Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

Abstract

A method of treating Parkinson's disease in warm-blooded animals comprising administering to warm-blooded animals in need thereof an effective amount of a compound of the formula wherein the substituents are defined as in the specification

1 - 21 . (canceled)  
   
   
       22 . A method of treating Parkinson's disease in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula  
     
       
         
         
             
             
         
       
     
     in racemic, enantiomeric form or any combination of these forms,  
     in which 
 A is  
                     
 in which Q is selected from the group consisting of H, —OR 22 , —NR 23 R 24 , phenyl optionally substituted by at least one substituent independently selected from the group consisting of  z OH, cyano, nitro, alkyl, alkoxy or —NR 10 R 11  and a group with two substituents representing together a methylenedioxy or ethylenedioxy, or Q is selected from the group consisting of —COPh, —SO 2 Ph or —CH 2 Ph, said COPh, —SO 2 Ph or —CH 2 Ph optionally substituted on its aromatic parts by at least one independently alkyl or alkoxy or halogen,  
 R 10  and R 11  are independently selected from the group consisting of hydrogen, alkyl and —COR 12 , or R 10  and R 11  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently selected from the group consisting of O, N and S,  
 R 12  is selected from the group consisting of hydrogen, alkyl, alkoxy and —NR 13 R 14 ,  
 R 13  and R 14  are independently hydrogen or alkyl, or R 13  and R 14  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group consisting of O, N and S,  
 R 22  is selected from the group consisting of hydrogen, alkyl and aryl optionally substituted by at least one substituent selected from the group consisting of alkyl, —OH, halogen, nitro and alkoxy,  
 R 23  and R 24  are independently selected from the group consisting of hydrogen, alkyl and —CO—R 25 ,  
 R 25  is alkyl,  
 and R 19 , R 20  and R 21  are independently selected from the group consisting of hydrogen, halogen, —OH, —SR 26 , alkyl, cycloalkyl, alkenyl, alkoxy, cyano, nitro, —SO 2 NHR 49 , —CONHR 55 , —S(O) q R 56 , —NH(CO)R 57 , —CF 3 , —OCF 3  and —NR 27 R 28 ,  
 R 27  and R 28  are independently selected from the group consisting of hydrogen, alkyl and —COR 29 , or R 27  and R 28  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently selected from the group consisting of O, N and S,  
 R 49  and R 55  are independently each time that they occur, hydrogen or alkyl or alkylcarbonyl,  
 q is an integer from 0 to 2,  
 R 56  and R 57  are, each time that they occur, hydrogen or alkyl or alkoxy,  
 R 29  is selected from the group consisting of hydrogen, alkyl, alkoxy and —NR 30 R 31 ,  
 R 30  and R 31  are independently selected from the group consisting of hydrogen and alkyl, or R 30  and R 31  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently selected from the group consisting of O, N and S,  
 Y is O;  
 R 1  is hydrogen, alkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, alkyl, alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, —(CH 2 ) g -Z 1 R 39 , —(CH 2 ) g —COR 40 , —(CH 2 ) g —NHCOR 70 , aryl, aralkyl, arylcarbonyl, heteroarylalkyl and aralkylcarbonyl, the aryl group of the aryl, aralkyl, arylcarbonyl, heteroarylalkyl or aralkylcarbonyl itself being optionally substituted by at least one substituent selected from the group consisting of alkyl halogen, alkoxy, nitro, cyano, cyanoalkyl, amino, alkylamino, dialkylamino, —(CH 2 ) k -Z 2 R 39  and —(CH 2 ) k —COR 40 —,  
 Z 1  and Z 2  are selected from the group consisting of a bond, —O—, —NR 41 — and —S—,  
 R 39  and R 41  are independently each time that they occur, selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cyanoalkyl,  
 R 40  is, independently each time that it occurs, selected from the group consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy and —NR 42 R 43 ,  
 R 42  and R 43  are independently, each time that they occur, selected from the group consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl and cyanoalkyl and R 2  is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl,  
 —(CH 2 ) g —NHCOR 71 , aralkyl and heteroarylalkyl optionally substituted on the aryl or heteroaryl by at least one member selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, cyano, nitro, amino, alkylamino and dialkylamino,  
 R 70  and R 71  are independently alkyl or alkoxy;  
 or R 1  and R 2 , taken together with the carbon atom which carries them, form a carbocycle with 3 to 7 members;  
 B is selected from the group consisting of hydrogen, alkyl, —(CH 2 ) g -Z 3 R 44  and carbocyclic aryl optionally substituted 1 to 3 times by a member selected from the group consisting of halogen, alkyl and alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino and a carbocyclic aryl,  
 Z 3  is selected from the group consisting of a bond, —O—, NR 45 — and —S—,  
 R 44  and R 45  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, allenyl, allenylalkyl and cyanoalkyl;  
 Ω is —NR 46 R 47 ;  
 R 46  and R 47  are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, —(CH 2 ) g -Z 4 R 50 , —(CH 2 ) k —COR 51 , —(CH 2 ) k —COOR 51 , —(CH 2 ) k —CONHR 51 , —SO 2 R 51 , aryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl, heteroaryl, pyridinylalkyl or pyridinylcarbonyl, the aryl or heteroaryl of said aryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl, heteroaryl, pyridinylalkyl or pyridinylcarbonyl being optionally substituted by at least one member independently selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, nitro, cyano, cyanoalkyl, amino, alkylamino, dialkylamino, -Z 5 R 50 , —(CH 2 ) k —COR 51  and —(CH 2 ) k —COOR 51 ,  
 Z 4  and Z 5  are selected from the group consisting of a bond, —O—, —NR 52 — and —S—, or R 46  and R 47  taken together form with the nitrogen atom a non-aromatic heterocycle with 4 to 8 ring members, the elements of the chain being selected from the group consisting of —CH(R 53 )—, —NR 54 —, —O—, —S— and —CO—,  
 R 50  and R 52  are independently each time that they occur, selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, allenyl, allenylalkyl and cyanoalkyl,  
 R 51  is, independently each time that they occur, selected from the group consisting of hydrogen, cycloalkyl and cycloalkylalkyl in which the cycloalkyl has 3 to 7 carbon atoms, alkyl of 1 to 8 carbon atoms, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, alkoxyalkyl, —NR 58 R 59 , aryl or aralkyl, said aryl or aralkyl optionally substituted by at least one member selected from the group consisting of halogen, alkyl and alkoxy,  
 R 58  and R 59  are independently a member selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, allenyl, allenylalkyl and cyanoalkyl,  
 R 53  and R 54  are independently a member selected from the group consisting of hydrogen or —(CH 2 ) k -Z 7 R 60  and —(CH 2 ) k —COR 61 ,  
 Z 7  is a member selected from the group consisting of a bond, —O—, —NR 62 — and —S—,  
 R 60  and R 62  are independently a member selected from the group consisting of hydrogen, alkyl, alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl or pyridinylcarbonyl, the aryl or pyridinyl of the aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl or pyridinylcarbonyl being optionally substituted by at least one substituent selected from the group consisting of alkyl, halogen, nitro, alkoxy, cyano, cyanoalkyl, —(CH 2 ) k -Z 8 R 63  and —(CH 2 ) k —COR 64 ,  
 R 61  is a member selected from the group consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy and —NR 65 R 66 ,  
 R 65  and R 66  are independently selected from the group consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl and cyanoalkyl,  
 Z 8  is a member selected from the group consisting of a bond, —O—, —NR 67 — and —S—,  
 R 63  and R 67  are independently a member selected from the group consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl and cyanoalkyl,  
 R 64  is a member of the group consisting of hydrogen, alkyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy and —NR 68 R 69 ,  
 R 68  and R 69  are independently a member selected from the group consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl cyanoalkyl,  
 and R 48  is a member selected from the group consisting of hydrogen, alkyl, alkynyl and cyanoalkyl;  
 g and p, each time that they occur, being independently integers from 1 to 6, and k and n, each time that they occur, being independently integers from 0 to 6;  
 or a salt thereof sufficient to treat Parkinson's disease.  
 
   
   
       23 . The method of  claim 22  wherein 
 A is                          in which Q is selected from the group consisting of —OR 22 , —SR 22 , —NR 23 R 24 , phenyl optionally substituted by at least one member selected from the group consisting of halogen, OH, cyano, nitro, alkyl, alkoxy and —NR 10 R 11  and a group of two substituents together being methylenedioxy or ethylenedioxy, or Q is selected from the group consisting of —COPh, —OPh, —SPh, —SO 2 Ph or —CH 2 Ph, said —COPh, —OPh, —SPh, —SO 2 Ph or —CH 2 Ph being optionally substituted on its aromatic part by at least one member selected from the group consisting of alkyl, alkoxy and halogen,    R 10  and R 11  are independently selected from the group consisting of hydrogen, alkyl, or    R 10  and R 11  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 ring members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently selected from the group consisting of O, N and S,    R 22  is selected from the group consisting of hydrogen, alkyl and aryl optionally substituted by at least one member selected from the group consisting of alkyl, OH, halogen, nitro and alkoxy,    R 23  and R 24  are, independently, hydrogen, or alkyl or —CO—R 25 ,    R 25  is alkyl,    and R 19 , R 20  and R 21  are independently selected from the group consisting of hydrogen, halogen, OH, SR 26 , alkyl, cycloalkyl, alkenyl, alkoxy, cyano, nitro, —SO 2 NHR 49 , —CONHR 55 , —S(O) q R 56 , —NH(CO)R 57 , —CF 3 , —OCF 3  and —NR 27 R 28 ,    R 26  is hydrogen or alkyl,    R 27  and R 28  are independently selected from the group consisting of hydrogen, alkyl and —COR 29 , or R 27  and R 28  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 ring members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being selected from the group consisting of O, N and S,    R 49  and R 55  are, independently each time that they occur, hydrogen or alkyl or alkylcarbonyl,    q is an integer from 0 to 2,    R 56  and R 57  are, independently each time that they occur, hydrogen or alkyl or alkoxy,    R 29  is selected from the group consisting of hydrogen, alkyl, alkoxy and —NR 30 R 31 ,    R 30  and R 31  are independently selected from the group consisting of hydrogen, alkyl, or    R 30  and R 31  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 ring members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being selected from the group consisting of O, N and S.    
   
   
       24 . The method of  claim 22  wherein 
 A is                          in which Q is —OR 22 , —SR 22 , —NR 23 R 24 , phenyl optionally substituted by at least one member selected from the group consisting of halogen, OH, cyano, nitro, alkyl, alkoxy and —NR 10 R 11 ,    R 10  and R 11  are independently selected from the group consisting of hydrogen or alkyl, or    R 10  and R 11  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 ring members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being selected from the group consisting of O, N and S,    R 22  is selected from the group consisting of hydrogen, alkyl and aryl optionally substituted by at least one member selected from the group consisting of alkyl, OH, halogen, nitro and alkoxy,    R 23  and R 24  are, independently, hydrogen or alkyl,    and R 19 , R 20  and R 21  are independently selected from the group consisting of hydrogen, halogen, OH, —SR 26 , alkyl, alkenyl, alkoxy and —NR 27 R 28 ,    R 26  is hydrogen or alkyl,    R 27  and R 28  are independently selected from the group consisting of hydrogen, alkyl, or    R 27  and R 28  form together with the nitrogen atom an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being selected from the group consisting of O, N and S.    
   
   
       25 . The method of  claim 24  wherein 
 A is                          in which Q is selected from the group consisting of —OR 22 , —SR 22  and phenyl substituted by OH and optionally by at least one member selected from the group consisting of halogen, OH, alkyl and alkoxy,    R 22  is hydrogen or alkyl,    and R 19 , R 20  and R 21  are independently selected from the group consisting of hydrogen, halogen, OH, —SR 26 , alkyl and alkoxy,    R 26  is hydrogen or alkyl.    
   
   
       26 . The method of  claim 25  wherein 
 the compound corresponds to formula (I) 3  in which Y is O    A is                          in which Q is —OH, two of the R 19 , R 20  and R 21  are selected from the group consisting of alkyl, alkoxy, alkylthio, amino, alkylamino and dialkylamino and the third is selected from the group consisting of hydrogen, alkyl, alkoxy, alkylthio, amino, alkylamino and dialkylamino, or Q is phenyl substituted by —OH and at least one member selected from the group consisting of halogen, —OH, alkyl, alkoxy and —NR 10 R 11 , R 10  and R 11  are independently hydrogen or alkyl.    
   
   
       27 . The method of  claim 26  wherein A is  
     
       
         
         
             
             
         
       
     
     in which Q is —OH, two of the R 19 , R 20  and R 21  are alkyl and the third is H, or Q is phenyl substituted by —OH and at least one alkyl.  
   
   
       28 . The method of  claim 22  wherein Y is O; 
 A is                          in which Q is —OH, two of the R 19 , R 20  and R 21  are alkyl and the third is hydrogen, or in which Q is phenyl substituted by —OH and at least one alkyl;    B is hydrogen;    n is 0 or 1;    R 1  and R 2  both are hydrogen;    and Ω is —NR 46 R 47 , R 46  is selected from the group consisting of hydrogen, alkyl, alkynyl, hydroxyalkyl and cyanoalkyl and R 47  is hydrogen or alkyl or R 46  and R 47  form together with the nitrogen atom which carries them a non-aromatic heterocycle with 5 to 7 ring members, the additional members are —CH 2 — or —NH—.    
   
   
       29 . The method of  claim 22 , wherein the compound is selected from the group consisting of 
 -2,6-ditert-butyl-4-(4-{2-[methyl(2-propynyl)amino]ethyl}-1,3-oxazol-2-yl)phenol;    -3-[{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}(methyl)amino]-propanenitrile;    -2,6-ditert-butyl-4-{4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl}phenol-hydrochloride and [{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl}(methyl)amino]acetonitrile    and the pharmaceutically acceptable salts of the latter.