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Vla-4 antagonists

An alkyl, selected technology, applied in the field of VLA-4 antagonists, can solve the problems of short half-life, unsuitable for oral administration, poor pharmacokinetic properties, etc.

Inactive Publication Date: 2008-04-16
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, further characterization demonstrates that this compound has very poor pharmacokinetic properties, such as low oral bioavailability, moderate to high levels of plasma clearance and short half-life, making it unsuitable for oral administration

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] (R, S, S)-N-{N-[(3-methylsulfonylphenyl)sulfonyl]-4(R)-cyclobutylamino-(L)-proline Aminoacyl}-4-[(3′,5′-dichloro-isonicotinyl)amino]-(L)-phenylalanine ethyl ester

[0137]

[0138] Step A: N-BOC-4(R)-cyclobutylamino-L-proline, methyl ester

[0139]

[0140] To a solution of N-BOC-cis-hydroxy-L-proline methyl ester (60g, 0.25mol) and N,N-diisopropylethylamine (100mL, 0.57mol) in dichloromethane (800mL) Trifluoromethanesulfonic anhydride was added within 45 minutes at -20°C. After continued stirring at -20°C for 45 minutes, cyclobutylamine (55 g, 0.78 mol) was added in one portion and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with 1N NaOH (250 mL) and saturated aqueous NaHCO3 (250 mL). The organic layer was separated, dried with brine, dried over magnesium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography on silica gel with CH 2 Cl 2 to EtOAc to 5% MeOH / EtOAc) to ...

Embodiment 2

[0149]

[0150] (R, S, S)-N-{N-[3-methylsulfonylphenyl)sulfonyl]-4(R)cyclobutylamino-(L)-prolyl Base}-4-[(3′,5′-dichloro-isonicotinyl)amino]-(L)-phenylalanine

[0151] To N-{N-[(3-methylsulfonylbenzenesulfonyl)-cyclobutylamino-(L)-prolyl}-4-[(3′,5′-dichloro-isonicotinyl) To a solution of amino]-(L)-phenylalanine ethyl ester (compound of Example 1, 4.794 g, 6.378 mmol) in 40 mL of acetonitrile was added 15.93 mL of 1N NaOH. After stirring at room temperature for 2 h, the reaction was quenched with 8 mL of 2N HCl to make the reaction solution slightly acidic. The reaction was diluted with 450 mL of THF / EtOAc (1:3 v / v) and washed with water (100 mL×2). After evaporation of the solvent, the residue was dissolved in 100 mL of acetonitrile and lyophilized to afford 4.6 g (99%) of the title product. 1 H NMR (500MHz, CD 3 OD): δ8.62(s, 2H), 8.3 3(s, 1H), 8.20(d, 1H), 7.90(d, 1H), 7.76(t, 1H), 7.60(d, 2H), 7.34( d, 2H), 4.49(dd, 1H), 4.44(dd, 1H), 3.70(dd, 1H), 3.63(m, 1H), ...

Embodiment 3

[0153]

[0154] N-{N-[3-methylsulfonylphenyl)sulfonyl]-3(S)-tert-butylamino-(L)-prolyl}-4- [(3′,5′-Dichloro-isonicotinyl)amino]-(L)-phenylalanine, ethyl ester

[0155] Step A: N-[(-methylsulfonylphenyl)sulfonyl]-3(S)-hydroxy-(L)-proline, methyl ester

[0156] To a solution of (3S)-hydroxy-(L)-proline (Acros, 1.223 g, 9.324 mmol) and sodium carbonate (2.08 g, 19.63 mmol) in 30 mL of water was added powdered 3-methyl Sulfonylbenzenesulfonyl chloride (2.5 g, 9.815 mmol). After stirring at room temperature overnight, the reaction mixture was acidified with concentrated hydrochloric acid (pH=3), and the product was extracted with ethyl acetate (3×30 mL). Dry organic extracts (MgSO 4 ), filtered and concentrated to dryness. The residue was then dissolved in dichloromethane (10 mL) and methanol (10 mL), and trimethylsilyldiazomethane (2M in ether) was added at 0 °C until the color persisted to yellow. After stirring at room temperature for 15 minutes, the mixture was con...

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Abstract

Substituted N-[N-(sulphonylphenyl)sulfonyl-prolyl]-phenylalanine 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 late antigen-4"; CD49d / CD29; or α4β1) is an integrin expressed on all leukocytes, but in addition to platelets and mature neutrophils, including dendritic cells and macrophages -like cells and are key mediators of cell-cell and cell-matrix interactions in these cell types. Ligands for VLA-4 include vascular cell adhesion molecule-1 (VCAM-I), the CS-I domain of fibronectin (FN), and the matrix protein, osteopontin. Neutralizing anti-α4 antibodies or blocking peptides that inhibit the interaction between VLA-4 and its ligands have been shown to be effective in several arterial models for the prevention and treatment of diseases including eradication, multiple sclerosis, inflammatory venereal bowel disease, multiple myeloma, and rheumatoid arthritis. [0002] A humanized monoclonal antibody against α4, natalizumab (Tysabri®, Elan / Biogen), has been shown to be effective in multiple sclerosis (D.H.Miller et al., New England Journal ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/40A61K31/44A61K31/445C07D207/09C07D209/02C07D401/12
CPCC07K5/06139A61K38/00A61P1/00A61P1/04A61P7/06A61P9/00A61P11/02A61P11/06A61P11/08A61P19/02A61P25/28A61P27/02A61P29/00A61P35/00A61P35/02A61P37/06A61P37/08A61P43/00
Inventor 刘平C·琼斯T·S·雷格尔
Owner MERCK & CO INC
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