New pharmaceutical active compounds

Abstract

The present invention provides optionally substituted and/or annulated compounds of formula (I) wherein X, Y, Z and A is each independently carbon or nitrogen, and at least two of X, Y, Z and A are carbon; and pharmaceutically acceptable salts thereof with the proviso that: 3-(1H-Indol-3-yl)-1H-quinoxalin-2-one, 3-(2-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one, and 3-(1,2-Diphenyl-1H-indol-3-yl)-1H-quinoxalin-2-one are excluded from compounds of formula (I). The invention includes the use of compounds of formula (I) in medical therapy, particularly in the therapy of conditions requiring inhibition of protein kinase C.

1 . An optionally substituted and/or annulated compound of formula (I):  
                   
       wherein X, Y, Z and A is each independently carbon or nitrogen, and at least two of X, Y, Z and A are carbon;  
       and pharmaceutically acceptable salts thereof,  
       with the proviso that: 
 3-(1H-Indol-3-yl)-1H-quinoxalin-2-one,  
 3-(2-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one, and  
 3-(1,2-Diphenyl-1H-indol-3-yl)-1H-quinoxalin-2-one  
 are excluded from compounds of formula (I).  
 
     
     
         2 . A compound according to    claim 1   , of formula (IA):  
                   
       wherein X, Y, Z and A are as defined in    claim 1   , 
 R 1 , R 2 , R 3 , and R 4  is each independently H, hydroxy, amino, nitro, halo, C 1-6  alkyl, phenylC 1-6  alkyl, C 1-6  alkoxy, haloC 1-6  alkyl, carboxyC 1-6  alkyl ester or R 1  and R 2  or R 2  and R 3  or R 3  and R 4  form an annulated aromatic ring, or when the atom to which it would be attached is nitrogen, is absent;  
 R 5  and R 6  is each independently H, C 1-6  alkyl, hydroxyC 1-6  alkyl, aminoC 1-6  alkyl, phenylC 1-6  alkyl, carboxyC 1-6  alkyl, C 1-6  alkenyl, (phenylC 1-3  alkoxy)C 1-3  alkyl, (C 1-6  acyloxy)C 1-6  alkyl, (C 1-6  alkoxycarbonyl)C 1-6  alkyl, (mono- or di-C 1-6  alkyl)aminoC 1-6  alkyl, (C 1-6  alkyl)aminocarbonylC 1-6  alkyl, (C 1-6  acylamino)C 1-6  alkyl, (aminoC 1-3  alkylphenyl)C 1-3  alkyl, or aminodeoxysugar;  
 R 7  and R 8  is each independently H, amino, nitro, hydroxy, halogen,  
 C 1-6  alkoxy, phenylC 1-6  alkoxy or carboxyC 1-6  alkyl ester;  
 R 9  is H, C 1-6  alkyl, phenyl, halophenyl or phenylC 1-6  alkyl and wherein when R 5  and R 9  together comprise3-5 carbons they may be linked to generate a cyclic moiety which may be aminoC 1-6  alkyl substituted;  
 and wherein at least one of R 1  to R 9  is not H and wherein when the only one of R 1  to R 9  which is not H is R 9 , R 9  is not methyl;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         3 . A compound according to    claim 2   , wherein at least one of R 5  and R 6  is aminoC 1-6 alkyl.  
     
     
         4 . A compound according to any of    claims 1    to    3   , wherein at least one of Y and Z is substituted.  
     
     
         5 . A compound according to any one of    claims 1    to    4   , wherein at least one of Y and Z is substituted with halo, methoxy or carboxylic ester.  
     
     
         6 . A compound according to any one of    claims 1    to    5    wherein position 5 of the indole is substituted.  
     
     
         7 . A compound according to any one of    claims 2    to    6    wherein R 9  is H or alkyl.  
     
     
         8 . A compound according to any one of    claims 2    to    7    wherein R 5  or R 6  is an aminodeoxysugar, comprising a six membered ring.  
     
     
         9 . A compound according to any one of    claims 2    to    7    wherein R 5  and R 9  together form a six membered ring.  
     
     
         10 . A compound according to any one of    claims 1    to    9    wherein three or four of X,Y,Z and A are carbon.  
     
     
         11 . A compound according to any one of    claims 2    to    10    wherein R 1  and R 2 , or R 2  and R 3 , or R 3  and R 4  form an annulated aromatic ring.  
     
     
         12 . The compounds: 
 3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-ammonium acetate,    3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-methoxycarbonyl-indol-1-yl]-propyl-ammonium acetate,    3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-methoxycarbonyl-indol-1-yl]-propyl-ammonium acetate,    3-[5-Methoxycarbonyl-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[3-(4-tert-Butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-methoxycarbonyl-indol-1-yl]propyl-ammonium acetate,    3-[3-(4-(3-Ammoniumpropyl)-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-ammonium bis trifluoroacetate,    Dimethyl-{3-[3-(1-methyl-1H-indol-3-yl)-2-oxo-2H-quinoxalin-1-yl]-propyl}-ammonium trifluoroacetate,    3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[6-Benzyloxy-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[5-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[2-(4-Chloro-phenyl)-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[2-(4-Chloro-phenyl)-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-ethyl-indol-1-yl]-propyl-ammonium acetate,    3-[3-(5-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-1-yl]-propyl-ammonium acetate,    3-[6-Nitro-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    4-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]benzyl-ammonium acetate,    3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]benzyl-ammonium trifluoroacetate,    3-[3-(4-Benzyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium trifluoroacetate;    and other pharmaceutically acceptable salts thereof.    
     
     
         13 . The compound: 
 3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,    and other pharmaceutically acceptable salts thereof.    
     
     
         14 . A free amine of a compound according to    claim 12   .  
     
     
         15 . A compound according to any one of    claims 1    to    13   , for use in medical therapy.  
     
     
         16 . A compound according to    claim 15    wherein the medical therapy is the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders.  
     
     
         17 . Use of a compound according to any one of    claims 1    to    13    in the manufacture of a medicament for use in the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders.  
     
     
         18 . A method for the treatment of an inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorder, wherein a therapeutically effective amount of a compound according to any one of    claims 1    to    13    is administered to a mammal in the need of such treatment.  
     
     
         19 . A pharmaceutical composition wherein the active ingredient is a compound according to any one of    claims 1    to    13   .  
     
     
         20 . A compound of formula (II):  
                   
       wherein X, Y, Z, A, are as defined in    claim 1   ; R 1  to R 9  are as defined in    claim 2    and at least one of R 5  and R 6  carries a protected amino, carboxy or hydroxy group, or  
       a compound of formula (III)  
                 
 
       wherein R 5 , R 7 , R 8 , and R 9  are as defined in    claim 2   , but when R 5  carries an amino, carboxy or hydroxy groups, such group is in a protected form; and LG is a leaving group.  
     
     
         21 . A process for the preparation of a compound according to    claim 2    when at least one of R 5  and R 6  of formula (IA) carries an amino, carboxy or hydroxy group, and pharmaceutically acceptable salts thereof, comprising: 
 a) deprotecting a compound of formula (II) corresponding to formula (IA) but in which at least one of R 5  and R 6  carries protected amino, carboxy or hydroxy groups, or  
 b) converting a compound of formula (IA), in which at least one of R 5  and R 6  carries amino or carboxy groups 
 i) to a pharmaceutically acceptable salt thereof, or vice versa; or  
 ii) a pharmaceutically acceptable salt of a compound of formula (IA) into a different pharmaceutically acceptable salt; or  
 when R 6  is hydrogen, comprising reacting a compound of formula (III):  
                 
 
 wherein R 5 , R 7 , R 8 , and R 9  are as defined in    claim 2    and LG is a leaving group, with a compound of formula (IV):  
                 
 
 wherein R 1 -R 4  are as defined in    claim 2    and A, X, Y, and Z are as defined in    claim 1   ; and when R 5  in formula (III) carries an amino, carboxy or hydroxy groups such groups are suitably protected and the protecting group removed in a subsequent deprotecting step; or  
 when R 6  is other than H, comprising reacting a compound of formula (II) which corresponds to formula (I), but in which R 6  is H, with a suitable alkylating agent in the presence of a base and wherein when R 5  in formula (II) or the alkylating agent carries an amino, carboxy or hydroxy group, such group is suitably protected and the protecting group removed in a subsequent deprotecting step.