Propanoic acid derivatives that inhibit binding of integrins to their receptors

A technology of derivatives and compounds, applied in the field of preparations for disease states, can solve problems such as uncontrollable leukocyte migration, tissue damage, blood cell influx, etc.

Inactive Publication Date: 2008-01-09
ENCYSIVE PHARM INC NEW YORK NEW
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 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 blood cells into the lesion, causing extensive tissue damage

Method used

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  • Propanoic acid derivatives that inhibit binding of integrins to their receptors
  • Propanoic acid derivatives that inhibit binding of integrins to their receptors
  • Propanoic acid derivatives that inhibit binding of integrins to their receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0112]

[0113] Process 4

[0114] Scheme 5, shown below, illustrates the method of Example 13.

[0115]

[0116] Process 5

[0117] Scheme 6, shown below, illustrates the method introduced in Example 14.

[0118]

[0119] Process 6

[0120] Scheme 7, shown below, illustrates the method introduced in Example 15.

[0121]

[0122] Process 7

[0123] Flowchart 8 shown below illustrates the method introduced in Example 16.

[0124]

[0125] Process 8

[0126] Scheme 9, shown below, illustrates the method introduced in Example 17.

[0127]

[0128] Process 9

[0129] Flowchart 10 shown below illustrates the method introduced in Example 18.

[0130]

[0131] Process 10

[0132] Flowchart 11 shown below illustrates the method introduced in Example 19.

[0133]

[0134] Process 11

[0135] Flowchart 12 shown below illustrates the method introduced in Example 20.

[0136]

[0137] Process 12

[0138] Flowchart 13 shown below illustrates the meth...

Embodiment 1

[0177] Compound 8(3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-benzyl- 5-methyl-2-oxo-1(2H)-pyridyl)hexanoylamino)propanoic acid.

[0178]

[0179] The structures of the compounds indicated by numbers in this example are shown in Scheme 1 above.

[0180] step 1 : A solution of 540 mg of methyl 2-aminocaproic acid hydrochloride 1 in 20 ml of dichloromethane was washed with excess saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to afford 365 mg of methyl 2-aminocaproate as a colorless oil. This material was mixed with 5 ml benzene, 0.28 ml propionaldehyde and excess magnesium sulfate. After stirring for 15 minutes, the reaction mixture was filtered and concentrated in vacuo to afford 420 mg of compound 2 as a colorless oil. Compound 2 was used directly without further purification.

[0181] step 2 : Under a positive nitrogen atmosphere, add 0.80 ml of triethylamine and 964 mg of 3-phenylpro...

Embodiment 2

[0190] Synthesize the compound 12(3S)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridine shown below according to the method of Example 1 Base) hexanoylamino)-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid,

[0191]

[0192] The exception in the method is to replace compound 6 in step 5 with compound A shown below.

[0193]

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Abstract

A method for the inhibition of the binding of alpha<4>beta<1> 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 the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which alpha<4>beta<1> is involved.

Description

field of invention [0001] The present invention mainly relates to α 4 beta 1 Inhibition of integrin binding to its receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds inhibiting this binding, pharmaceutically active compositions comprising such compounds and the use of such compounds as described above, or for the control or prevention of alpha 4 beta 1 Agents of the disease states involved. Background of the invention [0002] White blood cells play a major role in the inflammatory response when tissues are attacked or damaged by microorganisms. One of the most important aspects of the inflammatory response involves the process of cell adhesion. Generally, white blood cells circulate through the bloodstream. However, when tissue is infected or damaged, white blood cells recognize the invaded or damaged tissue, bind to capillary walls, and migrate through the capillaries into the affected tissue. These ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C315/00C07C229/00C07C321/00C07C205/00C07D229/00A61K31/192A61K31/33A61K31/4166A61K31/4184A61K31/4412A61K31/443A61K31/465A61K31/497A61K31/498A61K31/501A61K31/505A61K31/517A61P1/04A61P3/10A61P7/00A61P9/10A61P11/06A61P17/00A61P19/02A61P25/00A61P29/00A61P37/06C07C233/00C07D213/30C07D213/64C07D215/02C07D235/04C07D239/36C07D317/60C07D405/12C07D409/14
CPCC07D213/64C07D317/60C07D405/12C07D409/14A61P1/04A61P11/06A61P17/00A61P19/02A61P25/00A61P25/28A61P29/00A61P31/10A61P35/00A61P35/02A61P35/04A61P37/06A61P37/08A61P43/00A61P7/00A61P9/10A61P3/10
Inventor R·J·比迪格G·W·霍兰德J·M·卡斯尔W·李R·V·马克特I·L·斯科特C·吴
Owner ENCYSIVE PHARM INC NEW YORK NEW
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