
anhydrous THF (10 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (10 mL, vigorous evolution of gas).
The solution was concentrated to a white solid, which was
partitioned between 5N sodium hydroxide (25 mL) and ether (50 mL).
The organic layer was separated and the aqueous extracted with
ether (50 mL). The combined organic solution was washed with water
(25 mL), dried (Mg.sub.2SO.sub.4), and concentrated in vacuo. The
residue was dissolved in methanol (23 mL), treated with 4N
HCl/dioxane (7 mL), then stirred at room temperature for 16 h and
at 55.degree. C. for 4 h. The solution was concentrated in vacuo
and the residue triturated from ether to afford
1-(3-chloro-4-fluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (100 mg, 20%) as a white solid. MS (M+1) 240.1.
.sup.1H NMR (CDCl.sub.3) .delta. 1.13-1.20 (m, 1H) 1.51 (t, J=7.22
Hz, 3H) 1.93-2.02 (m, 1H) 2.36 (dd, J=6.64, 4.69 Hz, 1H) 2.95-3.30
(m, 4H) 3.92 (dd, J=10.84, 5.17 Hz, 1H) 4.10 (dd, J=10.93, 5.27 Hz,
1H) 7.01-7.15 (m, 2H) 7.23 (dd, J=6.74, 2.25 Hz, 1H). .sup.13C NMR
(CDCl.sub.3) .delta..quadrature. 11.22, 16.63, 22.99, 31.42, 55.52,
58.68, 124.82, 126.25, 126.49, 126.96, 127.82, 129.06, 13:2.68,
133.44, 135.59.
D. Synthesis of
1-(3-Fluoro-4-methylphenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00194##
[0298] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(1.0 g, 5 mmol) and 3-fluoro-4-methylphenyl boronic acid (830 mg,
5.4 mmol) in dioxane (15 mL) under nitrogen was degassed with a
stream of nitrogen for 10 min, treated with cesium fluoride (1.6 g,
10.8 mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3
mmol), then stirred at room temperature for 1 h and at 40.degree.
C. for 45 min. The mixture was then cooled and diluted with
methylene chloride (50 mL). The mixture was filtered through
Celite.RTM. (rinse filter cake with methylene chloride) and the
brown filtrate concentrated in vacuo. The residue was dissolved in
methylene chloride and filtered through a column of silica gel
(eluted with methylene chloride) to afford a pale yellow solid,
which was triturated from cold petroleum ethers to afford
arylmaleimide intermediate (888 mg, 80%) as a pale yellow
solid.
[0299] A stirred suspension of sodium hydride oil dispersion (60%,
152 mg, 3.8 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.59 g,
4.2 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (888 mg, 3.81 mmol) was added in one portion
and the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane, loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (297 mg, 31%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.13 (t, J=7.13 Hz, 3H)
1.73-1.84 (m, 2H) 2.24-2.29 (m, J=1.95 Hz, 1H) 2.68 (dd, J=8.00,
3.90 Hz, 1H) 3.42-3.53 (m, 2H) 7.01-7.12 (m, 2H) 7.18 (t, J=7.91
Hz, 1H).
[0300] A stirred ice-cooled solution of 1.0N borane/THF (9.6 mL,
9.6 mmol) under nitrogen was treated dropwise with a solution of
the above bicyclic diimide intermediate (297 mg, 1.2 mmol) in
anhydrous THF (10 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (10 mL, vigorous evolution of gas).
The solution was concentrated to a white solid, which was
partitioned between 5N sodium hydroxide (25 mL) and ether (50 mL).
The organic layer was separated and the aqueous extracted with
ether (50 mL). The combined organic solution was washed with water
(25 mL), dried (Mg.sub.2SO.sub.4), and concentrated in vacuo. The
residue was dissolved in methanol (23 mL), treated with 4N
HCl/dioxane (7 mL), then stirred at room temperature for 16 h and
at 55.degree. C. for 4 h. The solution was concentrated in vacuo
and the residue triturated from ether to afford
1-(3-fluoro-4-methylphenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
hydrochloride(165 mg, 63%) as a white solid. MS (M+1) 220. .sup.1H
NMR (CDCl.sub.3) .quadrature. 1.13 (t, J=7.61 Hz, 1H) 1.48 (t,
J=7.22 Hz, 3H) 1.91-2.00 (m, 1H) 2.20-2.23 (m, J=1.76 Hz, 3H) 2.25
(dd, J=6.64, 4.69 Hz, 1H) 3.13-3.24 (m, 3H) 3.24-3.36 (m, 1H) 3.87
(dd, J=10.93, 5.27 Hz, 1H) 4.05 (dd, J=10.84, 5.37 Hz, 1H)
6.76-6.88 (m, 2H) 7.03-7.16 (m, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 11.13, 14.40, 16.54, 23.05, 30.69, 51.49, 55.26, 58.39,
113.92, 122.62, 124.36, 132.11, 137.89, 160.27, 162.72.
E. Synthesis of
1-(3-Methyl-4-fluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00195##
[0302] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(1.0 g, 5 mmol) and 3-methyl-4-fluorophenyl boronic acid (830 mg,
5.4 mmol) in dioxane (15 mL) under nitrogen was degassed with a
stream of nitrogen for 10 min, treated with cesium fluoride (1.6 g,
10.8 mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3
mmol), then stirred at room temperature for 1 h and at 40.degree.
C. for 45 min. The mixture was then cooled and diluted with
methylene chloride (50 mL). The mixture was filtered through
Celite.RTM. (rinse filter cake with methylene chloride) and the
brown filtrate concentrated in vacuo. The residue was dissolved in
methylene chloride and filtered through a column of silica gel
(eluted with methylene chloride) to afford a pale yellow solid,
which was triturated from cold petroleum ethers to afford
arylmaleimide intermediate (982 mg, 88%) as a pale yellow
solid.
[0303] A stirred suspension of sodium hydride oil dispersion (60%,
170 mg, 4.2 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.60 g,
4.6 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (982 mg, 4.2 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane, loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (460 mg, 50%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.13 (t, J=7.13 Hz, 3H)
1.73-1.84 (m, 2H) 2.24-2.29 (m, J=1.95 Hz, 1H) 2.68 (dd, J=8.00,
3.90 Hz, 1H) 3.42-3.53 (m, 2H) 7.01-7.1:2 (m, 2H) 7.18 (t, J=7.91
Hz, 1H).
[0304] A stirred ice-cooled solution of 1.0N borane/THF (15 mL, 15
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (470 mg, 1.9 mmol) in anhydrous
THF (10 mL). The solution was stirred at room temperature for 15
min, refluxed for 4 h, cooled on an ice bath, and carefully treated
dropwise with 6N HCl (10 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (25 mL) and ether (50 mL). The organic
layer was separated and the aqueous extracted with ether (50 mL).
The combined organic solution was washed with water (25 mL), dried
(Mg.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL),
then stirred at room temperature for 16 h and at 55.degree. C. for
4 h. The solution was concentrated in vacuo and the residue
triturated from ether to afford
1-(3-methyl-4-fluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (400 mg, 89%) as a white solid. MS (M+1) 220. .sup.1H
NMR (CDCl.sub.3) .delta. 1.10 (t, J=7.61 Hz, 1H) 1.47 (t, J=7.22
Hz, 3H) 1.88-1.97 (m, 1H) 2.18-2.21 (m, 1H) 2.21-2.23 (m, J=2.54,
2.54 Hz, 3H) 3.10-3.22 (m, 3H) 3.23-3.33 (m, 1H) 3.86 (dd, J=11.03,
5.37 Hz, 1H) 4.03 (dd, J=10.93, 5.47 Hz, 1H) 6.87-7.03 (m, 3H).
.sup.13C NMR (CDCl.sub.3) .delta. .quadrature. 11.13, 14.76, 16.05,
22.60, 30.71, 51.47, 55.39, 58.87, 115.61, 125.67, 126.44, 130.74,
133.59, 159.54, 161.98.
F. Synthesis of
1-(2,4-Difluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00196##
[0306] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(0.7 g, 3.43 mmol) and 2,4-difluorophenyl boronic acid (0.85 g, 5.4
mmol) in dioxane (15 mL) under nitrogen was degassed with a stream
of nitrogen for 10 min, treated with cesium fluoride (1.6 g, 10.8
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol),
then stirred at room temperature for 0.5 h and at 45.degree. C. for
30 min then at 65.degree. C. for 45 min. The mixture was cooled and
diluted with methylene chloride (50 mL). The mixture was filtered
through Celite.RTM. (rinse filter cake with methylene chloride) and
the brown filtrate concentrated in vacuo. The residue was dissolved
in methylene chloride and filtered through a column of silica gel
(eluted with methylene chloride 60% and ethyl acetate 40%) to
afford a yellowish solid, which was triturated from cold petroleum
ethers to afford arylmaleimide intermediate (922 mg, 80%) as
yellowish solid.
[0307] A stirred suspension of sodium hydride oil dispersion (60%,
155 mg, 3.89 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (922 mg, 3.89 mmol) was added in one portion
and the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane, loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (460 mg, 59%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.14 (t, J=7.13 Hz, 3H)
1.76-1.83 (m, 1H) 1.83-1.93 (m, 1H) 2.61 (dd, J=8.40, 3.71 Hz, 1H)
3.41-3.55 (m, 2H) 6.77-6.95 (m, 2H) 7.27-7.37 (m, 1H).
[0308] A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (460 mg, 2.2 mmol) in anhydrous
THF (10 mL). The solution was stirred at room temperature for 15
min, refluxed for 4 h, cooled on an ice bath, and carefully treated
dropwise with 6N HCl (10 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (25 mL) and ether (50 mL). The organic
layer was separated and the aqueous extracted with ether (50 mL).
The combined organic solution was washed with water (25 mL), dried
(Mg.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL),
then stirred at room temperature for 16 h and at 55.degree. C. for
4 h. The solution was concentrated in vacuo and the residue
triturated from ether to afford
1-(2,4-difluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (250 mg, 62%) as a white solid. MS (M+1) 224. .sup.1H
NMR (CDCl.sub.3) .delta. 1.15 (t, J=7.71 Hz, 1H) 1.46 (t, J=7.22
Hz, 3H) 1.84-1.93 (m, 1H) 2.17-2.25 (m, 1H) 3.06-3.21 (m, 3H)
3.27-3.36 (m, 1H) 3.84-3.99 (m, 2H) 6.68-6.88 (m, 2H) 7.14-7.25 (m,
1H). .sup.13C NMR (CDCl.sub.3) .delta..quadrature. 11.04, 13.78,
22.38, 26.60, 51.46, 55.16, 58.09, 104.50, 112.05, 132.29.
G. Synthesis of
1-(2,4-Dichlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00197##
[0310] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(0.7 g, 3.43 mmol) and 2,4-dichlorophenylboronic acid (1.03 g, 5.4
mmol) in dioxane (15 mL) under nitrogen was degassed with a stream
of nitrogen for 10 min, treated with cesium fluoride (1.6 g, 10.8
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol),
then stirred at room temperature for 0.5 h and at 45.degree. C. for
30 min then at 65.degree. C. for 45 min. The mixture was cooled and
diluted with methylene chloride (50 mL). The mixture was filtered
through Celite.RTM. (rinse filter cake with methylene chloride) and
the brown filtrate concentrated in vacuo. The residue was dissolved
in methylene chloride and filtered through a column of silica gel
(eluted with methylene chloride 60% and ethyl acetate 40%) to
afford a yellowish solid, which was triturated from cold petroleum
ethers to afford arylmaleimide intermediate (1.32 g, 87%) as
yellowish solid.
[0311] A stirred suspension of sodium hydride oil dispersion (60%,
165 mg, 4.1 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.58 g,
4.5 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (1.1 g, 4.1 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane, loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (603 mg, 52%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.15 (t, 3H) 1.86 (dd,
J=4.88, 3.71 Hz, 1H) 1.93 (dd, J=8.20, 4.88 Hz, 1H) 2.57 (dd,
J=8.30, 3.81 Hz, 1H) 3.44-3.53 (m, 2H) 7.29 (d, J=1.17 Hz, 2H) 7.45
(t, J=1.17 Hz, 1H).
[0312] A stirred ice-cooled solution of 1.0N borane/THF (5 mL, 5
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (200 mg, 0.7 mmol) in anhydrous
THF (10 mL). The solution was stirred at room temperature for 15
min, refluxed for 4 h, cooled on an ice bath, and carefully treated
dropwise with 6N HCl (10 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (25 mL) and ether (50 mL). The organic
layer was separated and the aqueous extracted with ether (50 mL).
The combined organic solution was washed with water (25 mL), dried
(Mg.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL),
then stirred at room temperature for 16 h and at 55.degree. C. for
4 h. The solution was concentrated in vacuo and the residue
triturated from ether to afford
1-(2,4-dichlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (115 mg, 47%) as a white solid. MS (M+1) 256.1.
.sup.1H NMR (CDCl.sub.3) .delta..quadrature. 1.16-1.23 (m, 1H) 1.47
(t, J=6.44 Hz, 3H) 1.87-1.93 (m, 1H) 2.23-2.31 (m, 1H) 3.10-3.28
(m, 3H) 3.36-3.48 (m, 1H) 3.81-3.98 (m, 2H) 7.19-7.32 (m, 3H).
.sup.13C NMR (CDCl.sub.3) .delta..quadrature. 11.13, 14.34, 23.43,
30.37, 51.57, 55.36, 57.48, 128.15, 129.96, 133.00, 133.69, 135.27,
136.11.
H. Synthesis of
1-(Naphthalen-2-yl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00198##
[0314] A stirred solution/suspension of 3-bromo-1-ethylmaleimide
(1.0 g, 5 mmol) and naphthalene-2-boronic acid (930 mg, 5.4 mmol)
in dioxane (15 mL) under nitrogen was degassed with a stream of
nitrogen for 10 min, treated with cesium fluoride (1.6 g, 10.8
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol),
then stirred at room temperature for 1 h and at 40.degree. C. for
45 min. The mixture was then cooled and diluted with methylene
chloride (50 mL). The mixture was filtered through Celite.RTM.
(rinse filter cake with methylene chloride) and the brown filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride and filtered through a column of silica gel (eluted with
methylene chloride) to afford a pale yellow solid, which was
triturated from cold petroleum ethers to afford arylmaleimide
intermediate (925 mg, 75%) as a pale yellow solid.
[0315] A stirred suspension of sodium hydride oil dispersion (60%,
145 mg, 3.68 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.52 g,
4.05 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (925 mg, 3.68 mmol) was added in one portion
and the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (466 mg, 48%) as a very pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.16 (t, J=7.13 Hz, 3H)
1.82-1.90 (m, 1H) 1.95 (dd, J=8.20, 4.69 Hz, 1H) 2.80 (dd, J=8.20,
3.71 Hz, 1H) 3.43-3.59 (m, 2H) 7.43-7.54 (m, 3H) 7.73-7.92 (m,
4H).
[0316] A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (466 mg, 1.76 mmol) in
anhydrous THF (10 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (10 mL, vigorous evolution of gas).
The solution was concentrated to a white solid, which was
partitioned between 5N sodium hydroxide (25 mL) and ether (50 mL).
The organic layer was separated and the aqueous extracted with
ether (50 mL). The combined organic solution was washed with water
(25 mL), dried (Mg.sub.2SO.sub.4), and concentrated in vacuo. The
residue was dissolved in methanol (23 mL), treated with 4N
HCl/dioxane (7 mL), then stirred at room temperature for 16 h and
at 55.degree. C. for 4 h. The solution was concentrated in vacuo
and the residue triturated from ether to afford
1-(naphthalene-2-yl)-3-ethyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (110 mg, 20%) as a white solid. MS (M+1) 238. .sup.1H
NMR (CDCl.sub.3) .delta. 1.29 (t, J=7.42 Hz, 1H) 1.53 (t, J=6.44
Hz, 3H) 2.07-2.14 (m, 1H) 2.3:3-2.41 (m, 1H) 3.16-3.26 (m, 2H)
3.26-3.38 (m, 2H) 3.95 (d, 1H) 4.20 (d, J=7.22 Hz, 1H) 7.23 (s, 1H)
7.42-7.54 (m, 2H) 7.63 (s, 1H) 7.73-7.86 (m, 3H). .sup.13C NMR
(CDCl.sub.3) .delta..quadrature. 158.83, 156.34, 135.62, 129.93,
127.57, 121.54, 117.17, 59.78, 57.35, 53.99, 30.68, 23.06, 19.05,
16.29.
Example X
Preparation of 1-Aryl-3-isopropyl-3-aza-bicyclo[3.1.0]hexane
Hydrochlorides Using Reaction Scheme 16
A. Synthesis of 3-Bromo-1-(1-methylethyl)maleimide
##STR00199##
[0318] A cooled (5.degree. C.) stirred solution of maleic anhydride
(29.4 g, 0.30 mole) in anhydrous ether (150 mL) under nitrogen was
treated dropwise over 45 min with a solution of isopropylamine
(35.5 g, 0.60 mole) in anhydrous ether (100 mL) at a rate to keep
the pot temp <20.degree. C. The mixture was then stirred at
10.degree. C. for 15 min, filtered, and the filter cake rinsed with
anhydrous ether and dried in vacuo to afford a white solid. This
was taken up in acetic anhydride (250 mL), treated with anhydrous
sodium acetate (12.3 g, 0.15 mole), and heated to 75.degree. C.
with stirring for 4.5 h, then at 100.degree. C. for 1.5 h. The
mixture was concentrated in vacuo and the residue taken up in
methylene chloride (300 mL), washed with saturated aqueous sodium
bicarbonate (200 mL), water (200 mL), dried (MgSO.sub.4), and
concentrated in vacuo. The residue was distilled (approx. 5 mm
pressure) to afford two products; one an N-isopropylmaleimide that
distilled at 82.degree. C. (13.0 g), the other an acetate adduct of
N-isopropylmaleimide that distilled at 154.degree. C. (12.9 g). The
acetate adduct was dissolved in 4:1 acetonitrile/triethylamine (100
mL), heated to 65.degree. C. for 4 h, then concentrated in vacuo.
The residue was dissolved in methylene chloride and filtered
through a pad of silica gel (eluted with methylene chloride) to
afford an additional 3.5 g of N-isopropylmaleimide. Total yield was
16.5 g of N-isopropylmaleimide (40%).
[0319] A stirred ice-cold solution of N-isopropylmaleimide (16.4 g,
0.118 mole) in carbon tetrachloride (12 mL) under nitrogen was
treated dropwise with bromine (6.41 mL, 0.25 mole) at a rate to
keep the pot temp <9.degree. C., then stirred at 3.degree. C.
for 2 h, during which time the mixture formed a solid cake. The
cake was maintained under a stream of nitrogen to allow excess
bromine and CCl.sub.4 to evaporate. The reaction mixture was then
placed under vacuum to remove the remaining solvent. Ethanol (100
mL) was added to the flask, followed by sodium acetate (11 g, 0.134
mole), and the mixture was refluxed for 16 h with stirring. The
cooled solution was filtered through Celite.RTM. (filter cake
rinsed with methylene chloride), and the filtrate concentrated in
vacuo, dissolved in methylene chloride, filtered through a pad of
alumina (eluted with methylene chloride), and re-concentrated in
vacuo. The residue was dissolved in 2:1 petroleum ether/methylene
chloride, loaded onto a column of silica gel, and eluted
successively with 2:1 petroleum ethers/CH.sub.2Cl.sub.2, 1:1
petroleum ethers/CH.sub.2Cl.sub.2, and CH.sub.2Cl.sub.2 alone to
afford the subject compound (16.45 g, 64% yield) as a pale yellow,
low melting solid. No MS (M+1) peak observed. .sup.1H NMR
(CDCl.sub.3) .delta. 6.78 (s, 1H), 4.30-4.40 (m, 1H), 1.37 (d, 6H,
J=8 Hz))
B. Synthesis of
1-(2,4-dichlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00200##
[0321] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
3,4-difluorophenylboronic acid (987 mg, 6.25 mmol) in dioxane (15
mL) under nitrogen was degassed with a stream of nitrogen for 10
min, treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 40.degree. C. for 3 h. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a pale yellow solid, which was triturated from
cold petroleum ethers to afford arylmaleimide intermediate (1.024
g, 82%) as a very pale yellow solid. No MS (M+1) peak. .sup.1H NMR
(CDCl.sub.3) .delta. 7.83 (m, 1H), 7.67 (m, 1H), 7.24 (m, 1H), 6.64
(s, 1H), 4.39 (m, 1H), 1.43 (d, 6H, J=7 Hz).
[0322] A stirred suspension of sodium hydride oil dispersion (60%,
140 mg, 3.5 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethylsulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (879 mg, 3.5 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (793 mg, 85%) as a white solid. No MS
(M+1) peak. .sup.1H NMR (CDCl.sub.3) .delta. 7.29 (m, 1H),
7.07-7.20 (m, 2H), 4.24 (m, 1H), 2.68 (m, 1H), 1.71-1.76 (m, 2H),
1.34 (m, 6H).
[0323] A stirred ice-cooled solution of 1.0N borane/THF (21 mL, 21
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (780 mg, 2.94 mmol) in
anhydrous THF (14 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (12 mL, vigorous evolution of gas).
The solution was concentrated to a white solid, which was
partitioned between 5N sodium hydroxide (30 mL) and ether (60 mL).
The organic layer was separated and the aqueous extracted with
ether (60 mL). The combined organic solution was washed with water
(2.times.35 mL), dried (Mg.sub.2SO.sub.4), and concentrated in
vacuo. The residue was dissolved in methanol (30 mL), treated with
4N HCl/dioxane (10 mL), stirred at room temperature for 60 h (only
16 h needed), and at 55.degree. C. for 4 h. The solution was
concentrated in vacuo and the residue was triturated from ether
containing a little acetonitrile to afford
1-(3,4-difluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (585 mg, 73%) as a white solid. MS (M+1) 238.2.
.sup.1H NMR (CDCl.sub.3) .delta. 7.08 (m, 2H), 6.92 (m, 1H), 4.02
(m, 1H), 3.84 (m, 1H), 3.35 (m, 2H), 3.22 (m, 1H), 2.39 (m, 1H),
1.96 (m, 1H), 1.51 (d, 6H, J=6 Hz), 1.10 (m, 1H). .sup.13C NMR
(CDCl.sub.3) .delta..quadrature. 151.82, 149.34, 135.59, 123.85,
118.08, 116.89, 59.75, 57.30, 53.97, 30.80, 23.19, 19.04,
16.34.
C. Synthesis of
L-(3-chloro-4-fluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00201##
[0325] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
3-chloro-4-fluorophenylboronic acid (1.09 g, 6.25 mmol) in dioxane
(15 mL) under nitrogen was degassed with a stream of nitrogen for
10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 40.degree. C. for 45 min. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a pale yellow solid, which was triturated from
cold petroleum ethers to afford arylmaleimide intermediate (1.10 g,
82%) as a pale yellow solid. No MS (M+1) peak. .sup.1H NMR
(CDCl.sub.3) .delta. 8.03 (m, 1H), 7.80 (m, 1H), 7.20-7.30 (m, 1H),
6.65 (s, 1H). 4.40 (m, 1H), 1.43 (d, 6H, J=7 Hz).
[0326] A stirred suspension of sodium hydride oil dispersion (60%,
140 mg, 3.5 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (937 mg, 3.5 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was dissolved in 1:1
methylene chloride/heptane, loaded onto a silica gel column and
eluted with 1:1, 2:1, then 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (628 mg, 64%) as a very pale yellow
oil. No MS (M+1) peak. .sup.1H NMR (CDCl.sub.3) .delta. 7.48 (m,
1H), 7.27 (m, 1H), 7.14 (m, 1H), 4.23 (m, 1H), 2.69 (m, 1H), 1.74
(m, 2H), 1.34 (m, 614).
[0327] A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (620 mg, 2.2 mmol) in anhydrous
THF (10 mL). The solution was stirred at room temperature for 15
min, refluxed for 4 h, cooled on an ice bath, and carefully treated
dropwise with 6N HCl (10 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (25 mL) and ether (50 mL). The organic
layer was separated and the aqueous extracted with ether (50 mL).
The combined organic solution was washed with water (25 mL), dried
(Mg.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL),
then stirred at room temperature for 16 h and at 55.degree. C. for
4 h. The solution was concentrated in vacuo and the residue
triturated from ether to afford
1-(3-chloro-4-fluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
hydrochloride (520 mg, 81%) as a white solid. MS (M+1) 254.1.
.sup.1H NMR. (CDCl.sub.3) .delta. 7.25 (m, 1H), 7.08 (m, 2H), 4.04
(m, 1H), 3.85 (m, 1H), 3.35 (m, 2H), 3.21 (m, 1H), 2.39 (m, 1H),
1.97 (m, 1H), 1.50 (d, 6H, J=7 Hz), 1.10 (m, 1H). .sup.13C NMR
(CDCl.sub.3) .delta..quadrature. 158.83, 156.34, 135.62, 129.93,
127.57, 121.54, 117.17, 59.78, 57.35, 53.99, 30.68, 23.06, 19.05,
16.29.
D. Synthesis of
1-(3-Fluoro-4-methylphenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00202##
[0329] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
3-fluoro-4-methylphenylboronic acid (962 mg, 6.25 mmol) in dioxane
(15 mL) under nitrogen was degassed with a stream of nitrogen for
10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 40.degree. C. for 1 h. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a yellow solid, which was triturated from
petroleum ethers to afford arylmaleimide intermediate (1.11 g, 90%)
as a pale yellow solid. No MS (M+1) peak. .sup.1H NMR (CDCl.sub.3)
.delta. 7.60 (m, 2H), 7.24 (m, 1H), 6.62 (s, 1H), 4.39 (m, 1H),
2.32 (br s, 3H), 1.43 (d, 6H, J=7 Hz).
[0330] A stirred suspension of sodium hydride oil dispersion (60%,
140 mg, 3.5 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (866 mg, 3.5 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual oil was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, 2:1, and 3:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (633 mg, 69%) as a white solid. MS
(M+1) 262.1. .sup.1H NMR (CDCl.sub.3) .delta. 7.17 (m, 1H), 7.09
(m, 1H), 7.04 (m, 1H), 4.24 (m, 1H), 2.64 (m, 1H), 2.26 (br s, 3H),
1.70-1.80 (m, 2H), 1.34 (m, 6H).
[0331] A stirred ice-cooled solution of 1.0N borane/THF (17 mL, 17
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (619 mg, 2.37 mmol) in
anhydrous THF (11 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (10 mL, vigorous evolution of gas).
The solution was concentrated to a white solid, which was
partitioned between 5N sodium hydroxide (25 mL) and ether (50 mL).
The organic layer was separated and the aqueous extracted with
ether (50 mL). The combined organic solution was washed with water
(2.times.30 mL), dried (Mg.sub.2SO.sub.4), and concentrated in
vacuo. The residue was dissolved in methanol (23 mL), treated with
4N HCl/dioxane (7 mL), then stirred at room temperature for 60 h
(only requires 14 h) and at 55.degree. C. for 4 h. The solution was
concentrated in vacuo and the residue triturated from ether to
afford
1-(3-fluoro-4-methylphenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (538 mg, 84%) as a white solid. MS (M+1) 234.2.
.sup.1H NMR (CDCl.sub.3) .delta. 7.11 (m, 1H), 6.82 (m, 2H), 4.02
(m, 1H), 3.83 (m, 1H), 3.32 (m, 2H), 3.23 (m, 1H), 2.35 (m, 1H),
2.21 (s, 3H), 1.94 (s, 1H), 1.51 (d, 6H, J=7 Hz), 1.10 (m, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 132.13, 124.39, 124.22, 122.68,
114.06, 113.84, 59.68, 57.22, 53.98, 30.88, 23.16, 19.02, 16.58,
14.41.
E. Synthesis of
1-(4-Fluoro-3-methylphenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00203##
[0333] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
4-fluoro-3-methylphenylboronic acid (962 mg, 6.25 mmol) in dioxane
(15 mL) under nitrogen was degassed with a stream of nitrogen for
10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 40.degree. C. for 1 h. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a yellow solid, which was triturated from cold
petroleum ethers to afford arylmaleimide intermediate (1.14 g, 92%)
as a very pale yellow solid. No MS (M+1) peak. .sup.1H NMR
(CDCl.sub.3) .delta. 7.77 (m, 1H), 7.72 (m, 1H), 7.06 (m, 1H), 6.58
(s, 1H), 4.38 (m, 1H), 2.32 (br s, 3H), 1.43 (d, 6H, J=7 Hz).
[0334] A stirred suspension of sodium hydride oil dispersion (60%,
140 mg, 3.5 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (866 mg, 3.5 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual oil was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, then 2:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (510 mg, 56%) as a colorless oil. No
MS (M+1) peak. .sup.1H NMR (CDCl.sub.3) .delta. 7.23 (m, 1H), 7.16
(m, 1H), 6.99 (m, 1H), 4.23 (m, 1H), 2.63 (m, 1H), 2.27 (br s, 3H),
1.72 (m, 2H), 1.34 (m, 6H).
[0335] A stirred ice-cooled solution of 1.0N borane/THF (7.5 mL,
7.5 mmol) under N.sub.2 was treated dropwise with a solution of the
above bicyclic diimide intermediate (268 mg, 1.026 mmol) in
anhydrous THF (5 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (5 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (15 mL) and ether (30 mL). The organic
layer was separated and the aqueous extracted with ether (30 mL).
The combined organic solution was washed with water (2.times.15
mL), dried (Mg.sub.2SO.sub.4), and concentrated in vacuo. The
residue was dissolved in methanol (12 mL), treated with 4N
HCl/dioxane (4 mL), and stirred at room temperature for 14 h and at
55.degree. C. for 4 h. The solution was concentrated in vacuo and
the residue triturated from ether to afford
1-(4-fluoro-3-methylphenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (230 mg, 83%) as a white solid. MS (M+1) 234.2.
.sup.1H NMR (CDCl.sub.3) .delta. 6.96 (m, 3H), 4.03 (m, 1H), 3.86
(m, 1H), 3.29 (m, 2H), 3.17 (m, 1H), 2.34 (m, 1H), 2.24 (s, 3H),
1.93 (m, 1H), 1.52 (d, 6H, J=7 Hz), 1.09 (m, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 161.52, 159.56, 133.69, 130.66, 126.39,
125.50, 115.48, 59.48, 57.57, 53.98, 30.70, 22.57, 18.87, 15.83,
14.58.
F. Synthesis of
1-(2,4-Difluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00204##
[0337] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
2,4-difluorophenylboronic acid (987 mg, 6.25 mmol) in dioxane (15
mL) under nitrogen was degassed with a stream of nitrogen for 10
min, treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 60.degree. C. for 1 h. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a pale yellow solid, which was triturated from
cold petroleum ethers to afford arylmaleimide intermediate (941,
75%) as a very pale yellow solid. No MS (M+1) peak. .sup.1H NMR
(CDCl.sub.3) .delta. 8.33 (m, 1H), 6.88-7.02 (m, 2H), 6.85 (m, 1H),
4.40 (m, 1H), 1.43 (d, 6H, J=7 Hz).
[0338] A stirred suspension of sodium hydride oil dispersion (60%,
140 mg, 3.5 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (879 mg, 3.5 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residue was dissolved in 1:1
methylene chloride/heptane and loaded onto a silica gel column and
eluted with 1:1, 3:2, and 2:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (292 mg, 32%) as a pale yellow solid.
MS (M+1) 266.1. .sup.1H NMR (CDCl.sub.3) .delta. 7.31 (m, 1H),
6.82-6.92 (m, 2H), 4.24 (m, 1H), 2.57 (m, 1H), 1.84 (m, 1H), 1.74
(m, 1H), 1.35 (m, 6H).
[0339] A stirred ice-cooled solution of 1.0N borane/THF (8 mL, 8
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (290 mg, 1.093 mmol) in
anhydrous THF (5 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (5 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (15 mL) and ether (30 mL). The organic
layer was separated and the aqueous extracted with ether (30 mL).
The combined organic solution was washed with water (20 mL), dried
(Mg.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methanol (15 mL), treated with 4N HCl/dioxane (5 mL),
and stirred at room temperature for 60 h (needed only 14 h) and at
55.degree. C. for 4 h. The solution was concentrated in vacuo and
the residue triturated from ether to afford
1-(2,4-difluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (280 mg, 94%) as a white solid. MS (M+1) 238.2.
.sup.1H NMR (CDCl.sub.3) .delta. 7.21 (m, 1H), 6.82 (m, 2H), 3.88
(m, 2H), 3.39 (m, 1H), 3.31 (m, 1H), 3.18 (m, 1H), 2.32 (m, 1H),
1.86 (m, 1H), 1.49 (m, 6H), 1.14 (m, 1H). .sup.13C NMR (CDCl.sub.3)
.delta..quadrature..quadrature. 164.19, 161.70, 132.36, 121.03,
112.13, 104.48, 59.33, 56.71, 53.61, 26.77, 22.61, 18.82, 13.69
G. Synthesis of
1-(2,4-Dichlorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00205##
[0341] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
2,4-dichlorophenylboronic acid (1.19 g, 6.25 mmol) in dioxane (15
mL) under nitrogen was degassed with a stream of nitrogen for 10
min, treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 60.degree. C. for 1 h. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a pale yellow oil, which was triturated from
cold petroleum ethers to afford arylmaleimide intermediate (11.038
g, 73%) as a white solid. No MS (M+1) peak. .sup.1H NMR
(CDCl.sub.3) .delta. 7.68 (m, 1H), 7.52 (m, 1H), 7.34 (m, 1H), 6.94
(s, 1H), 4.40 (m, 1H), 1.44 (d, 6H, J=7 Hz).
[0342] A stirred suspension of sodium hydride oil dispersion (60%,
140 mg, 3.5 mmol) in anhydrous tetrahydrofuran (30 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.55 g,
4.25 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (995 mg, 3.5 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 3 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.50 mL), and the
combined extracts washed with water (30 mL), dried (MgSO.sub.4),
and concentrated in vacuo. The residual oil was dissolved in 1:1
methylene chloride/heptane, loaded onto a silica gel column and
eluted with 1:1, then 2:1 methylene chloride/heptane to afford
bicyclic diimide intermediate (523 mg, 50%) as a pale yellow solid.
No MS (M+1) peak. .sup.1H NMR (CDCl.sub.3) .delta. 7.44 (m, 1H),
7.28 (m, 2H), 4.25 (m, 1H), 2.51 (m, 1H), 1.90 (m, 1H), 1.81 (m,
1H), 1.35 (d, 6H, J=7 Hz).
[0343] A stirred ice-cooled solution of 1.0N borane/THF (12 mL, 12
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (498 mg, 1.67 mmol) in
anhydrous THF (8 mL). The solution was stirred at room temperature
for 15 min, refluxed for 4 h, cooled on an ice bath, and carefully
treated dropwise with 6N HCl (7 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (20 mL) and ether (40 mL). The organic
layer was separated and the aqueous extracted with ether (40 mL).
The combined organic solution was washed with water (2.times.25
mL), dried (Mg.sub.2SO.sub.4), and concentrated in vacuo. The
residue was dissolved in methanol (15 mL), treated with 4N
HCl/dioxane (5 mL), and stirred at room temperature for 60 h
(needed only 14 h) and at 55.degree. C. for 4 h. The solution was
concentrated in vacuo and the residue triturated from ether to
afford
1-(2,4-dichlorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (347 mg, 68%) as a white solid. MS (M+1) 270.1.
.sup.1H NMR (CDCl.sub.3) .delta..quadrature. 7.39 (d, 1H, J=2 Hz),
7.29 (d, 1H, J=8 Hz), 7.23 (dd, 1H, J=8 Hz, 2 Hz), 3.83 (m, 2H),
3.48 (m, 1H), 3.30 (m, 2H), 2.39 (m, 1H), 1.88 (m, 1H), 1.50 (m,
6H), 1.16 (m, 1H). .sup.13C NMR. (CDCl.sub.3) .delta..quadrature.
136.06, 135.20, 133.78, 133.76, 129.92, 128.12, 59.36, 56.03,
53.73, 30.46, 23.51, 18.94, 14.25.
H. Synthesis of
1-(2-Naphthyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00206##
[0345] A stirred solution/suspension of
3-bromo-1-(1-methylethyl)maleimide (1.09 g, 5 mmol) and
naphthalene-2-boronic acid (1.08 g, 6.25 mmol) in dioxane (15 mL)
under nitrogen was degassed with a stream of nitrogen for 10 min,
treated with cesium fluoride (1.8 g, 11.8 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (0.25 g, 0.3 mmol), then stirred
at room temperature for 1 h and at 40.degree. C. for 2 h. The
mixture was then cooled and diluted with methylene chloride (50
mL). The mixture was filtered through Celite.RTM. (rinse filter
cake with methylene chloride) and the brown filtrate concentrated
in vacuo. The residue was dissolved in methylene chloride and
filtered through a column of silica gel (eluted with methylene
chloride) to afford a solid, which was triturated from petroleum
ethers to afford the arylmaleimide intermediate (1.045 g, 79%) as a
bright yellow solid. No MS (M+1) peak. .sup.1H NMR (CDCl.sub.3)
.delta. 8.67 (br s, 1H), 7.75-7.95 (m, 4H), 7.54 (m, 2H), 6.76 (s,
1H), 4.44 (m, 1H), 1.47 (d, 6H, J=7 Hz).
[0346] A stirred suspension of sodium hydride oil dispersion (60%,
120 mg, 3.0 mmol) in anhydrous tetrahydrofuran (25 mL) under
nitrogen was treated with trimethyl-sulfoxonium chloride (0.52 g,
4.0 mmol), then refluxed for 2.5 h and cooled (50.degree. C.). The
above arylmaleimide (796 mg, 3.0 mmol) was added in one portion and
the mixture stirred at 50.degree. C. for 2 h, cooled on an ice
bath, and quenched with saturated ammonium chloride (10 mL). The
product mixture was extracted with ether (2.times.40 mL) and the
combined extracts were rinsed with water (30 mL), dried
(MgSO.sub.4), and concentrated in vacuo. The residue was dissolved
in petroleum ethers containing a little methylene chloride, loaded
onto a silica gel column, and eluted with 15% ethyl
acetate/petroleum ethers to afford bicyclic diimide intermediate
(577 mg, 69%) as an orange solid. MS (M+1) 280.2. .sup.1H NMR
(CDCl.sub.3) .delta. 7.80-7.90 (m, 4H), 7.50 (m, 3H), 4.28 (m, 1H),
2.77 (m, 1H), 1.90 (m, 1H), 1.81 (m, 1H), 1.38 (m, 6H).
[0347] A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16
mmol) under nitrogen was treated dropwise with a solution of the
above bicyclic diimide intermediate (560 mg, 2.0 mmol) in anhydrous
THF (10 mL). The solution was stirred at room temperature for 15
min, refluxed for 8 h, cooled on an ice bath, and carefully treated
dropwise with 6N HCl (7 mL, vigorous evolution of gas). The
solution was concentrated to a white solid, which was partitioned
between 5N sodium hydroxide (25 mL) and ether (50 mL). The organic
layer was separated and the aqueous extracted with ether
(2.times.25 mL). The combined organic solution was washed with
water (25 mL), dried (Mg.sub.2SO.sub.4), and concentrated in vacuo.
The residue was dissolved in methanol (20 mL), treated with 4N
HCl/dioxane (7 mL), and stirred at room temperature for 14 h and at
55.degree. C. for 4 h. The solution was concentrated in vacuo and
the residue triturated from ether to afford
1-(2-naphthyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (337 mg, 67%) as a white solid. MS (M+1) 252.2.
.sup.1H NMR (CDCl.sub.3) .delta. 7.81 (m, 3H), 7.63 (br s, 1H),
7.50 (m, 2H), 7.24 (m, 1H), 4.18 (m, 1H), 3.94 (m, 1H), 3.35 (m,
3H), 2.49 (m, 1H), 2.11 (m, 1H), 1.57 (d, 6H, J=6 Hz), 1.27 (m,
1H). .sup.13C NMR (CDCl.sub.3) .delta..quadrature. 135.66, 133.21,
132.41, 128.77, 127.65, 127.54, 126.67, 126.20, 126.07, 124.75,
59.49, 57.23, 54.01, 31.29, 22.93, 18.90, 16.31.
Example XI
Preparation of 1-Aryl-3-aza-bicyclo[3.1.0]hexane hydrochlorides
Using Reaction Scheme 17
A. Synthesis of 3-Bromo-1-(3,4-dimethoxybenzyl)maleimide
##STR00207##
[0349] A solution of bromomaleic anhydride (Aldrich, 20.0 g, 0.113
mole) in anhydrous tetrahydrofuran (100 mL) under nitrogen was
treated dropwise with a solution of 3,4-dimethoxybenzylamine (20.0
g, 0.1196 mole) in anhydrous THF (40 mL) over 30 min, and the
stirred mixture was then refluxed for 3 h and maintained at room
temperature for 20 h. The mixture was concentrated in vacuo,
suspended in acetic anhydride (135 mL), treated with anhydrous
sodium acetate (6.15 g, 75 mmol), and heated to 50.degree. C. with
stirring under nitrogen for 4 h (solids dissolved after a few
minutes). The mixture was concentrated in vacuo and dissolved in
methylene chloride (300 mL). The solution was washed with saturated
aqueous sodium bicarbonate (150 mL), then with water (150 mL),
dried (Na.sub.2SO.sub.4), and concentrated in vacuo to a brown
residue. This was dissolved in methylene chloride and passed
through a column of silica gel (.about.400 mL volume) and eluted
with methylene chloride to afford a tan solid, which was
recrystallized from ethyl acetate/heptane (2 crops) to afford
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (24.75 g, 67%) as a pale
tan solid. NO MS (M+1) peak. .sup.1H NMR (CDCl.sub.3) .delta.
6.89-6.94 (m, 2H), 6.84 (s, 1H), 6.78 (d, 1H, J=8 Hz), 4.63 (s,
2H), 3.86 (s, 3H), 3.84 (s, 3H).
B. Synthesis of 1-(3,4-Difluorophenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00208##
[0351] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.14 g, 3.5 mmol) and
3,4-difluorophenylboronic acid (0.71 g, 4.5 mmol) in anhydrous
dioxane (10 mL) under nitrogen was degassed over 10 min with a
stream of nitrogen, then treated with cesium fluoride (1.3 g, 8.5
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.17 g, 0.21
mmol), stirred 1 h at room temperature, then 2 h at 40.degree. C.
The mixture was cooled, diluted with methylene chloride (50 mL),
stirred a few minutes, filtered through Celite.RTM. (rinse with
methylene chloride), and the filtrate concentrated in vacuo. The
residue was dissolved in methylene: chloride and loaded onto a
silica gel column and the product eluted with 3% ethyl
acetate/methylene chloride to afford a yellow solid, which was
triturated from petroleum ethers to afford the intermediate
arylmaleimide (954 mg, 76%) as a very pale yellow solid. NO MS
(M+1) peak. .sup.1H NMR (CDCl.sub.3) .delta. 7.84 (m, 1H), 7.68 (m,
1H), 7.24 (m, 1H), 6.93-6.99 (m, 2H), 6.80 (m, 1H), 6.70 (s, 1H),
4.66 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H).
[0352] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (431 mg, 3.35 mmol) in anhydrous
tetrahydrofuran (10 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.4N, 1.2 mL, 2.85 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (900 mg, 2.5 mmol) in anhydrous THF
(10 mL) was heated to 50.degree. C., then added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 2 h, and cooled on an ice bath.
Saturated aqueous ammonium chloride (2 mL) was added to quench, and
the mixture was diluted with methylene chloride (75 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 1%, 2%, then 3% ethyl acetate/methylene
chloride to afford the intermediate bicyclic diimide (602 mg, 65%)
as a pale yellow gum. MS (M+1) 374.2. .sup.1H NMR (CDCl.sub.3)
.delta. 7.28 (m, 1H), 7.15 (m, 1H), 7.08 (m, 1H), 6.87-6.92 (m,
2H), 6.78 (m, 1H), 4.50 (m, 2H), 3.85 (s, 2H), 3.84 (s, 2H), 2.72
(m, 1H), 1.72 (m, 2H).
[0353] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (10.6 mL, 10.6 mmol) under nitrogen was
treated slowly with a solution of the above intermediate bicyclic
diimide (597 mg, 1.6 mmol) in anhydrous THF (7 mL), stirred 1 h at
room temperature, refluxed for 6 h, and cooled (5.degree. C.).
Water (0.4 mL), 150/% sodium hydroxide (0.4 mL), and water (1.2 mL)
were carefully added dropwise, followed by additional THF to
facilitate stirring. The suspension was stirred 15 min, filtered
through Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (345 mg, 63%) as a colorless viscous
oil. MS (M+1) 346.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.03 (m, 1H),
6.86-6.95 (m, 2H), 6.78-6.85 (m, 3H), 3.88 (s, 3H), 3.86 (s, 3H),
3.60 (m, 2H), 3.22 (m, 1H), 3.0:5 (m, 1H), 2.53 (m, 2H), 1.64 (m,
1H), 1.52 (m, 1H), 0.75 (m, 1H).
[0354] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(345 mg, 1.00 mmol) and anhydrous potassium carbonate (311 mg, 2.25
mmol) in anhydrous methylene chloride (8 mL) in a pressure tube
equipped with a stirbar was treated with 1-chloroethyl
chloroformate (322 mg, 2.25 mmol), closed, and stirred at
45.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (10
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (3.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
taken up in ether, filtered through Celite.RTM., and the filtrate
treated with 2N HCl/ether (0.75 mL, 1.5 mmol). The suspension was
stirred, the solid salt collected by filtration, rinsed with ether,
and dried in vacuo to afford
1-(3,4-difluorophenyl)-3-azabicyclo[3.1.0]hexane, hydrochloride
(118 mg, 51%) as a white solid. MS (M+1) 196.0. .sup.1H NMR
(CDCl.sub.3) .delta. 10.31 (br s, 1H), 9.83 (br s, 1H), 7.11 (m,
1H), 7.00 (m, 1H), 6.93 (m, 1H), 3.75 (m, 1H), 3.50-3.70 (m, 3H),
1.94 (m, 1H), 1.60 (m, 1H), 1.20 (m, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 151.83, 149.30, 135.20, 123.66, 118.07, 116.84, 50.91,
47.73, 31.02, 23.61, 15.74.
C. Synthesis of 1-(4-Fluoro-3-trifluoromethylphenyl)
3-azabicyclo[3.1.0]hexane Hydrochloride
##STR00209##
[0356] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.63 g, 5.0 mmol) and
4-fluoro-3-(trifluoromethyl)phenylboronic acid (1.35 g, 6.5 mmol)
in anhydrous dioxane (15 mL) under nitrogen was degassed over 10
min with a stream of nitrogen, then treated with cesium fluoride
(2.0 g, 13.2 mmol) and Cl.sub.2Pd(dppf). CH.sub.2Cl.sub.2 (Aldrich,
0.25 g, 0.30 mmol), stirred 1 h at room temperature, then 2 h at
40.degree. C. The mixture was cooled, diluted with methylene
chloride (70 mL), stirred a few minutes, filtered through
Celite.RTM. (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride and loaded onto a silica gel column and the product eluted
with methylene chloride to afford product, which was triturated
from petroleum ethers to afford the intermediate arylmaleimide
(1.05 g, 51%) as a yellow solid. NO MS (M+1) peak. .sup.1H NMR
(CDCl.sub.3) .delta. 7.69 (m, 1H), 7.36 (m, 1H), 7.04 (m, 1H),
6.92-6.99 (m, 3H), 6.79 (m, 1H), 4.68 (s, 2H), 3.87 (s, 3H), 3.85
(s, 3H).
[0357] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (434 mg, 3.375 mmol) in anhydrous
tetrahydrofuran (10 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.4N, 1.17 mL, 2.80 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (1.023 g, 2.5 mmol) in anhydrous THF
(10 mL) was heated to 50.degree. C. and added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 2 h, and cooled on an ice bath.
Saturated aqueous ammonium chloride (3 mL) was added to quench, and
the mixture was diluted with methylene chloride (75 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 2% ethyl acetate/methylene chloride to afford
the intermediate bicyclic diimide (602 mg, 65%) as a pale yellow
foam. MS (M+1) 423.9. .sup.1H NMR (CDCl.sub.3) .delta. 7.64 (m,
1H), 7.56 (m, 1H), 7.28 (m, 1H), 6.88 (m, 2H), 6.79 (m, 1H), 4.53
(m, 2H), 3.85 (br s, 6H), 2.71 (m, 1H), 1.91 (m, 1H), 1.76 (m,
1H).
[0358] An ice-cooled, stirred solution of 1N borane/THF (7.5 mL,
7.5 mmol) under nitrogen was treated dropwise with a solution of
the above intermediate bicyclic diimide (390 mg, 0.92 mmol) in
anhydrous tetrahydrofuran (4 mL), then stirred for 45 min at room
temperature and for 4 h at reflux and cooled on an ice bath. 6N HCl
(5 mL) was carefully added dropwise, and the mixture was
concentrated in vacuo and the white solid residue partitioned
between 5N NaOH (15 mL) and ether (50 mL). The organic layer was
separated and the aqueous was extracted with ether (2.times.30 mL).
The combined organic solution was dried (MgSO.sub.4), concentrated
in vacuo, dissolved in methanol (15 mL), treated with 4N
HCl/dioxane (5 mL), then stirred at room temperature for 18 h and
at 60.degree. C. for 4 h. The solution was concentrated in vacuo
and the residue dissolved in methanol (25 mL), treated with
DOWEX.RTM. 550A-OH resin (3 g), stirred for 15 min, filtered, and
the filtrate concentrated in vacuo to afford the intermediate
dimethoxybenzyl bicyclic amine (272 mg, 75%) as a colorless glass.
MS (M+1) 396.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.43 (m, 2H), 7.12
(m, 1H), 6.86 (m, 1H), 6.78-6.82 (m, 2H), 3.88 (s, 3H), 3.86 (s,
3H), 3.59 (m, 2H), 3.19 (m, 1H), 3.08 (m, 1H), 2.62 (m, 1H), 2.43
(m, 1H), 1.74 (m, 1H), 1.50 (m, 1H), 0.77 (m, 1H).
[0359] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(276 mg, 0.698 mmol) and anhydrous potassium carbonate (207 mg, 1.5
mmol) in anhydrous methylene chloride (5.5 mL) in a pressure tube
equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.21 mL, 1.93 mmol), closed, and stirred at
40.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (10
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (1.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
dissolved in methylene chloride, loaded onto a silica gel column,
and eluted with 5% ethanol/methylene chloride, then with 10% (9:1
ethanol/ammonia)/methylene chloride to afford an oil, which was
dissolved in ether (3 mL), treated with 2N HCl/ether (0.5 mL, 1.0
mmol), stirred a few minutes, filtered, rinsed with ether,
collected, and dried in vacuo to afford
1-(4-fluoro-3-trifluoromethylphenyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (91 mg, 46%) as a white solid. MS (M+1) 246.0.
.sup.1H NMR (CDCl.sub.3) .delta. 10.35 (br s, 1H), 9.87 (br s, 1H),
7.55 (m, 1H), 7.46 (m, 1H), 7.21 (m, 1H), 3.60-3.80 (m, 3H), 3.51
(m, 1H), 2.03 (m, 1H), 1.68 (m, 1H), 1.22 (m, 1H). .sup.13C NMR
(CDCl.sub.3) .delta. 134.80, 126.95, 126.56, 124.44, 123.64,
120.93, 50.19, 47.27, 26.85, 22.28, 13.56.
D. Synthesis of
1-(3-Fluoro-4-methoxyphenyl)-3-azabicyclo[13.1.0]hexane
Hydrochloride
##STR00210##
[0361] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.14 g, 3.5 mmol) and
3-fluoro-4-methoxyphenylboronic acid (765 mg, 4.5 mmol) in
anhydrous dioxane (10 mL) under nitrogen was degassed over 10 min
with a stream of nitrogen, then treated with cesium fluoride (1.3
g, 8.5 mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.17
g, 0.21 mmol), stirred 1 h at room temperature, then 2 h at
40.degree. C. The mixture was cooled, diluted with methylene
chloride (50 mL), stirred a few minutes, filtered through
Celite.RTM. (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride and loaded onto a silica gel column and the product eluted
with 3% ethyl acetate/methylene chloride to afford product, which
was triturated from petroleum ethers to afford the intermediate
arylmaleimide (1.123 g, 86%) as a yellow solid. MS (M+1) 372.1.
.sup.1H NMR (CDCl.sub.3) .delta. 7.76 (m, 1H), 7.71 (m, 1H), 7.01
(m, 1H), 6.93-6.99 (m, 2H), 6.80 (m, 1H), 6.60 (s, 1H), 4.65 (s,
2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H).
[0362] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (515 mg, 4.00 mmol) in anhydrous
tetrahydrofuran (12 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.4N, 1.42 mL, 3.4 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (1.114 g, 3.0 mmol) in anhydrous THF
(13 mL) was heated to 50.degree. C., and added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 1.5 h, and cooled on an ice bath.
Saturated aqueous ammonium chloride (2 mL) was added to quench, and
the mixture was diluted with methylene chloride (75 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 2%, then 3% ethyl acetate/methylene chloride to
afford the intermediate bicyclic diimide (622 mg, 54%) as a pale
beige solid. MS (M+1) 386.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.14
(m, 1H), 7.07 (m, 1H), 6.94 (m, 1H), 6.87-6.92 (m, 2H), 6.78 (m,
1H), 4.50 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 2.67
(m, 1H), 1.74 (m, 1H), 1.67 (m, 1H).
[0363] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (10.6 mL, 10.6 mmol) under nitrogen was
treated slowly with a solution of the above intermediate bicyclic
diimide (617 mg, 1.6 mmol) in anhydrous THF (7 mL), stirred 1 h at
room temperature, refluxed for 6 h, and cooled (5.degree. C.).
Water (0.4 mL), 15% sodium hydroxide (0.4 mL), and water (1.2 mL)
were carefully added dropwise, followed by additional THF to
facilitate stirring. The suspension was stirred 20 min, filtered
through Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (362 mg, 63%) as a colorless viscous
oil. MS (M+1) 358.3. .sup.1H NMR (CDCl.sub.3) .delta. 6.78-6.88 (m,
6H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.59 (m, 2H), 3.20
(m, 1H), 3.04 (m, 1H), 2.53 (m, 2H), 1.61 (m, 1H), 1.46 (m, 1H),
0.73 (m, 1H).
[0364] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(358 mg, 1.00 mmol) and anhydrous potassium carbonate (311 mg, 2.25
mmol) in anhydrous methylene chloride (8 mL) in a pressure tube
equipped with a stirbar was treated with 1-chloroethyl
chloroformate (322 mg, 2.25 mmol), closed, and stirred at
45.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (10
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (3.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
taken up in ether, filtered through Celite.RTM., and the filtrate
treated with 2N HCl/ether (0.75 mL, 1.5 mmol). The suspension was
stirred for awhile, the solid salt collected by filtration, rinsed
with ether, and dried in vacuo to afford
1-(3-fluoro-4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (125 mg, 51%) as a white solid. MS (M+1) 208.0.
.sup.1H NMR (CDCl.sub.3) .delta. 10.27 (br s, 1H), 9.76 (br s, 1H),
6.88-6.95 (m, 3H), 3.86 (s, 3H), 3.72 (m, 1H), 3.40-3.65 (m, 3H),
1.89 (m, 1H), 1.54 (m, 1H), 1.18 (m, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 153.72, 147.27, 131.04, 123.51, 115.58, 113.92, 56.56,
51.08, 47.80, 30.95, 23.32, 15.39.
E. Synthesis of
1-(3-Fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00211##
[0366] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.31 g, 4.0 mmol) and
3-fluoro-4-methylphenylboronic acid (770 mg, 5.0 mmol) in anhydrous
dioxane (12 mL) under nitrogen was degassed over 10 min with a
stream of nitrogen, then treated with cesium fluoride (1.5 g, 9.9
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.20 g, 0.245
mmol), stirred 1 h at room temperature, then 2 h at 40.degree. C.
The mixture was cooled, diluted with methylene chloride (60 mL),
stirred a few minutes, filtered through Celite.RTM. (rinse with
methylene chloride), and the filtrate concentrated in vacuo. The
residue was dissolved in methylene chloride and loaded onto a
silica gel column and the product eluted with 2% ethyl
acetate/methylene chloride to afford the intermediate arylmaleimide
(1.12 g, 79%) as a yellow solid. MS (M+1) 356.1. .sup.1H NMR
(CDCl.sub.3) .delta. 7.63 (m, 1H), 7.59 (m, 1H), 7.24 (m, 1H),
6.94-6.99 (m, 2H), 6.80 (m, 1H), 6.68 (s, 1H), 4.65 (s, 21H), 3.87
(s, 3H), 3.84 (s, 3H), 2.31 (s, 3H).
[0367] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (534 mg, 4.15 mmol) in anhydrous
tetrahydrofuran (15 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.5N, 1.4 mL, 3.45 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (1.10 g, 3.1 mmol) in anhydrous THF
(10 mL) was heated to 50.degree. C., and added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 2 h, and cooled on an ice bath.
Saturated aqueous ammonium chloride (2 mL) was added to quench, and
the mixture was diluted with methylene chloride (60 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 2% ethyl acetate/methylene chloride to afford
the intermediate bicyclic diimide (615 mg, 54%) as a viscous pale
yellow oil. MS (M+1) 370.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.16
(m, 1H), 7.08 (m, 1H), 7.02 (m, 1H), 6.87-6.93 (m, 2H), 6.78 (m,
1H), 4.50 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.69 (m, 1H), 2.25
(br s, 3H), 1.76 (m, 1H), 1.68 (m, 1H).
[0368] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (11.5 mL, 11.5 mmol) under nitrogen was
treated slowly with a solution of the above intermediate bicyclic
diimide (650 mg, 1.76 mmol) in anhydrous THF (10 mL), stirred 1 h
at room temperature, refluxed for 6 h, and cooled (5.degree. C.).
Water (0.45 mL), 15% sodium hydroxide (0.45 mL), and water (1.35
mL) were carefully added dropwise, followed by additional THF to
facilitate stirring. The suspension was stirred 15 min, filtered
through Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (347 mg, 58%) as a colorless viscous
oil. MS (M+1) 3422. .sup.1H NMR (CDCl.sub.3) .delta. 7.05 (m, 1H),
6.88 (m, 1H), 6.73-6.83 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 3.59
(m, 2H), 3.23 (m, 1H), 3.04 (m, 3H), 2.54 (m, 2H), 2.21 (br s, 3H),
1.65 (m, 1H), 1.50 (m, 1H), 0.76 (m, 1H).
[0369] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(336 mg, 0.984 mmol) and anhydrous potassium carbonate (286 mg,
2.07 mmol) in anhydrous methylene chloride (8 mL) in a pressure
tube equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.29 mL, 2.71 mmol), closed, and stirred at
40.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (12
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (2.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
taken up in ether, filtered through Celite.RTM., and the filtrate
treated with 2N HCl/ether (0.50 mL, 1.0 mmol). The suspension was
stirred, the solid salt collected by filtration, rinsed with ether,
and dried in vacuo to afford
1-(3-fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (127 mg, 57%) as a white solid. MS (M+1) 192.1.
.sup.1H NMR (CDCl.sub.3) .delta. 10.29 (br s, 1H), 9.80 (br s, 1H),
7.11 (m, 1H), 6.78-6.88 (m, 2H), 3.75 (m, 1H), 3.50-3.65 (m, 3H),
2.22 (s, 3H), 1.92 (m, 1H), 1.57 (m, 1H), 1.19 (m, 1H). .sup.13C
NMR (CDCl.sub.3) .delta. 162.72, 137.90, 132.05, 124.30, 122.66,
114.08, 50.75, 47.72, 31.06, 23.57, 15.85, 14.38.
F. Synthesis of
1-(4-Fluoro-3-methylphenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00212##
[0371] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.0 g, 3.06 mmol) and
4-(4-fluoro-3-methyl)phenyl boronic acid (0.52 g, 3.4 mmol) in
anhydrous dioxane (10 mL) under nitrogen was degassed over 10 min
with a stream of nitrogen, then treated with cesium fluoride (1.3
g, 8.5 mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.17
g, 0.21 mmol), stirred 1 h at room temperature, then 2 h at
40.degree. C. The mixture was cooled, diluted with methylene
chloride (50 mL), stirred a few minutes, filtered through
Celite.RTM. (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride and loaded onto a silica gel column and the product eluted
with 3% ethyl acetate/methylene chloride to afford a yellow solid,
which was triturated from petroleum ethers to afford the
intermediate arylmaleimide (940 g, 79%) as a pale yellow solid.
[0372] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (370 mg, 2.86 mmol) in anhydrous
tetrahydrofuran (15 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.4N, 1.1 mL, 2.03 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (0.94 g, 2.6 mmol) in anhydrous THF
(10 mL) was heated to 50.degree. C., and added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 2 h and cooled on an ice bath.
Saturated aqueous ammonium chloride (1 mL) was added to quench, and
the mixture was diluted with methylene chloride (75 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 3% ethyl acetate/methylene chloride to afford
the intermediate bicyclic diimide (400 mg, 50%) as a very pale
yellow viscous oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.63-1.70 (m,
1H) 1.74 (dd, J=8.16, 4.63 Hz, 1H) 2.21-2.31 (m, J=1.87 Hz, 3H)
2.67 (dd, J=8.22, 3.58 Hz, 1H) 3.85 (d, J=2.76 Hz, 6H) 4.50 (dd,
2H) 6.82-7.03 (m, 2H) 7.08-7.24 (m, 1H).
[0373] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (3.6 mL, 10 mmol) under nitrogen was treated
slowly with a solution of the above intermediate bicyclic diimide
(400 mg, 1.2 mmol) in anhydrous THF (7 mL), stirred 1 h at room
temperature, refluxed for 6 h, and cooled (5.degree. C.). Water
(0.4 mL), 15% sodium hydroxide (0.4 mL), and water (1.2 mL) were
carefully added dropwise, followed by additional THF to facilitate
stirring. The suspension was stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (280 mg, 58%) as a colorless viscous
oil.
[0374] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(280 mg, 0.76 mmol) and anhydrous potassium carbonate (215 mg,
1.55:mmol) in anhydrous methylene chloride (5 mL) in a pressure
tube equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.221 mL, 1.55 mmol), closed, and stirred at
45.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (7
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (2.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
taken up in ether, filtered through Celite.RTM., and the filtrate
treated with 2N HCl/ether (0.6 mL, 1.2 mmol). The suspension was
stirred a few minutes, the solid salt collected by filtration,
rinsed with ether, and dried in vacuo to afford
1-(4-fluoro-3-methylphenyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (100 mg, 47%) as a light beige solid. MS (M+1) 192.1.
.sup.1H NMR (CDCl.sub.3) .delta. 1.10 (t, J=7.61 Hz, 1H) 1.88-1.97
(m, 1H) 2.18-2.21 (m, 1H) 2.21-2.23 (m, J=2.54, 2.54 Hz, 3H)
3.10-3.22 (m, 3H) 3.23-3.33 (m, 1H) 3.86 (dd, J=11.03, 5.37 Hz, 1H)
4.03 (dd, J=10.93, 5.47 Hz, 1H) 6.87-7.03 (m, 3H). .sup.13C NMR
(CDCl.sub.3) .delta..quadrature. 16.05, 22.60, 30.71, 51.47, 55.39,
58.87, 115.61, 125.67, 126.44, 130.74, 133.59, 159.54, 161.98.
G. Synthesis of 1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00213##
[0376] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.0 g, 3.06 mmol) and
2-naphthaleneboronic acid (0.59 g, 3.4 mmol) in anhydrous dioxane
(10 mL) under nitrogen was degassed over 10 min with a stream of
nitrogen, then treated with cesium fluoride (1.3 g, 8.5 mmol) and
Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.17 g, 0.21 mmol),
stirred 1 h at room temperature, then 2 h at 40.degree. C. The
mixture was cooled, diluted with methylene chloride (50 mL),
stirred a few minutes, filtered through Celite.RTM. (rinse with
methylene chloride), and the filtrate concentrated in vacuo. The
residue was dissolved in methylene chloride and loaded onto a
silica gel column and the product eluted with 3% ethyl
acetate/methylene chloride to afford a yellow solid, which was
triturated from petroleum ethers to afford the intermediate
arylmaleimide (690 g, 83%) as a pale yellow solid.
[0377] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (261 mg, 2.03 mmol) in anhydrous
tetrahydrofuran (15 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.4N, 1.1 mL, 2.03 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (0.690 g, 2.6 mmol) in anhydrous THF
(10 mL) was heated to 50.degree. C. and added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 2 h and cooled on an ice bath.
Saturated aqueous ammonium chloride (1 mL) was added to quench, and
the mixture was diluted with methylene chloride (75 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 3% ethyl acetate/methylene chloride to afford
the intermediate bicyclic diimide (400 mg, 50%) as a very pale
yellow viscous oil. .sup.1H NMR (CDCl.sub.3) .delta. 1.78 (dd,
J=4.59, 3.61 Hz, 1H) 1.91 (dd, J=8.20, 4.69 Hz, 1H) 2.81 (dd,
J=8.20, 3.71 Hz, 1H) 3.86 (d, J=4.30 Hz, 6H) 4.54 (dd, 2H)
7.38-7.55 (m, 3H) 7.74-7.90 (m, 4H).
[0378] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (3.6 mL, 10 mmol) under nitrogen was treated
slowly with a solution of the above intermediate bicyclic diimide
(360 mg, 1.0 mmol) in anhydrous THF (7 mL), stirred 1 h at room
temperature, refluxed for 6 h, and cooled (5.degree. C.). Water
(0.4 mL), 15% sodium hydroxide (0.4 mL), and water (1.2 mL) were
carefully added dropwise, followed by additional THF to facilitate
stirring. The suspension was stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (350 mg, 55%) as a colorless viscous
oil.
[0379] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(340 mg, 0.95 mmol) and anhydrous potassium carbonate (290 mg, 2.1
mmol) in anhydrous methylene chloride (5 mL) in a pressure tube
equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.301 mL, 2.2 mmol), closed, and stirred at
45.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (7
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (2.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
taken up in ether, filtered through Celite.RTM., and the filtrate
treated with 2N HCl/ether (0.6 mL, 1.2 mmol). The suspension was
stirred a few minutes, the solid salt collected by filtration,
rinsed with ether, and dried in vacuo to afford
1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride (95
mg, 53%) as a light beige solid. MS (M+1) 210.1. .sup.1H NMR
(DMSO-d.sub.6) .delta..quadrature. 1.14-1.23 (m, 1H) 1.49 (t,
J=5.27 Hz, 1H) 2.13-2.27 (m, 1H) 3.30-3.43 (m, 1H) 3.57 (d, J=7.81
Hz, 2H) 3.62-3.81 (m, 1H) 7.35 (dd, J=8.59, 1.76 Hz, 1H) 7.39-7.53
(m, 2H) 7.71-7.91 (m, 4H). .sup.13C NMR (DMSO-d.sub.6) .delta.
16.44, 24.13, 31.37, 47.45, 49.92, 125.43, 125.74, 126.40, 127.03,
128.10, 128.74, 132.38, 133.55, 137.64,
H. Synthesis of
1-(6-Methoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00214##
[0381] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.31 g, 4.0 mmol) and
6-methoxynaphthalene-2-boronic acid (1.01 g, 5.0 mmol) in anhydrous
dioxane (12 mL) under nitrogen was degassed over 10 min with a
stream of nitrogen, then treated with cesium fluoride (1.5 g, 9.9
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.20 g, 0.245
mmol), stirred 1 h at room temperature, then 2 h at 40.degree. C.
The mixture was cooled, diluted with methylene chloride (60 mL),
stirred a few minutes, filtered through Celite.RTM. (rinse with
methylene chloride), and the filtrate concentrated in vacuo. The
residue was dissolved in methylene chloride and loaded onto a
silica gel column and the product eluted with 2% ethyl
acetate/methylene chloride to afford the intermediate arylmaleimide
(1.10 g, 68%) as a yellow solid. MS (M+1) 404.2. .sup.1H NMR
(CDCl.sub.3) .delta. 8.62 (m, 1H), 7.82 (m, 1H), 7.75 (m, 2H), 7.18
(m, 1H), 7.12 (m, 1H), 6.97-7.02 (m, 2H), 6.81 (m, 1H), 6.76 (s,
1H), 4.69 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H).
[0382] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (482 mg, 3.75 mmol) in anhydrous
tetrahydrofuran (12 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.5N, 1.2 mL, 3.00 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (1.09 g, 2.7 mmol) in anhydrous THF
(12 mL) was heated to 50.degree. C. and added quickly in one
portion to the above heated suspension. The mixture was then
stirred at 50.degree. C. for 2 h and cooled on an ice bath.
Saturated aqueous ammonium chloride (2 mL) was added to quench, and
the mixture was diluted with methylene chloride (60 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 2% ethyl acetate/methylene chloride to afford
the intermediate bicyclic diimide (543 mg, 48%) as a pale orange
solid. MS (M+1) 418.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.78 (m,
1H), 7.67-7.75 (m, 2H), 7.42 (m, 1H), 7.15 (m, 1H), 7.11 (m, 1H),
6.90-6.95 (m, 2H), 6.79 (m, 11H), 4.54 (m, 2H), 3.91 (s, 3H), 3.86
(s, 3H), 3.85 (s, 3H), 2.77 (m, 1H), 1.88 (m, 1H), 1.75 (m,
1H).
[0383] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (8 mL, 8 mmol) under nitrogen was treated
slowly with a solution of the above intermediate bicyclic diimide
(534 mg, 1.28 mmol) in anhydrous THF (6 mL), stirred 1 h at room
temperature, refluxed for 6 h, and cooled (5.degree. C.). Water
(0.3 mL), 15% sodium hydroxide (0.3 mL), and water (0.9 mL) were
carefully added dropwise, followed by additional THF to facilitate
stirring. The suspension was stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (345 mg, 69%) as a white solid. MS
(M+1) 390.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.64 (m, 2H), 7.52
(m, 1H), 7.20 (m, 1H), 7.07-7.13 (m, 2H), 6.92 (m, 1H), 6.79-6.87
(m, 2H), 3.90 (brs, 6H), 3.87 (s, 3H), 3.64 (m, 2H), 3.35 (m, 1H),
3.11 (m, 1H), 2.70 (m, 1H), 2.58 (m, 1H), 1.78 (m, 1H), 11.56 (m,
1H), 0.87 (m, 1H).
[0384] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(325 mg, 0.8344 mmol) and anhydrous potassium carbonate (243 mg,
1.76 mmol) in anhydrous methylene chloride (6.5 mL) in a pressure
tube equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.25 mL, 2.3 mmol), closed, and stirred at
40.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (10
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (1.0 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
taken up in ether containing a little methylene chloride, filtered
through Celite.RTM., and the filtrate treated with 2N HCl/ether
(0.60 mL, 1.2 mmol). The suspension was stirred and the solid salt
collected by filtration, rinsed with ether, suspended in
acetonitrile, filtered, collected and dried in vacuo to afford
1-(6-methoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (151 mg, 66%) as a white solid. MS (M+1) 240.1.
.sup.1H NMR (DMSO-d6) .delta..delta. 9.90 (br s, 1H), 9.57 (br s,
1H), 7.73 (m, 3H), 7.31 (m, 1H), 7.26 (m, 1H), 7.13 (m, 1H), 3.83
(s, 31H), 3.71 (m, 1H), 3.45-3.55 (m, 2H), 3.39 (m, 1H), 2.14 (m,
1H), 1.43 (m, 1H), 1.14 (m, 1H). .sup.13C NMR (DMSO-d6)
.delta..quadrature. 157.78, 134.96, 133.67, 129.58, 128.96, 127.66,
125.96, 125.74, 119.53, 106.41, 55.82, 50.17, 47.55, 31.24, 23.87,
16.09.
I. Synthesis of
1-(16-Ethoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00215##
[0386] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.31 g, 4.0 mmol) and
6-ethoxynaphthalene-2-boronic acid (1.08 g, 5.0 mmol) in anhydrous
dioxane (12 mL) under nitrogen was degassed over 10 min with a
stream of nitrogen, then treated with cesium fluoride (1.5 g, 9.9
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.20 g, 0.245
mmol), stirred 1 h at room temperature, then 2 h at 40.degree. C.
The mixture was cooled, diluted with methylene chloride (60 mL),
stirred a few minutes, filtered through Celite.RTM. (rinse with
methylene chloride), and the filtrate concentrated in vacuo. The
residue was dissolved in methylene chloride and loaded onto a
silica gel column and the product eluted with 2% ethyl
acetate/methylene chloride to afford the intermediate arylmaleimide
(1.36 g, 81%) as a yellow solid. No MS (M+1) peak observed. .sup.1H
NMR (CDCl.sub.3) .delta. 8.62 (m, 1H), 7.81 (m, 1H), 7.74 (m, 2H),
7.17 (m, 1H), 7.10 (m, 1H), 6.96-7.02 (m, 2H), 6.81 (m, 1H), 6.75
(s, 1H), 4.69 (s, 2H), 4.16 (q, 2H, J=7 Hz), 3.88 (s, 3H), 3.84 (s,
3H), 1.48 (t, 3H, J=7 Hz).
[0387] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (515 mg, 4.00 mmol) in anhydrous
tetrahydrofuran (15 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.5N, 1.32 mL, 3.30 mmol) and gradually
warmed to 50.degree. C. over 30 minutes. Meanwhile, a solution of
the intermediate arylmaleimide (1.23 g, 2.95 mmol) in anhydrous THF
(10 mL) was heated to 50.degree. C., then added quickly in one
portion to the above heated suspension, and the mixture was stirred
at 50.degree. C. for 2 h, then cooled on an ice bath. Saturated
aqueous ammonium chloride (3 mL) was added to quench, and the
mixture was diluted with methylene chloride (70 mL), dried
(MgSO.sub.4), filtered through Celite.RTM. (rinse with methylene
chloride), and concentrated in vacuo. The residue was dissolved in
methylene chloride, loaded onto a silica gel column, and the
product eluted with 2% ethyl acetate/methylene chloride to afford
the intermediate bicyclic diimide (700 mg, 55%) as a pale orange
viscous oil. MS (M+1) 432.2. .sup.1H NMR (CDCl.sub.3) .delta. 7.77
(m, 1H), 7.70 (m, 2H), 7.41 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H),
6.90-6.95 (m, 2H), 6.79 (m, 1H), 4.54 (m, 2H), 4.14 (q, 2H, J=7
Hz), 3.86 (s, 3H), 3.85 (s, 3H), 2.77 (m, 1H), 1.88 (m, 1H), 1.75
(m, 1H), 1.47 (t, 3H, J=7 Hz).
[0388] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (11 mL, 11 mmol) under nitrogen was treated
slowly with a solution of the above intermediate bicyclic diimide
(690 mg, 1.60 mmol) in anhydrous THF (10 mL), stirred 1 h at room
temperature, refluxed for 6 h, and cooled (5.degree. C.). Water
(0.45 mL), 15% sodium hydroxide (0.45 mL), and water (1.35 mL) were
carefully added dropwise, followed by additional THF to facilitate
stirring. The suspension was stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 4:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (415 mg, 64%) as a white solid. MS
(M+1) 404.8. .sup.1H NMR (CDCl.sub.3) .delta. 7.63 (m, 2H), 7.51
(m, 1H), 7.19 (m, 1H), 7.06-7.13 (m, 2H), 6.91 (m, 1H), 6.85 (m,
1H), 6.81 (m, 1H), 4.13 (q, 2H, J=7 Hz), 3.89 (s, 3H), 3.87 (s,
3H), 3.63 (m, 2H), 3.35 (m, 1H), 3.10 (m, 1H), 2.70 (m, 1H), 2.58
(m, 1H), 1.77 (m, 1H), 1.56 (m, 1H), 1.46 (t, 3H, J=7 Hz), 0.87 (m,
1H).
[0389] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(403 mg, 1.00 mmol) and anhydrous potassium carbonate (290 mg, 2.1
mmol) in anhydrous methylene chloride (8 mL) in a pressure tube
equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.30 mL, 2.75 mmol), closed, and stirred at
40.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (12
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (1.5 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
dissolved in methylene chloride, loaded onto a silica gel column,
and eluted with 10% (9:1 ethanol/ammonia)/methylene chloride to
afford a white solid. This was taken up in anhydrous ether
containing a little methylene chloride, treated with 2N HCl/ether
(0.6 mL, 1.2 mmol), stirred, filtered, collected, and dried in
vacuo to afford
1-(6-ethoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (148 mg, 51%) as a white solid. MS (M+1) 254.1.
.sup.1H NMR (DMSO-d6) .delta. 9.93 (br s, 1H), 9.62 (br s, 11H),
7.73 (m, 3H), 7.31 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 4.10 (q,
2H, J=7 Hz), 3.71 (m, 1H), 3.51 (m, 2H), 3.38 (m, 1H), 2.15 (m,
1H), 1.44 (m, 1H), 1.36 (t, 3H, J=7 Hz), 1.14 (m, 1H). .sup.13C NMR
(DMSO-d6) .delta..quadrature. 156.11, 133.98, 132.81, 128.71,
128.27, 127.98, 126.73, 125.04, 118.89, 106.21, 62.84, 49.27,
46.64, 30.36, 2:2.96, 15.38, 14.54.
J. Synthesis of
1-(4-Methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00216##
[0391] A stirred solution of
3-bromo-1-(3,4-dimethoxybenzyl)maleimide (3.26 g, 10.0 mmol) and
4-methylnaphthalene-1-boronic acid (2.33 g, 12.5 mmol) in anhydrous
dioxane (30 mL) under nitrogen was degassed over 10 min with a
stream of nitrogen, then treated with cesium fluoride (4.0 g, 26
mmol) and Cl.sub.2Pd(dppf).CH.sub.2Cl.sub.2 (Aldrich, 0.50 g, 0.61
mmol), stirred 1 h at room temperature, then 2 h at 40.degree. C.
The mixture was cooled, diluted with methylene chloride (125 mL),
stirred a few minutes, filtered through Celite.RTM. (rinse with
methylene chloride), and the filtrate concentrated in vacuo. The
residue was dissolved in methylene chloride and loaded onto a
silica gel column and the product eluted with 3% ethyl
acetate/methylene chloride to afford a solid, which was triturated
from petroleum ethers to afford the intermediate arylmaleimide
(3.555 g, 92%) as a yellow solid. MS (M+1) 388.2. .sup.1H NMR
(CDCl.sub.3) .delta. 8.07 (m, 1H), 8.00 (m, 1H), 7.50-7.62 (m, 2H),
7.39 (m, 1H), 7.00-7.05 (m, 2H), 6.82 (m, 1H), 6.78 (s, 1H), 4.74
(s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.73 (s, 3H).
[0392] A cooled (-20.degree. C.) stirred solution of
trimethylsulfoxonium chloride (1.48 g, 11.5 mmol) in anhydrous
tetrahydrofuran (35 mL) under nitrogen was treated dropwise with
n-butyllithium/hexane (2.5N, 4.0 mL, 10 mmol) and gradually warmed
to 50.degree. C. over 30 minutes. Meanwhile, a solution of the
intermediate arylmaleimide (3.50 g, 9.0 mmol) in anhydrous THF (35
mL) was heated to 50.degree. C. and added quickly in one portion to
the above heated suspension. The mixture was then stirred at
50.degree. C. for 2 h and cooled on an ice bath. Saturated aqueous
ammonium chloride (5 mL) was added to quench, and the mixture was
diluted with methylene chloride (200 mL), dried (MgSO.sub.4),
filtered through Celite.RTM. (rinse with methylene chloride), and
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and the product eluted
with 2% ethyl acetate/methylene chloride to afford first recovered
starting material (680 mg), then the intermediate bicyclic diimide
(411 mg, 14% based on recovered starting material) as a pale tan
solid. MS (M+1) 402.2. .sup.1H NMR (CDCl.sub.3) .delta. 8.04 (m,
1H), 7.78 (m, 1H), 7.55 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 7.28
(m, 1H), 6.92-6.98 (m, 2H), 6.80 (m, 1H), 4.58 (m, 2H), 3.87 (s,
31H), 3.83 (s, 3H), 2.71 (m, 1H), 2.69 (s, 3H), 1.95 (m, 1H), 1.90
(m, 1H).
[0393] A cooled (5.degree. C.) stirred solution of 1N lithium
aluminum hydride/THF (6 mL, 6 mmol) under nitrogen was treated
slowly with a solution of the above intermediate bicyclic diimide
(370 mg, 0.922 mmol) in anhydrous THF (5 mL), stirred h at room
temperature, refluxed for 6 h, and cooled (5.degree. C.). Water
(0.23 mL), 15% sodium hydroxide (0.23 mL), and water (0.70 mL) were
carefully added dropwise, followed by additional THF to facilitate
stirring. The suspension was stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in methylene
chloride, loaded onto a silica gel column, and eluted with 3:1
methylene chloride/ethyl acetate to afford the intermediate
dimethoxybenzyl bicyclic amine (252 mg, 73%) as a viscous colorless
oil. MS (M+1) 374.3. .sup.1H NMR (CDCl.sub.3) .delta. 8.35 (m, 1H),
8.00 (m, 1H), 7.51 (m, 2H), 7.37 (m, 1H), 7.24 (m, 1H), 6.90 (m,
1H), 6.76-6.84 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.62 (m, 2H),
3.32 (m, 1H), 3.20 (m, 1H), 2.82 (m, 1H), 2.67 (s, 3H), 2.55 (m,
1H), 1.76 (m, 1H), 1.62 (m, 1H), 0.80 (m, 1H).
[0394] A mixture of the intermediate dimethoxybenzyl bicyclic amine
(240 mg, 0.643 mmol) and anhydrous potassium carbonate (187 mg,
1.35 mmol) in anhydrous methylene chloride (5 mL) in a pressure
tube equipped with a stirbar was treated with 1-chloroethyl
chloroformate (0.19 mL, 1.77 mmol), closed, and stirred at
40.degree. C. for 4 h. The tube was cooled, opened, and the
contents filtered (rinse with methylene chloride), and the filtrate
concentrated in vacuo. The residue was dissolved in methanol (8
mL), refluxed for 1 h, cooled, treated with DOWEX.RTM. 550A-OH
resin (1 g, prerinsed with methanol), stirred a few minutes,
filtered, and the filtrate concentrated in vacuo. The residue was
dissolved in ether, treated with 2.0N HCl/ether (0.4 mL, 0.8 mmol),
the suspension stirred a few minutes, filtered, rinsed with ether,
collected, and dried in vacuo to afford
1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (149 mg, 89%) as a white solid. MS (M+1) 224.1.
.sup.1H NMR (CDCl.sub.3) .delta. 10.35 (br s, 1H), 9.93 (br s, 1H),
8.12 (m, 1H), 8.03 (m, 1H), 7.56 (m, 2H), 7.37 (m, 1H), 7.25 (m,
1H), 3.86 (m, 2H), 3.74 (m, 1H), 3.50 (m, 1H), 2.67 (s, 3H), 2.06
(m, 1H), 1.78 (m, 1H), 1.24 (m, 1H). .sup.13C NMR (CDCl.sub.3)
.delta. 135.42, 133.17, 131.95, 126.68, 126.40, 126.15, 125.33,
124.70, 51.94, 48.04, 30.87, 22.44, 19.74, 14.76.
Example XII
Preparation of 1-Aryl-3-aza-bicyclo[3.1.0]hexane hydrochlorides
Using Reaction Scheme 4
A. Synthesis of
1-(3-Fluoro-4-trifluoromethoxyphenyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00217##
[0396] An ice-cooled (3.degree. C.) stirred suspension of sodium
amide (460 mg, 11.5 mmol) in anhydrous tetrahydrofuran (15 mL)
under nitrogen was treated with a solution of
3-fluoro-4-(trifluoromethoxy)phenylacetonitrile (1.10 g, 5.0 mmol)
in anhydrous THF (5 mL) and stirred at room temperature for 2 h,
then recooled on an ice bath. Epichlorohydrin (0.52 mL, 6.0 mmol)
was added via syringe in one portion, and the mixture was stirred
at room temperature for 1 h, cooled on an ice bath, and quenched
with saturated aqueous ammonium chloride (5 mL). The product
mixture was taken up in ethyl acetate (70 mL) and the organic layer
was separated. The aqueous was extracted with ethyl acetate (15
mL), and the combined organic solution was dried (MgSO.sub.4),
concentrated in vacuo, dissolved in methylene chloride, and loaded
onto a silica gel column. The product was eluted with 3:1 methylene
chloride/ethyl acetate to afford the intermediate
hydroxymethylcyclopropylnitrile (887 mg, 65%) as a pale yellow
viscous oil (3:1 syn/anti isomers by NMR). The compound was
somewhat impure, but used as is.
[0397] An ice-cooled (3.degree. C.) stirred solution of 1N LAH/THF
(4.5 mL, 4.5 mmol) under nitrogen was treated dropwise with a
solution of the intermediate hydroxymethylcyclopropylnitrile (826
mg, 3.00 mmol) and the mixture was stirred on an ice bath for 2 h,
then carefully quenched with water (0.17 mL), 15% sodium hydroxide
(0.17 mL), and water (0.50 mL). The suspension was diluted with THF
to facilitate stirring, then stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in anhydrous
1,2-dichloroethane (14 mL) under nitrogen, cooled (3.degree. C.),
and treated dropwise with thionyl chloride (0.235 mL, 3.2 mmol).
After stirring at room temperature for 3 h, the solution was
concentrated in vacuo and the residue taken up in water (10:mL) and
made basic with 5N sodium hydroxide (3 mL). The aqueous solution
was extracted with methylene chloride (4.times.20 mL) and the
combined organic solution washed with water (30 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methylene chloride and loaded onto a silica gel column
and eluted with 10% (9:1 ethanol/ammonia)/methylene chloride to
afford the bicyclic amine free base (149 mg, 19%) as a pale yellow
oil. MS (M+1) 262.1. Compound carried through below was somewhat
impure, but was used as is.
[0398] A stirred solution of the bicyclic amine (144 mg, 0.55 mmol)
in anhydrous ether (5 mL) was treated with 2.0N HCl/ether (0.5 mL,
1.0 mmol), stirred a few minutes, filtered, rinsed with ether,
collected, and dried in vacuo to afford
1-(3-fluoro-4-trifluoromethoxyphenyl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (107 mg, 65%) as a white solid. MS (M+1) 262.1.
.sup.1H NMR (CDCl.sub.3) .delta..quadrature. 10.35 (br s, 1H), 9.89
(br s, 1H), 7.26 (m, 1H), 6.97-7.07 (m, 2H), 3.78 (m, 1H),
3.55-3.70 (m, 3H), 1.99 (m, 1H), 1.65 (m, 1H), 1.24 (m, 1H).
.sup.13C NMR (CDCl.sub.3) .delta. 155.76, 153.23, 139.09, 124.15,
123.28, 116.30, 50.35, 47.44, 30.80, 23.74, 15.92.
B. Synthesis of 1-(Naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00218##
[0400] An ice-cooled (3.degree. C.) stirred suspension of sodium
amide (2.3 g, 60 mmol) in anhydrous tetrahydrofuran (15 mL) under
nitrogen was treated with a solution of 1-naphthaleneacetonitrile
(5 g, 30 mmol) in anhydrous THF (5 mL) and stirred at room
temperature for 2 h, then recooled on an ice bath. Epichlorohydrin
(2.3 mL, 30 mmol) was added via syringe in one portion, and the
mixture was stirred at room temperature for 1 h, cooled on an ice
bath, and quenched with saturated aqueous ammonium chloride (5 mL).
The product mixture was taken up in ethyl acetate (70 mL) and the
organic layer was separated. The aqueous was extracted with ethyl
acetate (15 mL), and the combined organic solution was dried
(MgSO.sub.4), concentrated in vacuo, dissolved in methylene
chloride, and loaded onto a silica gel column. The product was
eluted with 3:1 methylene chloride/ethyl acetate to afford the
intermediate hydroxymethylcyclopropylnitrile (2 g, 30%) as a pale
yellow viscous oil (3:1 syn/anti isomers by NMR).
[0401] An ice-cooled (3.degree. C.) stirred solution of 1N LAH/THF
(5.6 mL, 11.2 mmol) under nitrogen was treated dropwise with a
solution of the intermediate hydroxymethylcyclopropylnitrile (2.0
g, 8.97 mmol) and the mixture was stirred on an ice bath for 2 h,
then carefully quenched with water (0.17 mL), 15% sodium hydroxide
(0.17 mL), and water (0.50 mL). The suspension was diluted with THF
to facilitate stirring, then stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in anhydrous
1,2-dichloroethane (14 mL) under nitrogen, cooled (3.degree. C.),
and treated dropwise with thionyl chloride (0.235 mL, 3.2 mmol).
After stirring at room temperature for 3 h, the solution was
concentrated in vacuo and the residue taken up in water (10 mL) and
made basic with 5N sodium hydroxide (3 mL). The aqueous solution
was extracted with methylene chloride (4.times.20 mL) and the
combined organic solution washed with water (30 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methylene chloride and loaded onto a silica gel column
and eluted with 10% (9:1 ethanol/ammonia)/methylene chloride to
afford the bicyclic amine free base (600 mg, 73%) as a pale yellow
oil.
[0402] A stirred solution of the bicyclic amine (100 mg, 3.96 mmol)
in anhydrous ether (5 mL) was treated with 2.0N HCl/ether (0.5 mL,
1.0 mmol), stirred a few minutes, filtered, rinsed with ether,
collected, and dried in vacuo to afford
1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride (100
mg, 85%) as a white solid. MS (M+1) 211.1. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.02-1.10 (m, 1H) 1.58 (t, J=5.08 Hz, 1H)
2.05-2.16 (m, 1H) 3.24 (d, J=10.93 Hz, 1H) 3.48 (dd, J=11.42, 5.95
Hz, 1H) 3.69 (dd, J=11.23, 5.95 Hz, 1H) 3.71-3.82 (m, 1H) 7.46 (dd,
J=8.20, 7.03 Hz, 1H) 7.50-7.58 (m, 1H) 7.56-7.65 (m, 2H) 7.82-7.89
(m, 1H) 7.95 (d, J=7.42 Hz, 1H) 8.10 (d, J=8.40 Hz, 1H). .sup.13C
NMR (DMSO-d.sub.6) .delta. 14.28, 22.74, 30.75, 47.76, 51.73,
124.72, 126.29, 126.62, 127.23, 128.89, 129.47, 132.81, 134.08,
135.16.
C. Synthesis of
1-(4-Fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00219##
[0404] An ice-cooled (3.degree. C.) stirred suspension of 1 M
sodium hexamethyldisilazane (17.2 mL, 17.2 mmol) in anhydrous
tetrahydrofuran (15 mL) under nitrogen was treated with a solution
of 4-fluoronaphthalen-1-acetonitrile (1.6 g, 8.6 mmol) in anhydrous
THF (5 mL) and stirred at room temperature for 2 h, then recooled
on an ice bath. Epichlorohydrin (0.75 mL, 9.5 mmol) was added via
syringe in one portion, and the mixture was stirred at room
temperature for 1 h, cooled on an ice bath, and quenched with
saturated aqueous ammonium chloride (5 mL). The product mixture was
taken up in ethyl acetate (70 mL) and the organic layer was
separated. The aqueous was extracted with ethyl acetate (15 mL),
and the combined organic solution was dried (MgSO.sub.4),
concentrated in vacuo, dissolved in methylene chloride, and loaded
onto a silica gel column. The product was eluted with 3:1 methylene
chloride/ethyl acetate to afford the intermediate
hydroxymethylcyclopropylnitrile (1 g, 50%) as a pale yellow viscous
oil (3:1 syn/anti isomers by NMR).
[0405] An ice-cooled (3.degree. C.) stirred solution of 1N LAH/THF
(2.6 mL, 5.2 mmol) under nitrogen was treated dropwise with a
solution of the intermediate hydroxymethylcyclopropylnitrile (10 g,
4.2 mmol) and the mixture was stirred on an ice bath for 2 h, then
carefully quenched with water (0.17 mL), 15% sodium hydroxide (0.17
mL), and water (0.50 mL). The suspension was diluted with THF to
facilitate stirring, then stirred 15 min, filtered through
Celite.RTM. (filter cake rinsed with THF), and the filtrate
concentrated in vacuo. The residue was dissolved in anhydrous
1,2-dichloroethane (14 mL) under nitrogen, cooled (3.degree. C.),
and treated dropwise with thionyl chloride (0.235 mL, 3.2 mmol).
After stirring at room temperature for 3 h, the solution was
concentrated in vacuo and the residue taken up in water (10 mL) and
basified with 5N sodium hydroxide (3 mL). The aqueous solution was
extracted with methylene chloride (4.times.20 mL) and the combined
organic solution washed with water (30 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
dissolved in methylene chloride and loaded onto a silica gel column
and eluted with 10% (9:1 ethanol/ammonia)/methylene chloride to
afford the bicyclic amine free base (400 mg, 40%) as a pale yellow
oil.
[0406] A stirred solution of the bicyclic amine (100 mg, 0.44 mmol)
in anhydrous ether (5 mL) was treated with 2.0N HCl/ether (0.5 mL,
1.0 mmol), stirred a few minutes, filtered, rinsed with ether,
collected, and dried in vacuo to afford
1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (100 mg, 85%) as a white solid. MS (M+1) 228.1.
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.06 (t, J=6.93 Hz, 1H) 1.58 (t,
J=5.08 Hz, 1H) 2.03-2.19 (m, 1H) 3.16-3.28 (m, 1H) 3.47 (dd,
J=11.42, 5.95 Hz, 1H) 3.68 (dd, J=11.13, 5.86 Hz, 1H) 3.76 (s, 1H)
7.29 (dd, J=10.64, 7.91 Hz, 1H) 7.47-7.81 (m, 3H) 8.08 (d, J=8.00
Hz, 1H) 8.15 (d, J=8.40 Hz, 1H). .sup.13C NMR (DMSO-d.sub.6)
.delta. 22.77, 30.27, 47.72, 51.66, 109.93, 121.39, 123.69, 125.06,
127.40, 128.44, 131.58, 134.08.
Example XIII
Preparation of 1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane Using
Reaction Scheme 11
A. Synthesis of
3-Methyl-1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00220##
[0408] A stirred solution/suspension of
1-(1-naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (500 mg, 2.4 mmol)
in 1,2-dichloromethane (12 mL) was treated with 37% aqueous
formaldehyde (1.2 mL, 24 mmol), then with sodium
triacetoxyborohydride (2.5 g, 12 mmol), stirred for 3 h, then
treated with 1N sodium hydroxide (5 mL). The organic layer was
separated and the aqueous solution was extracted with methylene
chloride containing 2-propanol (2.times.10 mL). The combined
organic solution was dried (MgSO.sub.4) and concentrated in vacuo
to afford 3-methyl-1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane
(76 mg, 84%, essentially pure without chromatography). This was
dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether
(0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with
ether, collected, and dried in vacuo to afford
3-methyl-1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane,
hydrochloride (72 mg, 82%) as a white solid. MS (M+1) 224.1.
.sup.1H NMR (DMSO-d.sub.6) .delta. 0.97 (dd, J=7.71, 6.54 Hz, 1H)
1.97-2.10 (m, 1H) 2.14-2.24 (m, 1H) 2.77-2.81 (m, J=4.69, 4.69 Hz,
3H) 3.20-3.31 (m, 1H) 3.67-3.76 (m, 2H) 3.94 (dd, J=11.13, 5.08 Hz,
1H) 7.47 (dd, J=8.20, 7.03 Hz, 1H) 7.51-7.58 (m, 1H) 7.59-7.66 (m,
2H) 7.88 (d, J=8.20 Hz, 1H) 7.95 (d, J=7.61 Hz, 1H) 8.15 (d, J=8.40
Hz, 1H); .sup.13C (DMSO-d.sub.6) .delta. 14.53, 22.27, 30.45,
56.77, 60.55, 124.71, 126.25, 126.65, 127.30, 128.31, 128.94,
129.41, 132.98, 134.02, 134.97
B. Synthesis of
3-Methyl-1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00221##
[0410] A stirred solution/suspension of
1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (215 mg, 0.95
mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueous
formaldehyde (0.5 mL, 9.5 mmol), then with sodium
triacetoxyborohydride (1.25 g, 4.75 mmol), stirred for 3 h, then
treated with 1N sodium hydroxide (5 mL). The organic layer was
separated and the aqueous solution was extracted with methylene
chloride containing a little 2-propanol (2.times.10 mL). The
combined organic solution was dried (MgSO.sub.4) and concentrated
in vacuo to afford
1-(4-fluoronaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (150
mg, 65%, essentially pure without chromatography). This was
dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether
(0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with
ether, collected, and dried in vacuo to afford
3-methyl-1-(4-fluoronaphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane,
hydrochloride (150 mg, 82%) as a white solid. MS (M+1) 242.1.
.sup.1H NMR (DMSO-d.sub.6) .delta. 0.91-1.01 (m, 1H) 2.01-2.09 (m,
1H) 2.13-2.24 (m, 1H) 2.72-2.84 (m, J=4.69 Hz, 3H) 3.16-3.30 (m,
1H) 3.72 (q, J=5.60 Hz, 2H) 3.93 (dd, J=11.23, 5.17 Hz, 1H) 7.31
(dd, J=10.74, 8.01 Hz, 1H) 7.48-7.79 (m, 3H) 8.07 (d, J=8.20 Hz,
1H) 8.20 (d, J=8.40 Hz, 1H). .sup.13C (DMSO-d.sub.6) .delta. 14.51,
22.36, 29.97, 56.72, 60.47, 109.90, 121.34, 123.61, 125.04, 127.43,
128.50, 131.39, 134.24 157.08.
C. Synthesis of
1-(4-Methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00222##
[0412] A stirred solution/suspension of 1-(4-methyl
naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (85 mg, 0.38 mmol) in
1,2-dichloromethane (12 mL) was treated with 37% aqueous
formaldehyde (0.23 mL, 3.0 mmol), then with sodium
triacetoxyborohydride (318 mg, 1.5 mmol), stirred for 3 h, then
treated with 1N sodium hydroxide (5 mL). The organic layer was
separated and the aqueous solution was extracted with methylene
chloride containing 2-propanol (2.times.10 mL). The combined
organic solution was dried (MgSO.sub.4) and concentrated in vacuo
to afford
1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (76
mg, 84%, essentially pure without chromatography). This was
dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether
(0.3.5 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with
ether, collected, and dried in vacuo to afford
1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane,
hydrochloride (72 mg, 82%) as a white solid. MS (M+1) 238.1.
.sup.1H NMR (CDCl.sub.3) .delta..quadrature. 12.70 (br s, 1H), 8.16
(m, 1H), 8.04 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 7.26 (m, 1H),
4.20 (m, 1H), 4.06 (m, 1H), 3.50 (m, 1H), 3.14 (m, 1H), 2.90 (d,
3H, J=5 Hz), 2.68 (s, 3H), 2.40 (m, 1H), 2.13 (m, 1H), 1.22 (m,
1H). .sup.13C NMR (CDCl.sub.3) .delta. 135.73, 133.21, 131.70,
126.81, 126.35, 126.33, 125.41, 124.54, 61.65, 57.62, 41.52, 30.97,
22.37, 19.75.
Example XIV
Preparation of 1-Aryl-3-aza-bicyclo[3.1.0]hexane and
1-Aryl-3-methyl-3-aza-1-bicyclo[3.1.0]hexane Using Reaction Schemes
5, 6 and 13
A. Synthesis of Cyclopropanecarbonitriles
(1) Synthesis of
(1S,2R)-2-Hydroxymethyl-1-naphthyl-cyclopropancarbonitrile as
Representative Procedure for (1)-(6)
##STR00223##
[0414] To a stirring solution of 1-naphthylacetonitrile (15 g,
0.090 moles) in anhydrous THF (150 mL) at -15 to -10.degree. C.
under nitrogen, was added 90 mL of sodium bis (trimethylsilyl)amide
(NaHMDS, 1M in THF) slowly via addition funnel while keeping the
temperature below -5.degree. C. The resulting brown mixture was
stirred for 0.75 h between -10.degree. C. and 0.degree. C.
R-epichlorohydrin (8.3 g, 0.090 moles in 10 mL of THF) was added
slowly over 15 minutes while keeping the temperature below
-10.degree. C. The mixture was stirred between -10.degree. C. and
0.degree. C. for 0.5 h then NaHMDS (90 mL, 0.090 moles) was added
while keeping the temperature between -10.degree. C. and
-15.degree. C. The mixture was stirred for 45 minutes then warmed
to room temperature, stirred 30 min and quenched with 40 mL of
water. The mixture was stirred 5 minutes, allowed to settle and the
layers were separated. The lower aqueous layer was re-extracted
with EtOAc (.about.75 mL). The organics were combined, washed with
100 mL of saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated to provide an oil. Chromatography through a short
silica gel plug eluting with EtOAc/Heptane (5-50%) afforded 6.8 g
of product. .sup.1H NMR shows a mixture of diastereomers
(.about.3:1 cis/trans). The product was carried forward to
reduction without further characterization. .sup.1H NMR (400 MHz,
CDCl.sub.3, partial assignment) .delta. 1.53-1.66 (m, 2H),
1.85-1.95 (m, 1H), 3.18 (br. s., 1H), 3.85-3.96 (m, 1H), 4.13-4.22
(m, 1H), 7.31-7.39 (m, 1H), 7.43-7.55 (m, 2H), 7.57-7.65 (m, 1H),
7.78-7.91 (m, 2H), 8.46-8.54 (m, 1H).
(2) (1R,2S)-2-Hydroxymethyl-1-naphthyl-cyclopropancarbonitrile
##STR00224##
[0416] Yield=34%; .sup.1H NMR (400 MHz, CDCl.sub.3, partial
assignment) .delta. 1.53-1.66 (m, 2H), 1.85-1.95 (m, 1H), 3.18 (br.
s., 1H), 3.85-3.96 (m, 1H), 4.13-4.22 (m, 1H), 7.31-7.39 (m, 1H),
7.43-7.55 (m, 2H), 7.57-7.65 (m, 1H), 7.78-7.91 (m, 2H), 8.46-8.54
(m, 1H).
(3) (1 S,2R)-2-Hydroxymethyl-2-naphthyl-cyclopropancarbonitrile
##STR00225##
[0418] Yield=63%; .sup.1H NMR (400 MHz, CDCl.sub.3, partial
assignment) .delta. 1.59-1.66 (m, 1H), 1.68-1.74 (m, 1H), 1.98-2.07
(m, 1H), 2.41 (br. s., 1H), 3.85 (dd, J=12.10, 8.30 Hz, 1H),
4.07-4.13 (m, 1H), 7.33 (dd, J=8.49, 2.05 Hz, 1H), 7.45-7.53 (m,
2H), 7.77-7.87 (m, 4H).
(4) (1R,2S)-2-Hydroxymethyl-2-naphthyl-cyclopropancarbonitrile
##STR00226##
[0420] Yield=56%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.64-1.73 (m, 3H), 1.94-2.07 (m, 2H), 3.97 (dd, J=11.91, 8.69 Hz,
1H), 4.28 (dd, J=11.91, 5.08 Hz, 1H), 7.39-7.45 (m, 1H), 7.48-7.59
(m, 2H), 7.62-7.68 (m, 1H), 7.88 (dd, J=15.18, 8.15 Hz, 2H), 8.48
(dd, J=8.49, 0.78 Hz, 1H).
(5) (1S,2R)-2-Hydroxymethyl-1-(3-fluoro-4-methylphenyl)
cyclopropancarbonitrile
##STR00227##
[0422] Yield--not isolated; .sup.1H NMR (400 MHz, CDCl.sub.3,
partial assignment) .delta. 1.44 (dd, J=6.98, 6.00 Hz, 1H), 1.72
(dd, J=9.42, 5.91 Hz, 1H), 1.83-1.93 (m, 1H), 2.19-2.44 (m, 4H),
3.77 (dd, J=12.10, 8.30 Hz, 1H), 4.00-4.08 (m, 1H), 6.88-7.01 (m,
2H), 7.08-7.21 (m, 1H).
(6) (1R,2S)-2-Hydroxymethyl-1-(3-fluoro-4-methylphenyl)
cyclopropancarbonitrile
##STR00228##
[0424] Yield=40%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24
(t, J=7.13 Hz, 1H), 1.56 (d, J=8.10 Hz, 1H), 1.83-1.92 (m, 1H),
2.23 (d, J=1.76 Hz, 3H), 2.46 (br. s., 1H), 3.76 (dd, J=12.06, 8.25
Hz, 1H), 4.03 (dd, J=12.10, 5.17 Hz, 1H), 6.92 (dd, J=10.54, 1.85
Hz, 1H), 6.98 (dd, J=7.91, 1.95 Hz, 1H), 7.02-7.21 (m, 1H).
(7) Synthesis of
(1S,2R)-2-Hydroxymethyl-1-(4-chloro-3-trifluoromethylphenyl)
cyclopropancarbonitrile as Representative Procedure for
(7)-(12)
##STR00229##
[0426] To a stirring solution of
4-chloro-3-trifluoromethylphenylacetonitrile (11 g, 0.050 moles) in
anhydrous THF (100 mL) at -18.degree. C. under nitrogen, was added
1.95 g (0.050 mmoles 1 eq) of sodium amide in one portion. The
resulting mixture was stirred for 1 h between -15.degree. C. and
-5.degree. C. The dark mixture was cooled to -15.degree. C. and
R-epichlorohydrin (4.6 g, 0.050 moles in 10 mL of THF) was added
slowly over 15 minutes while keeping the temperature below
-10.degree. C. The mixture was stirred between -15.degree. C. and
-5.degree. C. for 0.75 h then cooled to -15.degree. C. and another
1 equivalent (1.95 g) of sodium amide was added in one portion. The
mixture was stirred for 3.5 h while allowing to warm to between -10
and +5.degree. C. then allowed to warm to room temperature and
quenched with 50 mL of saturated NH.sub.4Cl. The mixture was
stirred 5 minutes, allowed to settle and the layers were separated.
The lower aqueous layer was re-extracted with EtOAc (2.times.50
mL). The organics were combined, washed with 100 mL of saturated
NaCl, dried over Na.sub.2SO.sub.4, filtered and concentrated to a
dark oil. Chromatography through a short silica gel plug eluting
with EtOAc/Heptane (5-35%) afforded 5.5 g (40%) of product as a
dark red oil. .sup.1H NMR shows a mixture of diastereomers. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 1.42-1.52 (m, 1H), 1.59-1.72 (m,
1H), 1.89-1.99 (m, 1H), 2.08 (br. s., 1H), 3.79 (dd, J=12.08, 8.33
Hz, 1H), 4.12 (dd, J=12.13, 4.90 Hz, 1H), 7.42-7.55 (m, 1H),
7.56-7.63 (m, 1H), 7.67-7.76 (m, 1H).
(8) (1R,2S)-2-Hydroxymethyl-1-(4-chloro-3-trifluoromethylphenyl)
cyclopropancarbonitrile
##STR00230##
[0428] Yield=60%; H NMR (400 MHz, CDCl.sub.3) .delta. 1.42-1.52 (m,
1H), 1.59-1.72 (m, 1H), 1.89-1.99 (m, 1H), 2.08 (br. s., 1H), 3.79
(dd, J=12.08, 8.33 Hz, 1H), 4.12 (dd, J=12.13, 4.90 Hz, 1H),
7.42-7.55 (m, 1H), 7.56-7.63 (m, 1H), 7.67-7.76 (m, 1H).
(9) (1S,2R)-2-Hydroxymethyl-1-(4-chloro-3-fluorophenyl)
cyclopropancarbonitrile
##STR00231##
[0430] Yield=41%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.57-1.65 (m, 2H), 1.84-1.95 (m, 1H), 2.61 (q, J=5.27 Hz, 1H),
3.68-3.78 (m, 1H), 4.01-4.11 (m, 1H), 7.02-7.10 (m, 1H), 7.29-7.40
(m, 1H).
(10) (1R,2S)-2-Hydroxymethyl-1-(4-chloro-3-fluorophenyl)
cyclopropancarbonitrile
##STR00232##
[0432] Yield=39%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.55-1.65 (m, 2H), 1.84-1.95 (m, 1H), 2.61 (q, J=5.27 Hz, 1H),
3.68-3.78 (m, 1H), 4.01-4.11 (m, 1H), 7.00-7.10 (m, 1H), 7.31-7.40
(m, 1H).
(11) (1S,2R)-2-Hydroxymethyl-1-(3-chloro-4-fluorophenyl)
cyclopropancarbonitrile
##STR00233##
[0434] Yield=20%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.36-1.46 (m, 1H), 1.55-1.64 (m, 1H), 1.84-1.94 (m, 1H), 2.07-2.20
(m, 1H), 3.76 (dd, J=12.10, 8.40 Hz, 1H), 4.05-4.12 (m, 1H),
7.10-7.15 (m, 1H), 7.17-7.23 (m, 1H), 7.33-7.37 (m, 1H)
(12) (1R,2S)-2-Hydroxymethyl-1-(3-chloro,4-fluorophenyl)
Cyclopropancarbonitrile
##STR00234##
[0436] Yield=34%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.37-1.46 (m, 1H), 1.54-1.65 (m, 1H), 1.77 (dd, J=9.47, 5.95 Hz,
1H), 1.83-1.95 (m, 1H), 3.76 (dd, J=12.10, 8.40 Hz, 1H), 4.06-4.13
(m, 1H), 7.12-7.16 (m, 1H), 7.17-7.22 (m, 1H), 7.33-7.38 (m,
1H).
B. Synthesis of Cyclopropyl Methanol Compounds
(1) Synthesis of
(1R,2S)-(2-Aminomethyl-2-(1-naphthyl)cyclopropyl)-methanol as
Representative Procedure for (1)-(6)
##STR00235##
[0438] To a stirring slurry of lithium aluminum hydride (LAH),
(2.31 g, 0.061 moles) in THF (30 mL) at 0-5.degree. C. was added a
solution of crude nitrile, A(1) (6.8 g, (0.030 moles) in 80 mL of
THF), slowly via addition funnel while keeping the temperature
below 10.degree. C. The mixture was stirred for 45 minutes while
warming to -15.degree. C., after which time, no starting material
was observed by TLC analysis (SiO.sub.2 plate, EtOAc/Heptane 1:1).
The reaction was carefully quenched by the dropwise addition of
H.sub.2O (2.5 mL) followed by 2.5 mL of 15% NaOH and lastly 8 mL of
H.sub.2O. The resulting off white slurry was stirred for 1 h then
filtered through a Celite pad, washing with 2.times.50 mL of EtOAc.
The filtrate was concentrated to a pale yellow oil. Chromatography
on silica gel eluting with CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
(20:1:0.1 to 10:1:0.1) afforded 3.3 g (47%) of pure amino alcohol
as a light brown colored oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.01-1.09 (m, J=5.22, 5.22 Hz, 1H), 1.15 (dd, J=8.64, 4.93
Hz, 1H), 1.70 (br. s., 1H), 1.77-1.89 (m, 1H), 2.52 (br. s., 1H),
3.34-3.56 (m, J=11.52, 11.52 Hz, 2H), 3.58-3.69 (m, 1H), 4.17-4.30
(m, J=11.23 Hz, 2H), 7.39-7.55 (m, 3H), 7.56-7.62 (m, 1H), 7.77 (d,
J=8.20 Hz, 1H), 7.84-7.91 (m, 1H), 8.28 (br. s., 1H).
(2) (1S,2R)-(2-Aminomethyl-2-(1-naphthyl)cyclopropyl)-methanol
##STR00236##
[0440] Yield=47%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.00-1.09 (m, 1H) 1.13 (dd, 0.1=8.59, 4.78 Hz, 1H) 1.81-1.93 (m,
1H) 2.61-3.05 (m, 4H) 3.41-3.51 (m, 1H) 3.55-3.64 (m, 1H) 4.17-4.28
(m, 1H) 7.39-7.57 (m, 3H) 7.65 (d, J=6.93 Hz, 1H) 7.73-7.80 (m, 1H)
7.85-7.91 (m, 1H) 8.30 (br. s., 1H).
(3) (1R,2S)-(2-Aminomethyl-2-(2-naphthyl)cyclopropyl-methanol
##STR00237##
[0442] Yield=56%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.79-0.79 (m, 1H), 1.03 (dd, J=8.59, 4.78 Hz, 1H), 1.83-1.93 (m,
1H), 2.54 (br. s., 3H), 2.64 (d, J=12.59 Hz, 1H), 3.40 (dd,
J=12.15, 11.08 Hz, 1H), 3.53 (dd, J=12.59, 0.78 Hz, 1H), 4.17 (dd,
J=12.20, 5.47 Hz, 1H), 7.41-7.54 (m, 3H), 7.77-7.83 (m, 3H), 7.85
(d, J=1.37 Hz, 1H).
(4) (1S,2R)-(2-Aminomethyl-2-(2'-naphthyl)cyclopropyl-methanol
##STR00238##
[0444] Yield=55%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80
(t, J=5.12 Hz, 1H), 0.82 (m, 1H), 1.03 (dd, J=8.59, 4.78 Hz, 1H),
1.82-1.94 (m, 1H), 2.47-2.70 (m, J=12.59 Hz, 4H), 3.40 (dd,
J=12.15, 11.08 Hz, 1H), 3.53 (dd, J=12.59, 0.78 Hz, 1H), 4.17 (dd,
J=12.20, 5.47 Hz, 1H), 7.41-7.54 (m, 3H), 7.77-7.84 (m, 3H), 7.85
(d, J=1.37 Hz, 1H).
(5)
(1R,2S)-(2-Aminomethyl-2-(3-fluoro,4-methylphenyl)cyclopropyl)-methano-
l
##STR00239##
[0446] Yield=38%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.67-0.75 (m, J=5.17, 5.17 Hz, 1H), 0.93 (dd, J=8.59, 4.78 Hz, 1H),
1.66-1.77 (m, 1H), 2.23 (d, J=1.85 Hz, 3H), 2.56 (d, J=12.59 Hz,
1H), 2.95 (br. s., 3H), 3.32 (dd, J=12.25, 10.98 Hz, 1H), 3.43 (dd,
J=12.54, 0.83 Hz, 1H), 4.10 (dd, J=12.30, 5.47 Hz, 1H), 6.99-7.15
(m, 3H).
(6)
(1S,2R)-(2-Aminomethyl-2-(3-fluoro,4-methylphenyl)cyclopropyl)-methano-
l
##STR00240##
[0448] Yield=43%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.72
(t, J=5.17 Hz, 1H), 0.93 (dd, J=8.59, 4.78 Hz, 1H), 1.65-1.77 (m,
1H), 2.23 (d, J=1.85 Hz, 3H), 2.56 (d, J=12.59 Hz, 1H), 2.95 (br.
s., 3H), 3.32 (dd, J=12.25, 10.98 Hz, 1H), 3.43 (dd, J=12.54, 0.83
Hz, 1H), 4.10 (dd, J=12.30, 5.47 Hz, 1H), 6.95-7.17 (m, 3H).
(7) Synthesis of
(1R,2S)-(2-Aminomethyl-2-(4-chloro-3-trifluoromethylphenyl)cyclopropyl)-m-
ethanol as Representative Procedure for (7)-(12)
##STR00241##
[0450] To a stirring solution of
(1S,2R)-2-Hydroxymethyl-1-(4-chloro-3-trifluoromethylphenyl)
cyclopropancarbonitrile prepared according to Example XIV.A(7)
above (5.5 g mg, 20 mmoles) in THF (75 mL) at room temperature
under nitrogen was added 29.9 mL (60 mmoles) of BH.sub.3.Me.sub.2S
(2M in THF). The reaction flask was fitted with a Dean Stark trap
and the mixture was heated to a gentle reflux. The mixture was
refluxed for 3 h while distilling out solvent and Me.sub.2S (about
20-25 mL was collected). No starting nitrile was observed by TLC
analysis (SiO.sub.2 plate, EtOAc/Heptane 1:1). The mixture was
cooled to room temperature and carefully quenchedwith MeOH (10 mL)
then added 20 mL of 6N HCl and refluxed for 0.5 h. The mixture was
cooled to room temperature, basified with solid K.sub.2CO.sub.3.
The resulting slurry was diluted with EtOAc (75 mL), filtered and
concentrated to a pale yellow oil. Chromatography on silica gel
eluting with CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (50:1:0.1 to
10:1:0.1) afforded 2.35 g (42%) of the pure amino alcohol as a pale
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.72-0.84 (m,
1H), 0.87-0.99 (m, J=7.86, 4.44 Hz, 1H), 1.57-1.78 (m, J=21.57 Hz,
2H), 2.60 (d, J=12.98 Hz, 1H), 2.92 (s, 3H), 3.24-3.48 (m, 2H),
3.53-3.71 (m, J=3.61 Hz, 1H), 4.02-4.17 (m, 1H), 7.37-7.55 (m, 2H),
7.66 (s, 1H).
(8) (1S,2R)-(2-Aminomethyl-2-(4-chloro,3-trifluoromethylphenyl)
Cyclopropyl)-Methanol
##STR00242##
[0452] Yield=35%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.80
(t, J=5.31 Hz, 1H), 0.94 (dd, J=8.69, 5.03 Hz, 1H), 1.61-1.77 (m,
1H), 2.61 (d, J=12.90 Hz, 1H), 2.83 (br. s., 3H), 3.33 (dd,
J=12.26, 10.98 Hz, 1H), 3.38-3.46 (m, 1H), 4.10 (dd, J=12.31, 5.35
Hz, 1H), 7.40-7.46 (m, 1H), 7.47-7.53 (m, 1H), 7.67 (d, J=2.01 Hz,
1H).
(9)
(1R,2S)-(2-Aminomethyl-2-(4-chloro-3-fluorophenyl)cyclopropyl)-methano-
l
##STR00243##
[0454] Yield=56%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.73-0.79 (m, 1H), 0.94 (dd, J=8.71, 5.01 Hz, 1H), 1.65-1.77 (m,
1H), 2.54-2.62 (m, J=12.69 Hz, 1H), 2.78 (d, J=10.74 Hz, 3H), 3.32
(dd, J=12.30, 10.93 Hz, 1H), 3.40-3.48 (m, 1H), 4.10 (dd, J=12.40,
5.37 Hz, 1H), 7.09-7.20 (m, 2H), 7.28-7.36 (m, 1H).
(10)
(1S,2R)-(2-Aminomethyl-2-(4-chloro,3-fluorophenyl)cyclopropyl)-methan-
ol
##STR00244##
[0456] Yield=37%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.74-0.80 (m, 1H), 0.95 (dd, J=8.69, 4.98 Hz, 1H), 1.66-1.78 (m,
1H), 2.01 (br. s., J=74.09 Hz, 3H), 2.59 (d, J=12.69 Hz, 1H), 3.3:3
(dd, J=12.30, 10.93 Hz, 1H), 3.44 (dd, J=12.74, 0.93 Hz, 1H), 4.11
(dd, J=12.35, 5.42 Hz, 1H), 7.11-7.15 (m, 1H), 7.18 (dd, J=10.01,
2.00 Hz, 1H), 7.33 (t, J=7.96 Hz, 1H).
(11) (1R,2S)-(2-Aminomethyl-2-(3-chloro,4-fluorophenyl)cyclopropyl)
Methanol
##STR00245##
[0458] Yield=47%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.74
(t, J=5.22 Hz, 1H), 0.93 (dd, J=8.69, 4.88 Hz, 1H), 1.61-1.75 (m,
1H), 2.57 (d, J=12.79 Hz, 1H), 2.72 (br. s., 3H), 3.31 (dd,
J=12.30, 10.93 Hz, 1H), 3.39 (dd, J=12.79, 0.98 Hz, 1H), 4.10 (dd,
J=12.30, 5.37 Hz, 1H), 7.07 (t, J=8.69 Hz, 1H), 7.22-7.29 (m, 1H),
7.43 (dd, J=7.08, 2.20 Hz, 1H).
(12)
(1S,2R)(2-Aminomethyl-2-(3-chloro,4-fluorophenyl)cyclopropyl)-methano-
l
##STR00246##
[0460] Yield=55%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.75
(m, 1H), 0.93 (dd, J=8.69, 4.88 Hz, 1H), 1.61-1.75 (m, 1H), 2.59
(d, J=12.79 Hz, 1H), 2.74 (br. s., 3H), 3.31 (dd, J=12.30, 10.93
Hz, 1H), 3.39 (dd, J=12.79, 0.98: Hz, 1H), 4.10 (dd, J=12.30, 5.37
Hz, 1H), 7.07 (t, J=8.69 Hz, 1H), 7.23-7.28 (m, 1H), 7.45 (dd,
J=7.08, 2.20 Hz, 1H).
C. Synthesis of various naphthyl and phenyl
3-azabicyclo[3.1.0]hexane Hydrochlorides
(1) Synthesis of 1S,5R-(-)-1-(1-naphthyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride as Representative Procedure for (1)-(6)
##STR00247##
[0462] To a stirring solution of
(1R,2S)-(2-Aminomethyl-2-(1-naphthyl)cyclopropyl)-methanol prepared
according to Example: XIVB(1) above (3.2 g, 0.014 moles) in 35 mL
of dichloroethane (DCE), at room temperature under nitrogen, was
added 1.2 mL (0.017 moles, 1.2 eq) of SOCl.sub.2 slowly via syringe
while keeping the temperature below 50.degree. C. (Note: The
reaction exotherms from 22.degree. C. to 45.degree. C.) The
resulting mixture was stirred for 3.5 h at room temperature after
which time, TLC analysis (SiO.sub.2 plate,
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (10:1:0.1)) showed no starting
material remaining. The mixture was quenched with 40 mL of water
and the layers were separated. The organic layer was washed with
H.sub.2O (2.times.50 mL). The aqueous layers were combined, made
basic with 10N NaOH to pH=10 (pH paper) and extracted with
2.times.100 mL of CH.sub.2Cl.sub.2. The combined organics were
dried over Na.sub.2SO.sub.4, filtered and concentrated to an oil.
The oil was dissolved in MeOH (20 mL), treated with 15 mL of 2M
HCl/Et.sub.2O and concentrated in vacuo to a suspension. The slurry
was diluted with 25 mL of Et.sub.2O, filtered and washed with 35 mL
of Et.sub.2O. The solid product was dried overnight (29 mmHg,
50.degree. C.) to give 1 g (29%) of pure product as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.22 (t, J=7.37 Hz, 1H),
1.58 (dd, J=6.00, 4.73 Hz, 1H), 2.03-2.10 (m, 1H), 3.25-3.27 (m,
1H), 3.42 (d, J=11.52 Hz, 1H), 3.64 (d, J=11.62 Hz, 1H), 3.74-3.85
(m, 2H), 7.32-7.39 (m, 1H), 7.40-7.48 (m, 2H), 7.48-7.55 (m, 1H),
7.75 (d, J=8.20 Hz, 1H), 7.79-7.85 (m, 1H), 8.04 (d, J=8.30 Hz,
1H), .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 14.54, 22.43,
30.89, 48.01, 51.89, 123.92, 125.60, 126.24, 126.93, 129.04,
129.17, 133.55, 134.04, LC/MS (nm/z M.sup.+1) 210.0,
[.alpha.].sub.D (c=1, MeOH), =-54.4.
(2) 1R,5S-(+)-1-(1-naphthyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00248##
[0464] Yield=29%; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
1.24-1.32 (m, 1H), 1.32-1.37 (m, 1H), 2.23-2.31 (m, 1H), 3.47 (d,
J=11.71 Hz, 1H), 3.66 (d, J=11.71 Hz, 1H), 3.85 (d, J=11.62 Hz,
1H), 3.93 (dd, J=11.67, 3.95 Hz, 1H), 7.46 (dd, J=8.25, 7.08 Hz,
1H), 7.50-7.57 (m, 1H), 7.57-7.65 (m, 2H), 7.86 (d, J=8.30 Hz, 1H),
7.89-7.95 (m, 1H), 8.17 (d, 0.1=8.49 Hz, 1H), .sup.13C NMR (101
MHz, METHANOL-d.sub.4) .delta. 22.36, 30.65, 30.65, 48.09, 51.99,
123.78, 125.47, 125.89, 126.50, 128.65, 128.88, 133.87, 134.28,
LC/MS (m/z M.sup.+1 210.0), [.alpha.].sub.D (c=1, MeOH),
=+55.6.
(3) 1S,5R-(-)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00249##
[0466] Yield=32%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.33-1.40 (m, J=7.52, 7.52 Hz, 1H), 1.67 (dd, J=6.64, 4.69 Hz, 1H),
2.03-2.11 (m, 1H), 3.63-3.80 (m, 3H), 3.85-3.94 (m, J=11.23, 5.95
Hz, 1H), 7.23-7.29 (m, 1H), 7.43-7.52 (m, 2H), 7.66 (d, J=1.56 Hz,
1H), 7.75-7.83 (m, 3H), 9.81-9.98 (in, J=7.81 Hz, 1H), 10.38 (s,
1H), .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 15.56, 23.47,
31.79, 47.87, 510.99, 125.01, 126.38, 126.42, 126.84, 127.78,
127.86, 128.95, 132.67, 133.46, 135.50, LC/MS (m/z M.sup.+1 210.1),
[.alpha.].sub.D (c=1, MeOH), =-82.2.
(4) 1R,5S-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00250##
[0468] Yield=30%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.14-1.23 (m, 1H), 1.44-1.50 (m, 1H), 2.17-2.26 (m, 1H), 3.36-3.43
(m, 1H), 3.47-3.61 (m, 2H), 3.75 (d, J=11.23 Hz, 1H), 7.36 (dd,
J=8.59, 1.85 Hz, 1H), 7.42-7.53 (m, 2H), 7.80 (d, J=1.56 Hz, 1H),
7.82-7.90 (m, 3H), 9.76 (br. s., 1H), .sup.13C NMR (101 MHz,
DMSO-d.sub.6) .delta. 16.41, 24.11, 31.36, 47.50, 49.97, 125.43,
125.76, 126.41, 127.04, 128.07, 128.15, 128.74, 132.39, 133.55,
137.62,), LC/MS (m/z M.sup.+1 210.1, [.alpha.].sub.D (c=1, MeOH),
=+66.0.
(5) 1S,5R-(-)-1-(3-fluoro,
4-methylphenyl)-3-azabicyclo[3.1.0]hexane Hydrochloride
##STR00251##
[0470] Yield=64%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
0.99-1.08 (m, 1H), 1.39-1.45 (m, 1H), 2.05-2.13 (m, 1H), 2.17 (d,
J=1.37 Hz, 3H), 3.28-3.35 (m, 1H), 3.35-3.48 (m, 2H), 3.63 (d,
J=10.64 Hz, 1H), 6.97 (dd, J=7.81, 1.76 Hz, 1H), 7.05 (dd, J=11.32,
1.76 Hz, 1H), 7.19 (t, J=8.10 Hz, 1H), 9.70 (br. s., 1H), 9.96 (br.
s., 2H), .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta. 14.43 (d,
J=3.16 Hz) 16.59, 24.15, 30.72 (d, J=2.01 Hz) 47.30, 49.70, 113.87
(d, J=22.92 Hz) 122.91 123.01, 132.18 (d, J=5.66 Hz) 140.21 (d,
J=7.86 Hz) 161.31 (d, J=242.57 Hz), LC/MS (m/z M.sup.+1 192.1),
[.alpha.].sub.D (c=1, MeOH), =-58.4.
(6) 1R,5S-(+)-1-(3-fluoro,4-methylphenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00252##
[0472] Yield=95%* crude; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.00-1.09 (m, 1H), 1.36-1.44 (m, 1H), 2.05-2.14 (m, 1H),
2.17 (d, J=1.46 Hz, 3H), 3.32 (d, J=11.13 Hz, 1H), 3.37-3.47 (m,
2H), 3.63 (d, J=11.13 Hz, 1H), 6.97 (dd, J=7.81, 1.85 Hz, 1H), 7.05
(dd, J=11.32, 1.76 Hz, 1H), 7.20 (t, J=8.15 Hz, 1H), 9.74 (br. s.,
2H), .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta. 14.44 (d, J=3.16
Hz), 16.54, 24.13, 30.71 (d, J=2.11 Hz, 1 C) 47.34, 49.73, 113.89
(d, J=22.91 Hz) 122.92 (d, J=13.90 Hz), 123.03, 132.19 (d, J=5.75
Hz), 140.19 (d, J=7.86 Hz), 161.32 (d, J=242.47 Hz), LC/MS (m/z
M.sup.+1 192.1), [.alpha.].sub.D (c=1, MeOH), =.+-.55.8
(7) Synthesis of 1
S,5R-(-)-1-(4-chloro-3-trifluoromethylphenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride as Representative Procedure for (7)-(12)
##STR00253##
[0474] To a stirring solution of
(1R,2S)-(2-aminomethyl-2-(4-chloro-3-trifluoromethylphenyl)cyclopropyl)-m-
ethanol prepared according to Example XIV B(7) above (2.35 g, 8.4
mmoles) in 50 mL of dichloroethane (DCE), at room temperature under
nitrogen, was added 0.8 mL (10.1 mmoles, 1.3 eq) of SOCl.sub.2
slowly via syringe while keeping the temperature below 40.degree.
C. The resulting mixture was stirred for 2 h at room temperature
after which time, TLC analysis (SiO.sub.2 plate,
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (10:1:0.1)) showed remaining no
starting material. The mixture was quenched with 125 mL of water,
diluted with CH.sub.2Cl.sub.2 (75 mL) stirred 2-3 minutes, allowed
to settle and the layers were separated. The organic layer was
washed with H.sub.2O (75 mL). The aqueous layers were combined,
made basic with 10N NaOH to pH=10 (pH paper) and extracted with
2.times.100 mL of CH.sub.2Cl.sub.2. The combined organics were
dried over Na.sub.2SO.sub.4, filtered and concentrated to an oil.
The oil was dissolved in MeOH (40 mL), treated with 20 mL of 2M
HCl/Et.sub.2O, concentrated to .about.5-10 mL total volume and then
diluted with 30 mL of Et.sub.2O and 5 mL of heptane. The resulting
slurry was filtered and washed with 35 mL of cold Et.sub.2O. The
solid product was dried overnight (.about.29 mmHg, 50.degree. C.)
to give 1.8 g (72%) of pure product as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.01-1.07 (m, 1H), 1.13-1.18 (m, 1H),
1.77-1.85 (m, 1H), 3.19-3.33 (m, 3H), 3.42 (d, J=11.13 Hz, 1H),
5.10 (brs, 2H), 7.29 (dd, J=8.20, 2.15 Hz, 1H), 7.42 (d, J=8.40 Hz,
1H), 7.47 (d, J=2.34 Hz, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3)
.delta. 15.81, 23.59, 31.02, 47.75, 50.68, 121.35, 124.07, 126.38,
129.14 (d, J=31.45 Hz), 131.63 (d, J=1.72 Hz), 131.94 (d, J=0.96
Hz), 132.21, 13; 7.50, LC/MS (m/z M.sup.+1 262.0), [.alpha.].sub.D
(c=1, MeOH), =-54.2.
(8)
1R,5S-(+)-1-(4-chloro,3-trifluoromethylphenyl)-3-azabicyclo[3.1.0]hexa-
ne Hydrochloride
##STR00254##
[0476] Yield=43%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.17-1.26 (m, 1H), 2.03-2.11 (m, J=6.64 Hz, 1H), 2.30-2.38 (m,
J=6.30, 4.44 Hz, 1H), 2.87-2.98 (m, J=2.15 Hz, 3H), 3.20-3.29 (m,
1H), 3.31-3.41 (m, 1H), 3.89-4.00 (m, 1H), 4.09-4.18 (m, 1H),
7.28-7.35 (m, 1H), 7.44-7.52 (m, 2H), 12.78 (br. s., 1H); .sup.13C
NMR (101 MHz, CDCl.sub.3) .delta. 15.95, 23.64, 31.02, 47.75,
50.68, 121.35, 124.07, 126.51, 129.12 (d, J=31.45 Hz), 131.62 (d,
J=1.72 Hz), 131.96 (d, J=0.96 Hz), 132.21, 137.50, LC/MS (m/z
M.sup.+1 262.0), [.alpha.].sub.D (c=1, MeOH), =+58.3.
(9) 1S,5R-(-)-1-(4-chloro-3-fluorophenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00255##
[0478] Yield=68%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.16-1.27 (m, J=7.52, 7.52 Hz, 1H), 1.58-1.69 (m, 1H), 1.91-2.04
(m, 1H), 3.49-3.169 (m, J=5.47 Hz, 3H), 3.72-3.83 (m, J=11.03, 5.76
Hz, 1H), 6.87-7.01 (m, 2H), 7.34 (t, J=7.91 Hz, 1H), 9.86 (s, 1H),
10.32 (s, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 16.14,
23.91, 30.99 (d, J=1.82 Hz), 47.67, 50.55, 115.67 (d, J=21.76 Hz),
120.32 (d, J=17.55 Hz), 123.72 (d, J=3.64 Hz), 131.25, 139.17 (d,
J=6.71 Hz) 158.35 (d, J=250.24 Hz), LC/MS (m/z M.sup.+1 212.0),
[.alpha.].sub.D, (c=-1, MeOH), =-76.0.
(10)
1R,5S-(+)-1-(4-chloro,3-fluorophenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00256##
[0480] Yield=31%; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
1.20 (dd, J=6.54, 4.90 Hz, 1H), 1.26-1.32 (m, 1H), 2.17-2.24 (m,
1H), 3.51 (d, J=11.53 Hz, 1H), 3.59-3.71 (m, 2H), 3.76 (d, J=11.35
Hz, 1H), 7.09-7.15 (m, 1H), 7.23 (dd, J=10.48, 2.15 Hz, 1H), 7.43
(t, J=8.05 Hz, 1H); .sup.13C NMR (101 MHz, METHANOL-d.sub.4)
.delta. 15.34, 23.74, 30.60 (d, J=1.92 Hz), 50.31, 115.43 (d,
J=22.05 Hz), 119.25 (d, J=17.74 Hz), 123.90 (d, J=3.55 Hz), 130.79,
140.30 (d, J=7.09 Hz), 158.16 (d, J=247.84 Hz), LC/MS (m/z M.sup.+1
212.0), [.alpha.].sub.D (c=1, MeOH), =+64.0.
(11)
1S,5R-(-)-1-(3-chloro,4-fluorophenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00257##
[0482] Yield=34%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21
(t, J=7.42 Hz, 1H), 1.59 (dd, J=6.64, 4.88 Hz, 1H), 1.91-1.99 (m,
1H), 3.45-3.68 (m, 3H), 3.75 (dd, J=11.23, 6.15 Hz, 1H), 7.05-7.14
(m, 2H), 7.21-7.27 (m, 1H), 9.84 (s, 1H), 10.32 (s, 1H); .sup.13C
NMR (101 MHz, CDCl.sub.3) .delta. 15.62, 23.53, 30.92, 47.76,
50.99, 117.20 (d, J=21.29 Hz), 121.63 (d, J=18.03 Hz), 127.46 (d,
J=7.29 Hz), 129.99, 135.29 (d, J=3.93 Hz), 157.58 (d, J=249.76 Hz),
LC/MS (m/z M.sup.+1 212.1); [.alpha.].sub.D (c=1, MeOH),
=-42.8.
(12)
1R,5S-(+)-1-(3-chloro,4-fluorophenyl)-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00258##
[0484] Yield=59%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.15-1.24 (m, 1H), 1.60 (dd, J=6.54, 4.78 Hz, 1H), 1.90-1.97 (m,
1H), 3.47-3.69 (m, 3H), 3.74 (dd, J=11.27, 6.10 Hz, 1H), 7.04-7.12
(m, 2H), 7.21-7.26 (m, 1H), 9.81 (br. s., 1H), 10.26 (br. s., 1H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 19.22, 27.40, 34.82,
51.77, 54.96, 121.04 (d, J=21.38 Hz), 125.37 (d, J=18.03 Hz),
131.53 (d, J=7.29 Hz), 133.94, 139.23 (d, J=3.93 Hz), 161.48 (d,
J=249.38 Hz), LC/MS (m/z M.sup.+1 212.1), [.alpha.].sub.D (c=1,
MeOH), =+41.4.
D. Synthesis of Various Napthyl and
phenyl-3-methyl-3-azabicyclo[3.1.0]hexane Hydrochloride Using the
Representative Procedure Shown in Example XIV(C)(7)
(1) 1S,5R-(-)-1-(1-naphthyl)-3-methyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00259##
[0486] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.22-1.31 (m, 1H),
2.14-2.21 (m, 1H), 2.45 (d, J=6.50 Hz, 1H), 2.91 (d, J=4.76 Hz,
3H), 3.11-3.23 (m, 1H), 3.46-3.55 (m, 1H), 4.08 (dd, J=11.07, 5.31
Hz, 1H), 4.19-4.27 (m, 1H), 7.39-7.64 (m, 4H), 7.83 (d, J=8.14 Hz,
1H), 7.87-7.93 (m, 1H), 8.11-8.20 (m, 1H), 12.85 (br. s, 1H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 15.05, 22.11-22.56 (m, 1
C) 30.92, 41.35, 57.25-57.70 (m, 1 C) 61.37, 124.02, 125.67,
126.41, 127.12, 129.18, 132.72, 133.51, 134.03, LC/MS (m/z M.sup.+1
224.1); [.alpha.].sub.D (c=1, MeOH), =-60.6.
(2) 1R,5S-(+)-1-(1-naphthyl)-3-methyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00260##
[0488] Yield=58%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
0.93-1.03 (m, 1H), 2.01 (br. s., 1H), 2.14-2.25 (m, 1H), 2.79 (s,
3H), 3.19-3.34 (m, 1H), 3.89-4.01 (m, 1H), 7.48 (dd, J=8.10, 7.22
Hz, 1H), 7.52-7.58 (m, 1H), 7.59-7.66 (m, 2H), 7.88 (d, J=8.20 Hz,
1H), 7.96 (d, J=7.61 Hz, 1H), 8.16 (d, J=8.40 Hz, 1H), 11.30 (br.
s., 1H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta. 14.56, 22.27,
30.46, 40.33, 56.83, 60.63, 124.73, 126.25, 126.65, 127.29, 128.92,
129.41, 132.98, 134.02, [.alpha.].sub.D (c=1, MeOH), =+64.2.
(3) 1S,5R-(-)-1-(2-naphthyl)-3-methyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00261##
[0490] Yield=60%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.27-1.34 (m, 1H), 2.08-2.15 (m, 1H), 2.29 (dd, J=6.88, 4.73 Hz,
1H), 2.92 (d, J=4.69 Hz, 3H), 3.31-3.42 (m, 2H), 3.95 (dd, J=11.03,
5.27 Hz, 1H), 4.18 (dd, J=10.84, 5.27 Hz, 1H), 7.20-7.27 (m, 1H),
7.43-7.53 (m, 2H), 7.62 (d, J=1.66 Hz, 1H), 7.74-7.85 (m, 3H),
12.64 (br. s., 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta.
16.40, 23.41, 31.85, 41.48, 57.47, 60.56, 124.70, 126.19, 126.52,
126.99, 127.73, 127.90, 129.08, 132.69, 133.43, 135.34, LC/MS (m/z
M.sup.+1 224.1, [.alpha.].sub.D (c=1, MeOH), =-88.6.
(4) 1R,5S-(+)-1-(2-naphthyl)-3-methyl-3-azabicyclo[3.1.0]hexane
Hydrochloride
##STR00262##
[0492] Yield=80%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.14-1.22 (m, 1H), 1.89 (dd, J=5.91, 5.03 Hz, 1H), 2.17-2.24 (m,
1H), 2.81 (d, J=4.49 Hz, 3H), 3.45-3.54 (m, 1H), 3.60-3.69 (m, 2H),
3.95 (dd, J=10.88, 5.03 Hz, 1H), 7.35-7.53 (m, 3H), 7.76-7.89 (m,
4H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) .delta. 16.13-16.48 (m, 1
C) 24.17, 31.18, 40.32, 56.68, 58.96-59.19 (m, 1 C) 125.38, 125.78,
126.45, 127.08, 128.04, 128.17, 128.73, 132.42, 133.511, 137.43,
LC/MS (m/z M.sup.+1 210.1), [.alpha.].sub.D (c=1, MeOH),
=+77.8.
(5)
1S,5R-(-)-1-(3-fluoro,4-methylphenyl)-3-methyl-3-azabicyclo[3.1.0]Hexa-
ne Hydrochloride
##STR00263##
[0494] Yield=63%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.01-1.09 (m, 1H) 1.76-1.84 (m, 1H) 2.05-2.12 (m, 1H) 2.17 (d,
J=1.37 Hz, 3H) 2.76 (d, J=4.20 Hz, 3H) 3.38-3.53 (m, 2H) 3.56 (dd,
J=10.98, 4.83 Hz, 1H) 3.83 (dd, J=10.93, 4.88 Hz, 1H) 6.98 (dd,
J=7.86, 1.71 Hz, 1H) 7.08 (dd, J=11.32, 1.56 Hz, 1H) 7.19-7.25 (m,
1H) 11.35 (br. s., 1H); .sup.13C NMR (101 MHz, DMSO-d.sub.6)
.delta. ppm 14.44 (d, J=3.1 Hz) 16.22, 24.24, 30.54 (d, J=1.2 Hz)
56.55, 58.86, 113.94 (d, J=22.7 Hz) 122.96, 123.19 132.18 (d, J=5.7
Hz) 139.95 (d, J=7.8 Hz) 161.32 (d, J=242.8 Hz), LC/MS (m/z
M.sup.+1 206.0), [.alpha.].sub.D (c=1, MeOH), =-69.6.
(6)
1R,5S-(+)-1-(3-fluoro,4-methylphenyl)-3-methyl-3-azabicyclo[3.1.0]Hexa-
ne Hydrochloride
##STR00264##
[0496] Yield=63%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.02-1.10 (m, 1H) 1.68-1.74 (m, 1H), 2.05-2.12 (m, 1H), 2.18 (d,
J=1.56 Hz, 3H), 2.77 (d, J=4.30 Hz, 3H), 3.38-3.52 (m, 2H), 3.58
(dd, J=11.08, 4.83 Hz, 1H), 3.84 (dd, J=10.98, 4.93 Hz, 1H), 6.98
(dd, J=7.81, 1.76, Hz, 1H), 7.08 (dd, J=11.32, 1.66 Hz, 1H), 7.21
(t, J=8.10 Hz, 1H), 11.09 (br. s., 1H); .sup.13C NMR (101 MHz,
DMSO-d.sub.6) .delta. 14.45 (d, J=3.16 Hz), 16.22, 24.22, 30.51,
40.30, 56.65, 58.94, 113.93 (d, J=22.9 Hz), 123.05 (d, J=3.26 Hz),
123.18, 132.19 (d, J=5.6 Hz), 139.90 (d, J=8.0 Hz), 161.32 (d,
J=242.5 Hz), LC/MS (m/z M.sup.+206.1), [.alpha.].sub.D (c=1, MeOH),
=+48.0.
(7) Synthesis of
1S,5R-(-)-1-(4-chloro-3-trifluoromethylphenyl)-3-methyl-3-azabicyclo[3.1.-
0]hexane Hydrochloride
##STR00265##
[0498] To a stirring solution of amine hydrochloride (0.8 g, 3
mmoles) in 75 mL of dichloroethane (DCE), at room temperature under
nitrogen, was added 2.1 mL (28 mmoles, 9.2 eq) of formaldehyde
(37%) followed by 2.98 g (14 mmoles) of sodium
triacetoxyborohydride. The resulting mixture was stirred for 1-2 h
at room temperature after which time, LC/MS analysis showed one
main peak corresponding to the desired product. The mixture was
quenched with 20 mL of 1M NaOH, allowed to settle and the layers
were separated. The aqueous layer was washed with 40 mL of
CH.sub.2Cl.sub.2. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to an oil. The oil was
dissolved in MeOH (5 mL) and treated with an excess of 2M
HCl/Et.sub.2O. An additional 15 mL of
Et.sub.2O/acetonitrile/heptane (2:1:1) was added. The resulting
suspension was cooled to 0-5.degree. C. and filtered, washing the
product cake with Et.sub.2O (10 mL). The product was dried
overnight (.about.29 mmHg, 50.degree. C.) to give 520 mg (62%) of
pure product as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.17-1.23 (m, 1H), 2.03-2.09 (m, 1H), 2.33 (dd, J=6.93,
4.78 Hz, 1H), 2.92 (d, J=4.59 Hz, 3H), 3.22-3.31 (m, J=9.18 Hz,
1H), 3.34-3.42 (m, 1H), 3.92 (dd, J=11.03, 5.27 Hz, 1H), 4.11 (dd,
J=10.84, 5.27 Hz, 1H), 7.31 (dd, J=8.30, 2.05 Hz, 1H), 7.47 (d,
J=8.20 Hz, 1H), 7.51 (d, J=2.05 Hz, 1H), 12.74 (br. s., 1H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 15.76-15.97 (m, 1 C)
23.64-23.81 (m, 1 C) 30.90-31.04 (m, 1 C) 47.56-47.70 (m, 1 C)
50.56-50.72 (m, 1 C) 121.25-121.44 (m, 1 C) 123.97-124.16 (m, 1 C)
126.35-126.74 (m, 1 C) 129.01-129.41 (m, 1 C), 131.69, 131.93,
137.42, LC/MS (m/z M.sup.+1 276.0), [.alpha.].sub.D (c=1, MeOH),
=-60.2
(8)
1R,5S-(+)-1-(4-chloro,3-trifluoromethylphenyl)-3-methyl-3-azabicyclo[3-
.1.0]hexane Hydrochloride
##STR00266##
[0500] Yield 80%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.17-1.25 (m, 1H), 2.03-2.10 (m, 1H), 2.33 (dd, J=6.98, 4.73 Hz,
1H), 2.92 (d, J=4.69 Hz, 3H), 3.23-3.31 (m, 1H), 3.34-3.44 (m, 1H),
3.92 (dd, J=10.98, 5.22 Hz, 1H), 4.11 (dd, J=10.84, 5.27 Hz, 1H),
7.32 (dd, J=8.30, 2.05 Hz, 1H), 7.44-7.55 (m, 2H), 12.74 (br. s.,
1H); .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 16.31, 23.59,
31.04, 41.35, 57.16, 60.04, 121.34, 124.06, 126.53 (q, J=5.27 Hz),
129.20 (d, J=31.54 Hz), 131.82, 132.01, 132.35 (m), LC/MS (m/z
M.sup.+1 276.1), [.alpha.].sub.D (c=1, MeOH), =+41.4.
(9)
1S,5R-(-)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexa-
ne Hydrochloride
##STR00267##
[0502] Yield=81%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.10-1.27 (1H), 1.97-2.07 (m, 1H), 2.29 (br. s., 1H), 2.91 (s, 3H),
3.19-3.39 (m, 2H), 3.90 (br. s., 1H), 4.02-4.17 (m, 1H), 6.91 (d,
J=7.81 Hz, 1H), 7.00 (d, J=9.66 Hz, 1H), 7.35 (t, J=7.71 Hz, 1 H);
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 16.09-17.22 (m, 1 C)
23.85, 31.04, 41.65, 57.32, 60.14, 115.67 (d, J=-21.8 Hz), 120.48
(d, J=17.5 Hz) 123.72, 131.36, 138.97, 158.37 (d, J=250.3 Hz),
LC/MS (nm/z M.sup.+1 226.0), [.alpha.].sub.1) (c=1, MeOH),
=-79.8.
(10)
1R,5S-(+)-1-(4-chloro,3-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]Hex-
ane Hydrochloride
##STR00268##
[0504] Yield=87%; .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
1.27 (t, J=7.71 Hz, 1H), 1.47 (dd, J=6.78, 4.83 Hz, 1H), 2.17-2.26
(m, 1H), 2.98 (s, 3H), 3.61 (d, J=11.32 Hz, 1H), 3.80 (d, J=1.32
Hz, 1H), 4.03 (d, J=11.23 Hz, 1H), 7.10-7.16 (m, 1H), 7.26 (dd,
J=10.45, 2.05 Hz, 1H), 7.43 (t, J=8.10 Hz, 1H); .sup.13C NMR (101
MHz, METHANOL-d4) .delta. 14.25, 15.29, 23.70, 39.83, 57.24, 59.59,
115.42 (d, J=22.24 Hz, 1 C) 119.36 (d, J=17.74 Hz, 1 C) 123.87 (d,
J=3.64 Hz, 1 C) 130.81, 140.03, 158.16 (d, J=247.84 Hz, 1 C), LC/MS
(m/z M.sup.+1 226.0), [.alpha.].sub.D (c=1, MeOH), =+61.6.
(11)
1S,5R-(-)-1-(3-chloro,4-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]Hex-
ane Hydrochloride
##STR00269##
[0506] Yield=78%; 1H NMR (400 MHz, CDCl.sub.3) .delta. 1.03-1.16
(m, 1H) 1.84-2.01 (m, 2H) 2.84 (s, 3H) 3.17-3.30 (m, 1H) 3.29-3.41
(m, 1H) 3.80 (d, J=10.84 Hz, 1H) 3.97 (d, J=10.84 Hz, 1H) 6.97-7.11
(m, 2H) 7.18-7.29 (m, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3)
.delta. 15.88, 18.47, 23.27, 30.72, 40.96, 57.26, 60.30, 117.17 (d,
J=21.4 Hz), 121.50 (d, J=17.9 Hz), 127.51 (d, J=7.2 Hz), 129.90,
134.98 (d, J=3.7 Hz), 157.56 (d, J=249.8 Hz), LC/MS (m/z M.sup.+1
225.7), [.alpha.].sub.D (c=1, MeOH), =-46.2.
(12)
1R,5S-(+)-1-(3-chloro,4-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]Hex-
ane Hydrochloride
##STR00270##
[0508] Yield 59%; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.14
(t, J=7.81 Hz, 1H) 1.93-2.01 (m, 1H) 2.19 (dd, J=6.74, 4.69 Hz, 1H)
2.91 (d, J=4.59 Hz, 3H) 3.23-3.32 (m, 1H) 3.37-3.46 (m, 1H) 3.86
(dd, J=10.88, 5.12 Hz, 1H) 4.02 (dd, J=10.84, 5.17 Hz, 1H)
7.06-7.11 (m, 2H) 7.26-7.31 (m, 1H); .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 15.83, 23.43, 30.91, 41.26, 57.23, 60.20-60.54
(m, J=0.6 Hz), 117.26 (d, J=21.3 Hz), 121.61 (d, J=18.1 Hz), 127.61
(d, J=7.3 Hz, 130.00, 135.14 (d, J=3.9 Hz), 157.61 (d, J=249.9 Hz,
157.63, LC/MS (m/z M.sup.+1 225.9), [.alpha.].sub.D (c=1, MeOH),
=+60.5.
Example XV
Preparation of 1-Aryl-4-methyl-3-aza-bicyclo[3.1.0]hexane Using
Reaction Scheme 21
A. Preparation of
(.+-.)-1-(3,4-dichloro-phenyl)-(r/s)-2-hydroxymethyl-cyclopropanecarbonit-
rile
##STR00271##
[0510] To an oven-dried, three-necked, 500 mL round-bottomed flask
was added the compound 3,4-dichlorobenzonitrile and THF with
stirring under argon. The solution was cooled to -25.degree. C. in
a dry ice/MeCN bath and charged with 5.3 g of sodium amide. The
resulting yellow suspension became orange upon stirring and was
warmed to ambient temperature over 2 hours. The brown mixture was
cooled to -25.degree. C. and epichlorohydrin was added drop-wise
over 10 minutes followed by a second equivalent of sodium amide in
one portion. The golden brown mixture was stirred at -25.degree. C.
and warmed to 15.degree. C. over 8 h. The dark red-colored mixture
was poured (with stirring) into 500 mL of saturated ammonium
chloride. The organic phase: was separated and dried over magnesium
sulfate for 12 h. The mixture was filtered and concentrated under
reduced pressure and dried to afford 31 g of red oil. Half of the
material was loaded onto a silica gel (250 g) column and eluted
first with hexane. Later the polarity was increased to 10% EtOAc in
hexanes and finally to 20% EtOAc in hexanes. Tubes containing the
product were combined and concentrated, and dried under a high
vacuum to give the product as a mixture of diastereomers. Yield:
6.8 g (42%); LCMS: (+) ESI: m/z=242 [M].sup.+; .sup.1H NMR (300
MHz, CDCl.sub.3, peaks corresponding to syn isomer listed) .delta.
7.43 (m, 2H, ArH), 7.7.14 (m, 1H, ArH), 4.09 (dd, 1H, CHOH, J=12 Hz
and 4.8 Hz), 3.74 (dd, 1H, CHOH, J=12 Hz and 8.4 Hz), 2.73 (bs, 1H,
OH), 1.91 (m, 1H, ArCCH.sub.2CH), 1.62 (m, 2H, ArCCH.sub.2CH).
B. Preparation of
(+))-1-aminomethyl-1-(3',4'-dichlorophenyl)cylcopropyl-(r/s)-2-methanol
##STR00272##
[0512] An oven-dried, 500 mL round-bottomed flask was charged with
LAH (2.13 g, 0.056 mole) and diethyl ether (210 mL). The mixture
was cooled to <5.degree. C. by ice bath, and after 10 min, a
solution of carbonitrile (6.8 g, 0.028 mole) in diethyl ether (90
mL) was added via addition funnel over 30 min after which the
contents were stirred at ice-bath temperature for 3 h. The reaction
slurry was quenched carefully by slow addition of 25% aq. NaOH
solution (5.5 mL) and stirred at ice-bath temperature for 45 min.
Water (5 mL) was added and the contents filtered and washed with
ether (2.times.50 mL). The combined filtrate was concentrated under
reduced pressure and dried under a high vacuum pump overnight to
afford a colorless thick liquid. Yield: 6.0 g (87%); LCMS: (+) ESI:
m/z=246 [M].sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature.: 7.50 (d, 1H, ArH), 7.40 (d, 1H, ArH), 7.24
(dd, 1H, ArH), 4.32 (dd, 1H, CHOH), 3.43 (d, 1H, CH.sub.2N), 3.34
(dd, 1H, CHOH), 2.60 (d, 1H, CH.sub.2N), 1.71 (m, 1H,
ArCCH.sub.2CH), 0.94 (dd, 1H, ArCC{right arrow over (H)}.sub.2CH),
0.77 (m, 1H, ArCCH.sub.2CH).
C. Preparation of
(.+-.)-2-hydroxymethyl-1-(3',4'-dichlorophenyl)-cyclopropylmethyl-(r/s)-c-
arbamic acid tert-butylester
##STR00273##
[0514] Boc anhydride (5.91 g, 0.026 mole) was added in one portion
to a stirred solution of amino alcohol in anhydrous DCM (150 mL),
and the reaction mixture stirred at ambient temperature under argon
for 4.5 h. Water (200 mL) was added to the reaction mixture and the
organic layer separated. The organic layer was washed with brine
(100 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to
give N-boc amino alcohol as a colorless liquid that became a
colorless glass upon standing. The material was used without
further purification. Yield: 9.0 g (quantitative); LCMS: (+) ESI:
m/z=368 [M+Na].sup.+.
D. Preparation of
(+)-4-oxo-1-(3',4',-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexan-3-carboxyli-
c acid tert-butyl ester
##STR00274##
[0516] PDC (23 g, 0.06 mole) was added in one portion to a stirred
mixture of N-boc amino alcohol (9.0 g, 0.026 mole) and molecular
sieves (23 g) in anhydrous DCM (200 mL). The resulted dark brown
reaction mixture was stirred at ambient temperature under argon for
3.5 h. The reaction mixture was diluted with diethyl ether (50 mL),
filtered through a plug of Celite.RTM. using a sintered funnel and
washed with dichloromethane (3.times.50 mL). The dark brown
filtrate was concentrated to give a thick brown liquid which was
purified via column chromatography using approximately 250 g
silica. The column was first eluted with 100% hexanes, changing the
gradient to 9:1 hexanes:EtOAc, then 8:2 hexanes: EtOAc. Tubes
containing the product were combined, concentrated, and dried on a
high vacuum pump overnight to give the desired product. Yield: 4.1
g (49%); LCMS: (+) ESI: m/z=364 [M+Na].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta..quadrature.: 7.43 (d, 1H, ArH), 7.36 (d, 1H,
ArH), 7.09 (dd, 1H, ArH), 4.03 (dd, 1H, CH.sub.2N), 3.91 (d, 1H,
CH.sub.2N), 2.30 (d, 1H, ArCCH.sub.2CH), 1.60 (m, 1H,
ArCCH.sub.2CH), 1.54 (s, 9H, tert-Bu), 1.34 (m, 1H,
ArCCH.sub.2CH).
E. Preparation of
(.+-.)-1-tert-butyloxycarbonylaminomethyl-(r/s)-2-acetyl-1-(3',4'-dichlor-
ophenyl)-cyclopropane
##STR00275##
[0518] A solution of methyl lithium-ether (3.4 mL, 5.42 mmole,
1.6M) was added drop wise via a syringe to a stirred solution of
N-boc lactam (1.6 g, 4.7 mmole) in anhydrous THF cooled at
dry-ice/acetone bath temperature. The reaction mixture was stirred
with cooling (<-78.degree. C.) for 3 h and then warmed to
ambient temperature. The reaction mixture was quenched with 1N aq
HCl solution (20 mL) and then extracted with ethyl acetate
(2.times.20 mL). The combined organic layer was washed with brine
(20 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated to
result in a yellow liquid. The compound was purified via column
chromatography on silica (.about.100 g) eluting with 10%
EtOAc-hexane and increasing to 20% EtOAc-hexanes. The desired
fractions were combined, concentrated under reduced pressure, and
dried to afford the desired product. Yield: 1.17 g (70%); LCMS: (+)
ESI: m/z=380 [M+Na].sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature.: 7.39 (m, 2H, ArH), 7.17 (dd, 1H, ArH), 4.50
(bs, 1H, NH), 3.52 (m, 2H, CH.sub.2N), 2.42 (s, 3H, CH.sub.3), 2.30
(d, 1H, ArCCH.sub.2CH), 1.66 (m, 1H, ArCCH.sub.2CH), 1.34 (s, 9H,
tert-Bu), 1.24 (m, 1H, ArCCH.sub.2CH).
F. Preparation of erythreo and threo
[1-(3,4-dichloro-phenyl)-2-(1-hydroxy-ethyl)-cyclopropylmethyl]-carbamic
Acid Tert-Butyl Esters
##STR00276##
[0520] The product from Example XV E above was added to methanol
and stirred at ambient temperature under Ar (g) in a 50 mL
round-bottomed flask. Potassium borohydride was added portion-wise
and the resulting suspension stirred overnight. A clear solution
was obtained. The resulting solution was partitioned between EtOAc
(10 mL) and water (10 mL). The aqueous layer was extracted with
EtOAc (2.times.10 mL) and the combined layers washed with brine (10
mL). The organic layer was dried over sodium sulfate for 2 hours
and filtered, concentrated under reduced pressure, and dried for 1
hour to afford a solid. The solid was purified on a filterpad of 20
g of silica eluting with 4/1 hexanes/EtOAc (v/v), switching to 1/1
hexanes/EtOAc (v/v) upon collection of the major spot. The second
(desired) diastereomer was collected, including undesired
diastereomer, yield: 0.321 g, 40%; and desired diastereomer, yield:
0.254 g, 32%; .sup.1H NMR, Undesired diastereomer: (300 MHz,
CDCl.sub.3) .delta..quadrature.: 7.34-40 (m, 21-, ArH), 7.15 (m,
1H, ArH), 4.93 (bs, 1H, NH), 3.50-61 (m, 3H, CH.sub.3), 3.25 (m,
2H, CH.sub.2N), 1.2-1.4 (m, 9H, tert-Bu), 0.95-1.0 (m, 1H,
ArCCH.sub.2), 0.54 (m, 1H, ArCCH.sub.2); Desired diastereomer 1-7:
(300 MHz, CDCl.sub.3) .delta..quadrature.: 7.37 (d, 1H, J=18 Hz,
ArH), 7.35 (m, 1H, ArH), 7.11 (m, 1H, ArH), 4.48 (bs, 1H, NH), 3.78
(m, 3H, CH.sub.3), 3.57 (m, 1H, CH.sub.2N), 3.37 (d, 1H, J=5 Hz,
CH.sub.2N), 3.32 (d, 1H, J=5 Hz, CHOH), 1.4 (s, 9H, tert-Bu), 1.23
(m, 1H, CH), 1.03 (m, 2H, ArCCH.sub.2).
G. Preparation of
(+)-1-(3,4-dichloro-phenyl)-(r)-4-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00277##
[0522] The compound from Example XV F above was added to DCM and
triethylamine and cooled in an ice bath under Ar (g) with stirring.
Methanesulfonyl chloride was added dropwise with stirring over 10
min, and the resulting suspension warmed to ambient temperature
overnight. The resulting yellow solution was washed with water
(2.times.10 mL) and the DCM layer dried over magnesium sulfate. The
mixture was filtered and concentrated under reduced pressure to
afford a yellow oil. This oil was dissolved in 0.8 mL of DCM and
cooled in an ice bath under Ar (g). To this was added 0.8 mL of TFA
and the resulting solution was stirred at ambient temperature for 1
hour. The solution was concentrated under reduced pressure,
quenched with concentrated NaOH, and extracted with ether
(2.times.10 mL). The organic extracts were combined and dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. The oil was purified on a 2000 micron prep plate eluting
with 10/1 CHCl.sub.3/MeOH (v/v) to afford the desired free base.
Yield: 0.030 g 15%; LCMS (+) ESI: in/z=242 [M+H].sup.+ (100); 244
[M+H].sup.+ (65); UV (.lamda..sub.max=218)=97%; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta..quadrature. 7.32-36 (m, 1H, ArH), 7.23-26
(m, 1H, ArH), 7.01-04 (m, 1H, ArH), 3.37 (q, 1H, J=7 Hz,
CHCH.sub.3), 3.20-25 (m, 2H, CH.sub.2N), 1.55 (m, 1H, CHCH.sub.2),
1.22 (m, 3H, CHCH.sub.3), 0.96 (m, 2H, ArCCH.sub.2); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 130.3, 129.3, 126.7, 55.7, 50.7, 32.4,
21.1, 15.8
H. Preparation of the Hydrochloride Salt of
(.+-.)-1-(3,4-dichloro-phenyl)-(r)-4-methyl-3-aza-bicyclo[3.1.0]hexane
[0523] To a vial was added 30 mg of the compound from Example XV F
above, 1 mL diethyl ether, and 0.2 mL 2N HCl in diethyl ether. A
white precipitate appeared in minutes and the suspension was
stirred at ambient temperature for 1 hour. The suspension was
filtered, collected, and dried to afford 18 mg of a white solid.
LCMS (+) ESI: m/z=242 [MH].sup.+ (100); 244 [MH+2].sup.+ (65); UV
(.lamda..sub.max=218)=95%; .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta..quadrature. 7.48-52 (m, 2H, ArH), 7.23-26 (m, 1H, ArH),
4.63 (s(br), 2H, NH.sub.2) 3.93 (q, 1H, J=7 Hz, CHCH.sub.3), 3.68
(m, 2H, CH.sub.2N), 2.08 (dd, 1H, J=8 Hz, 5 Hz, CHCH.sub.2), 1.45
(m, 3H, CHCH.sub.3), 1.29 (m, 1H, CH), 1.16 (m, 2H,
ArCCH.sub.2).
Example XVI
Preparation of 1-Aryl-4-methyl-3-aza-bicyclo[3.1.0]hexane and
1-Aryl-3,4-dimethyl-3-aza-bicyclo[3.1.0]hexane Using Reaction
Scheme 22
A. Preparation of
(.+-.)-5-(3',4'-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexan-2-one
##STR00278##
[0525] TFA (7.5 mL, 96 mmole) was added drop wise via a syringe
over a period of 10 min to a stirred and colorless solution of
N-boc lactam prepared according to Example XV, D above (4.1 g, 12
mmole) in anhydrous DCM (100 mL) at ice-bath temperature. The
resulting light brown solution was stirred at ambient temperature
for 6 h. The reaction mixture was concentrated and dissolved in
dichloromethane (100 mL). This solution was washed with saturated
aqueous NaHCO.sub.3 solution (50 mL), brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give an off-white
solid. It was dried on a high vacuum pump overnight. Yield: 2.7 g
(93%); LC MS: (+) ESI: m/z=242 [MH].sup.+.
B. Preparation of
(.+-.)-4-methyl-1-(3',4'-dichlorophenyl)-2,4-dehydro-3-aza-bicyclo[3.1.0]-
hexan-2-one
##STR00279##
[0527] A solution of TMSCl (0.52 mL, 4.1 mmole) in toluene (2 mL)
was added drop wise via syringe to a stirred suspension of lactam
(0.9 g, 3.72 mmole) and triethylamine (0.64 mL, 4.46 mmole) in
anhydrous toluene (12 mL) that was cooled in an ice-bath. The
resulting white turbid solution was stirred at 50.degree. (C for 4
h and then cooled in an ice-bath. The mixture was filtered through
a plug of Celite.RTM. eluting with hexanes:diethyl ether (1:1, 10
mL) and washed with additional hexanes:diethyl ether (1:1, 10 mL).
The combined filtrates were concentrated and dried under high
vacuum for 30 min. The residue was dissolved in anhydrous diethyl
ether (10 mL) and cooled using a dry-ice/acetone bath to a
temperature of approximately -30.degree. C. A solution of MeLi
(0.64 mL, 4.46 mmole) solution was added drop wise and continued
stirring at -30.degree. C. (bath temp) for 30 min. The cold bath
was removed and the contents stirred at ambient temperature for 1
h. The reaction mixture was quenched with addition to an aqueous
ammonium chloride solution (0.5 g in 12 mL) and the contents
stirred at ambient temperature for 30 min. The organic layer was
separated, washed with brine (25 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The oil was
dried under high vacuum for 2 h to give a yellow oil. The oil was
purified via chromatography on silica (100 g), first eluting with
hexanes: EtOAc (8:2), and gradually increasing the polarity to 7:3,
1:1, and finally 2:8 hexanes: EtOAc. Tubes containing the desired
product were combined and concentrated under reduced pressure and
dried under high vacuum overnight to afford the product. Yield: 0.6
g (71%); LCMS: (+) ESI: m/z=240 [M].sup.+.
C. Preparation of
(.+-.)-trans-4-methyl-1-(3',4'-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
##STR00280##
[0529] Sodium cyanoborohydride (0.24 g, 3.83 mmole) was added to a
stirred solution of imine (0.6 g, 2.5 mmole) in ethanol (8 mL). To
this mixture was added a solution of 1.2M HCl-ethanol (3.1 mL, 3.83
mmole) drop-wise. The resulting white suspension was stirred at
ambient temperature for 2 h. The reaction mixture was poured into a
mixture of brine (30 mL) and 2N aqueous NaOH solution (3 mL), and
extracted with ethyl acetate (3.times.20 mL). The combined organic
layer was washed with brine (20 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated and dried under high vacuum to give a
light yellow oil. The liquid was purified by chromatography on
silica (100 g), eluting first with 1% MeOH--CHCl.sub.3 and
gradually increasing the polarity to 2%, 3%, and finally to 5%
MeOH--CHCl.sub.3. Tubes containing the desired product were
combined, concentrated, and dried under high vacuum to afford the
product as colorless liquid. Yield: 0.3 g (47%); .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.35 (d, 1H, J=8.4 Hz, ArH), 7.28 (d, 1H,
J=2.1 Hz, ArH), 7.06 (dd, 1H, J=8.1 Hz and 2.1 Hz, ArH), 3.42 (m,
1H, --CHCH.sub.3), 3.16 (d, 1H, J=11.4 Hz, CH.sub.2N), 3.00 (dd,
1H, J=11.1 Hz, 0.6 Hz, CH.sub.2N), 1.73 (m, 1H, CHCH.sub.2), 1.14
(d, 3H, J=6.3 Hz, CHCH.sub.3), 1.01 (m, 1H, ArCCH.sub.2), 0.76 (m,
1H, ArCCH.sub.2); .sup.13C NMR (300 MHz, CDCl.sub.3) .delta.
144.94, 133.26, 131.54, 130.71, 130.05, 127.95, 56.35, 53.58,
33.74, 32.82, 17.36, 13.02; LC-MS: (+) ESI: m/z=242 [M].sup.+
(100); UV (.lamda..sub.max=218)=100%.
[0530] A solution of HCl-ether (2.0M, 6.6 mL, 1.32 mmole) was added
to a stirred solution of amine (0.16 g, 0.66 mmole) in anhydrous
diethyl ether (2 mL). The resulting white suspension was stirred at
ambient temperature for 30 min. The reaction mixture was filtered
and washed with cold anhydrous ether (5 mL) to give a bright white
solid, and further dried to a constant mass under high vacuum.
Yield: 0.172 g (94%); 1H NMR (300 MHz, CD.sub.3OD) .delta. 7.49 (m,
2H, ArH), 7.23 (dd, 1H, J=8.4 Hz, 2.1 Hz, ArH), 4.18 (m, 1H,
CHCH.sub.3), 3.71 (d, 1H, J=11.7 Hz, CH.sub.2N), 3.62 (dd, 1H,
J=11.7 Hz, 1.2 Hz CH.sub.2N), 2.22 (m, 1H, CHCH.sub.2), 1.44 (d,
3H, J=6.3 Hz, CHCH.sub.3), 1.20 (m, 1H, ArCCH.sub.2), 0.88 (m, 2H,
ArCCH.sub.2); LC-MS: (+) ESI: m/z=242 [M.sup.+] (100); UV
(.lamda..sub.max=218)=100%.
D. Preparation of
(.+-.)-n-methyl-trans-4-methyl-1-(3',4'-dichlorophenyl)-3-azabicyclo[3.1.-
0]hexane
##STR00281##
[0532] Amine (0.1 g, 0.41 mmole) and diisopropylethylamine (0.165
mL, 0.95 mmole) were dissolved in anhydrous DMF (1 mL) with
stirring at ambient temperature for 30 min. Iodomethane (0.033 mL,
0.54 mmole) was added and stirring continued at ambient temperature
for 20 h. The reaction mixture was concentrated and dried under
high vacuum for 1 h to give a semi-solid that was purified via
chromatography on silica eluting with 1% MeOH-EtOAc to afford the
product as a colorless glass. Yield: 0.061 g (58%); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.40 (d, 1H, J=8.1 Hz, ArH), 7.31 (d,
1H, J=2.1 Hz, ArH), 7.08 (dd, 1H, J=8.4 Hz, 2.1 Hz, ArH), 3.36 (d,
1H, J=9 Hz, CH.sub.2N), 2.74 (m, 1H, CHCH.sub.3), 2.71 (d, 1H, J=9
Hz, CH.sub.2N), 2.32 (s, 3H, CH.sub.3N), 1.86 (b, 1H,
ArCCH.sub.2CH), 1.35 (m, 1H, ArCCH.sub.2), 1.16 (d, 3H, J=6.3 Hz,
CHCH.sub.3), 0.73 (m, 1H, ArCCH.sub.2); .sup.13C NMR (300 MHz,
CDCl.sub.3) .delta. 144.9, 133.3, 131.5, 130.7, 129.6, 127.5, 63.3,
62.9, 40.2, 32.8, 30.9, 29.3, 16.3, 15.6; LC-MS: (+) ESI: m/z=256
[M].sup.+ (100).
[0533] A solution of HCl-ether (2.0M, 2.2 mL, 1.32 mmole) was added
to a solution of amine (0.06 g, 0.23 mmole) in anhydrous methanol
(2 mL) and stirred at ambient temperature for 30 min. The reaction
mixture was concentrated and dried under high vacuum to give an
off-white solid that was triturated with anhydrous diethyl ether
and filtered, washing with cold anhydrous ether (5 mL), and dried
under high vacuum to give an off white solid. Yield: 0.030 g (44%);
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.49 (m, 2H, ArH), 7.21
(dd, 1H, ArH, J=8.1 Hz, 2.1 Hz, CHCH.sub.3), 3.98 (m, 2H,
CH.sub.2N, CHCH.sub.3), 3.65 (m, 1H, CH.sub.2N), 2.93 (s, 1H,
NCH.sub.3), 2.28 (m, 1H, CHCH.sub.2), 1.46 (d, 31H, CHCH.sub.3,
J=6.3 Hz), 1.23 (m, 1H, ArCCH.sub.2), 0.89 (m, 1H, ArCCH.sub.2);
LC-MS: (+) ESI: m/z=256 [M].sup.+ (100); UV
(.lamda..sub.max=218)=100%.
Example XVII
Preparation of 1-Aryl-2-methyl-3-aza-bicyclo[3.1.0]hexane and
1-Aryl-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane Using Reaction
Scheme 23
A. Preparation of
(+)-1-(3,4-dichloro-phenyl)-3-aza-bicyclo[3.1.0]hexan-2-one
##STR00282##
[0535] 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione
and toluene were combined in a 500 mL round-bottomed flask and
stirred under Ar (g) for 10 min while cooling in an ice bath.
Red-Al.RTM. was added via addition funnel drop-wise over several
minutes. Upon complete addition, the ice bath was removed and the
reaction stirred at ambient temperature overnight. The reaction
mixture was cooled in an ice bath and 150 mL of 5N NaOH was
carefully added. The phases were separated and the aqueous phase
was extracted with toluene (2.times.100 mL), DCM (3.times.100 mL),
and the organic layers combined. The organic layer was washed with
brine (200 mL) and dried over sodium sulfate for 8 h. The mixture
was filtered, concentrated in vacuo, and dried to afford 5 g of a
dark brown semi-solid. The semi-solid was purified on a silica gel
column eluting with 20% EtOAc in hexanes increasing the polarity to
30% EtOAc and finally 50% EtOAc. The desired fractions containing
the product were combined, concentrated, and dried to afford a
light yellow solid. Yield: 2.0 g 30%; LCMS (+) ESI: m/z=242
[M].sup.+; m/z=264 [M+Na].sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature. 7.52 (d, 1H, ArH), 7.39 (d, 1H, ArH), 7.28 (dd,
1H, ArH), 6.02 (bs, 1H, NH), 3.64 (dd, 1H, NHCH.sub.2), 3.40 (d,
1H, NHCH.sub.2), 2.28 (m, 111H, NHCH.sub.2CH), 1.50 (dd, 1H,
ArCCH.sub.2), 1.26 (m, 1H, ArCCH.sub.2).
B. Preparation of
(+)-1-(3,4-dichloro-phenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-3-carboxylic
Acid Tert-Butyl Ester
##STR00283##
[0537] To a 50 mL, round-bottomed flask was added
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexan-2-one, a stir bar,
triethylamine, DMAP, and DCM. The resulting brown suspension was
stirred under Ar (g), and to this was added drop-wise, a solution
of di-tert-butyl dicarbonate in 4.1 mL of DCM over 10-15 min. The
suspension became a solution within 1 hour and stirring continued
overnight. The solution was quenched with isopropyl amine and
stirred at room temperature for 1 hour. The organic solution was
washed with 0.5N HCl (25 mL), water (25 mL), and brine (20 mL). The
organic layer was dried over magnesium sulfate for 1 hour,
filtered, concentrated, and dried. The brown tar was treated with
20 mL hexanes and placed in a freezer for 24 h. The resulting solid
was warmed to ambient temperature and triturated with hexanes. The
resulting powder was collected by vacuum filtration and dried under
high vacuum for 24 h to afford a powder. A second crop could be
collected by chromatography of the filtrate using 4/1 hex/EtOAc.
Yield: 1.21 g 43%; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature.: 7.50 (d, 1H, J=1.8 Hz, ArH), 7.39 (d, 1H,
J=9.0 Hz, ArH), 7.24-28 (m, 1H, ArH), 3.91 (dd, 1H, J=5.4 Hz,
CHCH.sub.2), 3.79 (d, 2H, J=9.0 Hz, CH.sub.2N), 1.45-1.58 (m, 1 OH,
tert-Bu, ArCCH.sub.2), 1.30 (t, 1H, J=4.8 Hz, ArCCH.sub.2).
C. Preparation of
(.+-.)-[2-acetyl-2-(3,4-dichloro-phenyl)-cyclopropylmethyl]-carbamic
Acid Tert-Butyl Ester
##STR00284##
[0539] To a flame-dried, 10 mL round-bottomed flask was added a
solution of
1-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic
acid tert-butyl ester in 2 mL of ether and 1.0 mL of THF under Ar
(g). The solution was cooled in a dry ice/acetone bath with
stirring. A solution of MeLi was added drop-wise and the resulting
orange colored mixture was stirred at -78.degree. C. for 3 hours.
The solution was warmed to ambient temperature and quenched with 15
mL of 1N HCl. The organic layer was extracted with EtOAc
(2.times.20 mL) and the combined layers washed with brine (20 mL).
The organic layer was dried over sodium sulfate for 2 hours and
filtered, concentrated under reduced pressure, and dried for 1 hour
to afford 1.1 g of a brown oil. The oil was purified on a filter
pad of silica eluting with 100/1 (v/v) CHCl.sub.3/MeOH. The desired
fractions were collected, concentrated under reduced pressure, and
dried to afford a yellow oil. Yield: 0.659 g 52%; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta..quadrature. 7.46 (d, 1H, J=2.1 Hz, ArH),
7.39 (d, 1H, J=5.4 Hz, ArH), 7.20 (dd, 1H, J=5.4, 2.1 Hz, ArH),
4.73 (m, 1H, NH), 3.41 (m, 1H, CH.sub.2N), 3.15 (m, 1H, CH.sub.2N),
2.04 (s, 3H, CH.sub.3), 1.80 (m, 1H, CHCH.sub.2N), 1.45-1.58 (m,
9H, tert-Bu), 1.20 (dd, 2H, J=4.5 Hz, ArCCH.sub.2).
D. Preparation of
(.+-.)-[2-(3,4-dichloro-phenyl)-(r/s)-2-(1-hydroxy-ethyl)-cyclopropylmeth-
yl]-carbamic Acid Tert-Butyl Ester
##STR00285##
[0541]
(.+-.)-[2-Acetyl-2-(3,4-dichlorophenyl)-cyclopropylmethyl]-carbamic
acid tert-butyl ester was added to methanol and stirred at ambient
temperature under Ar (g) in a 50 mL round-bottomed flask. Potassium
borohydride was added portion wise and the suspension stirred
overnight. The resulting suspension partitioned between EtOAc (10
mL) and water (10 mL). The aqueous layer was extracted with EtOAc
(2.times.10 mL), and the combined layers washed with brine (10 mL).
The organic layer was dried over sodium sulfate for 2 hours and
filtered, concentrated under reduced pressure, and dried for 1 hour
to afford 0.523 g of a white sticky solid. The solid was purified
on a filter pad of silica eluting with 4/1 hexanes/EtOAc (v/v),
switching to 6/4 hexanes/EtOAc (v/v) upon collection of the major
spot. The second (other) diastereomer was collected. The desired
compound is pale oil; Yield: 0.328 g 49%; The undesired
diastereomer is a white solid; Yield: 0.120 g 18%; .sup.1H NMR:
Desired diastereomer: (300 MHz, DMSO-d.sub.6) .delta..quadrature.
7.50-53 (m, 2H, J=2.1 Hz, ArH), 7.22-25 (dd, 1H, J=9.0 Hz, J=1.8
Hz, ArH), 6.91 (bs, 1H, OH), 4.26 (m, 1H.sub.1, NH), 3.50 (m, 1H,
CH.sub.2N), 3.32 (m, 1H, CH.sub.2N), 3.26 (m, 3H, CH.sub.3), 1.40
(s, 9H, tert-Bu), 1.02 (m, 2H, ArCCH.sub.2), 0.55 (m, 1H,
CHCH.sub.2N); Undesired diastereomer (not shown): (300 MHz,
CDCl.sub.3) .delta..quadrature. 7.57 (m, 1H, ArH), 7.50 (d, 1H,
J=8.1 Hz, ArH), 7.31 (dd, 1H, J=8.4 Hz, J=1.8 Hz, ArH), 7.11 (bs,
1H, OH), 4.63 (d, 1H, J=3.3 Hz, NH), 3.46 (m, 1H), 3.33 (s, 3H),
3.12 (m, 2H), 1.38 (s, 9H, tert-Bu), 1.30 (m, 1H), 0.85 (d, 2H,
J=6.0 Hz, ArCCH.sub.2), 0.78 (m, 1H, CHCH.sub.2N)
E. Preparation of
(.+-.)-1-(3,4-dichloro-phenyl)-(r/s)-2-methyl-3-aza-bicyclo[3.1.0]hexane
Hydrochloride
##STR00286##
[0543]
(.+-.)-[2-(3,4-dichlorophenyl)-(R/S)-2-(1-hydroxyethyl)-cyclopropyl-
methyl]-carbamic acid tert-butyl ester was added to DCM and
triethylamine and cooled in an ice bath under Ar (g) with stirring.
Methanesulfonyl chloride was added dropwise with stirring over 10
min and the resulting suspension warmed to ambient temperature
overnight. The resulting yellow solution was washed with water
(2.times.10 mL) and the DCM layer dried over magnesium sulfate. The
mixture was filtered and concentrated under reduced pressure to
afford a yellow oil. This oil was dissolved in 0.8 mL of DCM and
cooled in an ice bath under Ar (g). To this was added 0.8 mL of TFA
and the resulting solution was stirred at ambient temperature for 1
hour. The solution was concentrated under reduced pressure,
quenched with concentrated NaOH, and extracted with ether
(2.times.10 mL). The organic extracts were combined and dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. The oil was purified on a filter pad of silica eluting
with 10/1 CHCl.sub.3/MeOH (v/v), to afford the desired free base.
Yield: 0.065 g 30%; LCMS (+)ESI: m/z=242 [M+H].sup.+ (100); UV
(.lamda..sub.max=218)=95%; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature. 7.29-32 (m, 2H, ArH), 7.06 (dd, 1H, J=8.1 Hz,
J=2.1 Hz, ArH), 4.36 (s, 1H, NH), 3.53 (q, 1H, J=6.6 Hz,
CH.sub.2NH), 3.28 (dd, 1H, J=11 Hz, J=3.0 Hz, CH.sub.2NH), 3.00 (d,
1H, J=11 Hz, CH.sub.2NH), 1.81 (q, 1H, J=4 Hz, CHCH.sub.2), 1.01
(t, 1H, J=5 Hz, ArCCH.sub.2), 0.91 (d, 3H, J=7 Hz, CH.sub.3), 0.68
(dd, 1H, J=8 Hz, 5.4, ArCCH.sub.2); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta..quadrature. 140.9, 132.0, 121.2, 130.3, 130.0,
128.9, 57.6, 46.1, 37.0, 22.2, 18.9, 15.6.
[0544] To prepare the hydrochloride salt, 32 mg of free base, 1 mL
diethyl ether, and 0.2 mL 2N HCl in diethyl ether were added to a
vial. A white precipitate appeared in minutes and the suspension
was stirred at ambient temperature for 1 hour. The suspension was
filtered, collected, and dried to afford 27 mg of a pale yellow
solid. LCMS (+) ESI: m/z=242 [M+H].sup.+ (100); UV
(.lamda..sub.max=218)=95%; .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta..quadrature.: 7.60 (d, 1H, J=2 Hz, ArH), 7.52 (d, 1H, J=8
Hz, ArH), 7.33 (dd, 1H, J=8 Hz, J=2 Hz, ArH), 4.16 (q, 1H, J=7 Hz,
NH), 3.74 (dd, 1H, J=11 Hz, J=4 Hz, CHNH.sub.2), 3.46 (d, 1H, J=11
Hz, CH.sub.2NH.sub.2), 2.34 (q, 1H, J=5 Hz, CHCH.sub.2), 1.21 (m,
1H, ArCCH.sub.2), 1.14 (d, 3H, J=7 Hz, CH.sub.3), 1.01 (m, 1H,
ArCCH.sub.2).
F. Preparation of
(.+-.)-1-(3,4-dichloro-phenyl)-(r/s)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hex-
ane
##STR00287##
[0546] To a dried, 5 mL round-bottomed flask was added
(+)-1-(3,4-dichlorophenyl)-(R/S)-2-methyl-3-aza-bicyclo[3.1.0]hexane,
Hunig's Base, and DMF under Ar (g) with stirring. Methyl iodide was
added drop wise with stirring over 5 min and the resulting solution
stirred under ambient temperature overnight. The solution was
concentrated under reduced pressure and purified after drying. The
residue was purified by HPLC which failed to remove the impurities.
This was further purified on a prep TLC plate eluting with 20/1
CHCl.sub.3/MeOH (v/v). The desired band was collected, extracted
with CHCl.sub.3/MeOH, and concentrated after filtration to afford
the desired free: base. Yield: 0.005 g 15%; LCMS (+)ESI: m/z=256
[MH].sup.+ (100); 258 [MH+2].sup.+; (65); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta..quadrature.: 7.33 (d, H, J=12 Hz, ArH), 7.32
(d, 1H, J=2 Hz, ArH), 7.08 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.31 (q,
1H, J=6 Hz, CHNH.sub.2), 2.83 (s, 2H, CH.sub.2N), 2.32 (s, 3H,
NCH.sub.3), 1.79 (m, 1H, CH.sub.2CH), 1.40 (t(br), 1H,
ArCCH.sub.2), 0.73 (d, 3H, J=7 Hz, CHCH.sub.3), 0.60 (dd, 2H, J=8
Hz, 4 Hz, ArCCH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta..quadrature.: 131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9,
18.4, 11.6.
Example XVIII
Preparation of 1-Aryl-2-methyl-3-aza-bicyclo[3.1.0]hexane and
1-Aryl-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane Using Reaction
Scheme 24
A. Preparation of
(-)-1-(3,4-dichloro-phenyl)-2-methyl-3-aza-bicyclo[3.1.0]hex-2-ene
##STR00288##
[0548] To an oven dried, 25 mL, three-necked round-bottomed flask
was added
(.+-.)-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexan-2-one,
triethylamine in 6.6 mL of toluene under Ar (g) with stirring. A
solution of TMSCl in 1.1 mL of toluene was added drop wise over
several minutes. The mixture was heated at 40.degree. C. (for 4 h,
then cooled to 4.degree. C. in an ice bath, and to it was added 6.6
mL of hexanes/ether (1/1, v/v). The mixture was filtered, and the
filtrate concentrated under reduced pressure and dried under high
vacuum for 2 h to afford 770 mg of the intermediate that was used
in the next step. A flame-dried, 10 mL round-bottomed flask was
equipped with a stir bar, purged with Ar (g) and cooled to
-30.degree. C. in a dry ice/MeCN bath. The flask was charged with
methyl lithium, and to this was added a solution of the
intermediate in 2.85 mL of diethyl ether over 10 minutes. The
resulting yellow solution was stirred at -20 to -25.degree. C. for
30 minutes, followed by ambient temperature for 1 hour. The mixture
was poured into 4.9 mL of water containing 146 mg of ammonium
chloride and stirred for 30 min. The layers were separated and the
organic layer washed with brine (10 mL) and dried over sodium
sulfate for 1 hour. The mixture was filtered, concentrated under
reduced pressure, and dried under high vacuum to afford a yellow
oil (488 mg). The oil was chromatographed on a filter pad of silica
(12 g), eluting with 50/1 CHCl.sub.3/MeOH (v/v). The desired
fractions were collected, concentrated, and dried to afford the
desired compound as yellow oil. Yield: 0.409 g 52%; LCMS (+)ESI:
m/z=240 [MH].sup.+ (100), 242 [MH+2].sup.+ (60); UV
(.lamda..sub.m=218)=95%; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature. 7.40 (d, 1H, J=8 Hz, ArH), 7.35 (d, 1H, J=2 Hz,
ArH), 7.10 (dd, 1H, J=8 Hz, J=2 Hz, ArH), 4.09 (m, 1H, CH.sub.2N),
3.80 (d, 1H, J=17 Hz, CH.sub.2N), 2.09 (m, 114, CH.sub.2CH), 1.92
(m, 3H, CH.sub.3), 1.44 (dd, 1H, J =12 Hz, 4 Hz, ArCCH.sub.2), 0.60
(t, 1H, J=4 Hz, ArCCH.sub.2).
B. Preparation of
(.+-.)-1-(3,4-dichloro-phenyl)-(r/s)-2-methyl-3-aza-bicyclo[3.1.0]hexane
##STR00289##
[0550] To a dried, 25 mL round-bottomed flask purged with Ar (g)
was added product from Example XVIII A and EtOH. The mixture was
stirred at ambient temperature for 5 min. To this was added sodium
cyanoborohydride, followed by drop wise addition of 1.25 N HCl in
ethanol over 10 min. The resulting mixture was stirred at ambient
temperature for 2 hours. The solution was added to a mixture of
brine/2N NaOH (20 mL/1.5 mL) and extracted with EtOAc (3.times.20
mL). The organic layers were combined and washed with brine (10 mL)
and dried over magnesium sulfate for 1 hour. The mixture was
filtered and the filtrate concentrated under reduced pressure, and
dried under high-vacuum to afford 435 mg of an off-white wax. The
wax was purified on 20 g of silica (230-400 mesh), eluting with
50/1 and gradient to 10/1 CHCl.sub.3/MeOH (v/v). Two desired sets
of fractions was collected; each was concentrated under reduced
pressure and dried under high vacuum. Top set: yellow oil, yield:
0.154 g 37%; LCMS (+)ESI: m/z=242 [MH].sup.+ (100), 244
[MH+2].sup.+ (65); UV (.lamda..sub.max=218)=99%; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta..quadrature.: 7.36 (d, H, J=5 Hz, ArH),
7.34 (d, 1H, J=1 Hz, ArH), 7.11 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.41
(q, 1H, J=6 Hz, CH.sub.2N), 3.17 (dd, 1H, J=12 Hz, 3 Hz,
CH.sub.2N), 2.99 (d, 1H, J=12 Hz, CHCH.sub.3), 1.55 (m, 1H,
CH.sub.2CH), 1.08 (d, 3H, J=6 Hz, CH.sub.3), 0.77-0.87 (m, 2H,
ArCCH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta..quadrature.: 131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9,
18.4, 11.6; Bottom set: white solid, yield: 0.141 g 35%; LCMS
(+)ESI: m/z=242 [MH].sup.+ (100), 244 [MH+2].sup.+ (65); UV
(.lamda..sub.max=218)=99%; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta..quadrature.: 7.41 (d, H, J=8 Hz, ArH), 7.36 (d, 1H, J=2 Hz,
ArH), 7.12 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.75 (q, 1H, J=6 Hz,
CH.sub.2N), 3.44 (m, 1H, J=6 Hz, CH.sub.2N), 3.33 (d, 1H, J=8 Hz,
CHCH.sub.3), 1.75 (q, 1H, J=4 Hz, CH.sub.2CH), 1.30 (d, 3H, J=3H,
CH.sub.3), 1.10 (m, 2H, ArCCH.sub.2); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta..quadrature.: 139.0, 132.6, 131.3, 130.7, 130.6,
128.3, 60.5, 47.6, 36.0, 24.9, 14.4, 9.8.
Preparation of the Hydrochloride Salts
[0551] Top Set:
[0552] To a vial was added 50 mg of the yellow oil obtained from
the top set fractions as described above, 0.5 mL diethyl ether, and
0.12 mL 2N HCl in diethyl ether. A white precipitate appeared in
minutes and the suspension was stirred at ambient temperature for
one-half hour. The suspension was filtered, collected, and dried to
afford 55 mg of a white solid.
[0553] Bottom Set:
[0554] To a vial was added 52 mg of the white solid obtained from
the bottom set fractions as described above, 1.0 mL diethyl ether,
and 0.12 mL 2N HCl in diethyl ether. EtOH (0.5 mL) was added to
obtain a uniform solution. A white precipitate appeared in minutes
and the suspension was stirred al ambient temperature for one-half
hour. The suspension was filtered, collected, and dried to afford
40 mg of a white solid.
[0555] LCMS Top set: (+)ESI: m/z=242 [MH].sup.+ (100); 244
[MH+2].sup.+ (65); UV (.lamda..sub.max=254)=95%; Bottom set:
(+)ESI: m/z=242 [MH].sup.+ (100); 244 [MH+2].sup.+ (65); UV
(.lamda..sub.max=254)=95%
[0556] .sup.1H NMR Top set: (300 MHz, DMSO-d.sub.6)
.delta..quadrature.: 7.69 (d, 1H, J=2 Hz, ArH), 7.61 (d, 1H, J=8
Hz, ArH), 7.33 (dd, 1H, J=8 Hz, J=2 Hz, ArH), 4.00 (m, 1H,
CHCH.sub.3), 3.56 (m, 1H, CH.sub.2N), 3.26 (m, 1H, CH.sub.2N), 1.90
(m, 1H, CH.sub.2CH), 1.15-22 (m, 4H, CH.sub.3, ArCCH.sub.2), 1.01
(m, 1H, ArCCH.sub.2); Bottom set: (300 MHz, DMSO-d)
.delta..quadrature.: 7.69 (d, 1H, J=2 Hz, ArH), 7.61 (d, 1H, J=8
Hz, ArH), 7.33 (dd, 1H, J=8 Hz, J=2 Hz, ArH), 4.00 (m, 1H,
CHCH.sub.3), 3.56 (m, 1H, CH.sub.2N), 3.26 (m, 1H, CH.sub.2N), 1.90
(m, 1H, CH.sub.2CH), 1.15-22 (m, 4H, CH.sub.3, ArCCH.sub.2), 1.01
(m, 1H, ArCCH.sub.2)
C. Preparation of
(+)-1-(3,4-dichloro-phenyl)-(r/s)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane
##STR00290##
[0558] To an oven-dried, round-bottomed flask purged with Ar (g)
was added either the yellow oil obtained from the top set fractions
or the white solid obtained from the bottom set fractions as
described in Example XVIII B above in DMF and Hunig's base. The
mixture was stirred at ambient temperature for 5 min. To this was
added MeI, drop wise, with stirring. The resulting yellow mixture
was stirred at ambient temperature overnight. The solvent was
removed via rotary-evaporation and the residue treated with 1.0 mL
of 95% EtOH. The flaky white crystals/precipitate were collected by
vacuum filtration and dried under high vacuum. Nature of the
compound (from top set fractions): crystals, yield: 0.080 g 79%;
Nature of the compound (from bottom setfractions): amorphous solid,
yield: 0.042 g 40%.
[0559] LCMS
[0560] Top set: (+)ESI: m/z=256 [MH].sup.+ (100), 258 [MH+2].sup.+
(65); UV (.lamda..sub.max=218)=99%; Bottom set: (+)ESI: m/z=256
[MH].sup.+ (100), 258 [MH+2].sup.+ (65); UV
(.lamda..sub.max=218)=99%.
[0561] .sup.1H NMR
[0562] Top set: (300 MHz, CDCl.sub.3) .delta..quadrature.: 7.45 (d,
1H, J=9 Hz, ArH), 7.40 (m, 1H, ArH), 7.14 (dd, 1H, J=9 Hz, J=1 Hz,
ArH), 4.07 (dd, 1H, J=25 Hz, J=6 Hz, CH.sub.2N), 3.77 (q, 2H,
CH.sub.2N, CHCH.sub.3), 2.88 (d, 3H, J=5 Hz, NCH.sub.3), 2.29 (m,
1H, CHCH.sub.2), 1.89 (q, 1H, J=5 Hz, ArCCH.sub.2), 1.56-65 (m, 3H,
CHCH.sub.3), 1.24 (t, 1H, J=8 Hz, ArCCH.sub.2); Bottom set: (300
MHz, CDCl.sub.3) .delta..quadrature.: 7.43 (d, 1H, J=9 Hz, ArH),
7.4 (d, 1H, J=2 Hz, ArH), 7.14 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 4.06
(d, 1H, J=11 Hz, CH.sub.2N), 3.77 (m, 1H, CHCH.sub.3), 3.30 (m, 1H,
CHCH.sub.3), 2.88 (s, 3H, NCH.sub.3), 2.30 (m, 1H, CHCH.sub.2),
1.88 (q, 1H, J=4 Hz, ArCCH.sub.2), 1.63 (d, 3H, J=7 Hz,
CHCH.sub.3), 1.23 (t, 1H, J=8, ArCCH.sub.2).
[0563] .sup.13C NMR
[0564] Top set: (75 MHz, MeOH-d.sub.4) .delta..quadrature.: 139.6,
132.4, 132.1, 130.3, 70.2, 58.8, 39.6, 37.1, 23.4, 12.3, 11.3
Preparation of the Hydrochloride Salt
[0565] Bottom Set:
[0566] To a vial was added 47 mg of the white solid obtained from
the bottom set fractions as described in Example XVIII B above, 1.0
mL diethyl ether, and 0.12 mL 2N HCl in diethyl ether. EtOH (0.5
mL) was added to obtain a uniform solution. A yellow precipitate
appeared in minutes and the suspension was stirred at ambient
temperature for one-half hour. The suspension was filtered,
collected, and dried to afford 40 mg of a yellow solid. LCMS Bottom
set: (+)ESI: m/z=256 [MH].sup.+ (100), 258 [MH+2].sup.+ (65); UV
(.lamda..sub.max=218)=99%; .sup.1H NMR Bottom set: (300 MHz,
MeOH-d.sub.4) .delta..quadrature.: 7.68 (m, 1H, ArH), 7.54 (d, 1H,
J=8 Hz, ArH), 7.40 (in, 1H, ArH), 3.97 (q, 1H, J=6 Hz, CH.sub.2N),
3.76 (m, 1H, CH.sub.2N), 2.99 (m, 3H, NCH.sub.3), 2.0 (m, 1H,
CHCH.sub.3), 1.37 (d, 3H, J=9 Hz, CHCH.sub.3), 1.30 (t, 1H, J=5 Hz,
ArCCH.sub.2), 1.21 (m, 1H, ArCCH.sub.2).
Example XIX
Efficacy of Exemplary Compounds of the Invention for Inhibiting
Monoamine Neurotransmitter Uptake
[0567] The effects of exemplary compounds of the invention on the
cellular uptake of norepinephrine (NE), dopamine (DA) and serotonin
(5-HT) were tested in preparations of synaptosomes from different
rat brain regions using the previously-reported techniques
referenced below.
TABLE-US-00003 Reference Assay Origin Compound Bibliography
Norepinephrine (NE) Rat hypothalamus Protriptyline Perovic and
Uptake synaptosomes Muller (1995) Dopamine (DA) Rat striatum GBR
12909 Janowsky et al. uptake synaptosomes (1986) 5-HT uptake Rat
brain Imipramine Perovic and synaptosomes Muller (1995)
[0568] Whole brains were obtained from normal rats. Synaptosomal
preparations were made from either whole brain (5-HT), striatum
(DA) or hypothalamus (NE) by gentle disruption in 10 volumes (w/v)
of 0.32 M sucrose (0-4.degree. C.) using a Teflon-glass
homogenizer. The homogenate was then centrifuged at 1000.times.g
for 10 min. The supernatant was retained and centrifuged at 23000 g
for 20 min. The resulting pellet was gently resuspended in 200
volumes of 0.32 M sucrose (0-4.degree. C.) using the Teflon-glass
homogenizer. Aliquots (250 .mu.L) of this preparation were added to
tubes, along with 0.2 .mu.Ci/mL of [.sup.3H]5-HT, [.sup.3H]DA, or
[.sup.3H]NE, 200 .mu.L of the test compounds (to yield final
concentrations of 100 nM, 300 nM, 1 .mu.M, 3 .mu.M, 10 .mu.M, 30
.mu.M or 100 .mu.M) and 1 mL of Krebs-Ringer bicarbonate buffer (pH
7.4). The mixtures were incubated for either 15 (DA and 5-HT
uptake) or 20 (NE uptake) minutes at 37.degree. C. At the end of
this period, the assay was terminated by rapid filtration over
Whatman GF/C glass fiber filters. The filters were rinsed 3 times
with 4 ml of Krebs-Ringer bicarbonate buffer (0-4.degree. C.), and
the radioactivity retained on the filters measured by liquid
scintillation spectrometry.
[0569] Each assay was run according to the description of the
respective publications cited above, and according to the following
parameters/reagents/conditions.
TABLE-US-00004 Substrate/ Reaction Detection Assay Stimulus/Tracer
Incubation Product Method NE uptake [.sup.3H]NE 20 min. at
[.sup.3H]NE Scintillation (0.2 .mu.Ci/ml) 37.degree. C.
incorporation counting into synaptosomes DA uptake [.sup.3H]DA 15
min. at [.sup.3H]DA Scintillation (0.2 .mu.Ci/ml) 37.degree. C.
incorporation counting into synaptosomes 5-HT [.sup.3H]5-HT 15 min.
at [.sup.3H]5-HT Scintillation uptake (0.2 .mu.Ci/ml) 37.degree. C.
incorporation counting into synaptosomes
[0570] In each experiment, the respective reference compound was
tested concurrently with the test compounds in order to assess the
assay suitability. It was tested at several concentrations (for
IC.sub.50 value determination). The assay was considered valid if
the suitability criteria were met, in accordance with the
corresponding Standard Operating Procedure.
[0571] The results of these uptake inhibition assays are expressed
below as a percent of control values obtained in the presence of
the test compounds. Individual and mean values are presented with
the results. The IC.sub.50 values (concentration causing a
half-maximal inhibition of control values) were determined by
non-linear regression analysis of the inhibition curves using Hill
equation curve fitting.
TABLE-US-00005 TABLE 3 Neurotransmitter Uptake Inhibition by
1-Aryl-3-Aza-Bicyclo[3.1.0]Hexanes of the Invention Having Multiple
Substitutions on the Aryl Ring Uptake Uptake Uptake IC.sub.50 (nM)
IC.sub.50 (nM) IC.sub.50 (nM) Binding Binding Binding Structure NE
5-HT DA NET K.sub.i (nM) DAT K.sub.i (nM) SERT K.sub.i (nM)
##STR00291## 19 23 120 81 105 16 ##STR00292## 82 87 130 490 62 125
##STR00293## 15 56 80 32 13 88 ##STR00294## 140 45 190 585 46 113
##STR00295## 380 470 1000 1833 250 1667 ##STR00296## 550 590 1800
4000 220 2000 ##STR00297## 220 390 770 1073 170 2400 ##STR00298##
1500 1200 78 2200 240 6100 ##STR00299## 1700 3000 2200 1900 395
7600 ##STR00300## 400 2600 1200 1100 215 8900 ##STR00301## 3500
5100 8100 >10000 1100 16000 ##STR00302## 110 30 260 827 39 124
##STR00303## 64 170 330 510 25 330 ##STR00304## 530 100 430 5150 72
132 ##STR00305## 3800 2600 1500 9500 1700 3700 ##STR00306## 650 240
1500 9300 420 800 ##STR00307## 430 1100 7400 6600 ##STR00308## 87
400 1800 990 1900 1600 ##STR00309## 210 310 1400 1700 680 230
##STR00310## 107 186 572 ##STR00311## 86 79 770 350 640 190
##STR00312## 41 362 494 ##STR00313## 375 835 ##STR00314## 31 252
420 ##STR00315## 25 413 437 ##STR00316## 870 520 10000 6200 NC 500
##STR00317## 180 200 370 920 2200 540 ##STR00318## 138 266 457
##STR00319## 91 133 401 ##STR00320## 30 110 700 260 270 830
##STR00321## 20 836 383 ##STR00322## 54 702 917 ##STR00323## 4500
790 710 ##STR00324## 8400 4300 ##STR00325## 68 119 512 ##STR00326##
101 903 ##STR00327## <10 65 49 ##STR00328## 56 170 98
##STR00329## 98 31 350 520 68 6 ##STR00330## 57 <10 82
##STR00331## 169 117 147 ##STR00332## 82 82 208 ##STR00333## 18 14
91 ##STR00334## 202 700 563 ##STR00335## 39 210 360
[0572] Readily discernable from the foregoing results is the high
degree of diversity with respect to the biological activity changes
that were achieved by differentially altering aryl and aza
substituents to yield novel 1-aryl-3-azabicyclo[3.1.0]hexanes
according to the invention--whereby the absolute potency at any one
transporter may be altered dramatically, and in distinct patterns
among the exemplified compounds. Radical changes in the potency
ratio were evinced among the exemplary, multiple aryl-7
substituted, and combined multiple aryl- and aza-substituted,
compounds. The differential potency ratios for inhibition of
neurotransmitter uptake affecting dopamine, serotonin, and
norepinephrine transport yield profound and distinct therapeutic
potentials among the different, novel compounds of the invention.
Both the absolute changes in potency and the changes in potency
"ratio" demonstrated herein for exemplary compounds of the
invention would not have been expected or predictable with a
reasonable expectation of success by persons of ordinary skill in
the art
[0573] The data provided in Table 3 demonstrate that several of the
multiple aryl-substituted, and combined multiple aryl- and
aza-substituted, compounds are potent (nM) inhibitors of
norepinephrine and/or serotonin and/or dopamine uptake. As such,
the compounds and related formulations and methods of the invention
provide neurobiologically active tools for modulating biogenic
amine transport in mammalian subjects. These subjects may include
in vitro or ex vivo mammalian cell, cell culture, tissue culture,
or organ explants, as well as human and other mammalian individuals
21 presenting with, or at heightened risk for developing, a central
nervous system (CNS) disorder, including neuropsychiatric disorders
such as anxiety, or depression.
[0574] In certain embodiments, neurobiologically active
compositions comprising a multiple aryl-substituted, or combined
multiple aryl- and aza-substituted,
1-aryl-3-azabicyclo[3.1.0]hexane of the invention are effective to
inhibit cellular uptake of norepinephrine in a mammalian subject.
In other embodiments, these compositions will effectively inhibit
cellular uptake of serotonin in mammals. Other compositions of the
28 invention will be effective to inhibit cellular uptake of
dopamine in mammalian subjects.
[0575] As illustrated by the foregoing examples, additional
neurobiologically active compositions of the invention will be
effective to inhibit cellular uptake of multiple biogenic amine
neurotransmitters in mammalian subjects, for example,
norepinephrine and serotonin, norepinephrine and dopamine, or
serotonin and dopamine. In additional embodiments, the compositions
of the invention are effective to inhibit cellular uptake of
norepinephrine, serotonin and dopamine in mammalian subjects.
[0576] In further-detailed embodiments, as exemplified by the
results presented in Table 3, neurobiologically active compositions
of the invention surprisingly inhibit cellular reuptake of two, or
three, biogenic amines selected from norepinephrine, serotonin and
dopamine in a mammalian subject "non-uniformly" across an affected
range of multiple biogenic amine targets. The distinct double and
triple reuptake inhibition activity profiles demonstrated herein
for exemplary compounds of the invention illustrate the powerful
and unpredictable nature of the subject, multiple aryl-substituted,
and combined multiple aryl- and aza-substituted, compounds, and
further evince the ability to follow the teachings of the present
disclosure to produce, select, and employ other substituted
1-aryl-3-azabicyclo[3.1.0]hexanes according to the invention having
distinct activity profiles to fulfill additional therapeutic uses
within the invention for treating diverse CNS disorders.
[0577] In exemplary embodiments, differential reuptake inhibition
mediated by the compounds of the invention may yield a
profile/ratio of reuptake inhibition activities for all three
neurotransmitters, norepinephrine, dopamine, and serotonin,
respectively, in reuptake inhibition profiles/ratios as exemplified
in Table 3, selected from the following approximate inhibition
profiles/ratios: (2:1:1); (3:10:1); (2:5:1); (12:1:5); (15:1:12);
(3:8:5); (2:4:1); (3:1:2); and (2:4:1). Although these values are
approximate, they will correlate in a measurable way with novel in
vivo reuptake inhibition profiles/ratios as will be readily
determined by those skilled in the art.
[0578] In related embodiments, neurobiologically active
compositions of the invention inhibit cellular uptake of two, or
three, biogenic amine neurotransmitters non-uniformly, for example
by inhibiting uptake of at least one member of a group of
transmitters including norepinephrine, serotonin, and dopamine by a
factor of two- to ten-fold greater than a potency of the same
composition to inhibit uptake of one or more different
neurotransmritter(s). In exemplary embodiments, compositions of the
invention comprising a multiple aryl-substituted, or combined
multiple aryl- and aza-substituted,
1-aryl-3-azabicyclo[3.1.0]hexane, inhibit cellular uptake of
serotonin by a factor of at least approximately two-fold,
three-fold, five-fold, ten-fold or greater compared to a potency of
the same composition to inhibit uptake of norepinephrine, dopamine,
or both norepinephrine and dopamine. In other exemplary
embodiments, different 1-aryl-3-azabicyclo[3.1.0]hexanes of the
invention inhibit cellular uptake of dopamine by a factor of at
least approximately two-fold, three-fold, five-fold, ten-fold or
greater compared to a potency of the composition for inhibiting
uptake of norepinephrine, serotonin, or both norepinephrine and
serotonin. In additional exemplary embodiments, the compositions
described herein inhibit cellular uptake of norepinephrine by a
factor of at least approximately two-fold, three-fold, five-fold,
ten-fold or greater compared to a potency of the same composition
for inhibiting uptake of serotonin. In different exemplary
embodiments, compositions are provided that inhibit cellular uptake
of dopamine by a factor of at least approximately two-fold,
three-fold, five-fold, ten-fold or greater compared to a potency of
the composition for inhibiting uptake of serotonin. In yet
additional embodiments, neurobiologically active compositions are
provided that exhibit approximately equivalent potency for
inhibiting cellular uptake of norepinephrine and serotonin, while
at the same time inhibiting dopamine uptake by a factor of at least
approximately two-fold, three-fold, five-fold, ten-fold or greater
compared to a potency of the composition for inhibiting uptake of
norepinephrine and serotonin. In still other exemplary embodiments,
compositions of the invention exhibit approximately equivalent
potency for inhibiting cellular uptake of serotonin and dopamine,
while at the same time inhibiting norepinephrine by a factor of no
greater than approximately half the potency for inhibiting uptake
of serotonin and dopamine. In certain embodiments, compositions of
the invention exhibit approximately equivalent potency for
inhibiting cellular uptake of norepinephrine, serotonin, and
dopamine.
[0579] Compounds of the invention that inhibit uptake of
norepinephrine and/or, serotonin, and/or dopamine have a wide range
of therapeutic uses, principally to treat CNS disorders, including
various neuropsychiatric disorders, as described above. Certain CNS
disorders contemplated herein will be more responsive to a compound
of the invention that preferentially inhibits, for example,
dopamine uptake relative to norepinephrine and/or serotonin uptake,
as in the case of some forms of depression. Other disorders will be
determined to be more responsive to compounds of the invention that
more potently inhibit norepinenephrine reuptake relative to
serotonin reuptake and dopamine reuptake. Other CNS disorders, for
example, attention deficit hyperactivity disorder (ADHD), may
respond better to compounds of the invention that preferentially
inhibit dopamine and norepinephrine reuptake relative to serotonin
reuptake. Thus, the host of exemplary compounds described herein,
which provide a range of reuptake inhibition profiles/ratios, will
provide useful drug candidates for a diverse range of CNS
disorders, and will effectively treat specific disorders with lower
side effect profiles than currently available drugs.
[0580] It will be understood that the instant invention is not
limited to the particular formulations, process steps, and
materials disclosed herein as such formulations, process steps, and
materials may vary somewhat. It is also to be understood that the
terminology employed herein is used for the purpose of describing
particular embodiments only and is not intended to be limiting
since the scope of the present invention will be limited only by
the appended claims and equivalents thereof.
[0581] All publications and patents mentioned herein are
incorporated herein by reference for the purpose of describing and
disclosing, for example, the constructs and methodologies that are
described in the publications, which might be used in connection
with the presently described invention. The publications discussed
above and throughout the text are provided solely for their
disclosure prior to the filing date of the present application.
Nothing herein is to be construed as an admission that the
inventors are not entitled to antedate such disclosure by virtue of
prior invention.
REFERENCES
[0582] Skolnick, P. et al Eur. J. Pharmacol. 461:99 (2003) [0583]
Skolnick, P. et al., Life Sci. 73: 3175-3179 (2003) [0584]
Armarego, W. L. F. et. al., J. Chem. Soc. [Section C: Organic] 19:
3222-3229 (1971) [0585] Szalecki et al., patent publication PL
120095 B2, CAN 99:158251 [0586] Marrazzo, A. et al. Arkivoc 5:
156-159 (2004) [0587] Cabadio, S. et al., Fr. Bollettino Chimico
Farmaceutico 117: 331-42 (1971) [0588] Mouzin, G. et al., Synthesis
4: 304-305 (1978) [0589] Synthetic Communications 29: 4315-4319
(1999) [0590] Tetrahedron 45: 3683 (1989) [0591] "Nitrogen
Protecting Groups in Organic Synthesis", John Wiley and Sons, New
York, N.Y., 1981, Chapter 7 [0592] "Nitrogen Protecting Groups in
Organic Chemistry", Plenum Press, New York, N.Y., 1973, Chapter 2
[0593] Green, T. W. and Wuts, P.G.M. in "Protective Groups in
Organic Chemistry", 3rd edition, John Wiley & Sons, New York,
N.Y., 1999 [0594] Quick Reference to the Diagnostic Criteria From
DSM-IV (Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition), The American Psychiatric Association, Washington,
D.C., 1994 [0595] Perovic, S. and Muller, W. E.,
Arzneimittelforschung 45: 1145-1148 (1995) [0596] Janowsky, A. et
al., J. Neurochem. 46: 1272-1276 (1986) [0597] U.S. Pat. No.
6,132,724; Blum; Oct. 17, 2000 [0598] U.S. Pat. No. 4,122,193;
Scherm et al.; Oct. 24, 1978
* * * * *