Sterling Winthrop Inc.

Sanofi

Vertex Pharmaceuticals, Inc.

Sanofi Winthrop Inc.

Mohamed M Awad

Roland Ellwood Dolle

Joseph M Salvino

Prasad V Chaturvedula

Tina Morgan Ross

Stanley J Schmidt

Jasbir Singh

Denton W Hoyer

Brent D Douty

Peter R Seoane

David A Whipple

Wayne T Houck

David M Faunce

David G Sawutz

Catherine Prouty

Catherine P Prouty

James M Rinker

Mark A Ator

Irennegbe K Osifo

Eric P Lodge

Disclosed are compounds, compositions and methods for inhi.beta.iting interleukin-1.beta. protease activity, the compounds .alpha.-substituted methyl ketones having the formula (I) set forth herein. These compounds are inhibitors of IL-1.beta. converting enzyme and as such are useful as therapeutic agents for certain infectious diseases.

Peptide analogs as irreversible interleukin-1.beta. protease inhibitors

Compounds which Inhibit interleukin-1.beta. protease activity, pharmaceutical compositions containing the compounds and methods using the compounds are provided. The compounds have the formula ##STR1## wherein n is 0-2; each AA is Independently L-valine or L-alanine; R.sub.1 is selected from the group consisting of N-�4(N,N-dimethylaminomethyl)!benzoyl, N-benzoyloxycarbonyl, N-methyl-N-�4-(pyridyl)methyl!, N-�4-(pyddyl)methyl!carbonyl, N-3-(piperidinopropionyl), N-�4-(morpholinoethoxy)benzoyl, N-2-(quinuclidinyl)carbonyl, N-(3-pyridyl)methoxy carbonyl, N-(2-pyddyl)methoxy carbonyl, N-methyl-N-benzyl carbonyl, N-methyl-N-�2-(4-pyridyl)ethyl!carbonyl, and N-(N-phenylpiperazino) carbonyl; and R.sub.8, R.sub.9 and R.sub.10 are as defined below.

.alpha.-heteroaryloxymethyl ketones as interleukin - 1 .beta. converting

Compounds which inhibit interleukin-1.beta. protease activity, pharmaceutical compositions containing the compounds and methods using the compounds are provided. The compounds have the formula ##STR1## wherein n is 0-2; each AA is independently L-valine or L-alanine; R.sub.1 is selected from the group consisting of N-[4-(N,N-dimethylaminomethyl)]benzoyl, N-benzyloxycarbonyl, N-methyl-N-[4-(pyridyl)methyl], N-[4-(pyridyl)methyl]carbonyl, N-3-(piperidinopropionyl), N-[4-(morpholinoethoxy)benzoyl, N-2-(quinuclidinyl)carbonyl, N-(3-pyridyl)methoxy carbonyl, N-(2-pyridyl)methoxy carbonyl, N-methyl-N-benzyl carbonyl, N-methyl-N-[2-(4-pyridyl)ethyl]carbonyl, and N-(N-phenylpiperazino)carbonyl; and R.sub.8, R.sub.9, R.sub.10 are each independently hydrogen, lower alkyl, halo substituted methyl, carbalkoxy, benzyl, phenyl, or phenyl mono or disubstituted with fluoro, nitro, methoxy, chloro, trifluoromethyl or methanesulfonyl.

Heteroaryloxymethyl ketones as interleukin-1.beta.converting enzyme

Disclosed are nonpeptides having bradykinin antagonist activity of the formulae (I) and (II) ##STR1## or a pharmaceutically acceptable salt thereof therefor.

Nonpeptide bradykinin antagonists

Disclosed are nonpeptides having bradykinin antagonist activity of the formulae (I) and (II) ##STR1## or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing the compound and methods of treating diseased or pathological conditions using the pharmaceutical compositions.

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Westerly, RI, United States of America

Mohamed M Awad