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Vla-4 antagonists
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An alkyl, selected technology, applied in the field of VLA-4 antagonists, can solve the problems of low oral bioavailability, poor pharmacokinetic properties, unsuitable for oral administration, etc.
Inactive Publication Date: 2008-04-02
MERCK & CO INC
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[0119] To a solution of cyclopentanethiol (1 mL, 9.30 mmol) in absolute ethanol (9 mL) was added sodiummetal (215 mg, 9.35 mmol) and stirred until the metal was completely dissolved, then a portion of (2S,4S)-4-{[( 4-methylphenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.26 g, 3.15 mmol), the reaction mixture was kept at room temperature for 12 hr . The solution was diluted with DCM, washed with water, the aqueous layer was extracted with DCM, and the combined organic phases were dried (MgSO 4 ), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0-30% acetone in hexanes to afford the title compound as a colorless so...
[0134] (4R)-1-[(3-cyanophenyl)sulfonyl]-4-(cyclopentylthio)-L-prolyl-4-[(3,5-dichloro -Isonicotinoyl)amino]-L-phenylalanineethyl ester (300 mg, 0.403 mmol) was dissolved in MeCN (2 mL) and 1 N LiOH solution (1 mL, 1.00 mmol) was added. The reaction was carefully monitored by LCMS and quenched with acetic acid once complete (approximately 30 min) and evaporated to dryness. The residue was purified by reverse phase HPLC to afford the carboxylic acid as a colorless foam. 1 HNMR(d 3 -MeOD, 500MHz) δ8.62(s, 2H), 8.19(s, 1H), 8.01(m, 2H), 7.74(app t, 1H), 7.62(d, 2H), 7.34(d, 2H), 4.71(m, 1H), 4.30(dd, 1H), 3.80(dd, 1H), 3.21-3.38(m's, 2H), 3.07(dd, 1H), 2.96(m, 1H), 2.16(m, 1H), 1.90(m, 3H), 1.67(m, 2H), 1.54(m, 2H), 1.36(m, 1H), 1.27(m, 1H); LCMS(ESI) 714.4(M-H) - , 716.3(M+H) + .
[0135] The following examples of the present invention w...
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Abstract
4-Thio, 4-sulfinyl and 4-sulfonylproline derivatives of the present invention are antagonists of the VLA-4 integrin and are useful in the treatment, prevention and suppression of diseases mediated by VLA-4-binding and cell adhesion and activation. Moreover, the compounds of the present invention demonstrate significant receptor occupancy of VLA-4 bearing cells after oral administration and are suitable for once-, twice-, or thrice-a-day oral administration. This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
Description
Background of the invention [0001] VLA-4 ("Very New Antigen-4"; CD49d / CD29; or α 4 beta 1 ) is an integrin expressed on all leukocytes except platelets and mature neutrophils, including dendritic cells and macrophage-like cells, and is a key mediator of cell-cell and cell-matrix interactions in these cell types . Ligands of VLA-4 include vascular cell adhesion molecule-1 (VCAM-1), the CS-1 domain of fibronectin (FN), and matrix proteins, osteopontin. Neutralizing anti-α4 antibodies or blocking peptides that inhibit the interaction between VLA-4 and its ligands have been shown to be effective against diseases including asthma, multiple sclerosis, inflammatory bowel disease, multiple myeloma, and rheumatoid arthritis. Prophylactic and therapeutic effects in several animal models. [0002] anti-alpha 4 The human monoclonalantibody natalizumab (natalizumab) (Tysabri_, Elan / Biogen) has been shown to be effective against multiple sclerosis (D.H.Miller et al., New England Journ...
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