Indolyl-3-glyoxylic acid derivatives having antitumor action

Abstract

The invention relates to the use of N-substituted indole-3-glyoxylamides of the general formula I as antitumor agents and to a pharmaceutical composition having antitumor action, characterized in that it contains at least one of the compounds of the general formula 1, if appropriate also in the form of the physiologically tolerable acid addition salts or N-oxides. Furthermore, the invention also includes antitumor agents comprising as active compound one or more N-substituted indole-3-glyoxylamides according to the general formula 1 and, if appropriate, their physiologically tolerable acid addition salts and, if possible, N-oxides and a pharmaceutically utilizable carrier and/or diluent or auxiliary substance in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.

1 . N-substituted indole-3-glyoxylamides of the general formula 1 for use as antitumor agents,  
       
         
           
           
               
               
           
         
       
       where the radicals R, R 1 , R 2 , R 3 , R 4  and Z have the following meaning: 
 R=hydrogen, (C 1 -C 6 )-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring for its part can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C 1 -C 6 )-alkyl groups, halogen atoms or trifluoromethyl groups,  
 R is further the benzyloxycarbonyl group (Z group) and the tertiary-butoxycarbonyl radical (BOC radical), furthermore the acetyl group.  
 R 1  can be the phenyl ring, which is mono- or polysubstituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C 1 -C 6 )-alkylamino, (C 1 -C 6 )-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C 1 -C 6 -alkanols, or can be a pyridine structure of the formula 2 and its N-oxide[sic] 
                     
 and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R 5  and R 6 . The radicals R 5  and R 6  can be identical or different and have the meaning (C 1 -C 6 )-alkyl and the meaning (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl and further are the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.  
 R 1  can further be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore are [sic] the 2-, 3-, and 4- and 8-quinolyl structure substituted by (C 1 -C 6 )-alkyl, halogen, the nitro group, the amino group and the (C 1 -C 6 )-alkylamino radical, are [sic] a 2-, 3-, and [sic] 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, nitro, amino and (C 1 -C 6 )-alkoxycarbonylamino.  
 R 1 , in the case in which R=hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, can furthermore be the following radicals:  
 —CH 2 COOH; —CH(CH 3 )—COOH; —(CH 3 ) 2 —CH—(CH 2 ) 2 —CH—COO—; H 3 C—H 2 C—CH(CH 3 )—CH(COOH)—; HO—H 2 C—CH(COOH)—; phenyl-CH 2 —CH(COOH)—; (4-imidazolyl)-CH 2 —CH—(COOH)—; HN═(NH 2 )—NH—(CH 2 ) 3 —CH(COOH)—; H 2 N—(CH 2 ) 4 —CH(COOH)—; H 2 N—CO—CH 2 —CH—(COOH)—; HOOC—(CH 2 ) 2 —CH(COOH)—;  
 R 1 , in the case in which R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, can furthermore be the acid radical of a natural or unnatural amino acid, e.g. the α-glycyl, the α-sarcosyl, the α-seryl, the α-phenylalanyl, the α-histidyl, the α-prolyl, the α-arginyl, the α-lysyl, the α-asparagyl and the α-glutamyl radical, where the amino groups of the respective amino acids can be present unprotected or can be protected. A possible protective group of the amino function is the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R 1 , the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C 1 -C 6 -alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.  
 Furthermore, R 1  can be the allylaminocarbonyl-2-methylprop-1-yl group.  
 R and R 1  can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the formula III or a homopiperazine ring, provided R 1  is an aminoalkylene group, in which  
                     
 R 7  is an alkyl radical, is a phenyl ring which can be mono- or polysubstituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, halogen, the nitro group, the amino function and by the (C 1 -C 6 )-alkylamino group. R 7  is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl [sic] group.  
 R 2  can be hydrogen and the (C 1 -C 6 )-alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C 1 -C 6 )-alkyl group counting as R 2  can further be substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl structure, which can both in each case be mono- or polysubstituted by halogen, (C 1 -C 4 )-alkyl groups or (C 1 -C 4 )-alkoxy groups. R 2  is further the aroyl radical, where the aryl moiety on which this radical is based is the phenyl ring, which can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, carboxyl groups, carboxyl groups esterified with C 1 -C 6 -alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.  
 R 3  and R 4  can be identical or different and are hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkanoyl, (C 1 -C 6 )-alkoxy, halogen and benzyloxy. R 3  and R 4  can furthermore be the nitro group, the amino group, the (C 1 -C 4 )-mono or dialkyl-substituted amino group, and the (C 1 -C 6 )-alkoxycarbonylamino function or (C 1 -C 6 )-alkoxycarbonylamino-(C 1 -C 6 )-alkyl function.  
 Z is O and S.  
 
     
     
         2 . N-Substituted indole-3-gloxylamides [sic] according to  claim 1  with the formula 1a for use as antitumor agents,  
       
         
           
           
               
               
           
         
       
       where the radicals 
 R=hydrogen  
 R 1 =4-pyridyl, 4-fluorophenyl  
 R 2 =benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl  
 R 3  and R 4 =hydrogen and  
 Z is oxygen.  
 
     
     
         3 . Pharmaceutical composition having antitumor action characterized, in that it contains at least one of the compounds of the general formula 1 or 1a, optionally also they [sic] as acid addition salts, for example as salts of mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as, for example, acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2-hydroxyethanesulfonic acid [sic] and possibly their N-oxides.  
     
     
         4 . Use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically tolerable acid addition salts for the production of antitumor agents for the treatment of oncoses using these agents, namely in particular the following compounds or their salts with physiologically tolerable acids or if possible their N-oxides: 
 D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide    D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide    D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamide    D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide    D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide HCL [sic]   
     
     
         5 . Antitumor agents comprising as active agent one or more N-substituted indole-3-gloxylamides according to the general formula 1 or 1a and optionally their physiologically tolerable acid addition salts, but in particular one or more compounds according to  claim 4 .  
     
     
         6 . Antitumor agents comprising as active agent 
 D 24241 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide or its hydrochloride    
     
     
         7 . Antitumor agents comprising as active agent 
 D 24843 N-(Pyridin-4-yl)-(1-benzylindol-3-yl)glyoxylamide.    
     
     
         8 . Antitumor agents comprising as active agent 
 D 24850 N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamide    
     
     
         9 . Antitumor agents comprising as active agent 
 D 24851 N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide    
     
     
         10 . Antitumor agent comprising as active agent one or more N-substituted indole-3-gloxylamides according to the general formula 1 or 1a and optionally their physiologically tolerable acid addition salts and, if possible, N-oxides, but in particular one or more compounds according to  claim 4  and  6  to  8  and a pharmaceutically utilizable excipient and/or diluent or auxiliary in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.