Adenosine a2a receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders

Abstract

There is disclosed a method for the treatment or prevention of Extra Pyramidal syndrome (EPS), dystonia, restless leg syndrome (RLS) or periodic leg movement in sleep (PLMS) comprising the administration of an adenosine A2a receptor antagonist, alone or in combination with other agents useful for treating EPS, dystonia, RLS or PLMS.

1 . A method for the treatment or prevention of Extra-Pyramidal Syndrome or dystonia comprising administering a therapeutically effective amount of an adenosine A2a receptor antagonist to a patient in need thereof. 
   
   
       2 . The method of  claim 1  wherein the adenosine A2a antagonist is a compound of the formula 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or C 4 -C 6  cycloalkenyl; 
 X is C 2 -C 6  alkylene or —C(O)CH 2 —; 
 Y is —N(R 2 )CH 2 CH 2 N(R 3 )—, —OCH 2 CH 2 N(R 2 )—, —C—, —S—, —CH 2 S—, —(CH 2 ) 2 —NH—, or 
 
     
       
         
         
             
             
         
       
     
     and
 Z is R 5 -phenyl, R 5 -phenyl(C 1 -C 6 )alkyl, R 5 -heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —, R 6 —OC(O)—, R 7 —N(R 8 )—C(O)—, R 7 —N(R 8 )—C(S)—, 
 
     
       
         
         
             
             
         
       
     
     phenyl-CH(OH)—, or phenyl-C(═NOR 2 )—; or when Q is 
     
       
         
         
             
             
         
       
     
     Z is also phenylamino or pyridylamino; 
     or
 Z and Y together are 
 
     
       
         
         
             
             
         
       
       R 1  is 1 to 3 substituents independently selected from hydrogen, C 1 -C 6 -alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulfinyl, and C 1 -C 6  alkylsulfonyl; 
       R 2  and R 3  are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
       m and n are independently 2-3; 
       Q is 
     
     
       
         
         
             
             
         
       
       R 4  is 1-2 substituents independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or two R 4  substituents on the same carbon can form ═O; 
       R 5  is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —CN, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3 , acetyl, —NO 2 , hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )-alkoxy)(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy-(C 1 -C 6 )-alkoxy, carboxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkoxy, morpholinyl, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-SO—(C 1 -C 6 )alkoxy, tetrahydropyranyloxy, (C 1 -C 6 )alkylcarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyloxy(C 1 -C 6 )-alkoxy, —SO 2 NH 2 , phenoxy, 
     
     
       
         
         
             
             
         
       
     
     or adjacent R 5  substituents together are —O—CH 2 —O—, —O—CH 2 CH 2 —O—, —O—CF 2 —O— or —O—CF 2 CF 2 —O— and form a ring with the carbon atoms to which they are attached;
 R 6  is (C 1 -C 6 )alkyl, R 5 -phenyl, R 5 -phenyl(C 1 -C 6 )alkyl, thienyl, pyridyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl-OC(O)—NH—(C 1 -C 6 )alkyl-, di-((C 1 -C 8 )alkyl)aminomethyl, or 
 
     
       
         
         
             
             
         
       
       R 7  is (C 1 -C 6 )alkyl, R 5 -phenyl or R 5 -phenyl(C 1 -C 6 )alkyl; 
       R 8  is hydrogen or C 1 -C 6  alkyl; or R 7  and R 6  together are —(CH 2 ) p -A-(CH 2 ) q , wherein p and q are independently 2 or 3 and A is a bond, —CH 2 —, —S— or —O—, and form a ring with the nitrogen to which they are attached; 
       R 9  is 1-2 groups independently selected from hydrogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, halogen, —CF 3  and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; 
       R 10  is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —CN, —NH 2 , C 1 -C 6 alkylamino, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3  and —S(O) 0-2 (C 1 -C 6 )alkyl; 
       R 11  is H, C 1 -C 6  alkyl, phenyl, benzyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, di-((C 1 -C 6 ) alkyl)amino(C   1 -C 6 )alkyl, pyrrolidinyl(C 1 -C 6 )alkyl or piperidino(C 1 -C 6 )alkyl; 
       R 12  is H or C 1 -C 6  alkyl; and 
       R 13  is (C 1 -C 6 )alkyl-C(O)— or (C 1 -C 6 )alkyl-SO 2 —. 
     
   
   
       3 . The method of  claim 2  wherein the adenosine A2a receptor antagonist is selected from the group consisting of compounds of the formula 
     
       
         
         
             
             
         
       
     
     wherein R and Z-Y are as defined in the following table: 
     
       
         
               
               
             
                   
               
                 Z—Y— 
                 R 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
           
              
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof. 
   
   
       4 . The method of  claim 3  wherein the adenosine A2a receptor antagonist is 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof. 
   
   
       5 . The method of  claim 1  for treating or preventing Extra-Pyramidal Syndrome. 
   
   
       6 . The method of  claim 5  wherein the Extra-Pyramidal Syndrome has been caused by treatment with a typical antipsychotic agent or an atypical antipsychotic agent. 
   
   
       7 . The method of  claim 6  wherein the typical antipsychotic agent is selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene, and the atypical antipsychotic agent is selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone 
   
   
       8 . The method of  claim 5  further comprising administering an antipsychotic agent in combination with the adenosine A 2a  receptor antagonist. 
   
   
       9 . The method of  claim 8  wherein the antipsychotic agent is a typical antipsychotic agent selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene, or an atypical antipsychotic agent selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone. 
   
   
       10 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent EPS caused by treatment with antipsychotic agent, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A 2a receptor antagonist in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an effective amount of an antipsychotic agent. 
   
   
       11 . A method of  claim 1  for the treatment of idiopathic dystonia or dystonia caused by the use of cocaine. 
   
   
       12 . The method of  claim 1  for the treatment or prevention of dystonia caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant. 
   
   
       13 . The method of  claim 12  further comprising administering a tricyclic antidepressant, lithium or an anticonvulsant in combination with the adenosine A2a receptor antagonist. 
   
   
       14 . The method of  claim 13  wherein the tricyclic antidepressant is selected from the group consisting of perphenazine, amitriptyline, desipramine, doxepin, trimipramine and protriptyline, and the anticonvulsant is selected from the group consisting of phenyloin, carbamazepine and gabapentin. 
   
   
       15 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent dystonia caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A 2a  receptor antagonist in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an effective amount of a tricyclic antidepressant, lithium or an anticonvulsant. 
   
   
       16 . A method of treating restless leg syndrome or periodic leg movement in sleep comprising administering a therapeutically effective amount of an adenosine A2a receptor antagonist to a patient in need thereof. 
   
   
       17 . The method of  claim 16  wherein the adenosine A2a antagonist is a compound of the formula 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or C 4 -C 6  cycloalkenyl; 
 X is C 2 -C 6  alkylene or —C(O)CH 2 —; 
 Y is —N(R 2 )CH 2 CH 2 N(R 3 )—, —OCH 2 CH 2 N(R 2 )—, —O—, —S—, —CH 2 S—, —(CH 2 ) 2 —NH—, or 
 
     
       
         
         
             
             
         
       
     
     and
 Z is R 5 -phenyl, R 5 -phenyl(C 1 -C 6 )alkyl, R 5 -heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —, R 6 —OC(O)—, R 7 —N(R 8 )—C(O)—, R 7 —N(R 8 )—C(S)—, 
 
     
       
         
         
             
             
         
       
     
     phenyl-CH(OH), or phenyl-C(═NOR 2 )—; or when Q is 
     
       
         
         
             
             
         
       
     
     Z is also phenylamino or pyridylamino; 
     or
 Z and Y together are 
 
     
       
         
         
             
             
         
       
       R 1  is 1 to 3 substituents independently selected from hydrogen, C 1 -C 6 -alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulfinyl, and C 1 -C 6  alkylsulfonyl; 
       R 2  and R 3  are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
       m and n are independently 2-3; 
       Q is 
     
     
       
         
         
             
             
         
       
       R 4  is 1-2 substituents independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or two R 4  substituents on the same carbon can form ═O; 
       R 5  is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —CN, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3 , acetyl, —NO 2 , hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )-alkoxy)(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy-(C 1 -C 6 )-alkoxy, carboxy(C 1 -C 6 ) alkoxy, (C 1 -C 6 )-alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkoxy, morpholinyl, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-SO—(C 1 -C 6 )alkoxy, tetrahydropyranyloxy, (C 1 -C 6 )alkylcarbonyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyloxy(C 1 -C 6 )-alkoxy, —SO 2 NH 2 , phenoxy, 
     
     
       
         
         
             
             
         
       
     
     or adjacent R 5  substituents together are —O—CH 2 —O—, —O—CH 2 CH 2 —O—, —O—CF 2 —O— or —O—CF 2 CF 2 —O— and form a ring with the carbon atoms to which they are attached;
 R 6  is (C 1 -C 6 )alkyl, R 5 -phenyl, R 5 -phenyl(C 1 -C 6 )alkyl, thienyl, pyridyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 6 )alkyl-OC(O)—NH—(C 1 -C 6 )alkyl-, di-((C 1 -C 6 )alkyl)aminomethyl, or 
 
     
       
         
         
             
             
         
       
       R 7  is (C 1 -C 6 )alkyl, R 5 -phenyl or R 5 -phenyl(C 1 -C 6 )alkyl; 
       R 8  is hydrogen or C 1 -C 6  alkyl; or R 7  and R 8  together are —(CH 2 ) p -A-(CH 2 ) q , wherein p and q are independently 2 or 3 and A is a bond, —CH 2 —, —S— or —O—, and form a ring with the nitrogen to which they are attached; 
       R 9  is 1-2 groups independently selected from hydrogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, halogen, —CF 3  and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; 
       R 10  is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —CN, —NH 2 , C 1 -C 6 alkylamino, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3  and —S(O) 0-2 (C 1 -C 6 )alkyl; 
       R 11  is H, C 1 -C 6  alkyl, phenyl, benzyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl, pyrrolidinyl(C 1 -C 6 )alkyl or piperidino(C 1 -C 6 )alkyl; 
       R 12  is H or C 1 -C 6  alkyl; and 
       R 13  is (C 1 -C 6 )alkyl-C(O)— or (C 1 -C 6 )alkyl-SO 2 —. 
     
   
   
       18 . The method of  claim 16  further comprising administering levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron in combination with the adenosine A2a receptor antagonist. 
   
   
       19 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent restless leg syndrome or periodic leg movement in sleep, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A2a receptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of a dopamine agonist, benzodiazepine, opioid, anticonvulsant or iron.