Allosteric Modulators of the A1 Adenosine Receptor

Abstract

The present invention provides compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 and Q have a meaning as defined herein in the specification. The compounds of formula (I) are allosteric modulators of the A 1 adenosine receptor and, thus, may be employed for the treatment of conditions mediated by the A l adenosine receptor. Accordingly, the compounds of formula (I) may be employed for treatment of pain, in particular, chronic pain such as neuropathic pain; cardiac disease or disorder such as cardiac disarrhythmias, e.g., peroxysmal supraventricular tachycardia, angina, myocardial infarction and stroke; neurological disease or injury; sleep disorder; epilepsy; and depression.

What is claimed is: 
     
         1 . A method for the treatment of pain, cardiac disease or disorder, neurological disease or injury, sleep disorder, epilepsy and depression in mammals which method comprises administering to a mammal, in need thereof, a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl or substituted cycloalkyl; 
 R 2 , R 3 , and R 4  are, independently from each other, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy or substituted alkoxy; 
 Q is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         in which
 R 5  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or substituted acyl; 
 R 6  and R 7  are, independently from each other, hydrogen, C 1 -C 3  alkyl or C 1 -C 3  substituted alkyl; or 
 R 6  and R 7 , provided they are attached to the same carbon atom, combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring; 
 R 8 , R 9 , R 10 , R 11 , R 12  and R 13  are, independently from each other, hydrogen, C 1 -C 3  alkyl or C 1 -C 3  substituted alkyl; 
 X is N; 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A method according to  claim 1 , wherein
 R 1  is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A method according to  claim 2 , wherein Q is 
       
         
           
           
               
               
           
         
       
       in which
 R 5  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or substituted acyl; 
 R 6  and R 7  are, independently from each other, hydrogen, C 1 -C 3  alkyl or C 1 -C 3  substituted alkyl; or 
 R 6  and R 7 , provided they are attached to the same carbon atom, combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered spirocyclic ring; 
 R 8  and R 9  are, independently from each other, hydrogen, C 1 -C 3  alkyl or C 1 -C 3  substituted alkyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A method according to  claim 3 , wherein a compound of formula (I) is of formula (IA) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; 
 R 2 , R 3 , and R 4  are, independently from each other, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, cyano, alkoxy or substituted alkoxy; 
 R 5  is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, acyl or substituted acyl; 
 R 6 , R 7 , R 8  and R 9  are, independently from each other, hydrogen, C 1 -C 3  alkyl or C 1 -C 3  substituted alkyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A method according  claim 4 , wherein
 R 1  is hydrogen or C 1 -C 3  alkyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A method according to  claim 4 , wherein
 R 5  is monocyclic aryl optionally substituted by one to three substituents selected from the group consisting of halogen, cyano or trifluoromethyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A method according to  claim 4 , wherein
 R 2  and R 4  are hydrogen;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A method according to  claim 7 , wherein
 R 3  is halogen, cyano or trifluoromethyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A method according to  claim 4 , wherein
 R 2  and R 3  are hydrogen;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A method according to  claim 9 , wherein
 R 4  is halogen, cyano or trifluoromethyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A method according to  claim 4 , wherein
 R 6 , R 7 , R 8  and R 9  are, independently from each other, hydrogen or C 1 -C 3  alkyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method according to  claim 11 , wherein
 R 5  is monocyclic aryl optionally substituted by one to three substituents selected from the group consisting of halogen, cyano or trifluoromethyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method according to  claim 12 , wherein
 R 2  and R 4  are hydrogen;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A compound according to  claim 13 , wherein
 R 3  is halogen, cyano or trifluoromethyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A compound according  claim 14 , wherein
 R 1  is hydrogen or C 1 -C 3  alkyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A compound according to  claim 12 , wherein
 R 2  and R 3  are hydrogen;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A compound according to  claim 16 , wherein
 R 4  is halogen, cyano or trifluoromethyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A compound according  claim 17 , wherein
 R 1  is hydrogen or C 1 -C 3  alkyl;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method for the treatment of pain, cardiac disease or disorder, neurological disease or injury, sleep disorder, epilepsy and depression in mammals which method comprises administering to a mammal, in need thereof, a therapeutically effective amount of a compound selected from the group consisting of:
 {2-Amino-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-methylpiperazin-1-Amethyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[4-((4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[4-((4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[4-((4-methoxyphenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(pyrimidin-2-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3,4-dichlorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   4-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}benzonitrile;   {2-Amino-4-[(4-(3-chlorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2-fluorophenyl)-piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   1-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-2-(4-chlorophenyl)ethanone;   {2-Amino-4-[(4-(4-chlorobenzoyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(pyridin-4-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(benzo[d][1,3]dioxol-5-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   2-{4-[(5-Amino-4-(4-chlorobenzoyl)thiophen-3-yl)methyl]piperazin-1-yl}-1-(4-chlorophenyl)ethanone;   {2-Amino-4-[(4-(2,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-cyclohexylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-isopropyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-naphthalen-1-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3,4-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-cyclopentylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-cycloheptylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-chlorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-benzylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   (2-Amino-4-{[4-(2-(4-chlorophenypethyl)piperazin-1-yl]methyl}thiophen-3-yl)(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-fluorobenzyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-cyclooctylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   (2-Amino-4-{[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]methyl}thiophen-3-yl)(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,4-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,4,6-trifluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2-fluoro-4-chlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3,5-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,6-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(pyridin-3-yl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,5-dichlorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(2,3-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-(trifluoromethyl)phenyl]methanone;   {2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-(trifluoromethyl)phenyl]methanone;   {2-Amino-4-[(4-(2,6-difluorophenyl)piperazin-1-yl)methyl]thiophen-3-yl}[3-(trifluoromethyl)phenyl]methanone;   {2-Amino-4-[(4-(4-chlorophenyl)41,4]diazepan-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(7-(4-chlorophenyl)-2,7-diaza-spiro[4.4]non-2-yl)methyl]thiophen-3-yl }(4-chlorophenyl)methanone;   {2-Amino-4-[(5-(4-chlorophenyl)hexahydropyrrolo[3,4-c]pyrrol-2-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-5-methyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-5-methyl-4-[(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-bromophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-iodophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-5-methyl-4-[(4-(4-nitrophenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   4-{4-[(5-Amino-4-(4-chlorobenzoyl)-2-methylthiophen-3-yl)methyl]piperazin-1-yl}benzonitrile   {2-Amino-4-[(4-benzylpiperazin-1-yl)methyl)-5-methylthiophen-3-yl](4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-methoxyphenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4- chlorophenyl)methanone;   {2-Amino-5-methyl-4-[(4-p-tolylpiperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3,4-dichlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-5-methyl-4-[(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]thiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(3-chlorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-chloro-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   {2-Amino-4-[4-(4-fluorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-yl}(4-chlorophenyl)methanone;   [2-Amino-5-ethyl-4-[(4-phenylpiperazin-1-yl)methyl]thiophen-3-yl](4-chlorophenyl)methanone;   {2-Amino-4-[(4-(4-chlorophenyl)piperazin-1-yl)methyl]-5-ethylthiophen-3-yl}(4-chlorophenyl)methanone; and   {2-Amino-4-[(4-(3-fluorophenyl)piperazin-1-yl)methyl]-5-methylthiophen-3-yl}(4-chlorophenyl)methanone;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method according to  claim 1 , wherein the pain is neuropathic pain.