Novel d3 dopamine receptor agonists to treat dyskinesia in parkinson's disease

Abstract

The present invention provides a method of inhibiting, suppressing or preventing levodopa-induced dyskinesia in a patient suffering from Parkinson's Disease, comprising the step of administering to the patient a pharmaceutical composition comprising at least one compound of the invention. The present invention further provides a method of inhibiting, suppressing or preventing Parkinson's Disease in a patient, comprising the step of administering to the patient a pharmaceutical composition comprising at least one compound of the invention.

What is claimed is: 
     
         1 . At least one compound selected from the group consisting of:
 a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein in formula (I): 
          R 1 , R 2  and R 3  are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, substituted aryl-(C 1-3 )alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; 
          R 4  and R 5  are independently selected from the group consisting of H, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, and substituted aryl-(C 1-3 )alkyl; and, 
          n is 2, 3, 4 or 5; 
       
       a compound of formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
         wherein in formula (IIa) or (IIb): 
          R 1  and R 2  are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, substituted aryl-(C 1-3 )alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; 
          R 3  and R 4  are independently selected from the group consisting of H, C 1-6  alkyl, aryl, heteroaryl, and substituted C 1-6  alkyl; 
          R 5  is selected from the group consisting of H, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, and substituted aryl-(C 1-3 )alkyl; and, 
          m is 1, 2, 3 or 4; 
       
       2,7-diamino-5-(4-fluorophenyl)-4-oxo-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile; (Z)-2-(1H-benzo[d]imidazol-2-yl)-N′-hydroxy-3-(4-methoxyphenyl)propanimidamide; mixtures thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The at least one compound of  claim 1 , wherein in formula (I) R 1 , R 2  and R 3  are independently selected from the group consisting of H, cyano, halo, alkoxy, nitro, C 1-6  alkyl, and carboxy. 
     
     
         3 . The at least one compound of  claim 1 , wherein in formula (I) R 4  and R 5  are independently selected from the group consisting of H, C 1-6  alkyl, and substituted C 1-6  alkyl. 
     
     
         4 . The at least one compound of  claim 1 , wherein in formula (I) n is 2. 
     
     
         5 . The at least one compound of  claim 1 , wherein in formula (IIa) or (IIb) m is 1 or 2. 
     
     
         6 . The at least one compound of  claim 1 , which is selected from the group consisting of:
 2-amino-4-(2-chlorophenyl)butan-1-ol;   2-(3-aminohexyl)phenol;   4-(2-chlorophenyl)-butan-2-amine;   4-(2-chlorophenyl)-2-methylamino-butane;   4-(2-fluorophenyl)butan-2-amine;   4-(2-bromophenyl)butan-2-amine;   4-(2-iodophenyl)butan-2-amine;   4-(2-methoxyphenyl)butan-2-amine;   2-(3-aminobutyl)phenol;   3-(3,4-diethoxyphenyl)propan-1-amine;   4-(4-chlorophenyl)butan-2-amine;   4-(4-methoxyphenyl)butan-2-amine;   2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine;   1-(5-fluoro-1-methyl-1H-indol-3-yl)propan-2-amine;   1-(5-methoxy-1-methyl-1H-indol-3-yl)propan-2-amine;   2,7-diamino-5-(4-fluorophenyl)-4-oxo-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile;   (Z)-2-(1H-benzo[d]imidazol-2-yl)-N′-hydroxy-3-(4-methoxyphenyl)propanimidamide;   mixtures thereof, or a pharmaceutically acceptable salt thereof.   
     
     
         7 . A method of treating, ameliorating or preventing levodopa-induced dyskinesia in a patient suffering from Parkinson's Disease, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of:
 a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein in formula (I): 
          R 1 , R 2  and R 3  are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, substituted aryl-(C 1-3 )alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; 
          R 4  and R 5  are independently selected from the group consisting of H, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, and substituted aryl-(C 1-3 )alkyl; and, 
          n is 2, 3, 4 or 5; 
       
       a compound of formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
         wherein in formula (IIa) or (IIb): 
          R 1  and R 2  are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, substituted aryl-(C 1-3 )alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; 
          R 3  and R 4  are independently selected from the group consisting of H, C 1-6  alkyl, aryl, heteroaryl, and substituted C 1-6  alkyl; 
          R 5  is selected from the group consisting of H, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, and substituted aryl-(C 1-3 )alkyl; and, 
          m is 1, 2, 3 or 4; 
       
       2,7-diamino-5-(4-fluorophenyl)-4-oxo-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile; (Z)-2-(1H-benzo[d]imidazol-2-yl)-N′-hydroxy-3-(4-methoxyphenyl)propanimidamide; 
       mixtures thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 7 , wherein in formula (I) R 1 , R 2  and R 3  are independently selected from the group consisting of H, cyano, halo, alkoxy, nitro, C 1-6  alkyl, and carboxy. 
     
     
         9 . The method of  claim 7 , wherein in formula (I) R 4  and R 5  are independently selected from the group consisting of H, C 1-6  alkyl, and substituted C 1-6  alkyl. 
     
     
         10 . The method of  claim 7 , wherein in formula (I) n is 2. 
     
     
         11 . The method of  claim 7 , wherein in formula (IIa) or (IIb) m is 1 or 2. 
     
     
         12 . The method of  claim 7 , wherein the at least one compound is selected from the group consisting of:
 2-amino-4-(2-chlorophenyl)butan-1-ol;   2-(3-aminohexyl)phenol;   4-(2-chlorophenyl)-butan-2-amine;   4-(2-chlorophenyl)-2-methylamino-butane;   4-(2-fluorophenyl)butan-2-amine;   4-(2-bromophenyl)butan-2-amine;   4-(2-iodophenyl)butan-2-amine;   4-(2-methoxyphenyl)butan-2-amine;   2-(3-aminobutyl)phenol;   3-(3,4-diethoxyphenyl)propan-1-amine;   4-(4-chlorophenyl)butan-2-amine;   4-(4-methoxyphenyl)butan-2-amine;   2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine;   1-(5-fluoro-1-methyl-1H-indol-3-yl)propan-2-amine;   1-(5-methoxy-1-methyl-1H-indol-3-yl)propan-2-amine;   2,7-diamino-5-(4-fluorophenyl)-4-oxo-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile;   (Z)-2-(1H-benzo[d]imidazol-2-yl)-N′-hydroxy-3-(4-methoxyphenyl)propanimidamide;   mixtures thereof, or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The method of  claim 7 , wherein the composition further comprises a drug selected from the group consisting of levodopa, clozapine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride, a salt thereof and mixtures thereof. 
     
     
         14 . The method of  claim 7 , wherein the pharmaceutical composition is co-administered to the patient with a second pharmaceutical composition comprising levodopa. 
     
     
         15 . The method of  claim 7 , wherein the pharmaceutical composition is administered to the patient a given period of time before a second pharmaceutical composition comprising levodopa is administered to the patient. 
     
     
         16 . The method of  claim 15 , wherein the given period of time varies from about 2 minutes to about 24 hours. 
     
     
         17 . The method of  claim 7 , wherein the patient is human. 
     
     
         18 . A method of treating, ameliorating or preventing Parkinson's Disease in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of:
 a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein in formula (I): 
          R 1 , R 2  and R 3  are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, substituted aryl-(C 1-3 )alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; 
          R 4  and R 5  are independently selected from the group consisting of H, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, and substituted aryl-(C 1-3 )alkyl; and, 
          n is 2, 3, 4 or 5; 
       
       a compound of formula (IIa) or (IIb): 
       
         
           
           
               
               
           
         
         wherein in formula (IIa) or (IIb): 
          R 1  and R 2  are independently selected from the group consisting of H, cyano, hydroxyl, amino, acetamido, halo, alkoxy, nitro, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, substituted aryl-(C 1-3 )alkyl, carboxy, alkylcarboxy, formyl, alkyl-carbonyl, aryl-carbonyl, and heteroaryl-carbonyl; 
          R 3  and R 4  are independently selected from the group consisting of H, C 1-6  alkyl, aryl, heteroaryl, and substituted C 1-6  alkyl; 
          R 5  is selected from the group consisting of H, C 1-6  alkyl, substituted C 1-6  alkyl, heteroalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, aryl-(C 1-3 )alkyl, and substituted aryl-(C 1-3 )alkyl; and, 
          m is 1, 2, 3 or 4; 
       
       2,7-diamino-5-(4-fluorophenyl)-4-oxo-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile; (Z)-2-(1H-benzo[d]imidazol-2-yl)-N′-hydroxy-3-(4-methoxyphenyl)propanimidamide; 
       mixtures thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the at least one compound is selected from the group consisting of:
 2-amino-4-(2-chlorophenyl)butan-1-ol;   2-(3-aminohexyl)phenol;   4-(2-chlorophenyl)-butan-2-amine;   4-(2-chlorophenyl)-2-methylamino-butane;   4-(2-fluorophenyl)butan-2-amine;   4-(2-bromophenyl)butan-2-amine;   4-(2-iodophenyl)butan-2-amine;   4-(2-methoxyphenyl)butan-2-amine;   2-(3-aminobutyl)phenol;   3-(3,4-diethoxyphenyl)propan-1-amine;   4-(4-chlorophenyl)butan-2-amine;   4-(4-methoxyphenyl)butan-2-amine;   2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine;   1-(5-fluoro-1-methyl-1H-indol-3-yl)propan-2-amine;   1-(5-methoxy-1-methyl-1H-indol-3-yl)propan-2-amine;   2,7-diamino-5-(4-fluorophenyl)-4-oxo-3,4,5,6-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile;   (Z)-2-(1H-benzo[d]imidazol-2-yl)-N′-hydroxy-3-(4-methoxyphenyl)propanimidamide;   mixtures thereof, or a pharmaceutically acceptable salt thereof.   
     
     
         20 . The method of  claim 18 , wherein the composition further comprises at least one drug selected from the group consisting of levodopa, clozapine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride, a salt thereof and mixtures thereof. 
     
     
         21 . The method of  claim 18 , wherein the patient is further administered a second pharmaceutical composition comprising at least one drug selected from the group consisting of levodopa, clozapine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride, a salt thereof and mixtures thereof.