Imidazo [1,2-a] pyridin-3-yl-acetic acid hydrazides, processes, uses and compositions

Abstract

The invention provides novel imidazo[1,2-a]pyridin-3-yl-acetic acid hydrazides of formula (I) wherein R 1 , R 2 and R 3 have different meanings, and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. Compounds of formula (I) are useful for treating or preventing, in a human or non-human mammal, diseases associated with GABA A receptors modulation, anxiety, epilepsy, sleep disorders including insomnia, and for inducing sedation-hypnosis, anesthesia, sleep and muscle relaxation. The invention also provides synthetic processes for preparing said compounds.

1 ) A method for treating diseases associated with GABA A  receptor modulation in a human or non-human mammal, which comprises administering to said human or non-human mammal in need thereof a therapeutically effective amount, for treating diseases associated with the GABA A  receptor modulation, of an imidazo[1,2-a]pyridin-3-yl-acetic acid hydrazide compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is selected from the group consisting of hydrogen, linear or branched alkyl(C 1 -C 6 ), alkenyl(C 2 -C 6 ), alkynyl(C 2 -C 6 ) and cycloalkyl(C 3 -C 6 ); 
       R 2  and R 3  are independently selected from the group consisting of hydrogen, linear or branched alkyl(C 1 -C 6 ), alkenyl(C 2 -C 6 ), alkynyl(C 2 -C 6 ), cycloalkyl(C 3 -C 6 ) and R 4 CO, or both R 2  and R 3  can form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted, or a NCR 5 R 6  group; 
       R 4  is selected from the group consisting of linear or branched alkyl(C 1 -C 6 ), cycloalkyl(C 3 -C 6 ), aryl optionally substituted and heteroaryl optionally substituted; 
       R 5  is selected from the group consisting of hydrogen, linear or branched alkyl(C 1 -C 6 ), cycloalkyl(C 3 -C 6 ) and aryl optionally substituted; 
       R 6  is selected from the group consisting of linear or branched alkyl(C 1 -C 6 ), cycloalkyl(C 3 -C 6 ) and aryl optionally substituted; 
       or both R 5  and R 6  can form, together with the carbon atom to which they are attached, a 5-6 membered ring optionally substituted; and 
       pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. 
     
     
         2 ) The method according to  claim 1 , wherein R 1  is selected from the group consisting of hydrogen and methyl; and R 2  and R 3  are independently selected from the group consisting of hydrogen, acetyl and 2-thiophenecarbonyl, or both R 2  and R 3  form, together with the nitrogen atom to which they are attached, a heterocycle selected from the group consisting of 1-morpholinyl and 1,2,4-triazin-4-yl, or a NCR 5 R 6  group selected from the group consisting of ethylideneamino, isopropylideneamino and 4-chlorobenzylideneamino. 
     
     
         3 ) The method according to  claim 2 , wherein said compound is selected from the group consisting of:
 Thiophene-2-carboxylic acid N′-[2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetyl]-hydrazide;   (6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid N′-acetyl-hydrazide;   (6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid hydrazide;   2-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-N-morpholin-4-yl-acetamide;   2-(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-N-[1,2,4]triazol-4-yl-acetamide;   (6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid N-methyl-hydrazide;   (6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid (4-chlorobenzylidene)-hydrazide;   (6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethylidene-hydrazide; and   (6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid isopropylidene-hydrazide.   
     
     
         4 ) The method of  claim 1 , wherein the GABA A  receptor is an α 1 -GABA A  receptor. 
     
     
         5 ) The method of  claim 1 , wherein the GABA A  receptor is an α 2 -GABA A  receptor. 
     
     
         6 ) The method of  claim 1 , wherein the disease is anxiety in a human or non-human mammal. 
     
     
         7 ) The method of  claim 1 , wherein the disease is epilepsy in a human or non-human mammal. 
     
     
         8 ) The method of  claim 1 , wherein the disease is a sleep disorder in a human or non-human mammal. 
     
     
         9 ) The method of  claim 1 , wherein the disease is insomnia in a human or non-human mammal. 
     
     
         10 ) A method for inducing sedation-hypnosis in a human or non-human mammal, for inducing anesthesia in a human or non-human mammal, for modulating the necessary time to induce sleep and its duration in a human or non-human mammal, or for inducing muscle relaxation in a human or non-human mammal, which comprises administering to said human or non-human mammal in need thereof a therapeutically effective amount of an imidazo[1,2-a]pyridin-3-yl-acetic acid hydrazide compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is selected from the group consisting of hydrogen, linear or branched alkyl(C 1 -C 6 ), alkenyl(C 2 -C 6 ), alkynyl(C 2 -C 6 ) and cycloalkyl(C 2 -C 6 ); 
       R 2  and R 1  are independently selected from the group consisting of hydrogen, linear or branched alkyl(C 1 -C 6 ), alkenyl(C 2 -C 6 ), alkynyl(C 2 -C 6 ), cycloalkyl(C 2 -C 6 ) and R 4 CO, or both R 2  and R 3  can form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclic ring optionally substituted, or a NCR 5 R 6  group; 
       R 4  is selected from the group consisting of linear or branched alkyl(C 1 -C 6 ), cycloalkyl(C 3 -C 6 ), aryl optionally substituted and heteroaryl optionally substituted; 
       R 5  is selected from the group consisting of hydrogen, linear or branched alkyl(C 1 -C 6 ), cycloalkyl(C 3 -C 6 ) and aryl optionally substituted; 
       R 6  is selected from the group consisting of linear or branched alkyl(C 1 -C 6 ), cycloalkyl(C 3 -C 6 ) and aryl optionally substituted; 
       or both R 5  and R 6  can form, together with the carbon atom to which they are attached, a 5-6 membered ring optionally substituted; and 
       pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. 
     
     
         11 ) The method of  claim 10 , wherein said method is for inducing sedation-hypnosis in a human or non-human mammal. 
     
     
         12 ) The method of  claim 10 , wherein said method is for inducing anesthesia in a human or non-human mammal. 
     
     
         13 ) The method of  claim 10 , wherein said method is for modulating the necessary time to induce sleep and its duration in a human or non-human mammal. 
     
     
         14 ) The method of  claim 10 , wherein said method is for inducing muscle relaxation in a human or non-human mammal. 
     
     
         15 ) The method of  claim 1 , wherein the therapeutically effective amount of said compound is present with appropriate amounts of pharmaceutical excipients or carriers. 
     
     
         16 ) The method of  claim 10 , wherein the therapeutically effective amount of said compound is present with appropriate amounts of pharmaceutical excipients or carriers. 
     
     
         17 ) The method of  claim 1 , wherein said compound is administered orally, rectally or parenterally. 
     
     
         18 ) The method of  claim 10 , wherein said compound is administered orally, rectally or parenterally.