N-substituted indole-3glyoxylamides having anti-asthmatic, antiallergic and immunosuppressant/immuno-modulating action

Abstract

The invention relates to novel N-substituted indole-3-glyoxylamides, to processes for their preparation and to their pharmaceutical use. The compounds have antiasthmatic, antiallergic and immunosuppressant/immunomodulating actions.

1 . N-substituted indol-3-glyoxylamides of the formula  
       
         
           
           
               
               
           
         
       
       and their acid addition salts, 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. 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 benyl [sic] group which is mono- or polysubstituted in the phenyl moiety by (C 1 -C 6 )-alkyl groups halogen atoms or trifluoromethyl groups,  
 R 1  can be a phenyl ring which is mono- or polysubstituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, hydroxyl, benzyloxy, nitro, amino, (C 1 -C 6 )-alkylamino, (C 1 -C 6 )-alkoxy-carbonylamino and by a carboxyl group or a carboxyl group esterified by (C 1 -C 6 )-alkanols, or is a pyridin structure of the formula II  
                     where the pyridin structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substitutents 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 also the meaning (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and are furthermore the ethoxy-carbonylamino radical and the group carboxy-alkyloxy in which the alkyl group can have 1-4 C atoms,    
 R 1  can furthermore be a 2- or 4-pyrimidinyl-heterocycle or a pyridylmethyl radical in which CH 2  can be in the 2-, 3-, 4-position where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore are [sic] the 2-, 3- and 4-quinolyl structure substituted by (C 1 -C 6 )-alkyl, halogen, the nitro group, the amino group and the (C 1 -C 6 )-alkylamino radical, or are [sic] a 2-, 3- and 4-quinolyl methyl group, where the ring carbons of the pyridylmethyl and quinolylmethyl radical can be substituted by (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, nitro, amino and (C 1 -C 6 )-alkoxy-carbonylamino,  
 R 1  for the case where R is hydrogen 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-alanyl, the α-leucyl, the α-isoleucyl, 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 in unprotected or protected form and are possible protective groups for the amino function of the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) and also the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R 1 , the second, nonbonded 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 the methyl, ethyl or as the tert-butyl ester. R 1  can furthermore be the allylaminocarbonyl-2-methylprop-1-yl group. R and R 1 , together with the nitrogen atom to which they are bonded, can furthermore form a piperazine ring of the formula III or a homopiperazine ring if R 1  is an aminoalkylene group in which  
                     R 7  is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (C 1 -C 1 )-alkyl, (C 1 -C 6 )-alkoxy, halogen, the nitro group, the amino function, by (C 1 -C 6 )-alkylamino, the benzhydryl group and the bis-p-fluorobenzylhydryl group,    
 R 2  can be hydrogen or the (C 1 -C 6 )-alkyl group, where the alkyl group can be 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 furthermore be substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl structure, which in each case can both be mono- or polysubstituted by halogen, (C 1 -C 4 )-alkyl groups or (C 1 -C 4 )-alkoxy groups. R 2  is furthermore 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 by (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, hydroxyl, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cyclo-alkyl, (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 3 )-alkoxycarbonylamino function or the (C 1 -C 3 )-alkoxy-carbonylamino-(C 1 -C 3 )-alkyl function,  
 Z is O or S, 
 and where the designation alkyl, alkanol, alkoxy or alkylamino group for the radicals R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  is normally to be understood as meaning “straight-chain” and “branched” alkyl groups, where “straight-chain alkyl groups” can be, for example, radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl and “branched alkyl groups” designate, for example, radicals such as isopropyl or tert-butyl. “Cycloalkyl” is to be understood as meaning radicals such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, additionally the designation “halogen” represents fluorine, chlorine, bromine or iodine, and the designation “alkoxy group” represents radicals such as, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.  
 
 
     
     
         2 . Compounds according to claim  1   N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamide    N-(Pyridin-4-yl)-(4-methylindol-3-yl)glyoxylamide    N-(Pyridin-3-yl)-[1-(4-fluorobenzyl)-indol-3-yl]-glyoxylamide    N-(Pyridin-3-yl)-(1-benzylindol-3-yl)glyoxylamide    N-(Pyridin-3-yl)-[1-(2-chorobenzyl)indol-3-yl]-glyoxylamide    N-(4-Fluorophenyl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamide    N-(4-Nitrophenyl)-[1-(4-fluorobenzyl)indol-3-yl]-gloxylamide    N-(2-Chloropyridine-3-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide    N-(Pyridin-4-yl)-(-benzylindol-3-yl)glyoxylamide    N-(Pyridin-4-yl)-[1-(3-pyridylmethyl)indol-3-yl]-glyoxylamide    N-(4-Fluorophenyl)-[1-(2-pyridylmethyl)indol-3-yl]-glyoxyamide    N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]-glyoxylamide    N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]-glyoxylamide    N-(Pyridin-4-yl)-[1-(2-chlorobenzyl)indol-3-yl]-glyoxylamide    N-(Pyridin-2-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamide    N-(Pyridin-4-yl)-[1-(2-pyridylmethyl)indol-3-yl]-glyoxylamide    (4-Phenylpiperazin-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamide    N-(Pyridin-2-yl)-(1-benzylindol-3-yl)glyoxylamide    4-(Pyridin-4-yl)-piperazin-1-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide    N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-6-ethoxycarbonylaminoindol-3-yl]glyoxylamide    N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminoindol-3-yl]glyoxylamide    N-(Pyridin-4-)-[1-(4-fluorobenzyl)-6-cyclopentyloxycarbonylaminoindol-3-yl]glyoxylamide    N-(3,4,5-Trimethoxybenzyl)-N-(allylaminocarbonyl-2-methylprop-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamide    N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]glyoxylamide    N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]glyoxylamide    N-(Pyridin-4-yl-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminomethylindol-3-yl]glyoxylamide    
     
     
         3 . Use of the compounds of the formula I according to one of claims  1  and  2  for the production of a medicament.  
     
     
         4 . Use of the compounds of the formula I according to  claims 1  to  3  on their own or in combination with one another for the production of a medicament having antiasthmatic, antiallergic and immunosuppressant/immunomodulating action for transplantation and diseases such as, for example, psoriasis, rheumatoid disorders and chronic polyarthritis.  
     
     
         5 . Medicaments comprising at least one compound of the formula I according to one of claims  1  and  2  in addition to customary excipients and/or diluents or auxiliaries.  
     
     
         6 . Process for the production of a medicament, characterized in that a compound of the formula I according to one of claims  1  and  2  is processed with customary pharmaceutical excipients and/or diluents or other auxiliaries to give pharmaceutical preparations or brought into a therapeutically useable form.  
     
     
         7 . Medicaments according to  claims 1  to  6  in the form of tablets, coated tablets, capsules, solutions or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.  
     
     
         8 . Process for the preparation of N-substituted indole-3-glyoxylamides of the formula I according to claims  1  and  2 , in which R, R 1 , R 2 , R 3 , R 4  and Z have the meaning mentioned in  claim 1 , characterized in that 
 a) an indole derivative of the formula IV  
                     in which R 3  and R 4  have the meaning mentioned, is added to a suspended base in a protic, dipolar aprotic or nonpolar organic solvent, reacted with a reactive compound which carries the radical R 2  and where R 2  has the meaning mentioned, the 1-indole derivative of the formula V                          in which R 2 , R 3  and R 4  have the meaning mentioned, is reacted with a reactive compound of the formula VI   (C—Z—Hal) 2   VI   in which Z has the meaning oxygen and Hal is a halogen fluorine, chlorine, bromine or iodine, and then with a primary or secondary amine of the formula VII   HNRR 1   VII   in which R and R 1  have the meaning mentioned, in an aprotic or dipolar aprotic solvent and the target compound of the formula I is isolated,    
  or  
 b) an indole derivative of the formula IV  
                     in which R 3  and R 4  have the meaning mentioned, is reacted in an aprotic or nonpolar solvent with a reactive compound of the formula VI   (C—Z—Hal) 2   VI   in which Z has the meaning oxygen and Hal is a halogen fluorine, chlorine, bromine or iodine, and then in an aprotic or dipolar aprotic solvent with a primary or secondary amine of the formula VII   HNRR 1   VII   in which R and R 1  have the meaning mentioned, and then the 3 indole derivative of the formula VIII                          in which R, R 1 , R 2 , R 3 , R 4  and Z have the meaning mentioned, is reacted in a protic, dipolar aprotic or nonpolar organic solvent in the presence of a suspended base with a reactive compound which carries the radical R 2  and where R 2  has the meaning mentioned, and the target compound of the formula I is isolated.