Substituted benzenesulfonamides as inhibitors of alpha-4 beta-7 integrin activity
Inventors
Tokumasu, Munetaka • Noguchi, Masatsugu • KAWAHIRA, Mizuki • IWASAKI, Kana • Hayakawa, Nobuhiko • Miyanaga, Wataru • Saitou, Yuki • YAMAURA, Yui • ANDO, Ayatoshi • Tsuruta, Atsushi • Noguchi, Misato
Assignees
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Publication Number
US-10562898-B2
Publication Date
2020-02-18
Expiration Date
Abstract
Provided is a compound having α4 integrin inhibitory action.The compound is a sulfonamide derivative represented by the following formula (I), or pharmaceutically acceptable salt thereof: where R1 to R5, e to h, D, and B represent those as described in the specification.
Core Innovation
The invention relates to a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in which the structure is defined by a single bond or double bond and multiple substituent positions. The formula includes variables B, D, and R1 to R5, with allowed groups including hydroxy, OC1-10 alkyl, O-heterocyclyl, O-cilexetilyl, O-medoxomilyl, phenyl, heteroaryl, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, trifluoromethyl, phenyl, and heterocyclyl, and with options for fused ring formation.
In the compound definition, R1 and R2 are independently selected from hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, halogeno lower alkyl, hydroxy, or hydroxy lower alkyl, and may together form fused phenyl, fused C4-7 cycloalkyl, fused heteroaryl, or fused heterocyclyl structures. R3 is lower alkyl, R4 is hydrogen or lower alkyl, and R5 is lower alkylamino or a group selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl, heteroaryl, and heterocyclyl, with optional substitution and fused heteroaryl or fused heterocyclyl options.
The disclosed compounds are characterized as sulfonamide derivatives and are used as integrin inhibitors. The document also describes pharmaceutical compositions and therapeutic and prophylactic agents for treating integrin-dependent inflammatory disease, and includes analytical characterization for multiple closely related compounds supported by 1H NMR and ESI-MS [M+H]+ data.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim to formula (I) compound genus with extensive variable-controlled structural features, including B, D, and R1 to R5, plus dependent refinements and a method of use. Overall, the inventive coverage combines a structurally defined sulfonamide framework with an integrin-inhibition use claim.
Formula (I) compound with variable substituents
A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, with variables for bond type, B, D, and R1-R5, including allowed substituent classes and optional fused ring formation.
B and D substituent definitions
B is selected from hydroxy, OC1-10 alkyl, O-heterocyclyl, O-cilexetilyl, or O-medoxomilyl, and D is phenyl or heteroaryl optionally substituted with halogen, lower alkyl, lower alkoxy, and hydroxy.
R1 and R2 fusion options
R1 and R2 are independently hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, halogeno lower alkyl, hydroxy, or hydroxy lower alkyl, and may together form fused phenyl, fused C4-7 cycloalkyl, fused heteroaryl, or fused heterocyclyl.
R3, R4, and R5 substituent definitions
R3 is lower alkyl; R4 is hydrogen or lower alkyl; and R5 is lower alkylamino or a group selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl, heteroaryl, and heterocyclyl, each optionally substituted with halogen, cyano, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, phenyl, and heterocyclyl.
Integrin activity inhibition by administration
A method of inhibiting integrin activity in a subject by administering a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is directed to a broad formula (I) chemical scaffold with extensive substituent variability and fused-ring options, narrowed in dependent claims by specific substituent definitions and by a method claim for inhibiting integrin activity.
Stated Advantages
Integrin selectivity is asserted.
Oral administration is asserted.
Long-acting compound behavior is asserted.
Safety is asserted.
Activity in human blood is asserted.
Documented Applications
Therapeutic and prophylactic treatment of an integrin-dependent inflammatory disease using an integrin inhibitor.
Inhibiting integrin activity in a subject by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
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