Process for synthesizing aspartic and glutamic acid derivatives especially useful as intermediates in the manufacture of a caspase inhibitor

Abstract

The invention relates to novel diazoketone derivatives. The invention also relates to processes for homologation of these diazoketone derivatives. The processes are useful for preparing compounds that are caspase inhibitors.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Patent Application 60 / 328,065, filed Oct. 9, 2001.TECHNICAL FIELD OF THE INVENTION[0002]The invention relates to novel diazoketone derivatives. The invention also relates to processes for homologation of these diazoketone derivatives. The processes are useful for preparing compounds that are caspase inhibitors.BACKGROUND OF THE INVENTION[0003]Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, ischemic diseases and certain neurodegenerative disorders [see generally Science, 281, pp. 1283-1312 (1998); Ellis et al., Ann. Rev. Cell. Biol., 7, p. 663 (1991)].[0004]Caspases are a family of cysteine protease enzymes that are key mediators in the s...

AI Technical Summary

Benefits of technology

[0012]A process of this invention comprises the step of subjecting a diazoketone derivative of formula 1 to conditions that effect the rearrangement of 1 to form the corresponding homologation product 2:Homologation may be accomplished, for example, by reacting a compound of formula 1 in the presence of a base and a silver salt. Advantageously, this method preserves the chirality of the starting compound in the homologation product.

Problems solved by technology

However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacological properties, such as poor cellular penetration and cellular activity, poor oral absorption, poor stability and rapid metabolism [J. J. Plattner and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds.

This has hampered their development into effective drugs.

Existing processes for synthesizing aspartic and glutamic acid derivatives and their analogues as caspase inhibitors or as Intermediates for caspase inhibitors suffer from limited success and offer little control over stereochemistry [L. Revesz et al., Tetrahedron Lett., 35, pp.

These transformations result in the formation of enantiomeric mixtures, which would require tedious separation steps to obtain an enantiomerically pure aspartic or glutamic acid mimic.

Consequently, studies of the inhibitory activity of compounds with an aspartic or glutamic acid component generally refer to enantiomeric or diastereomeric mixtures, which may limit their effectiveness as enzyme inhibitors.

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