Vertex Pharmaceuticals, Inc.

Sterling Winthrop Inc.

Sanofi

Sanofi Winthrop Inc.

Sanoft

Stanley J Schmidt

Roland Ellwood Dolle

Prasad V Chaturvedula

Tina Morgan Ross

Catherine P Prouty

Denton W Hoyer

James M Rinker

Mark A Ator

Jasbir Singh

Mohamed M Awad

Joseph M Salvino

Irennegbe K Osifo

Todd L Graybill

Gary J Speier

David A Whipple

Catherine Prouty

Eric P Lodge

Mohamed M A Awad

Tina Morgan-Ross

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof:wherein

4-pyridazinecarboxamides and esters as interleukin-1&#x3b2;  converting enzyme inhibitors

Pyridazines as interleukin-1&bgr; converting enzyme inhibitors

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

Peptide analogs as irreversible interleukin-1&bgr; protease inhibitors

N-(pyrimidinyl)-aspartic acid analogs as interleukin-1&bgr; converting enzyme inhibitors

Disclosed are compounds, compositions and methods for inhibiting interleukin-1.beta. (IL-.beta.) protease activity. The compounds, N-(pyrimidinyl)-aspartic acid .alpha.-substituted methyl ketones and aspartic acid aldehydes, have the formula (I) set out herein. These compounds are inhibitors of 1.beta.-converting enzyme and as such are useful whenever such inhibition is desired. For example, they may be used as research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which 1L-.beta. protease activity is implicated.

N-(pyrimidinyl)-aspartic acid analogs as interleukin-1.beta. converting

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein R.sub.1 is a halogen, or an oxygen linked leaving group including an aromatic ether, an alkyl sulfonate, an aryl sulfonate, an alkyl phosphonate, an aryl phosphonate, an alkyl phosphate or aryl phosphate;

Pyridazines as interleukin-1.beta. converting enzyme inhibitors

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

Disclosed are compounds, compositions and methods for inhibiting interleukin-1.beta. (1L-.beta.) protease activity. The compounds, N-(pyrimidinyl)-aspartic acid .alpha.-substituted methyl ketones and aspartic acid aldehydes, have the formula (I) set out herein. These compounds are inhibitors of 1.beta.-converting enzyme and as such are useful whenever such inhibition is desired. For example, they may be used as research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which IL-.beta. protease activity is implicated.

Disclosed are compounds, compositions and methods for inhibiting interleukin-1.beta. protease activity. The compounds, bicyclic derivatives of aldehydes and .alpha.-substituted methyl ketones, have the formula (A) set out herein.

Fused-bicyclic lactams as interleukin-1.beta. converting enzyme

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 compounds of the formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein R.sub.1 is (CR.sub.5 R.sub.6).sub.n, (CR.sub.5 R.sub.6).sub.n,-aryl, (CR.sub.5 R.sub.6).sub.n -heteroaryl, X-(CR.sub.5 R.sub.6).sub.n, X-(CR.sub.5 R.sub.6).sub.n -aryl or X-(CR.sub.5 R.sub.6).sub.n -heteroaryl wherein aryl and heteroaryl may be optionally substituted;

Peptidic ketones as interleukin-1.beta.-converting enzyme inhibitors

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein R.sub.1 is (CR.sub.5 R.sub.6).sub.n, (CR.sub.5 R.sub.6).sub.n -aryl, (CR.sub.5 R.sub.6).sub.n -heteroaryl, X-(CR.sub.5 R.sub.6).sub.n, X-(CR.sub.5 R.sub.6).sub.n -aryl or X-(CR.sub.5 R.sub.6).sub.n -heteroaryl wherein aryl and heteroaryl may be optionally substituted;

Growing community of inventors

Chester Springs, PA, United States of America

Stanley J Schmidt