Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof

Abstract

This invention is related to carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones represented by Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: Y is oxygen or sulfur; R 1 , R 21 , R 22 and R 23 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; or R 22 and R 23 , together with the N, form a heterocycle; A 1 and A 2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is one or O, S, NR 24 , CR 25 R 26 , C(O), NR 24 C(O), C(O)NR 24 , SO, SO 2 or a covalent bond; where R 24 , R 25 and R 26 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl. The invention also is directed to the use of carbocycle and heterocycle substituted semicarbazones and thiosemicarbazones for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), for the treatment and prevention of otoneurotoxicity and eye diseases involving glutamate toxicity and for the treatment, prevention or amelioration of pain, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy and urinary incontinence.

What is claimed is:  
     
         1 . A method of treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Y is oxygen or sulfur;  
 R 1  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;  
 R 21 , R 22  and R 23  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 21 , is defined as above, and R 22  and R 23  together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of piperidine, piperazine and morpholine;  
 A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;  
 X is one or O, S, NR 24 , CR 25 R 26 , C(O), NR 24 C(O), C(O)NR 24 , SO, SO 2  or a covalent bond; where  
 R 24  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; and 
 R 25  and R 26  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;  
 provided when both Ar 1  and Ar 2  are phenyl and X is O or S, then said disorder is other than convulsions.  
 
 
     
     
         2 . The method according to  claim 1 , wherein A 1  and A 2  are both optionally substituted aryl moieties.  
     
     
         3 . The method according to  claim 1 , wherein 
 A 1  and A 2  are phenyl moieties, that are each independently optionally substituted by one or two substituents independently selected from the group consisting of halogen, C 1-6  alkyl, C 3-8  cycloalkyl, cyano, C 1-6  alkoxy and C 6-10  aryloxy;    Y is O;    R 1  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or C 6-10  aryl;    R 21 , R 22  and R 23  are independently hydrogen or C 1-6  alkyl; and    X is oxygen or sulfur.    
     
     
         4 . The method according to  claim 1 , wherein at least one of R 21 , R 22  and R 23  is C 1-6  alkyl.  
     
     
         5 . The method according to  claim 1 , wherein said compound is selected from the group consisting of: 
 4-phenoxybenzaldehyde semicarbazone;    4-(3,4-methylenedioxyphenoxy)benzaldehyde semicarbazone;    4-(4-fluorophenoxy)benzaldehyde semicarbazone;    4-(4-chlorophenoxy)benzaldehyde semicarbazone;    4-(4-bromophenoxy)benzaldehyde semicarbazone;    4-(4-methoxyphenoxy)benzaldehyde semicarbazone;    4-(4-trifluoromethylphenoxy)benzaldehyde semicarbazone;    4-(4-methylphenoxy)benzaldehyde semicarbazone;    4-(3,4-difluorophenoxy)benzaldehyde semicarbazone;    4-(4-chloro-2-fluorophenoxy)benzaldehyde semicarbazone;    4-(4-nitrophenoxy)benzaldehyde semicarbazone;    4-(3-methylphenoxy)benzaldehyde semicarbazone;    4-(4-t-butylphenoxy)benzaldehyde semicarbazone;    4-(4-propylphenoxy)benzaldehyde semicarbazone;    4-(4-s-butylphenoxy)benzaldehyde semicarbazone;    4-(4-bromophenoxy)acetophenone semicarbazone;    4-(4-fluorophenoxy)acetophenone semicarbazone;    4-(4-fluorophenoxy)-3-fluoroacetophenone semicarbazone;    4-(4-chlorophenoxy)acetophenone semicarbazone;    4-(4-bromophenoxy)propiophenone semicarbazone;    4-(4-fluorophenoxy)propiophenone semicarbazone;    4-(4-chlorophenoxy)propiophenone semicarbazone;    4-phenylmercaptobenzaldehyde semicarbazone;    4-(4-fluorophenylmercapto)benzaldehyde semicarbazone;    4-(4-chlorophenylmercapto)benzaldehyde semicarbazone;    4-cyclohexyloxybenzaldehyde semicarbazone;    4-cycloheptyloxybenzaldehyde semicarbazone;    4-(5-indanyloxy)benzaldehyde semicarbazone;    4-(6-quinolinyloxy)benzaldehyde semicarbazone;    4-(4-fluorophenoxy)-3-fluorobenzaldehyde semicarbazone;    4-(4-fluorophenoxy)cyclohexane-1-carboxaldehyde semicarbazone;    4-(tetrahydropyranyloxy)benzaldehyde semicarbazone;    4-(1-methyl-4-piperidinoxy)benzaldehyde semicarbazone;    4-(diphenylmethoxy)benzaldehyde semicarbazone;    4-(4-trifluoromethylphenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(diphenylmethoxy)benzaldehyde 2′-methylsemicarbazone;    4-benzylbenzaldehyde 2′-methylsemicarbazone;    4-(5-indanyloxy)benzaldehyde 2′-methylsemicarbazone;    4-(3,4-methylenedioxyphenoxy)benzaldehyde 2′-methylsernicarbazone;    3-fluoro-4-(3,4-methylenedioxyphenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(4-nitrophenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(4-fluorophenoxy)-3-fluorobenzaldehyde 2′-methylsemicarbazone;    4-(4-fluorophenoxy)benzaldehyde 4′-methylsemicarbazone; and    4-(4-fluorophenoxy)benzaldehyde 2′-methylsemicarbazone.    
     
     
         6 . The method according to  claim 1 , wherein said compound is selected from the group consisting of: 
 4-(2-pyridinoxy)benzaldehyde semicarbazone;    4-(3-pyridinoxy)benzaldehyde semicarbazone;    4-(4-pyridinoxy)benzaldehyde semicarbazone;    4-(4-chloro-2-pyridinoxy)benzaldehyde semicarbazone;    4-(2-pyrimidinoxy)benzaldehyde semicarbazone;    2-phenoxypyridine-5-carboxaldehyde semicarbazone;    2-(4-chlorophenoxy)pyridine-5-carboxaldehyde semicarbazone; and    2-(4-fluorophenoxy)pyridine-5-carboxaldehyde semicarbazone.    
     
     
         7 . A method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating, preventing or ameliorating neurodegenerative conditions; treating, preventing or ameliorating otoneurotoxicity and eye diseases involving glutamate toxicity; treating, preventing or ameliorating pain; treating, preventing or ameliorating manic depression; providing local anesthesia; or treating arrhythmias and urinary incontinence, comprising administering to a mammal in need of such treatment an effective amount of a compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Y is oxygen or sulfur;  
 R 1  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;  
 R 21 , R 22  and R 23  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 21 , is defined as above, and R 22  and R 23  together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of piperidine, piperazine and morpholine;  
 A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;  
 X is one or O, S, NR 24 , CR 25 R 26 , C(O), NR 24 C(O), C(O)NR 24 , SO, SO 2  or a covalent bond; where  
 R 24  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; and  
 R 25  and R 26  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl.  
 
     
     
         8 . The method according to  claim 7 , wherein method is for treating, preventing or ameliorating pain and said pain is one of neuropathic pain, surgical pain or chronic pain.  
     
     
         9 . The method according to  claim 7 , wherein: 
 A 1  and A 2  are phenyl moieties, that are each independently optionally substituted by one or two substituents independently selected from the group consisting of halogen, C 1-6  alkyl, C 3-8  cycloalkyl, cyanc, C 1-6  alkoxy and C 6-10  aryloxy;    Y is O;    R 1  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or C 6-10  aryl;    R 21 , R 22  and R 23  are independently hydrogen or C 1-6  alkyl; and    X is oxygen or sulfur.    
     
     
         10 . The method of  claim 7 , wherein: 
 A 1  is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A 2  is an optionally substituted heteroaryl or aryl group selected from the group consisting of pyridyl, pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and quinoxalinyl.    
     
     
         11 . The method of  claim 7 , wherein 
 A 1  is an optionally substituted aryl group selected from the group consisting of phenyl or naphthyl, and A 2  is an optionally substituted carbocycle or heterocycle selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, exo-norbornyl and cyclopentenyl.    
     
     
         12 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
 Y is oxygen or sulfur;  
 R 1  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;  
 R 21 , R 22  and R 23  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R 21 , is defined as above, and R 22  and R 23  together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of piperidine, piperazine and morpholine;  
 A 1  and A 2  are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted;  
 X is one or O, S, NR 24 , CR 25 R 26 , C(O), NR 24 C(O), C(O)NR 24 , SO, SO 2  or a covalent bond; where  
 R 24  is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; and  
 R 25  and R 26  are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;  
 provided that:  
 when X is O or S, and R 21 , R 22  and R 23  are hydrogen or alkyl, then A 1  and A 2  are not both phenyl, optionally substituted by one or two non-hydrogen substituents.  
 
     
     
         13 . A compound according to  claim 12 , wherein R 21 , R 22  and R 23  are independently hydrogen or alkyl.  
     
     
         14 . A compound according to  claim 12 , wherein at least one of R 21 , R 22  and R 23  is C 1-6  alkyl.  
     
     
         15 . A compound according to  claim 12 , wherein R 1  is hydrogen or alkyl.  
     
     
         16 . A compound according to  claim 12 , wherein X is O or S.  
     
     
         17 . A compound according to  claim 12 , wherein Y is oxygen.  
     
     
         18 . A compound according to  claim 12 , wherein 
 Y is oxygen;    R 1  is hydrogen, alkyl, haloalkyl, or aryl;    R 21 , R 22  and R 23  are independently hydrogen or alkyl;    Ar 1  is phenyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen;    Ar 2  is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, quinolinyl, quinoxalinyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen; and    X is O or S.    
     
     
         19 . A compound according to  claim 12 , wherein 
 Y is oxygen;    R 1  is hydrogen, alkyl, haloalkyl, or aryl;    R 21 , R 22  and R 23  are independently hydrogen or alkyl;    Ar 1  is pyridinyl, pyrimidinyl, 1,3,5-triazinyl, quinolinyl, furanyl, thiophenyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen,    Ar 2  is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethyelendioxyphenyl or naphthyl, optionally substituted with hydrogen, alkyl, haloalkyl, or halogen; and    X is O or S.    
     
     
         20 . A compound of  claim 12 , having Formula II or Formula III:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1 , R 21 , R 22 , R 23 , X, Y, A 1  and A 2  are as defined in  claim 12 , provided that A 1  and A 2  are other than optionally substituted phenyl; and  
 R 3 , R 4 , R 5  and R 6  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or  
 R 3  and R 4  or R 5  and R 6  form a bridge selected from the group consisting of 
 —OCH 2 O—, —OCF 2 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —OCH 2 CH 2 O—, —CH 2 N(R 7 )CH 2 —, —CH 2 CH 2 N(R 7 )CH 2 —, —CH 2 N(R 7 )CH 2 CH 2 — and —CH═CH—CH═CH—; where R 7  is hydrogen, alkyl or cycloalkyl;  
 
 R 8 , R 9 , R 10 , R 11  and R 12  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or  
 one of R 8  and R 9 , or R 9  and R 10 , or R 10  and R 11 , or R 11  and R 12  form a carbocycle or heterocycle selected from the group consisting of —OCH 2 O—, —OCF 2 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, CH 2 CH 2 O—, —CH 2 N(R 7 )CH 2 , —CH 2 CH 2 N(R 7 )CH 2 —, —CH 2 N(R 7 )CH 2 CH 2 — and —CH═CH—CH═CH—; where R 7  is hydrogen, alkyl or cycloalkyl.  
 
     
     
         21 . A compound of  claim 12 , having Formula IV or Formula V:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1 , R 21 , R 22 , R 23 , X, and Y are as defined in  claim 12;   
 A, B, C, D and E are independently nitrogen or carbon, provided that no more than three of A, B, C, D and E are nitrogen, and there is no substituent, except for oxygen, present on A, B, C, D or E when said A, B, C, D or E represents nitrogen;  
 R 3 , R 4 , R 5  and R 6  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or  
 R 3  and R 4  or R 5  and R 6  form a bridge selected from the group consisting of 
 —OCH 2 O—, —OCF 2 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCH 2 CH 2 O—, —CH 2 N(R 7 )CH 2 —, —CH 2 CH 2 N(R 7 )CH 2 —, —CH 2 N(R 7 )CH 2 CH 2 — and  
 —CH═CH—CH═CH—; where R 7  is hydrogen, alkyl or cycloalkyl; R 8 , R 9 , R 10 , R 11  and R 12  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or  
 
 one of R 8  and RP, or R 9  and R 10 , or R10 and R1  1 , or R 11  and R 12  form a carbocycle or heterocycle selected from the group consisting of CH 2 O—, —OCF 2 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCH 2 CH 2 O—, —CH 2 N(R 7 )CH 2 —, —CH 2 CH 2 N(R 7 )CH 2 —, —CH 2 N(R 7 )CH 2 CH 2 — and —CH═CH—CH═CH—; where R 7  is hydrogen, alkyl or cycloalkyl.  
 
     
     
         22 . A compound of  claim 12 , having the Formula VII or Formula VIII:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1 , R 21 , R 22 , R 23 , Y and X are as defined in  claim 12;   
 B 1  is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle; and  
 B 2  is an optionally substituted, saturated or partially unsaturated carbocycle or optionally substituted, saturated or partially unsaturated heterocycle;  
 R 3 , R 4 , R 5  and R 6  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, hetroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or  
 R 3  and R 4  or R 5  and R 6  form a bridge selected from the group consisting of 
 —OCH 2 O—, —OCF 2 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCH 2 CH 2 O—, —CH 2 N(R 7 )CH 2 —, —CH 2 CH 2 N(R 7 )CH 2 —, —CH 2 N(R 7 )CH 2 CH 2 — and  
 —CH═CH—CH═CH—; where R 7  is hydrogen, alkyl or cycloalkyl;  
 
 R 8 , R 9 , R 10 , R 11  and R 12  independently are hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or  
 one of R 8  and R 9 , or R 9  and R 10 , or R 10  and R 11 , or R 11  and R 12  form a carbocycle or heterocycle selected from the group consisting of —OCH 2 O—, —OCF 2 O—, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —OCH 2 CH 2 O—, —CH 2 N(R 7 )CH 2 —, —CH 2 CH 2 N(R 7 )CH 2 —, —CH 2 N(R 7 )CH 2 CH 2 — and —CH═CH—CH═CH—; where R 7  is hydrogen, alkyl or cycloalkyl.  
 
     
     
         23 . A compound according to  claim 22 , wherein B 1  is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyfl or piperidinyl.  
     
     
         24 . A compound according to  claim 22 , wherein B 2  is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl.  
     
     
         25 . A compound according to  claim 12 , wherein said compound is 
 4-(3,4-methylenedioxyphenoxy)benzaldehyde semicarbazone;    4-cycloheptyloxybenzaldehyde semicarbazone; and    4-(5-indanyloxy)benzaldehyde semicarbazone 4-cyclohexyloxybenzaldehyde semicarbazone;    4-(tetrahydropyranyloxy)benzaldehyde semicarbazone;    4-(1-methyl-4-piperidinoxy)benzaldehyde semicarbazone;    4-(diphenylmethoxy)benzaldehyde semicarbazone;    4-(4-fluorophenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(4-trifluoromethylphenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(diphenylmethoxy)benzaldehyde 2′-methylsemicarbazone;    4-benzylbenzaldehyde 2′-methylsemicarbazone;    4-(5-indanyloxy)benzaldehyde 2′-methylsemicarbazone;    4-(3,4-methylenedioxyphenoxy)benzaldehyde 2′-methylsemicarbazone;    3-fluoro-4-(3,4-methylenedioxyphenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(4-nitrophenoxy)benzaldehyde 2′-methylsemicarbazone;    4-(4-fluorophenoxy)-3-fluorobenzaldehyde 2′-methylsemicarbazone; and    4-(4-fluorophenoxy)benzaldehyde 4′-methylsemicarbazone.    
     
     
         26 . A compound according to  claim 12 , wherein said compound is selected from the group consisting of: 
 4-(2-pyridinoxy)benzaldehyde semicarbazone;    4-(3-pyridinoxy)benzaldehyde semicarbazone;    4-(4-pyridinoxy)benzaldehyde semicarbazone;    4-(4-chloro-2-pyridinoxy)benzaldehyde semicarbazone;    2-phenoxypyridine-5-carboxaldehyde semicarbazone;    2-(4-chlorophenoxy)pyridine-5-carboxaldehyde semicarbazone; and    2-(4-fluorophenoxy)pyridine-3-carboxaldehyde semicarbazone.    
     
     
         27 . A pharmaceutical composition, comprising the compound of any one of claims  12 - 26 , and a pharmaceutically acceptable carrier or diluent.