Interleukin-4 gene expression inhibitors

Abstract

This invention discloses and claims a class of indole and benzo(b)thiophene derivatives for use in treating allergy, asthma, rhinitis, dermatitis, B-cell lymphomas, tumors and diseases associated with bacterial, rhinovirus or respiratory syncytial virus (RSV) infections. The compounds of this invention are defined by the Formula (I): wherein X, Y, Z, R 1 , R 2 and R 3 are as defined in the specification; or a pharmaceutically acceptable salt thereof. In preferred embodiments of this invention it is also disclosed and claimed that the compounds of this invention are capable of modulating T helper (Th) cells, Th1/Th2, and thereby capable of inhibiting the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production.

1 . A method of treating rhinitis or dermatitis, which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound capable of inhibiting the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production, said compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X and Y are the same or different and are independently selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 perfluoroalkyl, C 1-6 perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituents each independently selected from C 1-6 alkyl, C 1-6  perfluoroalkyl, halogen, hydroxy or C 1-6 perfluoroalkyl or C 1-6  perfluoroalkoxy; 
         Z is N—R or S, wherein R is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonylC 1-6 alkyl, C 1-6 alkylcarbamoyl-C 1-6 alkyl and C 1-6 dialkylcarbamoylC 1-6 alkyl; 
         R 1  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6  perfluoroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di-C 1-6 alkyl-aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, aminoC 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, phenyl, diphenylC 1-6 alkyl and phenylC 1-6 alkyl, phenylcarbonylC 1-6 alkyl, phenoxyC 1-6 alkyl, wherein phenyl is optionally substituted with one or two substituents each independently selected from C 1-6 alkyl, C 1-6  perfluoroalkyl, halogen, hydroxy or C 1-6 perfluoroalkyl or C 1-6 perfluoroalkoxy; 
         R 3  is 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 4  is selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6  perfluoroalkyl, C 1-6  perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituents each independently selected from C 1-6 alkyl, C 1-6  perfluoroalkyl, halogen, hydroxy or C 1-6 perfluoroalkyl or C 1-6  perfluoroalkoxy; and 
           n is an integer from 0 to 4; and 
         
         R 2  is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 perfluoroalkyl, perfluoroaryl, indanyl, C 1-6 alkoxyC 1-6 alkyl, C 2-6 acyloxyC 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, C 1-6 alkoxycarbonyloxyC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxycarbonyloxy-C 1-6 alkyl, adamantyloxycarbonyloxyC 1-6 alkyl, C 3-8 cycloalkoxycarbonyl-C 1-6 alkyl, mono- or di-C 1-6 alkylamino-C 1-6 alkyl, C 3-8 azacycloalkylC 1-6 alkyl, mono- or di-C 1-6 alkylcarbamoyl-C 1-6 alkyl, C 3-8 azacycloalkylcarbonyloxyC 1-6 alkyl, benzylC 1-6 alkylcarbamoylC 1-6 alkyl, mono- or di-C 1-6 alkylcarbamoyloxyC 1-6 alkyl, C 3-8 azacycloalkylcarbonyloxy-C 1-6 alkyl, benzylC 1-6 alkylcarbamoyloxyC 1-6 alkyl, benzylcarbamoyloxyC 1-6 alkyl, C 1-6 alkoxycarbonylamino-oxo-C 1-6 alkyl, 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 5  is hydrogen or C 1-6 alkyl, 
           R 6  is C 1-6 alkyl, phenyl or tolyl, and 
           A is CH 2 , NH or O, 
         
         or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier. 
       
     
     
         2 . The method as set forth in  claim 1  wherein the treating is asthma. 
     
     
         3 . The method as set forth in  claim 1  wherein the treating is rhinitis. 
     
     
         4 . The method as set forth in  claim 1  wherein the treating is dermatitis. 
     
     
         5 . The method as set forth in  claim 1  wherein the compound is having:
 X and Y are the same or different and are independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 perfluoroalkyl, C 1-3 alkoxy, C 1-3 perfluoroalkoxy, phenyl and benzyl;   Z is N—R or S wherein R is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxycarbonylC 1-3 alkyl and C 1-3 dialkylcarbamoyl-C 1-3 alkyl;   R 1  is hydrogen, C 1-6 alkyl, or phenylC 1-6 alkyl;   R 3  is   
       
         
           
           
               
               
           
         
         
           wherein 
           R 4  is hydrogen, fluorine or C 1-6 allyl; and 
           n is an integer from 0 to 3: and 
         
         R 2  is selected from the group consisting of hydrogen, C 1-4 alkyl, perfluoroaryl, indanyl, C 1-3 alkoxyC 1-3 alkyl, C 2-5 acyloxyC 1-3 alkyl, C 1-3 alkoxycarbonylC 1-3 alkyl, C 1-4 alkoxycarbonyloxyC 1-4 alkyl, C 4-6 cycloalkoxycarbonyloxy-C 1-3 alkyl, adamantyloxycarbonyloxy-C 1-3 alkyl, mono- or di-C 1-3 alkylamino-C 1-3 alkyl, C 4-6 azacycloalkyl-C 1-3 alkyl, mono- or di-C 1-3 alkylcarbamoyl-C 1-3 alkyl, C 4-6 azacycloalkylcarbonylC 1-3 alkyl, benzylC 1-3 alkylcarbamoyl-C 1-6 alkyl, mono- or di-C 1-3 alkylcarbamoyloxyC 1-3 alkyl, C 3-8 azacycloalkylcarbonyloxyC 1-6 alkyl, benzylcarbamoyloxyC 1-3 alkyl, C 1-3 alkoxycarbonylamino-carbonylC 1-3 alkyl, 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 5  is hydrogen or C 1-3 alkyl, 
           R 6  is C 1-6 alkyl, phenyl or tolyl, and 
           A is O, 
         
         or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier. 
       
     
     
         6 . The method as set forth in  claim 1  wherein the compound is having:
 X and Y are the same or different and are independently selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methoxy, phenyl and benzyl;   Z is N—R or S wherein R is selected from the group consisting of hydrogen, methyl, ethoxycarbonylmethyl and diethylcarbamoylmethyl;   R 1  is hydrogen, methyl or propyl;   R 3  is   
       
         
           
           
               
               
           
         
         
           wherein 
           R 4  is hydrogen; and 
           n is an integer from 0 to 2; and 
         
         R 2  is selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, pentafluorophenyl, indanyl, methoxyethyl, ethoxypropyl, acetyloxymethyl, 2,2-dimethylpropionyloxymethyl, pentanoyloxymethyl, methoxycarbonyl-1-ethyl, ethoxycarbonylmethyl, iso-propoxycarbonyloxymethyl, tert-butoxycarbonyloxymethyl, cyclohexanoxycarbonyloxymethyl, adamantyloxycarbonyloxymethyl, diethylaminoethyl, dimethylaminoethyl, piperidinyl-1-ethyl, diethylcarbamoylmethyl, benzylethylcarbamoylmethyl, 2-azetidin-1-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, piperidine-1-carbonyloxymethyl, diethylcarbamoyloxymethyl, benzylcarbamoyloxymethyl, ethoxycarbonylamino-carbonylmethyl, 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 5  is hydrogen or methyl, 
           R 6  is methyl, phenyl or tolyl, and 
           A is O, 
         
         or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier. 
       
     
     
         7 . The method as set forth in  claim 1  wherein the compound is selected from the group consisting of: 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       6-trifluoromethyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       6-chloro-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       5-chloro-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       6-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       5-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       4-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, tert-butyl ester, 
       6-phenyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, tert-butyl ester, 
       5,6-dimethoxy-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       3-methoxy-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, tert-butyl ester, 
       3-(2-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       3-(pyrimidin-2-ylamino)-1H-indole-2-carboxylic acid ethyl ester, 
       5-fluoro-1-methyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       4-fluoro-1-methyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, tert-butyl ester, 
       5-chloro-1-methyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       6-chloro-1-methyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       1-methyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid maleate salt, 
       4-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid trifluoroacetate salt, 
       4-fluoro-1-methyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid trifluoroacetate salt, 
       5-methoxy-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid trifluoroacetate salt, 
       6-chloro-1-diethylcarbamoylmethyl-3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid ethyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid pentafluorophenyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid 2-diethylamino-ethyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid 2-dimethylamino-ethyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid 2-piperidin-1-yl-ethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (S)-1-methoxycarbonyl-ethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid ethoxycarbonylmethyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid 2-methoxyethyl ester, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid 3-ethoxypropyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid indan-5-yl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid diethylcarbamoylmethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-morpholin-4-yl-2-oxo-ethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-oxo-2-pyrrolidin-1-yl-ethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-azetidin-1-yl-2-oxo-ethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (benzyl-ethyl-carbamoyl)-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid diethylcarbamoyloxy-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid benzylcarbamoyloxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid piperidine-1-carbonyloxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid morpholine-4-carbonyloxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-ethoxycarbonylamino-2-oxy-ethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid iso-propoxycarbonyloxy-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 1,1,2-trimethylpropoxy-carbonyloxy-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid cyclohexyloxy-carbonyloxy-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid adamantan-1-yloxycarbonyloxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid acetoxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid pentanoyloxymethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-oxo-piperidin-1-ylmethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (benzoyl-ethoxycarbonylmethyl-amino)-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-oxo-pyrrolidin-1-ylmethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid 5-methyl-2-oxo-(1,3)dioxo-4-ylmethyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (phenyl-(toulene-4-sulfonyl)-amino)-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (benzenesulfonyl-methyl-amino)-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid (methyl-(toulene-4-sulfonyl)-amino)-methyl ester, 
       3-(pyridin-4-ylamino)-1H-indole-2-carboxylic acid tert-butoxycarbonyloxy-methyl ester, 
       3-(4-pyridinylamino)-benzo(b)thiophene-2-carboxylic acid ethyl ester, 
       6-fluoro-3-(4-pyridinylamino)-benzo(b)thiophene-2-carboxylic acid ethyl ester, ethyl 3-((4-pyridyl)amino-N-methyl)-benzo(b)thiophenyl-2-carboxylate, 
       3-(4-pyridinylamino)-6-trifluoromethyl-benzo(b)thiophene-2-carboxylic acid methane sulfonate salt, 
       3-(4-pyridinylamino)-benzo(b)thiophene-2-carboxylic acid hydrochloride salt, 
       3-(4-pyridinylamino)-6-trifluoromethyl-benzo(b)thiophene-2-carboxylic acid ethyl ester hydrochloride salt, 
       3-(propyl-4-pyridinylamino)-benzo(b)thiophene-2-carboxylic acid ethyl ester, 
       3-((3-phenylpropanoyl)methylamino)-1H-6-chloro-indole-2-carboxylic acid, 
       3-((benzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)amino)-6-chloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)amino)-6-chloro-1H-indole-2-carboxylic acid 2-dimethylamino-ethyl ester, 
       3-((4-chlorobenzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)benzylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((4-piperidineacyl)methylamino)-6-chloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester, 
       3-((benzoyl)methylamino)-5,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)ethylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)methylamino)-6-fluoro-1H-indole-2-carboxylic acid, 
       3-((2-benzylbenzoyl)amino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((3-fluorobenzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)benzylamino)-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester, 
       3-((phenylsulfonyl)amino)-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester, 
       3-((phenylsulfonyl)amino)-4,6-dichloro-1H-indole-2-carboxylic acid, and 
       3-((phenylsulfonyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid. 
     
     
         8 . The method as set forth in  claim 1  wherein the compound is selected from the group consisting of: 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, 
       3-((3-phenylpropanoyl)methylamino)-1H-6-chloro-indole-2-carboxylic acid, 
       3-((benzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)amino)-6-chloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)methylamino)-5,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)methylamino)-6-fluoro-1H-indole-2-carboxylic acid, 
       3-((4-chlorobenzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)benzylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((benzoyl)ethylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((2-benzylbenzoyl)amino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((3-fluorobenzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((4-piperidineacyl)methylamino)-6-chloro-1H-indole-2-carboxylic acid, 
       3-((phenylsulfonyl)amino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-((phenylsulfonyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid, 
       3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       6-trifluoromethyl-3-(4-pyridinylamino)-1H-indole-2-carboxylic acid, ethyl ester, 
       3-(pyrimidin-2-ylamino)-1H-indole-2-carboxylic acid ethyl ester, 
       3-((benzoyl)amino)-6-chloro-1H-indole-2-carboxylic acid 2-dimethylamino-ethyl ester, 
       3-((benzoyl)methylamino)-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester, 
       3-((benzoyl)benzylamino)-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester, and 
       3-((phenylsulfonyl)amino)-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester.