Semicarbazones having CNS activity and pharmaceutical preparations containing same

Abstract

A compound of general formula I below useful as an anticonvulsant for disorders of the central nervous system: wherein: R 1 , R 2 , R 3 and R 4 may be the same or different and each represents a hydrogen or halogen atom, or a C 1-9 alkyl, C 3-9 cycloalkyl, cyano, C 1-9 alkoxy or C 6-10 aryloxy group; R 5 represents a hydrogen atom or a C 1-9 alkyl, C 3-9 cycloalkyl or C 6-10 aryl group; and X is oxygen or sulfur; or a pharmaceutically-acceptable salt thereof. The compound may be adimistered orally for treating convulsions in humans or animals.

What we claim is:  
     
       1. A compound of the general formula I:                    
       wherein R 1 , R 2 , R 3  and R 4  may be the same or different and each represents hydrogen, halo, C 1-9 alkyl, C 3-9 cycloalkyl, cyano, C 1-9 alkoxy or C 6-10 aryloxy; R 5  represents hydrogen, C 1-9 alkyl, C 3-9 cycloalkyl or C 6-10 aryl; and X is oxygen or sulfur; with the proviso that: 
       a) if X is sulfur, then at least one of R 1  and R 2  is other than hydrogen or at least one of R 3  and R 4  is fluoro, C 1-9 alkyl, C 3-9 cycloalkyl, cyano, C 1-9 alkoxy or C 6-10 aryloxy; and  
       b) if X is oxygen, R 5  is hydrogen, methyl, or ethyl, and if one of R 1  and R 2  is chloro or methoxy or if one of R 3  and R 4  is methyl, then the other of R 1  and R 2  or the other of R 3  and R 4  is other than hydrogen; and  
       c) if X is oxygen, R 5  is hydrogen, methyl or ethyl, and if R 1  and R 2  are both hydrogen, then at least one of R 3  and R 4  is other than hydrogen and methyl;  
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound according to  claim 1  wherein at least one of R 1  and R 2  represents fluoro, R 3  and R 4  are each hydrogen, R 5  is hydrogen or C 1-3 alkyl, and X is O. 
     
     
       3. A compound according to  claim 1  wherein at least one of R 1  and R 2  represent fluoro, R 5  is hydrogen, and X represents oxygen. 
     
     
       4. 4-(4′-Fluorophenoxy)benzaldehyde semicarbazone or a pharmaceutically-acceptable salt thereof. 
     
     
       5. A method of preparing a compound of general  formula I:                    
       wherein: R 1 , R 2 , R 3  and R 4  may be the same or different and each represents a hydrogen or halogen atom, or a C 1-9 alkyl, C 3-9 cycloalkyl, cyano, C 1-9 alkoxy or C 6-10 aryloxy group; R 5  represents a hydrogen atom or a C 1-9 alkyl, C 3-9 cycloalkyl or C 6-10 aryl group; and X is oxygen or sulfur; except that R 1 , R 2 , R 3 , R 4  and R 5  may not all be hydrogen;  with the provisos that: 
       ( a )  if X is sulfur, then at least one of R   1    and R   2    is other than hydrogen or at least one of R   3    and R   4    is fluoro, C   1-9   alkyl, C   3-9   cycloalkyl, cyano, C   1-9   alkoxy or C   6-10   aryloxy; and    
       ( b )  if X is oxygen, and R   5    is hydrogen, methyl, or ethyl, and one of R   1    and R   2    is chloro, then  ( i )  the other of R   1    and R   2    is other than hydrogen or chloro, or  ( ii )  at least one of R   3    and R   4    is other than hydrogen; and    
       ( c )  if X is oxygen, and R   5    is hydrogen, methyl, or ethyl, and one of R   1    and R   2    is methoxy, then  ( i )  the other of R   1    and R   2    is other than hydrogen or methoxy, or  ( ii )  at least one of R   3    and R   4    is other than hydrogen; and    
       ( d )  if X is oxygen, and R   5    is hydrogen, methyl, or ethyl, and one of R   1    and R   2    is methyl, then  ( i )  the other of R   1    and R   2    is other than hydrogen or  ( ii )  at least one of R   3    and R   4    is other than hydrogen; and    
       ( e )  if X is oxygen, R   5    is hydrogen, methyl or ethyl, and R   1    and R   2    are both hydrogen, then at least one of R   3    and R   4    is other than hydrogen and methyl;    
       which method comprises forming an intermediate aryloxy- or arylthio-benzaldehydes or ketones by reacting a corresponding (thio)phenol with fluorobenzaldehyde or a fluoroaryl ketone in a solvent in the presence of potassium carbonate at temperatures in the range of 100° to 200° C. under a non-oxidizing gas, extracting the intermediate and then reacting the intermediate with semicarbazide and collecting the resulting precipitate of the desired compound.  
     
     
       6. A method of treating a human or animal patient for a disorder of the central nervous system, comprising administering to said patient an effective amount of a compound having the general formula I:                    
       wherein: R 1 , R 2 , R 3  and R 4  may be the same or different and each represents hydrogen, halo, C 1-9 alkyl, C 3-9 cycloalkyl, cyano, C 1-9 alkoxy or C 6-10 aryloxy; R 5  represents hydrogen, C 1-9 alkyl, C 3-9 cycloalkyl or C 6-10 aryl; and X is oxygen or sulfur; with the proviso that; :  
       a) at least one of R 1 , R 2 , R 3  or R 4  is other than hydrogen, or  
       b) R 5  is other than hydrogen, methyl and ethyl;  
       or a pharmaceutically acceptable salt thereof. 
     
     
       7. A method according to  claim 6  wherein said disorder exhibits convulsions or seizures. 
     
     
       8. A method according to  claim 6  wherein said disorder exhibits epileptic seizures. 
     
     
       9. A compound of  claim 1  which is selected from the group consisting of 4-(4-bromophenoxy)benzaldehyde semicarbazone; 4-(4-iodophenoxy)benzaldehyde semicarbazone; 4-(4-methylphenoxy)benzaldehyde semicarbazone; 4-(4-cyanophenoxy)benzaldehyde semicarbazone; 4-(2-fluorophenoxy)benzaldehyde semicarbazone; 4-(3-fluorophenoxy)benzaldehyde semicarbazone; 4-(2,3-difluorophenoxy)benzaldehyde semicarbazone; 4-(2,4-difluorophenoxy)benzaldehyde semicarbazone; 4-(2,5-difluorophenoxy)benzaldehyde semicarbazone; 4-(2,6-difluorophenoxy)benzaldehyde semicarbazone; 4-(3,4-difluorophenoxy)benzaldehyde semicarbazone; 4-(3,4-dichlorophenoxy)benzaldehyde semicarbazone; 4-(4-chloro-2-fluorophenoxy)benzaldehyde semicarbazone; 4-(2-chloro-4-fluorophenoxy)benzaldehyde semicarbazone; 4-(2-bromo-4-fluorophenoxy)benzaldehyde semicarbazone; 4-(2-methylphenoxy)benzaldehyde semicarbazone; 4-(3-methylphenoxy)benzaldehyde semicarbazone; 4-(4-ethylphenoxy)benzaldehyde semicarbazone; 4-(4-n-propylphenoxy)benzaldehyde semicarbazone; 4-(4-s-butylphenoxy)benzaldehyde semicarbazone; 4-(4-t-butylphenoxy)benzaldehyde semicarbazone; 4-(4-fluorophenoxy)acetophenone semicarbazone; 4-(4-bromophenoxy)acetophenone semicarbazone; 4-(4-fluorophenoxy)propiophenone semicarbazone; 4-(4-bromophenoxy)propiophenone semicarbazone; 4-(4-fluorophenylmercapto)benzaldehyde semicarbazone; 4-(4-chlorophenylmercapto)benzaldehyde semicarbazone; 4-(4bromophenylmercapto)benzaldehyde semicarbazone; 4-(4-methylphenylmercapto)benzaldehyde semicarbazone; and  4 (4-fluorophenylmercapto)acetophenone semicarbazone. 
     
     
       10. A composition comprising the compound of any one of claims  1 - 4  and  9 , and a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
       11. A method of treating a human or animal patient for a disorder of the central nervous system comprising administering to said patient an effective amount of a compound of any one of claims  1 - 4  and  9 , or a pharmaceutically acceptable salt thereof. 
     
     
       12. A method according to  claim 11 , wherein said disorder exhibits convulsions or seizures. 
     
     
       13. A method according to  claim 12 , wherein said disorder exhibits epileptic seizures. 
     
     
       14. A method according to  claim 6 , wherein said compound is administered as part of a composition comprising a pharmaceutically acceptable carrier. 
     
     
       15. A method according to  claim 11 , wherein said compound is administered as part of a composition comprising a pharmaceutically acceptable carrier. 
     
     
       16. A method according to  claim 6 , wherein X is oxygen.  
     
     
       17. A method according to  claim 6 , wherein one of R 1    and R   2    is halogen, and the other of R   1    and R   2    is hydrogen or halogen, R   3    and R   4    are each hydrogen, R   5    is hydrogen or C   1-3   alkyl, and X is O or S.    
     
     
       18. A method according to  claim 17 , wherein at least one of R 1    and R   2    is fluoro.    
     
     
       19. A method according to  claim 17 , wherein X is O.  
     
     
       20. A method according to  claim 6 , wherein said compound possesses an ED 50    from  1  to  5  mg/kg in a maximal electroshock screen in rate.    
     
     
       21. The method according to  claim 20 , wherein said compound possesses an ED 50    from  2  to  3  mg/kg in a maximal electroshock screen in rats.    
     
     
       22. A compound of general formula I:                    
       
         or a pharmaceutically acceptable salt thereof, wherein:  
       
       
         R 
         1  
         and R 
         2  
         are independently hydrogen or halogen;  
       
       
         R 
         3  
         and R 
         4  
         are each hydrogen;  
       
       
         R 
         5  
         is hydrogen or C 
         1-3 
         alkyl; and  
       
       
         X is O or S;  
       
       
         provided that R 
         1  
         and R 
         2  
         are not both hydrogen, R 
         1  
         and R 
         2  
         do not consist of hydrogen and chloro, and R 
         1  
         and R 
         2  
         are not both chloro.  
       
     
     
       23. A compound according to  claim 22 , wherein X is O.  
     
     
       24. A compound according to  claim 22 , wherein at least one of R 1    and R   2    is fluoro.    
     
     
       25. A compound according to  claim 22 , wherein R 5    is hydrogen.    
     
     
       26. A compound selected from the group consisting of: 
           4   -(   4   - bromophenoxy)benzaldehyde semicarbazone; and    
           4   -(   4   - iodophenoxy ) benzaldehyde semicarbozone;    
       
         or a pharmaceutically acceptable salt thereof.  
       
     
     
       27. A compound selected from the group consisting of: 
           4   -(   2   - fluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   3   - fluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 3   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 4   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 5   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 6   - difluorophenoxy ) benzaldehyde semicarbazone; and    
           4   -(   3 , 4   - difluorophenoxy ) benzaldehyde semicarbazone;    
       
         or a pharmaceutically acceptable salt thereof.  
       
     
     
       28. A compound selected from the group consisting of: 
           4   -(   4   - chloro -   2   - fluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2   - chloro -   4   - fluorophenoxy ) benzaldehyde semicarbazone; and    
           4   -(   2   - bromo -   4   - fluorophenoxy ) benzaldehyde semicarbazone;    
       
         or a pharmaceutically acceptable salt thereof.  
       
     
     
       29. A compound selected from the group consisting of: 
           4   -(   4   - fluorophenoxy ) acetophenone semicarbazone;    
           4   -(   4   - bromophenoxy ) acetophenone semicarbazone;    
           4   -(   4   - fluorophenoxy ) propiophenone semicarbazone;    
           4   -(   4   - bromophenoxy ) propiophenone semicarbazone;    
           4   -(   4   - fluorophenylmercapto ) benzaldehyde semicarbazone;    
           4   -(   4   - bromophenylmercapto ) benzaldehyde semicarbazone; and    
           4   -(   4   - fluorophenylmercapto ) acetophenone semicarbazone;    
       
         or a pharmaceutically acceptable salt thereof.  
       
     
     
       30. A compound of general formula I:                    
       
         or a pharmaceutically acceptable salt thereof, wherein:  
       
       
         R 
         1 
         , R 
         2 
         , R 
         3  
         and R 
         4  
         are independently hydrogen or halogen;  
       
       
         R 
         5  
         is hydrogen; and  
       
       
         X is O;  
       
       
         provided that R 
         1  
         and R 
         2  
         are not both hydrogen.  
       
     
     
       31. The compound  4 -(   4   - chlorophenoxy ) benzaldehyde semicarbazone or a pharmaceutically - acceptable salt thereof.    
     
     
       32. A compound of formula I:                    
       
         or a pharmaceutically acceptable salt thereof, wherein  
       
       
         R 
         1 
         , R 
         2 
         , R 
         3  
         and R 
         4  
         may be the same or different and each represents hydrogen, halo, C 
         1-9 
         alkyl, C 
         3-9 
         cycloalkyl, cyano, C 
         1-9 
         alkoxy or C 
         6-10 
         aryloxy;  
       
       
         R 
         5  
         represents hydrogen, C 
         1-9 
         alkyl, C 
         3-9 
         cycloalkyl or C 
         6-10 
         aryl; and  
       
       
         X is oxygen or sulfur;  
       
       
         with the provisos that:  
       
       ( a )  if X is sulfur, then at least one of R   1    and R   2    is other than hydrogen or at least one of R   3    and R   4    is fluoro, C   1-9   alkyl, C   3-9   cycloalkyl, cyano, C   1-9   alkoxy or C   6-10   aryloxy; and    
       ( b )  if X is oxygen, and R   5    is hydrogen, methyl, or ethyl, and one of R   1    and R   2    is chloro, then  ( i )  the other of R   1    and R   2    is other than hydrogen or chloro, or  ( ii )  at least one of R   3    and R   4    is other than hydrogen; and    
       ( c )  if X is oxygen, and R   5    is hydrogen, methyl, or ethyl, and one of R   1    and R   2    is methoxy, then  ( i )  the other of R   1    and R   2    is other than hydrogen or methoxy, or  ( ii )  at least one of R   3    and R   4    is other than hydrogen; and    
       ( d )  if X is oxygen, and R   5    is hydrogen, methyl, or ethyl, and one of R   1    and R   2    is methyl, then  ( i )  the other of R   1    and R   2    is other than hydrogen or  ( ii )  at least one of R   3    and R   4    is other than hydrogen; and    
       ( e )  if X is oxygen, R   5    is hydrogen, methyl or ethyl, and R   1    and R   2    are both hydrogen, then at least one of R   3    and R   4    is other than hydrogen and methyl.    
     
     
       33. A compound according to  claim 32 , wherein at least one of R 1    and R   2    represents fluoro, R   3    and R   4    are each hydrogen, R   5    is hydrogen or C   1-3   alkyl, and X is oxygen.    
     
     
       34. A compound according to  claim 32 , wherein at least one of R 1    and R   2    represent fluoro, R   5    is hydrogen, and X represents oxygen.    
     
     
       35.  4 -(   4   - Fluorophenoxy ) benzaldehyde semicarbazone or a pharmaceutically acceptable salt thereof.    
     
     
       36. The compound of  claim 32 , wherein said compound is selected from the group consisting of: 
           4   -(   4   - bromophenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - iodophenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - cyanophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2   - fluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   3   - fluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 3   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 4   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 5   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2 , 6   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   3 , 4   - difluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - chloro -   2   - fluorophenoxy ) benzaldehyde semicarbazone;    
           4   -(   2   - chloro -   4   -fluorophenoxy) benzaldehyde semicarbazone;    
           4   -(   2   - bromo -   4   -fluorophenoxy) benzaldehyde semicarbazone;    
           4   -(   4   - ethylphenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - n - propylphenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - s - butylphenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - t - butylphenoxy ) benzaldehyde semicarbazone;    
           4   -(   4   - fluorophenoxy ) acetophenone semicarbazone;    
           4   -(   4   - bromophenoxy ) acetophenone semicarbazone;    
           4   -(   4   - fluorophenoxy ) propiophenone semicarbazone;    
           4   -(   4   - bromophenoxy ) propiophenone semicarbazone;    
           4   -(   4   - fluorophenylmercapto ) benzaldehyde semicarbazone;    
           4   -(   4   - chlorophenylmercapto ) benzaldehyde semicarbazone;    
           4   -(   4   - bromophenylmercapto ) benzaldehyde semicarbazone;    
           4   -(   4   - methylphenylmercapto ) benzaldehyde semicarbazone; and    
           4   -(   4   - fluorophenylmercapto ) benzaldehyde semicarbazone.    
     
     
       37.  4 -(   3 , 4   - Dichlorophenoxy ) benzaldehyde semicarbazone or a pharmaceutically acceptable salt thereof.    
     
     
       38. A compound selected from the group consisting of: 
           4   -(   2   - methylphenoxy ) benzaldehyde semicarbazone;    
           4   -(   3   - methylphenoxy ) benzaldehyde semicarbazone; and    
           4   -(   4   - methylphenoxy ) benzaldehyde semicarbazone;    
       
         or a pharmaceutically acceptable salt thereof.  
       
     
     
       39. A composition comprising the compound of any one of claims  32 - 38  and a pharmaceutically acceptable diluent, excipient or carrier.  
     
     
       40. A method of treating a human or animal patient for a disorder of the central nervous system comprising administering to said patient an effective amount of a compound of any one of claims  32 - 38 , or a pharmaceutically acceptable salt thereof.  
     
     
       41. A method according to  claim 40 , wherein said disorder exhibits convulsions or seizures.  
     
     
       42. A method according to  claim 41 , wherein said disorder exhibits epileptic seizures.  
     
     
       43. A method according to  claim 40 , wherein said compound is administered as part of a composition comprising a pharmaceutically acceptable carrier.  
     
     
       44. The method of  claim 5 , wherein said method comprises: 
       ( i )  forming an intermediate aryloxy -  or arylthio - benzaldehyde or ketone by reacting a corresponding  ( thio ) phenol with fluorobenzaldehyde or a fluoroaryl ketone in a solvent in the presence of potassium carbonate at temperatures in the range of  100 ° to  200 ° C. under nitrogen;    
       ( ii )  monitoring for formation of said intermediate by thin layer chromatography;    
       ( iii )  adding water to the solvent containing said intermediate;    
       ( iv )  partitioning the intermediate into chloroform to form an intermediate solution;    
       ( v )  washing the intermediate solution with dilute aqueous sodium hydroxide;    
       ( vi )  drying the washed intermediate solution over anhydrous magnesium sulfate;    
       ( vii )  removing the chloroform from the dried and washed intermediate solution by solvent evaporation under vacuum to form an oil;    
       ( viii )  distilling said oil under reduced pressure to provide an extracted intermediate;    
       ( ix )  reacting the extracted intermediate with semicarbazide; and    
       ( x )  collecting the resulting precipitate of the desired compound.    
     
     
       45. The method of  claim 44 , wherein at ( i )  said solvent is dimethylacetamide.    
     
     
       46. The method of  claim 44 , wherein at ( i )  said temperature is about  155 ° C.    
     
     
       47. The method of  claim 44 , wherein at ( i )  the molar ratio of said corresponding  ( thio ) phenol and said fluorobenzaldehyde or fluoroaryl ketone is  0 . 15 : 0 . 14 .    
     
     
       48. The method of  claim 44 , wherein at ( v )  said dilute aqueous sodium hydroxide is about  4   %  sodium hydroxide and about  96   %  water  ( weight/volume ).