IP Library › Granted Patent US 8,404,848

Granted Patent B2

US 8,404,848 · App. 12/711,779 · Granted Mar 26, 2013

Derivatives of imidazo[1,2-a]pyridine-2-carboxamides, preparation method thereof and use of same in therapeutics

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Quick Facts

Patent No.: US 8,404,848
App. No.: 12/711,779
Granted: Mar 26, 2013
Kind: B2

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Abstract

The present invention is related to a compound of formula (I): wherein R 1 , R 2 , R 3 , R 4 and X are as defined herein, or an addition salt with an acid thereof, its pharmaceutical composition or use for treating or preventing diseases involving Nurr-1 nuclear receptors, also known as NR4A2, NOT, TINUR, RNR-1 and HZF3.

Claims (372)

1. A method for treating multiple sclerosis, cerebral trauma, epilepsy, osteoporosis, Parkinson's disease, Alzheimer's disease, tauopathy, schizophrenia, depression, or substance dependence in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of formula (I):

wherein:

X is phenyl optionally substituted by one or more groups chosen, independently of one another, from the group consisting of halogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy, and NRaRb;

R 1 is hydrogen, halogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy, amino or NRcRd, wherein the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxyl, amino, or (C 1 -C 6 )alkoxy;

R 2 is hydrogen,

(C 1 -C 6 )alkyl optionally substituted by one or more groups chosen, independently of one another, from the group consisting of hydroxyl, halogen, amino, NRaRb and phenyl,

(C 1 -C 6 )alkoxy optionally substituted by one or more groups chosen, independently of one another, from the group consisting of hydroxyl, halogen, amino, and NRaRb,

(C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl,

(C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy,

(C 2 -C 6 )alkenyl,

(C 2 -C 6 )alkynyl,

—CO—R 5 ,

—CO—NR 6 R 7 ,

—CO—O—R 8 ,

—NR 9 —CO—R 10 ,

—NR 11 R 12 ,

halogen,

cyano, or

phenyl optionally substituted by one or more groups chosen, independently of one another, from the group consisting of halogen, (C 1 -C 6 )alkoxy, NRaRb, —CO—R 5 , —CO—NR 6 R 7 , —CO—O—R 8 , (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkyl optionally substituted by one or more hydroxyl or NRaRb;

R 3 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen;

R 4 is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or fluorine;

R 5 is hydrogen, phenyl or (C 1 -C 6 )alkyl;

R 6 and R 7 are independently hydrogen or (C 1 -C 6 )alkyl, or

R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring optionally including another heteroatom chosen from the group consisting of N, O and S;

R 8 is (C 1 -C 6 )alkyl;

R 9 and R 10 are independently hydrogen or (C 1 -C 6 )alkyl;

R 11 and R 12 are independently (C 1 -C 6 )alkyl, or

R 11 and R 12 , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring optionally including another heteroatom chosen from the group consisting of N, O and S;

Ra and Rb are independently hydrogen or (C 1 -C 6 )alkyl, or

Ra and Rb, taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring;

Rc is hydrogen; and

Rd is (C 1 -C 6 )alkyl;

provided that:

at least one of R 1 , R 2 , R 3 and R 4 is other than hydrogen,

when R 3 is methyl, then X is unsubstituted,

when R 1 is methyl, then X is unsubstituted, and

when R 2 is chlorine, then X is not a para-fluorophenyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein X is phenyl.

3. The method according to claim 1 , wherein R 1 , R 3 and R 4 are hydrogen.

4. The method according to claim 1 , wherein the compound of formula (I) is:

6-Chloro-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

8-Methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(Dimethylamino)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(1-Hydroxy-1-methylethyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

N-(4-Fluorophenyl)-6-isopropenylimidazo[1,2-a]pyridine-2-carboxamide,

6-Chloro-N-(2-chlorophenyl)imidazo[1,2-a]pyridine-2-carboxamide,

N,6-Diphenylimidazo[1,2-c]pyridine-2-carboxamide,

N-Phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide,

6-Ethyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-Ethynyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-[3-(1-Hydroxy-1-methylethyl)phenyl]-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-[Hydroxy(phenyl)methyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-Acetyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide hydrochloride (1:1),

6-Isopropyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(1-Hydroxyethyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-Acetamido-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(Dimethylamino)-5-methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

5-Methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

7-Methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Bromo-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Fluoro-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6,8-Difluoro-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Bromo-5-methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Iodo-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Cyano-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(Hydroxymethyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Methoxy-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

N-(4-fluorophenyl)-6-(1-hydroxy-1-methylethyl)imidazo[1,2-c]pyridine-2-carboxamide,

6-Benzoyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Isopropenyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Chloro-N-(3-fluorophenyl)imidazo[1,2-c]pyridine-2-carboxamide,

6-Chloro-N-(3-chlorophenyl)imidazo[1,2-c]pyridine-2-carboxamide,

6-Chloro-N-(3-methoxyphenyl)imidazo[1,2-c]pyridine-2-carboxamide,

6-Chloro-N[4-(dimethylamino)phenyl]imidazo[1,2-c]pyridine-2-carboxamide,

6-Chloro-N-(4-chlorophenyl)imidazo[1,2-c]pyridine-2-carboxamide,

6-[2-(Hydroxymethyl)phenyl]-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-[3-(Hydroxymethyl)phenyl]-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-[4-(Hydroxymethyl)phenyl]-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(2-Formylphenyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(3-Formylphenyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

5,6-Dimethyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

Methyl 3-[2-(anilinocarbonyl)imidazo[1,2-c]pyridin-6-yl]benzoate,

6-(3-Acetylphenyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(3-Fluorophenyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(4-Methylphenyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(3-Methoxyphenyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-[3-(Aminomethyl)phenyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(3-Chlorophenyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(3-Carbamoylphenyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-[3-(1-Hydroxyethyl)phenyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(3-Methylphenyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(Diethylamino)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide or its hydrochloride (1:1),

6-[3-(Methylcarbamoyl)phenyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide or its hydrochloride (1:1),

6-Carbamoyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide,

6-(Dimethylamino)-N-(3-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide,

N-(2,5-Difluorophenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-2-carboxamide,

N-(2,3-Difluorophenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-2-carboxamide,

6-(Dimethylamino)-N-(2-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide,

N-(3-Fluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

N-(3,5-Difluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

N-(2-Chlorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

6-[3-(Hydroxymethyl)phenyl]-N-(3-methylphenyl)imidazo[1,2-a]pyridine-2-carboxamide,

N-(2,5-Difluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

N-(2,3-Difluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

N-(2-Fluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

N-(5-Chloro-2-fluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

6-Morpholin-4-yl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide or its hydrochloride (1:1),

6-Azetidin-1-yl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Iodo-5-methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

N-(3,5-Difluorophenyl)-6-iodoimidazo[1,2-c]pyridine-2-carboxamide,

N-(3-Chlorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-c]pyridine-2-carboxamide,

N-(3,5-Difluorophenyl)-6-(dimethylamino)imidazo[1,2-c]pyridine-2-carboxamide,

N-(2-Chlorophenyl)-6-(dimethylamino)imidazo[1,2-c]pyridine-2-carboxamide,

6-(Dimethylamino)-N[3-(trifluoromethoxy)phenyl]imidazo[1,2-c]pyridine-2-carboxamide,

N-(3-Chloro-2-fluorophenyl)-6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide,

6-(Dimethylamino)-N-(3-methylphenyl)imidazo[1,2-c]pyridine-2-carboxamide,

N-(3-Chlorophenyl)-6-(dimethylamino)imidazo[1,2-c]pyridine-2-carboxamide,

N-(5-Chloro-2-fluorophenyl)-6-(dimethylamino)imidazo[1,2-c]pyridine-2-carboxamide,

N-(3-Chloro-2-fluorophenyl)-6-(dimethylamino)imidazo[1,2-c]pyridine-2-carboxamide,

N-[3-(Difluoromethoxy)phenyl]-6-(dimethylamino)imidazo[1,2-c]pyridine-2-carboxamide, or

6-(Dimethylamino)-N-[3-(trifluoromethyl)phenyl]imidazo[1,2-c]pyridine-2-carboxamide.

5. A method for treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound for treating Parkinson's disease of formula (I):

wherein:

R 2 is hydrogen,

(C 1 -C 6 )alkyl optionally substituted by one or more groups chosen, independently of one another, from the group consisting of hydroxyl, halogen, amino, NRaRb and phenyl,

(C 1 -C 6 )alkoxy optionally substituted by one or more groups chosen, independently of one another, from the group consisting of hydroxyl, halogen, amino, and NRaRb,

(C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl,

(C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkoxy,

(C 2 -C 6 )alkenyl,

(C 2 -C 6 )alkynyl,

—CO—R 5 ,

—CO—NR 6 R 7 ,

—CO—O—R 8 ,

—NR 9 —CO—R 10 ,

—NR 11 R 12 ,

halogen,

cyano, or

R 3 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen;

R 4 is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy or fluorine;

R 5 is hydrogen, phenyl or (C 1 -C 6 )alkyl;

R 6 and R 7 are independently hydrogen or (C 1 -C 6 )alkyl, or

R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring optionally including another heteroatom chosen from the group consisting of N, O and S;

R 8 is (C 1 -C 6 )alkyl;

R 9 and R 10 are independently hydrogen or (C 1 -C 6 )alkyl;

R 11 and R 12 are independently (C 1 -C 6 )alkyl, or

R 11 and R 12 , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring optionally including another heteroatom chosen from the group consisting of N, O and S;

Ra and Rb are independently hydrogen or (C 1 -C 6 )alkyl, or

Ra and Rb, taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring;

Rc is hydrogen; and

Rd is (C 1 -C 6 )alkyl;

provided that:

at least one of R 1 , R 2 , R 3 and R 4 is other than hydrogen,

when R 3 is methyl, then X is unsubstituted,

when R 1 is methyl, then X is unsubstituted, and

when R 2 is chlorine, then X is not a para-fluorophenyl;

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 5 , wherein X is phenyl.

7. The method according to claim 5 , wherein R 1 , R 3 and R 4 are hydrogen.

8. The method according to claim 5 , wherein the compound of formula (I) is:

6-Chloro-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

8-Methyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(Dimethylamino)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(1-Hydroxy-1-methylethyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

N-(4-Fluorophenyl)-6-isopropenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Chloro-N-(2-chlorophenyl)imidazo[1,2-c]pyridine-2-carboxamide,

N,6-Diphenylimidazo[1,2-c]pyridine-2-carboxamide,

N-Phenyl-6-vinylimidazo[1,2-c]pyridine-2-carboxamide,

6-Ethyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Formyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Ethynyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-[3-(1-Hydroxy-1-methylethyl)phenyl]-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-[Hydroxy(phenyl)methyl]-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Acetyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide hydrochloride (1:1),

6-Isopropyl-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-(1-Hydroxyethyl)-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,

6-Acetamido-N-phenylimidazo[1,2-c]pyridine-2-carboxamide,