Human leukocyte elastase synthesis

The synthesis and inhibitory activity toward human leukocyte elastase of new 7a-methoxy and 7a-chloro (2-acyloxymethyl)cephem derivatives have been reported <2001EJM185>. Starting from 4-(/frt-butylcarbonyl)-7/3-amino-3-methyl-A3-cephem 1,1-dioxide 37, a practical and efficient route leading to the synthesis of 4-(/frt-butyl-carbonyl)-7a-methoxy-3-methyl-A3-cephem 1,1-dioxide 38, a key intermediate in the preparation of potent inhibitors of mammalian serine proteinases, has been reported <1998SL322>. The new synthetic pathway has allowed easy access to an array of 7-substituted cephem derivatives such as 39 and 40 (Scheme 6). 

Veale, C. A., Bernstein, R R., Bryant, C., et al. (1995) Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones. J. Med. Chem., 38, 98-108. 

Warner, P., Green, R. C., Gomes, B. and Strimpler, A. M. (1994) Non-peptidic inhibitors of human leukocyte elastase. 1. The design and synthesis of pyridone-containing inhibitors. J. Med. Chem., 37, 3090-3099. 

Non-Peptidic Inhibitors of Human Leukocyte Elastase. 1. The Design and Synthesis of Pyridone-Containing Inhibitors. 

R. Earley, S. Feeney, B. C. Gomes, B. J. Kosmider, G. B. Steelman, R. M. Thomas, E. P. Vacek, C. A. Veale, J. C. Williams, D. J. Wolanin, and S. A. Woolson, ]. Med. Chem., 37, 3313 (1994). Nonpeptidic Inhibitors of Human Leukocyte Elastase. 3. Design, Synthesis, X-Ray Crystallographic Analysis, and Structure-Activity Relationship for a Series of Orally Active 3-Amino-6-Phenylpyridin-2-ones. 

F. Rypdcek, W. R. Banks, D. Noskovd and G. A. Digenis, Synthetic macromolecular inhibitors of human-leukocyte elastase. 1. Synthesis of peptidyl carbamates boimd to water-soluble polymers — poly-a,jS-[N-(2-hydroxyethyl)-D,L-aspartamide] and poly-a-[N -(2-hydroxyethyl)-L-glutamine],/. Med. Chem., 37, 1850-1856 (1994). 

Two representative procedures are presented in detail. The first, preparation of Z-Gly-Leu-PheCH-Cl, involves deblocking of Z-PheCH-Cl and subsequent coupling of the deblocked chloromethyl ketone with Z-Gly-Leu-OH. This compound is an excellent inhibitor of chymotryp-sin and cathepsin G. The second procedure, that for Ac-Ala-Ala-Pro- ValCH-Cl, illustrates the synthesis of a peptide chloromethyl ketone from Boc-Val-OH with a minimum of isolation and purification along the way this compound is an excellent inhibitor of porcine pancreatic and human leukocyte elastase. ... 

Synthesis of Thieno[2,3-d][l,3]oxazln-4-ones as Inhibitors of Human Leukocyte Elastase... 

Cvetovich RJ, Chartran M, Hartner FW, Roberge C, Amato JS, Grabowski EJ. An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of lactam esters. J. Org. Chem. 1996 61 6575 580. 

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