U.S. patent application number 17/077530 was filed with the patent office on 2021-02-11 for compounds, pharmaceutical composition and their use in treating neurodegenerative diseases.
The applicant listed for this patent is CENTRE HOSPITALIER REGIONAL ET UNIVERSITAIRE DE LILLE (CHRU), UNIVERSITE DE LILLE 2 DROIT ET SANTE. Invention is credited to Pascal Carato, Marion Donnier-Marechal, Patricia Melnyk, Benedicte Oxombre-Vanteghem, Patrick Vermersch, Helene Zephir.
Application Number | 20210040034 17/077530 |
Document ID | / |
Family ID | 1000005170191 |
Filed Date | 2021-02-11 |
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United States Patent
Application |
20210040034 |
Kind Code |
A1 |
Melnyk; Patricia ; et
al. |
February 11, 2021 |
COMPOUNDS, PHARMACEUTICAL COMPOSITION AND THEIR USE IN TREATING
NEURODEGENERATIVE DISEASES
Abstract
The present invention is directed to novel compounds of Formula
(I), pharmaceutically acceptable salts or solvates thereof, and
their use. ##STR00001##
Inventors: |
Melnyk; Patricia;
(Annoeullin, FR) ; Vermersch; Patrick; (Marcq En
Baroeul, FR) ; Carato; Pascal; (Ronchin, FR) ;
Oxombre-Vanteghem; Benedicte; (Arneke, FR) ; Zephir;
Helene; (Lille, FR) ; Donnier-Marechal; Marion;
(St Jean de Moirans, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITE DE LILLE 2 DROIT ET SANTE
CENTRE HOSPITALIER REGIONAL ET UNIVERSITAIRE DE LILLE
(CHRU) |
Lille
Lille |
|
FR
FR |
|
|
Family ID: |
1000005170191 |
Appl. No.: |
17/077530 |
Filed: |
October 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16205637 |
Nov 30, 2018 |
10844008 |
|
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17077530 |
|
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15317742 |
Dec 9, 2016 |
10179761 |
|
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PCT/EP2015/063370 |
Jun 15, 2015 |
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16205637 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 209/44 20130101;
C07C 211/27 20130101; A61K 49/00 20130101; C07C 211/29 20130101;
C07D 209/08 20130101; C07C 255/57 20130101; C07C 311/37 20130101;
C07C 255/60 20130101; C07C 235/50 20130101; C07C 233/78 20130101;
C07C 237/10 20130101; C07C 237/20 20130101; C07C 237/34
20130101 |
International
Class: |
C07C 233/78 20060101
C07C233/78; C07C 255/57 20060101 C07C255/57; C07C 311/37 20060101
C07C311/37; C07C 211/27 20060101 C07C211/27; C07C 211/29 20060101
C07C211/29; C07C 235/50 20060101 C07C235/50; C07C 237/20 20060101
C07C237/20; C07C 237/34 20060101 C07C237/34; C07D 209/08 20060101
C07D209/08; A61K 49/00 20060101 A61K049/00; C07C 237/10 20060101
C07C237/10; C07C 255/60 20060101 C07C255/60; C07D 209/44 20060101
C07D209/44 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 16, 2014 |
EP |
14305919.4 |
Claims
1-18. (canceled)
19. A method of treating and/or preventing a sigma-1 receptor
related disease, comprising the step of administering an effective
amount of a compound Formula I, ##STR00048## or a pharmaceutically
acceptable salt or solvate thereof, to a patient in need thereof,
wherein X.sup.1 and X.sup.5 are independently selected from the
group consisting of hydrogen, halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, --NHCOOR', and
--COOR', wherein R' is methyl, ethyl, n-propyl, n-butyl,
iso-propyl, iso-butyl or tert-butyl; X.sup.2, X.sup.3, X.sup.4 are
independently selected from the group consisting of hydrogen,
chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro,
di(C1-C4-alkyl)amino, --NHCOOR', and --COOR', wherein R' is methyl,
ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; with
the proviso that at least one of X.sup.1, X.sup.2, X.sup.3,
X.sup.4, X.sup.5 is not hydrogen and that at least one of X.sup.2,
X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is --C(O)NH--, --NHC(O)--,
--SO.sub.2NH--, --NHSO.sub.2--, or --NH--; n is 0, 1 or 2; m is 1,
2, 3, 4 or 5; R.sup.1 is H or alkyl, and R.sup.2 is 5- or
6-membered arylalkyl, 5- or 6-membered cycloalkylalkyl, wherein the
cyclic moiety of said arylalkyl or cycloalkylalkyl is optionally
substituted by one or more substituents independently selected from
halogen; or R.sup.1 and R.sup.2 together with the nitrogen atom to
which they are attached, form a 5-membered heterocyclyl group,
which is fused to a 5- or 6-membered aryl group and which is
optionally substituted by one or more substituents independently
selected from C1-C3 alkyl, and wherein the resulting heterocyclic
moiety is optionally substituted by one or more substituents
independently selected from halogen.
20. The method according to claim 19, wherein the compound is
selected from the group consisting of:
N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,
N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,
N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,
N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,
N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,
N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,
N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,
N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,
4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,
N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a
pharmaceutically acceptable salt or solvate thereof.
21. The method according to claim 19, wherein the sigma-1 receptor
related disease is a neurodegenerative disease.
22. The method according to claim 21, wherein the neurodegenerative
disease is selected from the group consisting of multiple
sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's
disease, and Amyotrophic lateral sclerosis.
23. A method of diagnosing of a sigma-1 receptor related disease,
comprising the step of administering an effective amount of a
compound of Formula I: ##STR00049## or a pharmaceutically
acceptable salt or solvate thereof, to a patient in need thereof,
wherein X.sup.1 and X.sup.5 are independently selected from the
group consisting of hydrogen, halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, nitro, di(C1-C4-alkyl)amino, --NHCOOR', and
--COOR', wherein R' is methyl, ethyl, n-propyl, n-butyl,
iso-propyl, iso-butyl or tert-butyl; X.sup.2, X.sup.3, X.sup.4 are
independently selected from the group consisting of hydrogen,
chloro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro,
di(C1-C4-alkyl)amino, --NHCOOR', and --COOR', wherein R' is methyl,
ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl; with
the proviso that at least one of X.sup.2, X.sup.3, X.sup.4, X.sup.5
is not hydrogen and that at least one of X.sup.2, X.sup.3, X.sup.4
is not C1-C4-alkoxy; L is --C(O)NH--, --NHC(O)--, --SO.sub.2NH--,
--NHSO.sub.2--, or --NH--; n is 0, 1 or 2; m is 1, 2, 3, 4 or 5;
R.sup.1 is H or alkyl, and R.sup.2 is 5- or 6-membered arylalkyl,
5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said
arylalkyl or cycloalkylalkyl is optionally substituted by one or
more substituents independently selected from halogen; or R.sup.1
and R.sup.2 together with the nitrogen atom to which they are
attached, form a 5-membered heterocyclyl group, which is fused to a
5- or 6-membered aryl group and which is optionally substituted by
one or more substituents independently selected from C1-C3 alkyl,
and wherein the resulting heterocyclic moiety is optionally
substituted by one or more substituents independently selected from
halogen.
24. The method according to claim 23, wherein the compound is
selected from the group consisting of:
N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,
N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,
N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,
N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,
N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,
N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,
N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,
N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,
4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,
N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a
pharmaceutically acceptable salt or solvate thereof.
25. A diagnostic imaging composition, comprising a compound of
Formula I: ##STR00050## or a pharmaceutically acceptable salt or
solvate thereof and at least one pharmaceutically acceptable
carrier, diluent, excipient and/or adjuvant, wherein X.sup.1 and
X.sup.5 are independently selected from the group consisting of
hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro,
di(C1-C4-alkyl)amino, --NHCOOR', and --COOR', wherein R' is methyl,
ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or ten-butyl;
X.sup.2, X.sup.3, X.sup.4 are independently selected from the group
consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl,
C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, --NHCOOR', and
--COOR', wherein R' is methyl, ethyl, n-propyl, n-butyl,
iso-propyl, iso-butyl or tert-butyl; with the proviso that at least
one of X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and that
at least one of X.sup.2, X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is
--C(O)NH--, --NHC(O)--, --SO.sub.2NH--, --NHSO.sub.2--, or --NH--;
n is 0, 1 or 2; m is 1, 2, 3, 4 or 5; R.sup.1 is H or alkyl, and
R.sup.2 is 5- or 6-membered arylalkyl, 5- or 6-membered
cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or
cycloalkylalkyl is optionally substituted by one or more
substituents independently selected from halogen; or R.sup.1 and
R.sup.2 together with the nitrogen atom to which they are attached,
form a 5-membered heterocyclyl group, which is fused to a 5- or
6-membered aryl group and which is optionally substituted by one or
more substituents independently selected from C1-C3 alkyl, and
wherein the resulting heterocyclic moiety is optionally substituted
by one or more substituents independently selected from
halogen.
26. The diagnostic imaging composition according to claim 25,
wherein the compound is selected from the group consisting of:
N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,
N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,
N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,
N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,
N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,
N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,
N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,
N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,
4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,
N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a
pharmaceutically acceptable salt or solvate thereof.
27. A method of modulating sigma-1 receptor activity, comprising
the step of administering an effective amount of a compound of
Formula I: ##STR00051## or a pharmaceutically acceptable salt or
solvate thereof, to a patient in need thereof, wherein X.sup.1 and
X.sup.5 are independently selected from the group consisting of
hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, cyano, nitro,
di(C1-C4-alkyl)amino, --NHCOOR', and --COOR', wherein R' is methyl,
ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or tert-butyl;
X.sup.2, X.sup.3, X.sup.4 are independently selected from the group
consisting of hydrogen, chloro, C1-C4-alkyl, C1-C4-haloalkyl,
C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino, --NHCOOR', and
--COOR', wherein R' is methyl, ethyl, n-propyl, n-butyl,
iso-propyl, iso-butyl or tert-butyl; with the proviso that at least
one of X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and that
at least one of X.sup.2, X.sup.3, X.sup.4 is not C1-C4-alkoxy; L is
--C(O)NH--, --NHC(O)--, --SO.sub.2NH--, --NHSO.sub.2--, or --NH--;
n is 0, 1 or 2; m is 1, 2, 3, 4 or 5; R.sup.1 is H or alkyl, and
R.sup.2 is 5- or 6-membered arylalkyl, 5- or 6-membered
cycloalkylalkyl, wherein the cyclic moiety of said arylalkyl or
cycloalkylalkyl is optionally substituted by one or more
substituents independently selected from halogen; or R.sup.1 and
R.sup.2 together with the nitrogen atom to which they are attached,
form a 5-membered heterocyclyl group, which is fused to a 5- or
6-membered aryl group and which is optionally substituted by one or
more substituents independently selected from C1-C3 alkyl, and
wherein the resulting heterocyclic moiety is optionally substituted
by one or more substituents independently selected from
halogen.
28. The method according to claim 27, wherein the compound is
selected from the group consisting of:
N-[3-(benzylmethylamino)propyl]-4-propylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-butylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide,
N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide,
N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide,
N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide,
N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide,
N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2-bromobenzamide,
N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide,
N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide,
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide,
N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide,
N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide,
N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide,
N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide,
4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide,
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide,
N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide,
N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide,
N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide, and
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine, or a
pharmaceutically acceptable salt or solvate thereof.
Description
[0001] The present invention relates to novel compounds including
their pharmaceutically acceptable salts and solvates, which are
modulators, advantageously agonists of sigma-1 receptor (sigma-1,
G1R or Sig-1R) and are useful as therapeutic compounds,
particularly in the treatment, prevention and/or diagnosis of
neurodegenerative diseases.
BACKGROUND OF THE INVENTION
[0002] The sigma-1 receptor is an intracellular chaperone protein
that resides specifically at the endoplasmic reticulum
(ER)-mitochondrion interface, referred to as the
mitochondrion-associated ER membrane (MAM). It is expressed in the
central nervous system (CNS) in microglia, lymphocytes, neurons,
and oligodendrocytes and is known to be implicated in the
regulation of numerous neurotransmitters.
[0003] In the central nervous system (CNS), Sig-1Rs play a part in
complex biological processes, which include cocaine or
methamphetamine addiction, learning and memory, pain and
depression. Some reports using the molecular biological silencing
approach have implicated these receptors in neurodegenerative
disorders such as Alzheimer's disease, stroke, and neural
degeneration due to HIV infection.
[0004] Sig-1Rs are thus potential therapeutic targets in multiple
CNS diseases and a variety of Sig-1R agonists and antagonists have
been described.
[0005] Anavex 2-73
(1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine
hydrochloride) exhibits high affinity and selectivity to sigma-1
receptors and synergistic action with muscarinic and cholinergic
receptors. Additional activities have been demonstrated on
N-methyl-D-aspartate (NMDA) receptors. During in vitro and in vivo
preclinical studies in mice, Anavex 2-73 demonstrated
neuroprotective and anti-amnesic properties. Anavex 2-73 has been
shown to provide protection from oxidative stress, which damages
and destroys neurons and is believed to be a primary cause of
Alzheimer's disease. Anavex 2-73 is currently under Phase I
clinical trials.
[0006] Anavex 1-41
(1-(5,5-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine
hydrochloride) presents a mixed pharmacological activity involving
the modulation of both sigma-1 and muscarinic components showing
prominent anti-amnesic, anti-depressant at low sigma-1 agonistic
doses. In addition, it presents mixed pharmacological activity
involving the modulation of sodium and chloride channels.
[0007] Donepezil
((RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-o-
ne) is an acetylcholine esterase inhibitor having non-selective
sigma-1 agonistic activity. Donepezil is also an agonist of
muscarinic and nicotinic receptors, and is a marketed drug used in
the palliative treatment of Alzheimer's disease.
[0008] Other molecules having Sig-1R affinity are known but they
either lack subtype selectivity over Sig-2R or they have high
affinity for other receptors sites as do Anavex 1-41 and 2-73, and
donepezil.
[0009] Drugs having poor selectivity (i.e. modulating the activity
of multiple receptors) are more susceptible to inducing deleterious
side effects, in particular to patients who are already under other
medications.
[0010] There is therefore still a need for new selective
modulators, especially agonists, of sigma-1 receptor activity of
therapeutic value for the treatment and/or prevention of sigma-1
receptor related diseases, especially neurodegenerative diseases
such as multiple sclerosis, Alzheimer's disease, Parkinson's
disease, Huntington's disease, and Amyotrophic lateral
sclerosis.
SUMMARY OF THE INVENTION
[0011] The invention encompasses compounds of general Formula I,
their pharmaceutically acceptable salts and solvates as well as
methods of use of such compounds or compositions comprising such
compounds as modulators, especially agonists of sigma-1 receptor
activity.
[0012] In a general aspect, the invention provides compounds of
general Formula I:
##STR00002##
and pharmaceutically acceptable salts and solvates thereof, wherein
X.sup.1 and X.sup.5 are independently selected from the group
consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl,
cyano, nitro, di(C1-C4-alkyl)amino, --NHCOOR', and --COOR', wherein
R' is methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl or
tert-butyl; X.sup.2, X.sup.3, X.sup.4 are independently selected
from the group consisting of hydrogen, chloro, C1-C4-alkyl,
C1-C4-haloalkyl, C1-C4-alkoxy, cyano, nitro, di(C1-C4-alkyl)amino,
--NHCOOR', and --COOR', wherein R' is methyl, ethyl, n-propyl,
n-butyl, iso-propyl, iso-butyl or tert-butyl; with the proviso that
at least one of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not
hydrogen and that at least one of X.sup.2, X.sup.3, X.sup.4 is not
C1-C4-alkoxy; L is --C(O)NH--, --NHC(O)--, --SO.sub.2NH--,
--NHSO.sub.2--, or --NH--; n is 0, 1 or 2; m is 1, 2, 3, 4 or 5;
R.sup.1 is H or alkyl, and R.sup.2 is 5- or 6-membered arylalkyl,
5- or 6-membered cycloalkylalkyl, wherein the cyclic moiety of said
arylalkyl or cycloalkylalkyl is optionally substituted by one or
more substituents independently selected from halogen, preferably
fluoro; or R.sup.1 and R.sup.2 form together with the nitrogen atom
they are attached to a 5-membered heterocyclyl group, which is
fused to a 5- or 6-membered aryl group and which is optionally
substituted by one or more substituents independently selected from
C1-C3 alkyl, preferably methyl, and wherein the resulting
heterocyclic moiety is optionally substituted by one or more
substituents independently selected from halogen, preferably
fluoro.
[0013] In one embodiment, the compound of Formula I is not one,
more or all of the following: [0014]
N-[3-[benzyl(methyl)amino]propyl]-4-chlorobenzamide; [0015]
N-[3-[benzyl(methyl)amino]propyl]benzamide; [0016]
N-[3-[benzyl(methyl)amino]propyl]-4-fluorobenzamide; [0017]
N-[3-[benzyl(methyl)amino]propyl]-4-bromobenzamide; [0018]
N-[3-[benzyl(methyl)amino]propyl]-4-methoxybenzamide; [0019]
N'-benzyl-N-[(4-chlorophenyl)methyl]-N'-methylpropane-1,3-diamine;
and [0020]
N-[3-[benzyl(methyl)amino]propyl]-4-chlorobenzenesulfonamide.
[0021] In another aspect, the present invention provides a
pharmaceutical composition comprising at least one compound
according to the invention or a pharmaceutically acceptable salt or
solvate thereof and at least one pharmaceutically acceptable
carrier, diluent, excipient and/or adjuvant.
[0022] The invention also relates to the use of the above compounds
or their pharmaceutically acceptable salts and solvates as
modulators of sigma-1 receptor activity, preferably as agonists of
sigma-1 receptors.
[0023] The invention further provides the use of a compound
according to the invention or a pharmaceutically acceptable salt or
solvate thereof as a medicament. Preferably, the medicament is used
for the treatment and/or prevention of sigma-1 related
diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0024] As noted above, the invention relates to compounds of
Formula I, as well as their pharmaceutically acceptable salts and
solvates.
[0025] Preferred compounds of Formula I and pharmaceutically
acceptable salts and solvates thereof are those wherein one or more
of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, L, n, m, R', and
R.sup.2 are defined as follows:
X.sup.1 and X.sup.5 are independently selected from the group
consisting of hydrogen, fluoro, chloro, bromo, iodo, C1-C4-alkyl,
C1-C2-haloalkyl, cyano, nitro, and di(C1-C2-alkyl)amino, preferably
X.sup.1 and X.sup.5 are independently selected from the group
consisting of hydrogen, fluoro, chloro, bromo, C3-C4-alkyl,
trifluoromethyl, cyano, nitro, and dimethylamino, more preferably
X.sup.1 and X.sup.5 are independently selected from the group
consisting of hydrogen, fluoro, chloro, n-propyl, n-butyl, t-butyl,
trifluoromethyl, and dimethylamino, still more preferably X.sup.1
and X.sup.5 are independently selected from the group consisting of
hydrogen, chloro, trifluoromethyl, and dimethylamino; X.sup.2,
X.sup.3, X.sup.4 are independently selected from the group
consisting of hydrogen, chloro, C1-C4-alkyl, C1-C2-halo alkyl,
C1-C2-alkoxy, cyano, nitro, and di(C1-C2-alkyl)amino, preferably
X.sup.2, X.sup.3, X.sup.4 are independently selected from the group
consisting of hydrogen, chloro, C3-C4-alkyl, trifluoromethyl,
methoxy, cyano, nitro, and dimethylamino, more preferably X.sup.2,
X.sup.3, X.sup.4 are independently selected from the group
consisting of hydrogen, chloro, n-propyl, n-butyl, t-butyl,
trifluoromethyl, methoxy, and dimethylamino, still more preferably
X.sup.2, X.sup.3, X.sup.4, X.sup.5 are independently selected from
the group consisting of hydrogen, chloro, trifluoromethyl, and
dimethylamino; always with the proviso that at least one of
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 is not hydrogen and
that at least one of X.sup.2, X.sup.3, X.sup.4 is not
C1-C2-alkoxy/methoxy; n is 0 and L is selected from --C(O)NH--,
--NHC(O)--, --SO.sub.2NH--, preferably L is C(O)NH--;
n is 1 and L is --NH-- or --NHC(O)--;
[0026] m is 2, 3 or 4, preferably m is 2 or 3; R.sup.1 is H or
C1-C4-alkyl, preferably R.sup.1 is H or C1-C2 alkyl, more
preferably R.sup.1 is C1-C2 alkyl, still more preferably R.sup.1 is
methyl; R.sup.2 is 5- or 6-membered aryl-C1-C2-alkyl, 5- or
6-membered cycloalkyl-C1-C2-alkyl, wherein the cyclic moiety of
said arylalkyl or cycloalkylalkyl group is optionally substituted
by one or more substituents independently selected from halogen,
preferably fluoro, preferably R.sup.2 is benzyl, phenylethyl, or
cyclohexylmethyl, wherein the cyclic moiety of each of said
substituents is optionally substituted by one or more substituents
independently selected from halogen, preferably fluoro, more
preferably R.sup.2 is benzyl or phenylethyl, wherein the cyclic
moiety of each of said substituents is optionally substituted by
one or more substituents independently selected from halogen,
preferably fluoro, even more preferably R.sup.2 is benzyl,
optionally substituted by one or more substituents independently
selected from halogen, preferably fluoro; advantageously R.sup.2 is
5- or 6-membered aryl-C1-C2-alkyl, wherein the cyclic moiety of
each of said substituents optionally substituted by one or more
substituents independently selected from halogen, preferably
fluoro, preferably R.sup.2 is benzyl or phenylethyl, wherein the
cyclic moiety of each of said substituents is optionally
substituted by one or more substituents independently selected from
halogen, preferably fluoro, more preferably R.sup.2 is benzyl,
optionally substituted by one or more substituents independently
selected from halogen, preferably fluoro; R.sup.1 and R.sup.2 form
together with the nitrogen atom they are attached to a 5-membered
heterocyclyl group, which is fused to a phenyl group and which is
optionally substituted by one or more substituents independently
selected from C1-C2 alkyl, preferably methyl, and wherein the
resulting heterocyclic moiety is optionally substituted by one or
more substituents independently selected from halogen, preferably
fluoro, preferably R.sup.1 and R.sup.2 form together with the
nitrogen atom they are attached to a isoindolinyl group optionally
substituted by one or more substituents independently selected from
C1-C2 alkyl, preferably methyl, and halogen, preferably fluoro.
[0027] Other preferred compounds of Formula I as defined above and
pharmaceutically acceptable salts and solvates thereof are those
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 are as defined
as follows:
[0028] X.sup.1, X.sup.2, X.sup.4, X.sup.5 are hydrogen and X.sup.3
is chloro, C1-C4-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, cyano,
nitro, or dialkylamino, preferably X.sup.3 is chloro, C3-C4-alkyl,
trifluoromethyl, methoxy, cyano, nitro, or dimethylamino, more
preferably X.sup.3 is chloro, n-propyl, n-butyl, I-butyl,
trifluoromethyl or methoxy, more preferably X.sup.3 is chloro, or
trifluoromethyl, even more preferably X.sup.3 is chloro;
[0029] X.sup.2, X.sup.3, X.sup.4, X.sup.5 are hydrogen and X.sup.1
is fluoro, chloro, bromo, iodo, C1-C4-alkyl, C1-C2-haloalkyl,
cyano, nitro, or dialkylamino, preferably X.sup.1 is fluoro,
chloro, bromo, C3-C4-alkyl, trifluoromethyl, cyano, nitro, or
dimethylamino, more preferably X.sup.1 is fluoro, chloro, bromo,
n-propyl, n-butyl, t-butyl, trifluoromethyl, and dimethylamino,
more preferably X.sup.1 is chloro, bromo, trifluoromethyl, or
dimethylamino, even more preferably X.sup.1 is chloro or bromo;
[0030] X.sup.1, X.sup.3, X.sup.4, X.sup.5 are hydrogen and X.sup.2
is chloro, C1-C4-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, cyano,
nitro, or dialkylamino, preferably X.sup.2 is chloro, C3-C4-alkyl,
trifluoromethyl, methoxy, cyano, nitro, or dimethylamino, more
preferably X.sup.2 is chloro, n-propyl, n-butyl, 1-butyl,
trifluoromethyl, methoxy, and dimethylamino, more preferably
X.sup.2 is chloro, trifluoromethyl, methoxy, or dimethylamino, even
more preferably X.sup.2 is chloro, or dimethylamino;
[0031] X.sup.3, X.sup.4, and X.sup.5 are hydrogen and X.sup.1 and
X.sup.2 are independently selected from the group consisting of
chloro, C1-C4-alkyl, C1-C2-haloalkyl, cyano, nitro, and
dialkylamino, preferably X.sup.1 and X.sup.2 are independently
selected from the group consisting of chloro, C3-C4-alkyl,
trifluoromethyl, cyano, nitro, or dimethylamino, more preferably
X.sup.1 and X.sup.2 are independently selected from the group
consisting of chloro, n-propyl, n-butyl, t-butyl, trifluoromethyl,
and dimethylamino, more preferably X.sup.1 and X.sup.2 are
independently selected from the group consisting of chloro,
trifluoromethyl, and dimethylamino, even more preferably X.sup.1
and X.sup.2 are both chloro;
[0032] X.sup.2, X.sup.4, and X.sup.5 are hydrogen and X.sup.1 and
X.sup.3 are independently selected from the group consisting of
chloro, C1-C4-alkyl, C1-C2-haloalkyl, cyano, nitro, and
dialkylamino, preferably X.sup.1 and X.sup.3 are independently
selected from the group consisting of chloro, C3-C4-alkyl,
trifluoromethyl, cyano, nitro, or dimethylamino, more preferably
X.sup.1 and X.sup.3 are independently selected from the group
consisting of chloro, n-propyl, n-butyl, t-butyl, trifluoromethyl,
and dimethylamino, still more preferably X.sup.1 and X.sup.3 are
independently selected from the group consisting of chloro,
trifluoromethyl, and dimethylamino, even more preferably X.sup.1
and X.sup.3 are both chloro;
[0033] X.sup.1, X.sup.4, and X.sup.5 are hydrogen and X.sup.2 and
X.sup.3 are independently selected from the group consisting of
chloro, C1-C4-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, cyano, nitro,
and dialkylamino, preferably X.sup.2 and X.sup.3 are independently
selected from the group consisting of chloro, C3-C4-alkyl,
trifluoromethyl, methoxy, cyano, nitro, or dimethylamino, more
preferably X.sup.2 and X.sup.3 are independently selected from the
group consisting of chloro, n-propyl, n-butyl, t-butyl,
trifluoromethyl, methoxy, and dimethylamino, more preferably
X.sup.2 and X.sup.3 are independently selected from the group
consisting of chloro, trifluoromethyl, and dimethylamino, even more
preferably X.sup.2 and X.sup.3 are both chloro; or
[0034] X.sup.1, X.sup.3, and X.sup.5 are hydrogen and X.sup.2 and
X.sup.4 are independently selected from the group consisting of
chloro, C1-C4-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, cyano, nitro,
and dialkylamino, preferably X.sup.2 and X.sup.4 are independently
selected from the group consisting of chloro, C3-C4-alkyl,
trifluoromethyl, methoxy, cyano, nitro, or dimethylamino, more
preferably X.sup.2 and X.sup.4 are independently selected from the
group consisting of chloro, n-propyl, n-butyl, t-butyl,
trifluoromethyl, methoxy, and dimethylamino, more preferably
X.sup.2 and X.sup.4 are independently selected from the group
consisting of chloro, trifluoromethyl, and dimethylamino, even more
preferably X.sup.2 and X.sup.4 are both chloro.
[0035] In one embodiment, preferred compounds of Formula I are
those of Formula II:
##STR00003##
and pharmaceutically acceptable salts and solvates thereof, wherein
X.sup.3, m, R.sup.1, and R.sup.2 are as defined above with respect
to Formula I and any of its embodiments, with the proviso that
X.sup.3 is not hydrogen.
[0036] In one embodiment, the compounds of Formula II are those
wherein X.sup.3 is chloro, C1-C4-alkyl, C1-C2-haloalkyl,
C1-C2-alkoxy, cyano, nitro, or dialkylamino, preferably X.sup.3 is
chloro, C3-C4-alkyl, trifluoromethyl, methoxy, cyano, nitro, or
dimethylamino, more preferably X.sup.3 is chloro, n-propyl,
n-butyl, !-butyl, trifluoromethyl, methoxy, or dimethylamino, more
preferably X.sup.3 is chloro, trifluoromethyl, or dimethylamino,
even more preferably X.sup.3 is chloro, and/or m is 2, 3 or 4,
preferably 2 or 3, and/or R.sup.1 is methyl, and/or R.sup.2 is
benzyl optionally substituted by one or more substituents selected
from the group consisting of halogen, preferably fluoro.
[0037] In one embodiment, preferred compounds of Formula I are
those of Formula III:
##STR00004##
and pharmaceutically acceptable salts and solvates thereof, wherein
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, L, n and m are as
defined above with respect to Formula I and any of its embodiments;
p is 1 or 2, preferably 1; and X.sup.6, X.sup.7, X.sup.8, X.sup.9,
X.sup.10 are independently selected from H, halogen preferably
fluoro, preferably X.sup.6, X.sup.7, X.sup.8, X.sup.9, X.sup.10 are
all H.
[0038] In one embodiment, the compounds of Formula III are those of
Formula III-a:
##STR00005##
and pharmaceutically acceptable salts and solvates thereof, wherein
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, L, n, m and p are as
defined above with respect to Formula III.
[0039] In one embodiment, the compounds of Formula III-a are those
of Formula III-a-1:
##STR00006##
and pharmaceutically acceptable salts and solvates thereof, wherein
X.sup.3 is chloro, C1-C4-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy,
cyano, nitro, or dialkylamino, preferably X.sup.3 is chloro,
C3-C4-alkyl, trifluoromethyl, methoxy, cyano, nitro, or
dimethylamino, more preferably X.sup.3 is chloro, n-propyl,
n-butyl, t-butyl, trifluoromethyl, methoxy, or dimethylamino, more
preferably X.sup.3 is chloro, trifluoromethyl, or dimethylamino,
even more preferably X.sup.3 is chloro; m is 1, 2, 3 or 4,
preferably 1 or 3, more preferably 3; and/or p is 1 or 2,
preferably 1.
[0040] In one embodiment, the compounds of Formula III-a are those
of Formula III-a-2:
##STR00007##
wherein X.sup.3 is chloro, C1-C4-alkyl, C1-C2-haloalkyl,
C1-C2-alkoxy, cyano, nitro, or dialkylamino, preferably X.sup.3 is
chloro, C3-C4-alkyl, trifluoromethyl, methoxy, cyano, nitro, or
dimethylamino, more preferably X.sup.3 is chloro, n-propyl,
n-butyl, t-butyl, trifluoromethyl, methoxy, or dimethylamino, more
preferably X.sup.3 is chloro, trifluoromethyl, or dimethylamino,
even more preferably X.sup.3 is chloro;
[0041] L is --NHC(O)-- or --SO.sub.2NH--; and/or m is 2 or 3,
preferably 3.
[0042] In one embodiment, the compounds of Formula III-a are those
of Formula III-a-3:
##STR00008##
wherein X.sup.3 is chloro, C1-C4-alkyl, C1-C2-haloalkyl,
C1-C2-alkoxy, cyano, nitro, or dialkylamino, preferably X.sup.3 is
chloro, C3-C4-alkyl, trifluoromethyl, methoxy, cyano, nitro, or
dimethylamino, more preferably X.sup.3 is chloro, n-propyl,
n-butyl, !-butyl, trifluoromethyl, methoxy, or dimethylamino, more
preferably X.sup.3 is chloro, trifluoromethyl, or dimethylamino,
even more preferably X.sup.3 is chloro; L is --NHC(O)-- or --NH--;
and/or m is 1, 2 or 3, preferably 2 or 3.
[0043] Preferred compounds of Formula III-a-3 are those wherein L
is --NHC(O)-- and m is 2, or L is --NH-- and m is 3.
In one embodiment, the compounds of Formula I are those of Formula
IV:
##STR00009##
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.5, and m are as defined
above with respect to Formula I and any of its embodiments.
Preferred compounds of formula IV are those of Formula IV-a:
##STR00010##
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 are as
defined above with respect to Formula IV. Preferred compounds of
formulae IV and IV-a are those wherein X.sup.1, X.sup.2, X.sup.3,
X.sup.4, X.sup.5 are independently selected from hydrogen, chloro,
nitro, and trifluoromethyl; with the proviso that at least one of
X.sup.2, X.sup.3, X.sup.4, and X.sup.5 is not hydrogen. In one
embodiment, the compounds of Formula I are those of Formula V:
##STR00011##
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, and m are as
defined above with respect to Formula I and any of its embodiments.
Preferred compounds of formula V are those of Formula V-a:
##STR00012##
wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 are as
defined above with respect to Formula V. Preferred compounds of
formulae V and V-a are those wherein X.sup.2, X.sup.3, X.sup.4, are
independently selected from hydrogen, chloro, nitro, and
trifluoromethyl; with the proviso that at least one of X.sup.1,
X.sup.2, X.sup.3, X.sup.4, and X.sup.5 is not hydrogen.
[0044] Particularly preferred compounds of the invention are those
listed in Table 1 hereafter:
TABLE-US-00001 TABLE 1 Cpd no. Chemical name 3.1.2
N-[3-(benzylmethylamino)propyl]-4-propylbenzamide 3.1.3
N-[3-(benzylmethylamino)propyl]-4-butylbenzamide 3.1.4
N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide 3.1.5
N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide 3.1.6
N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide 3.1.7
N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide 3.1.8
N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide 3.1.9
N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide 3.1.10
N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide 3.1.11
N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide 3.1.12
N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide 3.1.15
N-[3-(is oindolin-2-yl)methylamino)propyl]-4-chlorobenzamide 3.1.20
N-[3-(benzylmethylamino)propyl]-2-bromobenzamide 3.1.23
N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide 3.1.24
N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide 3.1.25
N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide 3.1.26
N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide 3.1.28
N-[3-(benzylmethylamino)propyl]-3-methoxybenzamide 3.1.29
N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide 3.1.30
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide 3.1.31
N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide 3.1.32
N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide 3.1.33
N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide 3.1.34
N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide 3.1.36
N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide 3.1.37
N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide 3.2a
N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide 3.3a
4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide 3.4a
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide 3.4b
N-(4-nitrobenzyl)-3-(benzylmethylamino)propanamide 3.4c
N-(4-cyanobenzyl)-3-(benzylmethylamino)propanamide 3.4d
N-(2,4-dichlorobenzyl)-3-(benzylmethylamino)propanamide 3.4e
N-(3-chlorobenzyl)-3-(benzylmethylamino)propanamide 3.5a
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine
[0045] The compounds of the invention can be prepared by different
ways with reactions known by the person skilled in the art.
Reaction schemes as described in the example section illustrate by
way of example different possible approaches.
[0046] The compounds of the invention are indeed modulators,
preferably agonists of sigma-1 receptor. They further have the
advantage of being selective over the sigma-2 receptor. The
invention thus also provides the use of the compounds of the
invention or pharmaceutically acceptable salts, or solvates thereof
as agonists of sigma-1 receptor.
[0047] Accordingly, in a particularly preferred embodiment, the
invention relates to the use of compounds of Formula I and
subformulae in particular those of Table 1 above, or
pharmaceutically acceptable salts and solvates thereof, as sigma-1
agonists.
Applications
[0048] The compounds of the invention are therefore useful in the
prevention and/or treatment of sigma-1 receptor related diseases or
disorders.
[0049] The invention thus also relates to a compound of the
invention or a pharmaceutically acceptable salt or solvate thereof
for use in treating and/or preventing a sigma-1 receptor related
disease or disorder. Or in other terms, the invention also relates
to a method of treating and/or preventing a sigma-1 receptor
related disease or disorder, comprising the administration of a
therapeutically effective amount of a compound or pharmaceutically
acceptable salt or solvate of the invention, to a patient in need
thereof. Preferably the patient is a warm-blooded animal, more
preferably a human.
[0050] Sigma-1 receptor related diseases or disorders within the
meaning of the invention include, but are not limited to,
neurodegenerative diseases, psychiatric disorders, drug addiction,
pain and cancer.
[0051] Neurodegenerative diseases within the meaning of the present
invention include, but are not limited to multiple sclerosis (MS),
Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic
lateral sclerosis (ALS), stroke and dementia, the latter including,
without being limited thereto, Alzheimer's disease (AD), vascular
dementia, frontotemporal dementia, semantic dementia and dementia
with Lewy bodies. Preferred neurodegenerative diseases are multiple
sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's
disease, amyotrophic lateral sclerosis, and stroke. In a particular
preferred embodiment the neurodegenerative disease is multiple
sclerosis.
[0052] Psychiatric disorders within the meaning of the invention
include, but are not limited to, schizophrenia, depression, and
anxiety disorders,
[0053] The invention further provides the use of a compound of the
invention or a pharmaceutically acceptable salt or solvates thereof
for the manufacture of a medicament for use in treating and/or
preventing a sigma-1 receptor related disease or disorder.
Preferably the patient is a warm-blooded animal, more preferably a
human. The sigma-1 receptor related diseases or disorders are
preferably those defined above.
[0054] According to a further feature of the present invention,
there is provided a compound of the invention or a pharmaceutically
acceptable salt or solvate for use in modulating sigma-1 receptor
activity in a patient in need of such treatment, comprising
administering to said patient an effective amount of a compound of
the present invention, or a pharmaceutically acceptable salt or
solvate thereof. In other terms, the invention also provides a
method for modulating sigma-1 receptor activity, in a patient in
need of such treatment, which comprises administering to said
patient an effective amount of a compound of the present invention,
or a pharmaceutically acceptable salt or solvate thereof.
Preferably, the patient is a warm blooded animal, and even more
preferably a human.
[0055] According to one embodiment, the compounds of the invention,
their pharmaceutical acceptable salts or solvates may be
administered as part of a combination therapy. Thus, are included
within the scope of the present invention embodiments comprising
coadministration of, and compositions and medicaments which
contain, in addition to a compound of the present invention, a
pharmaceutically acceptable salt or solvate thereof as active
ingredient, additional therapeutic agents and/or active
ingredients. Such multiple drug regimens, often referred to as
combination therapy, may be used in the treatment and/or prevention
of any sigma-1 receptor related disease or disorder, particularly
those defined above.
[0056] Thus, the methods of treatment and pharmaceutical
compositions of the present invention may employ the compounds of
the invention or their pharmaceutical acceptable salts or solvates
thereof in the form of monotherapy, but said methods and
compositions may also be used in the form of multiple therapy in
which one or more compounds of Formula I or their pharmaceutically
acceptable salts or solvates are coadministered in combination with
one or more other therapeutic agents.
[0057] The invention also provides pharmaceutical compositions
comprising a compound of the invention or a pharmaceutically
acceptable salt or solvate thereof and at least one
pharmaceutically acceptable carrier, diluent, excipient and/or
adjuvant. As indicated above, the invention also covers
pharmaceutical compositions which contain, in addition to a
compound of the present invention, a pharmaceutically acceptable
salt or solvate thereof as active ingredient, additional
therapeutic agents and/or active ingredients.
[0058] Another object of this invention is a medicament comprising
at least one compound of the invention, or a pharmaceutically
acceptable salt or solvate thereof, as active ingredient.
[0059] Generally, for pharmaceutical use, the compounds of the
invention may be formulated as a pharmaceutical preparation
comprising at least one compound of the invention and at least one
pharmaceutically acceptable carrier, diluent, excipient and/or
adjuvant, and optionally one or more further pharmaceutically
active compounds.
[0060] By means of non-limiting examples, such a formulation may be
in a form suitable for oral administration, for parenteral
administration (such as by intravenous, intramuscular or
subcutaneous injection or intravenous infusion), for topical
administration (including ocular), cerebral administration, for
administration by inhalation, by a skin patch, by an implant, by a
suppository, etc. Such suitable administration forms which may be
solid, semi-solid or liquid, depending on the manner of
administration as well as methods and carriers, diluents and
excipients for use in the preparation thereof, will be clear to the
skilled person; reference is made to the latest edition of
Remington's Pharmaceutical Sciences.
[0061] The compounds of the invention are also useful as diagnostic
agents for diagnosing sigma-1 receptor related diseases or
disorders. Sigma-1 receptor related diseases or disorders that may
be diagnosed using the compounds, pharmaceutically acceptable salts
or solvates of the invention are those described above.
[0062] The invention thus also relates to a compound of the
invention or a pharmaceutically acceptable salt or solvate thereof
for use in the diagnosis, especially the in vivo diagnosis of a
sigma-1 receptor related disease or disorder.
[0063] In one embodiment, the diagnosis is an in vivo diagnosis
performed by positron emission tomography (PET) or single-photon
emission computed tomography (SPECT). The compounds of the
invention or pharmaceutically acceptable salts or solvates thereof
used in these methods are isotopically radiolabelled, preferably
with an isotope selected from the group consisting of .sup.11C,
.sup.13C, .sup.15O, and .sup.18F, more preferably with
.sup.18F.
[0064] In a variant of this embodiment, the compounds,
pharmaceutically acceptable salts and solvates of the invention are
those of Formula I and subformulae above, wherein the cyclic moiety
of R.sup.2 is optionally substituted by one or more substituents
independently selected from radioactive halogen isotopes,
preferably .sup.18F or wherein when R.sup.1 and R.sup.2 form
together with the nitrogen atom they are attached to a 5- or
6-membered heterocyclyl group, which is optionally fused to a 5- or
6-membered aryl group and which is optionally substituted by one or
more substituents independently selected from C1-C3 alkyl,
preferably methyl, the resulting heterocyclic moiety is substituted
by one or more substituents independently selected from radioactive
halogen isotopes, preferably .sup.15F.
[0065] The invention also provides a diagnostic composition,
especially a diagnostic imaging composition, comprising a compound
of the invention or a pharmaceutically acceptable salt or solvate
thereof and at least one pharmaceutically acceptable carrier,
diluent, excipient and/or adjuvant.
[0066] In one embodiment, the diagnostic composition is a
diagnostic composition for positron emission tomography (PET) or
single-photon emission computed tomography (SPECT). Compounds that
are particularly useful in this embodiment are those described
above with respect to the use of the compounds, pharmaceutically
acceptable salts and solvates of the invention in the in vivo
diagnosis performed by PET or SPECT.
Definitions
[0067] The definitions and explanations below are for the terms as
used throughout the entire application, including both the
specification and the claims.
[0068] Unless otherwise stated any reference to compounds of the
invention herein, means the compounds as such as well as their
pharmaceutically acceptable salts and solvates.
[0069] When describing the compounds of the invention, the terms
used are to be construed in accordance with the following
definitions, unless indicated otherwise.
[0070] The term "halo" or "halogen" means fluoro, chloro, bromo, or
iodo. Preferred halo groups are fluoro and chloro, fluoro being
particularly preferred.
[0071] The term "alkyl" by itself or as part of another substituent
refers to a hydrocarbyl radical of Formula C.sub.nH.sub.2n+1
wherein n is a number greater than or equal to 1.
[0072] The term "haloalkyl" alone or in combination, refers to an
alkyl radical having the meaning as defined above wherein one or
more hydrogens are replaced with a halogen as defined above.
Non-limiting examples of such haloalkyl radicals include
chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, 1,1,1-trifluoroethyl and the like. A preferred
haloalkyl radical is trifluoromethyl.
[0073] The term "cycloalkyl" as used herein is a monovalent,
saturated, or unsaturated monocyclic or bicyclic hydrocarbyl group.
Cycloalkyl groups may comprise 3 or more carbon atoms in the ring
and generally, according to this invention comprise from 3 to 10,
more preferably from 3 to 8 carbon atoms still more preferably from
3 to 6 carbon atoms. Examples of cycloalkyl groups include but are
not limited to cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
[0074] The terms "heterocyclyl", "heterocycloalkyl" or
"heterocyclo" as used herein by itself or as part of another group
refer to non-aromatic, fully saturated or partially unsaturated
cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11
member bicyclic, or containing a total of 3 to 10 ring atoms) which
have at least one heteroatom in at least one carbon atom-containing
ring. Each ring of the heterocyclic group containing a heteroatom
may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen
and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may
optionally be oxidized and the nitrogen heteroatoms may optionally
be quaternized. The heterocyclic group may be attached at any
heteroatom or carbon atom of the ring or ring system, where valence
allows.
[0075] The term "aryl" as used herein refers to a polyunsaturated,
aromatic hydrocarbyl group having a single ring (i.e. phenyl) or
multiple aromatic rings fused together (e.g. naphtyl), typically
containing 5 to 12 atoms; preferably 6 to 10, wherein at least one
ring is aromatic.
[0076] The term "heteroaryl" as used herein by itself or as part of
another group refers but is not limited to 5 to 12 carbon-atom
aromatic rings or ring systems containing 1 to 2 rings which are
fused together, typically containing 5 to 6 atoms; at least one of
which is aromatic, in which one or more carbon atoms in one or more
of these rings is replaced by oxygen, nitrogen and/or sulfur atoms
where the nitrogen and sulfur heteroatoms may optionally be
oxidized and the nitrogen heteroatoms may optionally be
quaternized.
[0077] The compounds of the invention containing a basic functional
group may be in the form of pharmaceutically acceptable salts.
Pharmaceutically acceptable salts of the compounds of the invention
containing one or more basic functional groups include in
particular the acid addition salts thereof. Suitable acid addition
salts are formed from acids which form non-toxic salts. Examples
include the acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, cyclamate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, saccharate,
stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate
and xinofoate salts.
[0078] Pharmaceutically acceptable salts of compounds of Formulae I
and subformulae may for example be prepared as follows:
[0079] (i) reacting the compound of Formula I or any of its
subformulae with the desired acid; or
[0080] (ii) converting one salt of the compound of Formula I or any
of its subformulae to another by reaction with an appropriate acid
or by means of a suitable ion exchange column.
[0081] All these reactions are typically carried out in solution.
The salt, may precipitate from solution and be collected by
filtration or may be recovered by evaporation of the solvent. The
degree of ionization in the salt may vary from completely ionized
to almost non-ionized.
[0082] The term "solvate" is used herein to describe a molecular
complex comprising the compound of the invention and one or more
pharmaceutically acceptable solvent molecules, for example,
ethanol. The term `hydrate` is employed when said solvent is
water.
[0083] The compounds of the invention include compounds of the
invention as hereinbefore defined, including all polymorphs and
crystal habits thereof, prodrugs and isomers thereof (including
optical, geometric and tautomeric isomers) and isotopically-labeled
compounds of the invention.
[0084] In addition, although generally, with respect to the salts
of the compounds of the invention, pharmaceutically acceptable
salts are preferred, it should be noted that the invention in its
broadest sense also includes non-pharmaceutically acceptable salts,
which may for example be used in the isolation and/or purification
of the compounds of the invention. For example, salts formed with
optically active acids or bases may be used to form
diastereoisomeric salts that can facilitate the separation of
optically active isomers of the compounds of the invention.
[0085] The term "patient" refers to a warm-blooded animal, more
preferably a human, who/which is awaiting or receiving medical care
or is or will be the object of a medical procedure.
[0086] The term "human" refers to subjects of both genders and at
any stage of development (i.e. neonate, infant, juvenile,
adolescent, adult). In one embodiment, the human is an adolescent
or adult, preferably an adult.
[0087] The terms "treat", "treating" and "treatment, as used
herein, are meant to include alleviating or abrogating a condition
or disease and/or its attendant symptoms.
[0088] The terms "prevent", "preventing" and "prevention", as used
herein, refer to a method of delaying or precluding the onset of a
condition or disease and/or its attendant symptoms, barring a
patient from acquiring a condition or disease, or reducing a
patient's risk of acquiring a condition or disease.
[0089] The term "therapeutically effective amount" (or more simply
an "effective amount") as used herein means the amount of active
agent or active ingredient (e.g. 61R agonist) which is sufficient
to achieve the desired therapeutic or prophylactic effect in the
individual to which it is administered.
[0090] The term "administration", or a variant thereof (e.g.,
"administering"), means providing the active agent or active
ingredient (e. g. a cylR agonist), alone or as part of a
pharmaceutically acceptable composition, to the patient in
whom/which the condition, symptom, or disease is to be treated or
prevented.
[0091] By "pharmaceutically acceptable" is meant that the
ingredients of a pharmaceutical composition are compatible with
each other and not deleterious to the patient thereof.
[0092] The term "agonist" as used herein means a ligand that
activates an intracellular response when it binds to a
receptor.
[0093] The term "pharmaceutical vehicle" as used herein means a
carrier or inert medium used as solvent or diluent in which the
pharmaceutically active agent is formulated and/or administered.
Non-limiting examples of pharmaceutical vehicles include creams,
gels, lotions, solutions, and liposomes.
[0094] The present invention will be better understood with
reference to the following examples and figures. These examples are
intended to representative of specific embodiments of the
invention, and are not intended as limiting the scope of the
invention.
FIGURES
[0095] FIG. 1. Results of the spontaneous alternation (a) and
passive avoidance assays (b) for compound 3.1.10.
[0096] FIG. 2. Validation of al action of compound 3.1.10. Data are
presented as mean.+-.sem.
[0097] FIG. 3. Amelioration of EAE by compound 3.1.10, preventive
treatment model. Data are presented as mean.+-.sem.
[0098] FIG. 4. Amelioration of EAE by compound 3.1.10, curative
treatment model. Data are presented as mean.+-.sem.
EXAMPLES
Chemistry Examples
[0099] All temperatures are expressed in .degree. C. and all
reactions were carried out at room temperature (RT) unless
otherwise stated.
[0100] .sup.1H-, and .sup.13C spectra were recorded on a 300 MHz
Bruker spectrometer. Chemical shifts (6) are given in ppm relative
to the internal standard solvent. LC/MS chromatograms were recorded
on a Waters Alliance 2695 system (X-Terra column, ionization mass
spectrometer). For some compounds mass spectra were recorded on a
MALDI-TOF Voyager-DE-STR (Applied Biosystems) apparatus.
[0101] Solvents, reagents and starting materials were purchased
from well known chemical suppliers such as for example Sigma
Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International,
Sopachem and Polymer labs and the following abbreviations are
used:
DCM: Dichloromethane,
DIEA: N,N-diisopropylethylamine,
DMF: N,N-dimethylformamide,
EtOH: Ethanol,
MeOH: Methanol,
[0102] RT: Room temperature,
HOBt: Hydroxybenzotriazole,
[0103] HBtu: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate, LCMS: Liquid chromatographymass spectrometry,
TLC: Thin layer chromatography, MW: Molecular weight,
eq: Equivalent.
##STR00013##
[0104] Reagents: (a): di-tert-butylcarbonate, triethylamine,
CH.sub.2Cl.sub.2; (b): HNR.sup.1R.sup.2, potassium carbonate, DMF
or CH.sub.3CN; (c): 3M HCl in dry dioxane; (d): HNR.sup.1R.sup.2,
potassium carbonate, DMF; (e): H.sub.2NNH.sub.2.H.sub.2O, EtOH
96.degree.; (f): bromochloroalkyl derivative, potassium carbonate,
CH.sub.3CN; (g): HNCH.sub.3 40%, potassium carbonate,
CH.sub.3CN.
##STR00014##
Reagents: (a): bromoalkylamine, CH.sub.2Cl.sub.2; (b):
chloroalkylacyl chloride, CH.sub.2Cl.sub.2.
##STR00015## ##STR00016##
Reagents: (a): triethylamine, CH.sub.2Cl.sub.2 (Y.dbd.Cl),
Procedure E1; (b): HOBt, HBtu, DIEA, CH.sub.2Cl.sub.2 (Y.dbd.OH),
Procedure E2; (c): HNR.sup.1R.sup.2, Procedure E3 (d): NaBH.sub.4,
MeOH, Procedure E4.
2. Preparation of Diamine Intermediates (Compounds 1.4-1.7): Scheme
1
Step 1: Preparation of tert-butyl-3-bromopropylcarbamate (Compound
1.2)
[0105] 3-Bromopropylamine (13.70 mmol, 3.0 g) was dissolved in 80
mL of dichloromethane. After addition of triethylamine (16.4 mmol,
2.32 mL) and di-tert-butylcarbonate (13.70 mmol, 3.0 g) the
resulting mixture was stirred at room temperature overnight. Then,
it was washed with 2.times.60 mL of a citric acid solution (5%) and
50 mL of saturated brine solution. The organic fraction was dried
over magnesium sulphate and concentrated to give the desired
product as yellow oil of sufficient purity for use without
purification in the next step. Yield: 97%.
Step 2: Preparation of Compounds 1.3
[0106] To a mixture of tert-butyl-3-bromopropylcarbamate 1.2 (5.6
mmol, 1.3 eq, 1.3 g) and N,N-disubstituted amine (4.3 mmol, 1 eq)
in 30 mL of DMF was added potassium carbonate (13.0 mmol, 3 eq, 1.8
g). The resulting mixture was heated at 70.degree. C. for 24 hours.
Then, the solvent was removed under reduced pressure and water (80
mL) added to the residue. The crude product was extracted with
3.times.60 mL of dichloromethane. The combined organic fractions
were washed with 60 mL of water and dried over magnesium sulphate.
The solvent was evaporated and the crude product collected as
yellow oil. Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)) was performed.
Example 1: Preparation of tert-butyl-3-[benzyl(methyl)amino]propyl
carbamate (Compound 1.3a)
[0107] The compound 1.3a was synthesized according to the procedure
by using tert-butyl-3-bromopropylcarbamate 1.2 (8.44 mmol, 2.0 g)
and N-methylbenzylamine (6.50 mmol, 0.9 mL). Yield: 74%. LCMS m/z
279.1 [M+H].sup.+, 223.1 [M+H-tertBut].sup.+.
Example 2: Preparation of
tert-butyl-3-[N-methyl-N-(2-phenylethyl)amino] propyl carbamate
(Compound 1.3b)
[0108] The compound 1.3b was synthesized according to the procedure
by using tert-butyl-3-bromopropylcarbamate 1.2 (8.44 mmol, 2.0 g)
and N-methylphenylethylamine (6.50 mmol, 1.0 mL). Yield: 81%. LCMS
(ESI.sup.+-tertBut): 237.0.
Example 3: Preparation of
tert-butyl-3-(isoindolin-2-yl)propylcarbamate (Compound 1.3c)
[0109] The compound 1.3c was synthesized according to the procedure
by using tert-butyl-3-bromopropylcarbamate 1.2 (8.44 mmol, 2.0 g)
and 2-isoindoline (6.50 mmol, 0.9 mL). Yield: 65%. LCMS m/z 221.0
[M+H-tertBut].sup.+.
Step 3: Preparation of Compounds 1.4
[0110] The compound 1.3 (1 eq) was dissolved in 72 mL of 3M HCl in
dry 1,4-dioxane. The resulting mixture was stirred at room
temperature overnight. Then, the solvent was removed under reduced
pressure to give the desired product of sufficient purity for use
without purification in the next step.
Example 1: Preparation of
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
(Compound 1.4a)
[0111] The compound 1.4a was synthesized according to the procedure
by using tert-butyl-3-[benzylmethylamino]propylcarbamate 1.3a (7.18
mmol, 1.8 g). Yield 98%. LCMS m/z 179.0 [M+H]
Example 2: Preparation of
N.sup.1-benzyl-N.sup.1-(2-phenylethyl)propane-1,3-diamine
dihydrochloride (Compound 1.4b)
[0112] The compound 1.4b was synthesized according to the procedure
by using
tert-butyl-3-[N-methyl-N-(2-phenylethyl)amino]propylcarbamate 1.3b
(7.18 mmol, 2.1 g). Yield: 88%. LCMS m/z 193.0 [M+H].sup.+
Example 3: Preparation of 3-(isoindolin-2-yl)propan-1-amine
dihydrochloride (Compound 1.4c)
[0113] The compound 1.4c was synthesized according to the procedure
by using tert-butyl-3-(isoindolin-2-yl)propylcarbamate 1.3c (7.18
mmol, 2.0 g). Yield: 83%. LCMS m/z 177.0 [M+H].sup.+.
Step 4: Preparation of Compounds 1.5
[0114] To a mixture of N-(bromoalkyl)phtalimide (1 eq) and
N,N-disubstituted amine (1.2 eq) in 30 mL of DMF was added
potassium carbonate (11.80 mmol, 2 eq, 1.6 g). The resulting
mixture was heated at 90.degree. C. for 16 hours. Then, inorganics
were eliminated by filtration and the solvent was removed under
reduced pressure. Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9.9:0.1 (v/v)) was performed.
Example 1: Preparation of
2-[2-(benzylmethylamino)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione
(Compound 1.5a)
[0115] The compound 1.5a was synthesized according to the procedure
by using N-(2-bromoethyl)phtalimide (5.9 mmol, 1.50 g) and
N-methylbenzylamine (7.1 mmol, 0.9 mL). Yield 52%. LCMS m/z 295.0
[M+H].sup.+.
Example 2: Preparation of
2-[4-(benzylmethylamino)butyl]-2,3-dihydro-1H-isoindole-1,3-dion
(Compound 1.5b)
[0116] The compound 1.5b was synthesized according to the procedure
by using N-(4-bromobutyl)phtalimide (5.9 mmol, 1.66 g) and
N-methylbenzylamine (7.1 mmol, 0.9 mL). Yield 53%. LCMS m/z 323.0
[M+H]
Example 3: Preparation of
2-[2-(N-methyl-N-(2-phenylethyl)amino)ethyl]-2,3-dihydro-1H-isoindole-1,3-
-dione (Compound 1.5c)
[0117] The compound 1.5c was synthesized according to the procedure
by using N-(2-bromoethyl)phtalimide (5.9 mmol, 1.50 g) and
N-methyl-N-(2-phenylethyl)amine (7.1 mmol, 0.9 mL). Yield 64%. LCMS
m/z 308.98 [M+H].sup.+.
Step 5: Preparation of Compounds 1.4
[0118] In 50 mL of ethanol 96.degree., was added a mixture of
2-[N,N-disubstituted amino
alkyl]-2,3-dihydro-1H-isoindole-1,3-dione (1 eq) and hydrazine
hydrate (10 eq). The resulting mixture was heated at reflux for 16
hours. The solution was removed under reduced pressure. The mineral
was eliminated by filtration and washed with ethyl acetate. The
filtrate was evaporated under reduced pressure to give an oily
residue. Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Oily purified product was dissolved in
EtOAc and ether saturated with gaseous HCl was added. The
corresponding hydrochloride product was filtered.
Example 1: Preparation of
N.sup.1-benzyl-N.sup.1-methylethane-1,2-diamine dihydrochloride
(Compound 1.4d)
[0119] The compound 1.4d was synthesized according to the procedure
by using
2-[2-(benzyl(methyl)amino)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione
(3.06 mmol, 0.9 g) and hydrazine hydrate (30.60 mmol, 1.5 mL).
Yield 55%. LCMS mz 165.0 [M-F1-1].sup.+.
Example 2: Preparation of
N.sup.1-benzyl-N.sup.1-methylbutane-1,4-diamine dihydrochloride
(Compound 1.4e)
[0120] The compound 1.4e was synthesized according to the procedure
by using
2-[4-(benzyl(methyl)amino)butyl]-2,3-dihydro-1H-isoindole-1,3-dione
(6.2 mmol, 2.0 g) and hydrazine hydrate (62.0 mmol, 3.1 mL). Yield
73%. LCMS m/z 193.0 [M+H]
Example 3: Preparation of
N.sup.1-(2-phenylethyl)-N.sup.1-methylethane-1,2-diamine
dihydrochloride (Compound 1.4f)
[0121] The compound 1.4f was synthesized according to the procedure
by using
2-[2-(N-methyl-N-(2-phenylethyl)amino)ethyl]-2,3-dihydro-1H-isoindo-
le-1,3-dione (3.06 mmol, 0.94 g) and hydrazine hydrate (30.60 mmol,
1.5 mL). Yield 67%. LCMS m/z 179.09 [M+H].sup.+.
Step 6: Preparation of Compounds 1.6
[0122] To a mixture of N,N-disubstituted amine (1 eq) and
bromochloroalkyl (1 eq) in 40 mL of DMF was added potassium
carbonate (1 eq). The resulting mixture was stirred at room
temperature for 1 day. Then, inorganics were eliminated by
filtration and the solvent was removed under reduced pressure to
give an oily residue. Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9.8:0.2 (v/v)) was performed.
Example 1: Preparation of 3-chloropropyl-N-benzylmethylamine
(1.6a)
[0123] The compound 1.6a was synthesized according to the procedure
by using N-methylbenzylamine (33.0 mmol, 4.0 mL) and
1-bromo-3-chloropropane (33.0 mmol, 9.7 mL). Yield: 95%. LCMS m/z
196.0, 198.0 [M+H].sup.+.
Step 7: Preparation of Compounds 1.7
[0124] In 5 mL of CH.sub.3CN was added a mixture of
chloroalkyl-N,N-disubstituted amine (1 eq) and methylamine 40% (20
eq). The resulting mixture was heated at reflux for 18 hours. The
solution was removed under reduced pressure to give an oily
residue. Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed.
Example 1: Preparation of
N.sup.1-benzyl-N.sup.1,N.sup.2-dimethylpropane-1,3-diamine
(Compound 1.7a)
[0125] The compound 1.7a was synthesized according to the procedure
by using 3-chloropropyl-N-benzylmethylamine (10.1 mmol, 2.0 g) and
methylamine 40% (202.0 mmol, 15.6 mL). Yield 88%. LCMS m/z 193.0
[M+H].sup.+.
3. Preparation of Intermediates Aryle Derivatives (Compounds
2.1-2.3): Scheme 2
Preparation of N-(3-bromopropyl)-4-chlorobenzamide (Compound
2.1)
[0126] To a solution of 3-bromopropylamine hydrobromide (2.86 mmol,
625 mg) in 10 mL of dichloromethane at 0.degree. C. was added
slowly a solution of 4-chlorobenzoyl chloride (2.86 mmol, 363
.mu.L) in 5 mL of dichloromethane. The resulting mixture was
stirred at room temperature for 12 hours. Then the solution was
diluted with dichloromethane and washed successively with HCl (2M)
solution, NaHCO.sub.3 saturated solution and NaCl solution. The
organic layer was dried over magnesium sulfate and evaporated. The
crude product 2.1 was purified by column chromatography
(DCM:cyclohexane, 5:5 (v/v)). Yield: 65%.
Preparation of 4-chloro-N-(4-chlorophenyl)butyramide (Compound
2.2)
[0127] To a solution of 4-chloroaniline (7.8 mmol, 1.0 g) in 15 mL
of dichloromethane at 0.degree. C. was added slowly a solution of
4-chlorobutyryl chloride (7.8 mmol, 878 .mu.L) in 5 mL of
dichloromethane. The resulting mixture was stirred at room
temperature for 12 hours. Then the reaction was quenched with 25 mL
of water and the product extract with 3.times.25 mL of DCM. The
combined organic fractions were dried over magnesium sulphate and
concentrated to give the desired product 2.2 with sufficient purity
to be used without purification in the next step. Yield: 87%.
Preparation of Compounds 2.3
[0128] To a solution of substituted benzylamine (6.5 mmol, 1 eq) in
AcOEt/H.sub.2O (20 mL/15 mL), was added potassium carbonate (13.1
mmol, 1.8 g, 2 eq) and 3-chloropropionyl chloride (7.8 mmol, 753
.mu.L). The resulting mixture was stirred at room temperature for 1
hour. The organic layer was washed successively with HCl (2M)
solution (20 mL), water (20 mL) and dried over magnesium sulphate.
The solution was removed under reduced pressure. The crude product
2.3 was washed with heptane and used in the next step.
Example 1: Preparation of N-(4-chlorobenzyl)-3-chloropropanamide
(Compound 2.3a)
[0129] The compound 2.3.a was synthesized according to the
procedure by using 4-chlorobenzylamine (6.5 mmol, 0.92 g). Yield:
60%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 7.35-7.30 (m, 2H,
H.sub.aro); 7.25-7.20 (m, 2H, H.sub.aro); 5.94 (br s, 1H, NH); 4.45
(d, J=6 Hz, 2H, CH.sub.2); 3.84 (t, J=6 Hz, 2H, CH.sub.2); 2.67 (t,
J=6 Hz, 2H, CH.sub.2).
Example 2: Preparation of N-(4-nitrobenzyl)-3-chloropropanamide
(Compound 2.3b)
[0130] The compound 2.3.b was synthesized according to the
procedure by using 4-nitrobenzylamine (6.5 mmol, 1.00 g). Yield:
69%. LCMS m/z 240.8 [M-H].sup.-.
Example 3: Preparation of N-(4-cyanobenzyl)-3-chloropropanamide
(Compound 2.3c)
[0131] The compound 2.3.c was synthesized according to the
procedure by using 4-cyanobenzylamine (6.5 mmol, 0.86 g). Yield:
65%. LCMS m/z 220.9 [M-H].sup.-.
Example 4: Preparation of
N-(2,4-dichlorobenzyl)-3-chloropropanamide (Compound 2.3d)
[0132] The compound 2.3.d was synthesized according to the
procedure by using 2,4-dichlorobenzylamine (6.5 mmol, 1.14 g).
Yield: 79%. LCMS m/z 263.8, 265.8, 267.9 [M-H].sup.-.
Example 5: Preparation of N-(3-chlorobenzyl)-3-chloropropanamide
(Compound 2.3e)
[0133] The compound 2.3.e was synthesized according to the
procedure by using 3-chlorobenzylamine (6.5 mmol, 0.92 g). Yield:
73%. LCMS m/z 231.9, 233.9, 235.9 [M+H].sup.+.
Example 6: Preparation of N-(3-Bromobenzyl)-3-chloropropanamide
(Compound 2.30
[0134] The compound 2.3.f was synthesized according to the
procedure by using 3-bromobenzylamine (6.5 mmol, 1.21 g). Yield:
67%. LCMS m/z 275.8, 277.8, 279.8 [M+H].sup.+.
4. General Procedures E: Synthesis of Compounds of the Invention:
Scheme 3
General Procedure E1:
[0135] A solution of N,N-disubstituted alkyldiamine 1.4 (1 eq), and
triethylamine (3 eq) in 10 mL of dichloromethane was cooled at
0.degree. C. A solution of substituted-benzoylchloride (1 eq) in 5
mL of dichloromethane was added slowly. The resulting mixture was
stirred at room temperature overnight. The solution was evaporated
under reduced pressure. An aqueous solution of 3% sodium hydroxide
(20 mL) was added and the mixture was stirred for 1 hour. The
solution was extracted with dichloromethane. The organic fraction
was dried over magnesium sulphate and concentrated to give an oily
product. The residue was purified by thick layer chromatography or
column chromatography.
General Procedure E2:
[0136] Reaction was carried out under nitrogen atmosphere. In 10 mL
of dichloromethane, benzoic acid (1 eq), HOBt (1.2 eq) and HBtu
(1.2 eq) were added and stirred at room temperature for 10 minutes.
A solution of N,N-disubstituted alkyldiamine 1.4 (1 eq) and DIEA
(15 eq) in dichloromethane was added to the reacting mixture. After
stirring at room temperature for 24 hours, the solvent was removed
under reduced pressure and dichloromethane was added to the
residue. The solution was washed with a solution of NaHCO.sub.3
(5%) then saturated NaCl solution. The organic layer was dried over
magnesium sulfate and evaporated under reduced pressure. The crude
product was purified by thick layer chromatography or column
chromatography.
General Procedure E3:
[0137] A solution of compound 2.2 or 2.3 (1 eq) in disubstituted
amine HNR.sup.1R.sup.2 (6 eq) was stirred at room temperature for
12 hours. A 5 mL amount of hexane was added and the white solid,
identified as disubstituted amine hydrochloride, was filtered. The
filtrate was concentrated and purified by thick layer
chromatography or column chromatography.
General Procedure E4:
[0138] A solution of substituted benzoylchloride (1 eq) and
N,N-disubstituted alkyldiamine 1.4 (1 eq) in MeOH (10 mL) was
stirred at room temperature for 16 hours. Then, sodium borohydride
(1.5 eq) was added and stirred for 3 hours. The mixture was
quenched with water (5 mL) and evaporated under reduce pressure.
The crude product was purified by thick layer chromatography or
column chromatography.
Example 1: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-propylbenzamide (Compound
3.1.2)
[0139] The compound 3.1.2 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.55 mmol, 138 mg), and 4-propylbenzoylchloride (0.55 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 61%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.90 (br s, 1H, NH); 7.60 (d, J=8.2 Hz, 2H,
H.sub.2, H.sub.6); 7.29-7.20 (m, 5H, H.sub.aro); 7.13 (d, J=8.1 Hz,
2H, H.sub.3, H.sub.5); 3.55 (t, J=6.0 Hz, 2H, CH.sub.2); 3.50 (s,
2H, CH.sub.2); 2.60 (m, 4H, 2 CH.sub.2); 2.23 (s, 3H, CH.sub.3);
1.80 (p, J=6.0 Hz, 2H, CH.sub.2); 1.62 (s, J=7.5 Hz, 2H, CH.sub.2);
0.95 (t, J=7.3 Hz, 2H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta.: 167.2 (CO); 146.1 (C.sub.aro); 138.4 (C.sub.aro); 132.2
(C.sub.aro); 129.3 (C.sub.aro); 128.5 (C.sub.aro); 128.4
(C.sub.aro); 127.2 (C.sub.aro); 126.9 (C.sub.aro); 63.3 (CH.sub.2);
57.1 (CH.sub.2); 42.1 (CH.sub.3); 40.2 (CH.sub.2); 37.9 (CH.sub.2);
25.5 (CH.sub.2); 24.3 (CH.sub.2); 14.2 (CH.sub.3). LCMS m/z 325.0
[M-EH].sup.+.
Example 2: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-butylbenzamide (Compound
3.1.3)
[0140] The compound 3.1.3 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.65 mmol, 163 mg), and 4-butylbenzoylchloride (0.65 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 30%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.97 (br s, 1H, NH); 7.60 (d, J=8.2 Hz, 2H,
H.sub.2, H.sub.6); 7.29-7.23 (m, 5H, H.sub.aro); 7.13 (d, J=8.2 Hz,
2H, H.sub.3, H.sub.5); 3.56 (m, 4H, 2CH.sub.2); 2.64 (m, 4H,
2CH.sub.2); 2.28 (s, 3H, CH.sub.3); 1.83 (p, J=6.1 Hz, 2H,
CH.sub.2); 1.62 (m, 2H, CH.sub.2); 1.35 (m, 2H, CH.sub.2); 0.97 (t,
J=7.1 Hz, 2H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.:
167.7 (CO); 146.7 (C.sub.aro); 138.0 (C.sub.aro); 132.5
(C.sub.aro); 129.8 (2 C.sub.aro); 128.8 (4 C.sub.aro); 127.9
(C.sub.aro); 127.3 (2 C.sub.aro); 63.5 (CH.sub.2); 57.1 (CH.sub.2);
41.9 (CH.sub.3); 40.3 (CH.sub.2); 35.9 (CH.sub.2); 33.7 (CH.sub.2);
25.7 (CH.sub.2); 22.6 (CH.sub.2); 14.3 (CH.sub.3). LCMS m/z 339.0
[M+H].sup.+.
Example 3: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-tert-butylbenzamide (Compound
3.1.4)
[0141] The compound 3.1.4 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.60 mmol, 150 mg), and 4-tertbutylbenzoylchloride (0.60
mmol, 100 mg). Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 27%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 8.03 (br s, 1H, NH); 7.63 (d,
J=8.5 Hz, 2H, H.sub.2, H.sub.6); 7.37 (d, J=8.5 Hz, 2H, H.sub.3,
H.sub.5); 7.29-7.24 (m, 5H, H.sub.aro); 3.57 (m, 4H, 2CH.sub.2);
2.63 (t, J=6.0 Hz, 2H, CH.sub.2); 2.28 (s, 3H, NCH.sub.3); 1.84 (p,
J=5.9 Hz, 2H, CH.sub.2); 1.32 (s, 9H, 3CH.sub.3). .sup.13C NMR (75
MHz, CDCl.sub.3) .delta.: 167.1 (CO); 154.4 (C.sub.aro); 137.8
(C.sub.aro); 131.8 (C.sub.aro); 129.5 (2 C.sub.aro); 128.4 (2
C.sub.aro); 127.4 (C.sub.aro); 126.8 (2 C.sub.aro); 125.3 (2
C.sub.aro); 63.1 (CH.sub.2); 56.9 (CH.sub.2); 41.5 (CH.sub.3); 40.1
(CH.sub.2); 34.8 (C); 31.2 (CH.sub.3); 25.3 (CH.sub.2). LCMS m/z
339.0 [M-F1-1]+.
Example 4: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-trifluoromethylbenzamide
(Compound 3.1.5)
[0142] The compound 3.1.5 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.48 mmol, 120 mg), and 4-trifluoromethylbenzoylchloride
(0.48 mmol, 100 mg). Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 57%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 8.50 (br s, 1H, NH); 7.78 (d,
J=8.2 Hz, 2H, H.sub.2, H.sub.6); 7.59 (d, J=8.2 Hz, 2H, H.sub.3,
H.sub.5); 7.28-7.21 (m, 5H, H.sub.aro); 3.63-3.55 (m, 4H, 2
CH.sub.2); 2.68 (t, J=5.8 Hz, 2H, CH.sub.2); 2.30 (s, 3H,
CH.sub.3); 1.85 (p, J=5.7 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 165.8 (CO); 138.0 (C.sub.aro); 129.5 (2
C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (C.sub.aro); 127.4 (2
C.sub.aro); 125.5 (2 C.sub.aro); 125.4 (2 C.sub.aro); 62.9
(CH.sub.2); 57.1 (CH.sub.2); 41.3 (CH.sub.3); 40.5 (CH.sub.2); 24.8
(CH.sub.2). LCMS mz 351.0, 352.0 [M+H].sup.+.
Example 5: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-fluorobenzamide (Compound
3.1.6)
[0143] The compound 3.1.6 was synthesized according to the
procedure E2 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.67 mmol, 170 mg), and 4-fluorobenzoic acid (0.67 mmol, 90
mg). Purification by thick layer chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 58%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 8.20 (br s, 1H, NH); 7.66 (m,
2H, H.sub.2, H.sub.6); 7.28-7.24 (m, 5H, H.sub.aro); 7.00 (t, J=9.1
Hz, 2H, H.sub.3, H.sub.5); 3.60-3.52 (m, 4H, 2 CH.sub.2); 2.65 (t,
J=6.1 Hz, 2H, CH.sub.2); 2.28 (s, 3H, CH.sub.3); 1.83 (p, J=6.0 Hz,
2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 166.1
(CO); 164.5 (C.sub.aro); 137.6 (C.sub.aro); 130.8 (C.sub.aro);
129.5 (2 C.sub.aro); 129.2 (2 C.sub.aro); 128.5 (2 C.sub.aro);
127.6 (C.sub.aro); 115.3 (2 C.sub.aro); 63.1 (CH.sub.2); 57.1
(CH.sub.2); 41.4 (CH.sub.3); 40.3 (CH.sub.2); 25.0 (CH.sub.2). LCMS
m/z 301.1, 302.1 [M+H].sup.+.
Example 6: Synthesis of
N-[3-(benzylmethylamino)propyl]-2-chlorobenzamide (Compound
3.1.7)
[0144] The compound 3.1.7 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.57 mmol, 143 mg), and 2-chlorobenzoylchloride (0.57 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 46%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.52 (dd, J=7.0 Hz, J=1.9 Hz, 1H, H.sub.6);
7.39-7.25 (m, 4H, NH, H.sub.3, H.sub.4, H.sub.5); 7.17-7.09 (m, 5H,
H.sub.aro); 3.54 (q, J=6.2 Hz, 2H, CH.sub.2); 3.49 (s, 2H,
CH.sub.2); 2.58 (t, J=6.3 Hz, 2H, CH.sub.2); 2.21 (s, 3H,
NCH.sub.3); 1.83 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 166.7 (CO); 137.9 (C.sub.aro); 136.0
(C.sub.aro); 130.8 (C.sub.aro); 130.7 (C.sub.aro); 130.1
(C.sub.aro); 129.5 (C.sub.aro); 128.9 (2 C.sub.aro); 128.3 (2
C.sub.aro); 127.2 (C.sub.aro); 126.9 (C.sub.aro); 62.6 (CH.sub.2);
56.0 (CH.sub.2); 41.8 (CH.sub.3); 39.7 (CH.sub.2); 25.3 (CH.sub.2).
LCMS m/z 317.0, 319.0 [M+H].sup.+.
Example 7: Synthesis of
N-[3-(benzylmethylamino)propyl]-3-chlorobenzamide (Compound
3.1.8)
[0145] The compound 3.1.8 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.57 mmol, 143 mg), and 3-chlorobenzoylchloride (0.57 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 8%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 8.22 (br s, 1H, NH); 7.78 (dd, J=1.5 Hz,
J=2.0 Hz, 1H, H.sub.2); 7.68 (d, J=8.0 Hz, 1H, H.sub.6); 7.52 (d,
J=7.8 Hz, 1H, H.sub.4); 7.52 (t, J=7.3 Hz, 1H, H.sub.5); 7.32-7.22
(m, 5H, H.sub.aro); 3.58-3.51 (m, 4H, 2CH.sub.2); 2.63 (t, J=7.5
Hz, 2H, CH.sub.2); 2.30 (s, 3H, CH.sub.3); 1.84 (p, J=6.4 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 165.8 (CO);
136.5 (C.sub.aro); 134.6 (C.sub.aro); 131.2 (C.sub.aro); 129.7
(C.sub.aro); 129.4 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (2
C.sub.aro); 127.5 (C.sub.aro); 125.0 (C.sub.aro); 63.1 (CH.sub.2);
56.7 (CH.sub.2); 41.6 (CH.sub.3); 40.4 (CH.sub.2); 24.8 (CH.sub.2).
LCMS m/z 317.0, 319.0 [M+H].sup.+.
Example 8: Synthesis of
N-[3-(2-(N-methylbenzyl)amino)ethyl]-4-chlorobenzamide (Compound
3.1.9)
[0146] The compound 3.1.9 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylethane-1,2-diamine dihydrochloride
1.4d (0.57 mmol, 135 mg), and 4-chlorobenzoylchloride (0.57 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 20%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.67 (d, J=8.6 Hz, 2H, H.sub.2, H.sub.6);
7.41 (d, J=8.6 Hz, 2H, H.sub.3, H.sub.5); 7.23-7.33 (m, 5H,
H.sub.aro); 6.78 (br s, 1H, NH); 3.56 (s, 2H, CH.sub.2); 3.51 (q,
J=5.2 Hz, 2H, CH.sub.2); 2.62 (t, J=5.9 Hz, 2H, CH.sub.2); 2.31 (s,
3H, NCH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 166.4
(CO); 138.6 (C.sub.aro); 137.5 (C.sub.aro); 133.1 (C.sub.aro);
129.4 (2 C.sub.aro); 129.1 (2 C.sub.aro); 128.9 (2 C.sub.aro);
128.7 (2 C.sub.aro); 127.4 (C.sub.aro); 62.3 (CH.sub.2); 54.9
(CH.sub.2); 42.1 (CH.sub.3); 37.1 (CH.sub.2). LCMS m/z 303.0, 305.0
[M+H].sup.+.
Example 9: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-chlorobenzamide (Compound
3.1.10)
[0147] The compound 3.1.10 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.57 mmol, 143 mg), and 4-chlorobenzoylchloride (0.57 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 55%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 8.25 (br s, 1H, NH); 7.60 (d, J=9 Hz, 2H,
H.sub.2, H.sub.6); 7.33-7.21 (m, 7H, H.sub.3, H.sub.5, H.sub.aro);
3.62-3.51 (m, 4H, 2CH.sub.2); 2.65 (t, J=5.4 Hz, 2H, CH.sub.2);
2.27 (s, 3H, NCH.sub.3); 1.83 (p, J=5.5 Hz, 2H, CH.sub.2). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.: 166.0 (CO); 137.8 (C.sub.aro);
137.3 (C.sub.aro); 133.1 (C.sub.aro); 129.4 (2 C.sub.aro); 128.6 (2
C.sub.aro); 128.5 (2 C.sub.aro); 128.4 (2 C.sub.aro); 127.5
(C.sub.aro); 63.2 (CH.sub.2); 57.2 (CH.sub.2); 41.5 (CH.sub.3);
40.5 (CH.sub.2); 25.0 (CH.sub.2). LCMS m/z 316.9, 318.9
[M+H].sup.+.
Example 10: Synthesis of
N-[4-(benzylmethylamino)butyl]-4-chlorobenzamide (Compound
3.1.11)
[0148] The compound 3.1.11 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylbutane-1,4-diamine dihydrochloride
1.4e (0.57 mmol, 151 mg), and 4-chlorobenzoylchloride (0.57 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 25%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.60 (d, J=9.2 Hz, 2H, H.sub.2, H.sub.6);
7.41 (br s, 1H, NH); 7.33-7.26 (m, 7H, H.sub.3, H.sub.5,
H.sub.aro); 3.53 (s, 2H, CH.sub.2); 3.45 (q, J=6.2 Hz, 2H,
CH.sub.2); 2.45 (t, J=6.4 Hz, 2H, CH.sub.2); 2.17 (s, 3H,
NCH.sub.3); 1.73-1.62 (m, 4H, 2CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 166.6 (CO); 137.7 (C.sub.aro); 137.3
(C.sub.aro); 133.3 (C.sub.aro); 129.3 (2 C.sub.aro); 128.6 (2
C.sub.aro); 128.5 (2 C.sub.aro); 128.4 (2 C.sub.aro); 127.4
(C.sub.aro); 61.8 (CH.sub.2); 56.7 (CH.sub.2); 42.1 (CH.sub.3);
39.9 (CH.sub.2); 27.1 (CH.sub.2); 24.8 (CH.sub.2). LCMS m/z 331.0,
333.0 [M+H].sup.+.
Example 11: Synthesis of
N-[3-(N-methyl-2-phenylethylamino)propyl]-4-chlorobenzamide
(Compound 3.1.12)
[0149] The compound 3.1.12 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-(2-phenylethyl)propane-1,3-diamine
dihydrochloride 1.4b (0.57 mmol, 151 mg), and
4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column
chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed.
Yield: 69%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 8.25 (br s,
1H, NH); 7.58 (d, J=8.3 Hz, 2H, H.sub.2, H.sub.6); 7.34 (d, J=8.4
Hz, 2H, H.sub.3, H.sub.5); 7.26-7.12 (m, 5H, H.sub.aro); 3.53 (q,
J=6.2 Hz, 2H, CH.sub.2); 2.82 (m, 2H, CH.sub.2); 2.75 (m, 2H,
CH.sub.2); 2.66 (t, J=6.0 Hz, 2H, CH.sub.2); 2.35 (s, 3H,
NCH.sub.3); 1.80 (p, J=5.9 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 165.9 (CO); 139.5 (C.sub.aro); 137.2
(C.sub.aro); 133.1 (C.sub.aro); 128.6 (4 C.sub.aro); 128.5 (2
C.sub.aro); 128.3 (2 C.sub.aro); 126.3 (C.sub.aro); 59.6
(CH.sub.2); 57.1 (CH.sub.2); 41.7 (CH.sub.3); 40.4 (CH.sub.2); 33.3
(CH.sub.2); 24.3 (CH.sub.2). LCMS mz 331.0, 333.0 [M+H].sup.+.
Example 12: Synthesis of
N-[3-(isoindolin-2-yl)methylamino)propyl]-4-chlorobenzamide
(Compound 3.1.15)
[0150] The compound 3.1.15 was synthesized according to the
procedure E1 by using 3-(isoindolin-2-yl)propane-1-amine
dihydrochloride 1.4c (0.57 mmol, 140 mg), and
4-chlorobenzoylchloride (0.57 mmol, 100 mg). Purification by column
chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed.
Yield: 36%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 9.00 (br s,
1H, NH); 7.48 (d, J=8.6 Hz, 2H, H.sub.2, H.sub.6); 7.31-7.21 (m,
4H, H.sub.aro); 7.03 (d, J=8.5 Hz, 2H, H.sub.3, H.sub.5); 4.02 (s,
4H, 2CH.sub.2); 3.63 (q, J=5.0 Hz, 2H, CH.sub.2); 3.05 (t, J=5.8
Hz, 2H, CH.sub.2); 1.89 (p, J=5.8 Hz, 2H, CH.sub.2). .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta.: 165.6 (CO); 139.2 (2 C.sub.aro);
137.1 (C.sub.aro); 132.6 (C.sub.aro); 128.4 (2 C.sub.aro); 128.2 (2
C.sub.aro); 127.2 (2 C.sub.aro); 122.4 (2 C.sub.aro); 58.6 (2
CH.sub.2); 55.3 (CH.sub.2); 40.8 (CH.sub.2); 25.9 (CH.sub.2). LCMS
m/z 315.0, 317.0 [M-EH].sup.+.
Example 13: Synthesis of
N-[3-(benzylmethylamino)propyl]-2-bromobenzamide (Compound
3.1.20)
[0151] The compound 3.1.20 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.45 mmol, 113 mg), and 2-bromobenzoylchloride (0.45 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 52%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.56 (dd, J=7.8 Hz, J=1.3 Hz, 1H, H.sub.6);
7.47 (br s, 1H, NH); 7.37 (dd, J=7.4 Hz, J=2.0 Hz, 1H, H.sub.3);
7.31 (td, J=7.3 Hz, J=1.2 Hz, 1H, H.sub.aro); 7.24 (td, J=7.4 Hz,
J=1.9 Hz, 1H, H.sub.aro); 7.16-7.07 (m, 5H, H.sub.aro); 3.52 (q,
J=6.2 Hz, 2H, CH.sub.2); 3.48 (s, 2H, CH.sub.2); 2.57 (t, J=6.1 Hz,
2H, CH.sub.2); 2.19 (s, 3H, NCH.sub.3); 1.80 (p, J=6.2 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 167.8 (CO);
138.6 (C.sub.aro); 138.0 (C.sub.aro); 133.2 (C.sub.aro); 130.8
(C.sub.aro); 129.0 (2 C.sub.aro); 128.9 (2 C.sub.aro); 128.3
(C.sub.aro); 127.4 (C.sub.aro); 127.1 (C.sub.aro); 119.5
(C.sub.aro); 62.6 (CH.sub.2); 56.1 (CH.sub.2); 41.8 (CH.sub.3);
39.6 (CH.sub.2); 25.3 (CH.sub.2). LCMS m/z 361.0, 363.0
[M+H].sup.+.
Example 14: Synthesis of
N-[3-(benzylmethylamino)propyl]-3-bromobenzamide (Compound
3.1.21)
[0152] The compound 3.1.21 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.45 mmol, 113 mg), and 3-bromobenzoylchloride (0.45 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 53%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 8.27 (br s, 1H, NH); 7.82 (t, J=1.8 Hz, 2H,
H.sub.2); 7.55 (m, 1H, H.sub.5); 7.28-7.17 (m, 7H, H.sub.4,
H.sub.6, H.sub.aro); 3.55 (m, 4H, 2CH.sub.2); 2.62 (t, J=6.0 Hz,
2H, CH.sub.2); 2.30 (s, 3H, NCH.sub.3); 1.83 (p, J=5.9 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 165.7 (CO);
137.6 (C.sub.aro); 136.7 (C.sub.aro); 134.0 (C.sub.aro); 130.3
(C.sub.aro); 129.9 (C.sub.aro); 129.4 (2 C.sub.aro); 128.5 (2
C.sub.aro); 127.6 (C.sub.aro); 125.4 (C.sub.aro); 122.6
(C.sub.aro); 63.1 (CH2); 56.8 (CH.sub.2); 41.8 (CH.sub.3); 40.4
(CH.sub.2); 24.9 (CH.sub.2). LCMS m/z 361.0, 363.0 [M+H].sup.+.
Example 15: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-bromobenzamide (Compound
3.1.22)
[0153] The compound 3.1.22 was synthesized according to the
procedure E2 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.65 mmol, 164 mg), and 4-fluorobenzoic acid (0.65 mmol, 130
mg). Purification by thick layer chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 67%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 8.29 (br s, 1H, NH); 7.54 (d,
J=9.1 Hz, 2H, H.sub.2, H.sub.6); 7.46 (d, J=9.2 Hz, 2H, H.sub.3,
H.sub.5); 7.33-7.20 (m, 5H, H.sub.aro); 3.65-3.47 (m, 4H, 2
CH.sub.2); 2.66 (t, J=5.9 Hz, 2H, CH.sub.2); 2.29 (s, 3H,
CH.sub.3); 1.84 (p, J=5.8 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 166.2 (CO); 137.5 (C.sub.aro); 133.5
(C.sub.aro); 131.6 (2 C.sub.aro); 129.5 (2 C.sub.aro); 128.6 (2
C.sub.aro); 128.5 (2 C.sub.aro); 127.7 (C.sub.m); 125.7
(C.sub.aro); 63.0 (CH.sub.2); 57.0 (CH.sub.2); 41.4 (CH.sub.3);
40.3 (CH.sub.2); 24.9 (CH.sub.2). LCMS m/z 360.9, 362.9
[M+H].sup.+.
Example 16: Synthesis of
N-[3-(benzylmethylamino)propyl]-2,3-dichlorobenzamide (Compound
3.1.23)
[0154] The compound 3.1.23 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.48 mmol, 120 mg), and 2,3-dichlorobenzoylchloride (0.48
mmol, 100 mg). Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 66%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 7.58 (br s, 1H, NH); 7.51 (dd,
J=7.9 Hz, J=1.6 Hz, 1H, H.sub.6); 7.32 (dd, J=7.7 Hz, J=1.6 Hz, 1H,
H.sub.4); 7.25 (m, 1H, H.sub.5); 7.17-7.07 (m, 5H, H.sub.aro); 3.55
(q, J=6.7 Hz, 2H, CH.sub.2); 3.48 (s, 2H, CH.sub.2); 2.58 (t, J=5.9
Hz, 2H, CH.sub.2); 2.21 (s, 3H, NCH.sub.3); 1.82 (p, J=6.0 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 166.2 (CO);
138.6 (C.sub.aro); 137.8 (C.sub.aro); 133.7 (C.sub.aro); 131.3
(C.sub.aro); 128.9 (C.sub.aro); 128.3 (2 C.sub.aro); 127.6 (2
C.sub.aro); 127.5 (C.sub.aro); 127.3 (C.sub.aro); 127.0
(C.sub.aro); 62.7 (CH.sub.2); 56.0 (CH.sub.2); 41.8 (CH.sub.3);
39.7 (CH.sub.2); 25.1 (CH.sub.2). LCMS m/z 351.0, 353.0
[M+H].sup.+.
Example 17: Synthesis of
N-[3-(benzylmethylamino)propyl]-2,4-dichlorobenzamide (Compound
3.1.24)
[0155] The compound 3.1.24 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.48 mmol, 120 mg), and 2,4-dichlorobenzoylchloride (0.48
mmol, 100 mg). Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 41%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 7.70 (br s, 1H, NH); 7.45 (d,
J=8.3 Hz, 1H, H.sub.6); 7.38 (d, J=2.0 Hz, 1H, H.sub.3); 7.26 (dd,
J=8.3 Hz, J=2.0 Hz 1H, H.sub.5); 7.19-7.07 (m, 5H, H.sub.aro); 3.53
(q, J=5.6 Hz, 2H, CH.sub.2); 3.47 (s, 2H, CH.sub.2); 2.56 (t, J=6.2
Hz, 2H, CH.sub.2); 2.20 (s, 3H, NCH.sub.3); 1.81 (p, J=6.0 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 165.7 (CO);
137.9 (C.sub.aro); 136.1 (C.sub.aro); 134.5 (C.sub.aro); 131.6
(C.sub.aro); 130.5 (C.sub.aro); 129.9 (C.sub.aro); 128.9 (2
C.sub.aro); 128.3 (2 C.sub.aro); 127.3 (C.sub.aro); 127.2
(C.sub.aro); 62.6 (CH.sub.2); 56.2 (CH.sub.2); 41.8 (CH.sub.3);
39.9 (CH.sub.2); 25.1 (CH.sub.2). LCMS mz 351.0, 353.0
[M+H].sup.+.
Example 18: Synthesis of
N-[3-(benzylmethylamino)propyl]-3,4-dichlorobenzamide (Compound
3.1.25)
[0156] The compound 3.1.25 was synthesized according to the
procedure E2 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.78 mmol, 197 mg), and 3,4-dichlorobenzoic acid (0.78 mmol,
150 mg). Purification by thick layer chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 31%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 8.44 (br s, 1H, NH); 7.82 (d,
0.1=2.0 Hz, 1H, H.sub.2); 7.47 (dd, J=8.2 Hz, J=2.0 Hz, 1H,
H.sub.6); 7.38 (d, J=8.3 Hz, 1H, H.sub.5); 7.31-7.22 (m, 5H,
H.sub.aro); 3.60 (s, 2H, CH.sub.2); 3.56 (q, J=6.1 Hz, 2H,
CH.sub.2); 2.68 (t, J=6.1 Hz, 2H, CH.sub.2); 2.33 (s, 3H,
CH.sub.3); 1.86 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 164.9 (CO); 135.4 (C.sub.aro); 134.5
(C.sub.aro); 132.9 (C.sub.aro); 130.4 (2 C.sub.aro); 129.5 (2
C.sub.aro); 129.3 (C.sub.aro); 128.6 (2 C.sub.aro); 127.8
(C.sub.aro); 126.1 (C.sub.aro); 62.8 (CH.sub.2); 56.7 (CH.sub.2);
41.4 (CH.sub.3); 40.3 (CH.sub.2); 24.7 (CH.sub.2). LCMS m/z 350.9,
352.9 [M+H].sup.+.
Example 19: Synthesis of
N-[3-(benzylmethylamino)propyl]-3,5-dichlorobenzamide (Compound
3.1.26)
[0157] The compound 3.1.26 was synthesized according to the
procedure E2 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.78 mmol, 197 mg), and 3,5-dichlorobenzoic acid (0.78 mmol,
150 mg). Purification by thick layer chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 34%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 8.42 (br s, 1H, NH); 7.55 (m,
2H, H.sub.2, H.sub.6); 7.44 (m, 1H, H.sub.4); 7.28-7.20 (m, 5H,
H.sub.aro); 3.57-3.51 (m, 4H, 2 CH.sub.2); 2.63 (t, J=6.1 Hz, 2H,
CH.sub.2); 2.32 (s, 3H, CH.sub.3); 1.82 (p, J=6.0 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 164.6 (CO);
137.7 (C.sub.aro); 137.5 (C.sub.aro); 135.3 (C.sub.aro); 130.9 (2
C.sub.aro); 129.3 (2 C.sub.aro); 128.5 (2 C.sub.aro); 127.6
(C.sub.aro); 125.7 (2 C.sub.aro); 63.0 (CH.sub.2); 56.7 (CH.sub.2);
41.8 (CH.sub.3); 40.7 (CH.sub.2); 24.8 (CH.sub.2). LCMS m/z 351.0,
353.0 [M+H].sup.+.
Example 20: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-bromo-2-fluorobenzamide (Compound
3.1.27)
[0158] The compound 3.1.27 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.42 mmol, 105 mg), and 4-bromo-2-fluorobenzoylchloride (0.42
mmol, 100 mg). Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 22%. .sup.1H
NMR (300 MHz, MeOD), .delta.: 7.60 (d, J=8.2 Hz, 1H, H.sub.6); 7.50
(m, 1H, H.sub.aro); 7.44 (m, 1H, H.sub.aro); 7.22-7.34 (m, 5H,
H.sub.aro); 3.59 (s, 2H, CH.sub.2); 3.43 (t, J=6.7 Hz, 2H,
CH.sub.2); 2.56 (t, J=7.1 Hz, 2H, CH.sub.2); 2.28 (s, 3H,
CH.sub.3); 1.85 (p, J=7.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 162.5 (CO); 132.9 (C.sub.aro); 129.5
(C.sub.aro); 128.7 (C.sub.aro); 128.4 (2 C.sub.aro); 128.1 (2
C.sub.aro); 125.1 (C.sub.aro); 119.8 (C.sub.aro); 119.4
(C.sub.aro); 62.4 (CH.sub.2); 55.3 (CH.sub.2); 41.4 (CH.sub.3);
29.7 (CH.sub.2); 25.4 (CH.sub.2). LCMS m/z 379.0, 381.0
[M+H].sup.+.
Example 21: Synthesis of
N-[3-(benzylinethylamino)propyl]-3-methoxybenzamide (Compound
3.1.28)
[0159] The compound 3.1.28 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.59 mmol, 148 mg), and 3-methoxybenzoylchloride (0.59 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 35%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 8.10 (br s, 1H, NH); 7.35 (m, 1H, H.sub.2);
7.28-7.14 (m, 7H, H.sub.5, H.sub.6, H.sub.aro); 7.11 (m, 1H,
H.sub.4); 3.78 (s, 3H, OCH.sub.3); 3.55 (m, 4H, 2CH.sub.2); 2.63
(t, 0.1=6.2 Hz, 2H, CH.sub.2); 2.28 (s, 3H, NCH.sub.3); 1.83 (p,
J=6.4 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.:
165.3 (CO); 159.7 (C.sub.aro); 137.6 (C.sub.aro); 136.2
(C.sub.aro); 129.4 (3 C.sub.aro); 128.4 (2 C.sub.aro); 127.4
(C.sub.aro); 118.8 (C.sub.aro); 117.6 (C.sub.aro); 112.1
(C.sub.aro); 63.0 (CH.sub.2); 56.8 (CH.sub.2); 55.3 (OCH.sub.3);
41.5 (NCH.sub.3); 40.2 (CH.sub.2); 25.2 (CH.sub.2). LCMS m/z 313.0
[M+H].sup.+.
Example 22: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-methoxybenzamide (Compound
3.1.29)
[0160] The compound 3.1.29 was synthesized according to the
procedure E2 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.98 mmol, 247 mg), and 4-methoxybenzoic acid (0.98 mmol, 150
mg). Purification by thick layer chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 73%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 7.97 (br s, 1H, NH); 7.67 (m,
2H, H.sub.2, H.sub.6); 7.32-7.24 (m, 5H, H.sub.aro); 6.84 (m, 2H,
H.sub.3, H.sub.5); 3.84 (s, 3H, OCH.sub.3); 3.60-3.52 (m, 4H, 2
CH.sub.2); 2.65 (t, J=6.0 Hz, 2H, CH.sub.2); 2.29 (s, 3H,
CH.sub.3); 1.85 (p, J=6.1 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 166.9 (CO); 162.0 (C.sub.aro); 137.2
(C.sub.aro); 129.6 (2 C.sub.aro); 128.8 (2 C.sub.aro); 128.5 (2
C.sub.aro); 127.7 (C.sub.aro); 125.0 (C.sub.aro); 113.6 (2
C.sub.aro); 62.9 (CH.sub.2); 56.7 (CH.sub.2); 55.4 (OCH.sub.3);
41.4 (CH.sub.3); 39.9 (CH.sub.2); 25.3 (CH.sub.2). LCMS m/z 313.1
[M+1-1].sup.+.
Example 23: Synthesis of
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide (Compound
3.1.30)
[0161] The compound 3.1.30 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.55 mmol, 138 mg), and 3-dimethylaminobenzoylchloride (0.55
mmol, 100 mg). Purification by column chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)) was performed. Yield: 11%. .sup.1H
NMR (300 MHz, CDCl.sub.3), .delta.: 7.90 (br s, 1H, NH); 7.28-7.24
(m, 5H, H.sub.aro); 7.22-7.19 (m, 2H, H.sub.2, H.sub.5); 6.92 (d,
J=7.5 Hz, 1H, H.sub.6); 6.82 (dd, J=8.1 Hz, J=2.2 Hz, 1H, H.sub.4);
3.62-3.51 (m, 4H, 2 CH.sub.2); 2.95 (s, 6H, 2 CH.sub.3); 2.64 (t,
=6.0 Hz, 2H, CH.sub.2); 2.31 (s, 3H, CH.sub.3); 1.85 (p, J=5.8 Hz,
2H, CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 162.4
(CO); 138.5 (C.sub.aro); 133.1 (2 C.sub.aro); 129.0 (2 C.sub.aro);
128.2 (2 C.sub.aro); 128.0 (2 C.sub.aro); 127.1 (C.sub.aro); 119.7
(C.sub.aro); 119.4 (C.sub.aro); 63.0 (CH.sub.2); 55.9 (CH.sub.2);
50.9 (CH2); 41.9 (3 CH.sub.3); 39.9 (CH.sub.2); 25.6 (CH.sub.2).
LCMS m/z 326.0 [M-F1-1].sup.+.
Example 24: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-cyanobenzamide (Compound
3.1.31)
[0162] The compound 3.1.31 was synthesized according to the
procedure E1 by using
N.sup.1-benzyl-N.sup.1-methylpropane-1,3-diamine dihydrochloride
1.4a (0.60 mmol, 150 mg), and 4-cyanobenzoylchloride (0.60 mmol,
100 mg). Purification by column chromatography (DCM:MeOH(NH.sub.3),
9:1 (v/v)) was performed. Yield: 7%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 8.61 (br s, 1H, NH); 7.71 (d, J=8.2 Hz, 2H,
H.sub.2, H.sub.6); 7.61 (d, J=8.3 Hz, 2H, H.sub.3, H.sub.5);
7.30-7.20 (m, 5H, H.sub.aro); 3.62 (q, J=6.4 Hz, 2H, CH.sub.2);
3.55 (s, 2H, CH.sub.2); 2.69 (t, J=5.8 Hz, 2H, CH.sub.2); 2.27 (s,
3H, CH.sub.3); 1.84 (p, J=6.0 Hz, 2H, CH.sub.2). .sup.13C NMR (75
MHz, CDCl.sub.3) .delta.: 165.3 (CO); 138.4 (C.sub.aro); 136.8
(C.sub.aro); 132.2 (2 C.sub.aro); 129.6 (2 C.sub.aro); 128.6 (2
C.sub.aro); 127.7 (2 C.sub.aro); 118.2 (C.sub.aro); 114.6
(C.sub.aro); 63.3 (CH.sub.2); 57.6 (CH.sub.2); 41.5 (CH.sub.3);
40.9 (CH.sub.2); 25.1 (CH.sub.2). LCMS m/z 308.0 [M+H].sup.+.
Example 25: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-nitrobenzamide (Compound
3.1.32)
[0163] The compound 3.1.32 was synthesized according to the
procedure E1 by using N.sup.1-dihydrochloride 1.4a (0.53 mmol, 133
mg), and 4-nitrobenzoylchloride (0.53 mmol, 100 mg). Purification
by column chromatography (DCM:MeOH(NH.sub.3), 9:1 (v/v)) was
performed. Yield: 50%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.:
8.68 (br s, 1H, NH); 8.17 (d, J=8.8 Hz, 2H, H.sub.2, H.sub.6); 7.79
(d, J=8.8 Hz, 2H, H.sub.3, H.sub.5); 7.32-7.22 (m, 5H, H.sub.aro);
3.65-3.56 (m, 4H, 2CH.sub.2); 2.72 (t, J=5.6 Hz, 2H, CH.sub.2);
2.32 (s, 3H, NCH.sub.3); 1.88 (p, J=5.7 Hz, 2H, CH.sub.2). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.: 166.7 (CO); 149.3 (C.sub.aro);
140.1 (C.sub.aro); 137.1 (C.sub.aro); 129.6 (2 C.sub.aro); 128.6 (2
C.sub.aro); 128.1 (2 C.sub.aro); 127.8 (C.sub.aro); 123.6 (2
C.sub.aro); 63.5 (CH.sub.2); 57.6 (CH.sub.2); 41.7 (CH.sub.3); 41.1
(CH.sub.2); 25.0 (CH.sub.2). LCMS m/z 328.0 [M+H].sup.+.
Example 26: Synthesis of
N-[3-(benzylmethylamino)propyl]-4-chlorobenzensulfonamide (Compound
3.2a)
[0164] The compound 3.2a was synthesized according to the procedure
E1 by using of M-benzyl-N.sup.1-methylpropane-1,3-diamine
dihydrochloride 1.4a (0.47 mmol, 118 mg), and 4-chlorobenzo
sulfonamide chloride (0.47 mmol, 100 mg). Purification by column
chromatography (petroleum ether:DCM:MeOH(NH.sub.3), 5:4:1 (v/v))
was performed. Yield: 60%. .sup.1H NMR (300 MHz, CDCl.sub.3),
.delta.: 7.76 (d, J=9.1 Hz, 2H, H.sub.2, H.sub.6); 7.47 (d, J=9.2
Hz, 2H, H.sub.3, H.sub.5); 7.36-7.22 (m, 5H, H.sub.aro); 3.46 (s,
2H, CH.sub.2); 3.05 (t, J=7.2 Hz, 2H, CH.sub.2); 2.45 (t, J=7.1 Hz,
2H, CH.sub.2); 2.18 (s, 3H, CH.sub.3); 1.67 (p, J=7.0 Hz, 2H,
CH.sub.2). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 138.8
(C.sub.aro); 138.7 (C.sub.aro); 137.9 (C.sub.aro); 129.3 (2
C.sub.aro); 129.0 (2 C.sub.aro); 128.6 (2 C.sub.aro); 128.5 (2
C.sub.aro); 127.4 (C.sub.aro); 62.8 (CH.sub.2); 56.8 (CH.sub.2);
44.0 (CH.sub.3); 41.9 (CH.sub.2); 24.7 (CH.sub.2). LCMS m/z 353.0,
355.0 [M+H].sup.+.
Example 27: Synthesis of
4-(benzylmethylamino)-N-(4-chlorophenyl)butanamide (Compound
3.3a)
[0165] The compound 3.3a was synthesized according to the procedure
E3 by using of 4-chloro-N-(4-chlorophenyl)butyramide 2.2 (1.29
mmol, 300 mg) and N-benzylmethylamine (7.75 mmol, 1 mL).
Purification by thick layer chromatography (cyclohexane:ethyl
acetate:MeOH(NH.sub.3), 4.5:4.5:1 (v/v)) was performed. Yield: 70%.
.sup.1H NMR (300 MHz, CDCl.sub.3), 9.63 (br s, 1H, NH); 7.45 (d,
J=9.1 Hz, 2H, H.sub.2, H.sub.6); 7.34-7.27 (m, 5H, H.sub.aro); 7.21
(d, J=9.0 Hz, 2H, H.sub.3, H.sub.5); 3.69 (s, 2H, CH.sub.2); 2.62
(t, 0.1=6.2 Hz, 2H, CH.sub.2); 2.51 (t, 0.1=7.0 Hz, 2H, CH.sub.2);
2.35 (s, 3H, CH.sub.3); 1.96 (p, J=6.1 Hz, 2H, CH.sub.2). .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta.: 171.4 (CO); 137.2 (C.sub.aro);
135.9 (C.sub.aro); 129.7 (2 C.sub.aro); 128.8 (2 C.sub.aro); 128.7
(2 C.sub.aro); 128.5 (2 C.sub.aro); 128.0 (C.sub.aro); 120.8
(C.sub.aro); 62.2 (CH.sub.2); 56.5 (CH.sub.2); 41.4 (CH.sub.3);
36.2 (CH.sub.2); 22.2 (CH.sub.2). LCMS m/z 317.2, 319.2
[M+H].sup.+.
Example 28: Synthesis of
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamide (Compound
3.4a)
[0166] The compound 3.4a was synthesized according to the procedure
E3 by using of N-(4-chlorobenzyl)-3-chloropropanamide 2.3 (0.21
mmol, 50 mg) and N-benzylmethylamine (1.29 mmol, 166 .mu.L).
Purification by thick layer chromatography (cyclohexane:ethyl
acetate:MeOH(NH.sub.3), 4.5:4.5:1 (v/v)). Yield: 67%. .sup.1H NMR
(300 MHz, CDCl.sub.3), .delta.: 8.65 (br s, 1H, NH); 7.34-7.19 (m,
7H, H.sub.2, H.sub.6, H.sub.aro); 7.09 (d, J=9.3 Hz, 2H, H.sub.3,
H.sub.5); 4.38 (d, J=6.1 Hz, 2H, CH.sub.2); 3.57 (s, 2H, CH.sub.2);
2.79 (t, J=6.2 Hz, 2H, CH.sub.2); 2.56 (t, J=6.0 Hz, 2H, CH.sub.2);
2.25 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.:
171.9 (CO); 137.2 (C.sub.aro); 133.1 (C.sub.aro); 129.3 (2
C.sub.aro); 129.2 (3 C.sub.aro); 128.8 (2 C.sub.aro); 128.6 (2
C.sub.aro); 127.9 (C.sub.aro); 62.0 (CH.sub.2); 53.0 (CH.sub.2);
42.6 (CH.sub.2); 40.7 (CH.sub.3); 32.4 (CH.sub.2). LCMS m/z 316.9,
318.9 [M+H].sup.+.
Example 29: Synthesis of
N-(4-chlorobenzyl)-3-(benzylmethylamino)propanamine (Compound
3.5a)
[0167] The compound 3.5a was synthesized according to the procedure
E4 by using commercially 4-chlorobenzaldehyde (0.55 mmol, 77 mg)
and N.sup.1-benzyl-/V-methylpropane-1,3-diamine 1.4a (0.55 mmol,
100 mg). Purification by thick layer chromatography
(DCM:MeOH(NH.sub.3), 9:1 (v/v)). Yield: 35%. .sup.1H NMR (300 MHz,
CDCl.sub.3), .delta.: 7.80 (br s, 1H, NH); 7.48 (d, J=8.4 Hz, 2H,
H.sub.2, H.sub.6); 7.33 (d, J=8.5 Hz, 2H, H.sub.3, H.sub.5);
7.30-7.26 (m, 3H, H.sub.aro); 7.13 (m, 2H, H.sub.aro); 4.00 (s, 2H,
CH.sub.2); 3.53 (s, 2H, CH.sub.2); 2.94 (t, J=6.5 Hz, 2H,
CH.sub.2); 2.60 (t, J=6.3 Hz, 2H, CH.sub.2); 2.27 (s, 3H,
CH.sub.3); 2.02 (p, J=6.2 Hz, 2H, CH.sub.2). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 136.5 (C.sub.aro); 135.3 (C.sub.aro); 131.2 (2
C.sub.aro); 130.3 (C.sub.aro); 129.4 (2 C.sub.aro); 129.3 (2
C.sub.aro); 128.6 (2 C.sub.aro); 127.8 (C.sub.aro); 62.2
(CH.sub.2); 55.4 (CH.sub.2); 50.9 (CH.sub.2); 47.3 (CH.sub.2); 41.5
(CH.sub.3); 22.6 (CH.sub.2). LCMS m/z 303.0, 305.0 [M+H].sup.+.
Example 30 Synthesis of
N-(2-(benzyl(methyl)amino)ethyl)-3-chlorobenzamide (Compound
3.1.33)
[0168] The compound 3.1.33 was synthesized according to the
procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg)
and 3-chlorobenzoyl chloride (0.91 mmol, 117 .mu.L). Purification
by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)).
Yield 35%. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 2.26 (s, 3H),
2.56 (t, 2H, J=7.1 Hz), 3.56 (q, 2H, J=5.0 Hz, J=7.5 Hz), 3.60 (s,
2H), 6.85 (s, 1H), 7.31 (m, 5H), 7.35 (t, 1H, J=7.5 Hz, J=7.5 Hz),
7.74 (m, 1H), 7.56 (d, 1H, J=1.5 Hz), 7.93 (m, 2H).sup.13C NMR (75
MHz, CDCl.sub.3) .delta.: 44.1, 57.6, 57.9, 64.9, 127.1, 127.8,
128.6, 128.2, 129.7, 130.0, 132.2, 134.4, 135.6, 138.6, 167.3 LCMS
m/z 302.1; 303.1 [M+H].sup.+.
Example 31: Synthesis of
N-(2-(benzyl(methyl)amino)ethyl)-2,4-dichlorobenzamide (Compound
3.1.34)
[0169] The compound 3.1.34 was synthesized according to the
procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg)
and 2,4-dichlorobenzoyl chloride (0.91 mmol, 107 .mu.L).
Purification by thick layer chromatography (DCM:MeOH(NH.sub.3),
9.1:1 (v/v)). Yield 35%. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.:
2.26 (s, 3H), 2.56 (t, 2H, J=7.1 Hz), 3.56 (q, 2H, J=5.0 Hz, J=7.5
Hz), 3.60 (s, 2H), 6.85 (s, 1H), 7.31 (m, 5H), 7.35 (t, 1H, J=7.5
Hz, J=7.5 Hz), 7.74 (m, 1H), 7.56 (d, 1H, J=1.5 Hz), 7.93 (m,
2H).sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 44.1, 57.6, 57.9,
64.9, 127.1, 127.8, 128.6, 128.2, 129.7, 130.0, 132.2, 134.4,
135.6, 138.6, 167.3 LCMS m/z 302.1; 303.1 [M+H].sup.+.
Example 32: Synthesis of
N-(2-(benzyl(methyl)amino)ethyl)-4-cyanobenzamide (Compound
3.1.36)
[0170] The compound 3.1.36 was synthesized according to the
procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg)
and 4-cyanobenzolyl chloride (0.91 mmol, 150 mg). Purification by
thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)). Yield
33%. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 2.34 (s, 3H), 2.65
(t, 2H, J=5.7 Hz), 3.55 (q, 2H, J=5.1 Hz, J=6.3 Hz), 3.59 (s, 2H),
6.96 (s, 1H), 7.35 (m, 5H), 7.52 (d, 2H, J=4.8 Hz), 8.29 (d, 2H,
J=9 Hz).sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 43.9, 57.5, 58.0,
64.7, 115.7, 118.0, 126.9, 128.0, 128.5, 131.7, 139.1, 167.9 LCMS
m/z 294.1[M+H].sup.+.
Example 33: Synthesis of
N-(2-(benzyl(methyl)amino)ethyl)-4-nitrobenzamide (Compound
3.1.37)
[0171] The compound 3.1.37 was synthesized according to the
procedure E3 by using N-(2-aminoethyl)benzamide (0.91 mmol, 150 mg)
and 4-nitrobenzoyl chloride (0.91 mmol, 110 mg). Purification by
thick layer chromatography (DCM:MeOH(NH.sub.3), 9.1:1 (v/v)). Yield
52%. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 2.34 (s, 3H), 2.65
(t, 2H, J=5.7 Hz), 3.55 (q, 2H, J=5.1 Hz, J=6.3 Hz), 3.59 (s, 2H),
6.96 (s, 1H), 7.35 (m, 5H), 7.52 (d, 2H, J=4.8 Hz), 8.29 (d, 2H,
J=9 Hz).sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 43.9, 57.5, 58.0,
64.7, 115.7, 118.0, 126.9, 128.0, 128.5, 131.7, 139.1, 167.9 LCMS
m/z 294.1[M+H].sup.+.
Example 34: Synthesis of
N-(4-Nitrobenzyl)-3-(benzylmethylamino)propanamide (Compound
3.4b)
[0172] The compound 3.4b was synthesized according to the procedure
E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3b (0.41 mmol,
100 mg) and N-benzylmethylamine (4.1 mmol, 531 .mu.L). Purification
by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)).
Yield: 37%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 9.00 (br s,
1H, NH); 8.15 (d, J=8.7 Hz, 2H, H.sub.aro); 7.40 (d, J=8.4 Hz, 2H,
H.sub.aro); 7.20 (m, 3H, H.sub.aro); 7.10 (m, 2H, H.sub.aro); 4.50
(d, J=6.0 Hz, 2H, CH.sub.2); 3.50 (s, 2H, CH.sub.2); 2.70 (t, J=6.2
Hz, 2H, CH.sub.2); 2.50 (t, J=6.2 Hz, 2H, CH.sub.2); 2.25 (s, 3H,
CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 172.6 (CO);
146.5 (C.sub.aro); 146.2 (C.sub.aro); 137.3 (C.sub.aro); 129.1
(C.sub.aro); 128.5 (C.sub.aro); 128.1 (C.sub.aro); 127.6
(C.sub.aro); 123.8 (C.sub.aro); 62.2 (CH.sub.2); 52.8 (CH.sub.2);
42.3 (CH.sub.3); 41.1 (CH.sub.2); 32.5 (CH.sub.2); 29.7 (CH.sub.2).
LCMS m/z 328.9 [M+H].sup.+.
Example 35: Synthesis of
N-(4-Cyanobenzyl)-3-(benzylmethylamino)propanamide (Compound
3.4c)
[0173] The compound 3.4c was synthesized according to the procedure
E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3c (0.44 mmol,
100 mg) and N-benzylmethylamine (4.4 mmol, 579 .mu.L). Purification
by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)).
Yield: 80%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 8.90 (br s,
1H, NH); 7.58 (d, J=6.3 Hz, 2H, H.sub.aro); 7.32 (d, J=8.1 Hz,
.sup.2H, H.sub.aro); 7.21 (m, 3H, H.sub.aro); 7.07 (m, 2H,
H.sub.aro); 4.43 (d, J=5.9 Hz, 2H, CH.sub.2); 3.48 (s, 2H,
CH.sub.2); 2.68 (t, J=5.6 Hz, 2H, CH.sub.2); 2.47 (t, J=5.5 Hz, 2H,
CH.sub.2); 2.21 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 172.7 (CO); 144.4 (C.sub.aro); 137.5
(C.sub.aro); 132.4 (C.sub.aro); 129.0 (C.sub.aro); 128.5
(C.sub.aro); 128.1 (C.sub.aro); 127.5 (C.sub.aro); 118.8
(C.sub.aro); 110.9 (C.sub.aro); 62.2 (CH.sub.2); 52.9 (CH.sub.2);
42.5 (CH.sub.3); 41.1 (CH.sub.2); 32.6 (CH.sub.2). LCMS m/z 308.0
[M+H].sup.+.
Example 36: Synthesis of
N-(2,4-Dichlorobenzyl)-3-(benzylmethylamino)propanamide (Compound
3.4d)
[0174] The compound 3.4d was synthesized according to the procedure
E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3d (0.37 mmol,
100 mg) and N-benzylmethylamine (3.7 mmol, 483 .mu.L). Purification
by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)).
Yield: 80%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 8.90 (br s,
1H, NH); 7.38 (d, J=1.9 Hz, 1H, H.sub.aro); 7.28 (d, J=8.3 Hz,
.sup.1H, H.sub.aro); 7.27-7.15 (m, 4H, H.sub.aro); 7.10 (m, 2H,
H.sub.aro); 4.45 (d, J=5.8 Hz, 2H, CH.sub.2); 3.50 (s, 2H,
CH.sub.2); 2.70 (t, J=6.1 Hz, 2H, CH.sub.2); 2.45 (t, J=5.6 Hz, 2H,
CH.sub.2); 2.18 (s, 3H, CH.sub.3). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.: 172.5 (CO); 137.5 (C.sub.aro); 134.8
(C.sub.aro); 134.3 (C.sub.aro); 133.7 (C.sub.aro); 131.1
(C.sub.aro); 129.2 (C.sub.aro); 129.0 (C.sub.aro); 128.4
(C.sub.aro); 127.5 (C.sub.aro); 127.3 (C.sub.aro); 62.2 (CH.sub.2);
53.1 (CH.sub.2); 41.0 (CH.sub.3); 40.5 (CH.sub.2); 32.6 (CH.sub.2).
LCMS m/z 350.97, 354.96, 352.93 [M+H].sup.+.
Example 37: Synthesis of
N-(3-Chlorobenzyl)-3-(benzylmethylamino)propanamide (Compound
3.4e)
[0175] The compound 3.4e was synthesized according to the procedure
E3 by using N-(4-chlorobenzyl)-3-chloropropanamide 2.3e (0.43 mmol,
100 mg) and N-benzylmethylamine (4.3 mmol, 555 .mu.L). Purification
by thick layer chromatography (DCM:MeOH(NH.sub.3), 9.7:0.3 (v/v)).
Yield: 68%. .sup.1H NMR (300 MHz, CDCl.sub.3), .delta.: 8.80 (br s,
1H, NH); 7.30-7.00 (m, 9H, H.sub.aro); 4.40 (d, =5.6 Hz, 2H,
CH.sub.2); 3.50 (s, 2H, CH.sub.2); 2.70 (t, J=6.0 Hz, 2H,
CH.sub.2); 2.48 (t, J=5.6 Hz, 2H, CH.sub.2); 2.20 (s, 3H,
CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 172.5 (CO);
140.8 (C.sub.aro); 137.5 (C.sub.aro); 134.4 (C.sub.aro); 129.9
(C.sub.aro); 129.0 (C.sub.aro); 128.5 (C.sub.aro); 127.8
(C.sub.aro); 127.5 (C.sub.aro); 127.4 (C.sub.aro); 125.9
(C.sub.aro); 62.2 (CH.sub.2); 53.1 (CH.sub.2); 42.5 (CH.sub.3);
40.1 (CH.sub.2); 32.6 (CH.sub.2). LCMS m/z 317.1, 319.1
[M+H].sup.+.
[0176] Compounds have been transformed into their hydrochloride
salts by solubilizing in MeOH, treating with HCl 1M until pH=1 and
then lyophilizing.
Biology Examples
1. Binding Assay to a Receptors
[0177] The .sigma. binding assays were performed according to
Ganapathy et al. (Ganapathy, M. E.; Prasad, P. D.; Huang, W.; Seth,
P.; Leibach, F. H.; Ganapathy, V. Molecular and ligand-binding
characterization of the sigma-receptor in the Jurkat human T
lymphocyte cell line. J. Pharmacol. Exp. Ther. 1999, 289, 251-260).
The .sigma..sub.1 binding assay was carried out by incubating
Jurkat cell membranes (10-20 mg protein per tube) with
[.sup.3H](+)-pentazocine (15 nM) and a range of concentrations of
tested compounds, at 37.degree. C. for 2 hours, in 5 mM Tris/HCl
buffer (pH=7.4). The .sigma..sub.2 binding assay was performed by
incubating Jurkat cell membranes (10-20 mg protein per tube) with
[.sup.3H]-DTG (25 nM) in presence of (+)-pentazocine (1 .mu.M) to
saturate .sigma..sub.1 receptors, and a range of concentrations of
tested compounds, at room temperature for 1 hour in 5 mM Tris/HCl
buffer (pH=7.4). The final assay volume was 0.5 mL. Binding was
terminated by rapid filtration through Wathman GF/B filters, which
were then washed with 5.times.1 mL ice-cold NaCl solution and
allowed to dry before bound radioactivity was measured using liquid
scintillation counting. Nonspecific binding was determined, in both
assays, under similar conditions, but in presence of 10 .mu.M
unlabeled haloperidol. Inhibition constants (KO were calculated
from the IC.sub.50 values according to the method of Cheng and
Prusoff (Cheng, Y.; Prusoff, W. H. Relationship between the
inhibition constant (KO and the concentration of inhibitor which
causes 50 percent inhibition (IC.sub.50) of an enzymatic reaction.
Biochem Pharmacol. 1973, 22 (23), 3099-108):
K t = IC 50 1 * L K d ##EQU00001##
Where IC.sub.50=Inhibitory concentration at 50% [0178]
L=Concentration of radioligand [0179] Kd=Affinity constant of
radioligand
[0180] The .sigma..sub.1 binding assay was carried out with
[.sup.3H](.+-.)-pentazocine (L=15 nM, K.sub.d=16 nM) as radioligand
and the .sigma..sub.2 binding assay with [.sup.3H]-DTG (L=25 nM,
K.sub.d=80.84 nM).
[0181] The results of the sigma-1 and sigma-2 binding assays (i.e.
the mean K.sub.i values for 2 or 3 independent experiments with
less than 10% deviation) are shown in Tables 2, 3 and 4
hereafter:
TABLE-US-00002 TABLE 2 ##STR00017## Com- Sigma 1 Sigma 2 pound
K.sub.i K.sub.i Ratio No.* X m --NR.sub.1R.sub.2 (nM) (nM)
.sigma..sub.2/.sigma..sub.1 3.1.2 4-n-Pr 3 ##STR00018## 3.7 160 43
3.1.3 4-n-Bu 3 ##STR00019## 7.3 49 7 3.1.4 4-t-Bu 3 ##STR00020##
1.6 nd 3.1.5 4-CF.sub.3 3 ##STR00021## 1.4 98 70 3.1.6 4-F 3
##STR00022## 20 470 24 3.1.7 2-Cl 3 ##STR00023## 47 >1200 >26
3.1.8 3-Cl 3 ##STR00024## 10 340 34 3.1.9 4-Cl 2 ##STR00025## 3.6
850 236 3.1.10 4-Cl 3 ##STR00026## 3.2 190 60 3.1.11 4-Cl 4
##STR00027## 1.7 20 12 3.1.12 4-Cl 3 ##STR00028## 4.3 200 47 3.1.15
4-Cl 3 ##STR00029## 19 nd 3.1.20 2-Br 3 ##STR00030## 42 >1200
>29 3.1.21 3-Br 3 ##STR00031## 3.9 350 90 3.1.22 4-Br 3
##STR00032## 2.1 160 76 3.1.23 2,3-Cl 3 ##STR00033## 10 310 31
3.1.24 2,4-Cl 3 ##STR00034## 1.3 310 238 3.1.25 3,4-Cl 3
##STR00035## 1.1 59 54 3.1.26 3,5-Cl 3 ##STR00036## 23 48 2 3.1.27
2-F-4-Br 3 ##STR00037## 2.9 Nd 3.1.28 3-OCH.sub.3 3 ##STR00038## 40
>1200 >30 3.1.29 4-OCH.sub.3 3 ##STR00039## 37 >1000
>27 3.1.30 3-N(CH.sub.3).sub.2 3 ##STR00040## 1.9 3.1.31 4-CN 3
##STR00041## 24 >1200 >50 3.1.32 4-NO.sub.2 3 ##STR00042##
4.3 360 84 3.1.34 3,4-Cl 2 ##STR00043## 6.5 110 17 3.1.36 4-CN 2
##STR00044## 1.2 170 142 3.1.37 4-NO.sub.2 2 ##STR00045## 3.6 1400
389 *compounds are evaluated as their hydrochloride salts.
TABLE-US-00003 TABLE 3 ##STR00046## Compound Sigma 1 Sigma 2 Ratio
No.* L m K.sub.i (nM) K.sub.i (nM) .sigma..sub.2/.sigma..sub.1 3.2a
SO.sub.2NH 3 5.8 200 35 3.3a NHCO 3 6.5 170 26 3.4a CH.sub.2NHCO 2
1.7 410 241 3.5a CH.sub.2NH 3 2.9 nd -- *compounds are evaluated as
their hydrochloride salts.
TABLE-US-00004 TABLE 4 ##STR00047## Compound Sigma 1 Sigma 2 Ratio
No.* (X).sub.n K.sub.i (nM) K.sub.i (nM)
.sigma..sub.2/.sigma..sub.1 3.4b 4-NO.sub.2 2.3 6500 2826 3.4c 4-CN
5.6 1800 321 3.4d 2,4-Cl 2.3 120 52 3.4e 3-Cl 0.63 200 317
*compounds are evaluated as their hydrochloride salts.
[0182] The present study shows that the compounds of the invention
have good signal affinities and are selective over sigma 2.
Especially compounds 3.1.9, 3.1.24, 3.4b and 3.5a have sigma 1
affinities in the nanomolecular range (1.3 to 3.6 nM) and excellent
sigma 2/sigma 1 selectivities between 236 and 2826.
2. Agonist Activity of Sigma-1 Receptor Ligand 3.1.10 in the
Dizocilpine-Induced Learning Deficits Test
[0183] The activity of compound 3.1.10 was evaluated on the
prevention of the dizocilpine-induced learning deficits measured
using two behavioral tests. The present experiment tested if its
anti-amnesic activity could be blocked by pre-treatment with the
reference sigma-1 receptor antagonist NE-100.
2.1 Study Plan Protocols and Materials
2.1.1. Experimental Design
[0184] Sixty (60) mice were used. Behavioral testing started one
week after the arrival of the animals in the AMYLGEN animal
facility. [0185] 5 treatment groups were designed and used as
follows:
TABLE-US-00005 [0185] Treatment group n 1. vehicle 1 + vehicle 2 12
2. dizocilpine + vehicle 2 12 3. dizocilpine (0.15 mg/kg i.p.) +
Cpd. 3.1.10 (0.5 mg/kg) 12 4. dizocilpine (0.15 mg/kg i.p.) + Cpd.
3.1.10 (0.5 mg/kg) + 12 5. dizocilpine (0.15 mg/kg i.p.) + NE-100
(3 mg/kg) 12 Total mice 60
[0186] Vehicle 1 was physiological saline for dizocilpine, DMSO 2%
in water for compound 3.1.10 [0187] Animals were used at day 1 in
the Y-maze test and at days 2 and 3 in the passive avoidance test,
with training at day 2 and retention at day 3. [0188] Test
compounds, compound 3.1.10 and/or NE-100 were administered 10 min
before dizocilpine (at 0.15 mg/kg i.p.) or vehicle. [0189]
Dizocilpine or vehicle 1 was administered 20 min before the Y-maze
test session on day 1. [0190] Dizocilpine or vehicle 1 was
administered 20 min before the passive avoidance training session
on day 2. [0191] Drugs were not injected before the retention
session on day 3. [0192] The whole experiment program was performed
in a single series experiment. [0193] Treatments were
randomized.
2.1.2. Animals
[0194] Male Swiss mice, 6 weeks old and weighing 30-35 g, from
JANVIER (Saint Berthevin, France), were housed in groups with
access to food and water ad libitum, except during experiments.
They were kept in a temperature and humidity controlled animal
facility on a 12 h/12 h light:dark cycle (lights on at 7:00 am).
Behavioral experiments were carried out between 09:00 am and 05:00
pm, in a sound attenuated and air-regulated experimental room, to
which mice were habituated at least 30 min. Mice were numbered by
marking their tail using permanent markers ad sacrificed
immediately after the passive avoidance retention session.
2.1.3. Test compounds [0195] Compound 3.1.10 of Example 10 above.
[0196] Dizocilpine ((+)-MK-801 maleate, CAS #77086-22-7, batch
9A/124751) was from Tocris Bioscience. [0197] NE-100 hydrochloride
(CAS #149409-57-4, batch 1B/124951) was from Tocris Bioscience.
[0198] All compounds were injected intraperitoneally (i.p.) in a
volume of 100 .mu.L, per 20 g of body weight, corresponding to 5
mL/kg.
2.1.4. Randomization of the Treatments
[0199] Treatment received by animals tested in series were
conterbalanced.
2.1.5. Mortality
[0200] No animal deceased following injection or during the
behavioral testing.
2.2. Behavioral Analyses
2.2.1. Spontaneous Alternation Performances
[0201] Animals were tested for spontaneous alternation performance
in the Y-maze, an index of spatial working memory. The Y-maze is
made of grey polyvinylchloride. Each arm is 40 cm long, 13 cm high,
3 cm wide at the bottom, 10 cm wide at the top, and converging at
an equal angle. Each mouse was placed at the end of one arm and
allowed to move freely through the maze during an 8 min session.
The series of arm entries, including possible returns into the same
arm, were checked visually. An alternation was defined as entries
into all three arms on consecutive occasions. The number of maximum
alternations was therefore the total number of arm entries minus
two and the percentage of alternation was calculated as: (actual
alternations/maximum alternations).times.100. Parameters included
the percentage of alternation (memory index) and total number of
arm entries (exploration index).
[0202] Animals showing an extreme behavior (alternation <20% or
>90% or number of arm entries <10) are usually discarded from
the calculations. 2 animals were discarded accordingly.
2.2.2. Step-Through Passive Avoidance Test
[0203] The apparatus is a two-compartments (15.times.20.times.15 cm
high) box with one illuminated with white polyvinylchloride walls
and the other darkened with black polyvinylchloride walls and a
grid floor. A guillotine door separates each compartment. A 60 W
lamp positioned 40 cm above the apparatus lights up the white
compartment during the experiment. Scrambled footshocks (0.3 mA for
3 s) could be delivered to the grid floor using a shock generator
scrambler (Lafayette Instruments, Lafayette, USA). The guillotine
door is initially closed during the training session. Each mouse
was placed into the white compartment. After 5 s, the door was
raised. When the mouse entered the dark compartment and placed all
its paws on the grid floor, the door was closed and the footshock
delivered for 3 s. The step-through latency (the latency spent to
enter the dark compartment) and the number of vocalizations was
recorded. The retention test was carried out after 24 h. Each mouse
was placed again into the white compartment. After 5 s, the door
was opened. The step-through latency was recorded up to 300 s. When
the mouse entered the dark compartment or 300 s has elapsed (they
were therefore manually placed in it), the escape latency (latency
to exit from the dark compartment) was recorded up to 300 s.
2.2.3. Statistical Analyses
[0204] All values, except passive avoidance latencies, were
expressed as mean.+-.S.E.M. Statistical analyses were performed
using two-way ANOVA (F value), with genotype and peptide treatment
as independent factors, followed by a Dunn's post-hoc multiple
comparison test.
[0205] Passive avoidance latencies do not follow a Gaussian
distribution, since upper cut-off times are set. They were
therefore analyzed using a Kruskal-Wallis non-parametric ANOVA (H
value), followed by a Dunn's multiple comparison test.
[0206] p<0.05 was considered as statistically significant.
2.3. Results
[0207] The results of the spontaneous alternation and passive
avoidance assays are represented in FIGS. 1a and 1b.
[0208] Compound 3.1.10 significantly attenuated the
dizocilpine-induced learning deficits, at 0.5 mg/kg in the Y-maze
test and in the passive avoidance test. The beneficial effect of
compound 3.1.10 in the two tests was prevented by treatment with
the sigma-1 antagonist NE-100 at 3 mg/kg, devoid of effect by
itself.
[0209] These results thus demonstrate the sigma-1 receptor effect
of compound 3.1.10.
3. In Vivo Assay to Assess Activity of Compound 3.1.10 in Rodent MS
Model
[0210] Experimental autoimmune encephalomyelitis (EAE) is an
unequivocal animal model of multiple sclerosis (MS), a
demyelitating disabling disease of the central nervous system
characterized by the inappropriate effect of reactive T and B
cells.
Materials and Methods
[0211] Animals. SJL/J mice were purchased from Janvier (Le
Genest-St-Isle, France) and bred under conventional barrier
protection at the Pasteur Institute (Lille, France). All experiment
protocols and procedures were in compliance with the European
Communities Council Directives of 24 Nov. 1986 (86/609/EEC) and
were approved by the local ethical committee (CEEA 102009R).
Efforts were made to minimize the number of animals used and their
suffering. Animals that reached severe hind limb paresis (clinical
grade 3) were isolated, and hydration and food access were
facilitated.
[0212] EAE induction and treatment. The method of EAE induction was
similar to previously published methods (Lee-Chang et al., Immunol
Lett. 2011 Mar. 30; 135(1-2):108-17). Randomized 9-week-old female
SJL/J mice were inoculated subcutaneously (s.c.) in the neck with
an emulsion containing 100 .mu.g of myelin proteolipid protein
(PLP).sub.139-151 peptide and an equal volume of Freund's complete
adjuvant (FCA) containing 4 mg/ml of heat-inactivated Mycobacterium
tuberculosis H37RA (Difco Laboratories, Detroit, Mich., USA) on day
0. Additionally, mice received 0.3 .mu.g of Bordetella pertussis
toxin (BPT) (Sigma-Aldrich, Saint Louis, Mich., USA)
intraperitoneally (i.p.) on days 0 and 3. Sham animals only
received saline injection. SJL/J mice that only received FCA and
BPT were also included in the experiments.
[0213] Compound 3.1.10 was dissolved in physiological saline.
Control animals received one administration of saline solution
(vehicle).
[0214] For validation of the .sigma.1 action, pretreatment BD1047
(N'-[2-(3,4-dichlorophenyl)ethyl]-N,N,N'-trimethylethane-1,2-diamine;
Costa B. R., Radesca L., Di Paolo L., Bowen W. D. J. Med. Chem.
1992, 35, 38-47) or saline, i.p.) was administered 20 min prior to
receiving compound 3.1.10 (i.p.). Injections were performed on the
onset of EAE (i.e. grade=2) and continued for the following 14
days. The clinical course was followed for 35 days. Three different
groups, EAE-vehicle, EAE-compound 3.1.10 (1 mg/kg), and EAE-DB1047
(10 mg/kg) compound 3.1.10 (1 mg/kg) were used per experiment with
7 animals per treatment group.
[0215] For preventive treatment, single compound 3.1.10 i.p.
injection was performed on day 0 (D0). Three different groups,
EAE-vehicle, EAE-compound 3.1.10 (0.5 mg/kg), and EAE-compound
3.1.10 (1 mg/kg), were used per experiment with 13-15 animals per
treatment group.
[0216] For curative treatment, p.o. administrations were performed
on the onset of EAE (i.e. grade=2) and treatment was continued for
the following 14 days. The clinical course was followed for 70
days. Three different groups, EAE-vehicle, EAE-compound 3.1.10 (0.5
mg/kg), and EAE-compound 3.1.10 (1 mg/kg), were used per experiment
with 7 animals per treatment group.
[0217] Mice showed no apparent toxic side effects of any treatment
protocols.
[0218] Clinical evaluation. Body weight and clinical signs of EAE
were monitored daily. The severity of clinical symptoms was scored
based on a standard neurological scoring system for EAE, as
follows: grade 0, no disease; grade 1, moderate tail hypotonia
and/or slight clumsy gait; grade 2, tail atony and/or clumsy gait;
grade 3, severe hind limb paresis; grade 4, paraplegia; grade 5,
tetraplegia. Scoring was performed in a blind fashion.
[0219] Serum anti-PLP enzyme-linked immunosorbent assay (ELISA).
Mice were deeply anesthetized with an i.p. injection of
pentobarbital. Serum samples were prepared from peripheral blood
obtained by cardiac puncture immediately before perfusion. Active
immunizations were verified by measuring anti-PLP.sub.139-151 IgG
antibody (Ab), as previously described (El Behi et al., (2007), J
Neuroimmunol 182:80-8).
Results
[0220] The validation of al action assay confirms that compounds of
the invention are active via the al receptor. The results are
represented in FIG. 2.
[0221] The assay using compound 3.1.10 in preventive treatment
demonstrates that compounds of the invention are useful in delaying
the onset of EAE in mice. The results are represented in FIG.
3.
[0222] The assay using compound 3.1.10 in curative treatment
demonstrates that compounds of the invention are useful in
alleviating the symptoms of EAE in mice. The results are
represented in FIG. 4.
[0223] EAE being an unequivocal animal model of multiple sclerosis
(MS), a demyelitating disabling disease of the central nervous
system characterized by the inappropriate effect of reactive T and
B cells, the above results show the usefulness of the compounds of
the invention, especially of compound 3.1.10, in the treatment and
prevention of multiple sclerosis (MS) in particular and 61 receptor
related diseases in general.
[0224] While embodiments of the invention have been illustrated and
described, it is not intended that these embodiments illustrate and
describe all possible forms of the invention. Rather, the words
used in the specification are words of description rather than
limitation ant it is understood that various changes may be made
without departing from the spirit and scope of the invention.
* * * * *