Pharmaceutically active compounds

Abstract

The present invention relates to compounds of formula (I) wherein: Ar 1 or Ar 2 is an optionally substituted indole, and the other group is an optionally substituted aromatic or heteroaromatic group, suitably an optionally substituted bicyclic heteroaromatic group, preferably an optionally substituted indole, X is O or S, R is H, OH, NH 2 , C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, and R 1 is H, C 1-6 alkyl, fluoro substituted C 1-6 alkyl, phenyl, benzyl, carboC 1-6 alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C 1-6 alkylcarbamoyl) and salts and solvates thereof and solvates of such salts, and the use of such compounds in medical therapies.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar 1  or Ar 2  is an optionally substituted indole, and the other group is an optionally substituted aromatic or heteroaromatic group, suitably an optionally substituted bicyclic heteroaromatic group, preferably an optionally substituted indole,  
 X is O or S,  
 R is H, OH, NH 2 , C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, and  
 R 1  is H, C 1-6 alkyl, fluoro substituted C 1-6 alkyl, phenyl, benzyl, carboC 1-6 alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C 1-6 alkylcarbamoyl)  
 and salts and solvates thereof and solvates of such salts.  
 
     
     
         2 . Compounds of formula (II) and (III)  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar is an optionally substituted aromatic or heteroaromatic group,  
 X is O or S,  
 R is H, OH, NH 2 , C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl,  
 R1 is H, C 1-6 alkyl, fluoro substituted C 1-6 alkyl, phenyl, benzyl, carboC 1-6 alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C 1-6 alkylcarbamoyl),  
 R2 is H, C 1-6 alkyl, haloC 1-6 alkyl, bensyl, C 1-3 alkoxy substituted bensyl, nitrileC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, (pyridinylmethyl)aminoC 1-6 alkyl, (mono- or di-C 1-6 alkyl)aminoC 1-6 alkyl, (mono- or di-C 1-6 haloalkyl)aminoC 1-6 alkyl, aminoC 3-7 cycloalkyl, (mono- or di-C 1-6  alkyl)aminoC 3-7 cycloalkyl, (aminoC 3-7 cycloalkyl)C 1-3 alkyl, (hydroxyC 1-6 alkyl)aminoC 1-6 alkyl, (aminoC 1-6 alkyl)aminoC 1-6 alkyl, (C 1-6 alkynyl)aminoC 1-6 alkyl, (bensyl)aminoC 1-6 alkyl, (mono- or di-C 1-3 alkoxy substituted bensyl)aminoC 1-6 alkyl, (aminoC 1-3 alkylphenyl)C 1-3 alkyl, (aminoC 1-3 alkylthiophenyl)C 1-3 alkyl, (aminoC 1-3 alkylpyridinyl)C 1-3 alkyl, guanidino C 1-6 alkyl, (guanidinoC 1-3 alkylphenyl)C 1-3 alkyl, amidinoC 1-6 alkyl or amidinothioC 1-6 alkyl or a group of the formula  
 —Z—(CH 2 ) n —Het  
 in which 
 Z is carbonyl or methylene  
 n is an integer of 0-5, and  
 Het is an optionally substituted 5- or 6-membered heterocyclic group,  
 
 R3 and R5 are each independently H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, nitro, nitrile, and  
 R4 is H, C 1-3 alkyl or together with R2, forms an annulated ring which may be substituted by hydroxyC 1-3 alkyl, amidinothioC 1-3 alkyl, or aminoC 1-3 alkyl,  
 and salts and solvates thereof and solvates of such salts.  
 
     
     
         3 . A compound according to  claim 2 , wherein Ar is an optionally substituted bicyclic aromatic or an optionally substituted bicyclic heteroaromatic group.  
     
     
         4 . A compound according to  claim 2  or  3 , wherein Ar is a heteroaromatic or a bicyclic heteroaromatic group containing a single heteroatom.  
     
     
         5 . A compound according to  claim 4 , wherein the heteroatom is N, O or S.  
     
     
         6 . A compound according to any one of  claims 2  to  5 , wherein Ar is selected from the group consisting of benzothiophene, naphthyl, phenoxyphenyl and optionally substituted indolyl.  
     
     
         7 . A compound according to  claim 6 , wherein Ar is an indolyl substituted with a group selected from the group consisting of aminopropyl, dimethylaminopropyl, aminobutyl, aminocyclopentyl, aminomethylbensyl and amidinothiopropyl.  
     
     
         8 . A compound according to any one of  claims 2  to  7 , in which X is O and R is H.  
     
     
         9 . A compound according to any one of  claims 2  to  8 , in which 
 R1 is H, methyl or a fluoro substituted C 1-6  alkyl, preferably CF 3 , and  
 R3 and R5 are independently H or methoxy.  
 
     
     
         10 . A compound according to any one of  claims 2  to  9 , in which 
 when R4 is H, R2 is H, methyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, (mono- or di-C 1-6 alkyl)aminoC 1-6 alkyl, aminoC 3-7 cycloalkyl, (mono- or di-C 1-6  alkyl)aminoC 3-7 cycloalkyl, guanidino C 1-6 alkyl, amidinoC 1-6 alkyl or amidinothioC 1-6 alkyl, or  
 when R2 and R4 together form an annulated ring, they together comprise 4 or 5 carbons.  
 
     
     
         11 . The compounds: 
 5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,    5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-benzo[b]thoiphenyl-1,3-dihydroimidazol-2-one,    5-[1-(3-Aminopropyl)-3-indolyl]-1-(1-naphthyl)-1,3-dihydroimidazol-2-one,    5-[1-{3-(Aminomethyl)benzyl }-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,    5-[1-(3-Aminopropyl)-1-indolyl]-1-(3-indolyl)-4-methyl-1,3-dihydroimidazol-2-one,    5-[1-(3-Amidinothiopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,    5-{1-[3-(N,N-Dimethylamino)propyl]-3-indolyl }-1-(3-indolyl)-1,3-dihydroimidazol-2-one, and    5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-4-phenyl-1,3-dihydroimidazol-2-one,    and salts and solvates thereof and solvates of such salts.    
     
     
         12 . A pharmaceutically acceptable salt of a compound as claimed in any one of  claims 1  to  11 .  
     
     
         13 . A compound according to any one of  claims 1  to  11 , or a salt according to  claim 12 , for use in medical therapy.  
     
     
         14 . A pharmaceutical formulation comprising a compound as claimed in any one of  claims 1  to  11  or a salt as claimed in  claim 12  as active ingredient, and a pharmaceutically acceptable adjuvant, diluent and/or carrier therefor.  
     
     
         15 . The use of a compound as claimed in any one of  claims 1  to  11  or a salt as claimed in  claim 12  in the manufacture of a medicament for use in medical therapy.  
     
     
         16 . A process for the synthesis of a compound of formula (I) as defined in  claim 1 , comprising converting a compound of formula (I) to a salt thereof, or vice versa, or converting a salt of a compound of formula (I) into a different salt.  
     
     
         17 . A process for the synthesis of a compound of formula (I) as defined in  claim 1 , comprising intramolecular condensation of a compound of formula (IV)  
       
         
           
           
               
               
           
         
       
       in which X, R, R1, Ar 1  and Ar 2  are as defined in  claim 1 .  
     
     
         18 . A process according to  claim 17 , wherein the condensation is performed under acidic conditions, preferably using acetic acid or scandium(III)trifluoromethane sulfonate, at a temperature in the range of from about 90° C. to about 130° C., suitably from 100° C. to 120° C. and preferably at about 100° C., for a period of time in the range of from about 5 min to about 6 h, suitably from 15 min to 3 h, preferably for about 1 h.  
     
     
         19 . A process for the synthesis of a compound of formula (II) or (III) as defined in  claim 2 , in which X is O, comprising synthesising by intramolecular condensation of a compound of formula (V) or (VI) respectively  
       
         
           
           
               
               
           
         
       
       in which Ar, R and R1-R5 are as defined in  claim 2 .  
     
     
         20 . A process for the synthesis of a compound of formula (V) or (VI) as defined in  claim 19 , in which Ar, R and R1-R5 are as defined in  claim 2  provided that R2 is not H, comprising reacting the appropriate isocyanate with a relevant alpha-ketoamine, either of which carries the R2 group, using standard techniques.  
     
     
         21 . A process for the synthesis of a compound of formula (I) as defined in  claim 1  or a compound of formula (II) or (III) as defined in  claim 2 , wherein the compound carries one or more functional groups which might be sensitive to or interfere with the reaction conditions in the processes according to any one of  claims 17  to  19 , comprising using a corresponding compound of formula (I), (II) or (III) respectively, in which the functional groups are suitably protected, followed by subsequent deprotection.  
     
     
         22 . A process for the synthesis of a compound of formula (V) or (VI) as defined in  claim 19 , in which R2 is not H, comprising alkylating, with an optionally substituted alkylating agent, compounds of formula (VII) and (VIII), respectively  
       
         
           
           
               
               
           
         
       
       in which Ar, R, R1-R5 are as defined in  claim 2 .  
     
     
         23 . A process according to  claim 22 , wherein the alkylating agent is selected from the group consisting of alkyl halides, alkyl halides carrying a dialkyl amino group and alkylating agents carrying a protected amino or hydroxy group.  
     
     
         24 . A process for the synthesis of a compound of formula (VII) or (VIII) as defined in  claim 22 , in which Ar, R, R1, R3, R4 and R5 are as defined in  claim 2 , comprising reacting the appropriate isocyanate with a relevant alpha-ketoamine by standard techniques.  
     
     
         25 . A process for the synthesis of a compound of formula (II) or (III) as defined in  claim 2 , in which at least one of R2 or Ar carries an amino or hydroxy group, and pharmaceutically acceptable salts thereof, comprising deprotecting a compound of formula (II) or (III), respectively, in which at least one of R2 or Ar carries a protected amino or hydroxy group.  
     
     
         26 . A process for the synthesis of a compound of formula (II) as defined in  claim 2 , in which X is O, R2 is alkyl and Ar is an indole substituted on the indole nitrogen with an alkyl carrying an amino or hydroxy group, comprising deprotecting a compound of formula (IX)  
       
         
           
           
               
               
           
         
       
       in which R6 is an alkyl carrying a protected amino or hydroxy group, t-Boc is a t-butoxycarbonyl group and R1, R3, R4 and R5 are as defined in  claim 2 .  
     
     
         27 . A process for the synthesis of a compound of formula (IX) as defined in  claim 26 , comprising selectively removing a Troc group from a compound of formula (X)  
       
         
           
           
               
               
           
         
       
       in which R2 is alkyl, Troc is a 2,2,2-trichloroethoxy carbonyl group, R1, R3, R4 and R5 are as defined in  claim 2 , followed by subsequent alkylation under standard conditions with an alkyl carrying a protected amino group or hydroxy group.  
     
     
         28 . A process for the synthesis of a compound of formula (X) as defined in  claim 27 , comprising introducing a butoxycarbonyl (Boc) group, under standard conditions, to a compound of formula (II) as defined in  claim 2  in which R is H and the Ar group is a Troc protected indole.  
     
     
         29 . A compound of formula (V) or (VI)  
       
         
           
           
               
               
           
         
       
       in which Ar, R and R1-R5 are as defined in  claim 2 .  
     
     
         30 . A compound of formula (VII) or (VIII)  
       
         
           
           
               
               
           
         
       
       in which Ar, R, R1-R5 are as defined in  claim 2 .  
     
     
         31 . A compound of formula (IX)  
       
         
           
           
               
               
           
         
       
       in which R6 is an alkyl carrying a protected amino or hydroxy group, t-Boc is a t-butoxycarbonyl group and R1, R3, R4 and R5 are as defined in  claim 2 .  
     
     
         32 . A compound of formula (X)  
       
         
           
           
               
               
           
         
       
       in which R2 is alkyl, t-Boc is a t-butoxycarbonyl group, Troc is a 2,2,2-trichloroethoxy carbonyl group, and R1, R3, R4 and R5 are as defined in  claim 2 .  
     
     
         33 . A method of medical therapy comprising the administration to an individual requiring such therapy, of a therapeutically effective amount of a compound as claimed in any of  claims 1  to  11  or a salt as claimed in  claim 12.