Novel aminoindanes

Abstract

The present invention relates to therapeutically active novel aminoindanes of formula (I). Also provided is a method of preparing compounds of formula (I), and pharmaceutical compositions comprising the compounds. The novel compounds act as modulators of metabotropic glutamate receptors and, as such, are useful in treating diseases of the central nervous system related to the metabotropic glutamate receptor system.

What is claimed is:  
     
         1 . A compound having structural formula (I):  
       
         
           
           
               
               
           
         
       
       stereoisomers thereof, or pharmaceutically acceptable salts or hydrates thereof, wherein: 
 R1, and R2 are selected from the group comprising: 
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 
 X is an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol;  
 Y is a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea and thiourea;  
 m is 0, 1; and  
 R3, R4, R5, R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof;  
 with the proviso:  
 i) when X is COOH, Y is NH 2 , R3=R4=R5=R6=H, then both R1 and R2 are not H at the same time;  
 ii) when n=0, X is COOH, Y is NH 2 , R1=R2=R6=H and one of the groups R3, R4 or 5 is COOH, then the remaining two groups of R3, R4 and R5 are not both H at the same time.  
 
     
     
         2 . The compound according to  claim 1 , wherein R1 is H, CO 2 H or CH 2 CO 2 H.  
     
     
         3 . The compound according to  claim 1 , wherein R2 is H, CO 2 H, or CH 2 CO 2 H.  
     
     
         4 . The compound according to  claim 1 , wherein said compound is selected from the group of compounds:  
       
         
           
           
               
               
           
         
       
     
     
         5 . A process for the preparation of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable metabolically-labile ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein: 
 R1, and R2 are selected from the group comprising: 
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 
 X is an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol;  
 Y is a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea and thiourea;  
 m is 0, 1; and  
 R3, R4, R5, R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof; which comprises:  
 b) hydrolyzing a compound of formula (IIa) or (IIb):  
                     
 wherein: R1, and R2 are selected from the group comprising:  
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n borono, —CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, wherein n=1, 2, 3, 4, 5, or 6; and  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof, R7 is a hydrogen atom or an acyl group. Preferred functional groups for R7 are hydrogen and C 2 -C 6  alkanoyl groups, such as acetyl; or  
 c) hydrolyzing a compound of formula (IIa) or (IIIb):  
                     
 wherein:  
 R1, R2, R3, R4, R5 and R6 are as defined above, R8 and R9 are each independently represent a hydrogen atom, a (C 2 -C 6 ) alkanoyl group, a (C 1 -C 4 ) alkyl group, a (C 3 -C 4 ) alkenyl group or a phenyl (C 1 -C 4 ) alkyl group wherein the phenyl is unsubstituted or substituted by halogen, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy, or a salt thereof, or  
 d) deprotecting a compound of formula (IVa) or (IVb)  
                     
 wherein: R1, R2, R3, R4, R5 and R6 are as defined above and R10 is a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R11 represents a hydrogen atom or a nitrogen protecting group;  
 whereafter, if necessary and/or desired, the following steps are carried out:  
 (i) resolving the compound of Formula I;  
 (ii) converting the compound of Formula I into a non-toxic metabolically labile ester or amide thereof and/or;  
 (iii) converting the compound of Formula I or a non-toxic metabolically labile ester or amide thereof into a pharmaceutically acceptable salt thereof.  
 
     
     
         6 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient, and a compound of structural formula (I):  
       
         
           
           
               
               
           
         
       
       or stereoisomers thereof, or pharmaceutically acceptable salts or hydrates thereof, wherein: 
 R1, and R2 are selected from the group comprising:  
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol, and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 X is an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, and isoxazol;  
 Y is a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea and thiourea;  
 m is 0, 1; and  
 R3, R4, R5, R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof.  
 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said compound is selected from the group of compounds:  
       
         
           
           
               
               
           
         
       
     
     
         8 . A use of an effective amount of a compound of structural formula (I):  
       
         
           
           
               
               
           
         
       
       or stereoisomers thereof, or pharmaceutically acceptable salts or hydrates thereof, in modulating one or more metabotropic glutamate receptor functions in warm blooded mammals, wherein said use comprises administering an effective amount of a compound of formula (I); wherein: 
 R1 and R2 are selected from the group comprising:  
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol, and —(CH 2 ) n -isoxazol, where n=l, 2, 3, 4, 5, or 6;  
 X is an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol;  
 Y is a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea and thiourea;  
 m is 0, 1; and  
 R3, R4, R5, R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl and pharmaceutically acceptable ester or salt thereof,  
 
     
     
         9 . A use of an effective amount of a compound of structural formula (I):  
       
         
           
           
               
               
           
         
       
       or stereoisomers thereof, or pharmaceutically acceptable salts or hydrates thereof, in treating a neurological disease or disorder selected from the group comprising: 
 cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia, stroke, cardiac arrest, spinal cord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, drug tolerance, withdrawal and cessation (i.e. opiates, benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation, anxiety and related disorders (e.g. panic attach), emesis, brain edema, chronic pain, sleep disorders, Tourette's syndrome, attention deficit disorder, and tardive dyskinesia, wherein said use comprises administering an effective amount of a compound of formula (I);  
 wherein: R1, and R2 are selected from the group comprising:  
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol, and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 X is an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol;  
 Y is a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea and thiourea;  
 m is 0, 1; and  
 R3, R4, R5, R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof.  
 
     
     
         10 . A use of an effective amount of a compound of structural formula (I):  
       
         
           
           
               
               
           
         
       
       or stereoisomers thereof, or pharmaceutically acceptable salts or hydrates thereof, in treating a psychiatric disease or disorder selected from the group comprising: schizophrenia, anxiety and related disorders (e.g. panic attack), depression, bipolar disorders, psychosis, and obsessive compulsive disorders, wherein said use comprises administering an effective amount of a compound of formula (I); 
 wherein: R1, and R2 are selected from the group comprising:  
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —CH 2 ) n -isoxazol, where n-1, 2, 3, 4, 5, or 6;  
 X is an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol and isoxazol;  
 Y is a basic group selected from the group comprising 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea and thiourea;  
 m is 0, 1; and R3, R4, R5, R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof.  
 
     
     
         11 . The use according to any one of claims  8 ,  9  and  10  wherein said compound is selected from the group of compounds comprising:  
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound of formula (IIa):  
       
         
           
           
               
               
           
         
       
       wherein: R1, and R2 are selected from the group consisting of: 
 i) H;  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof, R7 is a hydrogen atom or an acyl group. Preferred functional groups for R7 are hydrogen and (C 2 -C 6 ) alkanoyl groups, such as acetyl.  
 
     
     
         13 . A compound of formula (IIIa):  
       
         
           
           
               
               
           
         
       
       wherein: wherein: R1 and R2 are selected from the group consisting of: 
 i) H;  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R8 and R9 are each independently represent a hydrogen atom, a (C 2 -C 6 ) alkanoyl group, a (C 1 -C 4 ) alkyl group, a (C 3 -C 4 ) alkenyl group or a phenyl (C 1 -C 4 ) alkyl group wherein the phenyl is unsubstituted or substituted by halogen, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy, or a salt thereof.  
 
     
     
         14 . A compound of formula (IVa):  
       
         
           
           
               
               
           
         
       
       wherein: wherein: wherein: R1, and R2 are selected from the group consisting of: 
 i) H  
 iii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, (CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R10 is a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R11 is a hydrogen atom or a nitrogen protecting group; with the proviso, when R1=R2=R3=R4=R5=R6=H and:  
 i) R11 is H then R10 is other than methyl or ethyl; or  
 ii) R11is —CO 2 CH 2 C 6 H 5  then R10 is other than H or CH 3 .  
 
     
     
         15 . A compound of formula (IIb):  
       
         
           
           
               
               
           
         
       
       wherein: wherein: wherein: R1 and R2 are selected from the group consisting of: 
 i) H  
 iv) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R7 is a hydrogen atom or an acyl group. Preferred functional groups for R7 are hydrogen and (C 2 -C 6 ) alkanoyl groups, such as acetyl.  
 
     
     
         16 . A compound of formula (IIIb):  
       
         
           
           
               
               
           
         
       
       wherein: R1, and R2 are selected from the group consisting of: 
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH 2 ) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH 2 ) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R8 and R9 are each independently represent a hydrogen atom, a (C 2 -C 6 ) alkanoyl group, a (C 1 -C 4 ) alkyl group, a (C 3 -C 4 ) alkenyl group or a phenyl (C 1 -C 4 ) alkyl group wherein the phenyl is unsubstituted or substituted by halogen, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy, or a salt thereof.  
 
     
     
         17 . A compound of formula (IVb):  
       
         
           
           
               
               
           
         
       
       wherein: wherein: wherein: R1 and R2 are selected from the group consisting of: 
 i) H  
 ii) an acidic group selected from the group comprising carboxy, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —(CH2) n -carboxy, —(CH 2 ) n -phosphono, —(CH 2 ) n -phosphino, —(CH 2 ) n -sulfono, —(CH 2 ) n -sulfino, —(CH 2 ) n -borono, —(CH 2 ) n -tetrazol and —(CH2) n -isoxazol, where n=1, 2, 3, 4, 5, or 6;  
 R3, R4, R5 and R6 are independently H, nitro, amino, halogen, tritium, trifluoromethyl, trifluoroacetyl, sulfo, carboxy, carbamoyl, sulfamoyl, or pharmaceutically acceptable ester or salt thereof; R10 is a hydrogen atom or a carboxyl protecting group or a salt thereof, and R11 is a hydrogen atom or a nitrogen protecting group; with the proviso, when R1=R2=R3=R4=R5=R6=R10=H, then R11 is other than CO 2 t-Bu.