Interleukin-4 gene expression inhibitors

A method of treating allergy, asthma, rhinitis or dermatitis which comprises administering to a patient in need of said treatment a therapeutically effective amount of a compound capable of modulating T helper (Th) cells, Th1/Th2, which compound is of the formula:

• 110
• wherein
• X and Y are the same or different and are independently selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6perfluoroalkyl, C1-6perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituents each independently selected from C1-6alkyl, C1-6perfluoroalkyl, halogen, hydroxy or C1-6perfluoroalkyl or C1-6perfluoroalkoxy;
• Z is N—R or S, wherein R is selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonylC1-6alkyl, C1-6alkylcarbamoyl-C1-6alkyl and C1-6dialkylcarbamoylC1-6alkyl;
• R1 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6perfluoroalkyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di-C1-6alkyl- aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, aminoC1-6alkylcarbonyl, C1-6alkoxycarbonyl, phenyl, diphenylC1-6alkyl and phenylC1-6alkyl, phenylcarbonylC1-6alkyl, phenoxyC1-6alkyl, wherein phenyl is optionally substituted with one or two substituents each independently selected from C1-6alkyl, C1-6perfluoroalkyl, halogen, hydroxy or C1-6perfluoroalkyl or C1-6perfluoroalkoxy;
• R3 is
• 111
• wherein
• R4 is selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6perfluoroalkyl, C1-6perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituents each independently selected from C1-6alkyl, C1-6perfluoroalkyl, halogen, hydroxy or C1-6perfluoroalkyl or C1-6perfluoroalkoxy;
• and n is an integer from 0 to 4;
• and
• R2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6perfluoroalkyl, perfluoroaryl, indanyl, C1-6alkoxyC1-6alkyl, C2-6acyloxyC1-6alkyl, C1-6alkoxycarbonylC1-6alkyl, C1-6alkoxycarbonyloxyC1-6alkyl, C3-8cycloalkyl, C3-8cycloalkoxycarbonyloxy-C1-6alkyl, adamantyloxycarbonyloxyC1-6alkyl, C3-8cycloalkoxycarbonyl-C1-6alkyl, mono- or di-C1-6alkylamino-C1-6alkyl, C3-8azacycloalkylC1-6alkyl, mono- or di-C1-6alkylcarbamoyl-C1-6alkyl, C1-3-azacycloalkylcarbonyloxyC1-6alkyl, benzylC1-6alkylcarbamoylC1-6alkyl, mono- or di-C1-6alkylcarbamoyloxyC1-6alkyl, C3-8azacycloalkylcarbonyloxy-C1-6alkyl, benzylC1-6alkylcarbamoyloxyC1-6alkyl, benzylcarbamoyloxyC1-6alkyl, C1-6alkoxycarbonylamino-oxo-C1-6alkyl,
• 112
• wherein
• R5 is hydrogen or C1-6alkyl,
• R6 is C1-6alkyl, phenyl or tolyl, and
• A is CH2, NH or O,
• or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

The method as set forth in claim it 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 di ethylcarbamoyl methyl;
• R1 is hydrogen, methyl or propyl;
• R3 is
• 115
• wherein
• R4 is hydrogen;
• and
• n is an integer from 0 to 2;
• and
• R2 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,
• 116
• wherein
• R5 is hydrogen or methyl,
• R6 is methyl, phenyl or tolyl, and
• A is O,
• or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

A method of treating allergy, asthma, 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, which compound is of the formula:

• 117
• wherein
• X and Y are the same or different and are independently selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6perfluoroalkyl, C1-6perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituents each independently selected from C1-6alkyl, C1-6perfluoroalkyl, halogen, hydroxy or C1-6perfluoroalkyl or C1-6perfluoroalkoxy;
• Z is N—R or S, wherein R is selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonylC1-6alkyl, C1-6alkylcarbamoyl-C1-6alkyl and C1-6dialkylcarbamoylC1-6alkyl;
• R1 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6perfluoroalkyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, C1-6alkoxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di-C1-6alkyl- aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, aminoC1-6alkylcarbonyl, C1-6alkoxycarbonyl, phenyl, diphenylC1-6alkyl and phenylC1-6alkyl, phenylcarbonylC1-6alkyl, phenoxyC1-6alkyl, wherein phenyl is optionally substituted with one or two substituents each independently selected from C1-6alkyl, C1-6perfluoroalkyl, halogen, hydroxy or C1-6perfluoroalkyl or C1-6perfluoroalkoxy;
• R3 is
• 118
• wherein
• R4 is selected from the group consisting of hydrogen, halogen, nitro, amino, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6perfluoroalkyl, C1-6perfluoroalkoxy, phenyl and benzyl, wherein phenyl or benzyl is optionally substituted with one or two substituents each independently selected from C1-6alkyl, C1-6perfluoroalkyl, halogen, hydroxy or C1-6perfluoroalkyl or C1-6perfluoroalkoxy;
• and n is an integer from 0 to 4;
• and
• R2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6perfluoroalkyl, perfluoroaryl, indanyl, C1-6alkoxyC1-6alkyl, C2-6acyloxyC1-6alkyl, C1-6alkoxycarbonylC1-6alkyl, C1-6alkoxycarbonyloxyC1-6alkyl, C3-8cycloalkyl, C3-8cycloalkoxycarbonyloxy-C1-6alkyl, adamantyloxycarbonyloxyC1-6alkyl, C1-3-cycloalkoxycarbonyl-C1-6alkyl, mono- or di-C1-6alkylamino-C1-6alkyl, C3-8azacycloalkylC1-6alkyl, mono- or di-C1-6alkylcarbamoyl-C1-6alkyl, C3-8azacycloalkylcarbonyloxyC1-6alkyl, benzylC1-6alkylcarbamoylC1-6alkyl, mono- or di-C1-6alkylcarbamoyloxyC1-6alkyl, C1-3-azacycloalkylcarbonyloxy-C1-6alkyl, benzylC1-6alkylcarbamoyloxyC1-6alkyl, benzylcarbamoyloxyC1-6alkyl, C1-6alkoxycarbonylamino-oxo-C1-6alkyl,
• 119
• wherein
• R5 is hydrogen or C1-6alkyl,
• R6 is C1-6alkyl, phenyl or tolyl, and
• A is CH2, NH or O,
• or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.