U.S. patent application number 13/556328 was filed with the patent office on 2012-11-15 for derivatives of 2-oxoalkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same.
This patent application is currently assigned to SANOFI. Invention is credited to Marco BARONI, Francoise BONO, Sandrine DELBARY-GOSSART.
Application Number | 20120289518 13/556328 |
Document ID | / |
Family ID | 40305319 |
Filed Date | 2012-11-15 |
United States Patent
Application |
20120289518 |
Kind Code |
A1 |
BARONI; Marco ; et
al. |
November 15, 2012 |
DERIVATIVES OF 2-OXOALKYL-1-PIPERAZIN-2-ONE, PREPARATION METHOD
THEREOF AND THERAPEUTIC USE OF SAME
Abstract
The present invention relates to derivatives of
4-{2-[phenyl-3,6-dihydropyridin-1-yl]-2-oxoalkyl}-1-piperazin-2-one
and
4-{2-[phenyl-2,5-dihydropyrrol-1-yl]-2-oxoalkyl}-1-piperazin-2-one
having general formula (I): ##STR00001## in which A, B, m, R3 and n
are as defined herein. The invention also relates to the
preparation thereof and to the therapeutic use thereof.
Inventors: |
BARONI; Marco;
(Vanzago-Milano, IT) ; BONO; Francoise; (Toulouse,
FR) ; DELBARY-GOSSART; Sandrine; (Mauzac,
FR) |
Assignee: |
SANOFI
Paris
FR
|
Family ID: |
40305319 |
Appl. No.: |
13/556328 |
Filed: |
July 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12966408 |
Dec 13, 2010 |
8247404 |
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13556328 |
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PCT/FR2009/051117 |
Jun 12, 2009 |
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12966408 |
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Current U.S.
Class: |
514/253.13 ;
546/314 |
Current CPC
Class: |
A61P 17/02 20180101;
A61P 35/00 20180101; A61P 27/02 20180101; A61P 25/14 20180101; A61P
35/02 20180101; A61P 37/06 20180101; A61P 37/08 20180101; A61P
17/06 20180101; A61P 19/08 20180101; A61P 11/06 20180101; A61P
17/14 20180101; A61P 27/06 20180101; A61P 25/00 20180101; A61P
25/16 20180101; A61P 35/04 20180101; C07D 401/14 20130101; A61P
19/00 20180101; A61P 43/00 20180101; A61P 25/04 20180101; A61P
25/08 20180101; A61P 19/10 20180101; A61P 21/00 20180101; A61P
25/24 20180101; A61P 9/04 20180101; A61P 29/00 20180101; A61P 19/02
20180101; A61P 9/10 20180101; A61P 25/28 20180101; A61P 25/02
20180101; A61P 9/00 20180101; A61P 11/00 20180101; A61P 17/00
20180101; A61P 25/18 20180101 |
Class at
Publication: |
514/253.13 ;
546/314 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61P 25/08 20060101 A61P025/08; A61P 25/28 20060101
A61P025/28; A61P 25/16 20060101 A61P025/16; A61P 25/14 20060101
A61P025/14; A61P 25/00 20060101 A61P025/00; A61P 25/18 20060101
A61P025/18; A61P 25/24 20060101 A61P025/24; A61P 9/04 20060101
A61P009/04; A61P 9/10 20060101 A61P009/10; A61P 27/02 20060101
A61P027/02; A61P 27/06 20060101 A61P027/06; A61P 35/00 20060101
A61P035/00; A61P 35/04 20060101 A61P035/04; A61P 35/02 20060101
A61P035/02; A61P 11/00 20060101 A61P011/00; A61P 37/08 20060101
A61P037/08; A61P 11/06 20060101 A61P011/06; A61P 29/00 20060101
A61P029/00; A61P 37/06 20060101 A61P037/06; A61P 19/08 20060101
A61P019/08; A61P 19/10 20060101 A61P019/10; C07D 211/70 20060101
C07D211/70 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 13, 2008 |
FR |
0803298 |
Claims
1. A method for the prevention or treatment of a condition selected
from the group consisting of central and peripheral
neurodegenerative diseases, senile dementia, epilepsy, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, Down's syndrome,
prion diseases, amnesia, schizophrenia, depression, bipolar
disorder, amyotrophic lateral sclerosis, multiple sclerosis,
cardiovascular conditions, post-ischaemic cardiac damage,
cardiomyopathies, myocardial infarction, heart failure, cardiac
ischaemia, cerebral infarction, peripheral neuropathies, damage to
the optic nerve and to the retina, retinal pigment degeneration,
glaucoma, retinal ischaemia, macular degeneration, spinal cord
traumas, cranial traumas, atherosclerosis, stenoses, cicatrization
disorders, alopecia, cancers, tumours, metastases, leukaemias,
respiratory disorders, pulmonary inflammation, allergy, asthma,
chronic obstructive pulmonary disease, cutaneous, somatic,
visceral, and neurological pain, chronic neuropathic and
inflammatory pain, autoimmune diseases, rheumatoid arthritis,
ankylosing spondyl arthritis, psoriatic arthritis, plaque
psoriasis, bone fractures, bone diseases and osteoporosis, the
method comprising administering to a patient in need thereof an
effective dose of a compound of formula (I): ##STR00058## in which:
m is 0 or 1; A is: ##STR00059## and B is a hydrogen atom or A is a
hydrogen atom and B is: ##STR00060## R1 and R2, which may be
identical or different, are independently a hydrogen or halogen
atom, a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl,
C.sub.1-C.sub.2 perfluoroalkyl or C.sub.1-C.sub.4 alkoxy group or a
trifluoromethoxy group; n is 1 or 2; R3 is a group of formula:
##STR00061## where R4 and R5, which may be identical or different,
are located on any available positions, and are independently a
hydrogen or halogen atom, a hydroxyl, a C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2 perfluoroalkyl,
C.sub.1-C.sub.4 alkoxy group, a trifluoromethoxy group, a cyano
group, a COOH, COOalkyl, CONH.sub.2, CONR6R7 or NHCOR group; and R,
R6 and R7 are a C.sub.1-C.sub.6 alkyl; in the form of a base or of
an acid addition salt.
2. The method according to claim 1, wherein for the compound of
formula (I), R4 and R5, which may be identical or different, are
located on any available positions, and are independently
CONH.sub.2, CONR6R7 or NHCOR; in the form of a base or of an acid
addition salt.
3. The method according to claim 1, wherein for the compound of
formula (I): m is 1; A is: ##STR00062## and B is a hydrogen atom;
R1 and R2, which may be identical or different, are independently a
hydrogen or halogen atom, a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
fluoroalkyl, C.sub.1-C.sub.2 perfluoroalkyl or C.sub.1-C.sub.4
alkoxy group or a trifluoromethoxy group; n is 1 or 2; R3 is a
group of formula: ##STR00063## where R4 and R5, which may be
identical or different, are located on any available positions and
are independently a hydrogen or halogen atom, a hydroxyl, a
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2
perfluoroalkyl or C.sub.1-C.sub.4 alkoxy group, a trifluoromethoxy
group, a cyano group, or a COOH or COOalkyl group; in the form of a
base or of an acid addition salt.
4. The method according to claim 1, wherein for the compound of
formula (I), R1 is other than H; in the form of a base or of an
acid addition salt.
5. The method according to claim 1, wherein for the compound of
formula (I), R1 is in position -2-, -3- or -4- and is a chlorine
atom or a CF.sub.3 radical, and R2 is a hydrogen or a 3- or 4-Cl;
in the form of a base or of an acid addition salt.
6. The method according to claim 1, wherein for the compound of
formula (I), R3 is a 2-pyridynyl or a 2-pyrimidinyl, each
substituted with R4 and R5 as defined in claim 1; in the form of a
base or of an acid addition salt.
7. The method according to claim 1, wherein for the compound of
formula (I), n=1; in the form of a base or of an acid addition
salt.
8. The method according to claim 1, wherein for the compound of
formula (I), R1 is 3-CF.sub.3; R2 is 4-chloro; R3 is a 2-pyridyl
residue 5-substituted with a CF.sub.3; and n=1; in the form of a
base or of an acid addition salt.
9. The method according to claim 1, wherein the compound is
selected from the group consisting of:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl-
}-1-pyridin-2-ylpiperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyrid-
in-2-yl-piperazin-2-one;
4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(-
5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-ch-
loropyridin-2-yl)piperazin-2-one;
4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl-
}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl-
}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-pyridin-3-yl-piperazin-2-one;
1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-d-
ihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;
4-{2-oxo-2-[5-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl-
}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]eth-
yl}-1-pyridin-2-ylpiperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydropyrrol-1-yl]-2-oxoe-
thyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxo-
ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl)-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromet-
hylpyridin-2-yl)piperazin-2-one;
4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(-
5-trifluoromethylpyridin-2-yl)piperazin-2-one; and
4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-t-
rifluoromethylpyridin-2-yl)piperazin-2-one; in the form of a base
or of an acid addition salt.
10. A method for inhibiting p75.sup.NTR receptor dimerization
independently of its ligand, the method comprising administering to
a patient in need thereof an effective dose of a compound of
formula (I): ##STR00064## in which: m is 0 or 1; A is: ##STR00065##
and B is a hydrogen atom or A is a hydrogen atom and B is:
##STR00066## R1 and R2, which may be identical or different, are
independently a hydrogen or halogen atom, a C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2 perfluoroalkyl or
C.sub.1-C.sub.4 alkoxy group or a trifluoromethoxy group; n is 1 or
2; R3 is a group of formula: ##STR00067## where R4 and R5, which
may be identical or different, are located on any available
positions, and are independently a hydrogen or halogen atom, a
hydroxyl, a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl,
C.sub.1-C.sub.2 perfluoroalkyl, C.sub.1-C.sub.4 alkoxy group, a
trifluoromethoxy group, a cyano group, a COOH, COOalkyl,
CONH.sub.2, CONR6R7 or NHCOR group; and R, R6 and R7 are a
C.sub.1-C.sub.6 alkyl; in the form of a base or of an acid addition
salt.
11. The method according to claim 10, wherein for the compound of
formula (I), R4 and R5, which may be identical or different, are
located on any available positions, and are independently
CONH.sub.2, CONR6R7 or NHCOR; in the form of a base or of an acid
addition salt.
12. The method according to claim 10, wherein for the compound of
formula (I): m is 1; A is: ##STR00068## and B is a hydrogen atom;
R1 and R2, which may be identical or different, are independently a
hydrogen or halogen atom, a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
fluoroalkyl, C.sub.1-C.sub.2 perfluoroalkyl or C.sub.1-C.sub.4
alkoxy group or a trifluoromethoxy group; n is 1 or 2; R3 is a
group of formula: ##STR00069## where R4 and R5, which may be
identical or different, are located on any available positions and
are independently a hydrogen or halogen atom, a hydroxyl, a
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2
perfluoroalkyl or C.sub.1-C.sub.4 alkoxy group, a trifluoromethoxy
group, a cyano group, or a COOH or COOalkyl group; in the form of a
base or of an acid addition salt.
13. The method according to claim 10, wherein for the compound of
formula (I), R1 is other than H; in the form of a base or of an
acid addition salt.
14. The method according to claim 10, wherein for the compound of
formula (I), R1 is in position -2-, -3- or -4- and is a chlorine
atom or a CF.sub.3 radical, and R2 is a hydrogen or a 3- or 4-Cl;
in the form of a base or of an acid addition salt.
15. The method according to claim 10, wherein for the compound of
formula (I), R3 is a 2-pyridynyl or a 2-pyrimidinyl, each
substituted with R4 and R5 as defined in claim 10; in the form of a
base or of an acid addition salt.
16. The method according to claim 10, wherein for the compound of
formula (I), n=1; in the form of a base or of an acid addition
salt.
17. The method according to claim 10, wherein for the compound of
formula (I), R1 is 3-CF.sub.3; R2 is 4-chloro; R3 is a 2-pyridyl
residue 5-substituted with a CF.sub.3; and n=1; in the form of a
base or of an acid addition salt.
18. The method according to claim 10, wherein the compound is
selected from the group consisting of:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl-
}-1-pyridin-2-ylpiperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-pyridin-2-ylpiperazin-2-one;
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyrid-
in-2-yl-piperazin-2-one;
4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(-
5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-ch-
loropyridin-2-yl)piperazin-2-one;
4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl-
}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl-
}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-pyridin-3-yl-piperazin-2-one;
1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-d-
ihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one;
4-{2-oxo-2-[5-(3-trifluoromethyl
phenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-trifluoromethylpyridin-2--
yl)piperazin-2-one;
4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin-1-yl]eth-
yl}-1-pyridin-2-ylpiperazin-2-one;
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydropyrrol-1-yl]-2-oxoe-
thyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxo-
ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one;
4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromet-
hylpyridin-2-yl)piperazin-2-one;
4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(-
5-trifluoromethylpyridin-2-yl)piperazin-2-one; and
4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-t-
rifluoromethylpyridin-2-yl)piperazin-2-one; in the form of a base
or of an acid addition salt.
19. A compound of formula (IV) ##STR00070## in which A, B, m and n
are as defined in claim 1 and Hal is a halogen atom; with the
exception of
2-chloro-1-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone
and
2-chloro-1-[4-(4-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
in the form of a base or of an acid addition salt.
Description
[0001] The present invention relates to
4-{2-[phenyl-3,6-dihydropyridin-1-yl]-2-oxoalkyl}-1-piperazin-2-one
and
4-{2-[phenyl-2,5-dihydropyrrol-1-yl]-2-oxoalkyl}-1-piperazin-2-one
derivatives, to the preparation thereof and to the therapeutic use
thereof.
[0002] The compounds according to the present invention have an
affinity for the p75.sup.NTR neurotrophin receptor.
[0003] Neurotrophins belong to a family of proteins of which the
biological effect is in particular cell survival and
differentiation.
[0004] The p75.sup.NTR receptor, the receptor for all
neurotrophins, is a transmembrane glycoprotein of the tumour
necrosis factor (TNF) receptor family (W. J. Friedman and L. A.
Greene, Exp. Cell. Res., 1999, 253, 131-142). The p75.sup.NTR
receptor is expressed in several cell types, and several biological
functions have been attributed to said receptor: on the one hand,
modulation of the affinity of neurotrophins for tyrosine kinase
(trk) receptors; on the other hand, in the absence of trk,
induction of a signal for cell death by apoptosis. Moreover, the
neurotrophin precursors, proneurotrophins, are capable of binding
to p75.sup.NTR with a high affinity, and are considered to be
powerful p75.sup.NTR-dependent inducers of apoptosis in neurons and
certain cell lines.
[0005] At the level of the central nervous system, many studies
show that apoptosis occurs in several pathological conditions, such
as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's
disease, Parkinson's disease and Huntington's disease and prion
diseases. P75.sup.NTR is also known to be overexpressed in various
types of neurodegenerative diseases, such as Alzheimer's disease
and amyotrophic lateral sclerosis (ALS) (Longo F. M. et al., Curr.
Alzheimer Res. 2007;4: 503-506; Lowry K. S. et al., Amyotroph.
Lateral. Scler. Other. Motor. Neuron. Disord. 2001; 2:127-34).
[0006] Results suggest that p75.sup.NTR may play a predominant role
in the mechanisms resulting in post-ischaemic apoptotic neuron
death (P. P. Roux et al., J. Neurosci., 1999, 19, 6887-6896).
[0007] Results (V. Della-Bianca et al., J. Biol. Chem., 2001, 276:
38929-33), (S. Rabizadeh et al., Proc. Natl. Acad. Sci. USA,
1994,91, 10703-10706) support the hypothesis that p75.sup.NTR plays
an important role in neuron death induced by prion protein
infections (transmissible spongiform encephalopathy) or by
beta-amyloid protein (Alzheimer's disease).
[0008] The p75.sup.NTR receptor is also associated with the Nogo
receptor and involved in the signalling of the inhibitory effects
of these myelin proteins on axon growth. As a result the
p75.sup.NTR receptor plays a major role in the regulation of the
neuronal plasticity and in neuron-glia interactions, and thus
represents a therapeutic target of choice for promoting nerve
regeneration.
[0009] Beyond the nervous system and neurodegenerative diseases, it
has been suggested that p75.sup.NTR could play a role in
cardiovascular diseases, such as atherosclerosis and myocardial
ischaemia (M. L. Bochaton-Pialat et al., Am. J. Pathol., 1995,146,
1-6; H. Perlman, Circulation, 1997, 95, 981-987). Recent studies
show an increase in the expression of p75.sup.NTR and of
neurotrophins, and a massive apoptosis in atherosclerosis
lesions.
[0010] Several studies also suggest that p75.sup.NTR is an
inflammation mediator (Rihl M. et al., Ann. Rheum. Dis. 2005;
64(11):1542-9; Raychaudhuri S. P. et al., Prog. Brain. Res. 2004;
146: 433-7, Tokuoka S. et al., Br. J. Pharmacol. 2001, 134:
1580-1586).
[0011] P75.sup.NTR also plays an essential role in tumour
biology.
[0012] Many compounds are known to interact with the
trkA/NGF/p75.sup.NTR system or to have an NGF-type (nerve grown
factor) activity. Thus patent application WO 00/59893 describes
substituted pyrimidine derivatives which have an NGF-type activity
and/or which increase the activity of NGF on PC12 cells.
[0013] Patent application WO 03/104225 describes compounds which
exhibit affinity for P75.sup.NTR receptors. These compounds are
highly metabolized and exhibit high percentages of inhibition of
the hERG gene (the human Ether-a-go-go Related Gene).
[0014] The hERG gene encodes the K.sub.v11.1. protein of a
potassium ion channel. This protein is known for its contribution
to the electrical activity of the heart. When the ability of the
channel to conduct the electric current through the cell membrane
is inhibited by the action of medicaments, it may result in a
potentially fatal disorder called QT syndrome. A certain number of
medicaments have inhibited this protein, creating a concomitant
risk of sudden death as an adverse side effect. This has made hERG
inhibition a central question both in the regulation of medicaments
and in the development thereof (Sanguinetti M C, Tristani-Firouzi M
(March 2006). "hERG potassium channels and cardiac arrhythmia".
Nature 440 (7083): 463-9).
[0015] A subject of the present invention is novel compounds which
exhibit affinity for P75.sup.NTR receptors and which do not have
the drawbacks of high metabolization and of strong hERG inhibition
that the prior art compounds have. It therefore provides an
advantage for the development of new medicaments.
[0016] A subject of the present invention is the compounds
corresponding to the formula (I):
##STR00002##
in which: [0017] m is 0 or 1; [0018] A is:
[0018] ##STR00003## [0019] and B is a hydrogen atom or [0020] A is
a hydrogen atom and B is:
[0020] ##STR00004## [0021] R1 and R2, which may be identical or
different, are independently a hydrogen or halogen atom, a
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2
perfluoroalkyl or C.sub.1-C.sub.4 alkoxy group or a
trifluoromethoxy group; [0022] n is 1 or 2; [0023] R3 is a group of
formula:
##STR00005##
[0023] where R4 and R5, which may be identical or different, are
located on any available positions and are independently a hydrogen
or halogen atom, a hydroxyl, a C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2 perfluoroalkyl or
C.sub.1-C.sub.4 alkoxy group, a trifluoromethoxy group, a cyano
group, or a COOH, COOalkyl, CONH.sub.2, CONR6R7 or NHCOR group;
[0024] R, R6 and R7 are a C.sub.1-C.sub.6 alkyl.
[0025] The compounds of formula (I) may comprise one or more
asymmetrical carbon atoms. They may therefore exist in the form of
enantiomers or diastereoisomers. These enantiomers and
diastereoisomers and also mixtures thereof, including racemic
mixtures, form part of the invention.
[0026] The compounds of formula (I) may exist in the form of bases
or of addition salts with acids. Such addition salts form part of
the invention.
[0027] These salts may be prepared with pharmaceutically acceptable
acids, but the salts of other acids that are useful, for example,
for purifying or isolating the compounds of formula (I) also form
part of the invention.
[0028] In the context of the present invention: [0029] the term "a
halogen atom" is intended to mean: a fluorine, a chlorine, a
bromine or an iodine; [0030] the term "an alkyl group" is intended
to mean: a linear or branched, saturated aliphatic group. By way of
examples, mention may be made of a C.sub.1-C.sub.4 alkyl group
which may represent a methyl, ethyl, propyl, isopropyl, butyl,
isobutyl or tert-butyl; [0031] the term "a fluoroalkyl group" is
intended to mean: an alkyl group of which one or more hydrogen
atoms have been substituted with a fluorine atom; [0032] the term
"a perfluoroalkyl group" is intended to mean: an alkyl group of
which all the hydrogen atoms have been substituted with a fluorine
atom; [0033] the term "an alkoxy group" is intended to mean: an
--O-alkyl group where the alkyl group is as defined above.
[0034] Among the compounds of formula (I) which are subjects of the
invention, another group of compounds is constituted of those for
which R4 and R5, which may be identical or different, are located
on any available positions, and are independently CONH.sub.2,
CONR6R7 or NHCOR, R, R6 and R7 being defined as above;
in the form of bases or of addition salts with acids.
[0035] Among the compounds of formula (I) which are subjects of the
invention, another group of compounds is constituted of the
compounds of formula (I) in which: [0036] m is 1; [0037] A is:
##STR00006##
[0037] and B is a hydrogen atom; [0038] R1 and R2, which may be
identical or different, are independently a hydrogen or halogen
atom, a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 fluoroalkyl,
C.sub.1-C.sub.2 perfluoroalkyl or C.sub.1-C.sub.4 alkoxy group or a
trifluoromethoxy group; [0039] n is 1 or 2; [0040] R3 is a group of
formula:
##STR00007##
[0040] where R4 and R5, which may be identical or different, are
located on any available positions and are independently a hydrogen
or halogen atom, a hydroxyl, a C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 fluoroalkyl, C.sub.1-C.sub.2 perfluoroalkyl or
C.sub.1-C.sub.4 alkoxy group, a trifluoromethoxy group, a cyano
group, or a COOH or COOalkyl group; in the form of bases or of
addition salts with acids.
[0041] Among the compounds of formula (I) which are subjects of the
invention, another group of compounds is constituted of those for
which R1 is other than H, R2 being as defined above;
in the form of bases or of addition salts with acids.
[0042] Among the compounds of formula (I) which are subjects of the
invention, another group of compounds is constituted of the
compounds for which:
[0043] R1 is in position -2-, -3- or -4- of the phenyl and is a
halogen atom or more particularly a chlorine atom, or a CF.sub.3
radical, and R2 is a hydrogen or a 3- or 4-halogen, more
particularly a 3- or 4-Cl; or else R1 is in position 2-, 3- or 4-
and is a chlorine atom or a CF.sub.3 radical and R2 is a hydrogen
atom; or else R1 is in position 3- of the phenyl and is a CF.sub.3
radical, and R.sub.2 is in position 4- of the phenyl and is a
chlorine atom; or else R1 is in position 2- of the phenyl atom and
is a chlorine atom, and R2 is in position 3- of the phenyl and is a
chlorine atom; and/or
[0044] R3 is a 2-pyridynyl or a 2-pyrimidinyl, each substituted
with R4 and R5 as defined above; and/or
[0045] n=1;
[0046] in the form of bases or of addition salts with acids.
[0047] Among the compounds of this latter group, mention may be
made of the compounds of formula (I) for which:
[0048] R1 is 3-CF.sub.3;
[0049] R2 is 4-chloro;
[0050] R3 is a 2-pyridyl residue 5-substituted with a CF.sub.3;
and
[0051] n=1;
[0052] in the form of bases or of addition salts with acids.
[0053] Among the compounds of formula (I) which are subjects of the
invention, mention may in particular be made of the following
compounds: [0054] Compound No. 1:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0055]
Compound No. 2:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one; [0056] Compound
No. 3:
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one; [0057] Compound No. 4:
4-{2-oxo-2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl-
}-1-pyridin-2-ylpiperazin-2-one; [0058] Compound No. 5:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-pyridin-2-ylpiperazin-2-one; [0059] Compound No. 6:
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-pyrid-
in-2-yl-piperazin-2-one; [0060] Compound No. 7:
4-{2-[4-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(-
5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0061] Compound No.
8:
4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(6-ch-
loropyridin-2-yl)piperazin-2-one; [0062] Compound No. 9:
4-{2-[4-(3-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one; [0063] Compound No. 10:
4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl-
}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0064] Compound
No. 11:
4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoe-
thyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0065]
Compound No. 12:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-
-1-yl]-2-oxoethyl}-1-pyridin-3-ylpiperazin-2-one; [0066] Compound
No. 13:
1-(6-chloropyridin-3-yl)-4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-d-
ihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-2-one; [0067] Compound
No. 14:
4-{2-oxo-2-[5-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]e-
thyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0068]
Compound No. 15:
4-{2-oxo-2-[4-(3-trifluoromethoxylphenyl)-3,6-dihydro-2H-pyridin--
1-yl]ethyl}-1-pyridin-2-ylpiperazin-2-one; [0069] Compound No. 16:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-2,5-dihydro-pyrrol-1-yl]-2-oxo-
ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0070]
Compound No. 17:
4-{2-[4-(3,5-bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-y-
l]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
[0071] Compound No. 18:
4-{2-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-tr-
ifluoromethylpyridin-2-yl)piperazin-2-one; [0072] Compound No. 19:
4-{2-[4-phenyl-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-1-(5-trifluoromet-
hylpyridin-2-yl)piperazin-2-one; [0073] Compound No. 20:
4-{2-oxo-2-[5-(2,3-dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(-
5-trifluoromethylpyridin-2-yl)piperazin-2-one; [0074] Compound No.
21:
4-{2-oxo-2-[5-(3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}-1-(5-t-
rifluoromethylpyridin-2-yl)piperazin-2-one;
[0075] in the form of bases or of addition salts with acids.
[0076] In the subsequent text, the term "protective group Pg" is
intended to mean a group makes it possible, on the one hand, to
protect a reactive function such as a hydroxyl or an amine during a
synthesis and, on the other hand, to regenerate the intact reactive
function at the end of synthesis. Examples of protective groups and
also of the methods of protection and of deprotection are given in
"Protective Groups in Organic Synthesis", Green et al., 2nd Edition
(John Wiley & Sons, Inc., New York).
[0077] In accordance with the invention, the compounds of general
formula (I) are prepared according to the process which
follows.
##STR00008##
[0078] The compounds of formula (I) in which A, B, m, n and R3 are
as defined above, can be prepared by reaction of a compound of
formula (IV) as defined above, with a compound of formula (V) as
defined above according to methods known to those skilled in the
art as described in WO03/104225. More particularly, the process for
preparing the compounds of general formula (I) comprises the
reaction of a compound of formula (IV):
##STR00009##
in which A, B, m and n are as defined in general formula (I) and
Hal represents a halogen atom, for example chlorine, [0079] and of
a compound of general formula (V):
##STR00010##
[0079] in which R3 is as defined in general formula (I) in the
presence of a base, in a solvent as described in WO 03/104225.
Thus, by way of base, mention may be made of organic bases such as
triethylamine, N,N-diisopropylamine, diisopropylethylamine (DPEA),
or N-methylmorpholine or alkali metal carbonates or bicarbonates
such as potassium carbonate, sodium carbonate or sodium bicarbonate
and in the absence or in presence of an alkali metal iodide such as
potassium iodide or sodium iodide. The reaction is carried out
favourably in a solvent such as acetonitrile, N,N-dimethylformamide
(DMF), N-methylpyrrolidone (NMP), toluene or propan-2-ol, at a
temperature between ambient temperature and the reflux temperature
of the solvent. The term "ambient temperature" is intended to mean
a temperature between 5 and 25.degree. C. By way of example, the
reaction may be carried out in the presence of sodium bicarbonate,
and sodium iodide in a solvent such as DMF. The reaction is
preferably carried out in a microwave reactor.
[0080] In the products of general formula (I) thus obtained, R, R1,
R2, R4, R5, R6, and R7 can be modified by treatments commonly used
by those skilled in the art, such as, for example, by hydrolysis of
an ester group to give a carboxylic group.
[0081] The addition salts with an acid of the compounds of general
formula (I) may be obtained by addition of the appropriate acid to
the compound of formula (I) in the free base form.
[0082] The compounds of formula (IV), in which R1 and R2 are as
defined for the compounds of formula (I), can be prepared by
reaction of a compound of formula (II) with a compound of formula
(III) according to methods known to those skilled in the art for
example in presence of a base in a solvent as described in
WO03/104225.
[0083] More particularly, the compounds of formula (IV) can be
obtained by reaction of a corresponding compound of formula
(II):
##STR00011##
in which A, B and m are defined as in general formula (I);
optionally in the form of an addition salt with an acid, and of a
compound of formula (III):
##STR00012##
in which n and Hal are as defined in formula (IV) and Hal' is a
halogen atom, which may be identical or different. Preferably, Hal'
is a chlorine atom.
[0084] This reaction is generally carried out in the presence of a
base, such as triethylamine, N,N-diisopropylethylamine or
N-methylmorpholine, in a solvent such as dichloromethane,
chloroform, tetrahydrofuran or dioxane or a mixture of these
solvents and at a temperature of between 0.degree. C. and ambient
temperature. The compounds of formulae (II) and (III) are generally
commercially available or can be prepared according to methods
known to those skilled in the art.
[0085] The compounds of the formula (V), in which R3 is as defined
in formula (I), are prepared according to methods known to those
skilled in the art. They can be prepared, for example, according to
the process which follows:
##STR00013##
[0086] More particularly, the compound of formula (V) can be
prepared from a corresponding compound of formula (XI), in which R3
is as defined in formula (I) and Pg is a protective group for the
nitrogen atom, such as benzyl. This reaction can be carried out by
application or adaptation of any method known to those skilled in
the art; generally, this reaction is carried out in an acidic
medium, in the presence of a catalyst, such as Pd/C.
[0087] The compound of formula (XI) can be obtained from a compound
of formula (VIII) in which R3 is as defined in formula (I) and Pg
is a protective group, in the presence of a compound of formula
(VI). Generally, this reaction is carried out at a temperature
between ambient temperature and the boiling point of the reaction
mixture that may comprise water.
[0088] Alternatively, the compound of formula (XI) can be obtained
from a compound of formula (IX) by reaction with alkaline hydrides
in inert solvents such as toluene, dimethylformamide or dimethyl
sulphoxide, at a temperature of between ambient temperature and the
boiling point of the reaction mixture.
[0089] The compound of formula (IX) can be obtained from a compound
of formula (VIII) by reaction with ethyl bromoacetate or ethyl
chloroacetate in solvents such as butanol or acetone, in the
presence of a base such as potassium carbonate, at a temperature of
between ambient temperature and the boiling point of the reaction
mixture.
[0090] The compound of formula (VIII) can be obtained from a
compound of formula (VII) in which R3 is as defined in formula (I)
and X is a halogen atom, such as chlorine, in the presence of a
compound of formula (X) in which Pg is a protective group as
defined in formula (VIII). Generally, this reaction is carried out
at a temperature between ambient temperature and the boiling point
of the reaction mixture.
[0091] Optionally, the process according to the invention comprises
the subsequent step consisting in isolating the desired product
obtained.
[0092] According to another of its aspects, a subject of the
invention is also compounds of formula (IV)
##STR00014##
[0093] in which A, B, m and n are defined as in general formula (I)
and Hal is a halogen atom, for example chlorine; in the form of
bases or of addition salts with acids.
[0094] These compounds are of use as intermediates for synthesizing
the compounds of formula (I).
[0095] The starting compounds and the reactants, in Schemes 1 and
2, when the method for the preparation thereof is not described,
are commercially available or described in the literature, or else
can be prepared according to methods which are described therein or
which are known to those skilled in the art.
[0096] The following examples describe the preparation of certain
compounds in accordance with the invention. These compounds are not
limiting and merely illustrate the present invention. The numbers
of the compounds exemplified refer back to those given in the table
hereinafter, which illustrates the chemical structures and the
physical properties of some compounds according to the
invention.
[0097] The HPLC has been carried out using a ThermoElectron LCQ
Deca XP Max system equipped with a mass spectrometry ion trap
detector and a diode array detector.
[0098] The conditions for analysis by liquid chromatography coupled
to mass spectrometry (LC/UV/MS) are the following: [0099]
chromatographic system A [0100] Eluent A=H.sub.2O+0.01% TFA [0101]
Eluent B=CH.sub.3CN [0102] Gradient of 98% of A to 95% of B in 10
minutes, then elution with 95% of B for 5 minutes. [0103] Flow rate
0.5 ml/minute; temperature 40.degree. C. [0104] Injection of 2
.mu.L of solution at 0.1 mg/ml in a mixture of
CH.sub.3CN:H.sub.2O=9:1 [0105] chromatographic system B [0106]
Eluent A=H.sub.2O+0.05% TFA [0107] Eluent B=CH.sub.3CN+0.035% TFA
[0108] Gradient of 98% of A to 95% of B in 12 minutes, then elution
with 95% of B for 3 minutes. [0109] Flow rate 0.7 ml/minute;
temperature 40.degree. C. [0110] Injection of 2 .mu.L of solution
at 0.1 mg/ml in a mixture of CH.sub.3CN:H.sub.2O=9:1 [0111]
chromatographic system C [0112] Eluent A=ammonium acetate buffer 5
mM pH 6.5 [0113] Eluent B=CH.sub.3CN [0114] Gradient of 98% of A to
95% of B in 10 minutes, then elution with 95% of B for 5 minutes.
[0115] Flow rate 0.5 ml/minute; temperature 40.degree. C. [0116]
Injection of 2 .mu.L of solution at 0.1 mg/ml in a mixture of
CH.sub.3CN:H.sub.2O=9:1
[0117] The products are detected by UV at 220 nm.
[0118] The columns used are C18 columns with a particle size
between 2 and 4 .mu.m, preferably 3.5 .mu.m.
[0119] For the mass spectrometry part: [0120] Ionization mode:
positive electrospray (API-ES polarity+) [0121] Scanning from 120
to 1500 uma
[0122] The proton nuclear magnetic resonance (.sup.1H NMR) spectra
were recorded under the following conditions:
[0123] a) at 500 MHz on a Bruker machine equipped with an Avance
III console;
[0124] b) at 400 MHz on a Bruker machine equipped with an Avance I
console.
[0125] The chemical shifts are recorded in ppm with respect to the
TMS frequency.
[0126] The abbreviations used to characterize the signals are the
following: s=singlet, bs=broad singlet, m=multiplet, bm=broad
multiplet, d=doublet, bd=broad doublet, t=triplet,
q=quadruplet.
[0127] *=not integratable because of interference with a broad peak
due to water.
[0128] **=not integratable because of interference with a peak due
to the NMR solvent.
[0129] 2Xm=two partially superimposed multiplets.
[0130] Preparation 1
1-(5-Trifluoromethylpyridin-2-yl)piperazin-2-one hydrochloride
[0131] 10 g of 2-chloro-5-(trifluoromethyl)pyridine (compound of
formula (VII)) and 40.5 ml of N-benzylethylenediamine (compound of
formula (X)) are heated at 135.degree. C. for 6 hours in a
round-bottomed flask. The mixture is poured into water and the
resulting mixture is extracted with ethyl acetate. The resulting
product is dried and evaporated to dryness; the crude product thus
obtained is purified by flash chromatography. The isolated product
(compound of formula (VIII)), 14 g, is solubilized in 200 ml of a
2N solution of HCl. 30 g of trimeric glyoxal dihydrate (compound
VI), are added and the mixture is left stirring at ambient
temperature for 72 hours. It is extracted with ethyl acetate. The
resulting product is dried and evaporated to dryness; the crude
product thus obtained is purified by flash chromatography. The
isolated product (compound of formula (IX)), 10 g, is solubilized
in 450 ml of ethanol, and then 15 ml of a solution of isopropanol
saturated with HCl and 3 g of Pd/C at 10% are added. The mixture is
left to react under a hydrogen stream for 4 hours at a temperature
of 40.degree. C. The resulting product is filtered and evaporated
to dryness and 3 g of the title compound are obtained (compound of
formula (V)) Melting point 205-207.degree. C.
[0132] Preparation 2
1-(5-Methylpyridin-2-yl)piperazin-2-one hydrochloride
[0133] 4.7 g of 2-chloro-5-methylpyridine (compound of formula
(VII)) and 27.5 ml of N-benzylethylenediamine (compound of formula
(X)) are heated at 135.degree. C. for 5 hours in a round-bottomed
flask. The mixture is poured into water and the resulting mixture
is extracted with ethyl acetate. The resulting product is dried and
evaporated to dryness; the crude product thus obtained is purified
by flash chromatography. A product of 3.6 g is isolated (compound
of formula (VIII)).
[0134] 1.5 g of this product are solubilized in 3 ml of butanol.
0.85 g of potassium carbonate and 1.05 g of ethyl bromoacetate are
added and the mixture is heated at reflux temperature for 3 hours.
It is poured into water and extracted with ethyl acetate. The
resulting product is dried and evaporated to dryness; the crude
product thus obtained (2 g) is purified by flash chromatography.
The isolated product (compound of formula (IX)), 1 g, is then
solubilized in toluene and then this solution is slowly added,
under a stream of nitrogen, to a suspension of 0.25 g of sodium
hydride at 60% (NaH) in 25 ml of toluene. The mixture is heated at
the reflux temperature for 2 hours. It is poured into water and the
resulting mixture is extracted with ethyl acetate. The resulting
product is dried and evaporated under vacuum.
[0135] 0.6 g of crude product is obtained in the form of an oil
(compound of formula (IX)) which is solubilized in 25 ml of
ethanol, and then 1.5 ml of a solution of isopropanol saturated
with HCl and 0.3 g of 10% Pd/C are added. The mixture is left to
react under a hydrogen stream for 4 hours at a temperature of
40.degree. C. The resulting product is filtered and evaporated
under vacuum, and 0.3 g of the compound of the title (compound of
formula (V)) is obtained.
[0136] Preparation 3
2-Chloro-1-[4-[3-trifluoromethyl-4-chlorophenyl]-1-[3,6-dihydro-1(2H)pyrid-
inyl]]-1-ethanone
[0137]
4-[3-(Trifluoromethyl)-4-chlorophenyl]-3,6-dihydro-1(2H)-pyridine
hydrochloride (compound of formula (II)) (3.94 g) and 3.8 ml of
triethylamine in 33.5 ml of dichloromethane are cooled to 0.degree.
C. 2-Chloroacetyl chloride (compound of formula (III)) is added
dropwise and the mixture is left stirring for 1 h 30. Water is
added and the resulting mixture is extracted with dichloromethane.
The organic phase is dried over Na.sub.2SO.sub.4, filtered and
evaporated under vacuum.
[0138] 4.2 g of the compound are obtained in the form of an
amorphous solid (compound of formula (IV)).
EXAMPLE 1
Compound No. 1:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one and the
hydrochloride thereof
[0139] A mixture of compound of preparation 3 (0.49 mg), compound
of preparation 1 (0.4 mg), potassium carbonate (0.41 g), and sodium
iodide (0.45 g) in 7 ml of dimethylformamide is heated in a
microwave reactor at 180.degree. C. for 30 minutes. The reaction
mixture is poured into water and the resulting mixture is extracted
with ethyl acetate. The organic phase is dried over
Na.sub.2SO.sub.4, filtered and evaporated, to give 700 mg of crude
product in the form of an oil. The product is purified by silica
gel column chromatography, elution being carried out with a mixture
of cyclohexane/ethyl acetate=1/1. The hydrochloride is prepared by
adding a solution of hydrochloric acid in isopropanol. 200 g of the
title compound are obtained.
[0140] M+H.sup.+=m/z 547
[0141] .delta. (ppm, dmso-d6): 2.55 (bs, **); 2.63 (m, **);
3.43-3-54 (m, 2H); 3.65 (m, *); 3.75 (m,1H); 3.96 (bs, 2H); 4.18
(m, 6H); 6.40 (bs, 1H); 7.72 (d, J=8.4 Hz, 1H), 7.74-7.80 (m, 1H),
7.80-7.85 (m, 1H), 8.21 (d, J=9 Hz, 1H); 8.26 (dd, J.sub.1=9 Hz,
J.sub.2=2 Hz, 1H); 8.88 (s, 1H).
EXAMPLE 2
Compound No. 2:
4-{2-[4-(4-chloro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
-oxoethyl}-1-(5-methylpyridin-2-yl)piperazin-2-one and the
hydrochloride thereof
[0142] The compound of the title is obtained by carrying out the
procedure as described in Example 1, but using the compound of
preparation 2 in place of the compound of preparation 1.
[0143] M+H.sup.+=m/z 493
[0144] (Machine a). .delta. (ppm, dmso-d6): 2.32 (s, 3H), 2.56 (m,
1H), 2.65 (m, 1H), 3.10-3.60 (m, *), 3.64 (m, 1H), 3.77 (m, 1H),
3.98 (m, 2H), 4.05-4.51 (m, 6H), 6.41 (m, 1H), 7.69 (dd, J=8.4 and
2.0 Hz, 1H), 7.73 (d, 8.5 Hz, 1H), 7.75-7.81 (m, 2H), 7.83 (bd,
J=9.3 Hz, 1H), 8.31 (bd, J=2 Hz, 1H).
[0145] The table which follows illustrates the chemical structures
and the physical properties of some examples of compounds according
to the invention. In this table: [0146] in the "salt" column, "-"
represents a compound in the form of a free base, whereas "HCl"
represents a compound in the hydrochloride form.
TABLE-US-00001 [0146] TABLE ##STR00015## No. A B m R3 n Salt Mp
LCMS 1 ##STR00016## H 1 ##STR00017## 1 HCl 210- 211 MH+ 547 r.t.
7.6 Method A 2 ##STR00018## H 1 ##STR00019## 1 HCl 236- 239 MH+ 493
r.t. 6.5 Method A 3 ##STR00020## H 1 ##STR00021## 1 -- 141- 143 MH+
479 r.t. 7.9 Method C 4 ##STR00022## H 1 ##STR00023## 1 -- 104- 106
MH+ 445 r.t. 5.4 Method A 5 ##STR00024## H 1 ##STR00025## 1 HCl
160- 163 -- 6 ##STR00026## H 1 ##STR00027## 1 -- 112- 115 MH+ 411
r.t. 5.4 Method A 7 ##STR00028## H 1 ##STR00029## 1 -- 145- 146 MH+
513 r.t. 6.9 Method A 8 ##STR00030## H 1 ##STR00031## 1 HCl 180-
181 MH+ 445 r.t. 7.2 Method A 9 ##STR00032## H 1 ##STR00033## 1 HCl
147- 151 MH+ 479 r.t. 7.3 Method A 10 ##STR00034## H 1 ##STR00035##
1 -- 150- 152 MH+ 513 r.t. 7.9 Method C 11 ##STR00036## H 1
##STR00037## 1 Oxalate 161- 163 MH+ 513 r.t. 6.8 Method A 12
##STR00038## H 1 ##STR00039## 1 -- -- M+ = 479 r.t. 5.7 Method A 13
##STR00040## H 1 ##STR00041## 1 fumarate -- M+ = 513 r.t. 6.5
Method A 14 H ##STR00042## 1 ##STR00043## 1 Oxalate 172- 173 M+ =
513 r.t. 6.9 Method B 15 ##STR00044## H 1 ##STR00045## 1 Oxalate
165- 166 M+ = 529 r.t. 7.1 Method A 16 ##STR00046## H 0
##STR00047## 1 -- 210- 211 M+ = 533 r.t. 7.0 Method A 17
##STR00048## H 1 ##STR00049## 1 Oxalate 160- 161 M+ = 581 r.t. 8.1
Method C 18 ##STR00050## H 1 ##STR00051## 1 -- 130- 131 M+ = 459
r.t. 7.2 Method C 19 ##STR00052## H 1 ##STR00053## 1 -- 140- 142 M+
= 445 r.t. 6.0 Method A 20 H ##STR00054## 1 ##STR00055## 1 Oxalate
177- 178 M+ = 513 r.t. 6.6 Method A 21 H ##STR00056## 1
##STR00057## 1 Oxalate 194- 195 M+ = 475 r.t. 5.9 Method A
[0147] The compounds according to the invention were the subject of
biochemical studies.
[0148] Cell Culture:
[0149] The SH-SY-5Y strain (human neuroblastoma) is cultured
conventionally in a DMEM culture medium (Dulbecco's Modified
Eagle's Medium) (Gibco BRL, France) containing FCS (5%) (foetal
calf serum) (Boehringer Mannheim, Germany), sodium pyruvate (1 mM)
and glutamine (4 mM) in culture flasks coated with collagen (Becton
Dickinson, France).
[0150] The SK-N-BE parent strain (human neuroblastoma) and the Bep
75 clone, stably expressing the whole form of the human p75.sup.NTR
receptor (SK-N-BE Bep 75) are cultured conventionally in a RPMI
culture medium containing FCS (5%), sodium pyruvate (1 mM) and
glutamine (4 mM). For the SK-N-BE Bep 75 cells, hygromycin (200
.mu.l/20 ml of medium) is added as selection agent.
[0151] Study of the Binding of the .sup.125I NGF to the p75.sup.NTR
Receptor
[0152] The NGF binding study (nerve grown factor radiolabelled with
iodine-125, Amersham--2000 Ci/mmol) is carried out on a cell
suspension of the SK-N-BE Bep 75 strain in accordance with the
method described by Weskamp (Neuron, 1991, 6, 649-663). The
nonspecific binding is determined by measuring the total binding
after one hour of pre-incubation with the cells at 37.degree. C. in
the presence of non-radiolabelled NGF (1 .mu.M). The specific
binding is calculated by the difference between the total binding
measurement and the non-specific binding measurement. The
competition experiments are carried out using an iodinated NGF
(.sup.125I NGF) concentration of 0.3 nM. The concentrations
inhibiting 50% (IC.sub.50) of the binding of .sup.125I NGF to the
p75.sup.NTR receptor, of the compounds according to the invention
are low and vary from 10.sup.-6 to 10.sup.-11 M.
[0153] The compounds of formula (I) exhibit an activity in this
test, with IC.sub.50 values which range from 10.sup.-6 to
10.sup.-11 M.
[0154] For example, the compounds of examples Nos. 3 and 1 showed
an IC.sub.50 of 0.1 nM and 5.2 nM.
[0155] Study of the Dimerization of the p75.sup.NTR Receptor
Independently of its Ligand
[0156] The p75.sup.NTR receptor dimerization study is carried out
on a cell suspension of the SK-N-BE Bep 75 strain. The cells (2.5
10.sup.4 cells/well) are placed in wells (96-well plate) for 24 h,
and then preincubated for 1 h at 37.degree. C. in the presence or
absence of the compounds according to the invention. Supernatant is
then added, this supernatant being derived from the culture of
HEK293 human cells of renal origin expressing, after 48 h of
transfection, and secreting a soluble form of the p75.sup.NTR
receptor (extracellular part of the receptor) coupled to an
alkaline phosphatase, at the final concentration of 10 nM. The
quantification of the specific binding of the soluble p75.sup.NTR
receptor to the receptor present on SK-N-BE Bep 75 cells is
determined by measuring the alkaline phosphatase enzymatic activity
after incubation of the cells for 1 hour at 37.degree. C. in the
presence of the supernatant. After filtration and transfer of the
filters into 24-well plates, the alkaline phosphatase activity is
determined by adding CDP-Star chemiluminescent substrate
(ready-to-use, Roche). The concentrations inhibiting 50%
(IC.sub.50) of the dimerization of the p75.sup.NTR receptor, of the
compounds according to the invention, are low and vary from
10.sup.-6 to 10.sup.-11 M.
[0157] For example, the compounds of Examples No. 1, 2 and 3 showed
respectively IC.sub.50 values of 1.34 nM, 3.88 nM and 0.11 nM.
[0158] Measurement of Apoptosis
[0159] The cells (human neuroblastoma strains SH-SY-5Y and SK-N-BE
Bep 75) are placed in 35 mm diameter Petri dishes (Biocoat collagen
I), (10.sup.5 cells/well) in an appropriate culture medium
containing 5% of FCS for 24 h. The culture medium is then removed,
the cells are rinsed with PBS (Dulbecco's phosphate buffered
saline), and then either fresh medium containing 5% FCS, or medium
containing NGF (at the concentration of 10 ng/ml), or
.beta.-amyloid peptide (A.beta.1-40) (at the concentration of 10
.mu.M), is added, this being in the presence or absence of the
compounds according to the invention. The degrees of apoptosis are
measured 48 hours after the treatments in the case of the SH-SY-5Y
strain, and 24 hours after the treatments in the case of the
SK-N-BE Bep 75 strain, by quantification of the DNA
fragment-associated cytoplasmic histones (cell death detection
ELISA, Boehringer Mannheim, Germany). The degrees of apoptosis are
expressed as amount of oligonucleosomes/10.sup.5 cells. Each value
corresponds to the mean of 9 experimental points distributed over 3
independent experiments.
[0160] The compounds of formula (I) exhibit an inhibitory activity
on NGF-induced apoptosis, with IC.sub.50 values which range from
10.sup.-6 to 10.sup.-11 M. For example, the compound of Example No.
1 showed an IC.sub.50 of 1.61 nM and the compound of Example No. 5
showed an IC.sub.50 of 52 nM.
[0161] Thus, the binding of the compounds according to the
invention to the p75.sup.NTR receptor is reflected, on the one hand
at the biochemical level, by inhibition of the dimerization of the
receptor induced by neurotrophins, or independently of the ligand,
and, on the other hand, at the cellular level, by inhibition of the
proapoptotic effect mediated by the p75.sup.NTR receptor.
[0162] Thus, according to one of the subjects of the present
invention, the compounds of formula (I) exhibit a very advantageous
inhibitory activity on p75.sup.NTR receptor dimerization
independently of its ligand.
[0163] The compounds according to the invention can therefore be
used for the preparation of medicaments, in particular of
medicaments for use in preventing or treating any pathological
condition where the p75.sup.NTR receptor is involved.
[0164] Thus, according to another of its aspects, a subject of the
invention is medicaments which comprise a compound of formula (I),
or an addition salt of the latter with a pharmaceutically
acceptable acid.
[0165] According to another of its aspects, a subject of the
invention is a compound of formula (I), or an addition salt of the
latter with a pharmaceutically acceptable acid for the prevention
or treatment of the pathological conditions indicated below.
[0166] Thus, the compounds according to the invention can be used,
in humans or in animals, in the treatment or prevention of various
p75.sup.NTR-dependent conditions, such as central and peripheral
neurodegenerative diseases, for instance senile dementia, epilepsy,
Alzheimer's disease, Parkinson's disease, Huntington's chorea,
Down's syndrome, prion diseases, amnesia, schizophrenia,
depression, bipolar disorder; amyotrophic lateral sclerosis,
multiple sclerosis; cardiovascular conditions, for instance
post-ischaemic cardiac damage, cardiomyopathies, myocardial
infarction, heart failure, cardiac ischaemia, cerebral infarction;
peripheral neuropathies (of diabetic, traumatic or iatrogenic
origin); damage to the optic nerve and to the retina (retinal
pigment degeneration, glaucoma); retinal ischaemia; macular
degeneration; spinal cord traumas and cranial traumas;
atherosclerosis; stenoses; cicatrization disorders; alopecia.
[0167] The compounds according to the invention may also be used in
the treatment of cancers, for instance lung cancer, thyroid cancer,
pancreatic cancer, prostate cancer, cancer of the small intestine
and of the colon, or breast cancer, or in the treatment of tumours,
of metastases and of leukaemias.
[0168] The compounds according to the invention may also be used in
the treatment of respiratory disorders, for instance pulmonary
inflammation, allergy, asthma and chronic obstructive pulmonary
disease.
[0169] The compounds according to the invention may also be used in
the treatment of cutaneous pain (in the skin, the subcutaneous
tissues and the associated organs), somatic pain, visceral pain (in
the circulatory, respiratory, gastro-intestinal, or urogenital
system), and neurological pain.
[0170] The compounds according to the invention may be used in the
treatment of chronic neuropathic and inflammatory pain and in the
treatment of autoimmune diseases, such as rheumatoid arthritis.
[0171] The compounds according to the invention may also be used in
the treatment of diseases such as ankylosing spondyl arthritis,
psoriatic arthritis, or plaque psoriasis.
[0172] The compounds according to the invention may also be used in
the treatment of bone fractures, or in the treatment or the
prevention of bone diseases such as osteoporosis.
[0173] Thus, a subject of the present invention is a compound of
formula (I) according to the invention for preventing or treating
any pathological condition where the p75.sup.NTR receptor is
involved or more particularly the pathological conditions as
indicated above.
[0174] According to another of its aspects, the present invention
relates to pharmaceutical compositions comprising, as active
ingredients, a compound according to the invention. These
pharmaceutical compositions contain an effective dose of at least
one compound according to the invention, or a pharmaceutically
acceptable salt of said compound, and also at least one
pharmaceutically acceptable excipient.
[0175] Said excipients are chosen, according to the pharmaceutical
form and the method of administration desired, from among the
customary excipients which are known to those skilled in the
art.
[0176] In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular, intravenous,
topical, local, intratracheal, intranasal, transdermic or rectal
administration, the active ingredient of formula (I) above, or salt
thereof, may be administered in unit administration form, as a
mixture with conventional pharmaceutical excipients, to animals and
to human beings for the prevention or treatment of the disorders or
diseases above.
[0177] The suitable unit administration forms comprise oral
administration forms such as tablets, hard or soft gel capsules,
powders, granules and oral solutions or suspensions, sublingual,
buccal, intratracheal, intraocular and intranasal administration
forms, forms for administration by inhalation, topical
administration forms, parenteral, such as transdermal,
administration forms, subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms and implants. For
topical application, the compounds according to the invention may
be used in creams, gels, ointments or lotions.
[0178] By way of example, a unit administration form of a compound
according to the invention in tablet form may comprise the
following components:
TABLE-US-00002 Compound according to the invention 50.0 mg Mannitol
223.75 mg Sodium croscarmellose 6.0 mg Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg
[0179] The dose of active ingredient administered per day may reach
0.01 to 100 mg/kg, as one or more intakes, preferably 0.02 to 50
mg/kg. In general, the daily dose of the compound of the invention
will be the lowest effective dose of the compound capable of
producing a therapeutic effect.
[0180] There may be particular cases where higher or lower dosages
are appropriate; such dosages do not depart from the context of the
invention. According to the customary practice, the dosage suitable
for each patient is determined by the physician according to the
method of administration and the weight and response of said
patient.
[0181] According to another of its aspects, the present invention
also relates to a method of treating the pathological conditions
indicated above, which comprises the administration, to a patient,
of an effective dose of a compound according to the invention, or a
pharmaceutically acceptable salt thereof.
* * * * *