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Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof

A technology of derivatives and compounds, applied in the field of compounds that inhibit this binding, can solve the problems of leukocyte influx, uncontrollable leukocyte migration, tissue damage, etc.

Inactive Publication Date: 2009-07-08
ENCYSIVE PHARM INC NEW YORK NEW
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although leukocyte migration to the site of injury helps to fight infection and destroy foreign material, in many cases leukocyte migration can become uncontrollable with an influx of leukocytes into the lesion causing extensive tissue damage

Method used

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  • Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof
  • Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof
  • Carboxylic acid derivatives inhibiting the binding of integrins to receptors thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0584] (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridyl}amino)carbonyl Synthesis of ]amino}-3-(4-methylphenyl)propionic acid (10)

[0585] step 1: Compound 1 (20.8 g, 135 mmol) was dissolved in methanol (270 mL), and palladium on carbon (10% palladium dry weight basis, Degussa E101 NE / W type, ~50% water content, 5.75 g, 2.7 mmol Pd) was added . The atmosphere was replaced with hydrogen (switching between vacuum and balloon hydrogen 5 times), the mixture was stirred overnight, then filtered. The filtrate was concentrated in vacuo, the residue was taken up with a 1:1 hexane:ethyl acetate mixture, water and saturated NaHCO 3 , saturated NaHCO 3 Wash with a 4:1 mixture of brine. The organic layer was treated with MgSO 4 After drying and filtering, the filtrate was concentrated under reduced pressure to obtain compound 2 (12.43 g, 74%) as a white solid. This material was used without purification.

[0586] Step 2: Compound 2 (2.64 g, 21.3 mmol) w...

Embodiment 2

[0594] (3S)-3-{[({6-Methyl-2-oxo-1-(benzyl)-4-[(benzyl)oxy]-1,2-dihydro-3-pyridine Synthesis of yl}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (15)

[0595] step 1: To compound 11 (1.0g, 5.9mmol) and K 2 CO 3 Benzyl bromide (2.31 g, 13.5 mmol) was added to a suspension of (2.40 g, 17.6 mmol) in acetone (50 mL). After reflux overnight, the reaction was cooled and the mixture was partitioned between ethyl acetate and saturated NaHCO 3 between. The organic layer was washed with dilute HCl and brine, washed over MgSO 4 After drying and filtering, the filtrate was concentrated to obtain compound 12 (1.60 g, 80%).

[0596] Step 2: Compound 12 (0.30g, 0.86mmol), zinc powder (0.30g, 4.6mmol) and saturated NH 4 Aqueous Cl (0.30 mL) was mixed in MeOH (18 mL). The mixture was stirred at room temperature for 1 hour, then additional zinc powder (0.30 g, 4.6 mmol) was added. The resulting heterogeneous mixture was refluxed overnight. After filtering the hot mixture a...

Embodiment 3

[0600] (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridyl Synthesis of}amino)carbonyl]amino}-3-(4-methylphenyl)propionic acid (22)

[0601] step 1: To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF (120 mL) was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol) at 0°C. The mixture was stirred at 0°C for 15 minutes, then 2-chlorobenzyl chloride (12.3 g, 76.4 mmol) was added. After stirring overnight at 55°C, the mixture was poured into ice water and washed with Et 2 O washed twice. The aqueous layer was acidified and the resulting precipitate was filtered to give compound 16 (14.7 g, 85%).

[0602] Step 2: Under a dry nitrogen atmosphere at room temperature, the flask containing compound 16 (8.00 g, 28.6 mmol) was sealed with a rubber septum and a balloon, and POCl was added via a syringe. 3 (30.0ml, 322mmol). The nitrogen delivery line was removed and the reaction mixture was stirred overnight at 70°C, then pou...

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Abstract

A method for the inhibition of the binding of alpha4beta1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and to the use of such compounds either a above, or in formulations for the control or prevention of diseases states in which alpha4beta1 is involved.

Description

[0001] This application is a divisional application of the following applications: filing date: December 29, 2001; application number: 01145182.3; invention title: "a carboxylic acid derivative that inhibits the binding of integrin to its receptor". [0002] This application is a continuation-in-part of U.S. Patent Application Serial No. 09 / 707,068, filed November 6, 2000, which is a continuation-in-part of U.S. Patent Application Serial No. 09 / 565,920, filed May 5, 2000 A continuation-in-part, this application claims the benefit of US Provisional Patent Application Serial No. 60 / 132,971 filed May 7, 1999. technical field [0003] The present invention generally relates to the 4 beta 1 Inhibition of integrin binding to its receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The present invention also relates to compounds that inhibit this binding; pharmaceutically active compositions containing such compounds; and to said compounds in the above aspe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07D213/69C07D213/73C07D239/47C07D239/36C07D215/22C07D409/14C07C275/34A61K31/4412A61K31/44A61K31/4418A61K31/513A61K31/4704A61K31/4436A61K31/4025A61K31/216A61P43/00C07D498/04C07D221/04A61K31/435A61K31/495A61K31/50A61K31/505A61P1/00A61P3/10A61P9/10A61P11/06A61P19/02A61P25/00A61P29/00A61P35/00A61P35/02A61P37/02A61P37/08C07D207/416C07D211/86C07D213/02C07D213/62C07D213/72C07D215/38C07D221/16C07D237/16C07D237/22C07D239/28C07D239/46C07D317/46C07D317/60C07D401/04C07D401/12C07D403/12C07D405/12C07D409/06C07D409/12C07D413/04C07D413/06C07D413/12C07D417/06C07D471/04C07K14/78
CPCC07D417/06C07D471/04C07D237/22C07D403/12C07D213/75C07D405/12C07D409/12C07D215/22C07D409/14C07D413/12C07D409/06C07D413/06C07D401/12C07D221/04C07D317/60C07D239/47C07D221/16C07D401/04
Inventor R·J·比迪格Q·陈G·W·霍兰德J·M·卡斯尔W·李R·V·马克特I·L·斯科特C·吴E·R·戴克J·李
Owner ENCYSIVE PHARM INC NEW YORK NEW
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