US2008004316A1PendingUtilityA1
Novel aminopyridine derivatives as mGluR5 antagonists
Est. expiryMar 4, 2023(expired)· nominal 20-yr term from priority
A61P 9/10A61P 43/00A61P 25/16A61P 25/28A61P 25/30A61P 25/14A61P 25/22A61P 25/18A61P 25/34A61P 29/00A61P 25/24A61P 25/00A61P 25/36A61P 25/32A61P 25/06A61P 25/04C07D 213/73C07D 213/74
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Claims
Abstract
The invention relates to novel aminopyridine derivatives of formula (I) wherein R1 is methyl an R 4 and amino group —NR 6 R 7 and R 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.
Claims
exact text as granted — not AI-modified1 - 14 . (canceled)
15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
wherein
R 2 and R 3 are independently selected from hydrogen, C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
wherein
R 2 and R 3 are independently selected from hydrogen, C1-C6-alkyl;
R 9 , R 10 , R 11 , R 12 and R 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:
wherein
R 2 and R 3 are independently selected from hydrogen, C1-C6-alkyl;
R 14 and R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
wherein
R 2 and R 3 are independently selected from hydrogen, C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
wherein
R 2 and R 3 are independently selected from hydrogen, C1-C6-alkyl;
R 9 , R 10 , R 11 , R 12 and R 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:
wherein
R 2 and R 3 are independently selected from hydrogen, C1-C6-alkyl;
R 14 and R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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:
but excluding 3-amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine, wherein
R 1 is methyl
R 2 and R 3 are independently selected from hydrogen, halogen, nitro, C1-C6-alkyl;
R 4 is
R 6 and R 7 which may be the same or different are hydrogen or a group of formula: —X—R 8 wherein X is ═CH—N(R 8 ) 2 and R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl or heteroaryl-C1-C6-alkyl;
R 5 represents a group of formula
wherein
R 9 , R 10 , R 11 , R 12 and R 13 independently are hydrogen, halogen, cyano, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, carboxy-C1-C6-alkyl or carboxyaryl;
R 14 and R 15 independently are as defined for R 9 -R 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.Join the waitlist — get patent alerts
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