U.S. patent application number 11/717860 was filed with the patent office on 2008-01-03 for novel aminopyridine derivatives as mglur5 antagonists.
This patent application is currently assigned to Addex Pharmaceuticals SA. Invention is credited to Anne-Sophie Bessis, Christelle Bolea, Emmanuel Le Poul, Vincent Mutel, Jean-Philippe Rocher.
Application Number | 20080004316 11/717860 |
Document ID | / |
Family ID | 32964064 |
Filed Date | 2008-01-03 |
United States Patent
Application |
20080004316 |
Kind Code |
A1 |
Bolea; Christelle ; et
al. |
January 3, 2008 |
Novel aminopyridine derivatives as mGluR5 antagonists
Abstract
The invention relates to novel aminopyridine derivatives of
formula (I) wherein R1 is methyl an R.sub.4 and amino group
--NR.sub.6R.sub.7 and R.sub.5 forms an arylalkynyl- or
heteroarylalkynyl-group. The compounds are useful in the prevention
or treatment of central nervous system disorders as well as other
disorders modulated by mGluR5 receptors. ##STR1##
Inventors: |
Bolea; Christelle; (Carouge,
CH) ; Mutel; Vincent; (Pringy, FR) ; Rocher;
Jean-Philippe; (Vetraz-Monthoux, FR) ; Bessis;
Anne-Sophie; (Ferney-Voltaire, FR) ; Le Poul;
Emmanuel; (Cessy, FR) |
Correspondence
Address: |
EDWARDS ANGELL PALMER & DODGE LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Assignee: |
Addex Pharmaceuticals SA
Geneva
CH
|
Family ID: |
32964064 |
Appl. No.: |
11/717860 |
Filed: |
March 13, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11225490 |
Sep 2, 2005 |
7205411 |
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11717860 |
Mar 13, 2007 |
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PCT/IB04/00745 |
Mar 4, 2004 |
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11225490 |
Sep 2, 2005 |
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Current U.S.
Class: |
514/332 ;
514/352 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 25/28 20180101; A61P 25/18 20180101; A61P 25/34 20180101; A61P
9/10 20180101; C07D 213/73 20130101; A61P 25/16 20180101; A61P
25/14 20180101; A61P 25/06 20180101; A61P 29/00 20180101; A61P
25/32 20180101; A61P 25/22 20180101; C07D 213/74 20130101; A61P
43/00 20180101; A61P 25/36 20180101; A61P 25/00 20180101; A61P
25/30 20180101; A61P 25/24 20180101 |
Class at
Publication: |
514/332 ;
514/352 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 31/444 20060101 A61K031/444; A61P 25/00 20060101
A61P025/00; A61P 25/30 20060101 A61P025/30; A61P 29/00 20060101
A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 4, 2003 |
GB |
0304901.2 |
Jul 14, 2003 |
GB |
0316430.8 |
Claims
1-14. (canceled)
15. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula I: ##STR15## but
excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine,
wherein R.sub.1 is methyl R.sub.2 and R.sub.3 are independently
selected from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is
##STR16## R.sub.6 and R.sub.7 which may be the same or different
are hydrogen or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR17## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compounds; and a pharmaceutically
acceptable carrier and/or excipient.
16. A pharmaceutical composition of claim 15 wherein the compound
has the following formula I-A: ##STR18## wherein R.sub.2 and
R.sub.3 are independently selected from hydrogen, C1-C6-alkyl;
R.sub.5 represents a group of formula ##STR19## wherein R.sub.9,
R.sub.10, R.sub.11, R.sub.12 and R.sub.13 independently are
hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl,
C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl; R.sub.14 and
R.sub.15 independently are as defined for R.sub.9-R.sub.13 above;
or pharmaceutically acceptable salts, hydrates or solvates of such
compound.
17. A pharmaceutical composition of claim 15 wherein the compound
has the following formula I-B: ##STR20## wherein R.sub.2 and
R.sub.3 are independently selected from hydrogen, C1-C6-alkyl;
R.sub.9, R.sub.10, R.sub.11, R.sub.12 and R.sub.13 independently
are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl,
C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl; or
pharmaceutically acceptable salts, hydrates or solvates of such
compound.
18. A pharmaceutical composition of claim 15 wherein the compound
has the following formula I-C: ##STR21## wherein R.sub.2 and
R.sub.3 are independently selected from hydrogen, C1-C6-alkyl;
R.sub.14 and R.sub.15 independently are hydrogen, halogen, cyano,
nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy,
carboxy-C1-C6-alkyl or carboxyaryl; or pharmaceutically acceptable
salts, hydrates or solvates of such compound.
19. A pharmaceutical composition of claim 15 wherein said compound
is selected from: (6-Methyl-2-phenylethynyl-pyridin-3-yl)amine
N,N-Dimethyl-N'-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidine
(2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3-Methoxy-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(6-Methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine
(2-(4-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3,5-Difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(5-Fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
3-(3-Amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile
(2-(5-Chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3-Chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3-Fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine
(2-(3-Chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine and
pharmaceutically acceptable salts thereof.
20. A pharmaceutical composition of claim 15 wherein the
composition comprises
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
21. A method of treating or preventing a condition in a mammal, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of mGluR5 antagonists, comprising
administering to a mammal in need of such treatment or prevention,
an effective amount of a compound of the following formula I:
##STR22## but excluding
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R.sub.1 is methyl R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is ##STR23##
R.sub.6 and R.sub.7 which may be the same or different are hydrogen
or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR24## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound.
22. A method of claim 21 wherein the compound has the following
formula I-A: ##STR25## wherein R.sub.2 and R.sub.3 are
independently selected from hydrogen, C1-C6-alkyl; R.sub.5
represents a group of formula ##STR26## wherein R.sub.9, R.sub.10,
R.sub.11, R.sub.12 and R.sub.13 independently are hydrogen,
halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy,
carboxy-C1-C6-alkyl or carboxyaryl; R.sub.14 and R.sub.15
independently are as defined for R.sub.9-R.sub.13 above; or
pharmaceutically acceptable salts, hydrates or solvates of such
compound.
23. A method of claim 21 wherein the compound has the following
formula I-B: ##STR27## wherein R.sub.2 and R.sub.3 are
independently selected from hydrogen, C1-C6-alkyl; R.sub.9,
R.sub.10, R.sub.11, R.sub.12 and R.sub.13 independently are
hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl,
C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl; or
pharmaceutically acceptable salts, hydrates or solvates of such
compound.
24. A method of claim 21 wherein the compound has the following
formula I-C: ##STR28## wherein R.sub.2 and R.sub.3 are
independently selected from hydrogen, C1-C6-alkyl; R.sub.14 and
R.sub.15 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; or pharmaceutically acceptable salts, hydrates or
solvates of such compound.
25. A method of claim 21 wherein said compound is selected from:
(6-Methyl-2-phenylethynyl-pyridin-3-yl)amine
N,N-Dimethyl-N'-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidine
(2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3-Methoxy-phenylethynyl )-6-methyl-pyridin-3-yl)amine
(6-Methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine
(2-(4-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3,5-Difluoro-phenylethynyl )-6-methyl-pyridin-3-yl)amine
(2-(5-Fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
3-(3-Amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile
(2-(5-Chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3-Chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
(2-(3-Fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine
(2-(3-Chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine and
pharmaceutically acceptable salts thereof.
26. A method of claim 21 wherein the mammal is a human.
27. A method of claim 21 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
28. A method for treating or preventing a central nervous system
disorder selected from: tolerance or dependence, depression,
bipolar disorder, psychiatric disease such as psychotic disorders,
attention-deficit/hyperactivity disorder, Parkinson's disease,
memory impairment, Alzheimer's disease, dementia, delirium tremens,
neurodegeneration, neurotoxicity, ischemia comprising administering
to a mammal in need of such treatment or prevention, an effective
amount of a compound of the following formula I: ##STR29## but
excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine,
wherein R.sub.1 is methyl R.sub.2 and R.sub.3 are independently
selected from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is
##STR30## R.sub.6 and R.sub.7 which may be the same or different
are hydrogen or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR31## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound.
29. A method of claim 28 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
30. A method useful for treating or preventing inflammatory or
neuropathic pain comprising administering to a mammal in need of
such treatment or prevention, an effective amount of a compound
according to of the following formula I: ##STR32## but excluding
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R.sub.1 is methyl R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is ##STR33##
R.sub.6 and R.sub.7 which may be the same or different are hydrogen
or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR34## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound. and which compound
substantially does not penetrate the central nervous system.
31. A method of claim 30 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
32. A method of treating or preventing substance tolerance or
dependence, bulimia nervosa, anorexia nervosa, gambling dependence,
smoking dependence, sex dependence, substance withdrawal or
obsessive compulsive disorders comprising administering to a mammal
in need of such treatment or prevention, an effective amount of a
compound of the following formula I: ##STR35## but excluding
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R.sub.1 is methyl R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is ##STR36##
R.sub.6 and R.sub.7 which may be the same or different are hydrogen
or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR37## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound.
33. A method of claim 32 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
34. A method for treating or preventing alcohol, nicotine, cocaine,
amphetamine, benzodiazepine, opiate or alcohol abuse or addiction
comprising administering to a mammal in need of such treatment or
prevention, an effective amount of a compound of the following
formula I: ##STR38## but excluding
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R.sub.1 is methyl R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is ##STR39##
R.sub.6 and R.sub.7 which may be the same or different are hydrogen
or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR40## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound.
35. A method of claim 34 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
36. A method for treating or preventing anxiety, panic disorder,
phobia, posttraumatic stress disorder, generalized anxiety
disorder, acute stress disorder comprising administering to a
mammal in need of such treatment or prevention, an effective amount
of a compound of the following formula I: ##STR41## but excluding
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R.sub.1 is methyl R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is ##STR42##
R.sub.6 and R.sub.7 which may be the same or different are hydrogen
or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR43## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound.
37. A method of claim 36 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
38. A method for treating or preventing migraine comprising
administering to a mammal in need of such treatment or prevention,
an effective amount of a compound according to the following
formula I: ##STR44## but excluding
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R.sub.1 is methyl R.sub.2 and R.sub.3 are independently selected
from hydrogen, halogen, nitro, C1-C6-alkyl; R.sub.4 is ##STR45##
R.sub.6 and R.sub.7 which may be the same or different are hydrogen
or a group of formula: --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen, C1-C6-alkyl,
halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or
heteroaryl-C1-C6-alkyl; R.sub.5 represents a group of formula
##STR46## wherein R.sub.9, R.sub.10, R.sub.11, R.sub.12 and
R.sub.13 independently are hydrogen, halogen, cyano, nitro,
C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or
carboxyaryl; R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; or pharmaceutically acceptable salts,
hydrates or solvates of such compound.
39. A method of claim 38 wherein the administered compound is
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine.
Description
[0001] Extensive literature exists relating to pyridine compounds
however there is very little data concerning
3-amino-2-arylalkynyl-, 3-amino-2-heteroarylalkynyl-pyridine
derivatives which are agents of the invention. The present
invention relates to substituted 3-amino arylalkynyl-pyridines and
3-amino heteroarylalkynyl-pyridines.
[0002] U.S. Pat. No. 6,384,235B2 and Rodriguez et al. Angewandte
Chemie, International Edition 2000, 39, 14, 2488-2490 describes
3-amino-(2-phenylethynyl)pyridine as synthetic intermediates. WO
99/40091 discloses certain 3-amino-(2-phenylethynyl) pyridines as
synthetic intermediates which are subsequently ring closed.
[0003] WO 99/02497 describes certain 2-heteroalkynyl pyridines as
modulating mGluRs and a very broad generic disclosure. However,
none of the specifically disclosed compounds are 3-amino-2-aryl or
heteroaryl ethynyl pyridines. WO 02/46166 describes various
compounds having the structure phenyl-A-B as mGluR antagonists but
it has no disclosure of phenyl ethynylpyridines. The already known
structure in the field of mGluR5 ligands like
2-methyl-6-(phenylethynyl)-pyridine (MPEP) suffer from poor
bioavailability and selectivity (R. Kuhn et al. Amino Acids, 2002,
23, 207-211; N. D. P. Cosford et al. J. Med. Chem. 2003, 46,
204-206).
[0004] U.S. Pat. No. 6,187,777 describes the compound
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine as a
synthetic intermediate for compounds to modulate feeding
behaviour.
[0005] It has now surprisingly been found that amino pyridine
compounds of the invention show potent activity and selectivity on
mGluR5 receptor and demonstrate advantageous properties over
compounds of the prior art. Improvements have been observed in one
or more of the following characteristics of the compounds of the
invention: the selectivity for the target, the solubility, the
bioavailability, the brain penetration, the activity in behavioural
models of psychiatric and neurological disorders. They can be used
in the treatment or prevention of mGluR5 mediated disorders.
[0006] L-glutamate is the main excitatory neurotransmitter in the
mammalian brain and acts through two heterogeneous families of
receptors: ionotropic and metabotropic glutamate receptors (mGluR)
(Nakanishi S et al. 1998, Brain Res Brain Res Rev., 26:230-235). To
date eight subtypes of mGluR have been cloned and classified into
three groups on the basis of sequence similarities and
pharmacological properties.
[0007] mGluR1 and mGluR5 belong to group I and initiate cellular
responses through a G-protein mediated mechanism and are coupled to
phospholipase C and stimulate phosphoinositide hydrolysis (Schoepp
D D et al. 1999, Neuropharmacology, 38:1431-1476).
[0008] The mGluR5 receptor protein has been localized peripherally
in structures involved in nociceptive transmission and recent
findings suggest that mGluR5 antagonists can be used for the
treatment of inflammatory and neuropathic pain, chronic and acute
pain (B. A. Chizh in Amino Acids 2002, 23, 169-176).
[0009] mGluR5 receptors are also abundant in CNS throughout cortex,
hippocampus, caudate-putamen and nucleus accumbens. As these brain
areas are thought to be involved in emotional and motivational
processes, the mGluR5 receptor has been considered a potential drug
target for treatment of psychiatric and neurological disorders.
Treatable diseases are psychosis, epilepsy, schizophrenia,
Alzheimer's disease, cognitive disorders, memory deficits,
Parkinson's disease, hypoxia, ischemia, dementia caused by AIDS,
migraine, depression, mood disorders and anxiety disorders. Other
treatable indications are nicotine, cocaine, amphetamine,
benzodiazepine, opiate or alcohol abuse or addiction and substance
tolerance or dependence, bulimia nervosa, anorexia nervosa,
gambling dependence, smoking, sex dependence or obsessive
compulsive disorders (Brauner-Osborne H et al., 2000, J Med Chem.
43:2609-45; Bordi F and Ugolini A. 1999, Prog Neurobiol. 59:55-79;
Spooren W et al. 2003, Behav Pharmacol: 14:257-77).
[0010] The present invention relates to a method of treating or
preventing a condition in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of mGluR5 antagonists.
[0011] The present invention is concerned with novel aminopyridine
derivatives, and their uses, which conform to the general formula
##STR2##
[0012] wherein
[0013] R.sub.1 is methyl
[0014] R.sub.2 and R.sub.3 are independently selected from
hydrogen, halogen, nitro, C.sub.1-C.sub.6-alkyl;
[0015] R.sub.4 is ##STR3##
[0016] R.sub.6 and R.sub.7 which may be the same or different are
hydrogen or a group of formula: [0017] --X--R.sub.8 wherein X is
.dbd.CH--N(R.sub.8).sub.2 and R.sub.8 is hydrogen,
C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, aryl,
aryl-C.sub.1-C.sub.6-alkyl, heteroaryl or
heteroaryl-C.sub.1-C.sub.6-alkyl;
[0018] R.sub.5 represents a group of formula ##STR4##
[0019] wherein
[0020] R.sub.9, R.sub.10, R.sub.11, R.sub.12 and R.sub.13
independently are hydrogen, halogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkoxy, carboxy-C.sub.1-C.sub.6-alkyl or
carboxyaryl;
[0021] R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above; [0022] or pharmaceutically acceptable
salts, hydrates or solvates of such compounds for the prevention or
treatment of central nervous system (CNS) disorders as well as
other disorders modulated by mGluR5 receptors.
[0023] The compound
3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine as such is
disclaimed from the invention.
[0024] In the above definition, the term "C.sub.1-C.sub.6-alkyl"
includes groups such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
tert-pentyl, hexyl or the like. "Hydroxy-C.sub.1-C.sub.6-alkyl"
includes groups such as hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl
and the like. "C.sub.1-C.sub.6-alkoxy" includes groups such as
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
tert-butoxy, pentyloxy, hexyloxy or the like.
[0025] "Halogen" includes atoms such as fluorine, chlorine and
iodine. "Halo-C.sub.1-C.sub.6-alkyl" includes groups such as
chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, bromomethyl, 1-chloroethyl,
1,1-dichloroethyl, 2-chloroethyl, 2,2,2-trichloroethyl,
1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl, 3-chloropropyl, 3-fluoropropyl,
3-bromopropyl and the like. "Halo-C.sub.1-C.sub.6-alkoxy" includes
groups such as chloromethoxy, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and the
like.
[0026] "Carboxy-C.sub.1-C.sub.6-alkyl" includes groups such as
carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl,
5-carboxypenthyl, 6-carboxyhexyl or the like.
[0027] "Aryl" includes C.sub.6-C.sub.10 aryl groups such as phenyl,
1-naphtyl, 2-naphtyl and the like.
[0028] "Heteroaryl" includes 5-10 membered heterocyclic groups
containing 1 to 4 heteroatoms selected from oxygen, nitrogen or
sulphur to form a ring such as furyl (furan ring), benzofuranyl
(benzofuran), thienyl (thiophene), benzothiophenyl
(benzothiophene), pyrrolyl (pyrrole ring), imidazolyl (imidazole
ring), pyrazolyl (pyrazole ring), thiazolyl (thiazole ring),
isothiazolyl (isothiazole ring), triazolyl (triazole ring),
tetrazolyl (tetrazole ring), pyridil (pyridine ring), pyrazynyl
(pyrazine ring), pyrimidinyl (pyrimidine ring), pyridazinyl
(pyridazine ring), indolyl (indole ring), isoindolyl (isoindole
ring), benzoimidazolyl (benzimidazole ring), purinyl group (purine
ring), quinolyl (quinoline ring), phtalazinyl (phtalazine ring),
naphtyridinyl (naphtyridine ring), quinoxalinyl (quinoxaline ring),
cinnolyl (cinnoline ring), pteridinyl (pteridine ring), oxazolyl
(oxazole ring), isoxazolyl (isoxazole ring), benzoxazolyl
(benzoxazole ring), furazanyl (furazan ring) and the like.
[0029] "Heteroaryl-C.sub.1-C.sub.6-alkyl" includes groups wherein
examples of heteroaryl are the same as those illustrated in the
above definition, such as 2-furylmethyl, 3-furylmethyl,
2-thienylmethyl, 3-thienylmethyl, 2-imidazolylmethyl,
2-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,
4-pyridylmethyl, 2-quinolylmethyl and the like.
[0030] Preferred compounds of the present invention are compounds
of formula I-A depicted below ##STR5##
[0031] wherein
[0032] R.sub.2 and R.sub.3 are independently selected from
hydrogen, C.sub.1-C.sub.6-alkyl;
[0033] R.sub.5 represents a group of formula ##STR6##
[0034] wherein
[0035] R.sub.9, R.sub.10, R.sub.11, R.sub.12 and R.sub.13
independently are hydrogen, halogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, carboxy-C.sub.1-C.sub.6-alkyl or
carboxyaryl;
[0036] R.sub.14 and R.sub.15 independently are as defined for
R.sub.9-R.sub.13 above;
[0037] or pharmaceutically acceptable salts, hydrates or solvates
of such compounds.
[0038] More preferred compounds of the present invention are
compounds of formula I-B ##STR7##
[0039] wherein
[0040] R.sub.2 and R.sub.3 are independently selected from
hydrogen, C.sub.1-C.sub.6-alkyl;
[0041] R.sub.9, R.sub.10, R.sub.11, R.sub.12 and R.sub.13
independently are hydrogen, halogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, carboxy-C.sub.1-C.sub.6-alkyl or
carboxyaryl;
[0042] or pharmaceutically acceptable salts, hydrates or solvates
of such compounds.
[0043] Particularly preferred compounds of the present invention
are compounds of formula I-C ##STR8## wherein
[0044] R.sub.2 and R.sub.3 are independently selected from
hydrogen, C.sub.1-C.sub.6-alkyl;
[0045] R.sub.14 and R.sub.15 independently are hydrogen, halogen,
cyano, nitro, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, carboxy-C.sub.1-C.sub.6-alkyl or
carboxyaryl;
[0046] or pharmaceutically acceptable salts, hydrates or solvates
of such compounds.
[0047] Specifically preferred compounds are:
[0048] (6-Methyl-2-phenylethynyl-pyridin-3-yl)amine
[0049]
N,N-Dimethyl-N'-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidin-
e
[0050] (2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
[0051] (2-(3-Methoxy-phenylethynyl)-6-methyl-pyridin-3-yl)amine
[0052] (6-Methyl-2-pyridin-3-ylethynyl-pyridin-3-yl )amine
[0053] (2-(4-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
[0054]
(2-(3,5-Difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
[0055]
(2-(5-Fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
[0056] 3-(3-Amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile
[0057]
(2-(5-Chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
[0058] (2-(3-Chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
[0059]
(2-(3-Fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine
[0060]
(2-(3-Chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine
[0061] The present invention relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula (I) or
compositions comprising compounds of formula (I) together with
pharmaceutically acceptable carriers or excipients.
[0062] The present invention relates to a method of treating or
preventing a condition in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of mGluR5 antagonists.
[0063] The present invention relates to a method useful for
treating or preventing peripheral and central nervous system
disorders selected from: substance tolerance or dependence, anxiety
disorders, depression, mood disorders, psychiatric disease such as
psychosis, inflammatory or neuropathic pain, memory deficits,
Alzheimer's disease, Parkinson's disease, migraine, ischemia, drug
abuse and addiction.
[0064] The present invention relates to pharmaceutical compositions
which provide from about 0.01 to 1000 mg of the active ingredient
per unit dose. The compositions may be administered by any suitable
route. For example orally in the form of capsules, etc.,
parenterally in the form of solutions for injection, topically in
the form of unguents or lotions, ocularly in the form of eye-drops,
rectally in the form of suppositories, intranasally or
transcutaneously in the form of delivery system like patches.
[0065] The pharmaceutical formulations of the invention may be
prepared by conventional methods in the art; the nature of the
pharmaceutical composition employed will depend on the desired
route of administration. The total daily dose usually ranges from
about 0.05-2000 mg.
[0066] The invention also provides for use of compounds or
compositions as defined above in the manufacture of medicaments for
treatment or prevention of the stated disorders.
[0067] The compounds of Formula I may be prepared by general routes
of synthesis as disclosed in the following methods.
[0068] Scheme 1 illustrates the preparation of compounds of formula
I by reacting an alkyne derivative, for example ethynylbenzene,
with a substituted aminopyridine (or a precursor), for example
2-bromo-6-methyl-pyridin-3-ylamine. Thus in Scheme 1, R.sub.1,
R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.7 are as defined above
and Q includes halides such as Cl, Br, I or
trifluoromethanesulfonyl and paratoluenesulfonyl. This general
route of synthesis has been described in M. H. Norman et al. J.
Med. Chem. 2000, 43, 4288-4312. ##STR9##
[0069] This palladium catalyzed C--C coupling reaction requires a
catalyst such as PdCl.sub.2(PPh.sub.3).sub.2, Pd(PPh.sub.3).sub.4,
Pd(OAc).sub.2 or Pd on carbon in a suitable solvent like DMF,
acetonitrile or benzene. Typically a co-catalyst such as copper(I)
iodide and a base (e.g., triethylamine, diisopropylamine, KOAc . .
. ) will also be present in the reaction mixture. The coupling
reaction typically proceeds by allowing the reaction temperature to
warm slowly from about 0.degree. up to ambient temperature, or
heated to a temperature anywhere between 30.degree. C. and
150.degree. C. The reaction mixture is then maintained at a
suitable temperature for a time in the range of about 1 up to 24
hours, with about 12 hours typically being sufficient. The product
from the reaction can be isolated and purified employing standard
techniques, such as solvent extraction, chromatography,
crystallization, distillation, sublimation, and the like.
[0070] In another embodiment of the present invention, depicted in
Scheme 2, an alkynyl-substituted aminopyridine (or a precursor) is
reacted with a compound bearing a reactive functional group Q as
defined above. ##STR10##
[0071] Thus, in Scheme 2, R.sub.1, R.sub.2, R.sub.3, R.sub.5,
R.sub.6, R.sub.7, Q, the catalysts and reaction conditions are as
described for Scheme 1.
[0072] Another embodiment of the present invention is illustrated
in Scheme 3. A substituted aminopyridine (or a precursor) is
reacted with an alkene derivative, as described in C. Niu et al.
Tetrahedron, 1998, 54, 6311-6318, in a manner similar to the
procedure presented for Scheme 1. ##STR11##
[0073] The alkene derivative product from Scheme 3 may be converted
to an alkyne derivative using the approach outlined in Scheme 4.
##STR12##
[0074] This synthetic route refers to the methods described in G.
R. Newkome et al. J. Org. Chem. 1980, 45, 4380-4385 or F. Gasparini
et al. Bioorg. Med. Chem. Lett. 2002, 12, 407-410. The alkene
derivatives may be treated with a halogenating agent such as
chlorine or bromine in CHCl.sub.3 or CCl.sub.4. The resulting
halogenated derivatives are then treated with a suitable base such
as NaOH, KOH or KO.sup.tBu, which promotes a double elimination
reaction to afford the alkyne. The reaction is carried out in a
solvent like ethanol, tert-butanol, THF, etc. at an appropriate
temperature, usually between 0.degree. C. and 150.degree. C.
[0075] In another embodiment of the present invention, a
substituted aminopyridine (or a precursor) is reacted with an
aldehyde to provide a substituted alkene following the procedure
developed in D. Guay et al. Bioorg. Med. Chem. Lett. 1998, 8,
453-458. (Scheme 5) ##STR13##
[0076] Thus, in Scheme 5, G is PR.sub.3 or P(O)(OR).sub.2. The
reaction is carried out with suitable catalysts including bases
such as KH, NaH, n-butyllithium etc., in THF, acetonitrile,
benzene, etc., at an appropriate temperature, usually between about
0.degree. C. and 150.degree. C.
[0077] In yet another embodiment of the present invention, a
substituted heterocyclic aldehyde is reacted with a compound
containing an activated methylene to provide a substituted alkene
following the procedure developed in M. Cushman et al. J. Med.
Chem. 1991, 34, 2579-2588. (Scheme 6) ##STR14##
[0078] Thus, in Scheme 6, G, the catalysts and reaction conditions
are as described for Scheme 5.
[0079] The alkene products from the reactions in Scheme 5 and
Scheme 6 may be converted to an alkyne derivative using reagents
and conditions as described for Scheme 4.
[0080] Substituted aminopyridines of formula I-A can be obtained
from the corresponding nitropyridine compounds by a selective
reduction of the nitro moiety with the method described in S. Glase
et al. J. Med. Chem. 1996, 39, 3179-3187, using a mixture of Fe and
aqueous HCl as the reducing agent.
[0081] The reactions described in scheme 1 to 6 can lead to free
amino compounds when R.sub.6 and R.sub.7 are hydrogen. A subsequent
functionalisation into amidine compounds of the invention can be
performed according to standard methods familiar to those skilled
in the art of converting free amino derivatives.
[0082] The compounds of Formula I which are basic in nature can
form a wide variety of different pharmaceutically acceptable salts
with various inorganic and organic acids. These salts are readily
prepared by treating the base compounds with a substantially
equivalent amount of the chosen mineral or organic acid in a
suitable organic solvent such as methanol, ethanol or
isopropanol.
[0083] Pharmacology
[0084] Some of the compounds of Formula I have been tested
according to the following methods.
[0085] mGluR5 Binding Assay
[0086] Affinity of compounds of the invention was examined
following a radioligand binding technique using whole rat brain and
tritiated 2-methyl-6-(phenylethynyl)-pyridine ([.sup.3H]-MPEP) as a
ligand following similar methods to those described in F. Gasparini
et al. Bioorg. Med. Chem. Lett. 2002, 12, 407-409 and in J. F.
Anderson et al. J. Pharmacol. Exp. Ther. 2002, 303, 3,
1044-1051.
[0087] Membrane Preparation:
[0088] Cortices were dissected out from brains of 200-300 g
Sprague-Dawley rats (Charles River Laboratories, L'Arbresle,
France). Tissues were homogenized in 10 volumes (vol/wt) of
ice-cold 50 mM Hepes-NaOH (pH 7.4) using a Polytron disrupter
(Kinematica AG, Luzern, Switzerland) and centrifuged for 30 min at
40,000 g. (4.degree. C.). The supernatant was discarded and the
pellet washed twice by resuspension in 10 volumes 50 mM HEPES-NaOH.
Membranes were then collected by centrifugation and washed before
final resuspension in 10 volumes of 20 mM HEPES-NaOH, pH 7.4.
Protein concentration was determined by the Bradford method
(Bio-Rad protein assay, Reinach, Switzerland) with bovine serum
albumin as standard.
[0089] [.sup.3H]-MPEP Binding Experiments:
[0090] Membranes were thawed and resuspended in binding buffer
containing 20 mM HEPES-NaOH, 3 mM MgCl.sub.2, 100 mM NaCl, pH 7.4.
Competition studies were carried out by incubating for 1 h at
4.degree. C.: 3 nM [.sup.3H]-MPEP (46,85 Ci/mmol, Tocris, Cookson
Ltd, Bristol, U.K.), 50 .mu.g membrane and a concentration range of
0.03 nM-30 .mu.M of compounds, for a total reaction volume of 300
.mu.l. The non-specific binding was defined using 30 .mu.M MPEP.
Reaction was terminated by rapid filtration over glass-fiber filter
plates (Unifilter 96-well GF/B filter plates, Perkin-Elmer,
Schwerzenbach, Switzerland) using 4.times.400 .mu.l ice cold buffer
using cell harvester (Filtermate, Perkin-Elmer, Downers Grove,
USA). Radioactivity was determined by liquid scintillation
spectrometry using a 96-well plate reader (TopCount, Perkin-Elmer,
Downers Grove, USA).
[0091] Data Analysis:
[0092] The inhibition curves were generated using the Prism
GraphPad program (Graph Pad Software Inc, San Diego, USA). IC50
determinations were made from data obtained from 8 point
concentrations response curves using a nonlinear regression
analysis.
[0093] The compounds of this application as measured in the assay
described above have IC50 values in the range of less than 10
.mu.M. Preferred compounds include the examples n.degree. 3, 7, 10,
12 and 13 which have IC50 values of less than 30 nM.
[0094] In-Vitro Selectivity Profile
[0095] Compounds of the invention show an improved selectivity on
mGluR5 receptor.
[0096] This indicates a greater specificity and a better safety
profile.
[0097] In-Vivo
[0098] Compounds of the invention are effective in models
demonstrating the usefulness of the compounds for treating
neuropathic inflammatory pain (B. A. Chizh, Amino Acids 2002, 23,
169-176), anxiety (W. P. J. M. Spooren et al. J. Pharmacol. Exp.
Ther. 2000, 295, 3, 1267-1275; W. P. J. M. Spooren et al. Eur. J.
Pharmacol. 2002, 435, 161-170), Parkinson disease (N. Breysse et
al. J. Neurosci. 2003, 10, 23, 23, 8302-8309), migraine (P. De
Vries et al. 1999, 375, 61-74), depression (I. A. Paul and P.
Skolnick, Ann. N Y Acad. Sci. 2003, 1003, 250-72) and addictive
disorders (N. E. Paterson et al. Psychopharmacology 2003, 167,
257-264; C. Chiamulera et al. Nature Neurosci. 2001, 4, 9,
873-874).
[0099] The compounds of the present invention present a high
selectivity and affinity for mGluR5 receptor. As functional
antagonists, they are useful for the production of medications,
especially for the treatment or prevention of central nervous
system disorders as well as other disorders modulated by this
receptor.
[0100] Reasonable variations are not to be regarded as a departure
from the scope of the invention. It will be obvious that the thus
described invention may be varied in many ways by those skilled in
the art.
[0101] The following non-limiting examples are intending to
illustrate the invention. The physical data given for the compounds
exemplified are consistent with the assigned structure of those
compounds.
EXAMPLES
[0102] Unless otherwise noted, all starting materials were obtained
from commercial suppliers and used without further
purification.
[0103] Specifically, the following abbreviations may be used in the
examples and throughout the specification. TABLE-US-00001 .sup.1H
(proton) CHCl.sub.3 (chloroform) CuI (copper iodide) DCM
(dichloromethane) dec. (decomposition) DMSO[D.sub.6] (deuterated
dimethylsulfoxyde) h (hour) LC-MS (Liquid Chromatography Mass
Spectrometry) M (molar) MeOH (methanol) mg (milligrams) MHz
(megahertz) ml (milliliters) .mu.l (microliters) .mu.mol
(micromoles) mmol (millimoles) M.p. (melting point) NH.sub.4OH
(ammonium hydroxide) NaOH (sodium hydroxide) Na.sub.2SO.sub.4
(sodium sulphate) NMR (Nuclear Magnetic Resonance) PBr.sub.3
(Phosphorus tribromide) PdCl.sub.2(PPh.sub.3).sub.2
(Bis(triphenylphosphine) palladium (II) dichloride RT (Retention
Time)
[0104] All reactions are conducted under an inert atmosphere at
room temperature unless otherwise noted.
[0105] .sup.1H NMR spectra were recorded either on a Bruker ARX400
or on a Bruker 500 MHz. Chemical shifts are expressed in parts per
million (ppm, .delta. units). Coupling constants are in units of
hertz (Hz) Splitting patterns describe apparent multiplicities and
are designated as s (singulet), d (doublet), t (triplet), q
(quartet) and m (multiplet).
[0106] LC-MS spectra were recorded on a Waters Micromass ZQ 2996
system by the following conditions: Column 3.0*50 mm stainless
steel packed with 5 .mu.m XTerra RP C-18; flow rate 0.8 ml/min;
mobile phase: A phase=0.07% formic acid in water, B phase=0.07%
formic acid in acetonitrile. 0-0.5 min (A: 95%, B: 5%), 0.5-6.0 min
(A: 0%, B: 100%), 6.0-6.5 min (A: 95%, B: 5%), 6.5-7 min (A: 95%,
B: 5%); UV detection Diode Array: 200-400 nm; Injection volume: 5
.mu.l. All mass spectra were taken under electrospray ionisation
(ESI) methods.
[0107] Melting point determination was performed on a Buchi B-540
apparatus.
[0108] The reactions were monitored by thin-layer chromatography on
0.20 mm silica gel plates (60F.sub.254, Merck or G/UV.sub.254
Macherey Nagel) and visualized with UV light. Flash column
chromatography was performed on silica gel (220-440 mesh,
Fluka).
Example 1
(6-Methyl-2-phenylethynyl-pyridin-3-yl)amine hydrochloride
[0109] To a solution of Cul (10 mg, 50 .mu.mol) in triethylamine (5
ml) were added (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07
mmol) and (PPh.sub.3).sub.2PdCl.sub.2 (36 mg, 50 .mu.mol). The
reaction mixture was cooled to 0.degree. C. and phenylacetylene
(176 .mu.l, 1.60 mmol) was added. The reaction mixture was allowed
to warm to room temperature and then heated under reflux for 14 h.
The solvent was evaporated and the crude residue was purified by
flash chromatography (hexane/ethyl acetate 4:1) to yield 105 mg
(0.50 mmol, 47%) of (6-methyl-2-phenylethynyl-pyridin-3-yl)amine as
a yellow solid.
[0110] R.sub.f: 0.09 (Hexane/ethyl acetate 4:1). M. p.:
154-155.degree. C. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.: 2.47
(s, 3 H), 4.13-4.17 (br. s, 2 H), 6.93-7.01 (2 H), 7.34-7.39 (3 H),
7.57-7.63 (2 H).
[0111] (6-methyl-2-phenylethynyl-pyridin-3-yl)amine (105 mg, 0.50
mmol) was dissolved in CHCl.sub.3 (2 ml) and treated with 1.56 ml
(1.25 mmol) of 0.8 M hydrochloric acid solution in diethyl ether.
After evaporation of the solvent and trituration of the residue
with ethyl acetate, 107 mg (0.44 mmol, 87%) of the title
hydrochloride were obtained as a yellowish solid.
[0112] R.sub.f: 0.50 (Hexane/ethyl acetate 1:1). M. p.: 183.degree.
C. .sup.1H NMR (DMSO[D.sub.6], 400 MHz) .delta.: 2.57 (s, 3 H),
3.20-4.00 (br. s, 3 H), 7.51-7.57 (4 H), 7.71 (d, J=8.8 Hz, 1 H),
7.80-7.84 (2 H). LC-MS (RT): 2.14 min.; MS (ES+) gave m/z:
209.1.
Example 2
N,N-Dimethyl-N'-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidine
[0113] A solution of N,N-dimethylformamidedimethylacetal (80 .mu.l,
0.60 mmol) and (6-methyl-2-phenylethynyl-pyridin-3-yl)amine (102
mg, 0.49 mmol) from Example 1, in toluene (1 ml) was heated for 20
h, at 80.degree. C. The solvent was evaporated and the residue was
purified by flash chromatography (hexane/ethyl acetate 4:1) to give
24 mg (0.09 mmol, 15%) of
N,N-dimethyl-N'-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidi-
ne as a yellow oil.
[0114] R.sub.f: 0.17 (Hexane/ethyl acetate 4:1). .sup.1H NMR
(DMSO[D.sub.6], 400 MHz) .delta.: 2.42 (s, 3 H), 3.05 (s, 3 H),
3.07 (s, 3 H), 7.14 (d, J=8.8 Hz, 1 H), 7.32 (d, J=8.8 Hz, 1 H),
7.44-7.58 (4 H), 7.87 (s, 1 H), 7.93 (d, J=7.2 Hz, 1 H). LC-MS
(RT): 0.61 min.; MS (ES+) gave m/z: 264.1.
Example 3
(2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
hydrochloride
[0115] Following the same procedure as described in Example 1,
(2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted
with (PPh.sub.3).sub.2PdCl.sub.2 (36 mg, 0.05 mmol), Cul (10 mg,
0.05 mmol) and 1-ethynyl-3-fluorobenzene (148 .mu.l, 1.28 mmol) in
triethylamine (5 ml). The crude residue was purified by flash
chromatography (hexane/ethyl acetate 4:1) to yield 145 mg (0.64
mmol, 60%) of
(2-(3-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a pale
yellow solid. The hydrochloride of
(2-(3-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield 148 mg (0.56 mmol, 88%)
of the title hydrochloride as a yellow solid.
[0116] R.sub.f: 0.52 (Hexane/ethyl acetate 1:1). M. p.:
199-200.degree. C. (dec.). .sup.1H NMR (DMSO[D.sub.6], 400 MHz)
.delta.: 2.52 (s, 3 H), 6.20-7.24 (br. s, 2 H), 7.35-7.43 (m, 1 H),
7.48 (d, J=8.0 Hz, 1 H), 7.52-7.61 (2 H), 7.62-7.67 (m, 1 H),
7.68-7.72 (m, 1 H). LC-MS (RT): 2.26 min.; MS (ES+) gave m/z:
227.1. Anal. Calcd for C.sub.14H.sub.12ClFN.sub.2: C, 64.01%; H,
4.60%; Cl, 13.50%; F, 7.23%; N, 10.66%. Found: C, 63.30%; H, 4.62%;
Cl, 13.56%; F, 6.98%; N, 10.57%.
Example 4
(2-(3-Methoxy-phenylethynyl)-6-methyl-pyridin-3-yl)amine
[0117] Following the same procedure as described in Example 1,
(2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted
with (PPh.sub.3).sub.2PdCl.sub.2 (37 mg, 0.05 mmol), Cul (10 mg,
0.05 mmol) and 1-ethynyl-3-methoxy-benzene (204 .mu.l, 1.60 mmol)
in triethylamine (5 ml) during 1.5 h. The crude residue was
purified by flash chromatography (hexane/ethyl acetate 4:1) to
yield 118 mg (0.50 mmol, 46%) of
(2-(3-methoxy-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a
yellow brown solid.
[0118] R.sub.f: 0.30 (Hexane/ethyl acetate 1:1). M. p.:
165-166.degree. C. .sup.1H NMR (DMSO[D.sub.6], 400 MHz) .delta.:
2.60 (s, 3 H), 3.85 (s, 3 H), 7.11-7.16 (m, 1 H), 7.37-7.49 (3 H),
7.56 (d, J=8.4 Hz, 1 H), 7.77 (d, J=8.8 Hz, 1 H). LC-MS (RT): 2.31
min.; MS (ES+) gave m/z: 239.1.
Example 5
(6-Methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine
hydrochloride
[0119] Following the same procedure as described in Example 1,
(2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted
with (PPh.sub.3).sub.2PdCl.sub.2 (37 mg, 0.05 mmol), Cul (10 mg,
0.05 mmol) and 3-ethynyl-pyridine (110 mg, 1.07 mmol) in
triethylamine (1.6 ml). The crude residue was purified by flash
chromatography (DCM-DCM/MeOH 97:3) to yield 100 mg (0.48 mmol, 49%)
of (6-methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine as a yellow
powder. The hydrochloride of
(6-methyl-2-pyridin-3-ylethynyl-pyridin-3-yl)amine was prepared as
described in Example 1 to yield after trituration with pentane 145
mg (100%) of the title hydrochloride as a yellow solid.
[0120] M. p.: 156.4-158.degree. C. .sup.1H NMR (DMSO[D.sub.6], 500
MHz) .delta.: 2.54 (s, 3 H), 7.52 (d, J=9 Hz, 1 H), 7.61-7.68 (m, 1
H), 7.69 (d, J=9.0, 1 H), 8.25 (d, J=7.5, 1 H), 8.68-8.86 (br. s, 1
H), 8.93-9.15 (br. s, 1 H). LC-MS (RT): 0.65 min.; MS (ES+) gave
m/z: 210.1.
Example 6
(2-(4-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
hydrochloride
[0121] Following the same procedure as described in Example 1,
(2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted
with (PPh.sub.3).sub.2PdCl.sub.2 (36 mg, 0.05 mmol), Cul (10 mg,
0.05 mmol) and 1-ethynyl-4-fluorobenzene (184 .mu.l, 1.07 mmol) in
triethylamine (5 ml). The crude residue was purified by flash
chromatography (hexane/ethyl acetate 7:3) to yield 164 mg (0.72
mmol, 68%) of
(2-(4-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow
solid. The hydrochloride of
(2-(4-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield after trituration with
ethyl acetate 154 mg (0.51 mmol, 71%) of the title hydrochloride as
a yellow solid.
[0122] R.sub.f: 0.43 (hexane/ethyl acetate 1:1). M. p.: 122.degree.
C. (dec.). .sup.1H NMR (DMSO[D.sub.6], 400 MHz) .delta.: 2.53 (s, 3
H), 4.45-5.54 (br. s, 2 H), 7.36-7.43 (2 H), 7.52 (d, J=8.8 Hz, 1
H), 7.67 (d, J=8.8 Hz, 1 H), 7.82-7.89 (2 H). LC-MS (tr): 2.24
min.; MS (ES+) gave m/z: 227.1.
Example 7
(2-(3,5-Difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
hydrochloride
[0123] Following the same procedure as described in Example 1,
(2-bromo-6-methyl-pyridin-3-yl)amine (800 mg, 4.28 mmol) reacted
with (PPh.sub.3).sub.2PdCl.sub.2 (150 mg, 0.21 mmol), Cul (41 mg,
0.21 mmol) and ethynyltrimethylsilane (840 mg, 8.55 mmol) in
triethylamine (30 ml). The crude residue was purified by flash
chromatography (hexane/ethyl acetate 8:2) to yield 330 mg (1.61
mmol, 38%) of
(6-methyl-2-trimethylsilanylethynyl-pyridin-3-yl)amine as a beige
solid.
[0124] (6-methyl-2-trimethylsilanylethynyl-pyridin-3-yl)amine (330
mg, 1.61 mmol) was dissolved in MeOH (3 ml) and cooled to 0.degree.
C., to the resulting solution was added 1 M solution of NaOH (1.6
ml). The ice bath was removed and the reaction mixture was stirred
at room temperature for 4 h. 90 .mu.l of acetic acid was added. The
reaction mixture was partially concentrated and the residue was
extracted with ethyl acetate. The organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to yield 160 mg (1.21 mmole, 75%) of
(2-ethynyl-6-methyl-pyridin-3-yl)amine as a brown solid which was
used in the next step without further purification.
[0125] To a solution of Cul (4.3 mg, 23 .mu.mol) in triethylamine
(5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (60 mg,
0.45 mmol), (PPh.sub.3).sub.2PdCl.sub.2 (16 mg, 23 .mu.mol), and
1,3-difluoro-5-iodobenzene (109 mg, 0.45 mmol). The reaction
mixture was stirred at room temperature for 20 h. The solvent was
evaporated to afford a brown oil which was taken up in DCM and the
solution was washed with water. The aqueous phase was extracted
twice with DCM. The organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was
purified by flash chromatography (hexane/ethyl acetate 7:3) to
yield 64 mg (0.26 mmol, 58%) of
(2-(3,5-difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a
yellow solid.
[0126] The hydrochloride of
(2-(3,5-difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield after trituration with
diethyl ether 64 mg (0.20 mmol, 78%) of the title hydrochloride as
a yellow powder.
[0127] R.sub.f: 0.61 (hexane/ethyl acetate 1:1). M.p.: 212.degree.
C. (dec.). .sup.1H NMR (DMSO[D.sub.6], 400 MHz) .delta.: 2.49 (s, 3
H), 6.12-7.08 (br. s, 2 H), 7.44-7.55 (2 H), 7.56-7.68 (3 H).).
LC-MS (RT): 2.39 min.; MS (ES+) gave m/z: 245.0.
Example 8
(2-(5-Fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
hydrochloride
[0128] To a solution of Cul (11 mg, 0.06 mmol) in triethylamine (5
ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (40 mg, 0.30
mmol, described in Example 7), (PPh.sub.3).sub.2PdCl.sub.2 (21 mg,
0.06 mmol), and 3-fluoro-5-iodopyridine (111 mg, 0.45 mmol). The
reaction mixture was stirred at room temperature for 14 h. The
solvent was evaporated. The crude residue was purified by flash
chromatography (cyclohexane/ethyl acetate 7:3) to yield 15 mg (66
.mu.mol, 22%) of
(2-(5-fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine as a
yellow solid.
[0129] The hydrochloride of
(2-(5-fluoro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield after trituration with
ethyl acetate 6 mg (20 .mu.mol, 30%) of the title hydrochloride as
a brown semi-solid.
[0130] R.sub.f: 0.31 (cyclohexane/ethyl acetate 7:3). LC-MS (RT):
1.71 min.; MS (ES+) gave m/z: 228.0.
Example 9
3-(3-Amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile
hydrochloride
[0131] To a solution of Cul (2.4 mg, 12 .mu.mol) in triethylamine
(4 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (33 mg,
0.33 mmol described in Example 7), (PPh.sub.3).sub.2PdCl.sub.2 (8.8
mg, 12 .mu.mol), and 3-iodobenzonitrile (57 mg, 0.25 mmol). The
reaction mixture was stirred at room temperature for 48 h. The
solvent was evaporated and the crude residue was purified by flash
chromatography (cyclohexane/ethyl acetate 1:1) to yield 16 mg (69
.mu.mol, 21%) of
3-(3-amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile as a pale
yellow solid.
[0132] The hydrochloride of
3-(3-amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile was prepared
as described in Example 1 to yield after trituration with diethyl
ether 10 mg (33 .mu.mol, 47%) of the title hydrochloride as a
yellow powder.
[0133] R.sub.f: 0.36 (hexane/ethyl acetate 1:1). M. p.:
132.4-134.degree. C. LC-MS (RT): 2.13 min.; MS (ES+) gave m/z:
234.1.
Example 10
(2-(5-Chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine
hydrochloride
[0134] Following the same procedure as described in Example 1,
(2-bromo-6-methyl-pyridin-3-yl)amine (150 mg, 0.80 mmol) reacted
with (PPh.sub.3).sub.2PdCl.sub.2 (28 mg, 40 .mu.mol), Cul (8 mg, 40
.mu.mol) and 3-chloro-5-ethynyl-pyridine (165 mg, 1.20 mmol) in
triethylamine (5 ml). The crude residue was purified by flash
chromatography (hexane/ethyl acetate 7:3) to yield 141 mg (0.58
mmol, 72%) of
(2-(5-chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine as a
yellow solid.
[0135] The hydrochloride of
(2-(5-chloro-pyridin-3-ylethynyl)-6-methyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield 152 mg (0.48 mmol, 83%)
of the title hydrochloride as a yellow solid.
[0136] R.sub.f: 0.12 (Hexane/ethyl acetate 1:1). M. p.: 193.degree.
C. (dec.). .sup.1H NMR (DMSO[D.sub.6], 400 MHz) .delta.: 2.59 (s, 3
H),), 5.81-7.41 (br. s, 2 H), 7.58 (d, J=8.8 Hz, 1 H), 7.73 (d,
J=8.8 Hz, 1 H), 8.43-8.44 (m, 1 H), 8.79 (d, J=1.6 Hz, 1 H), 8.89
(d, J=2.0 Hz, 1 H). LC-MS (RT): 2.03 min.; MS (ES+) gave m/z:
244.0.
Example 11
(2-(3-Chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine
hydrochloride
[0137] To a solution of Cul (5.0 mg, 28 .mu.mol) in triethylamine
(5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (75 mg,
0.57 mmol described in Example 7), (PPh.sub.3).sub.2PdCl.sub.2 (20
mg, 28 .mu.mol), and 1-chloro-3-iodobenzene (135 mg, 0.57 mmol).
The reaction mixture was stirred at room temperature for 4 h. The
solvent was evaporated to afford a brown oil which was taken up in
DCM and the solution was washed with water. The aqueous phase was
extracted twice with DCM. The organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was
purified by flash chromatography (hexane/ethyl acetate 7:3) to
yield 54 mg (0.22 mmol, 39%) of
(2-(3-chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow
solid.
[0138] The hydrochloride of
(2-(3-chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield after trituration with
diethyl ether 51 mg (0.16 mmol, 73%) of the title hydrochloride as
a yellow powder.
[0139] R.sub.f: 0.57 (hexane/ethyl acetate 1:1). M. p.: 195.degree.
C. (dec.). .sup.1H NMR (DMSO[D.sub.6], 400 MHz) .delta.: 2.51 (s, 3
H), 6.43-7.11 (br. s, 2 H), 7.50 (d, J=8.4 Hz, 1 H), 7.52-7.58 (m,
1 H), 7.59-7.69 (2 H), 7.72 (d, J=8.0 Hz, 1 H), 7.97 (s, 1 H).
LC-MS (RT): 2.54 min.; MS (ES+) gave m/z: 243.0. Anal. Calcd for
C.sub.14H.sub.12Cl.sub.2N.sub.2+0.5 H.sub.2O: C, 58.35%; H, 4.55%;
Cl, 24.61%; N, 9.72%. Found: C, 58.15%; H, 4.49%; Cl, 24.60%; N,
9.48%.
Example 12
(2-(3-Fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine
hydrochloride
[0140] To a solution of 1.80 g (11.0 mmol) of
2-chloro-4,6-dimethyl-pyridin-3-ylamine (prepared as described in
J. M. Klunder et al. J. Med. Chem., 35, 1992, 1887-1897) in toluene
(10 ml) was added PBr.sub.3 (18 ml). The reaction mixture was
stirred for 48 h under reflux. After cooling the reaction mixture,
it was poured onto ice, basified with NaOH 2 M solution (400 ml)
and the aqueous phase was extracted twice with ethyl acetate. The
combined organic phases were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was
purified by flash chromatography (cyclohexane/ethyl acetate 7:3) to
yield 2.31 g (38%) of 2-bromo-4,6-dimethyl-pyridin-3-ylamine
containing small amount of 2-chloro-4,6-dimethyl-pyridin-3-ylamine
as a yellow oil.
[0141] To a solution of Cul (41 mg, 0.2 mmol) in triethylamine (12
ml) were added 2-bromo-4,6-dimethyl-pyridin-3-ylamine (870 mg, 4.33
mmol), (PPh.sub.3).sub.2PdCl.sub.2 (152 mg, 0.22 mmol), and
1-ethynyl-3-fluorobenzene (500 .mu.l, 4.33 mmol). The reaction
mixture was stirred for 30 min. at room temperature and for 3 h
under reflux. The solvent was evaporated and the crude residue was
purified by flash chromatography (cyclohexane/ethyl acetate 4:1) to
yield 745 mg (3.10 mmol, 72%) of
(2-(3-fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine as a
brown solid.
[0142] The hydrochloride of
(2-(3-fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield after trituration with
pentane 680 mg (2.46 mmol, 79%) of the title hydrochloride as a
yellow powder.
[0143] R.sub.f: 0.37 (cyclohexane/ethyl acetate 7:3). M. p.:
210.degree. C. .sup.1H NMR (DMSO[D.sub.6], 500 MHz) .delta.: 2.33
(s, 3 H), 2.51 (s, 3 H), 6.31-6.72 (br. s, 3 H), 7.36-7.42 (m, 1
H), 7.47 (s, 1 H), 7.53-7.59 (m, 1 H), 7.60-7.63 (m, 1 H),
7.70-7.74 (m, 1 H). LC-MS (tr): 2.29 min.; MS (ES+) gave m/z:
241.1. Anal. Calcd for C.sub.15H.sub.14ClFN.sub.2: C, 65.10%; H,
5.10%; Cl, 12.81%; F, 6.87%; N, 10.12%. Found: C, 64.73%; H, 4.97%;
Cl, 12.78%; F, 6.71%; N 9.87%.
Example 13
(2-(3-Chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine
hydrochloride
[0144] To a solution of Cul (5.7 mg, 30 .mu.mol) in triethylamine
(1.6 ml) were added 2-bromo-4,6-dimethyl-pyridin-3-ylamine (120 mg,
0.60 mmol, described in Example 12), (PPh.sub.3).sub.2PdCl.sub.2
(21 mg, 30 .mu.mol), and 1-ethynyl-3-chlorobenzene (98 mg, 0.72
mmol). The reaction mixture was stirred for 30 min. at room
temperature and for 3 h under reflux. The solvent was evaporated
and the crude residue was purified by flash chromatography
(cyclohexane/ethyl acetate 4:1) to yield 39 mg (0.15 mmol, 25%) of
(2-(3-chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine as a
brown oil.
[0145] The hydrochloride of
(2-(3-chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine was
prepared as described in Example 1 to yield after trituration with
pentane 25 mg (85 .mu.mol, 57%) of the title hydrochloride as a
yellow powder.
[0146] R.sub.f: 0.37 (cyclohexane/ethyl acetate 7:3). M. p.:
204.degree. C. LC-MS (tr): 2.56 min.; MS (ES+) gave m/z: 257.0.
[0147] Typical examples of recipes for the formulation of the
invention are as follows:
[0148] 1) Tablets TABLE-US-00002 Compound of the example 3 5 to 50
mg Di-calcium phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium
stearate 5 mg Potato starch ad 200 mg
[0149] In this example, the compound of the example 3 can be
replaced by the same amount of any of the described examples 1 to
13.
[0150] 2) Suspension:
[0151] An aqueous suspension is prepared for oral administration so
that each 1 milliliter contains 1 to 5 mg of one of the described
example, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium
benzoate, 500 mg of sorbitol and water ad 1 ml.
[0152] 3) Injectable
[0153] A parenteral composition is prepared by stirring 1.5% by
weight of active ingredient of the invention in 10% by volume
propylene glycol and water.
[0154] 4) Ointment TABLE-US-00003 Compound of the example 3 5 to
1000 mg Stearyl alcohol 3 g Lanoline 5 g White petroleum 15 g Water
ad 100 g
[0155] In this example, the compound 3 can be replaced by the same
amount of any of the described examples 1 to 13.
[0156] Reasonable variations are not to be regarded as a departure
from the scope of the invention. It will be obvious that the thus
described invention may be varied in many ways by those skilled in
the art.
* * * * *