Sulfonylpyrazole and sulfonylpyrazoline carboxamidine derivatives as 5-ht6 antagonists

Abstract

This invention concerns compounds of the general formula (1): and derivatives thereof, which are antagonists of 5-HT 6 receptors, wherein the symbols have the meanings given in the description. The invention also concerns methods for the preparation of these compounds, to novel intermediates useful for their synthesis, and to uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in treating at least on disease or condition chosen from Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes.

1 - 27 . (canceled) 
     
     
         28 . A package comprising (i) a compound of formula (1) or a pharmacologically acceptable salt thereof, and (ii) instructions for the use thereof in the treatment of at least one disease or condition chosen from Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity, and type-2 diabetes,
 wherein the compound of formula (1) is:   
       
         
           
           
               
               
           
         
         or a tautomer, stereoisomer, N-oxide, or a pharmacologically acceptable salt of any of the foregoing, wherein: 
         R 1  is chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, and a phenyl group optionally substituted with one or more halogen atoms; 
         R 2  and R 3  independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, an alkyl(C 1-4 )—O-alkyl(C 1-4 )-phenyl group optionally substituted with one or more halogen atoms, and a phenyl group optionally substituted with one or more halogen atoms, or 
         R 1  and R 2 , together with the carbon atoms marked ‘a’ and ‘b’ form a C 5-8 -cycloalkyl ring, or 
         R 2  and R 3 , together with the carbon atom marked ‘b’ form a C 3-8 -cycloalkyl ring, or 
         R 2  and R 3 , together with the carbon atom marked ‘b’ form an optionally substituted C 5-8 -heterocycloalkyl ring; 
         R 4  and R 5  independently are chosen from hydrogen, an unsubstituted alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, an optionally substituted monocyclic aromatic group, an optionally substituted fused-bicyclic aromatic group, an optionally substituted monocyclic hetero-aromatic group, and an optionally substituted fused-bicyclic hetero-aromatic group; 
         R 3  and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 3-8 -cycloalkyl ring, or 
         R 3  and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form an optionally substituted C 5-8 -heterocycloalkyl ring; 
         R 6  and R 7  independently are chosen from a hydrogen atom, an alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, a (C 1-3 )alkoxy group, a dialkyl(C 1-3 )-amino-alkyl(C 1-3 ) group, an optionally substituted monocyclic, fused bicyclic aromatic, or hetero-aromatic group, an optionally substituted C 5-8 -cycloalkyl group, and an optionally substituted C 5-8 -heterocycloalkyl group, or 
         R 6  and R 7 , together with the nitrogen atom to which they are attached, form an optionally substituted C 5-8 -heterocycloalkyl group; and 
         R 8  is chosen from an optionally substituted monocyclic aromatic group, an optionally substituted fused-bicyclic aromatic group, an optionally substituted monocyclic hetero-aromatic group, an optionally substituted fused-bicyclic hetero-aromatic group, an -CR 9 ═CR 10 -aryl group wherein R 9  and R 10  independently are chosen from hydrogen, an alkyl-(C 1-3 ) group, an -C≡C-aryl group, an optionally substituted piperidinyl group, and a group —NR 11 R 12 , wherein R 11  and R 12  independently are chosen from hydrogen, an alkyl-(C 1-3 ) group, and an optionally substituted phenyl or benzyl group. 
       
     
     
         29 . The package according to  claim 28 , wherein:
 R 1  is hydrogen, or R 1  and R 2 , together with the carbon atoms marked ‘a’ and ‘b’ form a cyclohexyl ring;   R 2  and R 3  independently are chosen from hydrogen and an alkyl(C 1-3 ) group, or R 2  and R 3 , together with the carbon atom marked ‘b’ form a cyclopentyl or cyclohexyl ring;   R 4  and R 5  independently are chosen from hydrogen and an alkyl(C 1-3 ) group, or R 3  and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 3-8 -cycloalkyl ring; and   R 6  and R 7  independently are chosen from a hydrogen atom, an alkyl(C 1-3 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, a methoxy group, a cyclohexyl group, a benzyl group, and a 4-piperidinyl group.   
     
     
         30 . The package according to  claim 28 , wherein the moiety: 
       
         
           
           
               
               
           
         
         is chosen from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 1  and R 2 , together with the carbon atoms marked ‘a’ and ‘b’ form a C 5-8 -cycloalkyl ring, or, 
         R 2  and R 3 , together with the carbon atom marked ‘b’ form a C 3-8 -cycloalkyl or an optionally substituted C 5-8 -hetero-cycloalkyl ring, or 
         R 3  and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form a C 3-8 -cycloalkyl, or, 
         R 3  and R 4 , together with the carbon atoms marked ‘b’ and ‘c’ form an optionally substituted C 5-8 -heterocycloalkyl ring, 
         R 6  and R 7  independently are chosen from a hydrogen atom, an alkyl(C 1-4 ) group, an alkyl(C 1-4 ) group substituted with one or more halogen atoms, a (C 1-3 )alkoxy group, a dialkyl(C 1-3 )-amino-alkyl(C 1-3 ) group, an optionally substituted monocyclic or fused bicyclic aromatic or hetero-aromatic group, an optionally substituted C 5-8 -cycloalkyl or a C 5-8 -heterocycloalkyl group, and a benzyl group, or 
         R 6  and R 7 , together with the nitrogen atom to which they are attached, form an optionally substituted C 5-8 -hetero-cycloalkyl group, and 
         R 8  is an optionally substituted monocyclic, or a fused-bicyclic aromatic or a hetero-aromatic group, or 
         R 8  is a -CR 9 ═CR 10 -aryl group wherein R 9  and R 10  independently are chosen from hydrogen and an alkyl-(C 1-3 ) group, or 
         R 8  is chosen from an -C≡C-aryl group, an optionally substituted piperidinyl group, a —NR 11 R 12  group, wherein R 11  and R 12  independently are chosen from hydrogen, an alkyl-(C 1-3 ) group, and an optionally substituted phenyl or benzyl group. 
       
     
     
         31 . The package according to  claim 28 , wherein the moiety: 
       
         
           
           
               
               
           
         
         is chosen from: 
       
       
         
           
           
               
               
           
         
       
     
     
         32 . The package according to  claim 28 , wherein the compound of formula (1) is a compound chosen from: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The package according to  claim 28 , wherein R 1 , R 4 , R 5  and R 6  are hydrogen, R 2  and R 3  independently are an alkyl(C 1-3 ) group, or R 2  and R 3 , together with the carbon atom marked ‘b’ form a cyclopentyl, or cyclohexyl ring, and R 7  is an alkyl(C 1-3 ) group. 
     
     
         34 . The package according to  claim 28 , wherein the compound of formula (I) is an optically active enantiomer. 
     
     
         35 . The package according to  claim 28 , wherein either one, or both, of the two potentially asymmetric carbon atoms in the pyrazoline ring of the compound of formula (I), is a levorotatory enantiomer. 
     
     
         36 . The package according to  claim 28 , wherein either one, or both, of the two potentially asymmetric carbon atoms in the pyrazoline ring of the compound of formula (I), is a dextrorotatory enantiomer.