U.S. patent application number 12/440852 was filed with the patent office on 2010-02-11 for azabicyclic compounds as inhibitors of monoamines reuptake.
Invention is credited to Barbara Bertani, Romano Di Fabio, Fabrizio Micheli, Giovanna Tedesco, Silvia Terreni.
Application Number | 20100035914 12/440852 |
Document ID | / |
Family ID | 38561834 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100035914 |
Kind Code |
A1 |
Bertani; Barbara ; et
al. |
February 11, 2010 |
AZABICYCLIC COMPOUNDS AS INHIBITORS OF MONOAMINES REUPTAKE
Abstract
The present invention relates to novel compounds of formula
(I)', and pharmaceutically acceptable salts, prodrugs or solvates
thereof: ##STR00001## wherein R.sub.1 is hydrogen or C.sub.1-4
alkyl; R.sub.2 is a group A, K or W wherein A is ##STR00002## K is
an .alpha. or .beta. naphthyl group, optionally substituted by 1 or
2 groups R.sub.18, each of them being the same or different; and W
is ##STR00003## and wherein G is a 5,6-membered monocyclic
heteroaryl group, or a 8- to 11-membered heteroaryl bicyclic group;
wherein G may be substituted by (R.sub.15).sub.p, which can be the
same or different; p is an integer from 0 to 5; R.sub.3 is selected
from the group consisting of: hydrogen, fluorine, and C.sub.1-4
alkyl; or corresponds to a group X or X.sub.1; R.sub.4 is selected
from the group consisting of: hydrogen, fluorine, and C.sub.1-4
alkyl; or corresponds to a group X or X.sub.1; R.sub.5 is hydrogen
or C.sub.1-4 alkyl; R.sub.7 is hydrogen or C.sub.1-4 alkyl; or is a
group X, X.sub.1, X.sub.2 or X.sub.3; wherein X is ##STR00004##
X.sub.1 is ##STR00005## X.sub.2 is ##STR00006## and X.sub.3 is
##STR00007## R.sub.6 is hydrogen or C.sub.1-4 alkyl; or is a group
X or X.sub.1; R.sub.9 is C.sub.1-4alkyl; R.sub.10 is selected from
the group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.8 is a 5-6 membered heterocycle group,
which may be substituted by one or two substituents selected from
the group consisting of: halogen, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy and C.sub.1-4alkanoyl; R.sub.11
is selected from the group consisting of: hydrogen, halogen,
hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.12 is selected
from the group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.13 is selected from the group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.14 is selected from the group consisting of: hydrogen,
halogen, hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.15 is selected
from the group consisting of: halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.16 is hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl or C.sub.3-6cycloalkylC.sub.1-3alkyl; R.sub.17
is hydrogen or C.sub.1-4alkyl; R.sub.18 is selected from the group
consisting of: halogen, cyano, and C.sub.1-4alkyl; R.sub.19 is
haloC.sub.1-2alkyl; and n is 1 or 2; with the proviso that: if
R.sub.2 is A, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.10, R.sub.11, R.sub.13, and R.sub.14 are hydrogen, and
R.sub.12 is fluorine, R.sub.1 is C.sub.1-4 alkyl; if R.sub.2 is A,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.10, R.sub.11,
R.sub.13, and R.sub.14 are hydrogen, and R.sub.1 is methyl,
R.sub.12 is halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl or SF.sub.5; or corresponds to a group R.sub.8;
and processes for their preparation, intermediates used in these
processes, pharmaceutical compositions containing them and their
use in therapy, as serotonin (5-HT), dopamine (DA) and
norepinephrine (NE), re-uptake inhibitors.
Inventors: |
Bertani; Barbara; (Verona,
IT) ; Di Fabio; Romano; (Verona, IT) ;
Micheli; Fabrizio; (Verona, IT) ; Tedesco;
Giovanna; (Verona, IT) ; Terreni; Silvia;
(Verona, IT) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION;CORPORATE INTELLECTUAL PROPERTY-US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Family ID: |
38561834 |
Appl. No.: |
12/440852 |
Filed: |
September 7, 2007 |
PCT Filed: |
September 7, 2007 |
PCT NO: |
PCT/EP07/59381 |
371 Date: |
March 11, 2009 |
Current U.S.
Class: |
514/299 ;
546/112 |
Current CPC
Class: |
A61P 15/08 20180101;
A61P 29/00 20180101; A61P 31/18 20180101; A61P 25/14 20180101; A61P
3/04 20180101; A61P 15/10 20180101; A61P 25/00 20180101; A61P 25/24
20180101; C07D 221/04 20130101; A61P 25/32 20180101; A61P 43/00
20180101; A61P 25/22 20180101; A61P 25/06 20180101; A61P 25/34
20180101; A61P 25/28 20180101; A61P 25/20 20180101 |
Class at
Publication: |
514/299 ;
546/112 |
International
Class: |
A61K 31/435 20060101
A61K031/435; C07D 221/02 20060101 C07D221/02; A61P 25/24 20060101
A61P025/24 |
Claims
1. A pharmaceutical composition comprising a compound of formula
(A)' or a pharmaceutically acceptable salt, solvate or prodrug
thereof: ##STR00211## wherein R.sub.1 is hydrogen or
C.sub.1-4alkyl; R.sub.2 is a group A, K or W wherein A is
##STR00212## K is an .alpha. or .beta. naphthyl group, optionally
substituted by 1 or 2 groups R.sub.18, each of them being the same
or different; and W is ##STR00213## and wherein G is a 5- or
6-membered monocyclic heteroaryl group, or a 8- to 1'-membered
heteroaryl bicyclic group; wherein G may be substituted by
(R.sub.15).sub.p, which can be the same or different; p is an
integer from 0 to 5; R.sub.3 is selected from the group consisting
of: hydrogen, fluorine, and C.sub.1-4 alkyl; or corresponds to a
group X or X.sub.1; R.sub.4 is selected from the group consisting
of: hydrogen, fluorine, and C.sub.1-4 alkyl; or corresponds to a
group X or X.sub.1; R.sub.5 is hydrogen or C.sub.1-4 alkyl; R.sub.7
is hydrogen or C.sub.1-4 alkyl; or is a group X, X.sub.1, X.sub.2
or X.sub.3; wherein X is ##STR00214## X.sub.1 is ##STR00215##
X.sub.2 is ##STR00216## and X.sub.3 is ##STR00217## R.sub.6 is
hydrogen or C.sub.1-4 alkyl; or is a group X or X.sub.1; R.sub.9 is
C.sub.1-4alkyl; R.sub.10 is selected from the group consisting of:
hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.8 is a 5-6 membered heterocycle group, which may be
substituted by one or two substituents selected from the group
consisting of: halogen, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy and C.sub.1-4alkanoyl; R.sub.11 is selected from
the group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.12 is selected from the group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.13 is selected from the group consisting of: hydrogen,
halogen, hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.14 is selected
from the group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.15 is selected from the group consisting
of: halogen, hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.16 is hydrogen,
C.sub.1-4alkyl, C.sub.3-6cycloalkyl or
C.sub.3-6cycloalkylC.sub.1-3alkyl; R.sub.17 is hydrogen or
C.sub.1-4alkyl; R.sub.18 is selected from the group consisting of:
halogen, cyano, and C.sub.1-4alkyl; R.sub.19 is haloC.sub.1-2alkyl;
and n is 1 or 2; and a pharmaceutically acceptable carrier.
2. A compound of formula (I)' or a pharmaceutically acceptable
salt, solvate or prodrug thereof: ##STR00218## wherein is hydrogen
or C.sub.1-4 alkyl; is a group A, K or W wherein A is ##STR00219##
K is an .alpha. or .beta. naphthyl group, optionally substituted by
1 or 2 groups R.sub.18, each of them being the same or different;
and W is ##STR00220## and wherein G is a 5,6-membered monocyclic
heteroaryl group, or a 8- to 1'-membered heteroaryl bicyclic group;
wherein G may be substituted by (R.sub.15).sub.p, which can be the
same or different; p is an integer from 0 to 5; R.sub.3 is selected
from the group consisting of: hydrogen, fluorine, and C.sub.1-4
alkyl; or corresponds to a group X or X.sub.1; R.sub.4 is selected
from the group consisting of: hydrogen, fluorine, and C.sub.1-4
alkyl; or corresponds to a group X or X.sub.1; R.sub.5 is hydrogen
or C.sub.1-4 alkyl; R.sub.7 is hydrogen or C.sub.1-4 alkyl; or is a
group X, X.sub.1, X.sub.2 or X.sub.3; wherein X is ##STR00221##
X.sub.1 is ##STR00222## X.sub.2 is ##STR00223## and X.sub.3 is
##STR00224## R.sub.6 is hydrogen or C.sub.1-4 alkyl; or is a group
X or X.sub.1; R.sub.9 is C.sub.1-4alkyl; R.sub.10 is selected from
the group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.8 is a 5-6 membered heterocycle group,
which may be substituted by one or two substituents selected from
the group consisting of: halogen, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy and C.sub.1-4alkanoyl; R.sub.11
is selected from the group consisting of: hydrogen, halogen,
hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.12 is selected
from the group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.13 is selected from the group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.14 is selected from the group consisting of: hydrogen,
halogen, hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.15 is selected
from the group consisting of: halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.16 is hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl or C.sub.3-6cycloalkylC.sub.1-3alkyl; R.sub.17
is hydrogen or C.sub.1-4alkyl; R.sub.18 is selected from the group
consisting of: halogen, cyano, and C.sub.1-4alkyl; R.sub.19 is
haloC.sub.1-2alkyl; and n is 1 or 2; with the proviso that: if
R.sub.2 is A, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.10, R.sub.11, R.sub.13, and R.sub.14 are hydrogen, and
R.sub.12 is fluorine, R.sub.1 is C.sub.1-4 alkyl; if R.sub.2 is A,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.10, R.sub.11,
R.sub.13, and R.sub.14 are hydrogen, and R.sub.1 is methyl,
R.sub.12 is halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl or SF.sub.5; or corresponds to a group
R.sub.8.
3. A compound as claimed in claim 2, which is a compound of formula
(IC) ##STR00225## wherein R.sub.1, R.sub.2, R.sub.7 and R.sub.17
are as defined for compounds of formula (I)', or a pharmaceutically
acceptable salt, solvate or prodrug thereof.
4. A compound as claimed in claim 2, which is a compound of formula
(ID) ##STR00226## wherein R.sub.2, R.sub.16 and n are as defined
for compounds of formula (I)', or a pharmaceutically acceptable
salt, solvate or prodrug thereof.
5. A compound of Formula (ID) according to claim 4, wherein n is
1.
6. A compound as claimed in claim 2, which is a stereochemical
isomer, having a single absolute configuration at stereogenic
centers named 1 and 6, of formula (I)'' ##STR00227## wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and
R.sub.17 are as defined as above for compounds of formula (I)', or
a pharmaceutically acceptable salt, solvate or prodrug thereof.
7. A compound of formula (I)', as claimed in claim 2, selected from
the group consisting of:
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo-[-
4.1.0]heptane;
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane;
(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[-
4.1.0]heptane;
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methan-
ol; [(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;
[(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
(1R,4S,6S/1S,
4R,6R)-6-(3,4-dichlorophenyl)-4-methyl-1-[(methyloxy)methyl]-3-azabicyclo-
[4.1.0]heptane;
(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicycl-
o[4.1.0]heptane;
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane;
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0-
]heptane;
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azab-
icyclo[4.1.0]heptane; (1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane; (1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane; (1S,6R/1R,
6S)-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4-
.1.0]heptane;
(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane;
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0-
]heptane; (1R,6S or
1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e; (1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e;
(1S,6R/1R,6S)-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabi-
cyclo[4.1.0]heptane;
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl-
}-3-azabicyclo[4.1.0]heptane; and (1S,6R,7R/1R, 6S,
7S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hepta-
ne; or a pharmaceutically acceptable salt, solvate or prodrug
thereof.
8. A compound of formula (I)', as claimed in claim 2, which is
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane; or a pharmaceutically acceptable salt, solvate or prodrug
thereof.
9. A method of treating a condition for which inhibition of
serotonin (5-HT), dopamine (DA) and norepinephrine (NE), is
beneficial, which comprises administering to a human in need
thereof an effective amount of a compound of claim 2, or a
pharmaceutically acceptable salt, solvate or prodrug thereof.
10. A method as claimed in claim 9, wherein the condition to be
treated is depression.
11-15. (canceled)
16. A method of treating a condition for which inhibition of
serotonin (5-HT), dopamine (DA) and norepinephrine (NE), is
beneficial, which comprises administering to a human in need
thereof an effective amount of a compound of formula (A)' as
described in claim 1 or a pharmaceutically acceptable salt, solvate
or prodrug thereof.
17. A method as claimed in claim 16, wherein the condition to be
treated is depression.
18-21. (canceled)
22. A pharmaceutical composition comprising a compound as claimed
in claim 2, or a pharmaceutically acceptable salt, solvate or
prodrug thereof and a pharmaceutically acceptable carrier.
23. A method of treating a condition for which inhibition of
serotonin (5-HT), dopamine (DA) and norepinephrine (NE), is
beneficial, which comprises administering to a human in need
thereof an effective amount of a compound of claim 7, or a
pharmaceutically acceptable salt, solvate or prodrug thereof.
24. A method as claimed in claim 23, wherein the condition to be
treated is depression.
25. A pharmaceutical composition comprising a compound as claimed
in claim 7, or a pharmaceutically acceptable salt, solvate or
prodrug thereof and a pharmaceutically acceptable carrier.
Description
[0001] The present invention relates to novel compounds, processes
for their preparation, intermediates used in these processes,
pharmaceutical compositions containing them and their use in
therapy, as serotonin (5-HT), dopamine (DA) and norepinephrine
(NE), re-uptake inhibitors.
[0002] Brain tissue is constituted of neuronal cells which are able
to communicate with each other via specific cellular structures
named synapses. The exchange of signals between neurons in the
synapses happens through neurochemical messengers named
neurotransmitters, acting on specific target protein molecules,
both post and pre-synaptic, referred to as receptors. Monoamines
represent a family of small neurotransmitter molecules sharing
common chemical features, and include serotonin (5-HT), dopamine
(DA) and norepinephrine (NE).
[0003] Monoamine neurotransmitters are released into the synaptic
cleft between neurons and interact with receptors present on the
membrane of the target cells. The switch of the neurochemical
signal occurs mainly by removal of the neurotransmitter molecules
through other protein molecules referred to as monoamine
transporters (SERT for 5-HT, DAT for DA and NET for NE).
Transporters are able to bind neurotransmitter molecules and move
them into the presynaptic terminals, this cellular mechanism
referred to as re-uptake. Pharmacological inhibition of the
re-uptake process can cause an increase of monoamine at synaptic
level and as a consequence an enhancement of the physiological
activity of neurotransmitters.
[0004] Serotonergic neurotransmission in the brain is mediated by a
large family of receptors comprising both the G-protein coupled
receptors and ligand-gated ion channels including 14 subtypes, and
is involved in a vast variety of physiologic functions.
[0005] Compounds endowed of inhibitory properties at the SERT are
predicted to have the ability to treat in mammals, including
humans, a variety of disorders associated with this neural system,
for example eating disorders, major depression and mood disorders,
obsessive compulsive disorders, panic disorders, alcoholism, pain,
memory deficits and anxiety. Included among these disorders are
disorders related to depression, such as pseudodementia or Ganser's
syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome
or late luteal phase syndrome, tobacco abuse, panic disorder,
post-traumatic syndrome, memory loss, dementia of ageing, acquired
immunodeficiency syndrome dementia complex, memory dysfunction in
ageing, social phobia, attention deficit hyperactivity disorder,
chronic fatigue syndrome, premature ejaculation, erectile
difficulty, anorexia nervosa, disorders of sleep, autism, mutism or
trichotillomania.
[0006] Major depression is an affective disorder, or disorder of
mood, characterized by several symptoms including feeling of
profound sadness, worthlessness, despair and loss of interest in
all pleasures (anhedonia), recurrent thoughts of death, mental
slowing, loss of energy, an inability to take decision, often
associated with anxiety and agitation. These symptoms are
persistent and can range from mild to severe.
[0007] The pathophysiology of major depression is poorly understood
being a multifactorial syndrome and, due to this, several
neurotransmitter systems have been implicated. However, it is
generally believed that the disorder stems from a decrease in the
synaptic concentration of monoamine neurotransmitters, mainly NE
and 5-HT, in critical brain areas, leading to the "monoamine
theory" of depression.
[0008] Several lines of preclinical and clinical evidence indicate
that an enhancement of serotonin-mediated neurotransmission might
be effective in the treatment of major depression and actually the
selective serotonin re-uptake inhibitors (SSRIs) have come to
dominate the therapy of depression over the last two decades.
Fluoxetine, the first SSRI to be introduced, is the prototype of
this group. Other members include Paroxetine, Sertraline,
Fluvoxamine, Citalopram.
[0009] However, it is not clear exactly how these agents act to
relieve depression. As with other classes of antidepressant, there
is a lag of several weeks before the onset of the mood-elevating
effect, despite the rapid blockade of the serotonin re-uptake. It
is presumed that secondary adaptive changes must occur at
serotonergic synapses after chronic administration of SSRIs i.e.
down-regulation of release-regulating autoreceptors and increased
neurotransmitter release. The delayed onset of anti-depressant
effect is considered to be a serious drawback to currently used
SSRIs. Moreover, although there is generally good tolerability of
SSRIs, the elevation of 5-HT levels at central and peripheral
synapses leads to stimulation of receptor subtypes like 5-HT.sub.2c
and 5-HT.sub.3, which contributes to agitation and restless, along
with gastrointestinal and sexual side-effects.
[0010] The success of the SSRIs rekindled interest in the
development of selective norepinephrine re-uptake inhibitors
(SNRIs) as potential antidepressants. A number of such compounds
have been synthesized, e.g. Nisoxetine, Maprotiline, Tomoxetine and
Reboxetine. Furthermore, many compounds, including old tricyclic
antidepressants, have a mixed NET and SERT inhibition profile,
like. Imipramine and Amitriptyline (with SERT potency>NET) and
Desipramine, Nortriptyline, and Protriptyline (NET
potency>SERT).
[0011] The pharmacological manipulation of the DAT can in principle
have the ability to elevate DA levels in the mesolimbic system,
reversing the anhedonia that is a core symptom of major depression.
A DAT inhibition component, in combination with a blockade of SERT
and NET, can also have the ability to improve the lack of
motivation and attention and enhance cognitive deficits seen in
depressed patients. On the other hand, blockade of DAT has to be
carefully managed in order to avoid potential reinforcing effects
and abuse liability. However compounds with DAT inhibition in their
pharmacology, such as Dexmethylphenidate, Methylphenidate and
Bupropion, have been successfully marketed. Clinical studies
indicate that patients with poor response to SSRIs benefit from
combination therapy with agents that enhance dopaminergic tone. As
a result, compounds with a strong SERT inhibiting activity combined
with a well balanced NET blockade and moderate DAT inhibiting
activity may therefore provide a replacement for current
combination therapies for treating unresponsive patients, providing
greater efficacy and therapeutic flexibility with a more rapid
onset of anti-depressant effect.
[0012] Due to their valuable DAT inhibition, the compounds of the
present invention are considered useful for the treatment of
Parkinsonism, depression, obesity, narcolepsy, drug addiction or
misuse, including cocaine abuse, attention-deficit hyperactivity
disorders, Gilles de la Tourettes disease and senile dementia.
Dopamine re-uptake inhibitors enhance indirectly via the dopamine
neurones the release of acetylcholine and are therefore also useful
for the treatment of memory deficits, e.g. in Alzheimers disease,
presenile dementia, memory dysfunction in ageing, and chronic
fatigue syndrome. Noradrenaline re-uptake inhibitors are considered
useful for enhancing attention, alertness, arousal, vigilance and
for treating depression.
[0013] One object of the present invention is to provide novel
pharmaceutical compositions comprising compounds which are
serotonin (5-HT), dopamine (DA) and norepinephrine (NE) re-uptake
inhibitors.
[0014] Furthermore, the object of the present invention is to
provide novel compounds which are serotonin (5-HT), dopamine (DA)
and norepinephrine (NE) re-uptake inhibitors.
[0015] In a first aspect, the present invention provides a
pharmaceutical composition comprising a compound of formula (A) or
a pharmaceutically acceptable salt, solvate or prodrug thereof:
##STR00008##
wherein R.sub.1 is hydrogen or C.sub.1-4alkyl; R.sub.2 is a group
A, K or W wherein
A is
##STR00009##
[0016] K is an .alpha. or .beta. naphthyl group, optionally
substituted by 1 or 2 groups R.sub.18, each of them being the same
or different; and
W is
##STR00010##
[0017] and wherein G is a 5,6-membered monocyclic heteroaryl, or a
8- to 11-membered heteroaryl bicyclic group; such G may be
substituted by (R.sub.15).sub.p, which can be the same or
different; p is an integer from 0 to 5; R.sub.3 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.4 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.5 is hydrogen or
C.sub.1-4 alkyl; R.sub.7 is hydrogen or C.sub.1-4 alkyl; or is a
group X, X.sub.1, X.sub.2 or X.sub.3; wherein
X is
##STR00011##
[0018] X.sub.3 is
##STR00012##
[0019] X.sub.2 is
##STR00013##
[0020] and
X.sub.3 is
##STR00014##
[0021] R.sub.8 is hydrogen or C.sub.1-4 alkyl; or is a group X or
X.sub.1; R.sub.9 is C.sub.1-4alkyl; R.sub.10 is selected from a
group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.8 is a 5-6 membered heterocycle group,
which may be optionally substituted by one or two substituents
selected from a group consisting of: halogen, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy and
C.sub.1-4alkanoyl; R.sub.11 is selected from a group consisting of:
hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
[0022] R.sub.12 is selected from a group consisting of: hydrogen,
halogen, hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; [0023] R.sub.13 is
selected from a group consisting of: hydrogen, halogen, hydroxy,
cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; [0024] R.sub.14 is selected from a group
consisting of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
[0025] R.sub.15 is selected from a group consisting of: halogen,
hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; [0026] R.sub.16 is
hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl or
C.sub.3-6cycloalkylC.sub.1-3alkyl; [0027] R.sub.17 is hydrogen or
C.sub.1-4alkyl; [0028] R.sub.18 is selected from a group consisting
of: halogen, cyano, C.sub.1-4alkyl; [0029] R.sub.19 is
haloC.sub.1-2alkyl; [0030] n is 1 or 2; and a pharmaceutically
acceptable carrier.
[0031] Compound 6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane shown
below
##STR00015##
has been disclosed in the patent application No WO2004072025
("Preparation of N-aryl heterocycles as melanin concentrating
hormone (MCH) antagonists") wherein it has been used as an
intermediate for synthesis of final compounds. No therapeutic use
has been indicated for this compound in the patent application.
[0032] Compound 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane shown
below
##STR00016##
has been disclosed in the publication titled "A Novel and Selective
Monoamine Oxidase B substrate" Rimoldi, J. et al., Bioorganic and
Medicinal Chemistry (2005), 13 (20), 5808-5813. Nonetheless, no
therapeutic use has been indicated for this compound.
[0033] In another aspect, the invention provides a method for the
treatment of a mammal, including man, in particular for the
treatment of disorders or diseases responsive to the serotonin
(5-HT), dopamine (DA) and norepinephrine (NE), re-uptake inhibiting
activity of the compounds, comprising administration of an
effective amount of a compound of formula (A) as above defined or a
pharmaceutically acceptable salt, solvate or prodrug thereof.
[0034] In one embodiment, the invention provides a method of
treating a condition for which inhibition of serotonin (5-HT),
dopamine (DA) and norepinephrine (NE), is beneficial, which
comprises administering to a mammal (e.g. human) in need thereof an
effective amount of a compound of formula (A) as above defined or a
pharmaceutically acceptable salt, solvate or prodrug thereof.
[0035] In a further aspect, the invention provides a compound of
formula (A) as above defined or a pharmaceutically acceptable salt,
solvate or prodrug thereof for use in therapy.
[0036] In one embodiment, the invention provides a compound of
formula (A) as above defined or a pharmaceutically acceptable salt,
solvate or prodrug thereof, for use in the treatment of a condition
in a mammal for which inhibition of serotonin (5-HT), dopamine (DA)
and norepinephrine (NE) is beneficial.
[0037] In a still further aspect, the invention provides the use of
a compound of formula (A) as above defined or a pharmaceutically
acceptable salt, solvate or prodrug thereof, for the manufacture of
a medicament for the treatment of disorders or diseases responsive
to the serotonin (5-HT), dopamine (DA) and norepinephrine (NE),
re-uptake inhibiting activity.
[0038] In one embodiment, the invention provides the use of a
compound of formula (A) as above defined or a pharmaceutically
acceptable salt, solvate or prodrug thereof in the manufacture of a
medicament for the treatment of a condition in a mammal for which
inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine
(NE) is beneficial.
[0039] In one aspect, the present invention provides a compound of
formula (I) or a pharmaceutically acceptable salt, solvate or
prodrug thereof:
##STR00017##
wherein R.sub.1 is hydrogen or C.sub.1-4 alkyl; R.sub.2 is a group
A, K or W wherein
A is
##STR00018##
[0040] K is an .alpha. or .beta. naphthyl group, optionally
substituted by 1 or 2 groups R.sub.18, each of them being the same
or different; and
W is
##STR00019##
[0041] and wherein G is a 5,6-membered monocyclic heteroaryl, or a
8- to 11-membered heteroaryl bicyclic group; such G may be
substituted by (R.sub.15).sub.p, which can be the same or
different; p is an integer from 0 to 5; R.sub.3 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.4 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.5 is hydrogen or
C.sub.1-4alkyl; R.sub.7 is hydrogen or C.sub.1-4 alkyl; or is a
group X, X.sub.1, X.sub.2 or X.sub.3; wherein
X is
##STR00020##
[0042] X.sub.1 is
##STR00021##
[0043] X.sub.2 is
##STR00022##
[0044] and
X.sub.3 is
##STR00023##
[0045] R.sub.6 is hydrogen or C.sub.1-4alkyl; or is a group X or
X.sub.1; R.sub.9 is C.sub.1-4alkyl; R.sub.10 is selected from a
group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.5; R.sub.5 is a 5-6 membered heterocycle group,
which may be optionally substituted by one or two substituents
selected from a group consisting of: halogen, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy and
C.sub.1-4alkanoyl; R.sub.11, is selected from a group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.12;
R.sub.12 is selected from a group consisting of: hydrogen, halogen,
hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.13 is selected
from a group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.14 is selected from a group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.15 is selected from a group consisting of: halogen, hydroxy,
cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.16 is hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl or C.sub.3-6cycloalkylC.sub.1-3alkyl; R.sub.17
is hydrogen or C.sub.1-4alkyl; R.sub.18 is selected from a group
consisting of: halogen, cyano, C.sub.1-4alkyl; R.sub.19 is
haloC.sub.1-2alkyl; n is 1 or 2; with the proviso that: if R.sub.2
is A, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.10,
R.sub.11, R.sub.13, R.sub.14 are hydrogen, and R.sub.12 is
fluorine, R.sub.12 is C.sub.1-4 alkyl; if R.sub.2 is A, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.10, R.sub.11, R.sub.13,
R.sub.14 are hydrogen, and R.sub.1 is methyl, R.sub.12 is halogen,
hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8.
[0046] In another aspect, the present invention provides a compound
of formula (IF) or a pharmaceutically acceptable salt, solvate or
prodrug thereof:
##STR00024##
wherein R.sub.1 is hydrogen or C.sub.1-4alkyl; R.sub.2 is a group A
or W wherein
A is
##STR00025##
[0047] and
W is
##STR00026##
[0048] and wherein G is a 5,6-membered monocyclic heteroaryl, or a
8- to 11-membered heteroaryl bicyclic group; such G may be
substituted by (R.sub.15).sub.p, which can be the same or
different; p is an integer from 0 to 5; R.sub.3 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.4 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.5 is hydrogen or
C.sub.1-4 alkyl; R.sub.1 is hydrogen or C.sub.1-4alkyl; or is a
group X or X.sub.1 wherein
X is
##STR00027##
[0049] X.sub.1 is
##STR00028##
[0050] X.sub.2 is
##STR00029##
[0051] and
X.sub.3 is
##STR00030##
[0052] and wherein R.sub.7 is hydrogen or C.sub.1-4 alkyl; or is a
group X, X.sub.1, X.sub.2 or X.sub.3; R.sub.8 is a 5-6 membered
heterocycle group, which may be substituted by one or two
substituents selected from a group consisting of: halogen, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy and
C.sub.1-4alkanoyl; R.sub.9 is C.sub.1-4alkyl R.sub.10 is selected
from a group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.11 is selected from a group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.12 is selected from a group consisting of: hydrogen, halogen,
hydroxy, cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl,
C.sub.1-4alkoxy, haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and
SF.sub.5; or corresponds to a group R.sub.8; R.sub.13 is selected
from a group consisting of: hydrogen, halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.14 is selected from a group consisting
of: hydrogen, halogen, hydroxy, cyano, C.sub.1-4alkyl,
haloC.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkoxy,
C.sub.1-4alkanoyl and SF.sub.5; or corresponds to a group R.sub.8;
R.sub.15 is selected from a group consisting of: halogen, hydroxy,
cyano, C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.16 is hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl or C.sub.3-6cycloalkylC.sub.1-3alkyl; n is 1 or
2; with the proviso that: if one group of R.sub.11 or R.sub.13 is
not hydrogen, at least one group of R.sub.10, R.sub.12 or R.sub.14
is not hydrogen; if R.sub.2 is A, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.10, R.sub.11, R.sub.13, R.sub.14 are
hydrogen, and R.sub.12 is fluorine, R.sub.1 is not hydrogen; if
R.sub.2 is A, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.10, R.sub.11, R.sub.13, R.sub.14 are hydrogen, and R.sub.1 is
methyl, R.sub.12 is not hydrogen.
[0053] In a further aspect, the present invention provides a
compound of formula (IG) or a pharmaceutically acceptable salt,
solvate or prodrug thereof:
##STR00031##
wherein R.sub.1 is hydrogen or C.sub.1-4 alkyl;
R.sub.2 is
##STR00032##
[0054] p is an integer from 0 to 5; R.sub.3 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4 alkyl; or
corresponds to a group X or X.sub.1; R.sub.4 is selected in the
group consisting of: hydrogen, fluorine, and C.sub.1-4alkyl; or
corresponds to a group X or X.sub.1; R.sub.5 is hydrogen or
C.sub.1-4 alkyl; R.sub.6 is hydrogen or C.sub.1-4alkyl; or is a
group X or X.sub.1 wherein
X is
##STR00033##
[0055] X.sub.1 is
##STR00034##
[0056] X.sub.2 is
##STR00035##
[0057] and
X.sub.3 is
##STR00036##
[0058] and wherein R.sub.7 is hydrogen or C.sub.1-4alkyl; or is a
group X, X.sub.1, X.sub.2 or X.sub.3; R.sub.8 is a 5-6 membered
heterocycle group, which may be substituted by one or two
substituents selected from a group consisting of: halogen, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy and
C.sub.1-4alkanoyl; R.sub.9 is C.sub.1-4alkyl R.sub.10 is selected
from a group consisting of: halogen, hydroxy, cyano,
C.sub.1-4alkyl, haloC.sub.1-4alkyl, C.sub.1-4alkoxy,
haloC.sub.1-4alkoxy, C.sub.1-4alkanoyl and SF.sub.5; or corresponds
to a group R.sub.8; R.sub.11 is hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl or C.sub.3-6cycloalkylC.sub.1-4alkyl; n is 1 or
2.
[0059] Because of the presence of the fused cyclopropane ring,
compounds of formula (I) are believed to have a "cis" disposition
of the substituents (both groups R.sub.2 and R.sub.7 linked to the
bicyclic ring system are on the same face of this bicyclic ring
system).
[0060] It will be appreciated that compounds of formula (I) possess
at least two stereogenic centers, namely at position 1 and 6 in the
3-azabicyclo[4.1.0]heptane portion of the molecule. Thus, the
compounds may exist in two stereoisomers which are enantiomers with
respect to the stereogenic centers in the cyclopropane ring. It
will also be appreciated, in common with most biologically active
molecules that the level of biological activity may vary between
the individual stereoisomers of a given molecule. It is intended
that the scope of the invention includes all individual
stereoisomers (diastereoisomers and enantiomers) and all mixtures
thereof, including but not limited to racemic mixtures, which
demonstrate appropriate biological activity with reference to the
procedures described herein.
[0061] In one embodiment of the present invention compounds of
formula (I)' are provided which correspond to the compounds of
formula (I), or pharmaceutically acceptable salts, solvates or
prodrugs thereof, having "cis" disposition, represented by the bold
highlight of the two bonds near the cyclopropyl moiety:
##STR00037##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.17 are defined as above for compounds of formula
(I).
[0062] From now on throughout the document, the symbol ' (prime) is
used to identify compounds having "cis" disposition for the bonds
bearing groups R.sub.2 and R.sub.7, represented by the bold
highlight of the two bonds near the cyclopropyl moiety.
[0063] In one embodiment of the present invention, the bold
highlight of the two bonds near the cyclopropyl moiety bearing
groups R.sub.2 and R.sub.7, indicate, mixtures (including but not
limited to racemic mixtures) of those cis isomers.
[0064] In compounds of formula (I)' there are at least two
stereogenic centers, which are located in the cyclopropane portion,
as depicted below; through optical resolution of a mixture
containing the two stereoisomers which are enantiomers with respect
to the stereogenic centers at positions named 1 and 6, steroisomers
of compounds of formula (I)' having a single absolute configuration
at stereogenic centers named 1 and 6, may be obtained as shown in
the scheme below:
##STR00038##
[0065] Absolute configuration of stereogenic centers at position
named 1 and 6 may be assigned using Cahn-Ingold-Prelog nomenclature
based on groups' priorities.
[0066] In another embodiment of the present invention compounds of
formula (I)'' are provided which correspond to the compounds of
formula (I), or pharmaceutically acceptable salts, solvates or
prodrugs thereof, as stereochemical isomers having a "cis"
disposition for bonds bearing groups R.sub.2 and R.sub.7, and a
single but unknown configuration at stereogenic centers named 1 and
6:
##STR00039##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.17 are defined as above for compounds of formula
(I).
[0067] In the context of the present invention, the representation
shown above in compounds of formula (I)'' for the two bonds near
the cyclopropyl moiety bearing groups R.sub.2 and R.sub.7 indicate
a cis stereoisomer, which has a single but unknown absolute
configuration at stereogenic centers named 1 and 6.
[0068] It is intended in the context of the present invention that
stereochemical isomers of formula (I)'' are enriched in one
configuration at centers named 1 and 6. In one embodiment, the
isomers correspond to at least 90% e.e. (enantiomeric excess). In
another embodiment the isomers correspond to at least 95% e.e. In
another embodiment the isomers correspond to at least 99% e.e.
[0069] From now on throughout the document, the symbol '' (double
prime) is used to identify stereochemical isomers of the compounds
of the invention having "cis" disposition for the two bonds near
the cyclopropyl moiety bearing groups R.sub.2 and R.sub.7 and
indicated with the representation shown above for compounds of
formula (I)'', those stereoisomers having a single but unknown
absolute configuration at stereogenic centers named 1 and 6.
[0070] The absolute configuration of the optical isomers of some
compounds of the present invention was assigned using ab initio VCD
(vibrational circular dichroism).
[0071] Chiral molecules exhibit vibrational circular dichroism
(VCD). Vibrational circular dichroism (VCD) is the differential
interaction of a chiral molecule with left and right circularly
polarized infrared radiation during vibrational excitation.
[0072] The VCD spectrum of a chiral molecule is dependent on its
three-dimensional structure. Most importantly, the VCD spectrum of
a chiral molecule is a sensitive function of its absolute
configuration and, in the case of flexible molecules, of its
conformation. In principle, therefore, VCD permits the
determination of the structure of a chiral molecule. VCD spectra
were first measured in the 1970s. Subsequently, VCD instrumentation
has developed enormously in spectral range and in sensitivity.
Currently, VCD spectra of liquids and solutions can be measured
over the majority of the fundamental infrared (IR) spectral range
(v.gtoreq. 650 cm.sup.-1) with high sensitivity at acceptable
resolution (1-5 cm.sup.-1) using both dispersive and Fourier
Transform (FT) VCD instrumentation. Very recently, commercial FT
VCD instrumentation has become available, greatly enhancing the
accessibility of VCD spectra.
[0073] The use of VCD as a reliable method for the determination of
absolute configuration of chiral molecules is now well established
(see for example Shah R D, et al., Curr Opin Drug Disc Dev 2001;
4:764-774; Freedman T B, et al., Helv Chim Acta 2002; 85:1160-1165;
Dyatkin A B, et al. Chirality 2002; 14:215-219; Solladie'-Cavallo
A, Balaz Met al., Tetrahedron Assym 2001; 12:2605-2611; Nafie L A,
et al. Circular dichroism, principles and applications, 2nd ed. New
York: John Wiley & Sons; 2000. p 97-131; Nafie L A, et al. in:
Yan B, Gremlish H-U, editors. Infrared and Raman spectroscopy of
biological materials. New York: Marcel Dekker; 2001. p 15-54;
Polavarapu P L, et al., J Anal Chem 2000; 366:727-734; Stephens P
J, et al., Chirality 2000; 12:172-179; Solladie'-Cavallo A, et al.,
Eur J Org Chem 2002: 1788-1796).
[0074] The method entails comparison of observed IR and VCD spectra
with calculations of the spectra for a specific configuration and
provides information both on the absolute configuration and on the
solution conformation.
[0075] Given an experimental spectrum of a chiral molecule whose
absolute configuration and/or conformation are unknown and to be
determined, the general procedure is as follows: 1) all possible
structures are defined; 2) the spectra of these structures are
predicted; and 3) predicted spectra are compared to the
experimental spectrum. The correct structure will give a spectrum
in agreement with experiment; incorrect structures will give
spectra in disagreement with experiment.
[0076] VCD spectra are always measured simultaneously with
vibrational unpolarized absorption spectra ("infrared (IR)
spectra") and the two vibrational spectra together provide more
information than does the VCD spectrum alone. In addition,
vibrational unpolarized absorption spectra are automatically
predicted simultaneously with VCD spectra.
[0077] For ab initio assignments, VCD and unpolarized IR spectra
were calculated using the Gaussian 98 software package.
[0078] In one embodiment of the present invention compounds of
formula (IA) are provided that correspond to stereochemical isomers
of compounds of formula (I)', having the configuration shown in the
picture below at stereogenic centers at position named 1 and 6:
##STR00040##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.17 are defined as above for compounds of formula
(I), or pharmaceutically acceptable salts, solvates or prodrugs
thereof.
[0079] It is intended in the context of the present invention that
stereochemical isomers of formula (IA) are enriched in one
configuration at stereogenic centers named 1 and 6. In one
embodiment, the isomers correspond in one embodiment to at least
90% e.e. (enantiomeric excess). In another embodiment the isomers
correspond to at least 95% e.e. In another embodiment the isomers
correspond to at least 99% e.e.
[0080] From now on throughout the document, the suffix "A" in
brackets is used to identify stereochemical isomers of compounds of
the invention having the configuration shown above for compounds of
formula (IA) at stereogenic centers at positions named 1 and 6.
[0081] In another embodiment of the present invention compounds of
formula (IB) are provided that correspond to stereochemical isomers
of compounds of formula (I)', having the configuration shown in the
picture below at stereogenic centers at position named 1 and 6:
##STR00041##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.17 are defined as above for compounds of formula
(I), or pharmaceutically acceptable salts, solvates or prodrugs
thereof.
[0082] It is intended in the context of the present invention that
stereochemical isomers of formula (IB) are enriched in one
configuration at centers named 1 and 6. In one embodiment, the
isomers correspond in one embodiment to at least 90% e.e.
(enantiomeric excess). In another embodiment the isomers correspond
to at least 95% e.e. In another embodiment the isomers correspond
to at least 99% e.e.
[0083] From now on throughout the document, the suffix "B" in
brackets is used to identify stereochemical isomers of compounds of
the invention having the configuration shown above for compounds of
formula (IB) at stereogenic centers at positions named 1 and 6.
[0084] The term "C.sub.1-4alkyl" refers to an alkyl group having
from one to four carbon atoms, in all isomeric forms, such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and
tert-butyl.
[0085] The term `C.sub.3-C.sub.6 cycloalkyl group` as used herein
means a non aromatic monocyclic hydrocarbon ring of 3 to 6 carbon
atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl; while unsaturated cycloalkyls include cyclopentenyl and
cyclohexenyl, and the like.
[0086] The term `C.sub.3-6cycloalkylC.sub.1-3alkyl` as used herein
means an alkyl having from one to three carbon atoms wherein one
hydrogen atom is replaced with a C.sub.3-C.sub.6 cycloalkyl group
as above defined, for example methylcyclopropane.
[0087] The term "C.sub.1-4alkoxy" refers to a linear chain or
branched chain alkoxy (or "alkyloxy") group having from one to four
carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy and tert-butoxy.
[0088] The term `C.sub.1-4 alkanoyl group` as used herein may be a
linear or a branched chain alkanoyl group, for example acetyl,
ethylcarbonyl, n-propylcarbonyl, i-propyl carbonyl, n-butylcarbonyl
or t-butylcarbonyl and the like.
[0089] The term `halo C.sub.1-4 alkyl` as used herein means an
alkyl group having one or more carbon atoms and wherein at least
one hydrogen atom is replaced with halogen, preferably fluorine,
such as for example a trifluoromethyl group and the like.
[0090] The term `halo C.sub.1-4alkoxy group` as used herein may be
a C.sub.1-4 alkoxy group as defined before substituted with at
least one halogen, such as OCH.sub.2CF.sub.3, OCHF.sub.2, or
OCF.sub.3.
[0091] The term `halo C.sub.1-2 alkyl group` as used herein may be
a C.sub.1-2 alkyl group as defined before substituted with at least
one halogen, preferably fluorine, such as --CH.sub.2CF.sub.3,
--CHF.sub.2, or --CF.sub.3.
[0092] The term "SF.sub.5" refers to pentafluorosulfanyl.
[0093] The term "halogen" and its abbreviation "halo" refer to
fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Where the
term "halo" is used before another group, it indicates that the
group is substituted by one or more halogen atoms.
[0094] The term `5,6-membered monocyclic heteroaryl` as used herein
means an aromatic monocyclic heterocycle ring of 5 or 6 members and
having at least one heteroatom selected from nitrogen, oxygen and
sulfur, and containing at least 1 carbon atom.
[0095] Representative 5, 6 membered monocyclic heteroaryl groups
include (but are not limited to): furyl, thiophenyl, pyrrolyl,
pyridyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiazolyl,
isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
triazolyl and tetrazolyl.
[0096] The term `8, 11-membered bicyclic heteroaryl` as used herein
means an aromatic bicyclic heterocycle ring of 8 to 11 members and
having at least one heteroatom selected from nitrogen, oxygen and
sulfur, and containing at least 1 carbon atom.
[0097] Representative 8, to 11 membered bicyclic heteroaryl groups
include (but are not limited to): benzofuranyl, benzothiophenyl,
indolyl, isoindolyl, azaindolyl, quinolinyl, isoquinolinyl,
benzoxazolyl, benzimidazolyl, benzothiazolyl, quinazolinyl and
phthalazinyl.
[0098] The term 5-6 membered heterocycle means a 5-6 monocyclic
heterocyclic ring which is either saturated, unsaturated or
aromatic, and which contains from 1 to 4 heteroatoms independently
selected from nitrogen, oxygen and sulfur, and wherein the nitrogen
and sulfur heteroatoms may be optionally oxidized, and the nitrogen
heteroatom may be optionally quaternized. Heterocycles include
heteroaryl groups as defined above. The heterocycle may be attached
via any heteroatom or carbon atom. Thus, the term include (but is
not limited to) morpholinyl, pyridinyl, pyrazinyl, pyrazolyl,
thiazolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl,
isoxazolyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl,
valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0099] Any of these groups may be attached to the rest of the
molecule at any suitable position.
[0100] In one embodiment, R.sub.1 is hydrogen or C.sub.1-4alkyl
(for example methyl). In another embodiment, R.sub.1 is
hydrogen.
[0101] In one embodiment, R.sub.2 is a group A or K. In another
embodiment, R.sub.2 is a group A. In a further embodiment, R.sub.2
is a group K.
[0102] In one embodiment, the group K is a 0 naphthyl group.
[0103] In one embodiment, R.sub.3 is hydrogen or a group X. In
another embodiment, R.sub.3 is hydrogen.
[0104] In a further embodiment, R.sub.3 is a group X.
[0105] In one embodiment, R.sub.4 is hydrogen.
[0106] In one embodiment, R.sub.5 is hydrogen.
[0107] In one embodiment, R.sub.6 is hydrogen.
[0108] In one embodiment, R.sub.7 is hydrogen or a group X, X.sub.1
or X.sub.2. In another embodiment, R.sub.7 is hydrogen. In a
further embodiment, R.sub.7 is a group X, X.sub.1 or X.sub.2.
[0109] In one embodiment, R.sub.7 is a group X.
[0110] In one embodiment, R.sub.7 is a group X.sub.1.
[0111] In one embodiment, R.sub.7 is a group X.sub.2.
[0112] In one embodiment, n is 1 or 2. In another embodiment, n is
1.
[0113] In one embodiment, R.sub.16 is hydrogen, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl or C.sub.3-6cycloalkylC.sub.1-3alkyl. In
another embodiment, R.sub.16 is hydrogen or C.sub.1-4alkyl. In a
further embodiment, R.sub.16 is hydrogen. In a still further
embodiment, R.sub.16 is C.sub.1-4alkyl (for example methyl or
ethyl).
[0114] In one embodiment, R.sub.17 is hydrogen or C.sub.1-4alkyl.
In another embodiment, R.sub.17 is hydrogen.
[0115] In a further embodiment, R.sub.17 is C.sub.1-4alkyl (for
example methyl).
[0116] In one embodiment, R.sub.18 is halogen. In another
embodiment, R.sub.18 is chlorine.
[0117] In one embodiment, R.sub.10 is hydrogen.
[0118] In one embodiment, R.sub.14 is hydrogen.
[0119] In one embodiment, R.sub.10 is hydrogen.
[0120] In one embodiment, R.sub.11 is hydrogen, halogen,
haloC.sub.1-4alkyl, haloC.sub.1-4alkoxy. In another embodiment,
R.sub.11 is hydrogen, halogen (for example chlorine) or
haloC.sub.1-4alkyl (for example trifluoromethyl). In a further
embodiment, R.sub.11 is halogen (for example chlorine) or
haloC.sub.1-4alkyl (for example trifluoromethyl). In a still
further embodiment, R.sub.11 is chlorine.
[0121] In one embodiment, R.sub.12 is halogen, haloC.sub.1-4alkyl,
haloC.sub.1-4alkoxy. In another embodiment,
[0122] R.sub.12 is halogen (for example chlorine or fluorine),
haloC.sub.1-4alkyl (for example trifluoromethyl) or
haloC.sub.1-4alkoxy (for example trifluoromethoxy). In still
another embodiment, R.sub.12 is chlorine.
[0123] In one embodiment, R.sub.13 is hydrogen, halogen,
haloC.sub.1-4alkyl, haloC.sub.1-4alkoxy. In another embodiment,
R.sub.13 is hydrogen.
[0124] In one embodiment, a compound of formula (IC) or a
pharmaceutically acceptable salt, solvate or prodrug thereof is
provided, wherein R.sub.1, R.sub.2, R.sub.7 and R.sub.17 are as
defined for formula (I):
##STR00042##
[0125] In Formula (IC), in one embodiment, R.sub.1 is hydrogen or
C.sub.1-4 alkyl (for example methyl), R.sub.2 is a group A or K,
R.sub.7 is hydrogen or a group X, X.sub.1 or X.sub.2 and R.sub.17
is hydrogen or C.sub.1-4alkyl.
[0126] In Formula (IC), in a further embodiment, R.sub.1 is
hydrogen, R.sub.2 is a group A or K, R.sub.7 is hydrogen or a group
X, X.sub.1 or X.sub.2 and R.sub.17 is hydrogen.
[0127] In one embodiment, a compound of formula (ID) or a
pharmaceutically acceptable salt, solvate or prodrug thereof is
provided, wherein R.sub.7 is a group X and R.sub.2, R.sub.16 and n
are as defined for formula (I):
##STR00043##
[0128] In Formula (ID), in one embodiment, R.sub.2 is a group
A.
[0129] In Formula (ID), in another embodiment, R.sub.2 is a group
A, R.sub.16 is hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl or
C.sub.3-6cycloalkylC.sub.1-3alkyl, R.sub.10 is hydrogen, R.sub.14
is hydrogen, R.sub.11 is hydrogen, halogen, haloC.sub.1-4alkyl or
haloC.sub.1-4alkoxy, R.sub.12 is halogen, haloC.sub.1-4alkyl or
haloC.sub.1-4alkoxy, R.sub.13 is hydrogen, halogen,
haloC.sub.1-4alkyl or haloC.sub.1-4alkoxy and n is 1.
[0130] In Formula (ID), in one embodiment, R.sub.2 is a group
K.
[0131] In Formula (ID), in another embodiment, R.sub.2 is a group
K, which is an unsubstituted, naphtyl ring, R.sub.16 is hydrogen,
C.sub.1-4alkyl, C.sub.3-6cycloalkyl or
C.sub.3-6cycloalkylC.sub.1-3alkyl and n is 1.
[0132] In one embodiment, a compound of formula (IE) or a
pharmaceutically acceptable salt, solvate or prodrug thereof is
provided, wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.17 are as
defined for formula (I):
##STR00044##
[0133] In Formula (IE), in one embodiment, R.sub.1 is hydrogen,
R.sub.2 is a group A or K, R.sub.3 is a group X or X.sub.1 and
R.sub.17 is hydrogen or C.sub.1-4alkyl.
[0134] In Formula (IE), in another embodiment, R.sub.1 is hydrogen,
R.sub.2 is a group A, R.sub.3 is a group X, R.sub.17 is hydrogen,
R.sub.16 is hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl or
C.sub.3-6cycloalkylC.sub.1-4alkyl, R.sub.10 is hydrogen, R.sub.14
is hydrogen, R.sub.11 is hydrogen, halogen, haloC.sub.1-4alkyl or
haloC.sub.1-4alkoxy, R.sub.12 is halogen, haloC.sub.1-4alkyl or
haloC.sub.1-4alkoxy, R.sub.13 is hydrogen, halogen,
haloC.sub.1-4alkyl or haloC.sub.1-4alkoxy and n is 1.
[0135] In one embodiment, compounds of formula (IC), (ID) and (IE)
as above defined, having a single but unknown configuration at
stereogenic centers at position named 1 and 6, are provided. Those
compounds are named (IC)'', (ID)'' and (IE)''.
[0136] In another embodiment, compounds of formula (IC), (ID) and
(IE) as above defined, having the configuration shown above for
compounds of formula (IA) at stereogenic centers at position named
1 and 6, are provided. Those compounds are named (ICA), (IDA) and
(IEA).
[0137] In a further embodiment, compounds of formula (IC), (ID) and
(IE) as above defined, having the configuration shown above for
compounds of formula (IB) at stereogenic centers at position named
1 and 6, are provided. Those compounds are named (ICB), (IDB) and
(IEB).
[0138] In the context of the present invention all the aspects and
embodiments of the invention described for compounds of formula (I)
are intended to apply also to compounds of formula (A).
[0139] For example, corresponding embodiments to those described
for compounds of formula (I) are also provided for compounds of
formula (A) [i.e. compounds of formula (A)', (A)'', (AA), (AB),
(AC), (AD), (AE) etc.], pharmaceutically acceptable salts, solvates
and prodrug thereof being included in the present invention.
[0140] Certain groups/substituents included in the present
invention may be present as isomers. The present invention includes
within its scope all such isomers, including racemates,
enantiomers, tautomers and mixtures thereof.
[0141] Certain groups in compounds of formula (I) or in
intermediates used to prepare them, may exist in one or more
tautomeric forms. The present invention includes within its scope
all such tautomeric forms, including mixtures.
[0142] As used herein, the term "salt" refers to any salt of a
compound according to the present invention prepared from an
inorganic or organic acid or base, quaternary ammonium salts and
internally formed salts and also includes pharmaceutically
acceptable salts. Pharmaceutically acceptable salts are
particularly suitable for medical applications because of their
greater aqueous solubility relative to the parent compounds. Such
salts must clearly have a physiologically acceptable anion or
cation.
[0143] Salts of compounds of formula (I) may be prepared through
conventional methods and are included within the scope of the
present invention.
[0144] Certain of the compounds of the invention may form acid or
base addition salts with one or more equivalents of the acid or of
the base. The present invention includes within its scope all
possible stoichiometric and non-stoichiometric forms.
[0145] Pharmaceutically acceptable salts may also be prepared from
other salts, including other pharmaceutically acceptable salts, of
the compound of formula (I) using conventional methods.
[0146] Suitably pharmaceutically acceptable salts of the compounds
of the present invention include acid addition salts formed with
inorganic acids such as hydrochloric, hydrobromic, hydroiodic,
phosphoric, metaphosphoric, nitric and sulfuric acids, and with
organic acids, such as tartaric, acetic, trifluoroacetic, citric,
malic, lactic, fumaric, benzoic, naphtoic, formic, propionic,
glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic,
mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic,
glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic,
embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic,
stearic, sulfanilic, alginic, galacturonic and arylsulfonic, for
example benzenesulfonic and p-toluenesulfonic, acids; base addition
salts formed with alkali metals and alkaline earth metals and
organic bases such as N,N-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine), lysine and procaine; and internally formed
salts. Salts having a non-pharmaceutically acceptable anion or
cation are within the scope of the invention as useful
intermediates for the preparation of pharmaceutically acceptable
salts and/or for use in non-therapeutic, for example, in vitro,
situations.
[0147] Those skilled in the art of organic chemistry will
appreciate that many organic compounds can form complexes with
solvents in which they are reacted or from which they are
precipitated or crystallized. These complexes are known as
"solvates". For example, a complex with water is known as a
"hydrate". Solvates of the compounds of the invention are within
the scope of the invention. The compounds of formula (I) may
readily be isolated in association with solvent molecules by
crystallisation or evaporation of an appropriate solvent to give
the corresponding solvates.
[0148] In addition, prodrugs are also included within the context
of this invention. As used herein, the term "prodrug" means a
compound which is converted within the body, e.g. by hydrolysis in
the blood, into its active form that has medical effects.
Pharmaceutically acceptable prodrugs are described in T. Higuchi
and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the
A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra
"Improved oral drug delivery: solubility limitations overcome by
the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2)
115-130.
[0149] Prodrugs are generally prepared by modifying functional
groups in a way such that the modification is cleaved, either by
routine manipulation or in vivo, yielding the parent compound.
Prodrugs include, for example, compounds of this invention wherein
hydroxy, amine or sulfhydryl groups are bonded to any group that,
when administered to a patient, cleaves to form the hydroxy, amine
or sulfhydryl groups. Thus, representative examples of prodrugs
include (but are not limited to) acetate, formate and benzoate
derivatives of alcohol, sulfhydryl and amine functional groups of
the compounds of structure (I). Further, in the case of a
carboxylic acid (--COOH), esters may be employed, such as methyl
esters, ethyl esters, and the like. Esters may be active in their
own right and/or be hydrolysable under in vivo conditions in the
human body. Suitable pharmaceutically acceptable in vivo
hydrolysable ester groups include those which break down readily in
the human body to leave the parent acid or its salt.
[0150] Hereinafter, compounds of formula (I) and their
pharmaceutically acceptable salts, solvates and prodrugs defined in
any aspect of the invention (except intermediate compounds in
chemical processes) are referred to as "compounds of the
invention".
[0151] Furthermore, some of the crystalline forms of the compounds
of the present invention, may exist as polymorphs, which are
included in the present invention.
[0152] Those skilled in the art will appreciate that in the
preparation of the compounds of the invention, it may be necessary
and/or desirable to protect one or more sensitive groups in the
molecule to prevent undesirable side reactions. Suitable protecting
groups for use according to the present invention are well known to
those skilled in the art and may be used in a conventional manner.
See, for example, "Protective groups in organic synthesis" by T. W.
Greene and P. G. M. Wuts (John Wiley & sons 1991) or
"Protecting Groups" by P. J. Kocienski (Georg Thieme Verlag 1994).
Examples of suitable amino protecting groups include acyl type
protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic
urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and
substituted Cbz), aliphatic urethane protecting groups (e.g.
9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc),
isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type
protecting groups (e.g. benzyl, trityl, chlorotrityl). Examples of
suitable oxygen protecting groups may include for example alkyl
silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;
alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters
such as acetate.
[0153] The present invention also includes isotopically-labelled
compounds, which are identical to those recited in formula (I) and
following, but for the fact that one or more atoms are replaced by
an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of
isotopes that can be incorporated into compounds of the invention
and pharmaceutically acceptable salts thereof include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine,
iodine, and chlorine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C,
.sup.14C, .sup.15N, .sup.17O, .sup.18O, .sup.31P, .sup.32P,
.sup.35S, .sup.18F, .sup.38Cl, .sup.123I and .sup.125I.
[0154] Compounds of the present invention and non-pharmaceutically
acceptable salts thereof that contain the aforementioned isotopes
and/or other isotopes of other atoms are within the scope of the
present invention. Isotopically-labelled compounds of the present
invention, for example those into which radioactive isotopes such
as .sup.3H, .sup.14C are incorporated, are useful in drug and/or
substrate tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. .sup.11C and .sup.18F
isotopes are particularly useful in PET (positron emission
tomography), and .sup.125I isotopes are particularly useful in
SPECT (single photon emission computerized tomography), all useful
in brain imaging. Further, substitution with heavier isotopes such
as deuterium, i.e., .sup.2H, can afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements and,
hence, may be preferred in some circumstances. Isotopically
labelled compounds of the present invention and
non-pharmaceutically acceptable salts thereof can generally be
prepared by carrying out the procedures disclosed in the Schemes
and/or in the Examples below, by substituting a readily available
isotopically labelled reagent for a non-isotopically labelled
reagent.
[0155] In one embodiment, the compounds of the invention are
selected from the list consisting of: [0156]
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane; [0157]
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methano-
l; [0158]
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
and pharmaceutically acceptable salts, solvates, or prodrugs
thereof.
[0159] In another embodiment, the compounds of the invention are
selected from the list consisting of: [0160]
(1R,6S/1S,6R)-6-phenyl-3-azabicyclo[4.1.0]heptane; [0161]
(1R,6S)-6-phenyl-3-azabicyclo[4.1.0]heptane; [0162]
(1S,6R)-6-phenyl-3-azabicyclo[4.1.0]heptane; [0163]
(1R,6S/1S,6R)-6-[4-(trifluoromethyl)phenyl]-3-azabicyclo[4.1.0]heptane;
[0164]
(1R,6S/1S,6R)-6-[3-(trifluoromethyl)phenyl]-3-azabicyclo[4.1.0]hep-
tane; [0165]
(1S,6R)-6-(3,4-dichlorophenyl)-3-(1-methylethyl)-1-[(methyloxy)methyl]-3--
azabicyclo[4.1.0]heptane; and pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0166] In another embodiment, the compounds of the invention are
selected from the list consisting of: [0167]
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane; [0168]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane; [0169]
(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane;
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl-
]methanol; [0170] [(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;
[0171] [(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;
[0172]
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
[0173] (1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
[0174] (1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;
[0175]
(1S,4R,6R/1R,4S,6S)-6-(3,4-dichlorophenyl)-4-methyl-1-[(methyloxy)methyl]-
-3-azabicyclo[4.1.0]heptane; [0176]
(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicycl-
o[4.1.0]heptane; [0177]
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane; [0178]
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0-
]heptane; [0179]
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane; [0180] (1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane; [0181] (1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane; [0182]
(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3--
azabicyclo[4.1.0]heptane; [0183]
(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane; [0184]
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0-
]heptane; [0185] (1R,6S or
1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e; [0186] (1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e; [0187]
(1S,6R/1R,6S)-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]--
3-azabicyclo[4.1.0]heptane; [0188]
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl-
}-3-azabicyclo[4.1.0]heptane; [0189]
(1S,6R,7R/1R,6S,7S)-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyc-
lo[4.1.0]heptane; and pharmaceutically acceptable salts, solvates,
or prodrugs thereof.
[0190] In a further embodiment, the compounds of the invention are
selected from the list consisting of: [0191]
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane; [0192] (1R,6S or
1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-aza-
bicyclo[4.1.0]heptane; [0193] (1S,6R or
1R,6S)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-aza-
bicyclo[4.1.0]heptane; [0194]
(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane; [0195] (1S,6R or
1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]1-[(methyloxy)methyl]-3-azab-
icyclo[4.1.0]heptane; [0196] (1R,6S or
1S,6R)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-aza-
bicyclo[4.1.0]heptane; [0197]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane; (1S 16R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e; and pharmaceutically acceptable salts, solvates, or prodrugs
thereof.
[0198] In a still further embodiment, the compounds of the
invention are selected from the list consisting of: [0199]
(1S,6RY6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane; [0200] (1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e; and pharmaceutically acceptable salts, solvates, or prodrugs
thereof.
[0201] In another embodiment, the compound of the invention is
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane or a pharmaceutically acceptable salt thereof.
[0202] In a further embodiment, the compound of the invention is
(1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e or a pharmaceutically acceptable salt thereof.
[0203] In another embodiment, compound of the invention is: [0204]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane; [0205]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane hydrochloride; [0206]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane (2R,3R)-2,3-dihydroxybutanedioate (L-tartrate salt); [0207]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane butanedioate (Mono-Succinate salt); [0208]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane phosphate; or a solvate thereof.
[0209] The present invention also provides a process for preparing
a compound of formula (I) or a salt thereof as defined above.
[0210] Compounds of the invention may be prepared in a variety of
ways. In the following reaction schemes and hereafter, unless
otherwise stated R.sub.1 to R.sub.19, A, K, W, G, p, X, X.sub.1,
X.sub.2, X.sub.3 and n are as for compounds of formula (I).
[0211] Throughout the specification, general formulae are
designated by Roman numerals (I), (II), (III), (IV) etc. Subsets of
these general formulae are defined as (Ia), (Ib), (Ic) etc. . . .
(IVa), (IVb), (IVc) etc.
[0212] Compounds of the invention may be prepared according to the
following synthetic schemes.
Synthetic Schemes
[0213] Compounds of formula (Ib), i.e. compounds of formula (I)
wherein R.sub.1.dbd.C.sub.1-4alkyl, R.sub.7=a group X (wherein n=1
and R.sub.15.dbd.C.sub.1-4 alkyl or
C.sub.1-3alkylC.sub.3-6cycloalkyl) may be obtained starting from
compounds of formula (Ia) wherein R.sub.1.dbd.H and
R.sub.16.dbd.C.sub.1-4alkyl or C.sub.1-3alkylC.sub.3-6cycloalkyl,
according to Scheme 1, following standard alkylation procedures,
e.g. using a RY alkylating agent (R.dbd.C.sub.1-4 alkyl,
Y=halogen), such as CH.sub.31, a trialkylamine, such as TEA, in
DCM, at temperature between 0.degree. C. and room temperature.
[0214] Alternatively, compounds of formula (Ib) may be obtained
through reductive amination using a suitable aldehyde
RCHO(R.dbd.C.sub.1-3 alkyl), a reducing agent such as NaCNBH.sub.3.
in aprotic or protic solvent (e.g. Toluene, THF or MeOH), at
temperature between 80.degree. C. and room temperature.
##STR00045##
[0215] Compounds of formula (Ia), i.e. compounds of formula (I)
wherein R.sub.7=a group X (wherein n=1), may be obtained, according
to Scheme 2, starting from compounds of formula (II), wherein Pg is
a suitable N-protecting group, typically Boc or benzyl, through
deprotection of N-Pg group.
[0216] For example, for Boc removal, TFA in DCM at temperature
between 0.degree. C. and room temperature may be used.
[0217] For example, for N-benzyl removal, either H.sub.2 and Pd/C
or alfa-chloroethyl chloroformate at reflux in DCE and then in MeOH
may be used.
##STR00046##
[0218] Compounds of formula (IIb), i.e. compounds of formula (II)
wherein R.sub.16.dbd.C.sub.1-4alkyl or
C.sub.1-3alkylC.sub.3-6cycloalkyl and wherein Pg is a suitable
N-protecting group, typically Boc or benzyl, may be obtained
starting from compounds of formula (IIa), wherein R.sub.16.dbd.H,
according to Scheme 3, following standard alkylation procedures,
e.g. using a R.sub.16Y alkylating agent (R.sub.16.dbd.C.sub.1-4
alkyl or C.sub.1-3alkylC.sub.3-6cycloalkyl, Y=halogen), such as
CH.sub.31, in the presence of a strong base, such as NaH, in
aprotic solvent, e.g. DMF, at temperature between 0.degree. C. and
room temperature.
##STR00047##
[0219] Compounds of formula (IIa.sub.1), i.e. compounds of formula
(IIa) wherein R.sub.3.dbd.R.sub.4.dbd.H, may be obtained starting
from compounds of formula (III), wherein Pg is a suitable
N-protecting group, typically Boc or benzyl, according to Scheme 4,
through the standard Simmons-Smith cyclopropanation procedure
(using ZnEt.sub.2, CH.sub.2I.sub.2 in DCM).
##STR00048##
[0220] Compounds of formula (Ic), i.e. compounds of formula (I)
wherein R.sub.1.dbd.R.sub.3.dbd.R.sub.4.dbd.R.sub.16.dbd.H, may be
obtained starting from compounds of formula (III) wherein Pg is a
suitable N-protecting group, typically Boc, according to Scheme 5,
through Simmons-Smith cyclopropanation procedure (using ZnEt.sub.2,
CH.sub.2I.sub.2 in DCM) modified by adding an amine such as
2,6-bis(1,1-dimethylethyl)-4-methylpyridine.
##STR00049##
[0221] Compounds of formula (IIa.sub.1), i.e. compounds of formula
(IIa), wherein R.sub.3.dbd.R.sub.4.dbd.H and wherein Pg is a
suitable N-protecting group, typically Boc, may be obtained
starting from compounds of formula (Ic), according to Scheme 6,
following the standard procedures, for example using Boc anhydride
and TEA in DCM at temperature between 0.degree. C. and room
temperature.
##STR00050##
[0222] Compounds of formula (IIa.sub.2), i.e. compounds of formula
(IIa) wherein R.sub.3.dbd.R.sub.4.dbd.F, may be obtained starting
from compounds of formula (III), according to Scheme 7 using
dibromodifluoromethane following the method reported in the Journal
of Fluorine Chemistry (2003), 119(1), 75-80.
##STR00051##
[0223] Compounds of formula (IIa.sub.3), i.e. compounds of formula
(IIa) wherein R.sub.3.dbd.R.sub.4.dbd.CH.sub.3 may be obtained
starting from compounds of formula (III), according to Scheme 8 in
analogy with the method reported in Synlett (2002), (1), 176-178, a
modified Simmons-Smith cyclopropanation procedure in which
2,2-diiodopropane is used.
##STR00052##
[0224] Compounds of formula (III), may be obtained starting from
compounds of formula (IV), wherein Pg is a suitable N-protecting
group, typically Boc, according to Scheme 9, using appropriate
reducing agents, such as for example LiAlH.sub.4, in aprotic
solvent e.g. diethyl ether of THF, at temperature between 40 and
-10.degree. C.
##STR00053##
[0225] Compounds of formula (IV), may be obtained starting from
compounds of formula (V), according to Scheme 10, following the
standard Suzuky coupling procedure using the suitable aryl boronic
acids or boronate esters, Pd(PPh.sub.3).sub.4 and a base, e.g.
Na.sub.2CO.sub.3 in a mixture of solvent e.g. toluene, ethanol and
water at 80.degree. C.
##STR00054##
[0226] Compounds of formula (V), wherein --OTf represents a
triflate group, may be obtained according to Scheme 11, starting
from compounds of formula (VI), wherein Pg is a suitable
N-protecting group, typically Boc, by reaction with a base (eg
sodium hydride), and then with a triflating agent, such as
N-phenyltrifluoromethanesulfonimide, in an aprotic solvent (eg
DMF), at temperature between 0.degree. C. and room temperature.
##STR00055##
[0227] Compound of formula (VIa), wherein R.sub.5=.dbd.H, and Pg is
a suitable protecting group, such as Boc, may be obtained,
according to Scheme 12, by reacting the commercially available
compound of formula (VII), wherein R.sub.5.dbd.R.sub.6.dbd.H, with
Boc anhydride and TEA in DCM, at temperature between 0.degree. C.
and room temperature.
##STR00056##
[0228] Compounds of formula (VIb), wherein
R.sub.5.dbd.R.sub.6.dbd.CH.sub.3 and Pg is a suitable protecting
group, may be obtained, according to Scheme 13, through acylation
of compound (VIII), wherein R.sub.5.dbd.R.sub.6.dbd.CH.sub.3 and Pg
is a suitable protecting group, in analogy with the method reported
in J. Org. Chem., 1995, 60, 5825.
##STR00057##
[0229] Compounds of formula (VIII), wherein
R.sub.6.dbd.R.sub.5.dbd.CH.sub.3 and Pg is a suitable protecting
group, such as Boc, may be prepared starting from compound (IX),
wherein R.sub.6.dbd.R.sub.5.dbd.CH.sub.3, according to Scheme 14,
as reported in WO2002085886.
##STR00058##
[0230] Compounds of formula (Id), i.e. compounds of formula (I)
wherein R.sub.1.dbd.C.sub.1-4alkyl, may be obtained starting from
compounds of formula (Ie), according to Scheme 15, with analogous
procedures to those described above for Scheme 1.
##STR00059##
[0231] Compounds of formula (Ie.sub.1), i.e. compounds of formula
(I) wherein R.sub.6.dbd.R.sub.5.dbd.H or CH.sub.3, and
R.sub.3.dbd.R.sub.4.dbd.CH.sub.3 may be obtained, according to
Scheme 16, starting from compounds of formula (X), in analogy with
the method reported in Synlett (2002), (1), 176-178, a modified
Simmons-Smith cyclopropanation procedure in which 2,2-diiodopropane
is used, followed by usual N-Pg deprotection.
##STR00060##
[0232] Compounds of formula (Ie.sub.2), wherein
R.sub.6.dbd.R.sub.5.dbd.H or --CH.sub.3, and
R.sub.3.dbd.R.sub.4.dbd.F, may be obtained starting from compounds
of formula (X), according to Scheme 17, using
dibromodifluoromethane, as described in the Journal of Fluorine
Chemistry (2003), 119(1), 75-80, followed by usual N-Boc
deprotection.
##STR00061##
[0233] Compounds of formula (Ie.sub.3), i.e. compounds of formula
(I), wherein R.sub.6.dbd.R.sub.5.dbd.H or --CH.sub.3, and
R.sub.3.dbd.R.sub.4.dbd.H, may be obtained starting from compounds
of formula (X), according to Scheme 18, through the standard
Simmons-Smith cyclopropanation procedure, followed by usual N-Pg
deprotection.
##STR00062##
[0234] Compounds of formula (Ie.sub.4), i.e. compounds of formula
(I), wherein R.sub.6.dbd.R.sub.5.dbd.H or --CH.sub.3 and
R.sub.16.dbd.H, C.sub.1-4alkyl or
C.sub.1-3alkylC.sub.3-6cycloalkyl, may be obtained starting from
compounds of formula (X.sub.1), wherein R.sub.6.dbd.R.sub.5.dbd.H
or --CH.sub.3 and R.sub.10.dbd.H, C.sub.1-4alkyl or
C.sub.1-3alkylC.sub.3-3cycloalkyl and Pg is a suitable protecting
group, according to Scheme 19, after usual N-Pg deprotection.
##STR00063##
[0235] Compounds of formula (XIa), i.e. compounds of formula
(X.sub.1), wherein R.sub.1, .dbd.C.sub.1-4alkyl or
C.sub.1-4alkylC.sub.3-6cycloalkyl, may be obtained starting from
compounds of formula (XIb), as below defined, according to Scheme
20, through standard alkylation procedures, e.g. using a R.sub.16Y
alkylating agent (R.sub.16.dbd.C.sub.1-4alkyl, Y=halogen), such as
CH.sub.31, in the presence of a strong base, such as NaH, in
aprotic solvent, e.g. DMF, at temperature between 0.degree. C. and
room temperature.
##STR00064##
[0236] Compounds of formula (XIb), i.e. compounds of formula
(X.sub.1), wherein R.sub.16.dbd.H, may be obtained starting from
compounds of formula (XII), wherein R.sub.6.dbd.R.sub.5.dbd.H or
CH.sub.3 and Pg is a suitable protecting group, according to Scheme
21, in analogy with the method reported in Synlett (2002), (1),
176-178, using ethyl diazoacetate and rhodium acetate, in aprotic
solvent (e.g. DCE, DCM or MeCN), at temperature between room
temperature and 80.degree. C., followed by reduction of the ester
with an appropriate reducing agent, such as LiAlH.sub.4 or BH.sub.3
THF, at temperature between -20.degree. C. and 70.degree. C.
##STR00065##
[0237] Compounds of formula (XII), wherein
R.sub.6.dbd.R.sub.5.dbd.H or CH.sub.3 and Pg is a suitable
protecting group, may be obtained starting from compounds of
formula (XIII), according to Scheme 22 following the above cited
Suzuky coupling procedure, using the suitable aryl boronic acids or
esters.
##STR00066##
[0238] Compounds of formula (XIII), wherein
R.sub.8.dbd.R.sub.5.dbd.H or CH.sub.3, --OTf represents a triflate
group and Pg is a suitable protecting group, may be obtained
starting from compounds of formula (VIII), wherein
R.dbd.R.sub.5.dbd.H or CH.sub.3 and Pg is a suitable protecting
group, according to Scheme 23, by reaction with a base (eg sodium
hydride), then with a triflating agent, such as
N-phenyltrifluoromethanesulfonimide, in an aprotic solvent (eg
DMF), at temperature between 0.degree. C. and room temperature.
##STR00067##
[0239] Compounds of formula (If), i.e. compounds of formula (I)
wherein R.sub.1.dbd.C.sub.1-4 alkyl or
C.sub.1-3alkylC.sub.3-6cycloalkyl, R.sub.5.dbd.H, R.sub.6=a group X
(wherein n=1, R.sub.16.dbd.C.sub.1-4 alkyl) and R.sub.7.dbd.H, may
be obtained starting from compounds of formula (Ig), i.e. compounds
of formula (I) wherein R.sub.1.dbd.H, R.sub.5.dbd.H, R.sub.6=a
group X (wherein n=1, R.sub.16.dbd.C.sub.1-4 alkyl or
C.sub.1-3alkylC.sub.3-6cycloalkyl,) and R.sub.7.dbd.H, according to
Scheme 24, through standard alkylation procedures, e.g. using a
R.sub.1Y alkylating agent (R.sub.1.dbd.C.sub.1-4alkyl, Y=halogen),
such as CH.sub.31, a trialkylamine, such as TEA, in DCM, at
temperature between 0.degree. C. and room temperature.
Alternatively, compounds of formula (If) may be obtained by
reductive amination using a suitable aldehyde
RCHO(R.dbd.C.sub.1-3alkyl), a reducing agent such as NaCNBH.sub.3,
in aprotic or protic solvent e.g. Toluene, THF or MeOH, at
temperature between 80.degree. C. and room temperature.
##STR00068##
[0240] Compounds of formula (Ig), wherein
R.sub.16.dbd.C.sub.1-4alkyl or C.sub.1-3alkylC.sub.3-6cycloalkyl,
may be obtained starting from compounds of formula (XV), through
usual N-Pg deprotection procedures according to Scheme 25.
##STR00069##
[0241] Compounds of formula (XV), wherein
R.sub.3.dbd.R.sub.4.dbd.H, F or --CH.sub.3, R.sub.16.dbd.C.sub.1-4
alkyl or C.sub.1-3alkylC.sub.3-6cycloalkyl, may be obtained,
according to Scheme 26, starting from compounds of formula (XVI),
wherein R.sub.16.dbd.C.sub.1-4alkyl or
C.sub.1-3alkylC.sub.3-6cycloalkyl, through the method described
respectively in the Schemes 5, 6 and 7.
##STR00070##
[0242] Compounds of formula (XVI), wherein
R.sub.16.dbd.C.sub.1-4alkyl or C.sub.1-2alkylC.sub.3-6cycloalkyl,
may be obtained, according to Scheme 27, starting from compounds of
formula (XVII) through alkylation procedure using a suitable
alkylating agent (e.g. MeI) in the presence of a strong base (e.g.
NaH) in an aprotic solvent such as THF or DMF at temperature
between 0.degree. C. and room temperature.
##STR00071##
[0243] Compounds of formula (XVII), wherein Pg is a suitable
protecting group such as --CH.sub.2-Ph, may be obtained through the
Prins reaction as reported in European J. of Org. Chemistry, (15),
3336, 2004.
[0244] Compounds of formula (Ih), i.e. compounds of formula (I)
wherein
R.sub.6.dbd.R.sub.6.dbd.R.sub.5.dbd.R.sub.4.dbd.R.sub.3.dbd.R.sub.1.dbd.H-
, may be isolated through chromatographic separation from the
corresponding regioisomers of formula (XVIII), as depicted in
Scheme 28.
##STR00072##
[0245] Compounds of formula (Ih), i.e. compounds of formula (I)
wherein
R.sub.6.dbd.R.sub.5.dbd.R.sub.4.dbd.R.sub.3.dbd.R.sub.1.dbd.H, and
compounds of formula (XVIII) may be obtained by the respective
precursors, i.e. compounds of formula (XIX) and (XXX), by reduction
for example with borane in THF at refluxing temperature, according
to Scheme 29.
##STR00073##
[0246] Compounds of formula (XIX) and (XXX) may be obtained
starting from compounds of formula (XXXI) via Beckmann
rearrangement for example using tosyl chloride in acetone from room
temperature to reflux, according to Scheme 30.
##STR00074##
[0247] Compounds of formula (XXXI) may be prepared starting from
compounds of formula (XXXII), according to Scheme 31, for example
using hydroxylamine monohydrate in ethanol at room temperature.
##STR00075##
[0248] Compounds of formula (XXXII), may be prepared starting from
compounds of formula (XXXIII), according to Scheme 32, by
rearrangement of the appropriate propargylic aldehyde after
reaction with the allylic derivative (XXXIV) where M can be
SiMe.sub.2Cl or MgBr, as described in J. Am. Chem. Soc. 2004, 126,
8654.
##STR00076##
[0249] Compounds of formula (XXXIII) may be prepared by oxidation
for example with Dess-Martin periodinane in DCM at room temperature
from the appropriate alcohol (XXXV) according to Scheme 33.
##STR00077##
[0250] Compounds of formula (XXXV) may be prepared from propargyl
alcohol and appropriate Iodo arene (XXXVI), in analogy with the
method described in JOC, 2005, 70, 4043 and according to Scheme
34.
##STR00078##
[0251] Compounds of formula (IIa.sub.1), i.e. compounds of formula
(IIa) wherein R.sub.3.dbd.R.sub.4.dbd.H, Pg is a suitable
N-protecting group (typically Boc), may be obtained starting from
compounds of formula (XXXVII) as below defined, through reduction
with borane in THF at refluxing temperature, according to Scheme
35.
##STR00079##
[0252] Compounds of formula (XXXVII), wherein
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H, may be obtained
starting from compounds (XXXVIII), wherein
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H, through reaction
with sodium hydride in DMF, at temperature from 0.degree. C. to
room temperature, for 1-3 h, according to Scheme 36.
##STR00080##
[0253] Compounds of formula (XXXVIII), wherein
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H, may be obtained
starting from compounds (XXXIX) wherein R.sub.2 is an aromatic or
heteroaromatic group,
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H, through reaction
with mesyl chloride and TEA in DCM, at temperature from 0.degree.
C. to room temperature, according to Scheme 37.
##STR00081##
[0254] Compounds of formula (XXXIX), wherein
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H, may be obtained
starting from compounds (XL) wherein
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H and Pg a silyl
protective group (e.g: 1,1-dimethylethyl)diphenylsilane), for
example by standard Pg removal with TBAF in THF followed by
reaction with ammonium hydroxide in a mixture of solvents, such as
THF and methanol, at room temperature for several hours, according
to Scheme 38
##STR00082##
[0255] Compounds of formula (XL), wherein
R.sub.3.dbd.R.sub.4.dbd.R.sub.5.dbd.R.sub.6.dbd.H and Pg a silyl
protective group (e.g: 1,1-dimethylethyl)diphenylsilane), may be
obtained by reacting compounds (XLI) with diazomalonate (prepared
as described in Synthetic Communication, 1987, 17, 1709-1716) and
rhodium (II) acetate, at 100.degree. C., in analogy with the method
reported in WO/2005/058884, according to Scheme 39.
##STR00083##
[0256] Compounds of formula (XLI), wherein Pg is a silyl protective
group (e.g: 1,1-dimethylethyl)diphenylsilane), may be obtained
starting from compounds (XLII), wherein Pg is defined as before, by
the Suzuky coupling procedure using the appropriate aryl or
heteroaryl boronic acids or boronate esters, Pd(PPh.sub.3).sub.4
and a base (e.g. Na.sub.2CO.sub.3), in a mixture of solvent (e.g.
toluene, ethanol and water) at 80.degree. C., according to Scheme
40.
##STR00084##
[0257] When Pg corresponds to the meaning defined above in Scheme
39 and 40, the corresponding compound of formula (XLII),
[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane, can
be prepared by reacting the corresponding compound of formula
(XLIII), 3-bromo-3-buten-1-ol, with
chloro(1,1-dimethylethyl)diphenylsilane and imidazole in DCM, at
room temperature, according to Scheme 41.
##STR00085##
[0258] Alternatively, compounds of formula (Im), i.e. compounds of
formula (I) as above defined wherein R.sub.1, R.sub.3, R.sub.4,
R.sub.5, R.sub.6 are hydrogen and R.sub.7 is a group X (wherein
n=1), may be obtained from compounds of formula (XLIV) wherein Pg
is a N-protecting group, typically Boc, through deprotection of
N-Pg group according to Scheme 42. For example, when Pg is Boc,
using TFA in DCM at temperature between 0.degree. C. and room
temperature.
##STR00086##
[0259] Compounds of formula (XLIV) as above defined may be obtained
starting from compounds of formula (XLV), wherein R.sub.16.dbd.H,
following standard alkylation procedures according to Scheme 43,
e.g. using a R.sub.16Y alkylating agent such as MeI in the presence
of a strong base, such as NaH, in aprotic solvent, e.g. DMF, or
THF, at temperature between 0.degree. C. and room temperature.
##STR00087##
[0260] Compounds of formula (XLV) as above defined may be obtained
from compounds of formula (XLVI) where R.sub.j is an alkyl group,
according to Scheme 44, by simultaneous reduction of amide and
ester groups with BH.sub.3 or LiAlH.sub.4 in aprotic solvent,
mainly THF, at reflux and subsequent "in situ" nitrogen protection
with a Pg group, typically Boc, for example by using Boc anhydride
under basic conditions at room temperature.
##STR00088##
[0261] Compounds of formula (XLVI) may be obtained according to
Scheme 45 from compounds of formula (XLVII) wherein R.sub.j is as
above defined and L is a suitable leaving group, by nucleophilic
displacement of the leaving group (L) e.g. mesylate, with NH.sub.3
in MeOH under pressure in a hydrogenation apparatus (for example
Parr), followed under the same conditions by intramolecular
cyclisation of the intermediate amine to amide.
##STR00089##
[0262] Compounds of formula (XLVII) as above defined, may be
obtained according to Scheme 46 from compounds of formula (XLVIII),
wherein L is as above defined, by carbene mediated cyclopropanation
with dimethyl diazopropandioate and rhodium catalyst, for example
Rh.sub.2(OAc).sub.2, in chlorinated solvent, e.g, chlorobenzene or
DCE, at temperature between 40.degree. C. and 80.degree. C. If
asymmetric rhodium catalyst is used, the reaction can be
stereospecific.
##STR00090##
[0263] Compounds of formula (XLVIII), as above defined, may be
obtained according to Scheme 47 from compounds of formula (XLIX) by
suitable oxygen functionalisation aimed to obtain a leaving group
as mesylate or tosylate e.g. using methansulfonyl chloride or tosyl
chloride in DCM under basic condition at 0.degree. C. or room
temperature.
##STR00091##
[0264] Compounds of formula (XLIX) may be obtained according to
Scheme 48 from compounds of formula (L) following the standard
Suzuky coupling procedure using suitable boronic acids,
Pd(PPh.sub.3).sub.4 and a base e.g. Na.sub.2CO.sub.3 in a mixture
of solvents e.g. toluene, ethanol and water at 80.degree. C.
##STR00092##
[0265] Alternatively, compounds of formula (Im), i.e. compounds of
formula (I) as above defined wherein R.sub.1, R.sub.3, R.sub.4,
R.sub.5, R.sub.6 are hydrogen and R.sub.7 is a group X (wherein
n=1), may be obtained from compounds of formula (LXIV), wherein
groups R.sub.2 and R.sub.16 are defined as for formula (I), through
deprotection of t-butoxycarbonyl protecting group and contemporary
double bond reduction according to Scheme 49. For example, reaction
conditions may comprise treatment with trifluoroacetic acid and
triethylsilane in toluene at room temperature. Alternative reducing
agents may be used, for example Sodium triacetoxyboronhydride or
Sodium boronhydride. Alternative solvents may also be used, for
example dichloromethane, trifluorotoluene or chlorobenzene.
##STR00093##
[0266] Compounds of formula (LXIV), as above defined, may be
obtained from compounds of formula (LI), wherein group R.sub.2 is
defined as for formula (I), through alkylation of hydroxyl group
with an alkylating agent R.sub.16Y [wherein Y is a leaving group,
an halogen or a group --OSO.sub.2R(R=aryl or alkyl group)]
according to Scheme 50. For example, reaction conditions may
comprise treatment with potassium hydroxide in DMSO at room
temperature of compound of formula (LI) and consequent addition of
R.sub.16Y. Alternative bases may be used, for example sodium
hydroxide, potassium t-butoxide, cesium hydroxide or lithium
hydroxide. Alternative solvents may also be used, for example
dichloromethane or tetrahydrofurane.
##STR00094##
[0267] Compounds of formula (LI), as above defined, may be obtained
from compounds of formula (LII), wherein group R.sub.2 and X.sub.2
are defined as for formula (I), through reduction of the esther
moiety in group X.sub.2 according to Scheme 51. For example,
reaction conditions may comprise treatment with lithium
boronhydride and EtOH in THF at room temperature. Alternative other
reducing agents may be used, for example lithium aluminiumhydride,
sodiumboronhydride or diisobuylaluminium hydride.
##STR00095##
[0268] Compounds of formula (LII), as above defined, may be
obtained from compounds of formula (LIII), wherein group R.sub.2
and X.sub.2 are defined as for formula (I), through reaction with
an appropriate base in the presence of the appropriate alkylating
agent according to Scheme 52. For example, reaction conditions may
comprise treatment with Lithium t-butoxide and CH.sub.2ICl in
N-methylpyrrolidone at low temperature (for example -20 to
+10.degree. C.). Alternative alkylating agents may be used, for
example CH.sub.2I.sub.2. Alternative solvents may be used, for
example DMF or THF. Alternative bases may be used, for example LDA
or NaH.
##STR00096##
[0269] Compounds of formula (LIV), as above defined, may be
obtained from compounds of formula (LV), wherein group X.sub.2 is
defined as for formula (I), through coupling reaction with an
appropriate boronic acid R.sub.2B(OH).sub.2, wherein R.sub.2 is as
defined for compounds of formula (I), according to Scheme 53. For
example, reaction conditions may comprise treatment with
R.sub.2B(OH).sub.2 as above defined, in the presence of
Pd(OAc).sub.2, PPh.sub.3 and diisopropylethylamine toluene and
water at a temperature ranging from room temperature to 80.degree.
C. Alternative catalysts may be used, for example
Pd(PPh.sub.3).sub.4, PdCl.sub.2(dppf).
##STR00097##
[0270] Compounds of formula (LIV), as above defined, may be
obtained from compounds of formula (LV), wherein group X.sub.2 is
defined as for formula (I), through formation of the triflate
derivative according to Scheme 54. For example, reaction conditions
may comprise treatment with triflic anhydride, in the presence of
diisopropylethylamine and in toluene at a temperature ranging from
0.degree. C. to room temperature.
##STR00098##
[0271] Compounds of formula (In), i.e. compounds of formula (I)
wherein R.sub.1, R.sub.5, R.sub.6, R.sub.3, R.sub.4 are hydrogen
and R.sub.7 is a group X wherein n is 1, may be prepared according
to Scheme 55, through the procedures below described, starting from
compound of formula (LXII):
##STR00099## ##STR00100##
[0272] Example of Reaction conditions: a=EtOH, 8 hrs, RT;
b=BOC.sub.20; K.sub.2CO.sub.3, from 0.degree. C. to RT for 48 hrs;
c=EtONa, Toluene, from 0.degree. C. to RT, overnight; d=1) NaH and
1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfony]methanesulfonamide,
DMF, 1 h; 2) toluene/EtOH; R.sub.2B(OH).sub.2, K.sub.2CO.sub.3,
Pd(Ph.sub.3P).sub.4, 80.degree. C., 1 h.; e=LiAlH.sub.4, THF from
-20.degree. C. to RT, 2 h.; f=Et.sub.2Zn, CH.sub.2I.sub.2 DCM, RT,
overnight.; g=NaH, R.sub.18I, DMF, 0.degree. C. to RT.
[0273] Compounds of formula (Io), i.e. compounds of formula (I)
wherein R.sub.1, R.sub.5, R.sub.6, R.sub.3, R.sub.4 are hydrogen
and R.sub.1 is an alkyl group, may be prepared according to Scheme
56, starting from compounds of formula (XXX) through the procedures
below described:
##STR00101##
[0274] Example of Reaction conditions: a=R.sub.1Y, NaH, DMF;
b=R.sub.17MgBr, THF, NaCNBH.sub.3.
[0275] When a specific enantiomer or diastereoisomer of a compound
of formula (I)' or salts thereof, is required, this may be obtained
for example by resolution of a corresponding enantiomeric or
diastereoisomeric mixture using conventional methods.
[0276] Thus, for example, specific enantiomers or diastereoisomers
of the compounds may be obtained from the corresponding
enantiomeric or diastereoisomeric mixture using chiral
chromatographic methods such as for example chiral HPLC (for
reference procedure see for example separation of E2a and E3a, of
E5a and E6a, of E9a and E10a, of E19a and E20a, of E26a and
E27a).
[0277] Alternatively, specific enantiomers or diastereoisomers of
the compounds may be obtained from the corresponding enantiomeric
or diastereoisomeric mixture using chiral crystallization methods
such as precipitation with chiral acids (for reference procedure
see for example E34 and E35).
[0278] Furthermore a specific enantiomer or diastereoisomer of a
compound of the invention may be synthesised from the appropriate
optically active intermediate using any of the general processes
described herein.
[0279] Alternatively, a specific enantiomer or diastereoisomer of a
compound the invention may be synthesised from the appropriate
stereochemically enriched intermediate using any of the general
processes described herein and by combining it with any of the
conventional resolution methods above described.
[0280] Optically active intermediates or stereochemically enriched
intermediates, may be generated by resolution of a corresponding
enantiomeric or diastereosiomeric mixtures using conventional
methods (for reference procedure see for example P60), or by
performance of stereoselective reactions (for reference procedure
see for example P67) or by combining different resolution
techniques.
[0281] Also specific enantiomers or diastereoisomers of the
compounds may be obtained by combining conventional methods above
described.
[0282] The compounds of the present invention are useful in the
treatment of disorders or diseases responsive to the monoamine
neurotransmitter re-uptake inhibiting activity of the compounds.
This activity of the compounds of the invention may make them
useful in the treatment of Parkinsonism, depression, eating
disorders, sleep disorders, substance related disorders,
attention-deficit hyperactivity disorders, anxiety disorders,
cognition impairment, sexual dysfunctions, obsessive compulsive
spectrum disorders, Gilles de la Tourettes disease and senile
dementia, as well as other disorders sensitive to the monoamine
neurotransmitter re-uptake-inhibiting activity of the
compounds.
[0283] Within the context of the present invention, the terms
describing some indications used herein are classified in the
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition,
published by the American Psychiatric Association (DSM-IV) and/or
the International Classification of Diseases, 10th Edition
(ICD-10). The various subtypes of the disorders mentioned herein
are contemplated as part of the present invention. Numbers in
brackets after the listed diseases below refer to the
classification code in DSM-IV.
[0284] The term "depression" includes:
[0285] Depression and mood disorders including Major Depressive
Episode, Manic Episode, Mixed Episode and Hypomanic Episode;
Depressive Disorders including Major Depressive Disorder, Dysthymic
Disorder (300.4), Depressive Disorder Not Otherwise Specified
(311); Other Mood Disorders including Mood Disorder Due to a
General Medical Condition (293.83) which includes the subtypes With
Depressive Features, With Major Depressive-like Episode, With Manic
Features and With Mixed Features), Substance-Induced Mood Disorder
(including the subtypes With Depressive Features, With Manic
Features and With Mixed Features) and Mood Disorder Not Otherwise
Specified (296.80): Bipolar Disorders including Bipolar I Disorder,
Bipolar II Disorder (Recurrent Major Depressive Episodes with
Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and
Bipolar Disorder Not Otherwise Specified (296.80);
[0286] The term "anxiety disorders" includes:
[0287] Anxiety disorders including Panic Attack; Panic Disorder
including Panic Disorder without Agoraphobia (300.01) and Panic
Disorder with Agoraphobia (300.21); Agoraphobia; Agoraphobia
Without History of Panic Disorder (300.22), Specific Phobia
(300.29, formerly Simple Phobia) including the subtypes Animal
Type, Natural Environment Type, Blood-Injection-Injury Type,
Situational Type and Other Type), Social Phobia (Social Anxiety
Disorder, 300.23), Obsessive-Compulsive Disorder (300.3),
Posttraumatic Stress Disorder (309.81), Acute Stress Disorder
(308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder
Due to a General Medical Condition (293.84), Substance-Induced
Anxiety Disorder, Separation Anxiety Disorder (309.21), Adjustment
Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise
Specified (300.00):
[0288] The term "substance related disorder" includes:
[0289] Substance-related disorders including Substance Use
Disorders such as Substance Dependence, Substance Craving and
Substance Abuse; Substance-Induced Disorders such as Substance
Intoxication, Substance Withdrawal, Substance-induced Delirium,
Substance-induced Persisting Dementia, Substance-induced Persisting
Amnestic Disorder, Substance-induced Psychotic Disorder,
Substance-Induced Mood Disorder, Substance-induced Anxiety
Disorder, Substance-Induced Sexual Dysfunction, Substance-Induced
Sleep Disorder and Hallucinogen Persisting Perception Disorder
(Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence
(303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00),
Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol
Withdrawal Delirium, Alcohol-induced Persisting Dementia,
Alcohol-Induced Persisting Amnestic Disorder, Alcohol-induced
Psychotic Disorder, Alcohol-induced Mood Disorder, Alcohol-Induced
Anxiety Disorder, Alcohol-Induced Sexual Dysfunction,
Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not
Otherwise Specified (291.9); Amphetamine (or
Amphetamine-Like)-Related Disorders such as Amphetamine Dependence
(304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication
(292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication
Delirium, Amphetamine Induced Psychotic Disorder,
Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety
Disorder, Amphetamine-induced Sexual Dysfunction,
Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder
Not Otherwise Specified (292.9); Caffeine Related Disorders such as
Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder,
Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not
Otherwise Specified (292.9); Cannabis-Related Disorders such as
Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis
Intoxication (292.89), Cannabis Intoxication Delirium,
Cannabis-induced Psychotic Disorder, Cannabis-Induced Anxiety
Disorder and Cannabis-Related Disorder Not Otherwise Specified
(292.9); Cocaine-Related Disorders such as Cocaine Dependence
(304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89),
Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,
Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,
Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual
Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related
Disorder Not Otherwise Specified (292.9); Hallucinogen-Related
Disorders such as Hallucinogen Dependence (304.50), Hallucinogen
Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen
Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen
Intoxication Delirium, Hallucinogen-induced Psychotic Disorder,
Hallucinogen-induced Mood Disorder, Hallucinogen-Induced Anxiety
Disorder and Hallucinogen-Related Disorder Not Otherwise Specified
(292.9); Inhalant-Related Disorders such as Inhalant Dependence
(304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89),
Inhalant Intoxication Delirium, Inhalant-Induced Persisting
Dementia, Inhalant-induced Psychotic Disorder, Inhalant-Induced
Mood Disorder, Inhalant-induced Anxiety Disorder and
Inhalant-Related Disorder Not Otherwise Specified (292.9);
Nicotine-Related Disorders such as Nicotine Dependence (305.1),
Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not
Otherwise Specified (292.9); Opioid-Related Disorders such as
Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid
Intoxication (292.89), Opioid Withdrawal (292.0), Opioid
Intoxication Delirium, Opioid-Induced Psychotic Disorder,
Opioid-Induced Mood Disorder, Opioid-Induced Sexual Dysfunction,
Opioid-Induced Sleep Disorder and Opioid-Related Disorder Not
Otherwise Specified (292.9); Phencyclidine (or
Phencyclidine-Like)-Related Disorders such as Phencyclidine
Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine
Intoxication (292.89), Phencyclidine Intoxication Delirium,
Phencyclidine-Induced Psychotic Disorder, Phencydidine-Induced Mood
Disorder, Phencyclidine-Induced Anxiety Disorder and
Phencyclidine-Related Disorder Not Otherwise Specified (292.9);
Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as
Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative,
Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or
Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic
Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication
Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium,
Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-,
Hypnotic-, or Anxiolytic-Persisting Amnestic Disorder, Sedative-,
Hypnotic-, or Anxiolytic-Induced Psychotic Disorder, Sedative-,
Hypnotic-, or Anxiolytic-Induced Mood Disorder, Sedative-,
Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,
Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,
Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,
Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified
(292.9); Polysubstance-Related Disorder such as Polysubstance
Dependence (304.80); and Other (or Unknown) Substance-Related
Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous
Oxide;
[0290] The term "Sleep disorder" includes:
[0291] Sleep disorders including primary sleep disorders such as
Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia
(307.44), Narcolepsy (347), Breathing-Related Sleep Disorders
(780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia
Not Otherwise Specified (307.47); primary sleep disorders such as
Parasomnias such as Nightmare Disorder (307.47), Sleep Terror
Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia
Not Otherwise Specified (307.47); Sleep Disorders Related to
Another Mental Disorder such as Insomnia Related to Another Mental
Disorder (307.42) and Hypersomnia Related to Another Mental
Disorder (307.44); Sleep Disorder Due to a General Medical
Condition; and Substance-induced Sleep Disorder including the
subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed
Type;
[0292] The term "eating disorder" include:
[0293] Eating disorders such as Anorexia Nervosa (307.1) including
the subtypes Restricting Type and Binge-Eating/Purging Type;
Bulimia Nervosa (307.51) including the subtypes Purging Type and
Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating
Disorder; and Eating Disorder Not Otherwise Specified (307.50):
[0294] The term "Attention-Deficit/Hyperactivity Disorder"
includes:
[0295] Attention-Deficit/Hyperactivity Disorder including the
subtypes Attention-Deficit/Hyperactivity Disorder Combined Type
(314.01), Attention-Deficit/Hyperactivity Disorder Predominantly
Inattentive Type (314.00), Attention-Deficit/Hyperactivity Disorder
Hyperactive-impulse Type (314.01) and
Attention-Deficit/Hyperactivity Disorder Not Otherwise Specified
(314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such
as Conduct Disorder including the subtypes childhood-onset type
(321.81), Adolescent-Onset Type (312.82) and Unspecified Onset
(312.89), Oppositional Defiant Disorder (313.81) and Disruptive
Behaviour Disorder Not Otherwise Specified; and Tic Disorders such
as Tourette's Disorder (307.23);
[0296] The term "Cognition impairment" includes:
[0297] Cognition impairment including cognition impairment in other
diseases such as schizophrenia, bipolar disorder, depression, other
psychiatric disorders and psychotic conditions associated with
cognitive impairment, e.g. Alzheimer's disease;
[0298] The term "Sexual dysfunctions" includes:
[0299] Sexual dysfunctions including Sexual Desire Disorders such
as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion
Disorder (302.79); sexual arousal disorders such as Female Sexual
Arousal Disorder (302.72) and Male Erectile Disorder (302.72);
orgasmic disorders such as Female Orgasmic Disorder (302.73), Male
Orgasmic Disorder (302.74) and Premature Ejaculation (302.75);
sexual pain disorder such as Dyspareunia (302.76) and Vaginismus
(306.51); Sexual Dysfunction Not Otherwise Specified (302.70);
paraphilias such as Exhibitionism (302.4), Fetishism (302.81),
Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism
(302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3),
Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9);
gender identity disorders such as Gender Identity Disorder in
Children (302.6) and Gender Identity Disorder in Adolescents or
Adults (302.85); and Sexual Disorder Not Otherwise Specified
(302.9);
[0300] The term "Obsessive compulsive spectrum disorder"
includes:
[0301] Obsessive compulsive spectrum disorder including Obsessive
compulsive disorders (300.3), somatoform disorders including body
dysmorphic disorder (300.7) and hyperchondriasis (300.7), bulimia
nervosa (307.51), anorexia nervosa (307.1), eating disorders not
elsewhere classified (307.50) such as binge eating, impulse control
disorders not elsewhere classified (including intermitted explosive
disorder (312.34), compulsive buying or shopping, repetitive
self-mutilation, onychophagia, psychogenic excoriation, kleptomania
(312.32), pathological gambling (312.31), trichotillomania (312.39)
and internet addiction), paraphilia (302.70) and nonparaphilic
sexual addictions, Sydeham's chorea, torticollis, autistic
disorders (299.0), compulsive hoarding, and movement disorders,
including Tourette's syndrome (307.23).
[0302] All of the various forms and sub-forms of the disorders
mentioned herein are contemplated as part of the present
invention.
[0303] In an embodiment, compounds of the invention may be useful
as analgesics. For example they may be useful in the treatment of
chronic inflammatory pain (e.g. pain associated with rheumatoid
arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis
and juvenile arthritis); musculoskeletal pain; lower back and neck
pain; sprains and strains; neuropathic pain; sympathetically
maintained pain; myositis; pain associated with cancer and
fibromyalgia; pain associated with migraine; pain associated with
influenza or other viral infections, such as the common cold;
rheumatic fever; pain associated with functional bowel disorders
such as non-ulcer dyspepsia, non-cardiac chest pain and irritable
bowel syndrome; pain associated with myocardial ischemia; post
operative pain; headache; toothache; and dysmenorrhea.
[0304] Compounds of the invention may be useful in the treatment of
neuropathic pain. Neuropathic pain syndromes can develop following
neuronal injury and the resulting pain may persist for months or
years, even after the original injury has healed. Neuronal injury
may occur in the peripheral nerves, dorsal roots, spinal cord or
certain regions in the brain. Neuropathic pain syndromes are
traditionally classified according to the disease or event that
precipitated them. Neuropathic pain syndromes include: diabetic
neuropathy; sciatica; non-specific lower back pain; multiple
sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic
neuralgia; trigeminal neuralgia; and pain resulting from physical
trauma, amputation, cancer, toxins or chronic inflammatory
conditions. These conditions are difficult to treat and although
several drugs are known to have limited efficacy, complete pain
control is rarely achieved. The symptoms of neuropathic pain are
incredibly heterogeneous and are often described as spontaneous
shooting and lancinating pain, or ongoing, burning pain. In
addition, there is pain associated with normally non-painful
sensations such as "pins and needles" (paraesthesias and
dysesthesias), increased sensitivity to touch (hyperesthesia),
painful sensation following innocuous stimulation (dynamic, static
or thermal allodynia), increased sensitivity to noxious stimuli
(thermal, cold, mechanical hyperalgesia), continuing pain sensation
after removal of the stimulation (hyperpathia) or an absence of or
deficit in selective sensory pathways (hypoalgesia).
[0305] Compounds of the invention may also be useful in the
amelioration of inflammatory disorders, for example in the
treatment of skin conditions (e.g. sunburn, burns, eczema,
dermatitis, psoriasis); ophthalmic diseases such as glaucoma,
retinitis, retinopathies, uveitis and of acute injury to the eye
tissue (e.g. conjunctivitis); lung disorders (e.g. asthma,
bronchitis, emphysema, allergic rhinitis, respiratory distress
syndrome, pigeon fancier's disease, farmer's lung, chronic
obstructive pulmonary disease, (COPD); gastrointestinal tract
disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis,
gastritis varialoforme, ulcerative colitis, coeliac disease,
regional ileitis, irritable bowel syndrome, inflammatory bowel
disease, gastroesophageal reflux disease); other conditions with an
inflammatory component such as migraine, multiple sclerosis,
myocardial ischemia.
[0306] In one embodiment, compounds of the invention are useful in
the treatment of depression and anxiety disorders.
[0307] In another embodiment, compounds of the invention are useful
in the treatment of depression.
[0308] "Treatment" includes prophylaxis, where this is appropriate
for the relevant condition(s).
[0309] In an alternative or further aspect there is provided a
method for the treatment of a mammal, including man, in particular
in the treatment of disorders or diseases responsive to the
monoamine neurotransmitter re-uptake inhibiting activity of the
compounds, comprising administration of an effective amount of a
compound of the invention.
[0310] In one embodiment, the invention provides a method of
treating a condition for which inhibition of serotonin (5-HT),
dopamine (DA) and norepinephrine (NE), is beneficial, which
comprises administering to a mammal (e.g. human) in need thereof an
effective amount of a compound of the invention.
[0311] In another embodiment, the invention provides a method of
treating a condition for which inhibition of serotonin (5-HT),
dopamine (DA) and norepinephrine (NE), is beneficial, which
comprises administering to a mammal (e.g. human) in need thereof an
effective amount of
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane or a pharmaceutically acceptable salt thereof.
[0312] In a further embodiment, the invention provides a method of
treating depression which comprises administering to a mammal (e.g.
human) in need thereof an effective amount of
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane or a pharmaceutically acceptable salt thereof.
[0313] In another embodiment, the invention provides a method of
treating a condition for which inhibition of serotonin (5-HT),
dopamine (DA) and norepinephrine (NE), is beneficial, which
comprises administering to a mammal (e.g. human) in need thereof an
effective amount of (1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e or a pharmaceutically acceptable salt thereof.
[0314] In another aspect, the invention provides a compound of the
invention for use in therapy.
[0315] In a further embodiment, the invention provides a compound
of the invention for use in the treatment of a condition in a
mammal for which inhibition of serotonin (5-HT), dopamine (DA) and
norepinephrine (NE) is beneficial.
[0316] In one aspect, the invention provides the use of compounds
of the invention, for the manufacture of a medicament for the
treatment of disorders or diseases responsive to monoamine
neurotransmitter re-uptake inhibiting activity.
[0317] In one embodiment, the invention provides the use of a
compound of a compound of the invention in the manufacture of a
medicament for the treatment of a condition in a mammal for which
inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine
(NE) is beneficial.
[0318] In a further embodiment, the invention provides the use of
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of a condition in a
mammal for which inhibition of serotonin (5-HT), dopamine (DA) and
norepinephrine (NE) is beneficial.
[0319] In another embodiment, the invention provides the use of
(1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of a condition in a
mammal for which inhibition of serotonin (5-HT), dopamine (DA) and
norepinephrine (NE) is beneficial.
[0320] The compounds of the invention may also be used in
combination with other therapeutic agents. The invention thus
provides, in a further aspect, a combination comprising a compound
of the invention together with a further therapeutic agent.
[0321] The compounds of the invention may be used in combination
with the following agents to treat or prevent psychotic disorders:
i) antipsychotics; ii) drugs for extrapyramidal side effects, for
example anticholinergics (such as benztropine, biperiden,
procyclidine and trihexyphenidyl), antihistamines (such as
diphenhydramine) and dopaminergics (such as amantadine); iii)
antidepressants; iv) anxiolytics; and v) cognitive enhancers for
example cholinesterase inhibitors (such as tacrine, donepezil,
rivastigmine and galantamine).
[0322] The compounds of the invention may be used in combination
with antidepressants to treat or prevent depression and mood
disorders.
[0323] The compounds of the invention may be used in combination
with the following agents to treat or prevent bipolar disease: i)
mood stabilisers; ii) antipsychotics; and iii) antidepressants.
[0324] The compounds of the invention may be used in combination
with the following agents to treat or prevent anxiety disorders: i)
anxiolytics; and ii) antidepressants.
[0325] The compounds of the invention may be used in combination
with the following agents to improve nicotine withdrawal and reduce
nicotine craving: i) nicotine replacement therapy for example a
sublingual formulation of nicotine beta-cyclodextrin and nicotine
patches; and ii) bupropion.
[0326] The compounds of the invention may be used in combination
with the following agents to improve alcohol withdrawal and reduce
alcohol craving: i) NMDA receptor antagonists for example
acamprosate; ii) GABA receptor agonists for example tetrabamate;
and iii) Opioid receptor antagonists for example naltrexone.
[0327] The compounds of the invention may be used in combination
with the following agents to improve opiate withdrawal and reduce
opiate craving: i) opioid mu receptor agonist/opioid kappa receptor
antagonist for example buprenorphine; ii) opioid receptor
antagonists for example naltrexone; and iii) vasodilatory
antihypertensives for example lofexidine.
[0328] The compounds of the invention may be used in combination
with the following agents to treat or prevent sleeping disorders:
i) benzodiazepines for example temazepam, lormetazepam, estazolam
and triazolam; ii) non-benzodiazepine hypnotics for example
zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for
example aprobarbital, butabarbital, pentobarbital, secobarbita and
phenobarbital; iv) antidepressants; v) other sedative-hypnotics for
example chloral hydrate and chlormethiazole.
[0329] The compounds of the invention may be used in combination
with the following agents to treat anorexia: i) appetite stimulants
for example cyproheptidine; ii) antidepressants; iii)
antipsychotics; iv) zinc; and v) premenstral agents for example
pyridoxine and progesterones.
[0330] The compounds of the invention may be used in combination
with the following agents to treat or prevent bulimia: i)
antidepressants; ii) opioid receptor antagonists; iii) antiemetics
for example ondansetron; iv) testosterone receptor antagonists for
example flutamide; v) mood stabilisers; vi) zinc; and vii)
premenstral agents.
[0331] The compounds of the invention may be used in combination
with the following agents to treat or prevent autism: i)
antipsychotics; ii) antidepressants; iii) anxiolytics; and iv)
stimulants for example methylphenidate, amphetamine formulations
and pemoline.
[0332] The compounds of the invention may be used in combination
with the following agents to treat or prevent ADHD: i) stimulants
for example methylphenidate, amphetamine formulations and pemoline;
and ii) non-stimulants for example norepinephrine reuptake
inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists
(such as clonidine), antidepressants, modafinil, and cholinesterase
inhibitors (such as galantamine and donezepil).
[0333] The compounds of the invention may be used in combination
with the following agents to treat personality disorders: i)
antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv)
anxiolytics.
[0334] The compounds of the invention may be used in combination
with the following agents to treat or prevent male sexual
dysfunction: i) phosphodiesterase V inhibitors, for example
vardenafil and sildenafil; ii) dopamine agonists/dopamine transport
inhibitors for example apomorphine and buproprion; iii) alpha
adrenoceptor antagonists for example phentolamine; iv)
prostaglandin agonists for example alprostadil; v) testosterone
agonists such as testosterone; vi) serotonin transport inhibitors
for example serotonin reuptake inhibitors; v) noradrenaline
transport inhibitors for example reboxetine and vii) 5-HT1A
agonists, for example flibanserine.
[0335] The compounds of the invention may be used in combination
with the same agents specified for male sexual dysfunction to treat
or prevent female sexual dysfunction, and in addition an estrogen
agonist such as estradiol.
[0336] Antipsychotic drugs include Typical Antipsychotics (for
example chlorpromazine, thioridazine, mesoridazine, fluphenazine,
perphenazine, prochlorperazine, trifluoperazine, thiothixine,
haloperidol, molindone and loxapine); and Atypical Antipsychotics
(for example clozapine, olanzapine, risperidone, quetiapine,
aripirazole, ziprasidone and amisulpride).
[0337] Antidepressant drugs include serotonin reuptake inhibitors
(such as citalopram, escitalopram, fluoxetine, paroxetine and
sertraline); dual serotonin/noradrenaline reuptake inhibitors (such
as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake
inhibitors (such as reboxetine); tricyclic antidepressants (such as
amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline
and trimipramine); monoamine oxidase inhibitors (such as
isocarboxazide, moclobemide, phenelzine and tranylcypromine); and
others (such as bupropion, mianserin, mirtazapine, nefazodone and
trazodone).
[0338] Mood stabiliser drugs include lithium, sodium
valproate/valproic acid/divalproex, carbamazepine, lamotrigine,
gabapentin, topiramate and tiagabine.
[0339] Anxiolytics include benzodiazepines such as alprazolam and
lorazepam.
[0340] For use in medicine, the compounds of the present invention
are usually administered as a standard pharmaceutical composition.
The present invention therefore provides in a further aspect a
pharmaceutical composition comprising a compound of the invention
and a pharmaceutically (i.e physiologically) acceptable carrier.
The pharmaceutical composition can be for use in the treatment of
any of the conditions described herein.
[0341] In one embodiment, a pharmaceutical composition comprising
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier is provided.
[0342] The compounds of the invention may be administered by any
convenient method, for example by oral, parenteral (e.g.
intravenous), buccal, sublingual, nasal, rectal or transdermal
administration and the pharmaceutical compositions adapted
accordingly.
[0343] The compounds of the invention which are active when given
orally can be formulated as liquids or solids, for example syrups,
suspensions or emulsions, tablets, capsules and lozenges.
[0344] A liquid formulation will generally consist of a suspension
or solution of the compound or salt in a suitable liquid carrier(s)
for example an aqueous solvent such as water, ethanol or glycerine,
or a non-aqueous solvent, such as polyethylene glycol or an oil.
The formulation may also contain a suspending agent, preservative,
flavouring or colouring agent.
[0345] A composition in the form of a tablet can be prepared using
any suitable pharmaceutical carrier(s) routinely used for preparing
solid formulations. Examples of such carriers include magnesium
stearate, starch, lactose, sucrose and cellulose.
[0346] A composition in the form of a capsule can be prepared using
routine encapsulation procedures. For example, pellets containing
the active ingredient can be prepared using standard carriers and
then filled into a hard gelatin capsule; alternatively, a
dispersion or suspension can be prepared using any suitable
pharmaceutical carrier(s), for example aqueous gums, celluloses,
silicates or oils and the dispersion or suspension then filled into
a soft gelatin capsule.
[0347] Typical parenteral compositions consist of a solution or
suspension of the compound or salt in a sterile aqueous carrier or
parenterally acceptable oil, for example polyethylene glycol,
polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
Alternatively, the solution can be lyophilised and then
reconstituted with a suitable solvent just prior to
administration.
[0348] Compositions for nasal administration may conveniently be
formulated as aerosols, drops, gels and powders. Aerosol
formulations typically comprise a solution or fine suspension of
the active substance in a pharmaceutically acceptable aqueous or
non-aqueous solvent and are usually presented in single or
multidose quantities in sterile form in a sealed container, which
can take the form of a cartridge or refill for use with an
atomising device. Alternatively the sealed container may be a
unitary dispensing device such as a single dose nasal inhaler or an
aerosol dispenser fitted with a metering valve which is intended
for disposal once the contents of the container have been
exhausted. Where the dosage form comprises an aerosol dispenser, it
will contain a propellant which can be a compressed gas such as
compressed air or an organic propellant such as a
fluoro-chlorohydrocarbon. The aerosol dosage forms can also take
the form of a pump-atomiser.
[0349] Compositions suitable for buccal or sublingual
administration include tablets, lozenges and pastilles, wherein the
active ingredient is formulated with a carrier such as sugar and
acacia, tragacanth, or gelatin and glycerin.
[0350] Compositions for rectal administration are conveniently in
the form of suppositories containing a conventional suppository
base such as cocoa butter.
[0351] Compositions suitable for transdermal administration include
ointments, gels and patches.
[0352] In one embodiment, the composition is in unit dose form such
as a tablet, capsule or ampoule.
[0353] Each dosage unit for oral administration contains for
example from 0.5 to 250 mg (and for parenteral administration
contains for example from 0.05 to 25 mg) of a compound of the
invention calculated as the free base.
[0354] The pharmaceutically acceptable compounds of the invention
will normally be administered in a daily dosage regimen (for an
adult patient) of, for example, an oral dose of between 1 mg and
500 mg, for example between 1 mg and 400 mg, e.g. between 10 and
250 mg or an intravenous, subcutaneous, or intramuscular dose of
between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg,
e.g. between 1 and 25 mg of the compound of the formula (I) or a
salt thereof calculated as the free base, the compound being
administered 1 to 4 times per day, for example 1 to 2 time a day.
In one embodiment, the compound of the invention may be
administered once a day. Suitably the compounds will be
administered for a period of continuous therapy, for example for a
week or more.
[0355] For oral administration a typical dose may be in the range
of 1 to 200 mg per day, for example 60 to 200 mg per day.
[0356] When a compound of the invention or a pharmaceutically
acceptable derivative thereof is used in combination with a second
therapeutic agent active against the same disease state the dose of
each compound may differ from that when the compound is used alone.
Appropriate doses will be readily appreciated by those skilled in
the art. It will be appreciated that the amount of a compound of
the invention required for use in treatment will vary with the
nature of the condition being treated and the age and the condition
of the patient and will be ultimately at the discretion of the
attendant physician or veterinarian.
[0357] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above together with a pharmaceutically acceptable carrier
or excipient comprise a further aspect of the invention. The
individual components of such combinations may be administered
either sequentially or simultaneously in separate or combined
pharmaceutical formulations by any convenient route.
[0358] The invention is also directed to a novel kit-of-parts that
is suitable for use in the treatment of disorders as above defined
comprising a first dosage form comprising a compound of the
invention and a second dosage form comprising another therapeutic
agent, for simultaneous, separate or sequential administration.
[0359] When administration is sequential, either the compound of
the invention or the second therapeutic agent may be administered
first. When administration is simultaneous, the combination may be
administered either in the same or different pharmaceutical
composition.
[0360] When combined in the same formulation it will be appreciated
that the two compounds must be stable and compatible with each
other and the other components of the formulation. When formulated
separately they may be provided in any convenient formulation,
conveniently in such manner as are known for such compounds in the
art.
Biological Assays
Cell Biology
[0361] a) Generation of Stable LLCPK Cell Lines Expressing hSERT,
hNET, and hDAT
[0362] Stable cell line expressing human serotonin transporter
(hSERT) may be created by transfecting Lewis Lung Carcinoma Porcine
tubule Kidney (LLC-PK1 or LLCPK) cells with hSERT cloned into the
mammalian expression vector pcDNA3.1 Hygro(+).
[0363] Stable cell line expressing human norepinephrine transporter
(hNET) may be created by transfecting LLCPK cells with hNET cloned
into the mammalian expression vector pRC/CMV.
[0364] Stable cell line expressing human dopamine transporter
(hDAT) may be created by transfecting LLCPK cells with hDAT cloned
into the mammalian expression vector pDESTCDNA3.1.
[0365] One example of reference procedure for transfecting LLCPK
cells with hDAT, hSERT and hNET may be found in H. Gu, S. C. Wall
and G. Rudnick, J. Biol. Chem. (1994) 269 7124-7130.
[0366] Each cell line is cultured independently in Dulbecco's
modified Eagle's medium (DMEM) containing 10% of Foetal Bovine
Serum (FBS) supplemented with 400 .mu.g/ml hygromycin (hSERT) or
geneticin at 500 .mu.g/ml (hNET) or at 1000 .mu.g/ml (hDAT). Cells
are maintained at 37.degree. C. in a humidified environment
containing 5% CO.sub.2 in air.
b) Generation of BacMam Viruses for the Expression of hSERT, hNET,
and hDAT in Mammalian Cells
[0367] Membranes for the SPA-binding assays are produced by
HEK-293F cell infection with BacMam viruses generated for each
single human SERT, NET, and DAT transporter. hSERT and hDAT are
cloned into pFBMRfA vector whereas hNET is cloned into pFASTBacMam1
vector. The generation and use of BacMam viruses is described in
Condreay J P et al, Proc. Natl. Acad. Sci. USA, 1999, 96:127-132
and Hassan N J et al, Protein Expression and Purification, 47(2):
591-598, 2006.
Affinity to the Human Transporters SERT, NET and DAT
[0368] The affinities of the compounds of the invention for the
human serotonin transporter (SERT), human norepinephrine
transporter (NET) and for the human dopamine transporter (DAT) may
be determined by one of the assays described below. Such affinity
is typically calculated from the IC.sub.50 obtained in competition
experiments as the concentration of a compound necessary to
displace 50% of the radiolabeled ligand from the transporter, and
is reported as a "K.sub.i" value calculated by the following
equation:
K i = IC 50 1 + L / K D ##EQU00001##
where L=radioligand and K.sub.D=affinity of radioligand for
transporter (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).
In the context of the present invention pKi values (corresponding
to the antilogarithm of Ki) are used instead of Ki; pKi results are
only estimated to be accurate to about 0.3-0.5. a) Filtration
Binding Assay on Membranes Form hSERT, hNET, and hDAT LLCPK Cell
Lines
[0369] Membrane Preparation
[0370] hSERT-LLCPK or hDAT-LLCPK or hNET-LLCPK cell lines are used
for the membrane preparations for radioligand binding assays. Each
cell line is cultured independently in Dulbecco's modified Eagle's
medium (DMEM) containing 10% of Foetal Bovine Serum (FBS)
supplemented with 400 .mu.g/ml hygromycin (hSERT) or geneticin at
500 .mu.g/ml (hNET) or at 1000 .mu.g/ml (hDAT). When cells are at
70-80% of confluence, the culture medium is removed and the cells
harvested with phosphate buffered saline (PBS) containing 5 mM
EDTA. Cell suspension is centrifuged at 900 g for 5 minutes at
4.degree. C. The resultant pellets are re-suspended in 30-50
volumes of Assay Buffer (50 mM Tris pH 7.7 containing 120 mM NaCl,
5 mM KCl, 10 .mu.M pargyline and 0.1% ascorbic acid) and
homogenized using a glass-teflon Potter homogeniser and centrifuged
at 48000 g for 20 minutes at 4.degree. C. The resultant membrane
pellets are re-suspended in the same volume of Assay Buffer,
incubated for 20 minutes at 37.degree. C. and centrifuged as before
at 48000 g. The final protein concentration for each preparation is
adjusted to give approximately 480 .mu.g protein/ml for
hSERT-LLCPK, hDAT-LLCPK and hNET-LLCPK, as determined by the
Bio-Rad Protein Assay kit. Membranes are stored at -80.degree. C.
as 1 ml aliquots until required.
[0371] Filtration Assay Protocol for hSERT, hNET, and hDAT
[0372] General references for monoamine transporters filtration
binding assay may be: Michael J. Owens, et al, Neurotransmitter
receptor and transporter binding profile of antidepressants and
their metabolites, JPET, 283:1305-1322, 1997; Per Allard, Jan O.
Marcusson, Svate B. Ross, [3H]WIN-35,428 binding in the human
brain, Brain Res., 706: 347-350, 1996.
[0373] The affinity of the compounds of the invention to bind the
re-uptake site of SERT may be assessed using [.sup.3H]citalopram
filtration binding assay performed on hSERT-LLCPK cell membranes.
In details, competition binding assay is conducted in deep-well 96
well plate (1 ml, NUNC, cod.260252) in a total volume of 400 .mu.l,
with each concentration in duplicate, 4 .mu.l of test compound
(100.times. solution in neat DMSO as 7 point curve ranging from
10.sup.-6 to 10.sup.-12M, final concentration) or DMSO (to define
total binding) or a final concentration of 10 .mu.M fluoxetine in
DMSO (to define non-specific binding, NSB) are added to wells;
after this, 200 .mu.l of [N-Methyl-3H]citalopram (Amersham
Biosciences, 80 Ci/mmol) at the final concentration of 0.25 nM in
Assay Buffer, is added to all wells and finally the reaction is
started by adding 200 .mu.l/well of membranes diluted 1:80 in Assay
Buffer at concentration of about 2.5 .mu.g/well of protein. The
reaction is carried out at room temperature for 2 hours and then
stopped by rapid filtration through GF/B Unifilter 96-filterplate
(Perkin-Elmer) pre-soaked in 0.5% polyethylenimine (PEI) using a
Perkin-Elmer FilterMat-196 harvester. Filterplate is washed 3 times
with 1 ml/well ice-cold 0.9% NaCl solution. The plate is dried in
an oven for 60 min at 50.degree. C. then opaque bottom-seal is
placed on the underside of the plate and 50 .mu.l of Microscint 20
(Perkin-Elmer) added to each well. Plate is sealed with a TopSeal
and the radioactivity in the samples is counted for 4 min using
TopCount liquid scintillation counter (Packard-Perkin-Elmer) and
recorded as counts per minute (CPM).
[0374] Competition binding assay for hNET may be conducted
essentially as previously reported for hSERT in 96 well format and
in a final assay volume of 400 .mu.l, except for the use of
hNET-LLCPK cell membranes (1:40 dilution i.e. 4.8 .mu.g of
protein/well) and [.sup.3H]nisoxetine as radioligand (1.5 nM
[N-methyl-3H]nisoxetine, Amersham Biosciences, 84 Ci/mmol). 10
.mu.M desipramine is used for NSB.
[0375] Competition binding assay for hDAT may be conducted
essentially as previously reported for hSERT and hNET in 96 well
format and in a final assay volume of 400 .mu.l, except for the use
of hDAT-LLCPK cell membranes (1:20 i.e. 9.6 .mu.g of protein/well)
and [.sup.3H]WIN-35,428 as radioligand (10 nM
[N-Methyl-3H]WIN-35,428, Perkin Elmer, 85.6 Ci/mmol).
[0376] Furthermore, 10 .mu.M GBR-12909 is used for NSB and the
incubation time of the binding reaction is 1 hour at room
temperature.
b) Scintillation Proximity Assay (SPA) for Human DAT, NET and SERT
Binding
[0377] Transduction of HEK-293F Cells with hSERT/hDAT/hNET BacMam
Viruses
[0378] The HEK-293F suspension cell line (Invitrogen) is routinely
grown in 293_Freestyle Expression media (Invitrogen) in shake flask
suspension culture. The culture is transduced with the appropriate
transporter BacMam at a MOI (multiplicity of infection) of 100
virus particles per cell and incubated for 48 hrs at 37.degree. C.,
5% CO.sub.2 in air, shaken at 90 rpm in a humidified shaker
incubator. The culture is then harvested by centrifugation at 1000
g, 4.degree. C., for 10 minutes and the cell pellet stored at
-80.degree. C. until required.
Preparation of BacMam hSERT/hDAT/hNET-HEL293F Cell Membranes
[0379] Transduced cell pellets are re-suspended to 10.times. volume
with buffer-A (50 mM HEPES, 1 mM EDTA, 1 mM leupeptin, 25 ug/mL
bacitracin, 1 mM phenylmethylsulfonylfluoride, PMSF, 2 .mu.M
pepstatin A, pH 7.7) and homogenised with 2.times.15 second bursts
in a glass Waring blender. The homogenate is then centrifuged for
20 minutes at 500 g. Following this, the supernatant is pooled and
centrifuged at 13,000 g for 30 minutes. Pellets are then
re-suspended to 4.times. original pellet volume with buffer-B (50
mM TRIS pH 7.4, 130 mM NaCl) and forced through a 0.8 mm needle to
give a homogeneous suspension. Membrane aliquots are stored at
-80.degree. C. until required. The protein concentration is
quantified by Bradford assay.
[0380] SPA-Binding Assay Protocol for hSERT, hNET, and hDAT
[0381] The affinity of the compounds of the invention to the hSERT,
hNET or hDAT can be also assessed by using the [.sup.3H]citalopram,
[.sup.3H]nisoxetine or [.sup.3H]WIN-35,428 binding assays with the
SPA technology on BacMam-recombinant human SERT, NET and DAT
membranes produced as described before. With the SPA technology (GE
Healthcare, Amersham) only transporter-bound radioactivity can
elicit bead excitation thus no separation of the bound/unbound
radioligand is required.
[0382] The protocol for hSERT binding SPA is based on Trilux
beta-counter (Wallac, Perkin-Elmer). Briefly, 0.5 .mu.L of test
compound in neat DMSO (or 1 .mu.M fluoxetine as positive control)
is added by 50 .mu.L of the SPA mixture, containing 2 mg/mL SPA
beads (Amersham RPNQ0001), 4 .mu.g/mL hSERT Bacmam membranes, 0.01%
pluronic F-127, 2.5 nM [.sup.3H]citalopram in the assay buffer (20
mM HEPES, 145 mM NaCl, 5 mM KCl, pH 7.3). Incubation are performed
at room temperature for at least 2 hours. Counts are stable and
could be read up to 3 days.
[0383] Alternatively, hDAT hNET and hSERT SPA-binding assays are
performed by using a Viewlux beta-counter (Wallac, Perkin-Elmer)
with imaging PS-WGA beads (Amersham RPNQ0260) in a final assay
volume of 30 .mu.L and in a 384-well plate format (Greiner 781075).
Briefly, 0.3 .mu.L of test compound in neat DMSO and 0% and 100%
effect controls (DMSO for total binding and 10 or 1 .mu.M
indatraline as positive control) are added to the wells by using a
Hummingbird (Genomic Solutions), followed by the addition of 30
.mu.L of the SPA mixture, containing 1 mg/mL SPA beads (hSERT) or 2
mg/ml SPA beads (hDAT and hNET), 40 .mu.g/ml or 20 .mu.g/ml or 6
.mu.g/ml of hDAT or hNET or hSERT BacMam membranes, 0.02% pluronic
F-127, 10 nM [.sup.3H]WIN-35,428 or 10 nM [.sup.3H]nisoxetine or 3
nM [.sup.3H]citalopram for hDAT or hNET or hSERT binding SPA in the
assay buffer (20 mM HEPES, 145 mM NaCl, 5 mM KCl, pH 7.3-7.4).
Incubation is performed at room temperature for at least 2 hours,
best overnight in the dark. Bound radioactivity is recorded by
using a 600 s 6.times. binning and 613 nm emission filter with the
Viewlux instrument.
Compound Affinity Range for Human Transporters SERT, NET, and
DAT
[0384] The compounds of formula (I)' typically show pKi greater
than 4.5 towards each of the three transporters SERT, NET and DAT.
In one embodiment, the compounds of formula (I) typically show pKi
greater than 5.5 for each of the three transporters. In another
embodiment, the compounds of formula (I)' typically show pKi
greater than 6.5 for each of the three transporters. In a further
embodiment, the compounds of formula (I)' typically show pKi
greater than 7.5 for each of the three transporters.
[0385] In one embodiment, the present invention provides compounds
of formula (I)' having a hSERT pKi comprised between 7 and 8.5. In
another embodiment, the present invention provides compounds of
formula (I)' having a hSERT pKi comprised between 8.5 and 10.
[0386] In one embodiment, the present invention provides compounds
of formula (I) having a hDAT pKi comprised between 6.5 and 7.5. In
another embodiment, the present invention provides compounds of
formula (I)' having a hDAT pKi comprised between 7.5 and 8.5.
[0387] In one embodiment, the present invention provides compounds
of formula (I)' having a hNET pKi comprised between 6.5 and 7.5. In
another embodiment, the present invention provides compounds of
formula (I)' having a hNET pKi comprised between 7.5 and 8.5.
[0388] In one embodiment, the present invention provides compounds
of formula (I)' having a a hSERT pKi comprised between 8.5 and 10,
a hNET pKi comprised between 7.5 and 8.5 and a hDAT pKi comprised
between 7.5 and 8.5.
[0389] In one embodiment, the present invention provides compounds
of formula (I)' having a hSERT pKi comprised between 9 and 10, a
hNET pKi comprised between 8.0 and 8.5 and a hDAT pKi comprised
between 7.5 and 8.0.
EXAMPLES
[0390] The invention is further illustrated by the following
non-limiting examples.
[0391] In the procedures that follow, after each starting material,
reference to a Preparation or Example by number is typically
provided. This is provided merely for assistance to the skilled
chemist. The starting material may not necessarily have been
prepared from the batch referred to.
[0392] Where reference is made to the use of a "similar" or
"analogous" procedure, as will be appreciated by those skilled in
the art, such a procedure may involve minor variation, for example
reaction temperature, reagent/solvent amount, reaction time,
work-up conditions or chromatographic purification conditions.
[0393] Compounds are named using ACD/Name PRO 6.02 chemical naming
software (Advanced Chemistry Development Inc., Toronto, Ontario,
M5H2L3, Canada).
[0394] All temperatures refer to .degree. C.
[0395] Proton Magnetic Resonance (NMR) spectra are typically
recorded either on Varian instruments at 300, 400 or 500 MHz, or on
a Bruker instrument at 300 and 400 MHz. Chemical shifts are
reported in ppm (d) using the residual solvent line as internal
standard. Splitting patterns are designed as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR
spectra were recorded at a temperature ranging from 25 to
90.degree. C. When more than one conformer was detected the
chemical shifts for the most abundant one is reported.
[0396] Mass spectra (MS) are typically taken on a 4 II triple
quadrupole Mass Spectrometer (Micromass UK) or on a Agilent MSD
1100 Mass Spectrometer, operating in ES (+) and ES (-) ionization
mode or on an Agilent LC/MSD 1100 Mass Spectrometer, operating in
ES (+) and ES (-) ionization mode coupled with HPLC instrument
Agilent 1100 Series. In the mass spectra only one peak in the
molecular ion cluster is reported.
[0397] When HPLC walk-up retention time is reported, the analysis
is done on a HPLC Agilent 1100 Series Instrument with the following
method: Column: Luna C18 100 A 50.times.2 mm, 3 micron; Mobile
Phase: (MeCN+0.05% TFA)/(H2O+0.05% TFA) gradient 0/100 to 95/5 in 8
minutes; Flux 1 ml/min.
[0398] Flash silica gel chromatography was carried out on silica
gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over
Varian Mega Be--Si pre-packed cartridges or over pre-packed Biotage
silica cartridges.
[0399] In a number of preparations, purification was performed
using either Biotage manual flash chromatography (Flash+) or
automatic flash chromatography (Horizon or SP1) systems. All these
instruments work with Biotage Silica cartridges.
[0400] X-Ray Powder Diffraction (XRPD): It will be recognised that
spectra and diffraction data will vary slightly according to
various factors such as the temperature, concentration and
instrumentation used. The skilled person will recognise that XRPD
peak positions are affected by differences in sample height. The
peak positions quoted herein are thus subject to a variation. The
skilled person will also recognise that the relative intensities of
peaks may change due to preferred orientation effects.
[0401] Differential Scanning Calorimetry (DSC): It should be
recognized that the endotherm peak as measured is dependent under a
number of factors including the machine employed, the rate of
heating, the calibration standard, humidity and the purity of the
sample used. Melting points reported in the experimentals are
estimated on the basis of the onset of endotherm peaks registered
during DSC analysis.
[0402] The following abbreviations are used in the text:
TBAF=tetrabutylammonium fluoride, DCE=dichloroethane, Tic refers to
thin layer chromatography on silica plates, and dried refers to a
solution dried over anhydrous sodium sulphate, r.t. (RT) refers to
room temperature, Rt=retention time, DMSO=dimethyl sulfoxide;
DCM=dichloromethane; DMF=N,N'-dimethylformamide; MeOH=methanol; TEA
or Et.sub.3N=triethylamine; THF=tetrahydrofurane; EA, AcOEt or
EtOAc=ethyl acetate; cy=cyclohexane; EtOH=ethyl alcohol;
ZnEt.sub.2=diethylzinc; MTBE=methyl t-butyl ether;
TFA=trifluoroacetic acid; Et.sub.2O=diethyl ether; IPA=isopropyl
alcohol; DMPU=1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone;
SPE Cartridge=Solid Phase Extraction Cartridge; SCX
Cartridge=Strong
[0403] Cation Exchange Cartridge; MCX: mixed mode-cation exchange
cartridge; NH column: secondary amine functionalised silica
cartridge.
Preparation 1: 1-(1,1-dimethylethyl) 3-methyl
4-hydroxy-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P1)
##STR00102##
[0405] To a stirred solution of methyl
4-oxo-3-piperidinecarboxylate hydrochloride (14.94 g) in dry DCM
(250 mL), at 0.degree. C. and under a nitrogen atmosphere, TEA (43
mL) was added dropwise over 5 minutes. The mixture was stirred at
0.degree. C. for 5 minutes, then allowed to reach room temperature,
bis(1,1-dimethylethyl) dicarbonate (18.6 g) was then added in one
portion and the solution was left stirring overnight at room
temperature under Nitrogen. Saturated aqueous NH.sub.4Cl solution
(350 ml) was poured into the solution and the mixture was
transferred in a separator funnel. The reaction flask was washed
with DCM (100 ml) and this volume was poured into the separator
funnel. The phases were separated and the watery one was washed
with DCM (3.times.70 mL). The combined organic phases were dried on
anhydrous Na.sub.2SO.sub.4, the solvent removed under reduced
pressure, the crude product purified by flash-chromatography
(eluting with ethyl acetate/cyclohexane 1:3) to give the title
compound (19.8 g.).
[0406] NMR (.sup.1H, CDCl.sub.3): .delta. 11.95-12.02 (m, 1H) 4.07
(br. s., 2H) 3.77-3.82 (m, 3H) 3.58 (t, 2H) 2.34-2.43 (m, 2H)
1.46-1.50 (m, 9H)
Preparation 2: 1-(1,1-dimethylethyl) 3-methyl
4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (P2)
##STR00103##
[0408] Method A: to a stirred solution of 1-(1,1-dimethylethyl)
3-methyl 4-oxo-1,3-piperidine-dicarboxylate (500 mg, P1) in dry DMF
(5 mL) at 0.degree. C. and under a nitrogen atmosphere, NaH (60% on
mineral oil, 117 mg) was added portionwise and the reaction mixture
was stirred at 0.degree. C. for 10 minutes, then a solution of
N-phenyl-bis(trifluoromethanesulfonimide) (0.847 g) in dry DMF (2
mL) was added dropwise and stirring was continued for 0.5 h.
Saturated NH.sub.4Cl (30 mL) and diethyl ether (30 mL) were poured
into the reaction mixture, the phases were separated and the watery
one was washed with diethyl ether (3.times.15 mL). The combined
organic phases were dried on anhydrous Na.sub.2SO.sub.4 and the
solvent was removed under reduced pressure to give 1.5 g. of the
crude title compound.
[0409] Method B: to a stirred solution of 1-(1,1-dimethylethyl)
3-methyl 4-oxo-1,3-piperidinedicarboxylate (500 mg, P1) in dry THF
(12 mL) at 0.degree. C. and under a nitrogen atmosphere, NaH (60%
on mineral oil, 156 mg) was added portionwise and the reaction
mixture was stirred at 0.degree. C. for 30 minutes, then
N-phenyl-bis(trifluoromethanesulfonimide) (1.028 g) was added in
one portion and stirring was continued at 0.degree. C. for 1 hour
and at rt overnight. 10 g of ice were poured into the stirred
mixture and THF was evaporated at rt under reduced pressure. The
residue was taken up with ethyl acetate (30 mL) and the mixture was
washed with aqueous Na.sub.2CO.sub.3 (10%, 3.times.20 mL). The
organic layer was dried on anhydrous Na.sub.2SO.sub.4 and the
solvent was removed under reduced pressure, obtaining 1.7 g. of the
crude title compound.
[0410] The crude products from Method A and B were combined and
purified by flash-chromatography (eluting with ethyl
acetate/cycloexane 1:9) to give 1.340 g. of the title compound.
[0411] NMR (.sup.1H, CDCl.sub.3): .delta. 4.29 (br. s., 2H)
3.82-3.87 (m, 3H) 3.64 (t, 2H) 2.50-2.57 (m, 2H) 1.46-1.52 (m, 9H).
MS (m/z): 390 [MH]+, 412 [MNa]+.
Preparation 3: 1-(1,1-dimethylethyl) 3-methyl
4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P3)
##STR00104##
[0413] To a mixture of 1-(1,1-dimethylethyl) 3-methyl
4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (200 mg, P2), 3,4-dichlorophenylboronic acid (108 mg) and
Pd(PPh.sub.3).sub.4 (21 mg) under nitrogen, toluene (2.5 mL),
ethanol (2 mL) and Na.sub.2CO.sub.3 (aqueous 2M solution, 2 mL)
were added in sequence. The mixture was stirred at 80.degree. C.
for 1 hour then the reaction mixture was allowed to reach room
temperature. Saturated aqueous NH.sub.4Cl solution (15 mL) was
poured into the solution and the mixture was transferred in a
separator funnel. The mixture was extracted with ethyl acetate
(3.times.20 mL), the combined organic phases were dried on
anhydrous Na.sub.2SO.sub.4 and the solvent evaporated obtaining a
crude product that was purified by flash-chromatography (eluting
with ethyl acetate/cycloexane 1:3) to give the title compound (198
mg).
[0414] NMR (.sup.1H, CDCl.sub.3): .delta. 7.42 (d, 1H) 7.25 (d, 1H)
6.98 (dd, 1H) 4.26 (br. s., 2H) 3.61 (t, 2H) 3.55-3.58 (m, 3H) 2.47
(br. s., 2H) 1.50-1.54 (m, 9H)
Preparation 4:
1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(-
2H)-pyridinecarboxylate (P4)
##STR00105##
[0416] To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl
4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(538 mg, P3,) in dry diethyl ether (10 mL) under N.sub.2
atmosphere, at -20.degree. C., LiAlH.sub.4 (1M in diethyl ether, 1
mL) was added dropwise over 1 minute, the reaction mixture was left
stirring at -20.degree. for 15 minutes then aqueous saturated
NH.sub.4Cl solution (50 mL) and diethyl ether (50 mL) were poured
into the solution and the mixture was vigorously stirred for 20
minutes at room temperature. The phases were separated, and the
watery one was extracted with diethyl ether (3.times.20 mL). The
combined organic phases were dried on anhydrous Na.sub.2SO.sub.4
and the solvent was removed under reduced pressure, obtaining a
crude product that was purified by flash-chromatography (eluting
with ethyl acetate/cycloexane 1:3) to give the title compound (474
mg).
[0417] NMR (.sup.1H, DMSO-d6): .delta. 7.62 (d, 1H) 7.56 (d, 1H)
7.26 (dd, 1H) 4.90 (t, 1H) 4.02 (br. s., 2H) 3.79 (d, 2H) 3.49 (t,
2H) 2.35 (br. s., 2H) 1.42-1.46 (m, 9H)
Preparation 5:
(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)--
3-azabicyclo[4.1.0]heptane-3-carboxylate (P5)
##STR00106##
[0418] Method A:
[0419] To a stirred solution of CH.sub.2I.sub.2 (13.39 g) in dry
DCM (83 mL) under Argon atmosphere, at 0.degree. C., ZnEt.sub.2 (1M
in hexane, 25 mL) was added dropwise, the mixture was stirred at
0.degree. C. for 20 minutes and then cooled at -20.degree. C. At
this point a solution of
1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(-
2H)-pyridine-carboxylate (734 mg, P4) in dry DCM (3.5 mL) was added
dropwise, the reaction mixture was stirred for additional 30 mins,
then 40 mins at 0.degree. C. and overnight at room temperature.
Saturated aqueous NH.sub.4Cl solution (100 mL) was poured into the
reaction flask and the mixture was vigorously stirred for 10
minutes, the phases were separated and the organic layer was
evaporated under reduced pressure. The residue was taken up with
diethyl ether (50 mL) and this volume was added to the previous
NH.sub.4Cl solution: the total mixture was poured into a separator
funnel. The organic phase was treated with saturated NH.sub.4Cl
(3.times.20 mL), then with HCl (5%) (20 mL), the organic and
aqueous acidic phases were separated and submitted to two different
processing.
[0420] The organic phase was evaporated obtaining a crude product
(280 mg) that was purified by flash-chromatography (eluting with
ethyl acetate/cycloexane 1:3) to give the still impure title
compound (70 mg).
[0421] The watery phase was washed with diethyl ether (50 mL) and
strongly basified with NaOH 2N, then the basic solution was
extracted with diethyl ether (3.times.50 mL), the combined organic
phases were dried on anhydrous Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure, obtaining a crude material (210 mg)
containing as major component
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-
-yl]methanol)].
[0422] MS (m/z): 272 [MH].sup.+.
[0423] A portion of this crude material (159 mg) was dissolved in
dry DCM (5 mL) under Argon atmosphere and stirred at rt,
bis(1,1-dimethylethyl) dicarbonate (156 mg) was added at room
temperature and the mixture was left stirring overnight. The
solvent was evaporated under reduced pressure and the residue was
taken up with diethyl ether (15 mL). This solution was washed with
saturated NH.sub.4Cl (15 mL), the watery phase was extracted with
diethyl ether (3.times.10 mL), the combined organic phases were
dried on anhydrous Na.sub.2SO.sub.4 and the solvent was removed
under reduced pressure obtaining a crude product that was combined
with the previously obtained 70 mg of the impure title compound.
This material was again purified by flash-chromatography (eluting
with diethyl ether/n-hexane 1:2 to 1:1) to give a still impure
title compound as a mixture with
1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(-
2H)-pyridinecarboxylate (170 mg).
[0424] MS (m/z): 372 [MH].sup.+.
[0425] Method B: bis(1,1-dimethylethyl) dicarbonate (838 mg) was
added at room temperature to a solution of
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methan-
ol (840 mg, E4, impure compound obtained as described in E4, Method
A) in dry DCM (25 mL), and the mixture was stirred overnight. The
mixture was heated at 40.degree. C. for 2 hours and then cooled at
room temperature. Saturated NH.sub.4Cl (50 mL) and DCM (20 mL) were
added to the reaction mixture and, after stirring for 10 mins, the
phases were separated. The organic phase was evaporated and the
residue was dissolved in diethyl ether (50 mL). The organic phase
was washed with saturated NH.sub.4Cl (3.times.30 mL), was dried on
anhydrous Na.sub.2SO.sub.4 and the solvent was removed under
reduced pressure. The crude oil (920 mg) obtained was purified by
flash-chromatography (eluting with ethyl acetate/cyclohexane 1:3)
to give an impure title compound as a mixture with
1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(-
2H)-pyridine-carboxylate (260 mg) and impure 1,1-dimethylethyl
(1R,6S)-6-(3,4-dichlorophenyl)-1-[({[(1,1-dimethylethyl)oxy]carbonyl}oxy)-
methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (185 mg) [MS
(m/z): 472 [MH].sup.+].
[0426] 1,1-dimethylethyl
(1R,6S)-6-(3,4-dichlorophenyl)-1-[{[(1,1-dimethylethyl)oxy]carbonyl}oxy)m-
ethyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate was dissolved in
MeOH (7 mL) under argon and the stirred solution was cooled at
0.degree.. NaOH (0.5 M, 3 mL) was added dropwise and the mixture
was stirred for 20 mins at 0.degree. C., 30 mins at 50.degree. C.
and 1.5 hours at 70.degree. C. MeOH was evaporated under reduced
pressure, the watery residue was diluted with water (20 mL) and
extracted with diethyl ether (3.times.20 mL). The combined organic
phases were dried on anhydrous Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure to give another batch of the still
impure title compound as a mixture with
1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(-
2H)-pyridinecarboxylate (130 mg).
[0427] MS (m/z): 372 [MH].sup.+.
[0428] Method C: to a stirred solution of methyl
6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate
(P16, 0.19 g) in THF (3 mL), at 0.degree. C. and under a nitrogen
atmosphere, BH.sub.3THF complex (1M/THF, 2.38 mL) was added
dropwise, then the reaction mixture was allowed to reach RT and
stirred at reflux for 4 h. The reaction mixture was cooled to
0.degree. C. and the pH was adjusted to 2-3 with aqueous 20% HCl
solution, then the ice-bath was removed and the mixture was stirred
at RT for 15 min. DCM was added and the pH was brought to 8-9 with
aqueous 2N NaOH solution. The organic phase was washed with brine,
dried over Na.sub.2SO.sub.4 and the solvent evaporated under
reduced pressure. The crude product was dissolved in DCM,
Boc.sub.2O (0.136 g) was added and the reaction mixture stirred for
1 h at RT. The reaction was extracted with ether, the organic phase
washed with aqueous saturated NaHCO3 solution, brine, dried over
Na2SO4 and the solvent removed under reduced pressure to give 0.195
g of the crude Title compound as a colourless oil that was used
without any further purification.
Preparation 6:
(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-[(methyloxy)meth-
yl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (P6)
##STR00107##
[0430] To a stirred solution of (1S,6R/1R,6S)-1,1-dimethylethyl
6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-car-
boxylate (110 mg, P5, impure compound obtained as described in P5,
Method A) in dry THF (2 mL) under Argon atmosphere, at 0.degree.
C., NaH (60% on mineral oil, 11.7 mg) was added in one portion and
the stirring continued for 30 minutes. After this period CH.sub.3I
(18.2 .mu.L) was added dropwise and the reaction was allowed to
reach room temperature and stirred for 1.5 h, then an additional
amounts of NaH (5.3 mg) and CH.sub.3I (8.3 .mu.L) were added. The
reaction mixture was left stirring for 2 hour at room temperature,
then was cooled to 0.degree. C., aqueous saturated NH.sub.4Cl
solution (15 mL) and diethyl ether (20 mL) were added and the
mixture was vigorously stirred for 10 minutes at room temperature.
The phases were separated and the watery one was extracted with
diethyl ether (3.times.10 mL). The combined organic phases were
washed with brine (3.times.20 mL), dried on anhydrous
Na.sub.2SO.sub.4, the solvent evaporated obtaining a crude product
(106 mg) that was purified by flash-chromatography (eluting with
diethyl ether/n-hexane 40:60) to give the still impure titled
compound as a mixture with 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-5-[(methyloxy)methyl]-3,6-dihydro-1(2H)-pyridineca-
rboxylate (80 mg).
[0431] MS (m/z): 386 [MH].sup.+
Preparation 7: 3-(3,4-dichlorophenyl)-2-propyn-1-ol (P7)
##STR00108##
[0433] Method A: The title compound (2.94 g) was prepared in
analogy with the method described in JOC 2005, 70, 4043-4053
starting from 3,4-dichloroiodobenzene (4 g, two preparation were
carried out).
[0434] Method B: a mixture of 3,4-dichloroiodobenzene (300 mg),
propargyl alcohol (128 .mu.L), CuI (10 mg), K.sub.2CO.sub.3 (302
mg), Pd(PPh.sub.3).sub.4 (12 mg) in DMF (2 mL) was irradiated with
MicroWave at 100.degree. C. for 20 min. Aqueous saturated solution
NH.sub.4Cl was then added followed by DCM. After separation of the
two phases the organic layer was dried and evaporated in vacuo. The
crude product was purified by flash chromatography (eluting with
cyclohexane/ethyl acetate 7/3) to give the title compound (40
mg).
[0435] NMR (.sup.1H, CDCl.sub.3): .delta. 7.58 (s, 1H), 7.41 (d,
1H), 7.27 (d, 1H), 4.52 (d, 2H), 1.75 (t, 1H)
Preparation 8: 3-(3,4-dichlorophenyl)-2-propynal (P8)
##STR00109##
[0437] To a solution of 3-(3,4-dichlorophenyl)-2-propyn-1-ol (2.980
g, P7, from Method A and B described for P7) in dry DCM (74 mL) and
Dess-Martin periodinane (9.43 g) was added. The mixture was stirred
at room temperature over night. NaS.sub.2O.sub.3 (19 g) and
NaHCO.sub.3 saturated solution were then added to the mixture and
it was stirred at room temperature for 1 hour. Then the organic
phase was separated and washed with brine. The organic layer was
dried and concentrated under reduced pressure to give the crude
title product (2.9 g) that was used without further
purification.
[0438] NMR (.sup.1H, CDCl.sub.3): .delta. 9.48 (s, 1H), 7.73 (s,
1H), 7.55 (d, 1H), 7.42 (m, 1H).
Preparation 9:
(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one
(P9)
##STR00110##
[0440] The title compound was prepared in analogy with the method
described in J. Am. Chem. Soc. 2004, 126, 8654 from
3-(3,4-dichlorophenyl)-2-propynal (2.9 g, P8) in 880 mg yield as an
orange foam.
[0441] NMR (.sup.1H, CDCl.sub.3): .delta. 7.45 (d, 1H), 7.28 (s,
1H), 7.11 (d, 1H), 2.89 (m, 2H), 2.70 (d, 1H), 2.42 (d, 1H), 2.05
(m, 1H), 1.38 (m, 1H), 0.72 (m, 1H).
Preparation 10:
(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one oxime
(P10)
##STR00111##
[0443] To a solution of hydroxylamine mono hydrate (1.26 g) and
sodium acetate (2.3 g) in water (7 mL), a solution of
(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one
(0.860 g, P9) in ethanol (18 ml) was added at room temperature and
the reaction mixture was stirred over night. After ethanol
elimination under reduced pressure, the aqueous solution was
extracted with DCM. The organic phase was dried and concentrated
under reduced pressure to give the title compound (870 mg).
[0444] NMR (.sup.1H, CDCl.sub.3): .delta. 7.40 (d, 1H), 7.26 (m,
1H), 7.05 (m, 1H), 3.33-2.60 (m, 4H), 1.89 (m, 1H), 1.15 (m, 1H),
0.68 (m, 1H). MS (m/z): 256 [MH]+.
Preparation 11:
(1R,6R/1S,6S)-1-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one
and
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one
(P11)
##STR00112##
[0446] To a solution of
(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one oxime
(0.870 g, P10) in acetone (29 ml) sodium carbonate (solution 5% w/w
in water, 25 ml) was added. Then, under vigorous stirring, a
solution of tosyl chloride (969 mg) in acetone was added and the
mixture stirred at room temperature for 30 minutes. The reaction
mixture was heated at reflux for 4 h and at room temperature over
night. After acetone elimination under reduced pressure, the
residue was dissolved in NaHCO.sub.3 saturated solution and it was
extracted with DCM. The organic phase was dried and concentrated
under reduced pressure. The crude was purified by flash
chromatography (DCM/MeOH from 98/2 to 95/5) to give 640 mg of the
mixture of title compounds.
[0447] MS (m/z): 256 [MH]+.
Preparation 12:
[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane
(P12)
##STR00113##
[0449] The title compound was prepared in 8.7 g yield as a
colourless oil, following an analogous procedure to that reported
in WO2005058884, starting from 3-bromo-3-buten-1-ol (4 g),
chloro(1,1-dimethylethyl)diphenylsilane (8.27 ml), imidazole (2.34
g) and N,N-dimethyl-4-pyridinamine (0.025 g).
Preparation 13:
{[3-(3,4-dichlorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsila-
ne (P13)
##STR00114##
[0451] [(3-Bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane
(P12, 3.50 g) and (3,4-dichlorophenyl)boronic acid (2.06 g) were
dissolved in toluene (45 mL), the stirred solution was degassed,
then tetrakis(triphenylphosphine)palladium(0) (0.363 g) and ethanol
(33 mL) were added and the mixture was degassed again. A 2N aqueous
solution of Na.sub.2CO.sub.3 (24 mL) was added and the mixture was
heated to 80.degree. C. and stirred under nitrogen atmosphere for 3
h at this temperature. After cooling to RT, the reaction mixture
was extracted with ethyl ether, the organic phase was washed with
brine, dried over Na.sub.2SO.sub.4 and the solvent removed under
reduced pressure. The crude product was purified by flash
chromatography (eluting with cy/EA from 100/0 to 95/5) to give the
title compound (2.65 g) as a colourless oil.
[0452] NMR (.sup.1H, CDCl.sub.3): .delta. 7.55-7.69 (m, 4H),
7.40-7.47 (m, 3H), 7.34-7.40 (m, 4H), 7.32 (d, 1H), 7.11 (dd, 1H),
5.25 (dd, 2H), 3.75 (t, 2H), 2.28-3.12 (m, 2H), 0.62-1.26 (m,
9H).
Preparation 14: dimethyl
2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethy-
l)-1,1-cyclopropanedicarboxylate (P14)
##STR00115##
[0454]
{[3-(3,4-Dichlorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphen-
ylsilane (P13, 2.25 g), dimethyl diazopropanedioate (1.2 g)
(prepared in an analogous manner as reported in Synthetic
Communications, 17(4), 1709-16, 1987) and rodhium (II) acetate
dimer (0.060 g) were mixed together and heated at 100.degree. C.
for 40 min. After cooling, the residue was treated with DCM and the
mixture was filtered. The filtrate was evaporated under reduced
pressure and the crude product was purified by flash chromatography
(Cy/EA from 1/0 to 95/5) to give the title compound (2.38 g) as a
colourless oil.
[0455] NMR (.sup.1H, CDCl.sub.3): .delta. 7.51-7.61 (m, 4H),
7.25-7.47 (m, 8H), 7.05 (dd, 1H) 3.83 (s, 3H), 3.45 (s, 3H),
3.30-3.62 (m, 2H), 2.00-2.29 (m, 2H), 1.83 (d, 1H), 1.57 (s, 1H),
0.94-1.13 (m, 9H).
Preparation 15: methyl
1-(aminocarbonyl)-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)cyclopropaneca-
rboxylate (P15)
##STR00116##
[0457] Tetrabutylammonium fluoride (TBAF) (5.6 mL, 1.1 M/TFH) was
added dropwise to a stirred solution of dimethyl
2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethy-
l)-1,1-cyclopropanedicarboxylate (P14, 2.38 g) in THF (27 mL), at
0.degree. C. After 4 h the ice-bath was removed and the reaction
mixture was stirred for 3 h at RT. The solvent was removed under
reduced pressure, the residue was treated with ether and water, the
organic phase washed with brine, dried over Na.sub.2SO.sub.4 and
the solvent evaporated under vacuum to give the crude lactone
intermediate (2.08 g). This product was dissolved in a mixture of
THF (15 mL) and methanol (10 mL), at RT, aqueous NH.sub.4OH (28%,
16 mL) was added dropwise and the reaction mixture was stirred for
4 h. The mixture was concentrated under reduced pressure, the
residue was taken up with DCM and water, the organic phase was
washed with brine, dried over Na.sub.2SO.sub.4 and the solvent
evaporated under vacuum. The crude product was purified by FC
(eluting with DCM/methanol from 1/0 to 9/1) to give the title
compound (0.89 g) as a white foam.
[0458] NMR (.sup.1H, CDCl.sub.3): .delta. 8.14 (br. s., 1H), 7.60
(dd, 1H), 7.41-7.50 (m, 2H), 5.79 (br. s., 1H), 3.47-3.59 (m, 2H),
3.13-3.15 (m, 3H), 2.29-2.33 (m, 1H), 2.23-2.26 (m, 1H), 2.04-2.22
(m, 2H).
Preparation 16: methyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-c-
arboxylate (P16)
##STR00117##
[0460] a stirred solution of methyl
1-(aminocarbonyl)-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)cyclopropaneca-
rboxylate (P15, 0.46 g) in DCM (6 mL), at 0.degree. C.,
triethylamine (0.25 mL) was added followed by methanesulfonyl
chloride (0.16 mL). The ice-bath was removed and the reaction
mixture was stirred at RT for 3 h. The mixture was extracted with
further DCM, the organic phase washed with saturated NH.sub.4Cl,
brine, dried over Na.sub.2SO.sub.4 and the solvent evaporated under
reduced pressure to give 0.54 g of the intermediate mesylate as a
white foam. To a stirred solution of this product in DMF (6 mL), at
RT, NaI (0.22 g) was added followed by NaH (60% in oil, 63 mg)
portionwise, and the reaction mixture was stirred for 0.5 h. The
reaction mixture was extracted with ether and NH.sub.4Cl solution,
the organic phase washed with water, brine, dried over
Na.sub.2SO.sub.4 and the solvent evaporated under vacuum. The crude
product was purified by FC (eluting with cy/EA from 9/1 to 1/9) to
give the Title product (0.19 g).
[0461] NMR (.sup.1H, CDCl.sub.3): .delta. 7.45 (d, 1H) 7.39 (d, 1H)
7.19 (dd, 1H) 5.79 (br. s., 1H) 3.52 (s, 3H) 3.29-3.38 (m, 1H)
3.20-3.28 (m, 1H) 2.37 (td, 1H) 2.29 (d, 1H) 2.12-2.17 (m, 1H) 1.97
(d, 1H). MS (m/z): 314 [MH].sup.+.
Preparation 18: ethyl 3-{[3-(ethyloxy)-3-oxopropyl]amino}butanoate
(P18)
##STR00118##
[0463] A solution of ethyl 3-aminobutanoate (4.2 g) and of ethyl
2-propenoate (3.83 mL) in EtOH (20 mL) was stirred at room
temperature for 8 h. The solvent was evaporated under reduced
pressure and the residue purified by chromatography on NH column
eluting with a gradient from 100% cyclohexane to 90% ethyl
acetate/cyclohexane. The title compound was isolated as a
colourless oil, 3.9 g (MS (m/z): 232 [MH].sup.+.
Preparation 19: ethyl
3-{{[(1,1-dimethylethyl)oxy]carbonyl}[3-(ethyloxy)-3-oxopropyl]amino}buta-
noate (P19)
##STR00119##
[0465] A mixture containing ethyl
3-{[3-(ethyloxy)-3-oxopropyl]amino}butanoate (P18, 3.5 g),
1,4-dioxane (8.1 mL), water (16.2 mL) and a 5% solution of
potassium carbonate (8.4 mL) was cooled with an ice-bath.
Di-tert-butyl dicarbonate (3.51 mL) was added slowly with stirring.
The stirring was maintained for 15 min and then continued at room
temperature for 3 h. The mixture was left at room temperature for
48 hours. After concentration under reduced pressure, the residue
was extracted with diethyl ether (2.times.200 mL). The ethereal
phase was washed first with 1N HCl, then with water (20 mL) and
finally dried. Evaporation of the solvents afforded a crude
material (4.6 g) which was then used without further
purification.
[0466] NMR (.sup.1H, CDCl.sub.3): .delta. 4.08-4.20 (m, 4H),
3.64-3.72 (m, 1H), 3.32-3.53 (m, 2H), 2.39-2.74 (m, 4H), 1.43-1.52
(m, 9H), 1.19-1.33 (m, 9H)
Preparation 20:1-(1,1-dimethylethyl) 3-ethyl
4-hydroxy-6-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate and
1-(1,1-dimethylethyl) 3-ethyl
4-hydroxy-2-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P20)
##STR00120##
[0468] Ethyl
3-{{[(1,1-dimethylethyl)oxy]carbonyl}[3-(ethyloxy)-3-oxopropyl]amino}buta-
noate (P19, 2.5 g) was dissolved in toluene (15 mL) and added at
0.degree. C. to a solution of sodium ethoxide preformed by adding
slowly and portionwise sodium hydride 60% dispersed on mineral oil
(0.453 g) to a solution of ethanol (0.7 mL) in toluene (5 mL). The
mixture was stirred at room temperature overnight. Then the solvent
was evaporated under reduced pressure and the residue dissolved in
ethyl acetate (20 mL), washed with 1N HCl (20 mL), dried and
concentrated under vacuum. Purification by flash chromatography on
silica gel eluting with a gradient 5-50% ethyl acetate/cyclohexane
afforded the title compounds as pale yellow oil (0.7 g) as mixture
of regioisomers.
[0469] MS (m/z): 230 [M-56].sup.+, 186 [MH-100].sup.+.
Preparation 21: 1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-6-methyl-5,6-dihydro-1,3(2H-pyridinedicarboxylate
and 1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-2-methyl-5,6-dihydro-1,3(2M-pyridinedicarboxylate
(P21)
##STR00121##
[0471] To a stirred solution of a mixture of regioisomers
1-(1,1-dimethylethyl) 3-ethyl
6-methyl-4-oxo-1,3-piperidinedicarboxylate and
1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-2-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P20, 0.7 g) in dry DMF (6 mL) at 0.degree. C. under nitrogen,
sodium hydride 60% dispersed on mineral oil (0.118 g) was added
portionwise and the reaction mixture was stirred at 0.degree. C.
for 10 min. Then a solution of
1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide
(0.88 g) in dry DMF (1 mL) was added dropwise and stirring was
continued for 1 h. Saturated NH.sub.4Cl (10 mL) and diethyl ether
(30 mL) were poured into the reaction mixture. The organic phase
was separated, dried and concentrated under vacuum. The residue was
then purified by chromatography on silica gel eluting with a
gradient 5-50% ethyl acetate/cyclohexane.
[0472] The isolated material (MS (m/z): 440 [M+Na].sup.+, 362
[MH-56].sup.+), (0.65 g) was dissolved in a mixture toluene (15 mL)
and ethanol (11 mL); (3,4-dichlorophenyl)boronic acid (0.357 g) and
sodium carbonate 2.0M solution (4.7 mL) were added and the
suspension was degassed with a steam of nitrogen for few minutes.
Then Pd(Ph.sub.3P).sub.4 (0.045 g) was added and the reaction
mixture was heated to 80.degree. C. for 1 h. Then it was cooled to
room temperature, the solvent was evaporated under reduced pressure
and the residue partitioned between ethyl acetate (50 mL) and water
(50 mL). The organic layer was washed with brine (20 mL), dried and
concentrated. Purification by chromatography on silica gel eluting
with a gradient 5-25% ethyl acetatecyclohexane afforded the title
compounds as a mixture of regioisomers as pale yellow oil (0.45
g).
[0473] MS (m/z): 437 [M+Na].sup.+.
Preparation 22: 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2-methyl-3,6-dihydro-1(2H)-pyrid-
inecarboxylate (P22)
##STR00122##
[0475] A mixture of regioisomers 1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-6-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
and 1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-2-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P21, 0.45 g) was dissolved in toluene (15 mL) and cooled to
-20.degree. C. Lithium aluminium hydride 1.0M in THF (0.869 mL) was
added dropwise at -20.degree. C. and the mixture was stirred at
this temperature for 2 h. The reaction was then quenched with a
saturated solution of NH.sub.4Cl (10 mL) and diluted with ethyl
acetate (20 mL); the organic layer was separated, washed with water
(20 mL), dried and concentrated in vacuo. Purification by
chromatography on silica gel eluting with a gradient 100%
cyclohexane-50% cyclohexane/ethyl acetate afforded 240 mg of title
compound as colourless oil. The structure of the major regioisomer
was confirmed by nOe NMR experiments.
[0476] NMR (.sup.1H, CDCl.sub.3): .delta. 7.42 (d, 1H), 7.28 (d,
1H), 7.03 (dd, 1H), 4.52-4.63 (m, 1H), 4.44-4.45 (m, 1H), 3.97-4.09
(m, 2H), 3.69-3.79 (m, 1H), 2.69-2.81 (m, 1H), 2.00-2.08 (m, 1H),
1.47-1.54 (m, 9H), 1.38-1.43 (m, 1H), 1.19 (d, 3H).
Preparation 23:
({3-[4-chloro-3-(trifluoromethyl)phenyl]-3-buten-1-yl}oxy)(1,1-dimethylet-
hyl)diphenylsilane (P23)
##STR00123##
[0478] The title compound (1.85 g) was obtained starting from
[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (P12,
1.0 g) according to a similar procedure to that previously
described for Preparation 13.
[0479] NMR (.sup.1H, CDCl.sub.3): .delta. 7.17-7.22 (m, 1H),
7.08-7.15 (m, 4H), 6.83-6.98 (m, 7H), 6.77-6.80 (m, 1H), 4.87-4.91
(m, 1H), 4.69-4.74 (m, 1H), 3.22-3.30 (m, 2H), 2.22-2.29 (m, 2H),
0.50-0.56 (m, 9H).
Preparation 24:
dimethyl-2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-{[(1,1-dimethylethyl-
)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (P24)
##STR00124##
[0481] The title compound (1.92 g) was obtained as a colourless oil
starting from
({3-[4-chloro-3-(trifluoromethyl)phenyl]-3-buten-1-yl}oxy)(1,1-dimethylet-
hyl)diphenylsilane (P23, 1.85 g) according to a similar procedure
to that previously described for Preparation 14.
[0482] NMR (.sup.1H, CDCl.sub.3): .delta. 7.50-7.62 (m, 5H),
7.29-7.46 (m, 8H), 3.82-3.85 (m, 3H), 3.50-3.59 (m, 1H), 3.36-3.44
(m, 4H), 2.17-2.26 (m, 2H), 1.85-1.89 (m, 1H), 1.59-1.72 (m, 1H),
1.01-1.08 (m, 9H)
Preparation 25:
methyl-1-(aminocarbonyl)-2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-hydr-
oxyethyl)cyclopropanecarboxylate (P25)
##STR00125##
[0484] The title compound (0.64 g) was obtained as a white solid
after crystallization from DCM/5% hexane) by reacting dimethyl
2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-{[(1,1-dimethylethyl)(dipheny-
l)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (P24, 1.92 g) with
TBAF 1.1M in THF (4.7 mL) in THF 20 mL and then treating the crude
intermediate with NH.sub.4OH 28% (14 mL) in a mixture THF (10
mL)/MeOH (7 mL), according to a similar procedure to that
previously described for Preparation 15.
[0485] NMR (.sup.1H, CDCl.sub.3): .delta. 8.18 (br. s., 1H),
7.59-7.61 (m, 1H), 7.46-7.48 (m, 1H), 7.44-7.46 (m, 1H), 5.79 (br.
s., 1H), 3.48-3.58 (m, 2H), 3.14-3.15 (m, 3H), 2.30-2.33 (m, 1H),
2.23-2.26 (m, 1H), 2.05-2.22 (m, 2H)
Preparation 26: methyl
(1R,6S/1S,6R)-6-[4-chloro-3,4-trifluoromethyl)phenyl]-2oxo-3-azabicyclo[4-
.1.0]heptane-1-carboxylate (P26)
##STR00126##
[0487] The title compound (0.35 g) was obtained reacting methyl
1-(aminocarbonyl)-2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-hydroxyethy-
l)cyclopropanecarboxylate (P25, 0.64 g) with Et.sub.3N (0.37 mL)
and trifluoromethane sulfonyl chloride (0.19 mL) in DCM (10 mL) and
then treating the intermediate with sodium hydride 60% dispersed on
mineral oil (84 mg) in DMF (5 mL), according to a similar procedure
to that previously described for Preparation 16, Method A.
[0488] NMR (.sup.1H, CDCl.sub.3): .delta. 7.64-7.73 (m, 1H),
7.45-7.48 (m, 2H), 6.83 (br. s., 1H), 3.47-3.50 (m, 3H), 3.32-3.41
(m, 1H), 3.19-3.28 (m, 1H), 2.26-2.42 (m, 2H), 2.11-2.19 (m, 1H),
2.00-2.04 (m, 1H).
Preparation 27: 1,1-dimethylethyl
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3--
azabicyclo[4.1.0]heptane-3-carboxylate (P27)
##STR00127##
[0490] To a stirred solution of
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3-azabicyclo[4-
.1.0]heptane-1-carboxylate (P26, 0.35 g) in THF (8 mL), at
0.degree. C. and under a nitrogen atmosphere, BH.sub.3THF complex
(1M/THF, 4.03 mL) was added dropwise, then the reaction mixture was
allowed to reach RT and stirred at reflux for 4 h. The reaction
mixture was cooled to 0.degree. C. and the pH was adjusted to 2-3
with aqueous 20% HCl, then the ice-bath was removed and the mixture
was stirred at RT for 15 min. DCM was added and the pH was brought
to 8-9 with 2N NaOH. The organic phase was separated, dried over
Na.sub.2SO.sub.4 and the solvent evaporated under reduced pressure.
The crude product thus obtained (310 mg) was treated with
di-tert-butyl dicarbonate (220 mg) in DCM (10 mL) at at 0.degree.
C. and stirred under these conditions for 1 hour. Then NH.sub.4Cl
was added, the organic phase was separated and washed with
NaHCO.sub.3, brine, dried and evaporated under reduced pressure to
give a crude. This was the purified by flash chromathography
eluting with AcOEt/Cy 1:9 to 1:1 to afford the title compound (300
mg).
[0491] MS (m/z): 406 [MH].sup.+, 350 [MH-56].sup.+.
Preparation 28: 1-(1,1-dimethylethyl) 3-methyl
4-oxo-1,3-piperidinedicarboxylate (P28)
##STR00128##
[0493] To an ice cooled suspension of methyl
4-oxo-3-piperidinecarboxylate hydrochloride (15.01 g) in
dichloromethane (250 mL) was added bis(1,1-dimethylethyl)
dicarbonate (17.76 g), then triethylamine (27 mL) was added
dropwise. The resulting mixture was allowed to reach room
temperature and stirred for 4 h. Saturated NH.sub.4Cl was poured
into the reaction mixture and the phases were separated, the
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated under reduced pressure. Diethylether was added to the
residue and filtered over a celite pad. The solvent was removed
under reduced pressure to obtain the title compound (16.96 g).
[0494] MS (m/z): 258 [MH].sup.+, 202 [MH-56].sup.+.
Preparation 29: 1-(1,1-dimethylethyl) 3-methyl
4-(4-chlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P29)
##STR00129##
[0496] To an ice cooled solution of 1-(1,1-dimethylethyl) 3-methyl
4-oxo-1,3-piperidinedicarboxylate (P28, 8.5 g) in
N,N-dimethylformamide (85 mL), sodium hydride 60% in mineral oil
(1.46 g) was added and the resulting mixture was stirred for 10 min
at 0.degree. C. To the mixture was added a solution of
1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide
(12.39 g) in N,N-dimethylformamide (62 mL) and the resulting
mixture was allowed to room temperature and stirred for 1 h.
Diethylether and saturated NH.sub.4Cl were added. The aqueous layer
was washed with diethylether, and then the collected organic layers
were washed with water. The organic phase was dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The crude was purified by flash-chromatography (eluting with
cyclohexane/ethylacetate from 1/0 to 9/1) to obtain
1-(1,1-dimethylethyl) 3-methyl
4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (7.73 g). To a solution of this compound (3 g) and
(4-chlorophenyl)boronic acid (1.38 g) in toluene (41 mL), a
solution of Pd(PPh.sub.3).sub.4 (0.32 g) in ethanol (30 mL) was
added followed by Na.sub.2CO.sub.3 (2M, 22.5 mL) and the resulting
mixture was heated at 80.degree. C. for 2 h. The reaction mixture
was allowed to reach room temperature, then diethylether was added
and the phases were separated. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
The resulting crude was purified by flash-chromatography (eluting
with cyclohexane/ethylacetate from 1/0 to 8/2) to afford the title
compound (2.35 g).
[0497] MS (m/z): 352 [MH].sup.-, 296 [MH-56].sup.+.
Preparation 30: 1,1-dimethylethyl
4-(4-chlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylat-
e (P30)
##STR00130##
[0499] To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl
4-(4-chlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P29,
1.85 g) in diethylether (37.04 mL) at -20.degree. C., LiAlH.sub.4
1M solution in diethylether (3.68 mL) was added dropwise and the
resulting mixture was stirred at -20.degree. C. for 20 min. A
solution of HCl 2% in water (4.44 mL), diethylether and water were
added and the organic phase was separated, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to
obtain the title compound (1.487 g).
[0500] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.33 (d, 2H) 7.12 (d,
2H) 4.13 (s, 2H) 4.03 (s, 2H) 3.61 (t, 2H) 2.40 (s, 2H) 1.46-1.52
(m, 9H)
Preparation 31: 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]hep-
tane-3-carboxylate (P31).
##STR00131##
[0502] To an ice cooled suspension of diethylzinc (1M in hexane,
24.07 mL) in anhydrous dichloromethane (19.6 mL), diiodomethane
(3.88 mL) was added and the resulting mixture was stirred for 15
min. To the cooled mixture was rapidly added a solution of
1,1-dimethylethyl
4-(4-chlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylat-
e (P30, 1.04 g) in anhydrous dichloromethane (11.3 mL), allowed to
reach room temperature and then
2,6-bis(1,1-dimethylethyl)-4-methylpyridine (9.88 g) was added and
then the mixture stirred for 2 h. Aqueous HCl (1M, 30 mL) was added
and left stirring for 30 min. The organic phase was separated and
extracted with HCl, the acid phase was basified with NaOH 3M to
reach pH-12 and then extracted with diethylether. The organic layer
was separated, dried over Na.sub.2SO.sub.4, filtered and evaporated
under reduced pressure. The resulting crude was purified via
flash-chromatography (eluting with
dichloromethane/methanol/ammonia, 90(7.5/2.5) to obtain a mixture
of [6-(4-chlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol and
[4-(4-chlorophenyl)-1,2,5,6-tetrahydro-3-pyridinyl]methanol (190
mg), which was solubilized (188 mg) in anhydrous dichloromethane (8
mL). To that solution bis(1,1-dimethylethyl) dicarbonate (181.15
mg) was added and the resulting mixture was stirred for 2 h.
Triethylamine (0.055 mL) was then added dropwise and the mixture
stirred for 2 h. Dichloromethane (5 mL) and saturated NH.sub.4Cl
(10 mL) were added and the mixture was vigorously stirred for 10
min. The organic layer was separated, dried over Na.sub.2SO.sub.4,
filtered and evaporated under reduced pressure to obtain the title
compound, still impure for the presence of 1,1-dimethylethyl
4-(4-chlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylat-
e (270 mg).
[0503] MS (m/z): 338 [MH].sup.+, 282 [MH-56].sup.+; 324 [MH].sup.+,
270 [MH-56].sup.+.
Preparation 32: 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0-
]heptane-3-carboxylate (P32)
##STR00132##
[0505] Impure 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]hep-
tane-3-carboxylate (P31, 270 mg) and NaH (60% in mineral oil, 28.8
mg) was degassed with a steam of nitrogen, then
N,N-dimethylformamide (7.5 mL) was added at 0.degree. C. The
resulting mixture was allowed to reach room temperature and stirred
for 30 min. Iodomethane (0.099 mL) was added dropwise and left
stirring for 2 h. Three further additions of NaH (60% in mineral
oil, 9.6 mg, 9.6 mg and 19.2 mg rispectively) at 0.degree. C. and
of iodomethane (0.049 mL, 0.049 ml and 0.074 mL rispectively) were
made, and overall the mixture was stirred for 18 h. After this
period of time, ethylacetate, water and ice were poured into the
mixture and the phases were separated. The organic layer was washed
with brine, dried over Na.sub.2SO.sub.4 and evaporated under
reduced pressure to obtain the title compound impure for the
presence of 1,1-dimethylethyl
4-(4-chlorophenyl)-5-[(methyloxy)methyl]-3,6-dihydro-1(2H)-pyridinecarbox-
ylate (280 mg).
[0506] MS (m/z): 352 [MH].sup.+, 296 [MH-56].sup.+; 338
[MH].sup.+.
Preparation 33: 1-(1,1-dimethylethyl) 3-methyl
4-{4-[(trifluoromethyl)oxy]phenyl}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (P33)
##STR00133##
[0508] To a mixture of 1-(1,1-dimethylethyl) 3-methyl
4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (2.5 g, P2), {4-[(trifluoromethyl)oxy]phenyl}boronic acid (1.52
g) and Pd(PPh.sub.3).sub.4 (265 mg) under nitrogen, toluene (34
mL), ethanol (25 mL) and Na.sub.2CO.sub.3 (2M, 19 mL) were added in
sequence. The mixture was stirred at 80.degree. C. for 2 hours then
the reaction mixture was allowed to reach room temperature. The
aqueous phase was extracted with Et.sub.2O (2 times), the combined
organic phases were dried on anhydrous Na.sub.2SO.sub.4 and the
solvent was evaporated obtaining a crude product that was purified
by flash-chromatography (eluting with ethyl acetate/cyclohexane
from 1:9 to 3:7) to give the title compound (2.5 g)
[0509] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.10-7.27 (m, 4H)
4.13-4.35 (m, 2H) 3.57-3.68 (m, 2H) 3.53 (s. 3H) 2.30-2.58 (m, 2H)
1.53 (s, 9H); MS (m/z): 402 [MH].sup.+.
Preparation 34:
1,1-dimethylethyl-5-(hydroxymethyl)-4-{(4-[(trifluoromethyl)oxy]phenyl}-3-
,6-dihydro-1(2H)-pyridinecarboxylate (P34)
##STR00134##
[0511] To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl
4-{4-[(trifluoromethyl)oxy]phenyl}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (P33, 2 g) in dry diethyl ether (40 mL) under N.sub.2
atmosphere, at -20.degree. C., LiAlH.sub.4 (1M in diethyl ether,
3.6 mL) was added dropwise. The reaction mixture was left stirring
at -200 for 20 minutes then saturated NH.sub.4Cl and diethyl ether
were poured into the solution and the mixture was vigorously
stirred for 30 minutes at room temperature. The two phases were
separated, and the aqueous layer was extracted with diethyl ether.
The combined organic phases were dried on anhydrous
Na.sub.2SO.sub.4 and the solvent was removed under reduced
pressure, obtaining the title compound (1.69 g).
[0512] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.12-7.26 (m, 4H)
4.15 (s, 2H) 3.95-4.09 (m, 2H) 3.63 (t, 2H) 2.31-2.52 (m, 2H) 1.53
(s, 9H); MS (m/z): 374 [MH].sup.+.
Preparation 35:
(1S,6R/1R,6S)-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]hept--
1-yl)methanol (P35)
##STR00135##
[0514] To a stirred solution of CH.sub.2I.sub.2 (36 g) and
2,6-bis(1,1-dimethylethyl)-4-methylpyridine (28 g) in dry DCM (150
mL) under N.sub.2 atmosphere, at 0.degree. C., ZnEt.sub.2 (1M in
hexane, 68 mL) was added dropwise; the mixture was stirred at
0.degree. C. for 30 minutes and then cooled to -20.degree. C.
[0515] A solution of
1,1-dimethylethyl-5-(hydroxymethyl)-4-{4-[(trifluoromethyl)oxy]phenyl}-3,-
6-dihydro-1(2H)-pyridinecarboxylate (P34, 1.69 g) in dry DCM (50
mL) was added dropwise and the reaction mixture was stirred at
-20.degree. C. for 30 minutes, then overnight at room temperature.
HCl 1M was added into the reaction flask and the mixture was
vigorously stirred for 30 minutes; the two phases were separated
and the aqueous layer was basified with NaOH 3N. The basic solution
was extracted with diethyl ether (2 times). The combined organic
layers were concentrated in vacuo and the residue was taken up with
diethyl ether. This solution was washed with saturated NH.sub.4Cl
aqueous solution and the aqueous phase was basified with NaOH 3N.
The basic solution was extracted with diethyl ether (2 times). The
combined organic layers were dried on anhydrous Na.sub.2SO.sub.4
and the solvent was removed under reduced pressure obtaining the
title compound (170 mg).
[0516] NMR (.sup.1H, CDCl.sub.3): S ppm 7.36 (d, 2H) 7.16 (d, 2H)
3.39 (d, 1H) 3.05-3.29 (m, 3H) 2.64-2.86 (m, 2H) 1.85-2.07 (m, 2H)
1.05-1.13 (m, 1H) 0.96-1.05 (m, 1H); MS (m/z): 288 [MH].sup.+.
Preparation 36:
(1S,6R/1R,6S)-1,1-dimethylethyl-1-(hydroxymethyl)-6-{4-[(trifluoromethyl)-
oxy]phenyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate (P36)
##STR00136##
[0518] To a stirred solution of
(1S,6R/1R,6S)-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]hept--
1-yl)methanol (170 mg) (P35) in dry DCM (6 mL) under N.sub.2
atmosphere, at 0.degree. C., di-tert-butyl dicarbonate (129 mg) was
added and the reaction mixture was left stirring at 0.degree. C.
for 15 minutes. Saturated NH.sub.4Cl aqueous solution and DCM were
added to the solution and then the organic phase was separated,
dried and the solvent was removed under reduced pressure. The crude
was purified by flash-chromatography (eluting with
cyclohexane/ethyl acetate from 8:2 to 7:3) to give the title
compound (173 mg).
[0519] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.35 (d, 2H) 7.17 (d,
2H) 3.73-3.90 (m, 2H) 3.09-3.51 (m, 4H) 2.06-2.20 (m, 1H) 1.89-2.06
(m, 1H) 1.51 (s, 9H) 1.03-1.10 (m, 1H) 0.93-1.02 (m, 1H).
Preparation 37: 3-methyl 1-(phenylmethyl)
4-oxo-1,3-piperidinedicarboxylate (P37)
##STR00137##
[0521] To a stirred solution of 4-oxo-3-piperidinecarboxylate (5 g)
in dry DCM (50 ml), under N.sub.2 atmosphere, TEA (9 mL) was added
at rt and then, at 0.degree. C., benzylchloroformate (4.2 mL) was
added slowly and stirring was continued for 30 minutes at 0.degree.
C. and 1 h at RT. The mixture was quenched at 0.degree. C. with HCl
2N. The aqueous phase was extracted with DCM (2 times) and the
combined organic layers were washed with saturated NaCl aqueous
solution, dried and concentrated in vacuo to give the title
compound (7.5 g).
[0522] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 12.00 (s, 1H)
7.31-7.50 (m, 5H) 5.19 (s, 2H) 4.16 (s, 2H) 3.80 (s, 3H) 3.67 (t,
2H) 2.42 (s, 2H)
Preparation 38: 3-methyl 1-(phenylmethyl)
4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate
(P38)
##STR00138##
[0524] To a stirred solution of 3-methyl 1-(phenylmethyl)
4-oxo-1,3-piperidinedicarboxylate (7.5 g) (P37) in dry DMF (80 ml)
under N.sub.2 atmosphere at 0.degree. C., NaH 60% on mineral oil
(1.13 g) was added. After 10 min stirring at 0.degree. C.,
1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide
(9.64 g) was added and the mixture was stirred for 1 h. The mixture
was then quenched with saturated NH.sub.4Cl aqueous solution and
the phase was extracted with Et.sub.2O (2 times). The combined
organic layers were washed with saturated NaCl aqueous solution,
dried and concentrated under vacuum obtaining the title compound
(10 g).
[0525] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.34-7.46 (m, 5H)
5.19 (s, 2H) 4.38 (s, 2H) 3.85 (s, 3H) 3.72 (t, J=5.31 Hz, 2H) 2.55
(s, 2H); MS (m/z): 424 [MH].sup.+
Preparation 39: 3-methyl 1-(phenylmethyl)
4-[3-chloro-4-(trifluoromethyl)phenyl]-5,6-dihydro-1,3(2H)-pyridinedicarb-
oxylate (P39)
##STR00139##
[0527] To a stirred solution of 3-methyl 1-(phenylmethyl)
4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (3
g) (P38) and [3-chloro-4-(trifluoromethyl)phenyl]boronic acid
(1.826 g) in dry toluene (37 mL) under N.sub.2 atmosphere at
0.degree. C., Pd(PPh.sub.3).sub.4 (292 mg) dissolved in absolute
EtOH (26 ml), was added followed by Na.sub.2CO.sub.3 2M (21 mL).
The reaction mixture was heated to 80.degree. C. for 2 h. Et.sub.2O
was then added to the solution and the organic phase was separated.
The aqueous layer was extracted with Et.sub.2O and the combined
organic phases were washed with saturated NaCl aqueous solution,
dried and concentrated under vacuum. The crude was purified by
flash-chromatography (eluting with cyclohexane/ethyl acetate from
9:1 to 8:2) to give the title compound (3.03 g).
[0528] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.43-7.52 (m, 2H)
7.31-7.43 (m, 5H) 7.24 (d, 1H) 5.21 (s, 2H) 4.21-4.44 (m, 2H)
3.64-3.77 (m, 2H) 3.55 (s, 3H) 2.51 (s, 2H); MS (m/z): 454
[MH]+
Preparation 40: phenylmethyl
4-[3-chloro-4-(trifluoromethyl)phenyl]-5-(hydroxymethyl)-3,6-dihydro-1(2H-
)-pyridinecarboxylate (P40)
##STR00140##
[0530] To a stirred solution of 3-methyl 1-(phenylmethyl)
4-[3-chloro-4-(trifluoromethyl)phenyl]-5,6-dihydro-1,3(2H)-pyridinedicarb-
oxylate (P39, 3.03 g) in dry diethyl ether (60 mL) under N.sub.2
atmosphere, at -20.degree. C., LiAlH.sub.4 (1 M in diethyl ether,
6.25 mL) was added dropwise. The reaction mixture was left stirring
at -20.degree. for 20 minutes then saturated NH.sub.4Cl aqueous
solution and diethyl ether were added to the reaction mixture. The
two phases were separated and the aqueous layer was extracted with
diethyl ether. The combined organic phases were washed with brine,
dried on anhydrous Na.sub.2SO.sub.4 then the solvent was removed
under reduced pressure, obtaining a crude product that was purified
by flash-chromatography (eluting with cyclohexane/ethyl acetate
from 9:1 to 7:3) to give the title compound (700 mg).
[0531] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.30-7.56 (m, 8H)
5.21 (s, 2H) 4.25 (s, 2H) 3.94-4.08 (m, 2H) 3.72 (t, 2H) 2.44 (s,
2H); MS (m/z): 426 [MH]+
Preparation 41: (1S,6R/1R,6S)-phenylmethyl
6-[3-chloro-4-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3-azabicyclo[4.1-
.0]heptane-3-carboxylate (P41)
##STR00141##
[0533] To a stirred solution of CH.sub.2I.sub.2 (13.25 g) in dry
DCM, under N.sub.2 atmosphere, at 0.degree. C., ZnEt.sub.2 1M in
hexane (24 mL) was added and after 30 min the reaction mixture was
cooled to -20.degree. C. Phenylmethyl
4-[3-chloro-4-(trifluoromethyl)phenyl]-5-(hydroxymethyl)-3,6-dihydro-1(2H-
)-pyridinecarboxylate (700 mg) (P40) in dry DCM, was added (total
amount of DCM 60 ml); the solution was stirred for 30 min at
-20.degree. C. and at RT overnight. The reaction mixture was
quenched with HCl 0.1M and stirred for 30 min. The organic layer
was separated, washed with saturated NaCl aqueous solution, dried
and concentrated in vacuo. The crude was purified by
flash-chromatography (eluting with cyclohexane/ethyl acetate from
9:1 to 7:3) to give 430 mg of impure title compound in a mixture
with phenylmethyl
4-[3-chloro-4-(trifluoromethyl)phenyl]-5-(hydroxymethyl)-3,6-dihydro-1(2H-
)-pyridinecarboxylate (ratio=2:1 form NMR analysis).
[0534] MS (m/z): 440 [MH].sup.+, 426 [MH]+
Preparation 42: 3-methyl 1-(phenylmethyl)
4-(2-naphthalenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P42)
##STR00142##
[0536] The title compound was prepared according to a similar
procedure to that previously described for Preparation 33 in 2.28 g
yield starting from 3-methyl 1-(phenylmethyl)
4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (3
g, P38).
[0537] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.08-7.90 (m, 12H)
5.23 (s, 2H) 4.28-4.48 (m, 2H) 3.64-3.84 (m, 2H) 3.49 (s, 3H)
2.53-2.72 (bs, 2H)
Preparation 43: phenylmethyl
5-(hydroxymethyl)-4-(2-naphthalenyl)-3,6-dihydro-1(2H)-pyridinecarboxylat-
e (P43)
##STR00143##
[0539] The title compound was prepared according to a similar
procedure to that previously described for Preparation 34 in 1.275
g yield starting from 3-methyl 1-(phenylmethyl)
4-(2-naphthalenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (2.28
g, P42).
[0540] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.21-7.91 (m, 12H)
5.23 (s, 2H) 4.20-4.37 (m, 2H) 4.00-4.18 (m, 2H) 3.64-3.83 (m, 2H)
2.43-2.63 (m, 2H)
Preparation 44:
(1S,6R/1R,6S)-phenylmethyl-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-aza-
bicyclo[4.1.0]heptane-3-carboxylate (P44)
##STR00144##
[0541] Step a)
[0542] An impure batch of Phenylmethyl
(1R,6S)-1-(hydroxymethyl)-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane-3-
-carboxylate (850 mg) was prepared starting from
phenylmethyl-5-(hydroxymethyl)-4-(2-naphthalenyl)-3,6-dihydro-1(2H)-pyrid-
inecarboxylate (1.275 g) (P43) according to a similar procedure to
that previously described for Preparation 41.
Step b)
[0543] The title compound was prepared starting from Phenylmethyl
(1R,6S)-1-(hydroxymethyl)-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane-3-
-carboxylate (850 mg) according to a similar procedure to that
described for E14, Step A, in 600 mg yield.
[0544] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.04-7.90 (m, 12H)
5.20 (t, 2H) 4.01 (m, 1H) 3.78-3.92 (d, 1H) 3.44-3.56 (m, 2H)
3.16-3.24 (m, 1H) 3.10 (s, 3H) 2.98-3.03 (m, 1H) 2.16-2.30 (m, 1H)
1.95-2.12 (m, 1H) 1.16-1.25 (m, 1H) 1.01-1.12 (m, 1H); MS (m/z):
402 [MH]+
Preparation 45:
([3-(3-chloro-4-fluorophenyl)-3-buten-1-yl]oxy)(1,1-dimethylethyl)dipheny-
lsilane (P45)
##STR00145##
[0546] The title compound was prepared according to a similar
procedure to that previously described for Preparation 13 in 3.624
g yield starting from
[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (3.890
g, P12).
[0547] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.00-7.65 (m, 13H)
5.29 (m, 1H) 5.11 (m, 1H) 3.74 (t, 2H) 2.70 (t, 2H) 1.02 (s,
9H)
Preparation 46:
dimethyl-2-(3-chloro-4-fluorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)-
silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (P46)
##STR00146##
[0549] The title compound was prepared in 2.61 g yield starting
from
{[3-(3-chloro-4-fluorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)dipheny-
lsilane (P45, 3.624 g) and from dimethyl diazenylpropanedioate
(1.98 g) according to a similar procedure described for Preparation
14.
[0550] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.25-7.62 (m, 1H)
7.04-7.11 (m, 1H) 6.99 (t, 1H) 3.82 (s, 3H) 3.49-3.59 (m, 1H)
3.33-3.46 (m, 4H) 2.10-2.26 (m, 2H) 1.76-1.87 (m, 1H) 1.59-1.66 (m,
1H) 0.99-1.10 (m, 9H); MS (m/z): 569 [MH].sup.+
Preparation 47:
methyl-1-(aminocarbonyl)-2-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)cy-
clopropanecarboxylate (P47)
##STR00147##
[0552] The title compound was prepared in 1.05 g yield starting
from dimethyl
2-(3-chloro-4-fluorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)-
silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (2.61 g, P46)
according to a similar procedure to that previously described for
Preparation 15.
[0553] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 8.19 (s, 1H) 7.34 (d,
1H) 7.14-7.22 (m, 1H) 7.10 (t, 1H) 5.76 (s, 1H) 3.42-3.66 (m, 2H)
3.06-3.26 (m, 3H) 1.89-2.35 (m, 4H); MS (m/z): 316 [MH].sup.+
Preparation 48: (1S,6R/1R,6S)-methyl
6-(3-chloro-4-fluorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylat-
e (48)
##STR00148##
[0555] The title compound was prepared in 360 mg yield starting
from methyl
1-(aminocarbonyl)-2-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)cy-
clopropanecarboxylate (1.05 g, P47) according to a similar
procedure described for Preparation 16.
[0556] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.42 (dd, 1H)
7.21-7.27 (m, 1H) 7.10 (t, 1H) 5.83 (s, 1H) 3.53 (s, 3H) 2.85-3.42
(m, 2H) 2.33-2.48 (m, 1H) 2.24-2.32 (m, 1H) 2.09-2.22 (m, 1H) 1.99
(d, 1H); MS (m/z): 298 [MH].sup.+
Preparation 49: (1S,6R/1R,6S)-1,1-dimethylethyl
6-(3-chloro-4-fluorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane--
3-carboxylate (P49)
##STR00149##
[0558] The title compound was prepared in 184 mg yield starting
from
(1S,6R/1R,6S)-methyl-6-(3-chloro-4-fluorophenyl)-2-oxo-3-azabicyclo[4.1.0-
]heptane-1-carboxylate (360 mg, P48) according to a similar
procedure described for Preparation 5 (Method C).
[0559] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.37 (dd, 1H)
7.16-7.24 (m, 1H) 7.09 (t, 1H) 3.72-3.89 (m, 2H) 3.26-3.46 (m, 3H)
3.11-3.26 (m, 1H) 1.90-2.16 (m, 2H) 1.51 (s, 9H) 1.01 (dd, 2H)
Preparation 50:
(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy-
)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (P50)
##STR00150##
[0561] The title compound was prepared in 164 mg yield starting
from (1S,6R/1R,6S)-1,1-dimethylethyl
6-(3-chloro-4-fluorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane--
3-carboxylate (184 mg, P49) according to a similar procedure to
that described for Example 14, Step A.
[0562] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.38 (d, 1H)
7.14-7.23 (m, 1H) 7.07 (t, 1H) 3.86 (s, 1H) 3.70 (d, 1H) 3.27-3.42
(m, 2H) 3.15 (s, 3H) 3.00-3.11 (m, 1H) 2.86 (d, 1H) 1.92-2.13 (m,
2H) 1.44-1.54 (m, 9H) 0.90-1.03 (m, 2H)
Preparation 51: 1,1-dimethylethyl
(1R,6S1/S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane-3-carboxylate (P51)
##STR00151##
[0564] To a stirred solution of
(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)--
3-azabicyclo[4.1.0]heptane-3-carboxylate (P5, 0.1 g) in dry DMF (2
mL), under a nitrogen atmosphere, sodium hydride (60% in mineral
oil, 13 mg) was added and the stirring continued for 5 min. After
this period of time iodoethane (28 .mu.L) was added and the
reaction mixture was stirred overnight at RT. An additional amount
of sodium hydride (3 mg) and iodoethane (28 .mu.L) were added and
the mixture was stirred for further 4 h. Aqueous saturated
NaHCO.sub.3 solution was added and the mixture was extracted with
DCM. The organic phase was concentrated under vacuum and the crude
product was purified by flash-chromatography (eluting with cy/EA
from 1/0 to 8/2) to give the title compound (79 mg).
[0565] NMR (.sup.1H, MeOH-d.sub.4): .delta. 7.48 (s, 1H) 7.35 (d,
1H) 7.15 (d, 1H) 3.7-3.4 (m, 2H) 3.3 (m, 3H) 3.15 (m, 2H) 2.85 (d,
1H) 2.0 (m, 2H) 1.5 (s, 9H) 1.1 (t, 3H) 0.95 (m, 2H);
[0566] MS (m/z): 422 [M+Na].sup.+
Preparation 52: 1,1-dimethylethyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate
(P52)
##STR00152##
[0568] To a stirred solution of diisopropylamine (0.77 ml) in dry
THF (12 mL) at -78.degree. C. and under a nitrogen atmosphere,
butyl lithium (2.5M in hexane, 2.2 ml) was added and the reaction
mixture was stirred at -78.degree. C. for 15 minutes. DMPU (1.8 ml)
and a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate
(1 g) in THF (5 ml) were added and the reaction mixture was stirred
at -78.degree. C. for 2 hours. Then a solution of
N-phenyl-bis(trifluoromethanesulfonimide) (1.97 g) in THF (6 ml)
was added and stirring was continued at 0.degree. C. for 9 hours
and at room temperature per 16 h. The solvent was removed under
reduced pressure and the crude purified by flash-chromatography
(eluting with ethyl acetate/cycloexane 2:8) to give 1.375 g of the
title compound.
[0569] NMR (.sup.1H, CDCl.sub.3): .delta. 5.79 (br. s., 2H) 4.07
(m, 2H) 3.65 (m, 2H) 2.47 (m, 2H) 1.50 (s, 9H).
Preparation 53: 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-3,6-dihydro-1(2H-pyridinecarboxylate
(P53)
##STR00153##
[0571] To a mixture of 1,1-dimethylethyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate
(P52, 500 mg), 3,4-dichlorophenylboronic acid (330 mg) and
Pd(PPh.sub.3).sub.4 (50 mg) under nitrogen, toluene (6.5 mL),
ethanol (5 mL) and Na.sub.2CO.sub.3 (2M, 5 mL) were added in
sequence. The mixture was stirred at 80.degree. C. for 2 hours then
the reaction mixture was allowed to reach room temperature.
Saturated NH.sub.4Cl (30 mL) was poured into the solution and the
mixture was transferred in a separator funnel. The mixture was
extracted with ethyl acetate (3.times.40 mL), the combined organic
phases were dried on anhydrous Na.sub.2SO.sub.4 and the solvent
evaporated obtaining a crude product that was purified by
flash-chromatography (eluting with ethyl acetate/cycloexane 1:9) to
give the title compound (400 mg).
MS (m/z): 328 [MH]+
Preparation 54: 3-(1,1-dimethylethyl) 7-ethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-3,7-dicar-
boxylate and 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-6-[2-(ethyloxy)-2-oxoethyl]-3,6-dihydro-1(2m-pyrid-
inecarboxylate (P54)
##STR00154##
[0573] To a solution of 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (P53,
825 mg) in DCE (10 ml) was added rhodium acetate dimer (110 mg).
The mixture was heated at 40.degree. C. and a solution of ethyl
diazoacetate (0.31 ml) in DCE (2.5 ml) was added with a syringe
pump in 4 h maintaining the internal temperature at 50.degree. C.
during the addition. The solvent was removed under reduced pressure
and the crude purified by flash-chromatography (eluting with ethyl
acetate/cycloexane 2:8) to give 170 mg of a mixture of title
compounds.
MS (m/z): 414 [MH].sup.+
Preparation 55: 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-3-azabicyclo[4.1.0-
]heptane-3-carboxylate and 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)-3,6-dihydro-1(2H)-pyridinecarbo-
xylate (P55)
##STR00155##
[0575] To a stirred solution of (1,1-dimethylethyl) 7-ethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-3,7-dicar-
boxylate and 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-6-[2-(ethyloxy)-2-oxoethyl]-3,6-dihydro-1(2H)-pyri-
dinecarboxylate (P54, obtained following an analogous procedure to
that previously described for P54, 38 mg) in dry toluene (1 mL)
under N.sub.2 atmosphere, at -20.degree. C., LiAlH.sub.4 (1M in
diethyl ether, 0.37 mL) was added dropwise. The reaction mixture
was left stirring at -20.degree. for 1 hour then saturated
NH.sub.4Cl was added and the products extracted with ethyl acetate.
The phases were separated, the organic phase was dried over
Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure
to give a mixture of the title compounds as crude (30 mg).
[0576] MS (m/z): 372 [MH].sup.+
Preparation 56: 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane-3-carboxylate and 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-6-[2-(methyloxy)ethyl]-3,6-dihydro-1(2H)-pyridinec-
arboxylate (P56)
##STR00156##
[0578] To a stirred solution of 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-3-azabicyclo[4.1.0-
]heptane-3-carboxylate and 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)-3,6-dihydro-1(2H)-pyridinecarbo-
xylate (P55, 30 mg) in dry DMF (1 mL) under nitrogen atmosphere, at
0.degree. C., NaH (60% on mineral oil, 5 mg) was added and the
mixture stirred for 30 minutes at 0.degree. C. Methyl iodide (10
.mu.L) was added and the reaction was allowed to reach room
temperature and stirred for 2 h. Chilly water was added and the
product extracted with ethyl acetate. The organic phase was washed
with brine, dried over Na.sub.2SO.sub.4, and the solvent evaporated
under reduced pressure to give a mixture of the title compounds as
crude material (35 mg).
MS (m/z): 386 [MH]+
Preparation 57: 3-(1,1-dimethylethyl) 1-ethyl
(1S,6R/1R,6S)-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dica-
rboxylate (P57)
##STR00157##
[0579] Step a)
[0580] A 50-L Jacketed laboratory reactor was charged with lithium
tert-butoxide (1.85 Kg, 23.1 mol, 3 eq) and
1-methyl-2-pyrrolidinone (19.1 Kg). The mixture was stirred for -30
min, and the resulting solution was charged into a pressure vessel
for later use.
[0581] A clean, 50-L Jacketed laboratory reactor was charged with a
solution of 1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate in
toluene (prepared in a similar manner to that described in P72,
containing P72 in a theoretical amount of 3.09 Kg) through a 0.45
.mu.m Meissner.TM. in-line filter. The lines and filter were washed
with a small amount of toluene. The toluene was completely removed
from the reaction mixture by distillation under reduced pressure.
1-methyl-2-pyrrolidinone (16.0 Kg) was added and the resulting
solution cooled to 20.degree. C., and held overnight due to time
constraints. Chloroiodomethane (4.15 Kg, 3.05 eq) was charged into
the reactor, and the resulting slurry was cooled to -4.degree. C. A
portion of the previously prepared solution of lithium
tert-butoxide in 1-methyl-2-pyrrolidinone (16.9 Kg, -2.4 eq of
base) was added over 28 min, and the resulting solution was warmed
to 19.degree. C. and stirred for 80 min. Acetic acid (0.69 Kg, 1.5
eq) was added all at once, followed by a slow addition of water
(8.5 Kg) over .about.10 min. The mixture was stirred for -5 min,
and water (13.1 Kg) was added over 18 min. The resulting slurry was
cooled to 11.degree. C. and held for 100 min. The solids were
collected by filtration. Water (3.9 Kg) and methanol (9.21 Kg) were
charged into the reactor to rinse it, and the resulting aqueous
methanol solution was used to wash the product cake. The resulting
yellow solids were dried to a constant weight in a 55.degree. C.
vacuum oven to provide 2.57 Kg of the title compound in 81%
yield.
[0582] NMR (.sup.1H, CDCl.sub.3): .delta. 7.32 (2H, m), 7.08 (1H,
m), 6.62 (1H, br m), 5.13 (1H, br m), 4.24 (1H, br m), 3.76 (3H, br
m), 2.29 (1H, m), 1.56 (1H, m), 1.49 (9H, s), 0.91 (3H, br m)
Step B) (Recrystallization)
[0583] A 50-L jacketed laboratory reactor was charged with
(.+-.)-3-(1,1-dimethylethyl) 1-ethyl
(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dicarbox-
ylate (P57, 4.40 Kg, 11.0 moles, 1 eq) and heptane (15.1 Kg, 22.1
L, 5 vol). The resulting slurry is heated to approximately
80.degree. C. and filtered into a clean 50-L jacketed laboratory
reactor. The filter and lines were rinsed with heptane (3.0 Kg, 4.4
L, 1 vol) and the rinse was combined with the filtrate. The
solution was heated to 80.degree. C. and then cooled to 22.degree.
C. over 107 min. No crystals had formed so a small aliquot was
taken out. Crystals formed spontaneously in the aliquot and were
returned to the reactor which caused rapid crystallization. The
slurry was heated back to 80.degree. C. and cooled to 22.degree. C.
over 105 min. During the cool, a small aliquot was pulled at
52.degree. C. The wall of the vial holding the aliquot was
scratched to initiate crystallization and the resulting slurry was
combined with the bulk solution when its temperature had reached
47.degree. C. The solids were collected by filtration, the reactor
was rinsed with heptane (3.0 Kg, 4.4 L, 1 vol), and the rinse was
used to wash the filter cake. The solids were dried to a constant
weight in a 50-60.degree. C. vacuum oven to provide 2.954 Kg, 67%
yield, of title compound as an off-white solid.
[0584] NMR (.sup.1H. CDCl.sub.3): .delta. 7.35 (2H, m), 7.27
(CDCl.sub.3), 7.11 (1H, m), 6.65 (1H, br m), 5.16 (1H, br m), 4.27
(1H, br m), 3.79 (3H, br m), 2.32 (1H, m), 1.59 (1H, m), 1.52 (9H,
s), 0.94 (3H, br m)
Preparation 58: 1,1-dimethylethyl
(1S,6R/1R,6S)-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]h-
ept-4-ene-3-carboxylate (P58)
##STR00158##
[0586] 3-(1,1-dimethylethyl) 1-ethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-di-
carboxylate (P57, 39.97 g, 0.9694 mol, 1 eq) was dissolved in THF
(80 mL, 2 vol). A solution of 2M LiBH.sub.4 in THF (120 mL, 0.242
mol, 2.5 eq) was added and the resulting solution was cooled with a
room temperature water bath. Ethanol (28.5 mL, 0.485 mol, 5 eq) was
added over 65 min. The reaction was stirred for 40 min, and heptane
(200 mL, 5 vol) was added. Water was added (10 mL, 550 mole, 5.7
eq) over -10 min, and the resulting slurry was stirred for 15-20
min. More water was added (200 mL, 5 vol), the mixture was stirred
for 15 min, and the layers were allowed to settled, and separated.
The organic layer was washed with water (200 mL, 5 vol), and then
filtered through Whatman brand #2 filter paper and concentrated in
vacuo. The resulting oil was dried in a 60.degree. C. vacuum oven
for -72 h to provide 29.48 g, 82% yield, of title compound as a
glassy solid.
[0587] NMR (.sup.1H, CDCl.sub.3): .delta. 7.38 (2H, br m), 7.15
(1H, br m), 6.60 (1H, br m), 5.12 (1H, br m), 4.24 (1H, br m), 3.38
(2H, br m), 3.29 (1H, br m), 1.51 (10H, br m), 1.30 (1H br m).
Preparation 59: 1,1-dimethylethyl
(1S,6R/1R,6S)-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1-
.0]hept-4-ene-3-carboxylate (P59)
##STR00159##
[0589] 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0-
]hept-4-ene-3-carboxylate (P58, 28.4 g, 76.7 mmol) was dissolved in
DMSO (225 ml). The solution was then treated with potassium
hydroxide (powder, 17.2 g, 0.3 mol) and stirred for 15 min.
Iodomethane (9.5 ml, 0.15 mol) was added dropwise over 15 min and
the reaction stirred for 90 min at room temperature. It was then
quenched with water (115 ml) and MTBE (250 ml) and stirred for 1 h.
The phases were then separated and the top (organic) phase washed
with water (115 ml) and concentrated in vacuo to give the title
compound as an oil (32 g crude weight).
[0590] NMR (.sup.1H, CDCl.sub.3): .delta. 7.40 (1H, d, J=4 Hz),
7.37 (1H, d, J=8 Hz), 7.15 (1H, dd, J=8, 4 Hz), 6.55 (1H, br m),
5.08 (1H, br m), 4.19 (1H, br m), 3.27 (1H, br m), 3.10 (3H, br s),
3.04 (1H, br m), 2.96 (1H, br m), 1.49 (9H, br s), 1.42 (1H, d, J=4
Hz), 1.28 (1H, br m).
[0591] MS (m/z): 328 [M-t-Bu+2H]+
Preparation 60: 1,1-dimethylethyl
(1S,6R)-6-3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
pt-4-one-3-carboxylate (P60)
##STR00160##
[0593] 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]hept-4-ene-3-carboxylate (P59, 36 grams, 9.4 mmol) was
dissolved in 370 mL (5% IPA in heptane) and the two enantiomers
separated by chiral HPLC. Rt=5.7 min [Column used for processing:
Chiralpak AD, 20 um, 20.times.250 mm, (ambient temp.) Processing
parameters: Flow: 15 mL/min; Detection: 225 & 280 nm; Feed
stock: 100 mg/mL]
[0594] After the solvent was evaporated, the product was isolated
as an oil (16.2 g, optical purity, 99.2%).
Preparation 61: 3-(3,4-dichlorophenyl)-3-buten-1-ol (P61)
##STR00161##
[0596] In a round-bottomed flask equipped with mechanical stirrer,
under an argon atmosphere, 3,4-dichlorophenylboronic acid (128 g,
672 mmol) and 3-bromo-3-buten-1-ol (78 g, 517 mmol) were dissolved
in toluene (1230 ml) and ethanol (492 ml). To this solution,
tetrakis(triphenylphosphine)palladium(0) (29.8 g, 25.8 mmol) was
added followed by sodium carbonate 2M aqueous solution (517 ml,
1033 mmol). The resulting mixture was heated at an internal
temperature of 75.degree. C. After 30 minutes, a thick precipitate
formed. After 1 h, water (50 ml) was added to make the solid
re-dissolved and the reaction mixture turned slightly yellow
opalescent. At 3 h the reaction was worked-up. Flask was cooled
down to room T (a precipitate was formed) and the mixture was taken
up with aqueous NaHCO.sub.3 sat. solution (468 mL), water (468 mL)
and AcOEt (468 mL). At addition of water solid dissolved; phases
were separated and aqueous one back extracted with AcOEt
(2.times.936 mL). Combined organics were dried (Na.sub.2SO.sub.4),
concentrated under vacuum to give crude material (200 g) as black
thick oil. This oil was purified by silica gel flash
chromatography, eluting with cyclohexane/AcOEt from 8/2 to 7/3.
Evaporation of solvent afforded the title compound (73 g), as dark
thick oil.
[0597] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.51 (d, 1H), 7.41
(d, 1H), 7.26 (dd, 1H), 5.34-5.53 (m, 1H), 5.02-5.29 (m, 1H),
3.60-3.95 (m, 2H), 2.57-2.94 (m, 2H), 1.50 (t, 1H)
Preparation 62: 3-(3,4-dichlorophenyl)-3-buten-1-yl
methanesulfonate (P62)
##STR00162##
[0599] In a round-bottomed flask,
3-(3,4-dichlorophenyl)-3-buten-1-ol (P61, 73 g, 336 mmol) was
dissolved in DCM (900 ml) to give a yellow solution. Then
triethylamine (69.9 ml, 504 mmol) was added keeping the internal
temperature below +5.degree. C. with an ice bath. Methanesulfonyl
chloride (36.7 ml, 471 mmol) was then added dropwise in 30 min.
keeping the internal temperature below +5.degree. C. with an ice
bath. The mixture was allowed to reach room temperature while
stirring. After 3 h, the reaction mixture (suspension) was quenched
by careful addition of aqueous ammonium chloride sat. solution (400
ml) keeping the internal temperature below +10.degree. C. with an
ice bath. At the end of the addition the pH of the aqueous phase
was nearly 1. The two layers were separated. The aqueous layer was
back-extracted with DCM (3.times.300 mL). The combined organic
layers were washed with water (2.times.200 mL), dried
(Na.sub.2SO.sub.4), and evaporated to give a crude product (101 g)
that was purified over a silica gel pad (1000 g) eluting with
cyclohexane/EtOAc from 9/1 to 1/1 to afford the title compound
(90.8 g) as a dark yellow oil.
[0600] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.49 (d, 1H), 7.44
(d, 1H), 7.24 (dd, 1H), 5.46 (d, 1H), 5.25 (d, 1H), 4.32 (t, 2H),
2.98 (s, 3H), 2.93 (t, 2H)
[0601] HPLC (walk-up): Rt=5.37 min
Preparation 63: dimethyl
2-(3,4-dichlorophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopropaned-
icarboxylate (P63)
##STR00163##
[0603] In a round-bottomed flask,
3-(3,4-dichlorophenyl)-3-buten-1-yl methanesulfonate (P62, 90.8 g,
308 mmol) was dissolved in chlorobenzene (200 ml) to give a green
solution. Rhodium acetate dimer (6.80 g, 15.38 mmol) was added. The
suspension was warmed to an internal temperature of +65.degree. C.
and dimethyl diazopropanedioate (78 g, 492 mmol, for a reference
procedure of preparation see Synthetic Communication 1987, 17 (14),
1709-1716) dissolved in chlorobenzene (150 ml) was added dropwise
(during 2.5 hrs), keeping the internal temperature below
65-67.degree. C. At the end of the addition, the mixture was cooled
to room temperature. It was diluted with DCM (300 ml) and filtered
over a celite pad to separate the catalyst.
[0604] The solution was evaporated in vacuo to 1/3 of the volume
and the crude (277 g) purified over a silica pad (silica gel 1.3
Kg) eluting with cyclohexane/ethyl acetate from 7/3 to 1/1 to
afford the title compound (128.25 g).
[0605] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.41 (d, 1H), 7.39
(d, 1H), 7.15 (dd, 1H), 4.08-4.22 (m, 1H), 3.94-4.06 (m, 1H), 3.85
(s, 3H), 3.48 (s, 3H), 2.95 (s, 3H), 2.42 (dt, 1H), 2.21 (d, 1H),
1.89-2.03 (m, 1H), 1.82 (d, 1H)
[0606] HPLC (walk-up): Rt=5.15 min
Preparation 64: methyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-c-
arboxylate (P64)
##STR00164##
[0608] In a 5 L Parr reactor, dimethyl
2-(3,4-dichlorophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}1,1-cyclopropanedi-
carboxylate (P63, 158 g, 372 mmol) was dissolved in ammonia 2M in
methanol (3000 ml) to give a yellow solution. The solution was
warmed to +75.degree. C. and the resulting mixture was stirred at
this temperature overnight (internal pressure=2 atm). After 24 hrs,
reaction was complete. The solution was concentrated to obtain a
residue that was mixed with a residue (89.3 g) coming from an
analogous preparation performed on another batch of
2-(3,4-dichlorophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopropaned-
icarboxylate. The solvent was evaporated to obtain a crude oil (280
g). To this oil, AcOEt (5 L) and 1M aqueous HCl (2.5 L) were added
and the mixture was vigorously stirred for 30 min in a 10 L
reactor.
[0609] A diluted suspension (a mixture of organic phase, aqueous
phase and solid) was obtained. The solid was filtered, washed with
ethyl acetate and dried to afford a first batch of title compound
(54.9 g).
[0610] The organic and aqueous layers were separated. The organic
phase was then washed with aqueous HCl 1M (2 L), dried
(Na.sub.2SO.sub.4) and concentrated to 1/10 of the volume. A solid
precipitated out. It was filtered, washed with diethyl ether (150
ml) and dried under vacuum to afford a second batch of title
compound (34.4 g). The mother liquours of filtration were
concentrated in vacuo to obtain a brown oil. This residue was
triturated with ethyl ether (1.times.50 mL). The resulting solid
was filtered, washed with cold ethyl ether and dried to give a
third batch of title compound (7.27 g) as a off white solid.
[0611] The mother liquours were concentrated and chromatographed on
Biotage 75M (silica gel) eluting with AcOEt to give a solid that
was triturated in ethyl ether (35 ml) to give a fourth batch of
title compound (6.2 g).
[0612] An overall amount of 102.7 g of product was thus
obtained.
[0613] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.47 (d, 1H), 7.41
(d, 1H), 7.20 (dd, 1H), 5.73 (br. s., 1H), 3.54 (s, 3H), 3.07-3.41
(m, 2H), 2.32-2.45 (m, 1H), 2.28 (d, 1H), 2.17 (d, 1H), 1.93 (d,
1H)
Preparation 65: 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0-
]heptane-3-carboxylate (P65)
##STR00165##
[0614] Step a)
[0615] In a round-bottomed flask, methyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-c-
arboxylate (P64, 90 g, 286 mmol) was dissolved in THF (1450 ml) to
give a grey suspension. Borane tetrahydrofuran complex 1M (1633 ml,
1633 mmol) was added dropwise keeping the internal temperature
below +5.degree.. The resulting mixture was gently refluxed for 7
hrs. The mixture was cooled to +3.degree. C. and quenched by
careful addition of methanol (200 ml); then aqueous HCl 6M (450 ml)
was added keeping the internal temperature below +6.degree. C. The
mixture was stirred at room temperature for 5 h. The acidic
solution was concentrated under vacuum to remove THF, then water
(900 ml) was added. The pH of the final solution was nearly 1. This
solution was washed with ethyl ether (2.times.200 ml). The aqueous
solution was basified by portionwise addition of potassium
carbonate until pH 8-9, then THF (1200 ml) was added and the
resulting mixture used directly in the next step.
Step b)
[0616] A round-bottomed flask was charged with the mixture coming
from step a) (approximately 2700 ml, pH=8-9). Di-tert-butyl
dicarbonate (80 ml, 343 mmol) was added portionwise at room
temperature and the mixture was stirred overnight. The organic and
aqueous layers were separated. The aqueous layer was back-extracted
with ethyl acetate (3.times.600 mL). The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated to obtain a crude
oil (165 g) that was purified over a silica pad (silica gel 1500
g), eluting with cyclohexane/ethyl acetate 8/2 to give the title
compound (110 g) as a foamy colourless oil.
[0617] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.39-7.42 (m, 1H),
7.37 (d, 1H), 7.17 (d, 1H), 3.73-3.90 (m, 2H), 2.99-3.49 (m, 4H),
1.91-2.13 (m, 2H), 1.48 (s, 9H), 0.92-1.07 (m, 2H).
[0618] HPLC (walk-up): Rt=6.12 min
Preparation 66: 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane-3-carboxylate (P66)
##STR00166##
[0620] In a 1 L round-bottomed flask, 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0-
]heptane-3-carboxylate (P65, 47.56 g, 128 mmol) was dissolved in
THF (800 ml) to give a colourless solution. Sodium hydride (10.22
g, 256 mmol) was added keeping the internal temperature at
0.degree. C. After 30 min, MeI (15.98 ml, 256 mmol) was added
dropwise at the same temperature. The resulting mixture was stirred
overnight at room temperature.
[0621] The mixture was quenched by dropwise addition of aqueous
NaHCO.sub.3 sat. (500 ml) keeping the internal temperature below
+15.degree. C. The resulting suspension was filtered, the solid was
dissolved with water (200 ml). The two phases were separated and
the aqueous phase was extracted with ethyl acetate (3.times.200
ml). The combined organic layers, dried (Na.sub.2SO.sub.4), were
evaporated to give crude material (54 g) that was purified by
silica gel chromatography, eluting with cyclohexane/ethyl acetate
from 95/5 to 75/25 to give the title compound as a colourless oil
(42.33 g).
[0622] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.40-7.43 (m, 1H),
7.36 (d, 1H), 7.16 (d, 1H), 3.85 (d, 1H), 3.67 (d, 1H), 3.26-3.40
(m, 2H), 3.14 (s, 3H), 2.97-3.10 (m, 1H), 2.81-2.91 (m, 1H),
1.90-2.07 (m, 2H), 1.49 (s, 9H), 0.91-1.02 (m, 2H)
[0623] HPLC (walk-up): Rt=7.15 min
Preparation 67: dimethyl
(2S)-2-(3,4-dichlorophenyl)-2(2-[(methylsulfonyl)oxy]ethyl}-1,1-cycloprop-
anedicarboxylate and dimethyl
(2R)-2-(3,4-dichlorophenyl)-2-(2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopro-
panedicarboxylate (P67)
##STR00167##
[0625] 3-(3,4-dichlorophenyl)-3-buten-1-yl methanesulfonate (2.0 g,
6.78 mmol) and Rh2-[(S)-4-Cl-nttl]-4 (preparation of the catalyst
described in Helv. Chem. Act., vol. 88 (2005), p. 216 and ss.)
(0.105 g, 0.066 mmol) were dissolved in chlorobenzene (10 ml) at
25.degree. C. A solution of dimethyl diazopropanedioate (1.7 g,
10.75 mmol) in chlorobenzene (10 ml) was added dropwise in 2 h.
[0626] The chlorobenzene was evaporated and the residue
chromatographed over silica (230-400 Mesh) eluting with
cyclohexane/AcOEt 8/2, 7/3 to afford the title compound (2.65
g).
[0627] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.41 (d, 1H), 7.39
(d, 1H), 7.15 (dd, 1H), 4.08-4.22 (m, 1H), 3.94-4.06 (m, 1H), 3.85
(s, 3H), 3.48 (s, 3H), 2.95 (s, 3H), 2.42 (dt, 1H), 2.21 (d, 1H),
1.89-2.03 (m, 1H), 1.82 (d, 1H)
[0628] Chiral HPLC (Column: Chiralpak AD-H (25.times.0.46 cm);
Mobile phase: n-Hexane/Ethanol 70/30% v/v; Flow rate: 1.0 ml/min;
DAD:210-340: Enant1 (Rt=9.6 min)/Enant2 (Rt=11.7 min)=60/40 area
%
Preparation 68: 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-4-methyl-3-azabicy-
clo[4.1.0]heptane-3-carboxylate (P68)
##STR00168##
[0630] 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2-methyl-3,6-dihydro-1(2H)-pyrid-
inecarboxylate (P22, two batches prepared in an analogous manner to
that previously described for P22, 260 mg) were dissolved in DCM (5
mL). It was added at -20.degree. C. to a suspension obtained by
addition of diethylzinc 1.0M in hexane (4.19 mL) to a solution of
diiodomethane (0.676 mL) in DCM (10 mL). The suspension was stirred
at room temperature overnight. The reaction mixture was then
quenched with 20 mL of a saturated solution of NH.sub.4Cl and the
two phases were stirred for 30 min. The organic layer was washed
with brine (20 mL), dried and concentrated. Purification by
chromatography on silica gel eluting with a gradient 540% ethyl
acetate/cyclohexane afforded 75 mg of a colourless oil.
[0631] NMR (.sup.1H, CDCl.sub.3): .delta. 7.40-7.42 (m, 1H), 7.38
(d, 1H), 7.17 (dd, 1H), 3.39-3.48 (m, 2H), 3.20-3.27 (m, 1H), 2.44
(m, 1H), 2.06-2.16 (m, 1H), 1.81-1.91 (m, 1H), 1.61-1.69 (m, 1H),
1.47-1.50 (s, 9H), 1.24-1.28 (d, 3H), 0.84-0.94 (m, 2H).
Preparation 69: 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(methylsulfonyl)oxy]methyl}-3-az-
abicyclo[4.1.0]heptane-3-carboxylate (P69)
##STR00169##
[0633] 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0-
]heptane-3-carboxylate (P5, 132 mg) and triethyl amine (74 .mu.L)
were dissolved in DCM (5 mL). Methanesulfonyl chloride (38 .mu.L)
was added at room temperature. After overnight stirring, DCM and
NH.sub.4Cl saturated solution were added. The organic solvent was
evaporated obtaining the title compound (140 mg).
[0634] NMR (.sup.1H, CDCl.sub.3): .delta. 7.4 (m, 2H) 7.1 (d, 1H)
3.9 (d, 2H) 3.75 (m, 1H) 3.7 (s, 2H) 3.4 (m, 2H) 2.9 (m, 3H) 1.7
(m, 1H) 1.5 (s, 9H) 1.1-1.2 (dd, 2H); MS (m/z): 450 [MH]+
Preparation 70:1-(1,1-dimethylethyl) 3-ethyl
4-oxo-1,3-piperidinedicarboxylate (P70)
##STR00170##
[0636] To a suspension of 3-ethylcarboxylate-4-piperidone
hydrochloride (5 kg, 24.08 moles, Alfa Aesar) in heptane (12.7, kg)
was charged triethylamine (7.25 kg, Alfa Aesar) at room temperature
and the suspension was then stirred for 15 minutes.
Di-tert-butyldicarbonate (6.3 kg, 28.89 moles, 1.2 eq., Alfa Aesar)
was then added to the reaction over 20 minutes as a solution in
heptane (4.1 Kg) at room temperature. The reaction was stirred at
room temperature for approximately 40 min. Then water (25 L) was
charged to the reaction at room temperature and stirred for 15
minutes. The layers are then allowed to separate and the aqueous
layer removed. The organic layer was then washed with 1N HCl (25 L)
and water (22 L). The resulting organic layer was then concentrated
to an oil by vacuum distillation, with a jacket temperature of
20.degree. C. Once concentrated to an oil, ethanol (13.7 kg)/water
(17.5 kg) was then charged to the reaction and warmed to 50.degree.
C. Once reaction temperature has stabilized, the reaction is then
cooled to -10.degree. C. at a rate of 0.25.degree. C./min. The
reaction is held at -10.degree. C. for greater than 6 hours. The
resulting solids are then filtered, and the filtrate used to rinse
the reactor and wash the filter cake. The recovered solids are then
dried at room temperature under full vacuum with a N.sub.2 bleed.
Isolated 6354 grams of title compound (97% yield).
[0637] NMR (.sup.1H, DMSO-d6): .delta. ppm 1.13-1.30 (m, 3H) 1.40
(s, 9H) 2.32 (t, J=5.98 Hz, 2H) 3.48 (t, J=5.98 Hz, 2H) 3.95 (s,
2H) 4.21 (q, J=7.08 Hz, 2H)
Preparation 71: 1-(1,1-dimethylethyl) 3-ethyl
4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate (P71)
##STR00171##
[0639] 1-(1,1-Dimethylethyl) 3-ethyl
4-oxo-1,3-piperidinedicarboxylate (P70, 380.48 g, 1.40 moles) was
dissolved in toluene (2.97 Kg). The solution was stirred for 10
mins and then cooled to -7.degree. C. and then treated with
N,N-diisopropylethylamine (271.56 g, 2.10 mol) while maintaining
the reaction below -7.degree. C. After stirring the reaction
mixture for approximately 10 minutes, trifluoromethanesulfonic
anhydride (436.29 g, 1.55 mol) was added while maintaining the
temperature below 5.degree. C. The reaction mixture was stirred at
1.degree. C. for 31 minutes.
[0640] HPLC: Rt=2.69 min (HPLC instrument Agilent 1100 Series
analysis performed on a Agilent Zorbax SB C18 (50.times.3.0 mm, 1.8
um), mobile phase: water:acetonitrile:TFA (0.05%), gradient from 0
to 95% in 2.5 min, hold for 0.2 min, then re-equilibrate;
T=60.degree. C.; flow=1.5 mL/min)
Preparation 72: 1-(1,1-dimethylethyl) 3-ethyl
4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate
(P72)
##STR00172##
[0642] The 1-(1,1-dimethylethyl) 3-ethyl
4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxyl-
ate solution in toluene (coming from preparation described for P71)
was cooled to approximately -5.degree. C. Next
N,N-diisopropylethylamine (288.10 g, 2.23 mol), water (376.20 g),
triphenylphosphine (27.52 g, 0.105 mol), and palladium (II) acetate
trimer (7.88 g, 0.0117 mol) were added. The reaction mixture was
warmed to 21.degree. C. and stirred for 1 hour. Following the
addition of 3,4-dichlorophenylboronic acid (268.80 g, 1.41 mol),
the reaction mixture was heated to 70.degree. C. and stirred for 48
minutes (temperature briefly reached 87.4.degree. C. while
heating). The reaction was cooled to -6.4.degree. C. followed by
the addition of sodium hydroxide (1N, 3286 g) while maintaining the
reaction temperature below 5.degree. C. Next, the reaction mixture
was warmed to 20.degree. C. and stirred for 1 hour. The layers were
separated and carbon DARCO.RTM.G-60 (Activated Carbon)(57.57 g) was
added to the organic phase. After 2 hours, the reaction mixture was
filtered through celite 545. At this point, any remaining aqueous
layer was removed and the reaction mixture was cooled to 21.degree.
C. Next, sodium bisulfite (20% w/w solution in water, 4330 g) was
added while maintaining the reaction temperature below 28.degree.
C. The reaction mixture was stirred for 17 hours and 30 minutes
followed by layer separation. The organic layer was washed with
water (3792 g). After another layer separation, the organic layer
containing the title compound was ready to be use in the next
stage.
[0643] HPLC: Rt=2.94 min (HPLC instrument Agilent 1100 Series
analysis performed on a Agilent Zorbax SB C18 (50.times.3.0 mm, 1.8
um), mobile phase: water:acetonitrile:TFA (0.05%), gradient from 0
to 95% in 2.5 min, hold for 0.2 min, then re-equilibrate;
T=60.degree. C.; flow=1.5 mL/min)
Example 1
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane hydrochloride (E1)
##STR00173##
[0644] Step A
[0645] To a stirred solution of
(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-[(methyloxy)meth-
yl]-3-azabicyclo[4.1.0]heptane-3-carboxylate (80 mg, P6) in dry DCM
(5 mL) under argon atmosphere, at 0.degree. C., a solution of
CF.sub.3COOH (1.5 mL) in dry DCM (5 mL) was added dropwise and the
mixture was stirred at 0.degree. C. for 1.5 h. The solvent was
evaporated under reduced pressure, the residue kept under vacuum
for 2 hours and then purified by preparative HPLC obtaining the
trifluoroacetate salt of the title compound (40 mg) [System MDAP
FractionLynx--Mass Directed Autopurification System.TM.; Target
product: m/z 286 [M+H]+ (Column: Luna C18, 250.times.21 mm, 10 mm;
Mobile phase: A: H2O+0.1% TFA; B: CH.sub.3CN+0.1% TFA; Gradient:
from 20% (B) to 35% (B) in 30 min, ->100% in 3 min, then 100%
(B) for 2 min; Flow rate 17 ml/min; UV wavelength range 210-350 nm;
Mass range 100-900 amu (ES+); Ionization ES+)]
Step B
[0646] To a stirred solution of this material (18 mg) in dry
diethyl ether (10 mL) under Argon atmosphere, at 0.degree. C.,
aqueous NaOH (1M, 10 mL) was added dropwise and the mixture was
vigorously stirred for 10 minutes at room temperature. The phases
were separated and the watery one was extracted with diethyl ether
(2.times.10 mL), the combined organic phases were dried on
anhydrous Na.sub.2SO.sub.4 and the solvent removed under reduced
pressure obtaining the free base of the title compound (13 mg). To
a stirred solution of this compound (13 mg) in dry diethyl ether
(1.5 mL) under Argon atmosphere, at 0.degree. C., HCl (1M in
diethyl ether, 100 .mu.L) was added dropwise, the mixture was
stirred at 0.degree. C. for 10 minutes and for 30 minutes at room
temperature. The solvent was removed by decantation and the
precipitate was dried under high vacuum for 30 minutes and then for
further two hours to give the title compound as a white solid (15
mg).
[0647] NMR (.sup.1H, DMSO-d6): .delta. 8.71 (br. s., 2H) 7.73 (d,
1H) 7.59 (d, 1H) 7.41 (dd, 1H) 3.45 (d, 1H) 3.09-3.16 (m, 2H) 3.04
(s, 3H) 2.92 (d, 1H) 2.73-2.82 (m, 1H) 2.66 (d, 1H) 2.01-2.17 (m,
2H) 1.22-1.29 (m, 2H); MS (m/z): 286 [MH]+
Example 2a and 3a
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane (E2a) and
((1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]-
heptane (E3a)
[0648] 18 mg of the free base of
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane hydrochloride (E1) were submitted to semi-preparative
HPLC (chiral column Chiralpak AS-H, 250.times.21 mm, eluent A:
n-hexane; B: isopropanol+0.1% isopropyl amine, gradient isocratic
5% B, flow rate 14 ml/min, detection UV at 230 nm. Retention times
given were obtained using an analytical HPLC using a chiral column
Chiralpak AS-H, 250.times.4.6 mm, eluent A: n-hexane; B:
isopropanol+0.1% isopropyl amine, gradient isocratic 5% B, flow
rate 1 ml/min, detection UV at 210-340 nm.) obtaining:
[0649] Example 2a (Enantiomer 1, Rt.=7.99 min) and Example 3a
(Enantiomer 2, Rt.=14.92 min).
Determination of the Absolute Configuration of 2a and 3a:
[0650] Another batch of E2a and E3a was submitted for Ab Initio VCD
(vibrational circular dichroism) analysis to determine the absolute
configuration of these optical isomers. Example 2a (Enantiomer 1)
corresponded to
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane
##STR00174##
[0651] NMR (.sup.1H, CDCl.sub.3) .delta. ppm 7.43 (d, 1H), 7.36 (d,
1H), 7.18 (d, 1H), 3.31 (d, 1H), 3.12-3.15 (m, 3H), 3.08 (d, 1H),
2.95 (d, 1H), 2.83 (d, 1H), 2.73-2.80 (m, 1H), 2.63-2.70 (m, 1H),
1.91-2.00 (m, 1H), 1.79-1.87 (m, 1H), 0.99-1.04 (m, 2H)
[0652] Example 3a (Enantiomer 2) corresponded to
(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane
##STR00175##
[0653] NMR (.sup.1H, CDCl.sub.3) .delta. ppm 7.43 (d, 1H), 7.35 (d,
1H), 7.17 (dd, 1H), 3.31 (d, 1H), 3.13 (s, 3H), 3.08 (d, 1H), 2.95
(d, 1H), 2.83 (d, 1H), 2.72-2.80 (m, 1H), 2.62-2.70 (m, 1H),
1.89-2.00 (m, 1H), 1.77-1.87 (m, 1H), 0.94-1.07 (m, 2H)
Example 2a
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane (E2a)
##STR00176##
[0654] Method B:
[0655] 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]hept-4-ene-3-carboxylate (P60, 10 grams, 25.8 mmol) was
dissolved in toluene (100 mL). The solution was treated with
triethylsilane (3.6 grams, 4.96 mL, 31.1 mmol, 1.2 eq) followed by
trifluoroacetic acid (20 grams, 13.46 mL, 181.2 mmol, 7 eq). The
reaction was stirred at room temperature for 48 hrs, then quenched
with 1N sodium hydroxide (100 mL) and stirred for 10 min. The pH of
the mixture was approximately 13. The phases were separated and the
toluene phase was washed with 1N sodium hydroxide (100 mL) and
water (10 mL) then concentrated in vacuo to give the product as an
oil (8.5 grams).
[0656] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 0.98-1.04 (m, 2H)
1.75-1.87 (m, 2H) 1.89-1.99 (m, 1H) 2.59-2.70 (m, 1H) 2.71-2.80 (m,
1H) 2.82 (d, J=9.80 Hz, 1H) 2.94 (d, J=9.89 Hz, 1H) 3.07 (d,
J=12.91 Hz, 1H) 3.12 (d, J=1.01 Hz, 3H) 3.31 (d, J=12.82 Hz, 1H)
7.11-7.21 (m, 1H) 7.35 (dd, J=8.29, 0.96 Hz, 1H) 7.43 (d, J=2.11
Hz, 1H)
Method C:
[0657] (2R,3R)-2,3-bis[(phenylcarbonyl)oxy]butanedioic
acid-(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane (1:1) (E34, 37.8 g, 58.7 mmol,) were diluted in DCM
(500 ml) and treated with aqueous K.sub.2CO.sub.3 10% w/w (500 ml).
Phases were separated and the aqueous layer was back-extracted with
DCM (1.times.400 mL). The collected organic phases, dried
(Na.sub.2SO.sub.4), were evaporated to give title compound (17.4
g).
[0658] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.45 (s, 1H), 7.36
(d, 1H), 7.19 (d, 1H), 3.32 (d, 1H), 3.14 (s, 3H), 3.09 (d, 1H),
2.96 (d, 1H), 2.84 (d, 1H), 2.73-2.81 (m, 1H), 2.64-2.71 (m, 1H),
1.92-2.00 (m, 1H), 1.79-1.88 (m, 1H), 0.97-1.07 (m, 2H).
[0659] Chiral HPLC: (Column: AS-H (25.times.0.46 cm); Eluent:
n-Hexane/(2-propanol+0.1% isopropylamine) 95/5 v/v; Flow: 1 ml/min;
DAD: 210-340 nm; CD: 230 nm; Enant1 (Rt=7.828 min)/Enant2
(Rt=14,430 min)==98.88/1.12 area
[0660] Optical rotation analysis was performed on a further batch
of E2a; optical rotation was measured at 589 nm (sodium `D` line)
using a Rudolph Research Analytical AUTOPOL V polarimeter.
Experimental conditions: Cell: 0.5 dm (50 mm) thermostated
micro-cell held at 25.degree. C.; solvent: CCl.sub.4; conc.: 38
mg/450 .mu.l=8.4 gm/1200 ml. Observed Rotation:
.alpha.=-0.23.degree.; Specific rotaion [.alpha.].sub.D=-5.47.
Example 2b
(1S,6R)-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-
ane hydrochloride (E2b)
##STR00177##
[0661] Method A:
[0662] To a solution of
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane (E2a, amount obtained from the chiral semi-preparative HPLC
described above) in DCM (0.2 ml) was added 1 equivalent of HCl (1M
in Et.sub.2O), the solvent evaporated under vacuo and the material
thus obtained triturated with Et.sub.2O to give 5 mg of the title
compound as a white slightly hygroscopic solid.
Method B:
[0663]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.]heptane (E2a, 4.6 g, 16.07 mmol) was dissolved in Et.sub.2O (60
ml) and the solution cooled to 0.degree. C. (ice bath).
Hydrochloric acid 1M in diethyl ether (17.68 ml, 1.1eq.) was
dropwise added at 0.degree. C. under stirring. A white suspension
was formed and the mixture was stirred at 25.degree. C. for 2 hrs.
The solid was filtered, washed with diethyl ether (46 ml) and dried
under vacuum at 40.degree. C. for 12 hrs to give the title compound
(5.0 g) as white solid. 96% yield.
[0664] NMR (.sup.1H, DMSO-d6, 600 MHz): .delta.(ppm): 9.05 (bs,
2H), 7.77 (d, 1H), 7.59 (d, 1H), 7.45 (dd, 1H), 3.46 (d, 1H), 3.14
(m, 1H), 3.13 (d, 1H), 3.06 (s, 3H), 2.99 (d, 1H), 2.79 (m, 1H),
2.63 (d, 1H), 2.17 (m, 1H), 2.07 (m, 1H), 1.30 (d, 1H), 1.27 (d,
1H)
Example 3b
(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane hydrochloride (E3b)
##STR00178##
[0666] To a solution of
((1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]-
heptane (E3a, amount obtained from the chiral semi-preparative HPLC
described above) in DCM (0.2 ml) was added 1 equivalent of HCl (1M
in Et.sub.2O), the solvent evaporated under vacuo and the material
thus obtained triturated with Et.sub.2O to give 5 mg of the title
compound as a white slightly hygroscopic solid
Example 4
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methano-
l (E4)
##STR00179##
[0667] Method A:
[0668] 2,6-Bis(1,1-dimethylethyl)-4-methylpyridine (35.836 g) was
added under Argon atmosphere to a solution of CH.sub.2I.sub.2 (46.9
g) in dry DCM (260 mL), then ZnEt.sub.2 (1M in hexane, 87.5 mL) was
added dropwise at 0.degree. C. over 5 mins. After stirring at
0.degree. C. for 30 minutes, the reaction mixture was cooled at
-20.degree. C., a solution of 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarbox-
ylate (2 g, P4) in dry DCM (20 mL) was added dropwise and the
reaction mixture was stirred at -20.degree. C. for additional 30
mins and then overnight at room temperature. Aqueous HCl (1M, 300
mL) was added and the reaction mixture was vigorously stirred for
20 minutes, the phases were separated and the watery layer was
basified to pH=12 with NaOH 3M. The watery solution was extracted
with diethyl ether (3.times.150 mL), the organic phase was
evaporated and the residue was taken up with saturated NH.sub.4Cl
(100 mL) and diethyl ether (100 mL) and the mixture was vigorously
stirred for 10 mins, then the phases were separated. The watery
phase was washed with diethyl ether (3.times.50 mL), then was
basified to pH=12 with NaOH 3M and extracted with diethyl ether
(3.times.150 ml).
[0669] The combined organic phases were dried on anhydrous
Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure
to give 840 mg of impure material.
[0670] MS (m/z): 272 [MH].sup.+.
Method B:
[0671] To a stirred solution of methyl
6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate
(P16, 0.5 g) in THF (2.5 mL), at 0.degree. C. and under a nitrogen
atmosphere, BH.sub.3THF complex (1M/THF, 12.8 mL) was added
dropwise, then the reaction mixture was allowed to reach RT and
stirred at reflux for 5 h. 1 mL of MeOH and 5 mL of HCl 1.0M in
Et.sub.2O were added to the reaction mixture and the solution was
stirred at room temperature for 2 hours. The mixture was
concentrated under reduced pressure and the crude product was
purified by FC (eluting with DCM/methanol/aqueous 28% NH.sub.4OH
9/1/0.1) to give 82 mg of the title compound as a yellow oil.
Method C:
[0672]
(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxyme-
thyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (P5, 50 mg, impure
compound obtained as described in P5, Method A) was purified by
preparative HPLC (Column:Luna C18, 250.times.21 mm, 10 mm; mobile
phase: A: H2O+0.1% TFA; B: CH.sub.3CN+0.1% TFA; gradient: from 15%
(B) to 35% (B) in 30 min, ->100% in 3 min, then 100% (B) for 2
min; flow rate: 17 ml/min; UV wavelength range: 210-350 nm)
obtaining its trifluoroacetate salt (23 mg).
[0673] To a stirred solution of this product (23 mg) in dry diethyl
ether (10 mL) under argon atmosphere, at 0.degree. C., NaOH (1M, 10
mL) was added dropwise and the mixture was vigorously stirred for
10 minutes at room temperature then the phases were separated and
the watery one was extracted with diethyl ether (2.times.10 mL).
The combined organic phases were dried on anhydrous
Na.sub.2SO.sub.4 and the solvent was removed at reduced pressure
obtaining the free base of the title compound (16 mg).
Example 5a and 6a
[(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]meth-
anol (E5a) and [(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol
(E6a)
[0674]
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]-
methanol (E4, 82 mg) was submitted to semi-preparative HPLC (chiral
column Chiralpak AD-H, 25.times.4.6 cm, eluent A: n-hexane; B:
isopropanol+0.1% isopropylamine 70/30 v/v, flow rate 0.8 ml/min.,
detection UV at 230 nm.) obtaining:
[0675] [(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol
(E5a, Enantiomer 1, Rt.=6.263 min) and [(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol
(E6a, Enantiomer 2, Rt.=15.699 min).
Example 5b
[(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]meth-
anol hydrochloride (E5b)
[0676] To a solution of [(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol
(E5a, amount obtained from the preparation described above) in DCM
was added 1 equivalent of HCl (1M in Et.sub.2O), the solvent
evaporated in vacuo and the material thus obtained triturated with
Et.sub.2O to give 30 mg of the corresponding hydrochloride salt as
a white slightly hygroscopic solid.
Example 6b
[(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]meth-
anol (E6b)
[0677] To a solution of [(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol
(E6a, amount obtained from the preparation described above) in DCM
was added 1 equivalent of HCl (1M in Et.sub.2O), the solvent
evaporated in vacuo and the material thus obtained triturated with
Et.sub.2O to give 30 mg of the corresponding hydrochloride salt as
a white slightly hygroscopic solid.
[0678] NMR (.sup.1H, DMSO-d6): d ppm 8.78 (d, 2H) 7.76 (d, 1H) 7.58
(dd, 1H) 7.37-7.46 (m, 1H) 4.75 (t, 1H) 3.49-3.60 (m, 1H) 3.06-3.23
(m, 2H) 2.95-3.05 (m, 1H) 2.72-2.88 (m, 2H) 1.99-2.21 (m, 2H)
1.15-1.26 (m, 2H)
Example 7
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]-methano-
l hydrochloride (E7)
##STR00180##
[0680] To a stirred solution of
[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methan-
ol (E4, 16 mg) in dry diethyl ether (1.5 mL) under argon
atmosphere, at 0.degree. C., HCl (1M in diethyl ether, 0.12 ml) was
added dropwise, the mixture was stirred at 0.degree. C. for 10
minutes and for 30 minutes at room temperature. The solvent was
removed by decantation and the precipitate was dried under high
vacuum for 30 minutes to give the titled compound as white solid
(18 mg).
[0681] NMR (.sup.1H, DMSO-d6): .delta. 8.66 (br. s., 2H) 7.73 (d,
1H) 7.57 (d, 1H) 7.40 (dd, 1H) 4.75 (t, 1H) 3.52 (d, 1H) 3.06-3.18
(m, 2H) 2.93-3.03 (m, 1H) 2.70-2.83 (m, 2H) 1.99-2.17 (m, 2H)
1.15-1.24 (m, 2H); MS (m/z): 272 [MH].sup.+
Examples 8
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane
(E8)
##STR00181##
[0683] To a solution of
(1R,6R/1S,6S)-1-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one
and
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one
(640 mg, P11) in dry tetrahydrofurane (16 ml) borane THF (1M in
THF, 7.53 ml) was added under N.sub.2 and the mixture heated at
reflux for 3 h and at room temperature over night and then heated
at reflux for 2 h. The mixture was then cooled to 0.degree. C. and
methanol (8 mL) followed by hydrochloric acid (1M/ether, 25 mL)
were cautiously added monitoring gas evolution and the solution
stirred at room temperature over night. Solvents were then removed
in vacuo and potassium carbonate (10% solution) was added to the
residue. The aqueous layer was extracted with dichloromethane, then
the organic phase was washed with a NaCl saturated solution, dried
and concentrated under reduced pressure. The title compound was
separated by aminic cartridge (eluting with cyclohexanemethyl
acetate from 9/1 to 7/3) to give the title compound in 150 mg
yield.
[0684] NMR (.sup.1H, CDCl.sub.3): .delta. 7.37 (m, 2H), 7.15 (d,
1H), 3.35 (m, 1H), 3.12 (d, 1H), 2.78 (m, 2H), 2.05 (m, 2H), 1.35
(m, 1H), 1.04 (m, 1H), 0.94 (m, 1H); MS (m/z): 242 [MH].sup.+.
Example 9a and 10a
(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E9a) and
(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane
(E10a)
[0685]
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane
(E8, 150 mg) was submitted to semi-preparative HPLC (chiral column
Chiralpak AD-H, 25.times.4.6 cm, eluent A: n-hexane; B:
isopropanol+0.1% isopropylamine 99/1 v/v, flow rate 1 ml/min.
detection UV at 230 nm.) obtaining:
[0686] Example 9a (E9a, Enantiomer 1, Rt.=15.22 min) and Example
10a (E10a, Enantiomer 2, Rt.=15.33 min).
[0687] Determination of the absolute configuration of 9a and 10a: A
new batch of E9a (7 mg) and E10a (9 mg)(prepared following an
analogous procedure to that described below for 9B and 10B and then
treating the corresponding hydrochloride salts with NaOH to obtain
the free bases) was submitted to Ab Initio VCD (vibrational
circular dichroism) and comparative VCD analysis to determine the
absolute configuration of these optical isomers.
[0688] Example 9a (enantiomer 1) corresponded to
(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane
##STR00182##
[0689] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.32-7.37 (m, 2H),
7.10 (dd, 1H), 3.34 (dd, 1H), 3.07 (d, 1H), 2.51-2.79 (m, 2H),
1.97-2.08 (m, 1H), 1.85-1.97 (m, 1H), 1.21-1.36 (m, 1H), 0.92-1.01
(m, 1H), 0.81-0.91 (m, 1H)
[0690] Example 10a (enantiomer 2) corresponded to
(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane:
##STR00183##
[0691] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.32-7.37 (m, 2H),
7.10 (dd, 1H), 3.34 (dd, 1H), 3.07 (d, 1H), 2.51-2.79 (m, 2H),
1.97-2.08 (m, 1H), 1.85-1.97 (m, 1H), 1.21-1.36 (m, 1H), 0.92-1.01
(m, 1H), 0.81-0.91 (m, 1H)
Example 9b
(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane
hydrochloride (E9b)
##STR00184##
[0693] To a solution of
(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E9a, 40
mg) in DCM was added 1 equivalent of HCl (1M in Et.sub.2O), the
solvent evaporated in vacuo and the material thus obtained
triturated with Et.sub.2O to give 45 mg of the title compound as a
white slightly hygroscopic solid.
[0694] NMR (.sup.1H, MeOH-d.sub.4): .delta. ppm 7.52 (d, 1H) 7.45
(d, 1H) 7.28 (dd, 1.52 Hz, 1H) 3.46-3.65 (m, 7.07 Hz, 1H) 3.10 (d,
1H) 2.88-3.04 (m, 1H) 2.49-2.82 (m, 1H) 1.97-2.28 (m, 2H) 1.37-1.56
(m, 1H) 1.07-1.19 (m, 1H) 0.92-1.06 (m, 1H)
Example 10b
(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane
hydrochloride (E10b)
##STR00185##
[0696] To a solution of
(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E10a, 40
mg) in DCM was added 1 equivalent of HCl (1M in Et.sub.2O), the
solvent evaporated in vacuo and the material thus obtained
triturated with Et.sub.2O to give 45 mg of the title compound as a
white slightly hygroscopic solid.
[0697] NMR (.sup.1H, MeOH-d.sub.4): .delta. ppm 7.52 (d, 1H) 7.45
(d, 1H) 7.28 (dd, 1.52 Hz, 1H) 3.46-3.65 (m, 7.07 Hz, 1H) 3.10 (d,
1H) 2.88-3.04 (m, 1H) 2.49-2.82 (m, 1H) 1.97-2.28 (m, 2H) 1.37-1.56
(m, 1H) 1.07-1.19 (m, 1H) 0.92-1.06 (m, 1H)
Example 11
(1S,4R,6R/1R,4S,6S)-6-(3,4-dichlorophenyl)-4-methyl-1-[(methyloxy)methyl]--
3-azabicyclo[4.1.0]heptane (E11)
##STR00186##
[0699] 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-4-methyl-3-azabicy-
clo[4.1.0]heptane-3-carboxylate (P68, 70 mg) was dissolved in DMF
(30 mL) and cooled to 0.degree. C.; then sodium hydride 60%
dispersed on mineral oil (10.9 mg) was added portionwise. The
mixture was stirred at 0.degree. C. for 30 min and then iodomethane
(0.017 mL) was added. The mixture was slowly warmed to room
temperature and stirred for 1.5 h. Further 7.2 mg of sodium hydride
60% dispersed on mineral oil and 0.017 mL of iodomethane were added
and the mixture was stirred for an additional hour. The reaction
mixture was then quenched with a saturated solution of NH.sub.4Cl
(30 mL) and Et.sub.2O (30 mL) added. The aqueous phase was washed
with Et.sub.2O (3.times.30 mL), the organic phases combined, dried
over Na.sub.2SO.sub.4 and concentrated. Purification by
chromatography on silica gel eluting with a gradient 10%-30% ethyl
acetate/cyclohexane afforded a compound (50 mg) that was dissolved
in DCM (1.2 mL), cooled to 0.degree. C. and reacted with
trifluoroacetic acid (0.22 mL). The mixture was slowly warmed to
room temperature and stirred at this temperature for 2 h. The
volatiles were evaporated under vacuum and the residue purified by
SCX cartridge eluting first with MeOH and then with 2.0M NH.sub.3
in MeOH. Further purification by preparative HPLC afforded the
title compound, 20 mg.
[0700] XBridge PREP C18, 100.times.19 mm, 5 .mu.m
[0701] Mobile phase:H.sub.2O+0.1% TFA; B: CH.sub.3CN
[0702] Gradient:20(B) for 1 min, 20% to 35% (B) in 12 min, 35% to
100% (B) in 0.5 min, 100% (B) for 1.5 min
[0703] Flow rate:17 mL/min
[0704] NMR (.sup.1H, CDCl.sub.3): .delta. 7.46 (d, 1H), 7.33 (d,
1H), 7.20 (dd, 1H), 3.54 (d, 1H), 3.06-3.17 (m, 3H), 2.89-3.01 (m,
2H), 2.72 (d, 1H), 2.27-2.53 (m, 1H), 1.91-2.07 (m, 1H), 1.27-1.46
(m, 1H), 1.04 (d, 3H), 0.87-0.98 (m, 2H). MS (m/z): 300
[M+H].sup.+.
Example 12
(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo-
[4.1.0]heptane (E12)
##STR00187##
[0706]
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane (E2a, 25 mg) was dissolved in methanol (1 mL); acetic
acid (0.015 mL) was added followed by sodium triacetoxyborohydride
(27.8 mg) and formaldehyde 37% in water (0.06 mL). The reaction
mixture was stirred at room temperature overnight. Volatiles were
then evaporated and the residue partitioned between DCM (20 mL) and
aqueous sat NaHCO.sub.3 (20 mL) solution, dried and concentrated.
Purification by chromatography (NH column) eluting with a gradient
0-100% ethyl acetate-cyclohexane afforded the title compound (16
mg).
[0707] NMR (.sup.1H, CDCl.sub.3): .delta. 7.44 (d, 1H), 7.35 (d,
1H), 7.18 (dd, 1H), 3.15 (s, 3H), 2.90 (dd, 2H), 2.78 (d, 1H), 2.70
(d, 1H), 2.23-2.30 (m, 5H), 1.96-2.13 (m, 2H), 1.05 (d, 1H), 1.01
(d, 1H); MS (m/z): 300 [M+H].sup.+.
Example 13
(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo-
[4.1.0]heptane hydrochloride (E13)
##STR00188##
[0709]
(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-aza-
bicyclo[4.1.0]heptane (E12, 16 mg) was treated with hydrochloric
acid 1.0M in diethyl ether (0.064 mL). 0.5 mL of diethyl ether were
added and a colourless solid formed. Organic phase was removed
after decantation of the solid. Colouness solid obtained as a 5:1
mixture of isomers due protonation on the nitrogen atom (16
mg).
[0710] NMR (.sup.1H, DMSO-d6): .delta. 10.49 (br. s., 1H), 7.84 (d,
1H), 7.57-7.65 (m, 1H), 7.51-7.55 (m, 1H), 3.68-3.66 (m, 1H),
3.22-3.35 (m, 1H), 3.00-3.17 (m, 5H), 2.76-2.93 (m, 2H), 2.68-2.75
(m, 3H), 2.29-2.43 (m, 1H), 2.10-2.21 (m, 1H), 1.32 (d, 1H), 1.27
(d 1H) (peaks referred to the main species); MS (m/z): 300
[MH].sup.+.
Example 14
(1R,6S/1S,6R)-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-
-azabicyclo[4.1.0]heptane (E14)
##STR00189##
[0711] Step A
[0712] 1,1-dimethylethyl
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3--
azabicyclo[4.1.0]heptane-3-carboxylate (P27, 0.3 g) was dissolved
in DMF (5 mL) and cooled to 0.degree. C.; NaH 60% in mineral oil
(39 mg) was added and the reaction mixture was stirred at 0.degree.
C. for 30 minutes. Iodomethane (92 .mu.l) was then added and
mixture slowly warmed to room temperature. Further 2 addition of
NaH (20 mg) and MeI (50 .mu.l) each were done and the mixture
stirred for an overall time of 1.5 hours. The reaction mixture was
then quenched at 0.degree. C. with a saturated solution of
NH.sub.4Cl (5 mL) and diluted with diethyl ether (20 mL); the
organic phase was separated, washed with brine (20 mL), dried and
concentrated under vacuum. The crude mixture was then purified by
chromatography on silica gel eluting with a gradient 10-50%
ethylacetate/cyclohexane to afford 1,1-dimethylethyl
(1R,6S)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-az-
abicyclo[4.1.0]heptane-3-carboxylate as colourless oil (107
mg).
[0713] MS (m/z): 420 [MH].sup.+, 363 [M-56].sup.+.
Step B
[0714] 1,1-dimethylethyl
(1R,6S)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-az-
abicyclo[4.1.0]heptane-3-carboxylate coming from step A was
dissolved in DCM (4 mL) and TFA (0.2 mL) was added to the solution.
The reaction mixture was stirred at room temperature for 1 hour and
then volatiles were evaporated in vacuo. The residue was dissolved
in DCM (10 mL), washed with a saturated solution of NaHCO.sub.3 (10
mL), brine (10 mL), dried and concentrated under vacuum. The
residue was purified initially on a SCX cartridge eluting first
with MeOH followed by 2.0N NH.sub.3 in MeOH and then by
chromatography on silica gel eluting with a gradient 3% MeOH/DCM to
8% MeOH/DCM+2% 2.0N NH.sub.3 in MeOH to give 55 mg of the title
compound.
[0715] NMR (.sup.1H, CDCl.sub.3): .delta. 7.72 (d, 1H), 7.48-7.53
(m, 1H), 7.42-7.46 (m, 1H), 3.42 (d, 1H), 3.08-3.14 (m, 4H), 3.04
(d, 1H), 2.81-2.90 (m, 1H), 2.66-2.76 (m, 2H), 1.97-2.06 (m, 1H),
1.85-1.93 (m, 2H), 1.11 (d, 1H), 1.04 (d, 1H);); MS (m/z): 320
[MH].sup.+.
Example 15
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-
-3-azabicyclo[4.1.0]heptane hydrochloride (E15)
##STR00190##
[0717] To a solution of
(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane (E14, 55 mg) in DCM was added 1
equivalent of HCl (1M in Et.sub.2O), the solvent evaporated in
vacuo and the material thus obtained triturated with Et.sub.2O to
give 61 mg of the title compound as a white solid.
[0718] NMR (.sup.1H, DMSO-d6): .delta. 8.48-8.86 (m, 2H), 7.95 (s,
1H), 7.63-7.77 (m, 2H), 3.51 (d, 1H), 3.13-3.22 (m, 2H), 3.03 (s,
3H), 2.73-2.88 (m, 2H), 2.72-2.88 (m, 2H), 2.05-2.16 (m, 1H),
1.26-1.36 (m, 2H)); MS (m/z): 320 [MH].sup.+.
Example 16
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]-
heptane (E16).
##STR00191##
[0720] To an ice cooled solution of 1,1-dimethylethyl
(1R,6S/1S/6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0-
]heptane-3-carboxylate (P32, impure compound obtained with a
similar procedure to that previously described for P32, 280 mg) in
dichloromethane (5 mL) under nitrogen, trifluoroacetic acid (1 mL)
was added dropwise. The reaction mixture was allowed to room
temperature and then stirred for 1 h. The solvent was evaporated
under reduced pressure. The crude material was purified through a
SCX (5 g) column, then was submitted to preparative HPLC (column:
Luna AXIA C18, 100.times.21 mm, 5 um; Mobile phase: A: H2O+0.1%
TFA; B: CH.sub.3CN; Gradient: 15% (B) .delta. 35% (B) in 15 min
(curve 7*), 35% (B).fwdarw.100% (B) in 2 min, 100% (B) for 0.1 min;
Flow rate 17 ml/min; UV range: 210-350 nm; Mass range: 100-900 amu
(ES+); Ionization: ES+). The compound obtained was passed through a
SCX column to afford the title compound (70 mg).
[0721] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.25 (s, 4H) 3.30 (d,
1H) 3.08-3.14 (m, 4H) 2.85-2.91 (m, 2H) 2.63-2.80 (m, 2H) 1.81-1.99
(m, 2H) 0.99-1.05 (m, 2H).
Example 17
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]-
heptane hydrochloride (E17)
##STR00192##
[0723] To a solution of
(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0-
]heptane (E16, 70 mg) in anhydrous dichloromethane (2 mL) was added
HCl 1.0M in anhydrous diethylether (0.278 mL). The solvent was
evaporated under reduced pressure and the resulting solid was
triturated with anhydrous diethylether to give the title compound
(76 mg).
[0724] NMR (.sup.1H, DMSO-d.sub.6): .delta. ppm 8.33-9.07 (m, 2H)
7.44 (d, 2H) 7.38 (d, 2H) 3.47 (d, 1H) 3.15 (d, 1H) 3.07-3.19 (m,
1H) 3.00-3.07 (m, 3H) 2.94 (d, 1H) 2.74-2.84 (m, 1H) 2.58 (d, 1H)
2.09-2.23 (m, 1H) 1.96-2.09 (m, 1H) 1.27 (d, 1H) 1.21 (d, 1H)
Example 18
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1-
.0]heptane hydrochloride (E18)
##STR00193##
[0725] Step A
[0726] To a stirred solution of 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane-3-carboxylate (P51, 78 mg) in dry DCM (5 mL), under a
nitrogen atmosphere, trifluoroacetic acid (1.5 mL) was added and
the stirring continued for 2 hrs. After this period of time toluene
was added and the solvent evaporated obtaining a crude product that
was dissolved in DCM, the organic phase was washed with aqueous
concentrated NaHCO.sub.3 solution, the organic solvent evaporated.
The crude product was purified first by flash-chromatography
(eluting with DCM/(Methanol+1% 2N NH.sub.3 in MeOH) from 0 to 20%)
and then by LC-MS to give 27 mg of
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane, the free base of the title compound.
Step B
[0727] 10 mg of this compound were dissolved in DCM (1 ml) and 1
equivalent of 1N HCl in Et.sub.2O was added. The solvent was
removed in vacuo to give title compound (12 mg).
[0728] NMR (.sup.1H, MeOH-d.sub.4): .delta. 7.58 (d, 1H) 7.38 (d,
1H) 7.25 (dd, 1H) 3.64 (d, 1H) 3.15 (m, 5H) 2.79 (m, 1H) 2.57 (d,
1H) 2.11 (m, 2H) 1.19 (d, 1H) 1.12 (d, 1H) 0.98 (t, 3H);
[0729] MS (m/z): 300 [MH]+
Example 19a and 20a
(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[-
4.1.0]heptane (E19a) and (1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane (E20a)
[0730]
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicy-
clo[4.1.0]heptane hydrochloride (E18, 28 mg) was then submitted to
semi-preparative SFC to give the separated enantiomers, by using a
chiral column Chiralpak AD-H (25.times.4.6 cm), eluent
2-propanol+0.1% isopropylamine 13%, T 35.degree. C., P 100 bar,
flow rate 2.0 mL/min, detection DAD 210-340 nm, CD 225 nm.
obtaining:
[0731] Example 19a (Enantiomer 1, Rt.=14.36 min, 11 mg, colourless
oil, MS (m/z): 300 [MH].sup.+) and Example 20a (enantiomer 2,
Rt.=15.70 min, 7 mg, colourless oil, MS (m/z): 300 [MH]+).
Example 19b
(1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[-
4.1.0]heptane hydrochloride (E19b)
[0732] To a solution of (1R,6S or
1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane (E19a, 11 mg) in DCM (0.2 ml) was added 1 equivalent of HCl
(1M in Et.sub.2O), the solvent evaporated under vacuo and the
material thus obtained triturated with Et.sub.2O to give 8.9 mg of
the title compound as a white slightly hygroscopic solid.
[0733] MS (m/z): 300 [MH].sup.+
Example 20b
(1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[-
4.1.0]heptane hydrochloride (E20b)
[0734] To a solution of (1S,6R or
1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]hep-
tane (E20a, 7 mg) in DCM (0.2 ml) was added 1 equivalent of HCl (1M
in Et.sub.2O), the solvent evaporated under vacuo and the material
thus obtained triturated with Et.sub.2O to give 5.8 mg of the title
compound as a white slightly hygroscopic solid.
[0735] NMR (.sup.1H, MeOH-d.sub.4): .delta. 7.70 (d, 1H) 7.49 (d,
1H) 7.36 (dd, 1H) 3.75 (d, 1H) 3.37 (m, 1H) 3.26 (m, 3H) 3.15 (m,
1H) 2.89 (m, 1H) 2.69 (d, 1H) 2.23 (q, 2H) 1.29 (d, 1H) 1.23 (d,
1H) 1.13 (t, 3H); MS (m/z): 300 [MH].sup.+
Example 21
(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-a-
zabicyclo[4.1.0]heptane (E21)
##STR00194##
[0737] To a stirred solution of
(1S,6R/1R,6S)-1,1-dimethylethyl-1-(hydroxymethyl)-6-{4-[(trifluoromethyl)-
oxy]phenyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate (P36,173 mg)
in dry THF (3 mL) under N.sub.2 atmosphere, at 0.degree. C., NaH
(60% on mineral oil, 24 mg) was added and the stirring continued
for 30 minutes. CH.sub.3I (52 .mu.L) was added dropwise and the
reaction was slowly warmed to room temperature and stirred for 3 h.
Saturated NH.sub.4Cl aqueous solution was added and then the
mixture was concentrated in vacuo. The aqueous phase was extracted
with diethyl ether (2 times) and then the combined organic layers
were washed with saturated NaCl aqueous solution, dried on
anhydrous Na.sub.2SO.sub.4, and evaporated obtaining a crude
product. The crude was dissolved in dry DCM (4 mL) and TFA (3.5 mL)
was added under N.sub.2 atmosphere at 0.degree. C. The reaction was
slowly warmed to room temperature and stirred for 1 h. The mixture
was concentrated in vacuo and the residue was purified by a SCX
cartridge. The crude thus obtained was purified by HPLC
chromatography to give the title compound (35 mg).
[0738] Conditions LC: Column Luna AXIA C18, 100.times.21 mm, 5
.mu.m
[0739] Mobile phase A: H2O+0.1% TFA; B: CH.sub.3CN
[0740] Gradient: from 20% (B) to 35% (B) in 18 min, from 35% (B) to
80% (B) in 7 min, from 75% (B) to 100% (B) in 1 min, 100% (B) for 3
min.
[0741] Flow rate 17 ml/min
[0742] UV range 210-350 nm
[0743] Mass range 100-900 amu (ES+)
[0744] Ionization ES+
[0745] R.sub.t=3.37 min
[0746] MS (m/z): 302[M+H].sup.+
Example 22
(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-a-
zabicyclo[4.1.0]heptane hydrochloride (E22)
##STR00195##
[0748] To a stirred solution of
(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3--
azabicyclo[4.1.0]heptane (E21, 35 mg) in dry diethyl ether HCl (1M
in diethyl ether, 0.12 ml) was added dropwise. The solvent was
removed by decantation and the precipitate was dried under vacuum
to give the title compound as white solid (30 mg).
[0749] NMR (.sup.1H, MeOH-d.sub.4): .delta. ppm 7.52 (d, 2H) 7.24
(d, 2H) 3.72 (d, 1H) 3.27 (d, 1H) 3.25-3.21 (m, 1H) 3.16-3.12 (m,
3H) 3.07 (d, 1H) 2.97-2.84 (m, 1H) 2.74 (d, 1H) 2.32-2.12 (m, 2H)
1.31 (d, 1H) 1.22 (d, 1H)
Example 23
(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-
-3-azabicyclo[4.1.0]heptane (E23)
##STR00196##
[0750] Step A
[0751] To a stirred solution of (1S,6R/1R,6S)-phenylmethyl
6-[3-chloro-4-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3-azabicyclo[4.1-
.0]heptane-3-carboxylate (430 mg) (P41, impure compound coming from
preparation above described) in dry THF (6 mL) under N.sub.2
atmosphere, at 0.degree. C., NaH (60% on mineral oil, 59 mg) was
added and the stirring was continued for 30 minutes. CH.sub.3I (113
.mu.L) was added dropwise and the reaction was allowed to reach
room temperature and stirred overnight. Saturated NH.sub.4Cl
aqueous solution was added and then the mixture was concentrated in
vacuo. The aqueous phase was extracted with diethyl ether (2 times)
and then the combined organic layers were washed with saturated
NaCl aqueous solution, dried on anhydrous Na.sub.2SO.sub.4, and
evaporated obtaining a crude product. The crude was purified by
flash-chromatography (eluting with cyclohexane/ethyl acetate from
9:1 to 8:2) to give 300 mg of impure phenylmethyl
(1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-az-
abicyclo[4.1.0]heptane-3-carboxylate.
Step B
[0752] The impure product thus obtained was dissolved in dry
1,4-dioxane (6 mL) and to the solution a HCl 6N (1 mL) solution was
added. The reaction mixture was refluxed for 4 h and then further
HCl 6 N (2 mL) was added to the solution. It was stirred at RT
overnight and then refluxed for 5 h. The reaction was quenched with
aqueous NaOH 3N (pH=12) solution and extracted with Et.sub.2O (3
times). The combined organic layers were washed with saturated NaCl
aqueous solution, dried and concentrated in vacuo. The residue was
purified by a SCX cartridge. The crude thus obtained was purified
by HPLC chromatography to give the free base of the title compound
(20 mg).
[0753] Conditions LC chromatography: Column Gemini C18 AXIA,
50.times.21 mm, 5 .mu.m
[0754] Mobile phase A: NH.sub.4HCO3 10 mM aq. sol, pH=10; B:
CH3CN
[0755] Gradient: from 30% (B) to 35% (B) in 1 min, from 35% (B) to
75% (B) in 7 min, from 75% (B) to 100% (B) in 1 min, 100% (B) for 1
min.
[0756] Flow rate 17 ml/min UV range 210-350 nm
[0757] Mass range 100-900 amu (ES+)
[0758] Ionization ES+
[0759] R.sub.t=3.38 min
[0760] MS (m/z): 320[M+H]+
Example 24
(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-
-3-azabicyclo[4.1.0]heptane hydrochloride (E24)
##STR00197##
[0762] To a stirred solution of the
(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl-
]-3-azabicyclo[4.1.0]heptane (E23, 20 mg) in dry diethyl ether HCl
(1M in diethyl ether) was added dropwise. The solvent was removed
by decantation and the precipitate was dried under vacuum to give
the titled compound as white solid (21 mg).
[0763] NMR (free base, .sup.1H, CDCl.sub.3): .delta. ppm 7.71 (s,
1H) 7.46 (dd, 2H) 3.40 (d, 1H) 3.12 (s, 3H) 2.99-3.10 (m, 2H)
2.76-2.91 (m, 1H) 2.65-2.76 (m, 2H) 1.91-2.07 (m, 2H) 1.79-1.91 (m,
1H) 1.10 (d, 1H) 1.02 (d, 1H); MS (m/z): 320 [MH].sup.+
Example 25
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]-
heptane (E25)
##STR00198##
[0765] Phenylmethyl
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0-
]heptane-3-carboxylate (P44, 600 mg) was dissolved in 1,4-dioxane
(7 mL) and aqueous 6.0N HCl (7 mL) was added. The reaction mixture
was refluxed for 4 hours and then heated to 85.degree. C. for 18
hours. After cooling to room temperature, the aqueous phase was
washed with diethyl ether (30 mL), basified with 3.0M NaOH and
extracted with DCM (3.times.50 mL). Organics were combined, dried
over Na.sub.2SO.sub.4 and concentrated. The crude reaction was
purified by chromatography on silica gel eluting with 5% MeOH/DCM
at first and then with 5% MeOH/DCM+2% 2.0M NH.sub.3 in MeOH. The
title compound was obtained as colourless oil (145 mg).
[0766] NMR (.sup.1H, CDCl.sub.3): .delta. 7.77-7.86 (m, 3H),
7.72-7.76 (m, 1H), 7.42-7.52 (m, 3H), 3.37 (d, 1H), 3.18 (d, 1H),
3.10 (s, 3H), 3.02 (d, 1H), 2.80-2.89 (m, 2H), 2.70-2.79 (m, 1H),
1.96-2.08 (m, 2H), 1.25 (d, 1H), 1.11 (d, 1H);); MS (m/z): 268
[MH].sup.+.
Example 26a and 27a
(1R,6S or
1S,6R)-1-[(methyloxy)methyl]-6(2-naphthalenyl)-3-azabicyclo[4.1.-
0]heptane (E26a) and (1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e (E27a)
[0767]
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo-
[4.1.0]heptane (E25, 140 mg) were submitted to semi-preparative
HPLC using a chiral column Chiralcel OJ, 25.times.4.6 cm, eluent A:
n-hexane; B: ethanol 0.1% isopropylamine-85/15, flow rate 0.9
mL/min, detection UV at 228 nm obtaining:
[0768] Example 26a (Enantiomer 1, Rt.=5.77 min, 52 mg, colourless
oil) and Example 27a (Enantiomer 2, Rt.=7.40 min, 40 mg, colourless
oil).
Example 28
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]-
heptane hydrochloride (E28)
##STR00199##
[0770] To a solution
(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0-
]heptane (E25, 5 mg) in DCM was added 1 equivalent of HCl (1M in
Et.sub.2O), the solvent evaporated in vacuo and the material thus
obtained triturated with Et.sub.2O to give 5 mg of the
corresponding hydrochloride salt as a white solid.
[0771] MS (m/z): 268 [MH].sup.+.
Example 26b
(1R,6S or 1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3,
azabicyclo[4.1.0]heptane hydrochloride (E26b)
##STR00200##
[0773] To a solution of (1R,6S or
1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e (E26a, 52 mg) in DCM was added 1 equivalent of HCl (1M in
Et.sub.2O), the solvent evaporated in vacuo and the material thus
obtained triturated with Et.sub.2O to give 53 mg of the title
compound as a white solid.
[0774] NMR (.sup.1H, CDCl.sub.3): .delta. 7.24-7.32 (m, 4H),
7.09-7.14 (m, 1H), 6.90-6.98 (m, 2H), 3.32 (d, 1H), 2.76-2.88 (m,
2H), 2.60-2.65 (m, 1H), 2.54-2.58 (m, 3H), 2.40-2.49 (m, 1H),
2.24-2.29 (m, 1H), 1.99-2.10 (m, 1H), 1.76-1.84 (m, 1H), 0.92-0.95
(m, 1H), 0.80-0.84 (m, 1H); MS (m/z): 268 [MH].sup.+.
Example 27b
(1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1-
.0]heptane hydrochloride (E27b)
##STR00201##
[0776] To a solution of (1S,6R or
1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptan-
e (E27a, 40 mg) in DCM was added 1 equivalent of HCl (1M in
Et.sub.2O), the solvent evaporated in vacuo and the material thus
obtained triturated with Et.sub.2O to give 40 mg of the title
compound as a white solid.
[0777] NMR (.sup.1H, DMSO-d6): .delta. 7.83-7.90 (m, 3H), 7.80-7.83
(m, 1H), 7.60 (dd, 1H), 7.44-7.52 (m, 2H), 3.20-3.40 (m, 1H), 3.13
(d, 1H), 2.93-3.05 (m, 5H), 2.74-2.83 (m, 1H), 2.63 (d, 1H),
1.99-2.17 (m, 2H), 1.25-1.32 (m, 2H)); MS (m/z): 268
[MH].sup.+.
Example 29
(1S,6R/1R,6S)-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyc-
lo[4.00]heptane hydrochloride (E29)
##STR00202##
[0779] The title compound was prepared according to a similar
procedure to that described for Example 18 in 115 mg yield starting
from (1S,6R/1R,6S)-1,1-dimethylethyl
6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-
ane-3-carboxylate (164 mg, P50).
[0780] NMR (.sup.1H, DMSO-do): .delta. ppm 8.28 (s, 1H) 7.66 (d,
1H) 7.25-7.47 (m, 2H) 3.41 (d, 1H) 3.01-3.14 (m, 5H) 2.92 (d, 1H)
2.75 (d, 1H) 2.68 (d, 1H) 1.98-2.10 (m, 2H) 1.17-1.26 (m, 2H); MS
(m/z): 270 [MH].sup.+
Example 30
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1
{[(2,2,2-trifluoroethyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane
(E30)
##STR00203##
[0781] Step a)
[0782] To a stirred solution of 2,2,2-trifluoroethanol (12 .mu.l)
in DMF (1 mL) sodium hydride (60% in mineral oil, 5.7 mg) was added
followed, after 10 min, by a solution of 1-dimethylethyl
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(methylsulfonyl)oxy]methyl}-3-az-
abicyclo[4.1.0]heptane-3-carboxylate (P69, 60 mg), in DMF (2 mL).
After 4 hrs, further 2,2,2-trifluoroethanol (12 .mu.L) in DMF (1
mL) and sodium hydride (60% in mineral oil, 5.7 mg) were added.
After 2 days further 2,2,2-trifluoroethanol (12 .mu.L) in DMF (1
mL), and sodium hydride (5.7 mg) were added and the reaction was
heated to 60.degree. C. for 5 hrs. DCM and NaHCO.sub.3 saturated
solution were added and the solvent was removed under reduced
pressure to give 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl-
}-3-azabicyclo[4.1.0]heptane-3-carboxylate as crude (6 mg).
Step b)
[0783] The crude 1,1-dimethylethyl
(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl-
}-3-azabicyclo[4.1.0]heptane-3-carboxylate (6 mg, E30, Step a) was
dissolved in dry DCM (1 mL) and TFA (0.5 mL) was added. The
reaction mixture was stirred for 2 hrs and after this period of
time the solvent was evaporated to give a crude that was
redissolved in DCM. The organic phase was washed with NaHCO.sub.3
saturated solution, dried and concentrated. The crude product was
purified by flash-chromatography (eluting with
DCM/Methanol/NH.sub.3/MeOH 2N 49/1/1) to give the title compound
(3.9 mg).
[0784] NMR (.sup.1H, CDCl.sub.3): .delta. 7.5 (s, 1H) 7.45 (d, 1H)
7.35 (m, 1H), 3.9 (d, 2H) 3.7 (d, 1H) 3.6 (m, 2H) 3.25 (d, 1H) 3.15
(m, 2H) 2.3 (m, 1H) 2.2 (m, 1H) 1.25 (m, 2H).
Example 31
(1S,6R,7R/1R,6S,7S)-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicycl-
o[4.1.0]heptane (E31)
##STR00204##
[0786] To a stirred solution of 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane-3-carboxylate and 1,1-dimethylethyl
4-(3,4-dichlorophenyl)-6-[2-(methyloxy)ethyl]-3,6-dihydro-1(2H)-pyridinec-
arboxylate (P56, mg) in dry DCM (4 mL) trifluoroacetic acid (0.75
ml) was added. The mixture was stirred at room temperature for 2 h,
then the solvent was removed under reduced pressure and the crude
purified by flash chromatography (eluting with DCM:MeOH:
NH.sub.3aq=95:5:0.5) to give 10 mg of a mixture containing the
title compound. MS (m/z): 286 [MH].sup.+
(1S,6R,7R/1R,6S,7S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabic-
yclo[4.1.0]heptane (3.5 mg) was purified and separated from
4-(3,4-dichlorophenyl)-6-[2-(methyloxy)ethyl]-1,2,3,6-tetrahydropyridine
by semi-preparative HPLC using a chiral column Chiralpak AS-H,
eluent A: n-hexane; B: ethanol, gradient isocratic 30% B, flow rate
0.8 ml/min, detection UV at 225 nm.
[0787] NMR (.sup.1H, CDCl.sub.3): .delta. 7.37 (d, 1H) 7.33 (d, 1H)
7.13 (dd, 1H) 4.01 (dd, 1H) 3.78 (dd, 1H) 3.44 (s, 3H) 3.28-3.36
(m, 1H) 3.12-3.23 (m, 1H) 2.79-2.89 (m, 1H) 2.52-2.65 (m, 1H)
1.96-2.12 (m, 1H) 1.80-1.96 (m, 1H) 1.28-1.47 (m, 2H); MS (m/z):
286 [MH]+
Example 32
(1S,6R,1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane (E32)
##STR00205##
[0788] Method A:
[0789] The title compound may be obtained according to an analogous
procedure to that described above for compound E2a in Method B,
starting from 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]hept-4-ene-3-carboxylate (P59).
Method B:
[0790] In a round-bottomed flask, 1,1-dimethylethyl
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane-3-carboxylate (P66, 42.33 g, 110 mmol) was dissolved
in DCM (450 ml) to give a colourless solution. Trifluoroacetic acid
(103 ml, 1343 mmol) was added dropwise keeping the internal
temperature below +5.degree. C. with an ice bath. At the end of the
addition, the ice bath was removed and the mixture was stirred at
room temperature for 2 hrs.
[0791] The reaction was quenched by dropwise addition of aqueous
potassium carbonate sat. (250 ml) keeping the internal temperature
below +10.degree. C. with an ice bath. Then the mixture was diluted
with water (200 ml) and DCM (200 ml). The two phases were
separated. The aqueous phase was extracted with ethyl acetate
(2.times.150 ml) and the organic (milky solution) was evaporated
under vacuum and taken up with ethyl acetate (400 ml).
[0792] The combined organics were washed with brine (300 ml), dried
(Na.sub.2SO.sub.4) and evaporated under vacuum to obtain a yellow
oil (34 g). It was dissolved in diethyl ether (600 ml) and washed
with aqueous potassium carbonate 1M solution (3.times.200 ml). The
organic phase was dried (Na.sub.2SO.sub.4) and evaporated under
vacuum to afford the title compound (28.9 g) as colourless oil.
[0793] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.45 (s, 1H), 7.36
(d, 1H), 7.19 (d, 1H), 3.32 (d, 1H), 3.14 (s, 3H), 3.09 (d, 1H),
2.96 (d, 1H), 2.84 (d, 1H), 2.73-2.81 (m, 1H), 2.64-2.71 (m, 1H),
1.92-2.00 (m, 1H), 1.79-1.88 (m, 1H), 0.97-1.07 (m, 2H).
[0794] HPLC (walk-up): Rt=3.97 min
Example 33
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane (2R,3R)-2,3-dihydroxybutanedioate (L-tartrate salt) (E33)
##STR00206##
[0795] Method a)
[0796] 3.7 grams of material prepared by a procedure analogous to
the method of Step A of Example 38, omitting the azeotropic drying
step, was dissolved in isopropyl alcohol (60 ml, 16.7 vols), and to
the solution was added L-tartaric acid [(2R,3R)-(+)-Tartaric
acid](2.7 grams, 18.1 mmol, 1.4 eq) and the solution was then
heated to 80.degree. C. Once at temperature water (12 ml, 3.2 vols)
was then added and the solution stirred for 10 min. The resulting
solution was then cooled to 0.degree. C. at a rate of 0.2.degree.
C./min, and then held at 0.degree. C. for 7 hours. The resulting
slurry was then filtered and washed with isopropyl alcohol (10 ml,
2.7 vol) twice. The solid obtained was then dried under high vacuum
for 5 hours at 50.degree. C. to give an off white solid of the
title compound (3.7 grams, 8.5 mmol, 65% recovery).
[0797] NMR (.sup.1H, DMSO-d6): .delta. ppm 1.22 (s, 2H), 2.03 (t,
J=5.26 Hz, 2H), 2.67-2.79 (m, 2H), 2.83-2.90 (m, 1H), 3.04 (s, 4H),
3.11 (d, J=13.19 Hz, 1H), 3.43 (d, J=13.55 Hz, 1H), 3.85 (s, 2H),
7.33-7.39 (m, 1H), 7.56-7.60 (m, 1H), 7.68 (d, J=2.01 Hz, 1H).
[0798] MS (m/z): 286 [MH]+
Method b)
[0799] To 300.1 mg of
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane (E2a) and 157.3 mg of L-tartaric acid, 0.5 mL of
isopropylalcohol (IPA) was added with stirring. A further 0.5 mL
was added and the resulting solution heated using an air gun. Heat
was removed and a further 2.5 mL IPA added, this resulted in a
slurry to which an additional 1 mL of IPA was added to give
mobility (giving a total solvent volume of 4.5 mL IPA added). The
resulting slurry was temperature cycled between 0 and 40.degree. C.
for >24 hours. The sample was then filtered and the solid
obtained dried under vacuum at 70.degree. C. for 24 hours.
[0800] Diffractogram of Form 1 of the title compound E33 [batch
produced with method b)] is shown in FIG. 3.
[0801] XRPD Peaks* of Form 1 (with 5% or greater relative
intensity) of the title compound Example 33 are illustrated in the
Table 3 below (XRPD angles and d spacings are reported):
TABLE-US-00001 TABLE 3 Pos.[.degree.2Th.]] d-spacing[.ANG.] 4.8
18.3 9.5 9.3 11.7 7.6 13.1 6.8 13.6 6.5 15.5 5.7 15.9 5.6 16.9 5.2
17.2 5.2 17.5 5.1 17.9 4.9 18.8 4.7 23.5 3.8 23.9 3.7 24.5 3.6 24.9
3.6 26.3 3.4 26.5 3.4 26.9 3.3
[X-Ray Powder Diffraction (XRPD) analysis performed on a
PANalytical X'pert Pro powder diffractometer, Model PW3040/60,
serial number DY2599 using an X'Celerator detector. Acquisition
conditions: radiation: Cu K.sub..alpha., generator tension: 40 kV,
generator current: 40 mA, start angle: 2.0 .degree.2.theta., end
angle: 45.0 .degree.2.theta., step size: 0.017 .degree.2.theta.,
time per step: 32.3024 seconds. Sample prepared using zero
background (front fill) technique]
[0802] Onset of melting point/decomposition [E33, Form 1, batch
produced with method b)]: 198.degree. C. (TA instruments Q1000
serial number 01000-0577. Sample heated at 10.degree. C. min.sup.-1
in a crimped aluminium pan with a pin-hole lid).
[0803] DSC thermogram of Form 1 of the title compound Example 33
[batch produced with method b)] is shown in FIG. 4.
Method c)
[0804] To 500 mg of material prepared according to Step A of
Example 38, dissolved in methanol (5 mL), was charged L-tartaric
acid in methanol (1.21 mL, 1 mmol/mL). This was stirred for 15
minutes and a white precipitate formed. This was collected by
vacuum filtration and washed with methanol (2 mL) to obtain 246 mg
of title compound.
[0805] NMR (.sup.1H, DMSO-d6): .delta. ppm 1.24 (s, 2H) 1.99-2.14
(m, 2H) 2.47-2.53 (m, 1H) 2.67 (d, J=9.99 Hz, 1H) 2.72-2.83 (m, 1H)
2.92 (d, J=9.99 Hz, 1H) 3.05 (s, 3H) 3.12 (d, J=13.20 Hz, 1H) 3.47
(d, J=13.38 Hz, 1H) 3.92 (s, 2H) 7.39 (dd, J=8.34, 2.10 Hz, 1H)
7.59 (d, J=8.29 Hz, 1H) 7.70 (d, J=2.05 Hz, 1H)
[0806] Diffractogram of Form 1 of the title compound E33 is shown
in FIG. 5.
[0807] XRPD Peaks* of Form 1 of the title compound E33 [batch
produced with method c)] are illustrated in the Table 4 below (XRPD
angles and d spacings are reported):
TABLE-US-00002 TABLE 4 2-theta [.degree.] d-spacing [ ] 4.7 18.9
9.4 9.4 11.6 7.6 13.0 6.8 15.7 5.6 17.3 5.1 17.8 5.0 18.7 4.8 22.5
3.9 22.8 3.9 23.3 3.8 23.7 3.8 24.3 3.7 25.3 3.5 26.2 3.4 26.4 3.4
26.7 3.3 32.2 2.8 36.5 2.5 40.4 2.2 *Values shown here are rounded
to one decimal place. The diffraction pattern can shift to slightly
higher or lower 2.theta. values depending on sample
displacement.
[0808] [X Ray Powder Diffraction (XRPD) analysis was performed on a
PANalytical X'Pert-Pro MPD with Johansson Kal monochromator, using
X'Celerator detector. The acquisition conditions were as follows:
Radiation: Cu (Kal), 1.540598 angstroms (monochromatic); Detector:
X'Celerator; Tension: 45 kV; Current: 40 mA; Start angle:
2.0.degree. 2q; End angle: 50.0.degree. 2q; Step size:
0.02.degree.; Time/step: 40.0 sec; Scan speed: 0.05.degree./sec;
Incident beam: 2.degree. fixed anti-scatter slit, and programmable
divergence slit; Diffracted beam: 0.02 rad soller slit, and
programmable anti-scatter slit; Samples prepared on silicon zero
background sample holder)].
[0809] In one embodiment, unique and discriminating peaks* of Form
1 of the title compound E33 have been identified and are
illustrated in Table 5 below (XRPD angles and d spacings are
reported):
TABLE-US-00003 TABLE 5 2-theta [.degree.] d-spacing [ ] 4.7 18.9
9.4 9.4 15.7 5.6 18.7 4.8 22.5 3.9 23.3 3.8 23.7 3.8 24.3 3.7 26.7
3.3 36.5 2.5
[0810] Onset of melting point/decomposition [E33, Form 1, batch
produced with method c)]: 191.17.degree. C. (TA Instruments Model
01000 DSC; Pan: closed aluminium; Purge gas: N.sub.2, 50 mL/min;
Temp range: 30-300.degree. C., 15.degree. C./min).
[0811] DSC thermogram of Form 1 of the title compound E33 [batch
produced with method c)] is shown in FIG. 6.
[0812] The melt for Form 1 of the title compound E33 is followed by
degradation therefore the integration of the peak for different
samples can give slightly different Onset, Peak Max and Enthalpy
values.
Examples 34 and 35
(2R,3R)-2,3-bis[(phenylcarbonyl)oxy]butanedioic
acid-(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane (E34) and
(2S,3S)-2,3-bis[(phenylcarbonyl)oxy]butanedioic
acid-(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane (E35)
##STR00207##
[0813] Step a)
[0814] To a solution of
(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4-
.1.0]heptane (E32, 61.5 g, 215 mmol) in acetone (300 ml),
dibenzoyl-L-tartaric acid (115 g, 322 mmol), dissolved in acetone
(622 ml), was added dropwise during 1 h. A solid precipitated and
the mixture was stirred at room temperature for 2 h. The solid was
filtered, washed with acetone (2.times.100 ml) and dried under
vacuum to give compound E34 (35.8 g).
[0815] Chiral HPLC (Column: AS-H (25.times.0.46 cm), 5 micron;
Eluent: n-Hexane/(2-propanol+0.1 isopropylamine) 95/5 v/v; Flow: 1
ml/min; wavelength: 225 nm; retention times referred to salt
analysis): Enant1 (Rt=12.14 min)/Enant2 (Rt=17.29 min)=86/13 area
%
[0816] Mother liquors were concentrated under vacuum and the
residue was suspended in DCM (700 ml). It was washed with aqueous
potassium carbonate sat./water 1:1 (700 ml). The aqueous phase was
back-extracted with DCM (2.times.500 ml). The collected organic
phases, dried (Na.sub.2SO.sub.4), were evaporated to give residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(45 g).
[0817] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 7.45 (s, 1H), 7.36
(d, 1H), 7.19 (d, 1H), 3.32 (d, 1H), 3.14 (s, 3H), 3.09 (d, 1H),
2.96 (d, 1H), 2.84 (d, 1H), 2.73-2.81 (m, 1H), 2.64-2.71 (m, 1H),
1.92-2.00 (m, 1H), 1.79-1.88 (m, 1H), 0.97-1.07 (m, 2H).
[0818] Chiral HPLC: (Column: AS-H (25.times.0.46 cm), 5 micron;
Eluent: n-Hexane/(2-propanol+0.1 isopropylamine) 95/5 v/v; Flow: 1
ml/min; wavelength: 225 nm; retention times referred to free base):
Enant1/Enant2=34/62 area %
Step b)
[0819] To residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(45 g, 157 mmol), coming from step a), dissolved in acetone (220
ml), dibenzoyl-D-tartaric acid (85 g, 236 mmol), dissolved in
acetone (450 ml), was added dropwise during 45 min. A solid
precipitated and the resulting mixture was stirred at room
temperature for 2 h. The solid was filtered, washed with acetone
(2.times.100 ml) and dried under vacuum to give compound E35
(43.89).
[0820] Chiral HPLC: Enant1/Enant2=7.5/90.9 area % Mother liquors
were concentrated under vacuum and the residue was suspended in DCM
(700 ml).
[0821] It was washed with aqueous potassium carbonate sat./water
1:1 (700 ml). The aqueous phase was back-extracted with DCM
(2.times.500 ml). The collected organic phases, dried
(Na.sub.2SO.sub.4), were evaporated to give residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(25.6 g).
[0822] Chiral HPLC: Enant1/Enant2=54/35 area %
Step c)
[0823] To residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(25.6 g, 89 mmol), coming from step b), dissolved in acetone (125
ml), dibenzoyl-L-tartaric acid (48.1 g, 134 mmol), dissolved in
acetone (250 ml), was added dropwise during 1 h. A solid
precipitated and the resulting mixture was stirred at room
temperature for 2 hrs. The solid was filtered, washed with acetone
(2.times.100 ml) and dried under vacuum to afford the compound E34
(15 g).
[0824] Chiral HPLC: Enant1/Enant2=92.5/5.5 area %
[0825] Mother liquors were concentrated under vacuum and the
residue was suspended in DCM (350 ml). It was washed with aqueous
potassium carbonate sat./water 1:1 (350 ml). The aqueous phase was
back-extracted with DCM (2.times.300 ml). The collected organic
phases, dried (Na.sub.2SO.sub.4), were evaporated to give residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(18 g).
[0826] Chiral HPLC: Enant1/Enant2=37.7/49.7 area %
Step d)
[0827] To residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(18 g, 62.89 mmol), coming from step c), dissolved in acetone (90
ml), dibenzoyl-D-tartaric acid (33.8 g, 94.33 mmol), dissolved in
acetone (180 ml), was added dropwise during 45 min. A solid
precipitated and the resulting mixture was stirred at room
temperature for 2 h. The solid was filtered, washed with acetone
(2.times.80 ml) and dried under vacuum to give compound E35 (11
g).
[0828] Chiral HPLC: Enant1/Enant2=14.5/84.5 area %
[0829] Mother liquors were concentrated under vacuum and the
residue was suspended in DCM (500 ml).
[0830] It was washed with aqueous potassium carbonate sat./water
1:1 (500 ml). The aqueous phase was back-extracted with DCM
(2.times.300 ml). The collected organic phases, dried
(Na.sub.2SO.sub.4), were evaporated to give residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(12.6 g).
[0831] Chiral HPLC: Enant1/Enant2=49.2/31.2 area % Step e)
[0832] To residual
6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane
(12.6 g, 44 mmol), coming from step d), dissolved in acetone (65
ml), dibenzoyl-L-tartaric acid (23.66 g, 66 mmol), dissolved in
acetone (125 ml), was added dropwise during 1 h. A solid
precipitated and the resulting mixture was stirred at room
temperature for 2 hrs. The solid was filtered, washed with acetone
(2.times.100 ml) and dried under vacuum to afford compound E34 (3.1
g). 10.57% yield.
[0833] Chiral HPLC: Enant1/Enant2=94.1/5.0 area %
Step f) (2R,3R)-2,3-bis[(phenylcarbonyl)oxy]butanedioic
acid-(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.-
1.0]heptane (E34) coming from step a) (35.8 g, 55.54 mmol), step c)
(15 g, 23.27 mmol), step e) (3.1 g 4.8 mmol) and a further batch of
material (3.1 g, 4.8 mmol) of the same quality were suspended in
acetone (570 ml) and heated gently to reflux for 30 min. The
mixture was stirred for 2 hrs at room temperature. The solid was
filtered to give 47.25 g of white solid. This solid was suspended
in acetone (470 ml) and heated to reflux for 30 min. The mixture
was stirred for 2 h at room temperature. The solid was filtered to
give 41.80 g of white solid. This solid was suspended in acetone
(420 ml) and heated to reflux for 30 min. The mixture was stirred
for 2 h at room temperature The solid was filtered to give pure
compound E34 (38 g) as white solid.
[0834] NMR (.sup.1H, MeOH-d.sub.4): .delta. ppm 8.14 (d, 4H),
7.57-7.67 (m, 3H), 7.41-7.54 (m, 5H), 7.29-7.38 (m, 1H), 5.93 (s,
2H), 3.61-3.76 (m, 1H), 3.16-3.29 (m, 2H), 3.13 (s, 3H), 2.98-3.07
(m, 1H), 2.79-2.92 (m, 1H), 2.66-2.78 (m, 1H), 2.08-2.29 (m, 2H),
1.12-1.31 (m, 2H)
[0835] Chiral HPLC: Enant1/Enant2=99/1 area %
Example 36
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane butanedioate (Mono-Succinate salt) (E36)
##STR00208##
[0837] To 300.7 mg of
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane (E2a) and 123.4 mg of succinic acid, 0.5 mL of
isopropylalcohol (IPA) was added with stirring. A further 0.5 mL
was added and heat applied using an air gun to aid dissolution.
Further solvent additions of 2.times.0.5 mL, 1 mL, 0.5 mL and 1 mL
were added to achieve a mobile slurry (giving a total solvent
volume of 4.5 mL IPA added). The resulting slurry was temperature
cycled between 0 and 40.degree. C. for three days. The sample was
then filtered and the solid title compound obtained dried under
vacuum at 70.degree. C. for 24 hours.
[0838] NMR (.sup.1H, DMSO-d6): 7.67 (d, 1H), 7.59 (d, 1H), 7.36
(dd, 1H), 3.40 (d, 1H), 3.09 (d, 1H), 3.05 (s, 3H), 3.01 (m, 1H),
2.87 (d, 1H), 2.77-2.70 (m, 2H), 2.34 (s, 4H), 2.01 (m, 2H), 1.21
(m, 2H) [NMR analysis performed on a batch obtained with an
analogous procedure to that above described]
Example 37
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane phosphate (monophosphate salt) (E37)
##STR00209##
[0840] A solution was prepared with 301.5 mg
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
eptane (E2a, oil) and 0.2 mL aqueous isopropylalcohol 5% w/w water
(aq. IPA). To this solution 209.6 microL of phosphoric acid (5M in
water) was added with stirring. A further 0.1 mL of solvent was
added while stirring yielding a slurry. 0.3 mL and then 00.1 mL of
solvent were added to give a mobile slurry. (Total aq. IPA added
0.7 mL). The resulting slurry was temperature cycled between 0 and
40.degree. C. for 24 hours. The sample was then filtered and the
solid title compound obtained dried under vacuum at 70.degree. C.
for 24 hours.
[0841] The analytical data reported below for E37 were generated
using alternative batches of the compound.
[0842] NMR (.sup.1H, DMSO-d6): 7.63 (d, 1H), 7.56 (d, 1H), 7.36
(dd, 1H), 7.27 (d, 1H), 3.03 (s, 3H), 3.01 (d, 1H), 2.90 (d, 1H),
2.85 (m, 1H), 2.69 (d, 1H), 2.64 (m, 1H), 1.95 (m, 2H), 1.17 (m,
2H)
[0843] Diffractogram of Form 1 of the title compound E37 is shown
in FIG. 7.
[0844] XRPD Peaks* of Form 1 (with 5% or greater relative
intensity) of the title compound Example 37 are illustrated in the
Table 6 below (XRPD angles and d spacings are reported):
TABLE-US-00004 Pos.[.degree.2Th.] d-spacing[.ANG.] 5.1 17.4 10.2
8.7 12.0 7.3 13.3 6.7 16.8 5.3 18.5 4.8 18.9 4.7 19.9 4.5 20.4 4.4
21.2 4.2 22.0 4.0 22.5 4.0 23.2 3.8 24.0 3.7 25.3 3.5 25.7 3.5 26.6
3.4 27.5 3.2 28.4 3.1 29.6 3.0 30.8 2.9
[X-Ray Powder Diffraction analysis performed on a PANalytical
X.sub.1 pert Pro powder diffractometer, Model PW3040/60, serial
number DY2599 using an X.sub.1Celerator detector. Acquisition
conditions: radiation: Cu K.sub..alpha., generator tension: 40 kV,
generator current: 40 mA, start angle: 2.0 .degree.2.theta., end
angle: 45.0 .degree.2.theta., step size: 0.017 .degree.2.theta.,
time per step: 32.3024 seconds. Sample prepared using zero
background (front fill) technique.).
[0845] DSC thermogram of Form 1 of the title compound E37 is shown
in FIG. 8.
[0846] Onset of melting (E37, Form 1): 199.degree. C. (TA
instruments Q1000 serial number Q1000-0577. The sample was heated
at 10.degree. C. min.sup.-1 in a crimped aluminium pan with a
pin-hole lid).
[0847] The melt for Form 1 of the title compound E37 is followed by
degradation therefore the integration of the peak for different
samples can give slightly different Onset, Peak Max and Enthalpy
values.
Example 38
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]he-
ptane trifluoroacetate (ratio Ion:counterion not determined)
(E38)
##STR00210##
[0848] Step A:
[0849] 1,1-dimethylethyl
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]h-
ept-4-ene-3-carboxylate (P60, 11 g) was dissolved in toluene (110
ml). The solution was treated with triethylsilane (5.46 ml, 34.17
mmol), followed by trifluoroacetic acid (14.81 ml, 199.3 mmol). The
reaction was stirred at room temperature for 24 h, then quenched
with sodium hydroxide and stirred for 10 min. The pH of the mixture
was approximately 13. The phases were separated and the toluene
phase concentrated in vacuo to give a product intermediate as an
oil, which was further dried by performance of three
azeotropes.
Step B, Method A:
[0850] 3 g of the material produced in step A were dissolved in
ethyl acetate and heptane was added until the solution became
cloudy. The solution was heated until dissolution and then allowed
to cool. Crystals' formation was observed. The solid was then
filtered and 1 g of title compound was recovered.
Step B, Method B:
[0851] 6 g of the material produced in Step A were dissolved in 12
mL of ethyl acetate. Heptane (60 mL) was added to this solution and
the biphasic mixture was then heated to -70.degree. C. to obtain a
single phase solution. To this solution another portion of heptane
(60 mL) was added and the solution heated to reflux (90.degree.
C.). The solution was then allowed to cool while stirring to
67.degree. C., at which temperature it was seeded with crystals of
the title compound previously obtained as described in Step B,
Method A. The solution was then allowed to cool to room temperature
overnight.
[0852] The resulting precipitate was then filtered by vacuum
filtration and washed with heptane (5 mL). Title compound was
obtained (1.5 g) as a crystalline solid (25% recovery)
[0853] NMR (.sup.1H, CDCl.sub.3): .delta. ppm 1.23 (dd, 2H)
2.16-2.25 (m, 1H) 2.31-2.43 (m, 1H) 2.84 (d, J=9.99 Hz, 1H)
2.92-2.97 (m, 1H) 3.15 (s, 3H) 3.18-3.28 (m, 2H) 3.76 (d, J=13.20
Hz, 1H) 7.34-7.39 (m, 1H) 7.40-7.43 (m, 1H) 7.51 (d, J=1.96 Hz, 1H)
9.65 (s, 1H)
[0854] Diffractogram of Form 1 of the title compound E38 is
reported in FIG. 1. Peaks* of Form 1 of the title compound Example
38 are illustrated in the Table 1 below (XRPD angles and d spacings
are reported):
TABLE-US-00005 TABLE 1 2-theta [.degree.] d-spacing [ ] 5.1 17.3
10.0 8.8 10.2 8.6 10.6 8.3 15.4 5.7 18.6 4.8 19.3 4.6 20.6 4.3 21.0
4.2 21.4 4.1 22.2 4.0 23.3 3.8 23.5 3.8 25.5 3.5 25.9 3.4 26.0 3.4
30.4 2.9 31.2 2.9 35.5 2.5 39.5 2.3 *Values shown here are rounded
to one decimal place. The diffraction pattern can shift to slightly
higher or lower 2.theta. values depending on sample
displacement.
[0855] [X Ray Powder Diffraction (XRPD) analysis was performed on a
PANalytical X'Pert-Pro MPD with Johansson Kal monochromator, using
X'Celerator detector. The acquisition conditions were as follows:
Radiation: Cu (Kal), 1.540598 angstroms (monochromatic); Detector:
X'Celerator; Tension: 45 kV; Current: 40 mA; Start angle:
2.0.degree. 2q; End angle: 50.0.degree. 2q; Step size:
0.02.degree.; Time/step: 40.0 sec; Scan speed: 0.05.degree./sec;
Incident beam: 2.degree. fixed anti-scatter slit, and programmable
divergence slit; Diffracted beam: 0.02 rad soller slit, and
programmable anti-scatter slit; Samples prepared on silicon zero
background sample holder)].
[0856] In one embodiment, unique and discriminating peaks* of Form
1 of the title compound Example 38 have been identified and are
illustrated in Table 2 below (XRPD angles and d spacings are
reported):
TABLE-US-00006 TABLE 2 2-theta [.degree.] d-spacing [ ] 5.1 17.3
10.2 8.6 10.6 8.3 15.4 5.7 18.6 4.8 19.3 4.6 21.4 4.1 22.2 4.0
[0857] Onset of melting (E38, Form 1): 123.91.degree. C. (TA
Instruments Model Q100 DSC; Pan:closed aluminium; Purge gas:
N.sub.2, 40 mL/min; Temp range: 30-300.degree. C., 15.degree.
C./min). DSC thermogram of Form 1 of the title compound Example 38
is shown in FIG. 2.
[0858] It is to be understood that the present invention covers all
combinations of particular groups described herein above.
[0859] The application of which this description and claims forms
part may be used as a basis for priority in respect of any
subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described
herein. They may take the form of product, composition, process, or
use claims and may include, by way of example and without
limitation, the following claims.
* * * * *