Propanoic acid derivatives that inhibit binding of integrins to their receptors

Abstract

The present invention relates to methods of inhibiting the binding of α4β1 integrin to its receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit such binding; pharmaceutically active compositions containing such compounds; and Use of such compounds in the above aspects or in preparations for controlling or preventing disease states in which α4β1 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 affe...

Examples

Embodiment 12

[0131] Process 4

[0132] Scheme 5, shown below, illustrates the method of Example 13.

[0133] Process 5

[0134] Scheme 6, shown below, illustrates the method introduced in Example 14.

[0135] Process 6

[0136] Scheme 7, shown below, illustrates the method introduced in Example 15.

[0137] Process 7

[0138] Flowchart 8 shown below illustrates the method introduced in Example 16.

[0139] Process 8

[0140] Scheme 9, shown below, illustrates the method introduced in Example 17.

[0141] Process 9

[0142] Flowchart 10 shown below illustrates the method introduced in Example 18.

[0143] Process 10

[0144] Flowchart 11 shown below illustrates the method introduced in Example 19.

[0145] Process 11

[0146] Flowchart 12 shown below illustrates the method int...

Embodiment 1

[0186] 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.

[0187] The structures of the compounds indicated by numbers in this example are shown in Scheme 1 above.

[0188] 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.

[0189] Step 2: Add 0.80 ml of triethylamine and 964 mg of 3-phenylpropionyl chloride in 2 ml of ether to an ice-cooled solu...

Embodiment 2

[0198] 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, The exception in the method is to replace compound 6 in step 5 with compound A shown below.

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 affe...

Examples

Embodiment 12

[0131] Process 4

[0132] Scheme 5, shown below, illustrates the method of Example 13.

[0133] Process 5

[0134] Scheme 6, shown below, illustrates the method introduced in Example 14.

[0135] Process 6

[0136] Scheme 7, shown below, illustrates the method introduced in Example 15.

[0137] Process 7

[0138] Flowchart 8 shown below illustrates the method introduced in Example 16.

[0139] Process 8

[0140] Scheme 9, shown below, illustrates the method introduced in Example 17.

[0141] Process 9

[0142] Flowchart 10 shown below illustrates the method introduced in Example 18.

[0143] Process 10

[0144] Flowchart 11 shown below illustrates the method introduced in Example 19.

[0145] Process 11

[0146] Flowchart 12 shown below illustrates the method int...

Embodiment 1

[0186] 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.

[0187] The structures of the compounds indicated by numbers in this example are shown in Scheme 1 above.

[0188] 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.

[0189] Step 2: Add 0.80 ml of triethylamine and 964 mg of 3-phenylpropionyl chloride in 2 ml of ether to an ice-cooled solu...

Embodiment 2

[0198] 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, The exception in the method is to replace compound 6 in step 5 with compound A shown below.