IL17 and IFN-gamma inhibition for the treatment of autoimmune inflammation
Inventors
Leban, Johann • Tasler, Stefan • Saeb, Wael • Chevrier, Carine
Assignees
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Publication Number
US-8354436-B2
Publication Date
2013-01-15
Expiration Date
Abstract
The present invention relates to compounds of the general formula (I), and the pharmaceutically acceptable salt or solvate thereof, as anti-inflammatory and immunomodulatory agents.
Core Innovation
The invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof. The compounds are defined by substituent variables R1, Ar, Z, and Y, where R1 can be aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl, Ar and Z can be aryl, cycloalkyl, heterocyclyl or heteroaryl, and Y can be H, halogen, haloalkyl, alkyl or an alkylester, each optionally substituted by one or more substituents R′ and R″. R′ and R″ are independently defined by specified carbonyl-containing, sulfonyl-containing, nitrogen- and oxygen-containing, alkyl, aryl, heteroaryl, and halo substituent classes.
The described scaffold includes substituted isoxazole-containing heteroaryl compounds, with recurring example structures bearing a 2-chloro-6-fluorophenyl moiety and a substituted 1H-pyrazol-4-yl group having a trifluoromethyl substituent. The examples vary the aryl or heteroaryl group attached to the pyrazole nitrogen and the isoxazole substituent, including carboxylate, carboxamide, carbamates, carbohydrazide, carbonitrile, thioamide, and related carbonyl or sulfur-containing functional-group variations. Additional named examples include heteroaryl substituents such as thiazole, oxadiazole, thiadiazole, oxazole, furan, pyridinyl, pyrimidyl, morpholine, piperazine, and isoxazolidinyl.
The disclosure also includes treatment methods in which an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need. The stated use is treatment of inflammatory and autoimmune-related diseases and related conditions, and the examples further support substituted isoxazole-containing heteroaryl compounds as pharmaceutical embodiments and as compounds with reported in vitro activity values.
Claims Coverage
The consolidated claim coverage centers on formula (I) compounds and pharmaceutically acceptable salts with defined substituent variables. Across the independent claims, there are four inventive features: the general formula (I) scaffold, expanded substituent-variable definitions, a limitation that R1, Ar, Z and Y may not comprise more than three coupled substituents R′ and/or R″, and a treatment method using an effective amount of the compound.
Formula (I) compounds with defined substituent variables
A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is aryl, heteroaryl, cycloalkyl, heterocyclyl or alkyl; Ar and Z are aryl, cycloalkyl, heterocyclyl or heteroaryl; and Y is H, halogen, haloalkyl, alkyl or an alkylester, with R′ and R″ independently defined by the specified substituent sets.
Coupled substituent limitation for R1, Ar, Z and Y
R1, Ar, Z and Y may not comprise more than three coupled substituents R′ and/or R″.
Selected substituted isoxazole-containing heteroaryl compounds
Specific substituted isoxazole-containing heteroaryl compounds within the formula (I) framework, including compounds with a 2-chloro-6-fluorophenyl moiety, a substituted 1H-pyrazol-4-yl group, and varied aryl or heteroaryl substituents.
Treatment by administering an effective amount
A method of treating a subject in need by administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for inflammatory and autoimmune-related diseases and related conditions.
The claims are directed to a formula (I) compound family defined by substituent-variable selections and a cap on coupled substituents, with dependent coverage for specific substituted isoxazole-containing heteroaryl compounds and pharmaceutically acceptable salts, and a therapeutic method based on administration of an effective amount.
Stated Advantages
IC50 values against IL-17AA, IL-17FF, IFNγ, and T-cell proliferation are provided.
The compounds are linked to dual IL-17 and/or IFN-γ pathway inhibition in autoimmune inflammation.
Documented Applications
Treatment of inflammatory and autoimmune-related diseases and related conditions by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.
In vitro activity measurement for IL-17AA, IL-17FF, IFNγ, and T-cell proliferation using the example substituted isoxazole-containing heteroaryl compounds on formula (I).
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