Substituted oxazolidine calpain and/or cathepsin B inhibitors

An oxazolidinyl, alkyl technology, applied in the field of substituted oxazolidine calpain and/or cathepsin B inhibitors, which can solve the problem of impairing cell viability

Inactive Publication Date: 2002-07-31
AVENTIS PHARMA SA (US)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clearly, uncontrolled proteolysis of some or all of these structural and regulatory proteins can severely impair cell viability

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0081] Embodiment 1[4S-[3(R × ), 4α, 5β]]-[1-[[5-hydroxy-4-(phenylmethyl)-3-oxazolidinyl]carbonyl]-2-methylpropyl]-carbamic acid phenylmethyl Preparation of Esters (MDL104,903) Step A

[0082] Scheme VI, step A; Cbz-Val-Phe-OH (4.67 g, 11.7 mmol, obtained from Sigma Chemical Company, St. Louis, MO 63178) was mixed with paraformaldehyde (5 g) and p-toluenesulfonic acid monohydrate (500 mg , 2.6mmol) in benzene (120ml) solution was mixed. The reaction mixture was heated to reflux for approximately 23 hours with continuous removal of water through a Dean-Stark trap. The reaction mixture was then cooled to room temperature and concentrated in vacuo, the residue was dissolved in ethyl acetate (100ml), saturated aqueous sodium bicarbonate (60ml) was added with mixing, the layers were then separated and washed with ethyl acetate (2 x 50ml ) to extract the aqueous layer, combine the organic layer and the organic extract, dry with anhydrous magnesium sulfate,...

Embodiment 2

[0084] Embodiment 2[4S-[3(R × ), 4α, 5β]]-[1-[[5-(acetoxy)-4-(phenylmethyl)-3-oxazolidinyl]carbonyl]-2-methylpropyl]-carbamic acid Phenyl methyl ester (MDL104,860)

[0085] Route VII; the title compound (250mg, 0.6mmol) prepared in Example 1 and triethylamine (0.3mL) were dissolved in dichloromethane (20ml), then acetyl chloride (0.3mL, 4.2mL) was added to the solution at room temperature mmol), and the reaction mixture was stirred overnight, then the reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (30 mL) and 1N HCl (30 mL), the layers were separated, and the water was extracted with ethyl acetate (3×30 mL) layers, the organic layer and organic extract were combined, dried over anhydrous magnesium sulfate, passed through a short silica gel plug, and the filtrate was concentrated in vacuo. The residue was then purified by preparative thin layer chromatography (hexane / ethyl acetate, 80:20, silica gel) to afford th...

Embodiment 34

[0086] Embodiment 34-morpholine formic acid [4S-[3(R × ), 4α, 5β]]-3-[3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]butyl]-4-(phenylmethyl)-5 - Preparation of oxazolidinyl esters (MDL 105,803)

[0087] Route VII; the title compound (243mg, 0.59mmol) prepared in Example 1 was dissolved in dichloromethane (30ml), and under stirring, 4-dimethylaminopyridine (10mg, DMAP) was added, followed by triethylamine (0.2mL, 1.2mmol) and 4-morpholinecarbonyl chloride (0.1mL, 0.86mmol), the reaction mixture was stirred at room temperature for about 20 hours, the reaction mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate (50ml ) and 1N HCl (20 mL), the layers were separated, the organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate, passed through a short plug of silica gel, and the filtrate was concentrated in vacuo. The resulting white solid was recrystallized from ethyl acetate / hexane to give the...

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PUM

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Abstract

This invention relates to oxazolidine inhibitors of calpain and/or cathepsin B and to compositions containing them. As inhibitors of calpain and/or cathepsin B, the compounds are useful in the treatment of patients afflicted with acute or chronic neurodegenerative disorders.

Description

Background of the invention [0001] Neurological damage caused by insufficient vascular supply to the brain is a major cause of death and disability. Concerning the etiology of ischemic neuronal death, sustained release of intracellular calcium has been proposed to trigger various intracellular events that impair or deleterious to cellular function; Hong, Seung-Chyul et al., Stroke, 25, 663 -669 (1994); Siesjo, B.K., et al., J. Cereb. Blood Flow Metab., 9, 127-140 (1989); Siesjo, B.K., et al., J. Neurosurg, 77, 169-184 (1992) . Under physiological conditions, intracellular calcium levels must be carefully regulated to precisely maintain them. Decreased calcium homeostasis and increased intracellular calcium during ischemia lead to the inappropriate activation of several calcium-sensing mechanisms, which are detrimental to cellular function, the prime example of which is calcium-activated proteolysis. Continuous stimulation of the calcium-activated neuroneutral protease calle...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/06A61K31/42A61K31/421A61K31/535A61K31/5377A61K38/00A61P9/08A61P9/10A61P25/00A61P25/28A61P43/00C07D263/04C07D263/18C07K5/062
CPCC07D263/04A61P25/00A61P25/28A61P43/00A61P9/08A61P9/10
Inventor N·P·彼特S·米荷笛M·D·林尼克M·R·安格拉斯托H-O·吉姆
Owner AVENTIS PHARMA SA (US)
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