Inhibitors of interleukin-1.beta. converting enzyme

The present invention relates to novel classes of compounds which are inhibitors of interleukin-1.beta. converting enzyme. The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against interleukin-1 mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases. This invention also relates to methods for inhibiting ICE activity and methods for treating interleukin-1 mediated diseases using the compounds and compositions of this invention.

TECHNICAL FIELD OF THE INVENTION 
The present invention relates to novel classes of compounds which are 
inhibitors of interleukin-1.beta. converting enzyme ("ICE"). The ICE 
inhibitors of this invention are characterized by specific structural and 
physicochemical features. This invention also relates to pharmaceutical 
compositions comprising these compounds. The compounds and pharmaceutical 
compositions of this invention are particularly well suited for inhibiting 
ICE activity and consequently, may be advantageously used as agents 
against interleukin-1 ("IL-1") mediated diseases, including inflammatory 
diseases, autoimmune diseases and neurodegenerative diseases. This 
invention also relates to methods for inhibiting ICE activity and methods 
for treating interleukin-1 mediated diseases using the compounds and 
compositions of this invention. 
BACKGROUND OF THE INVENTION 
Interleukin 1 ("IL-1") is a major pro-inflammatory and immunoregulatory 
protein that stimulates fibroblast differentiation and proliferation, the 
production of prostaglandins, collagenase and phospholipase by synovial 
cells and chondrocytes, basophil and eosinophil degranulation and 
neutrophil activation. Oppenheim, J. H. et al, Immunology Today, 7, pp. 
45-56 (1986). As such, it is involved in the pathogenesis of chronic and 
acute inflammatory and autoimmune diseases. IL-1 is predominantly produced 
by peripheral blood monocytes as part of the inflammatory response and 
exists in two distinct agonist forms, IL-1.alpha. and IL-1.beta.. Mosely, 
B. S. et al., Proc. Nat. Acad. Sci., 84, pp. 4572-4576 (1987); Lonnemann, 
G. et al., Eur. J. Immunol., 19, pp. 1531-1536 (1989). 
IL-1.beta. is synthesized as a biologically inactive precursor, 
pIL-1.beta.. pIL-1.beta. lacks a conventional leader sequence and is not 
processed by a signal peptidase. March, C. J., Nature, 315, pp. 641-647 
(1985). Instead, pIL-1.beta. is cleaved by interleukin-1.beta. converting 
enzyme ("ICE") between Asp-116 and Ala-117 to produce the biologically 
active C-terminal fragment found in human serum and synovial fluid. 
Sleath, P. R., et al., J. Biol. Chem., 265, pp. 14526-14528 (1992); A. D. 
Howard et al., J. Immunol., 147, pp. 2964-2969 (1991). Processing by ICE 
is also necessary for the transport of mature IL-1.beta. through the cell 
membrane. 
ICE is a cysteine protease localized primarily in monocytes. It converts 
precursor IL-1.beta. to the mature form. Black, R. A. et al., FEBS Lett., 
247, pp. 386-390 (1989); Kostura, M. J. et al., Proc. Natl. Acad. Sci. 
USA, 86, pp. 5227-5231 (1989). ICE, or its homologues, also appears to be 
involved in the regulation of cell death or apoptosis. Yuan, J. et al., 
Cell, 75, pp. 641-652 (1993); Miura, M. et al., Cell, 75, pp. 653-660 
(1993); Nett-Fiordalisi, M. A. et al., J. Cell Biochem., 17B, p. 117 
(1993). In particular, ICE or ICE homologues are thought to be associated 
with the regulation of apoptosis in neurogenerative diseases, such as 
Alzheimer's and Parkinson's disease. Marx, J. and M. Baringa, Science, 
259, pp. 760-762 (1993); Gagliardini, V. et al., Science, 263, pp. 826-828 
(1994). 
ICE has been previously described as a heterodimer composed of two 
subunits, p20 and p10 (20 kDa and 10 kDa molecular weight, respectively). 
These subunits are derived from a 45 kDa proenzyme (p45) by way of a p30 
form, through an activation mechanism that is autocatalytic. Thornberry, 
N. A. et al., Nature, 356, pp. 768-774 (1992). The ICE proenzyme has been 
divided into several functional domains: a prodomain (p14), a p22/20 
subunit, a polypeptide linker and a p10 subunit. Thornberry et al., supra; 
Casano et al., Genomics, 20, pp. 474-481 (1994). 
Full length p45 has been characterized by its cDNA and amino acid 
sequences. PCT patent applications WO 91/15577 and WO 94/00154. The p20 
and p10 cDNA and amino acid sequences are also known. Thornberry et al., 
supra. Murine and rat ICE have also been sequenced and cloned. They have 
high amino acid and nucleic acid sequence homology to human ICE. Miller, 
D. K. et al., Ann. N.Y. Acad. Sci., 696, pp. 133-148 (1993); Molineaux, S. 
M. et al., Proc. Nat. Acad. Sci., 90, pp. 1809-1813 (1993). Knowledge of 
the primary structure of ICE, however, does not allow prediction of its 
tertiary structure. Nor does it afford an understanding of the structural, 
conformational and chemical interactions of ICE and its substrate 
pIL-1.beta. or other substrates or inhibitors. 
ICE inhibitors represent a class of compounds useful for the control of 
inflammation or apoptosis or both. Peptide and peptidyl inhibitors of ICE 
have been described. PCT patent applications WO 91/15577; WO 93/05071; WO 
93/09135; WO 93/14777 and WO 93/16710; and European patent application 0 
547 699. However, due to their peptidic nature, such inhibitors are 
typically characterized by undesirable pharmacologic properties, such as 
poor oral absorption, poor stability and rapid metabolism. Plattner, J. J. 
and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. 
Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. This 
has hampered their development into effective drugs. 
Accordingly, the need exists for compounds that can effectively inhibit the 
action of ICE, for use as agents for preventing and treating chronic and 
acute forms of IL-1 mediated diseases, including various cancers, as well 
as inflammatory, autoimmune or neurodegenerative diseases. 
SUMMARY OF THE INVENTION 
The present invention provides novel classes of compounds, and 
pharmaceutically acceptable derivatives thereof, that are useful as 
inhibitors of ICE. These compounds can be used alone or in combination 
with other therapeutic or prophylactic agents, such as antibiotics, 
immunomodulators or other anti-inflammatory agents, for the treatment or 
prophylaxis of diseases mediated by IL-1. According to a preferred 
embodiment, the compounds of this invention are capable of binding to the 
active site of ICE and inhibiting the activity of that enzyme. 
It is a principal object of this invention to provide novel classes of 
inhibitors of ICE. These novel classes of ICE inhibitors are characterized 
by the following structural and physicochemical features: 
a) a first and a second hydrogen bonding moiety, each of said moieties 
being capable of forming a hydrogen bond with a different backbone atom of 
ICE, said backbone atom being selected from the group consisting of the 
carbonyl oxygen of Arg-341, the amide --NH-- group of Arg-341, the 
carbonyl oxygen of Ser-339 and the amide --NH-- group of Ser-339; 
b) a first and a second moderately hydrophobic moiety, said moieties each 
being capable of associating with a separate binding pocket of ICE when 
the inhibitor is bound thereto, said binding pocket being selected from 
the group consisting of the P2 binding pocket, the P3 binding pocket, the 
P4 binding pocket and the P' binding pocket; and 
c) an electronegative moiety comprising one or more electronegative atoms, 
said atoms being attached to the same atom or to adjacent atoms in the 
moiety and said moiety being capable of forming one or more hydrogen bonds 
or salt bridges with residues in the P1 binding pocket of ICE. 
It is also an object of this invention to provide a method for 
identification, design or prediction of ICE inhibitors comprising the 
steps of: 
a) selecting a candidate compound of defined chemical structure comprising 
at least two hydrogen bonding moieties, at least two moderately 
hydrophobic moieties and one electronegative moiety comprising one or more 
electronegative atoms attached either to the same atom or to adjacent 
atoms in the electronegative moiety; 
b) determining a low-energy conformation for binding of said compound to 
the active site of ICE; 
c) evaluating the capability of said compound in said conformation to form 
at least two hydrogen bonds with the non-carbon backbone atoms of Arg-341 
and Ser-339 of ICE; 
d) evaluating the capability of said compound in said conformation to 
associate with at least two of the binding pockets of ICE selected from 
the group consisting of the P2 binding pocket, the P3 binding pocket, the 
P4 binding pocket and the P' binding pocket; 
e) evaluating the capability of said compound in said conformation to 
interact with the P1 binding pocket of ICE; and 
f) accepting or rejecting said candidate compound as an ICE inhibitor based 
on the determinations and evaluations carried out in the preceding steps. 
It is a further object of this invention to provide novel classes of ICE 
inhibitors represented by formulas: 
##STR1## 
ABBREVIATIONS AND DEFINITIONS 
______________________________________ 
Abbreviations 
Designation Reagent or Fragment 
______________________________________ 
Ala alanine 
Arg arginine 
Asn asparagine 
Asp aspartic acid 
Cys cysteine 
Gln glutamine 
Glu glutamic acid 
Gly glycine 
His histidine 
Ile isoleucine 
Leu leucine 
Lys lysine 
Met methionine 
Phe phenylalanine 
Pro proline 
Ser serine 
Thr threonine 
Trp tryptophan 
Tyr tyrosine 
Val valine. 
______________________________________ 
DEFINITIONS 
The following terms are employed herein: 
The term "active site" refers to any or all of the following sites in ICE: 
the substrate binding site, the site where an inhibitor binds and the site 
where the cleavage of substrate occurs. The active site is characterized 
by at least amino acid residues: 173, 176, 177, 178, 179, 180, 236, 237, 
238, 239, 244, 248, 283, 284, 285, 290, 338, 339, 340, 341, 342, 343, 344, 
345, 348, 352, 381, 383, using the sequence and numbering according to 
Thornberry et al., supra. 
The terms "P binding pocket", "S subsite", "S pocket", and the like, refer 
to binding subsites, or portions of the substrate binding site on the ICE 
molecule. The amino acid residues of the substrate are given designations 
according to their position relative to the scissile bond, i.e. the bond 
which is broken by the protease. The residues are designated P1, P2, etc., 
for those extending toward the N-terminus of the substrate and P1', P2', 
etc., for those extending toward the C-terminus of the substrate. The 
portions of an inhibitor which correspond to the P or P' residues of the 
substrate are also labeled P1, P1', etc., by analogy with the substrate. 
The binding subsites of the ICE molecule which receive the residues 
labeled P1, P1', etc., are designated S1, S1', etc., or may alternately be 
designated "the P1 binding pocket", "the P1' binding pocket", etc. I. 
Schechter and A. Berger, "On the Size of the Active Site in Proteases", 
Biochem. Biophys. Res. Commun., vol. 27, pp. 157-162 (1967).! 
The terms "P2 binding pocket" or "S2 subsite" of the ICE active site are 
equivalent and are defined as the space surrounded by amino acid residues 
Pro-290, Val-338 or Trp-340. 
The terms "P3 binding pocket" or "S3 subsite" of the ICE active site are 
equivalent and are defined as the space surrounded by amino acid residues 
Pro-177, Arg-178, Thr-180, Arg-341 or Pro-343. 
The terms "P4 binding pocket" or "S4 subsite" of the ICE active site are 
equivalent and are defined as the space surrounded by amino acid residues 
His-342, Met-345, Val-348, Arg-352, Asp-381, Arg-383 or Trp-340. 
The terms "P1 binding pocket" or "S1 subsite" of the ICE active site are 
equivalent and are defined as the space surrounded by amino acid residues 
Arg-179, His-237, Gln-283, or Arg-341. 
The terms "P' binding pocket" or "S' subsite" of the ICE active site are 
equivalent and are defined as the space surrounded by amino acid residues 
Phe-173, Ile-176, His-237, Gly-238, Ile-239, Cys-244 or His-248. 
The term "hydrophobic" refers to a moiety which tends not to dissolve in 
water and is fat-soluble. Hydrophobic moieties include, but are not 
limited to, hydrocarbons, such as alkanes, alkenes, alkynes, cycloalkanes, 
cycloalkenes, cycloalkynes and aromatic compounds, such as aryls, certain 
saturated and unsaturated heterocycles and moieties that are substantially 
similar to the side chains of hydrophobic natural and unnatural 
.alpha.-amino acids, including valine, leucine, isoleucine, methionine, 
phenylanine, .alpha.-amino isobutyric acid, alloisoleucine, tyrosine, and 
tryptophan. 
The term "moderately hydrophobic" refers to a hydrophobic moiety in which 
one or two carbon atoms have been replaced with more polar atoms, such as 
oxygen or nitrogen. 
The term "heterocycle" or "heterocyclic" refers to a stable mono- or 
polycyclic compound which may optionally contain one or two double bonds 
or may optionally contain one or more aromatic rings. Each heterocycle 
consists of carbon atoms and from one to four heteroatoms independently 
selected from a group including nitrogen, oxygen, and sulfur. As used 
herein, the terms "nitrogen heteroatoms" and "sulphur heteroatoms" include 
any oxidized form of nitrogen or sulfur and the quaternized form of any 
basic nitrogen. Heterocycles defined above include, for example, 
pyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinonlinyl, purinyl, 
pyrimidyl, indolinyl, benzimidazolyl, imidazolyl, imidazolinoyl, 
imidazolidinyl, quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, 
pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, 
thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, .beta.-carbolinyl, 
tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, 
benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, 
isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazolyl, 
benzodioxolyl, benzothienyl, tetrahydrothiophenyl and sulfolanyl. Further 
heterocycles are described in A. R. Katritzky and C. W. Rees, eds., 
Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis 
and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, New York 
(1984). 
The term "cycloalkyl" refers to a mono- or polycyclic group which contains 
3 to 15 carbons and may optionally contain one or two double bonds. 
Examples include cyclohexyl, adamantyl and norbornyl. 
The term "aryl" refers to a mono- or polycyclic group which contains 6, 10, 
12, or 14 carbons in which at least one ring is aromatic. Examples include 
phenyl, naphthyl and biphenyl. 
The term "heteroaromatic" refers to a mono- or polycyclic group which 
contains 1 to 15 carbon atoms and from 1 to 4 heteroatoms, each of which 
is selected independently from a group including sulphur, nitrogen and 
oxygen, and which additionally contains from 1 to 3 five or six membered 
rings, at least one of which is aromatic. 
The term "alpha-amino acid" (.alpha.-amino acid) refers to both the 
naturally occurring amino acids and other "non-protein" .alpha.-amino 
acids commonly utilized by those in the peptide chemistry arts when 
preparing synthetic analogues of naturally occurring peptides, including D 
and L forms. The naturally occurring amino acids are glycine, alanine, 
valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, 
tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, 
asparagine, glutamic acid, glutamine, .gamma.-carboxyglutamic acid, 
arginine, ornithine and lysine. Examples of "non-protein" alpha-amino 
acids include hydroxylysine, homoserine, homotyrosine, homophenylalanine, 
citrulline, kynurenine, 4-aminophenylalanine, 3-(2-naphthyl)-alanine, 
3-(1-naphthyl)-alanine, methionine sulfone, t-butyl-alanine, 
t-butylglycine, 4-hydroxyphenylglycine, aminoalanine, phenylglycine, 
vinylalanine, propargyl-glycine, 1,2,4-triazolo-3-alanine, 
4,4,4-trifluoro-threonine, thyronine, 6-hydroxytryptophan, 
5-hydro-xytryptophan, 3-hydroxykynurenine, 3-aminotyrosine, 
trifuoromethyl-alanine, 2-thienylalanine, (2-(4-pyridyl)ethyl)cysteine, 
3,4-dimethoxy-phenylalanine, 3-(2-thiazolyl)-alanine, ibotenic acid, 
1-amino-1-cyclopentanecarboxylic acid, 1-amino-1-cyclohexanecarboxylic 
acid, quisqualic acid, 3-trifuoromethylphenylalanine, 
4-trifuoro-methylphenylalanine, cyclohexylalanine, cyclo-hexylglycine, 
thiohistidine, 3-methoxytyrosine, elastatinal, norleucine, norvaline, 
alloisoleucine, homoarginine, thioproline, dehydroproline, hydroxyproline, 
isonipectotic acid, homoproline, cyclohexylglycine, 
.alpha.-amino-n-butyric acid, cyclohexylalanine, aminophenylbutyric acid, 
phenylalanines substituted at the ortho, meta, or para position of the 
phenyl moiety with one or two of the following: a (C.sub.1 -C.sub.4) 
alkyl, a (C.sub.1 -C.sub.4) alkoxy, halogen or nitro groups or substituted 
with a methylenedioxy group; .beta.-2- and 3-thienyl-alanine, .beta.-2- 
and 3-furanylalanine, .beta.-2-, 3- and 4-pyridylalanine, 
.beta.-(benzothienyl-2- and 3-yl)alanine, .beta.-(1- and 
2-naphthyl)alanine, O-alkylated derivatives of serine, threonine or 
tyrosine, S-alkylated cysteine, S-alkylated homocysteine, O-sulfate, 
O-phosphate and O-carboxylate esters of tyrosine, 3-sulfo-tyrosine, 
3-carboxy-tyrosine, 3-phospho-tyrosine, 4-methane sulfonic acid ester of 
tyrosine, 4-methane phosphonic acid ester of tyrosine, 3,5-diiodotyrosine, 
3-nitrotyrosine, .epsilon.-alkyl lysine, and delta-alkyl ornithine. Any of 
these .alpha.-amino acids may be substituted with a methyl group at the 
alpha position, a halogen at any aromatic residue on the .alpha.-amino 
side chain, or an appropriate protective group at the O, N, or S atoms of 
the side chain residues. Appropriate protective groups are disclosed in 
"Protective Groups In Organic Synthesis," T. W. Greene and P. G. M. Wuts, 
J. Wiley & Sons, N.Y., N.Y., 1991. 
The term ".alpha.-amino acid side chain residue" refers to a chemical 
moiety which is attached to the .alpha.-carbon of an alpha-amino acid. 
The term "bioisosteric replacement for --CO.sub.2 H" refers to group which 
may substitute for a carboxylic acid group in bioactive molecules. 
Examples of such groups are disclosed in Christopher A. Lipinski, 
"Bioisosteres in Drug Design" Annual Reports In Medical Chemistry, 21, pp. 
286-88 (1986), and in C. W. Thornber, "Isosterism and Molecular 
Modification in Drug Design" Chemical Society Reviews, pp. 563-580 (1979). 
The term "association" is used in reference to a condition of proximity 
between an inhibitor or portions thereof to an ICE molecule or portions 
thereof wherein the juxtaposition is energetically favored by 
electrostatic or van der Waals interactions. 
The term "hydrogen bond" refers to a favorable interaction that occurs 
whenever a suitable donor atom, X, bearing a proton, H, and a suitable 
acceptor atom, Y, have a separation of between 2.5 .ANG. and 3.5 .ANG. and 
where the angle X--H------Y is greater than 90 degrees. Suitable donor and 
acceptor atoms are well understood in medicinal chemistry (G. C. Pimentel 
and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. 
Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", 
Accounts of Chemical Research, 17, pp. 320-326 (1984)). 
The term "salt bridge" refers to the non-covalent attractive interaction 
between a positively charged moiety (P) and a negatively charged moiety 
(N) when the distance between the centers of mass of P and N is between 2 
and 6 Angstroms. In calculating the center of mass, atoms which may 
contain a formal charge and atoms immediately adjacent to these are 
included. For example, a salt bridge may be formed between the positively 
charged guanidinium side chain of an arginine residue and the negative 
charged carboxylate side chain of a glutamate residue. Salt bridges are 
well understood in medicinal chemistry (L. Stryer, Biochemistry, Freeman, 
San Francisco, (1975); K. A. Dill, "Dominant Forces in Protein Folding", 
Biochemistry, 29, No. 31, pp. 7133-7155, (1990)). 
The term "center of mass" refers to a point in three-dimensional space 
which represents a weighted average position of the masses that make up an 
object. 
The terms "backbone chain" and "backbone" refer to the portion of a 
polypeptide which comprises the repeating unit --CO--CH--NH--. 
The term "scaffold" refers to a structural building block which forms the 
basis of an ICE inhibitor according to this invention. Various moieties 
and functional groups are intended to be appended to the scaffold. The 
scaffolds of this invention are thus depicted having open valences. 
Various scaffolds of ICE inhibitors according to this invention include 
the portions: 
##STR2## 
In those scaffolds, the NH and CO or SO.sub.2 moieties represent a first 
and a second hydrogen bonding moiety, said moieties each being capable of 
forming a hydrogen bond with a backbone atom of ICE, said backbone atom 
being selected from the group consisting of the carbonyl oxygen of 
Arg-341, the amide --NH-- of Arg-341, the carbonyl oxygen of Ser-339 and 
the amide --NH-- of Ser-339. 
The term "substitute" refers to the replacement of a hydrogen atom in a 
compound with a substituent group. In the present invention, those 
hydrogen atoms which form a part of a hydrogen bonding moiety which is 
capable of forming a hydrogen bond with the carbonyl oxygen of Arg-341 of 
ICE or the carbonyl oxygen of Ser-339 of ICE are excluded from 
substitution. These excluded hydrogen atoms include those which comprise 
an --NH-- group which is alpha to a Z or a --CO-- group and are depicted 
as --NH-- rather than an X group or some other designation in the 
following diagrams: (a) through (t), (v) through (y), and (I) through 
(VIID). 
The term "straight chain" refers to a contiguous unbranching string of 
covalently bound members, i.e. atoms, which form a portion of a ring. The 
straight chain and the ring of which it forms a part may be substituted, 
but these substituents are not a part of the straight chain. 
The term "K.sub.i " refers to a numerical measure of the effectiveness of a 
compound in inhibiting the activity of a target enzyme such as ICE. Lower 
values of K.sub.i reflect higher effectiveness. The K.sub.i value is a 
derived by fitting experimentally determined rate data to standard enzyme 
kinetic equations (see I. H. Segel, Enzyme Kinetics, Wiley-Interscience, 
1975). 
The term "minimize" refers to the systematic altering of the atomic 
geometry of a molecule or molecular complex so that any further minor 
perturbation of the atomic geometry would cause the total energy of the 
system as measured by a molecular mechanics force-field to increase. 
Minimization and molecular mechanics force-fields are well understood in 
computational chemistry U. Burkert and N. L. Allinger, Molecular 
Mechanics, ACS Monograph 177, American Chemical Society, Washington, D.C. 
1982 pages 59-78!. 
The term "strain energy" is used in this application to refer to the 
difference between the free conformation energy of a compound and the 
bound conformation energy of that compound when bound to ICE. The strain 
energy can be determined by the following steps: Evaluate the energy of 
the molecule when it has the conformation necessary for binding to ICE. 
Then minimize and reevaluate the energy--this is the free conformation 
energy. The strain energy for binding of a potential inhibitor to ICE is 
the difference between the free conformation energy and the bound 
conformation energy. In a preferred embodiment, the strain energy of an 
inhibitor of the present invention is less than about 10 kcal/mol. 
The term "patient" as used in this application refers to any mammal, 
especially humans. 
The term "pharmaceutically effective amount" refers to an amount effective 
in treating or ameliorating an IL-1 mediated disease in a patient. The 
term "prophylactically effective amount" refers to an amount effective in 
preventing or substantially lessening IL-1 mediated disease in a patient. 
The term "pharmaceutically acceptable carrier or adjuvant" refers to a 
non-toxic carrier or adjuvant that may be administered to a patient, 
together with a compound of this invention, and which does not destroy the 
pharmacological activity thereof. 
The term "pharmaceutically acceptable derivative" means any 
pharmaceutically acceptable salt, ester, or salt of such ester, of a 
compound of this invention or any other compound which, upon 
administration to a recipient, is capable of providing (directly or 
indirectly) a compound of this invention or an anti-ICE active metabolite 
or residue thereof. 
Pharmaceutically acceptable salts of the compounds of this invention 
include, for example, those derived from pharmaceutically acceptable 
inorganic and organic acids and bases. Examples of suitable acids include 
hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, 
phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, 
tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, 
naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as 
oxalic, while not in themselves pharmaceutically acceptable, may be 
employed in the preparation of salts useful as intermediates in obtaining 
the compounds of the invention and their pharmaceutically acceptable acid 
addition salts. Salts derived from appropriate bases include alkali metal 
(e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and 
N--(C.sub.1-4 alkyl).sub.4.sup.+ salts. 
This invention also envisions the "quaternization" of any basic 
nitrogen-containing groups of the compounds disclosed herein. The basic 
nitrogen can be quaternized with any agents known to those of ordinary 
skill in the art including, for example, lower alkyl halides, such as 
methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl 
sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long 
chain halides such as decyl, lauryl, myristyl and stearyl chlorides, 
bromides and iodides; and aralkyl halides including benzyl and phenethyl 
bromides. Water or oil-soluble or dispersible products may be obtained by 
such quaternization. 
The ICE inhibitors of this invention may contain one or more "asymmetric" 
carbon atoms and thus may occur as racemates and racemic mixtures, single 
enantiomers, diastereomeric mixtures and individual diastereomers. All 
such isomeric forms of these compounds are expressly included in the 
present invention. Each stereogenic carbon may be of the R or S 
configuration. Although specific compounds and scaffolds exemplified in 
this application may be depicted in a particular stereochemical 
configuration, compounds and scaffolds having either the opposite 
stereochemistry at any given chiral center or mixtures thereof are also 
envisioned. 
The ICE inhibitors of this invention may comprise ring structures which may 
optionally be substituted at carbon, nitrogen or other atoms by various 
substituents. Such ring structures may be singly or multiply substituted. 
Preferably, the ring structures contain between 0 and 3 substituents. When 
multiply substituted, each substituent may be picked independently of any 
other substituent as long as the combination of substituents results in 
the formation of a stable compound. 
Combinations of substituents and variables envisioned by this invention are 
only those that result in the formation of stable compounds. The term 
"stable", as used herein, refers to compounds which possess stability 
sufficient to allow manufacture and administration to a mammal by methods 
known in the art. Typically, such compounds are stable at a temperature of 
40.degree. C. or less, in the absence of moisture or other chemically 
reactive conditions, for at least a week. 
DETAILED DESCRIPTION OF THE INVENTION 
In order that the invention herein described may be more fully understood, 
the following detailed description is set forth. 
We have discovered that compounds possessing the following novel 
combination of features are surprisingly effective ICE inhibitors: 
a) a first and a second hydrogen bonding moiety, each of said moieties 
being capable of forming a hydrogen bond with a different backbone atom of 
ICE, said backbone atom being selected from the group consisting of the 
carbonyl oxygen of Arg-341, the amide --NH-- group of Arg-341, the 
carbonyl oxygen of Ser-339 and the amide --NH-- group of Ser-339; 
b) a first and a second moderately hydrophobic moiety, said moieties each 
being capable of associating with a separate binding pocket of ICE when 
the inhibitor is bound thereto, said binding pocket being selected from 
the group consisting of the P2 binding pocket, the P3 binding pocket, the 
P4 binding pocket and the P' binding pocket; and 
c) an electronegative moiety comprising one or more electronegative atoms, 
said atoms being attached to the same atom or to adjacent atoms in the 
moiety and said moiety being capable of forming one or more hydrogen bonds 
or salt bridges with residues in the P1 binding pocket of ICE. 
Preferably, any moderately hydrophobic moiety associating with the P2 
binding pocket of ICE does so in such a way that: 
a) the distance from the center of mass of the moderately hydrophobic 
moiety in the P2 binding pocket to the carbonyl oxygen of Arg-341 of ICE 
is between about 7.1 .ANG. and about 12.5 .ANG.; 
b) the distance from the center of mass of the moderately hydrophobic 
moiety in the P2 binding pocket to the amide nitrogen of Arg-341 of ICE is 
between about 6.0 .ANG. and about 12 .ANG.; and 
c) the distance from the center of mass of the moderately hydrophobic 
moiety in the P2 binding pocket to the carbonyl oxygen of Ser-339 of ICE 
is between about 3.7 .ANG. and about 9.5 .ANG.. 
Preferably, any moderately hydrophobic moiety associating with the P3 
binding pocket of ICE does so in such a way that: 
a) the distance from the center of mass of the moderately hydrophobic 
moiety in the P3 binding pocket to the carbonyl oxygen of Arg-341 of ICE 
is between about 3.9 .ANG. and about 9.5 .ANG.; 
b) the distance from the center of mass of the moderately hydrophobic 
moiety in the P3 binding pocket to the amide nitrogen of Arg-341 of ICE is 
between about 5.4 .ANG. and about 11 .ANG.; and 
c) the distance from the center of mass of the moderately hydrophobic 
moiety in the P3 binding pocket to the carbonyl oxygen of Ser-339 of ICE 
is between about 7.0 .ANG. and about 13 .ANG.. 
Preferably, any moderately hydrophobic moiety associating with the P4 
binding pocket of ICE does so in such a way that: 
a) the distance from the center of mass of the moderately hydrophobic 
moiety in the P4 binding pocket to the carbonyl oxygen of Arg-341 of ICE 
is between about 4.5 .ANG. and about 7.5 .ANG.; 
b) the distance from the center of mass of the moderately hydrophobic 
moiety in the P4 binding pocket to the amide nitrogen of Arg-341 of ICE is 
between about 5.5 .ANG. and about 8.5 .ANG.; and 
c) the distance from the center of mass of the moderately hydrophobic 
moiety in the P4 binding pocket to the carbonyl oxygen of Ser-339 of ICE 
is between about 8 .ANG. and about 11 .ANG.. 
Preferably, any moderately hydrophobic moiety associating with the P' 
binding pocket of ICE does so in such a way that: 
a) the distance from the center of mass of the moderately hydrophobic 
moiety in the P' binding pocket to the carbonyl oxygen of Arg-341 of ICE 
is between about 11 .ANG. and about 16 .ANG.; 
b) the distance from the center of mass of the moderately hydrophobic 
moiety in the P' binding pocket to the amide nitrogen of Arg-341 of ICE is 
between about 10 .ANG. and about 15 .ANG.; and 
c) the distance from the center of mass of the moderately hydrophobic 
moiety in the P' binding pocket to the carbonyl oxygen of Ser-339 of ICE 
is between about 8 .ANG. and about 12 .ANG.. 
More preferably, all of the above associative conditions are met in the 
compounds of this invention. 
The practitioner skilled in the art will appreciate that there are a number 
of means to design the inhibitors of the present invention. These same 
means may be used to select a candidate compound for screening as an ICE 
inhibitor. This design or selection may begin with selection of the 
various moieties which fill binding pockets. 
There are a number of ways to select moieties to fill individual binding 
pockets. These include visual inspection of a physical model or computer 
model of the active site and manual docking of models of selected moieties 
into various binding pockets. Modeling software that is well known and 
available in the art may be used. These include QUANTA Molecular 
Simulations, Inc., Burlington, Mass., 1992!, SYBYL Molecular Modeling 
Software, Tripos Associates, Inc., St. Louis, Mo., 1992!, AMBER S. J. 
Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, and 
P. Weiner, J. Am. Chem. Soc., vol. 106, pp. 765-784 (1984)!, or CHARMM B. 
R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S Swaminathan, 
and M. Karplus, J. Comp. Chem. vol. 4, pp. 187-217 (1983)!. This modelling 
step may be followed by energy minimization with standard molecular 
mechanics forcefields such as CHARMM and AMBER. In addition, there are a 
number of more specialized computer programs to assist in the process of 
selecting the binding moieties of this invention. These include: 
1. GRID (Goodford, P. J. A Computational Procedure for Determining 
Energetically Favorable Binding Sites on Biologically Important 
Macromolecules. J. Med. Chem., 28, pp. 849-857 (1985)). GRID is available 
from Oxford University, Oxford, UK. 
2. MCSS (Miranker, A.; Karplus, M. Functionality Maps of Binding Sites: A 
Multiple Copy Simultaneous Search Method. Proteins: Structure; Function 
and Genetics, 11, pp. 29-34 (1991)). MCSS is available from Molecular 
Simulations, Burlington, Mass. 
3. AUTODOCK (Goodsell, D. S.; Olsen, A. J. Automated Docking of Substrates 
to Proteins by Simmulated Annealing. PROTEINS: Structure, Function and 
Genetics, 8, pp. 195-202 (1990)). AUTODOCK is available from the Scripps 
Research Institute, La Jolla, Calif. 
4. DOCK (Kuntz, I. D.; Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, 
T. E. A Geometric Approach to Macromolecule-Ligand Interactions. J. Mol. 
Biol., 161, pp. 269-288 (1982)). DOCK is available from the University of 
California, San Francisco, Calif. 
Once suitable binding moieties have been selected, they can be assembled 
into a single inhibitor. This assembly may be accomplished by connecting 
the various moieties to a central scaffold. The assembly process may, for 
example, be done by visual inspection followed by manual model building, 
again using software such as Quanta or Sybyl. A number of other programs 
may also be used to help select ways to connect the various moieties. 
These include: 
1. CAVEAT (Bartlett, P. A.; Shea, G. T.; Telfer, S. J.; Waterman, S. 
CAVEAT: A Program to Facilitate the Structure-Derived Design of 
Biologically Active Molecules. In "Molecular Recognition in Chemical and 
Biological Problems," Special Pub., Royal Chem. Soc., 78, pp. 182-196 
(1989)). CAVEAT is available from the University of California, Berkeley, 
Calif. 
2. 3D Database systems such as MACCS-3D (MDL Information Systems, San 
Leandro, Calif.). This area has been recently reviewed by Martin (Martin, 
Y. C. 3D Database Searching in Drug Design. J. Med. Chem., 35, pp. 
2145-2154 (1992)). 
3. HOOK (available from Molecular Simulations, Burlington, Mass.). 
In addition to the above computer assisted modeling of inhibitor compounds, 
the inhibitors of this invention may be constructed "de novo" using either 
an empty active site or optionally including some portions of a known 
inhibitor. Such methods are well known in the art. They include, for 
example: 
1. LUDI (Bohm, H. J. The Computer Program LUDI: A New Method for the De 
Novo Design of Enzyme Inhibitors. J. Comp. Aid. Molec. Design., 6, 61-78 
(1992)). LUDI is available from Biosym Technologies, San Diego, Calif. 
2. LEGEND (Nishibata, Y., Itai, A., Tetrahedron, 47, 8985 (1991)). LEGEND 
is available from Molecular Simultations, Burlington, Mass. 
3. LeapFrog (available from Tripos associates, St. Louis, Mo.). 
A number of techniques commonly used for modeling drugs may be employed 
(For a review, see: Cohen, N. C.; Blaney, J. M.; Humblet, C.; Gund, P.; 
Barry, D. C., "Molecular Modeling Software and Methods for Medicinal 
Chemistry", J. Med. Chem., 33, pp. 883-894 (1990)). There are likewise a 
number of examples in the chemical literature of techniques that can be 
applied to specific drug design projects. For a review, see: Navia, M. A. 
and Murcko, M. A., "The Use of Structural Information in Drug Design", 
Current Opinions in Structural Biology, 2, pp. 202-210 (1992). Some 
examples of these specific applications include: Baldwin, J. J. et al., 
"Thienothiopyran-2-sulfonamides: Novel Topically Active Carbonic Anhydrase 
Inhibitors for the Treatment of Glaucoma", J. Med. Chem., 32, pp. 
2510-2513 (1989); Appelt, K. et al., "Design of Enzyme Inhibitors Using 
Iterative Protein Crystallographic Analysis", J. Med. Chem., 34, pp. 
1925-1934 (1991); and Ealick, S. E. et al., "Application of 
Crystallographic and Modeling Methods in the Design of Purine Nucleotide 
Phosphorylase Inhibitors" Proc. Nat. Acad. Sci. USA, 88, pp. 11540-11544 
(1991). 
Using the novel combination of steps of the present invention, the skilled 
artisan can advantageously avoid time consuming and expensive 
experimentation to determine enzymatic inhibition activity of particular 
compounds. The method also is useful to facilitate rational design of ICE 
inhibitors and therapeutic and prophylactic agents against IL-1-mediated 
diseases. Accordingly, the present invention relates to such inhibitors. 
A variety of conventional techniques may be used to carry out each of the 
above evaluations as well as the evaluations necessary in screening a 
candidate compound for ICE inhibiting activity. Generally, these 
techniques involve determining the location and binding proximity of a 
given moiety, the occupied space of a bound inhibitor, the deformation 
energy of binding of a given compound and electrostatic interaction 
energies. Examples of conventional techniques useful in the above 
evaluations include: quantum mechanics, molecular mechanics, molecular 
dynamics, Monte Carlo sampling, systematic searches and distance geometry 
methods (G. R. Marshall, Ann. Rev. Pharmacol. Toxicol., 27, p. 193 
(1987)). Specific computer software has been developed for use in carrying 
out these methods. Examples of programs designed for such uses include: 
Gaussian 92, revision E.2 (M. J. Frisch, Gaussian, Inc., Pittsburgh, Pa. 
.COPYRGT.1993); AMBER, version 4.0 (P. A. Kollman, University of 
California at San Francisco, .COPYRGT.1993); QUANTA/CHARMM Molecular 
Simulations, Inc., Burlington, Mass. .COPYRGT.1992!; and Insight 
II/Discover (Biosysm Technologies Inc., San Diego, Calif. .COPYRGT.1992). 
These programs may be implemented, for instance, using a Silicon Graphics 
Indigo 2 workstation or IBM RISC/6000 workstation model 550. Other 
hardware systems and software packages will be known and of evident 
applicability to those skilled in the art. 
Different classes of active ICE inhibitors, according to this invention, 
may interact in similar ways with the various binding pockets of the ICE 
active site. The spatial arrangement of these important groups is often 
referred to as a pharmacophore. The concept of the pharmacophore has been 
well described in the literature (D. Mayer, C. B. Naylor, I. Motoc, and G. 
R. Marshall, J. Comp. Aided Molec. Design vol. 1, pp. 3-16 (1987); A. 
Hopfinger and B. J. Burke, in Concepts and Applications of Molecular 
Similarity, M. A. Johnson and G. M. Maggiora, ed., Wiley (1990)). 
Different classes of ICE inhibitors of this invention may also use 
different scaffolds or core structures, but all of these cores will allow 
the necessary moieties to be placed in the active site such that the 
specific interactions necessary for binding may be obtained. These 
compounds are best defined in terms of their ability to match the 
pharmacophore, i.e., their structural identity relative to the shape and 
properties of the active site of ICE. 
The ICE inhibitors of one embodiment of this invention comprise a first and 
a second hydrogen bonding moiety, a first and a second moderately 
hydrophobic moiety, and an electronegative moiety which comprise or are 
covalently bound to one of the following scaffolds: 
##STR3## 
The ICE inhibitors of another embodiment (A) of this invention are those of 
formula .alpha.: 
##STR4## 
wherein: X.sub.1 is CH or N; 
g is 0 or 1; 
each J is independently selected from the group consisting of --H, --OH, 
and --F, provided that when a first and second J are bound to a C and said 
first J is --OH, said second J is --H; 
m is 0, 1, or 2; 
T is --Ar.sub.3, --OH, --CF.sub.3, --CO--CO.sub.2 H, --CO.sub.2 H or any 
bioisosteric replacement for --CO.sub.2 H; 
R.sub.1 is selected from the group consisting of the following formulae, in 
which any ring may optionally be singly or multiply substituted at any 
carbon by Q.sub.1, at any nitrogen by R.sub.5, or at any atom by .dbd.O, 
--OH, --CO.sub.2 H, or halogen, and in which any saturated ring may 
optionally be unsaturated at one or two bonds: 
##STR5## 
R.sub.20 is selected from the group consisting of: 
##STR6## 
wherein each ring C is independently chosen from the group consisting of 
benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, 
isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl; 
R.sub.3 is 
--CN, 
--CH.dbd.CH--R.sub.9, 
--CH.dbd.N--O--R.sub.9, 
--(CH.sub.2).sub.1-3 --T.sub.1 --R.sub.9, 
--CJ.sub.2 --R.sub.9, 
--CO--R.sub.13, or 
##STR7## 
each R.sub.4 is independently selected from the group consisting of: --H, 
--Ar.sub.1, 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9, 
each T.sub.1 is independently selected from the group consisting of: 
--CH.dbd.CH--, 
--O--, 
--S--, 
--SO--, 
--SO.sub.2 --, 
--NR.sub.10 --CO--, 
--CO--, 
--O--CO--, 
--CO--O--, 
--CO--NR.sub.10 --, 
--O--CO--NR.sub.10 --, 
--NR.sub.10 --CO--O--, 
--NR.sub.10 --CO--NR.sub.10 --, 
--SO.sub.2 --NR.sub.10 --, 
--NR.sub.10 --SO.sub.2 --, and 
--NR.sub.10 --SO.sub.2 --NR.sub.10 --, 
each R.sub.5 is independently selected from the group consisting of: 
--H, 
--Ar.sub.1, 
--CO--Ar.sub.1, 
--SO.sub.2 --Ar.sub.1, 
--R.sub.9, 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, 
##STR8## 
R.sub.6 and R.sub.7 taken together form a saturated 4-8 member carbocyclic 
ring or heterocyclic ring containing --O--, --S--, or --NH--, or 
R.sub.7 is --H and R.sub.6 is 
--H 
--Ar.sub.1, 
--R.sub.9, or 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9 ; 
each R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
singly or multiply substituted by --OH, --F, or .dbd.O and optionally 
substituted with one or two Ar.sub.1 groups; 
each R.sub.10 is independently selected from the group consisting of --H or 
a C.sub.1-6 straight or branched alkyl group; 
each R.sub.13 is independently selected from the group consisting of 
--Ar.sub.2 and --R.sub.4 ; 
each Ar.sub.1 is a cyclic group independently selected from the set 
consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms 
and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 
15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being 
optionally benzofused, and a heterocycle group containing between 5 and 15 
ring atoms and between 1 and 3 rings, said heterocycle group containing at 
least one heteroatom group selected from --O--, --S--, --SO--, --SO.sub.2 
--, .dbd.N--, and --NH--, said heterocycle group optionally containing one 
or more double bonds, said heterocycle group optionally comprising one or 
more aromatic rings, and said cyclic group optionally being singly or 
multiply substituted by .dbd.O, --OH, perfluoro C.sub.1-3 alkyl, or 
--Q.sub.1 ; 
each Ar.sub.2 is independently selected from the following group, in which 
any ring may optionally be substituted by --Q.sub.1 : 
##STR9## 
Ar.sub.3 is a cyclic group selected from the set consisting of a phenyl 
ring, a 5-membered heteroaromatic ring, and a 6-membered heteroaromatic 
ring, said heteroaromatic rings comprising 1-3 heteroatom groups selected 
from --O--, --S--, --SO--, --SO.sub.2 --, .dbd.N--, and --NH--, said 
cyclic group optionally being singly or multiply substituted with .dbd.O, 
--OH, halogen, perfluoro C.sub.1-3 alkyl, or --CO.sub.2 H; 
each Q.sub.1 is independently selected from the group consisting of: 
--Ar.sub.1 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9, 
provided that when --Ar.sub.1 is substituted with a Q.sub.1 group which 
comprises one or more additional --Ar.sub.1 groups, said additional 
--Ar.sub.1 groups are not substituted with Q.sub.1 ; 
each X is independently selected from the group consisting of .dbd.N-- and 
.dbd.CH--; 
each X.sub.2 is independently selected from the group consisting of --O--, 
--CH.sub.2 --, --NH--, --S--, --SO--, and --SO.sub.2 ; each X.sub.3 is 
independently selected from the group consisting of --CH.sub.2 --, --S--, 
--SO--, and --SO.sub.2 --; 
each X.sub.4 is independently selected from the group consisting of 
--CH.sub.2 -- and --NH--; 
each X.sub.5 is independently selected from the group consisting of 
##STR10## 
X.sub.6 is CH or N, provided that when X.sub.6 is N in the R.sub.1 group 
labeled (o) and X.sub.5 is CH and X.sub.2 is CH.sub.2 the ring of the 
R.sub.1 group labeled (o) must be substituted by Q.sub.1 or benzofused; 
each Y is independently selected from the group consisting of --O-- and 
--S--; 
each Z is independently CO or SO.sub.2, 
each a is independently 0 or 1, 
each c is independently 1 or 2, 
each d is independently 0, 1, or 2, and 
each e is independently 0, 1, 2, or 3. 
The ICE inhibitors of another embodiment (B) of this invention are those of 
formula .alpha.: 
##STR11## 
wherein: X.sub.1 is --CH; 
g is 0 or 1; 
each J is independently selected from the group consisting of --H, --OH, 
and --F, provided that when a first and second J are bound to a C and said 
first J is --OH, said second J is --H; 
m is 0, 1, or 2; 
T is --OH, --CO--CO.sub.2 H, --CO.sub.2 H or any bioisosteric replacement 
for --CO.sub.2 H; 
R.sub.1 is selected from the group consisting of the following formulae, in 
which any ring may optionally be singly or multiply substituted at any 
carbon by Q.sub.1, at any nitrogen by R.sub.5, or at any atom by .dbd.O, 
--OH, --CO.sub.2 H, or halogen, any saturated ring may optionally be 
unsaturated at one or two bonds; and wherein R.sub.1 (e) and R.sub.1 (y) 
are optionally benzofused; 
##STR12## 
R.sub.20 is selected from the group consisting of: 
##STR13## 
wherein each ring C is independently chosen from the group consisting of 
benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, 
isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl; 
R.sub.3 is 
--CN, 
--CH.dbd.CH--R.sub.9, 
--CH.dbd.N--O--R.sub.9, 
--(CH.sub.2).sub.1-3 --T.sub.1 --R.sub.9, 
--CJ.sub.2 --R.sub.9, 
--CO--R.sub.13, or 
##STR14## 
each R.sub.4 is independently selected from the group consisting of: --H, 
--Ar.sub.1, 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9, 
each T.sub.1 is independently selected from the group consisting of: 
--CH.dbd.CH--, 
--O--, 
--S--, 
--SO--, 
--SO.sub.2 --, 
--NR.sub.10 --, 
--NR.sub.10 --CO--, 
--CO--, 
--O--CO--, 
--CO--O--, 
--CO--NR.sub.10 --, 
--O--CO--NR.sub.10 --, 
--NR.sub.10 --CO--O--, 
--NR.sub.10 --CO--NR.sub.10 --, 
--SO.sub.2 --NR.sub.10 --, 
--NR.sub.10 --SO.sub.2 --, and 
--NR.sub.10 --SO.sub.2 --NR.sub.10 --, 
each R.sub.5 is independently selected from the group consisting of: 
--H, 
--CO--Ar.sub.1, 
--SO.sub.2 --Ar.sub.1, 
--CO--NH.sub.2, 
--SO.sub.2 --NH.sub.2, 
--R.sub.9, 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, 
##STR15## 
R.sub.6 and R.sub.7 taken together form a saturated 4-8 member carbocyclic 
ring or heterocyclic ring containing --O--, --S--, or --NH--; or 
R.sub.7 is --H and R.sub.6 is: 
--H, 
--Ar.sub.1, 
--R.sub.9, 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9, or 
an .alpha.-amino acid side chain residue; 
each R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
singly or multiply substituted by --OH, --F, or .dbd.O and optionally 
substituted with one or two Ar.sub.1 groups; 
each R.sub.10 is independently selected from the group consisting of --H or 
a C.sub.1-6 straight or branched alkyl group; 
each R.sub.13 is independently selected from the group consisting of 
--Ar.sub.2, --R.sub.4 and 
##STR16## 
each Ar.sub.1 is a cyclic group independently selected from the set 
consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms 
and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 
15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being 
optionally benzofused, and a heterocycle group containing between 5 and 15 
ring atoms and between 1 and 3 rings, said heterocycle group containing at 
least one heteroatom group selected from --O--, --S--, --SO--, --SO.sub.2 
--, .dbd.N--, and --NH--, said heterocycle group optionally containing one 
or more double bonds, said heterocycle group optionally comprising one or 
more aromatic rings, and said cyclic group optionally being singly or 
multiply substituted by --NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, 
--NO.sub.2, --CN, .dbd.O, --OH, -perfluoro C.sub.1-3 alkyl, 
##STR17## 
each Ar.sub.2 is independently selected from the following group, in which 
any ring may optionally be singly or multiply substituted by --Q.sub.1 and 
--Q.sub.2 : 
##STR18## 
each Q.sub.1 is independently selected from the group consisting of 
--Ar.sub.1 
--O--Ar.sub.1 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9 ; 
each Q.sub.2 is independently selected from the group consisting of --OH, 
--NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, --NO.sub.2, --CN, 
--CF.sub.3, and 
##STR19## 
provided that when --Ar.sub.1 is substituted with a Q.sub.1 group which 
comprises one or more additional --Ar.sub.1 groups, said additional 
--Ar.sub.1 groups are not substituted with Q.sub.1 ; 
each X is independently selected from the group consisting of .dbd.N-- and 
.dbd.CH--; 
each X.sub.2 is independently selected from the group consisting of --O--, 
--CH.sub.2 --, --NH--, --S--, --SO--, and --SO.sub.2 --; 
each X.sub.3 is independently selected from the group consisting of 
--CH.sub.2 --, --S--, --SO--, and --SO.sub.2 --; 
each X.sub.4 is independently selected from the group consisting of 
--CH.sub.2 -- and --NH--; 
each X.sub.5 is independently selected from the group consisting of 
##STR20## 
X.sub.6 is CH or N, provided that when X.sub.6 is N in the R.sub.1 group 
labeled (o) and X.sub.5 is CH and X.sub.2 is CH.sub.2 the ring of the 
R.sub.1 group labeled (o) must be substituted by Q.sub.1 or benzofused; 
each Y is independently selected from the group consisting of --O-- and 
--S--, and --NH; 
each Z is independently CO or SO.sub.2, 
each a is independently 0 or 1, 
each c is independently 1 or 2, 
each d is independently 0, 1, or 2, and 
each e is independently 0, 1, 2, or 3, 
provided that when 
R.sub.1 is (f), 
R.sub.6 is an .alpha.-amino acid side chain residue, and 
R.sub.7 is --H, 
then (aa1) and (aa2) must be substituted with Q.sub.1 ; 
also provided that when 
R.sub.1 is (o), 
g is 0, 
J is --H, 
m is 1, 
R.sub.6 is an .alpha.-amino acid side chain residue, 
R.sub.7 is --H, 
X.sub.2 is --CH.sub.2 --, 
X.sub.5 is 
##STR21## 
X.sub.6 is 
##STR22## 
and R.sub.3 is 
##STR23## 
or --CO--R.sub.13, when R.sub.13 is: 
--CH.sub.2 --O--CO--Ar.sub.1, 
--CH.sub.2 --S--CO--Ar.sub.1, 
--CH.sub.2 --O--Ar.sub.1, 
--CH.sub.2 --S--Ar.sub.1, or 
--R.sub.4 when --R.sub.4 is --H; 
then the ring of the R.sub.1 (o) group must be substituted with Q.sub.1 or 
benzofused; and 
provided that when 
R.sub.1 is (w), 
g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H or --CO--NH--OH, 
X.sub.2 is O, 
R.sub.5 is benzyloxycarbonyl, and 
ring C is benzo, 
then R.sub.3 cannot be --CO--R.sub.13 when: 
R.sub.13 is --CH.sub.2 --O--Ar.sub.1 and 
Ar.sub.1 is 1-phenyl-3-chloro- or 3-trifluoromethyl-pyrazole-5-yl; or when 
R.sub.13 is --CH.sub.2 --O--CO--Ar.sub.1 and 
Ar.sub.1 is 2,6-dichlorophenyl. 
Preferred forms of the R.sub.1 group (a) for embodiments A and B are: 
##STR24## 
Preferred forms of the R.sub.1 group (b) are: 
##STR25## 
Preferred forms of the R.sub.1 group (c) are: 
##STR26## 
provided that when R.sub.1 is (c1), g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H, 
X is N, 
R.sub.5 is benzyloxycarbonyl, and 
R.sub.6 is --H, 
then R.sub.3 cannot be --CO--R.sub.13 when 
R.sub.13 is --CH.sub.2 --O--Ar.sub.1 and 
Ar.sub.1 is a chloro-substituted 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, 
or when 
R.sub.13 is --CH.sub.2 --O--CO--Ar.sub.1 and 
Ar.sub.1 is 2,6-dichlorophenyl, 
and when the 2-position of the scaffold ring is substituted with 
para-fluoro-phenyl; 
Preferred forms of the R.sub.1 group (d) are: 
##STR27## 
Preferred forms of the R.sub.1 group (e) are: 
##STR28## 
which is optionally benzofused; 
##STR29## 
provided that when R.sub.1 is (e4), g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H, 
R.sub.5 is benzyloxycarbonyl, and 
c is 1, 
then R.sub.3 cannot be --CO--R.sub.13 when 
R.sub.13 is --CH.sub.2 --O--Ar.sub.1 and 
Ar.sub.1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, wherein the phenyl is 
optionally substituted with a chlorine atom; or when 
R.sub.13 is --CH.sub.2 --O--CO--Ar.sub.1 and 
Ar.sub.1 is 2,6-dichlorophenyl, 
and when the 2-position of the scaffold ring is substituted with 
para-fluoro-phenyl; and 
also provided that when 
R.sub.1 is (e7), 
g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H or --CO--NH--OH, 
R.sub.5 is a protective group for the N atom of an amino acid side chain 
residue, and 
each c is 1, 
then R.sub.3 cannot be --CO--R.sub.13 when R.sub.13 is: 
--CH.sub.2 --O--CO--Ar.sub.1, 
--CH.sub.2 --S--CO--Ar.sub.1, 
--CH.sub.2 --O--Ar.sub.1, or 
--CH.sub.2 --S--Ar.sub.1. 
Preferred forms of the R.sub.1 group (g) are: 
##STR30## 
Preferred forms of the R.sub.1 group (h) are: 
##STR31## 
Preferred forms of the R.sub.1 group (i) are: 
##STR32## 
Preferred forms of the R.sub.1 group (j) are: 
##STR33## 
Preferred forms of the R.sub.1 group (k) are: 
##STR34## 
Preferred forms of the R.sub.1 group (1) are: 
##STR35## 
Preferred forms of the R.sub.1 group (m) are: 
##STR36## 
Preferred forms of the R.sub.1 group (n) are: 
##STR37## 
Preferred forms of the R.sub.1 group (o) are: 
##STR38## 
A preferred form of the R.sub.1 group (o) of embodiment B is: 
##STR39## 
wherein X.sub.2 is --O--, --S--, --SO.sub.2 --, or --NH--. 
For embodiments A and B, preferred forms of the R.sub.1 group (p) are: 
##STR40## 
Preferred forms of the R.sub.1 group (q) are: 
##STR41## 
Preferred forms of the R.sub.1 group (r) are: 
##STR42## 
Preferred forms of the R.sub.1 group (s) are: 
##STR43## 
Preferred forms of the R.sub.1 group (t) are: 
##STR44## 
Preferred forms of the R.sub.1 group (v) are: 
##STR45## 
A preferred form of the R1 group (w) of embodiment B is: 
##STR46## 
wherein X.sub.2 is --O--, --S--, --SO.sub.2 -- or --NH--. 
The preferred compounds of embodiments A and B of this invention are those 
which employ formula .alpha., wherein: 
X.sub.1 is CH; 
g is 0; 
J is --H; 
m is 0 or 1 and T is --Ar.sub.3, --CO--CO.sub.2 H, --CO.sub.2 H or any 
bioisosteric replacement for --CO.sub.2 H, or 
m is 1 or 2 and T is --OH, --CF.sub.3, or --CO.sub.2 H; 
more preferably m is 1 and T is --CO.sub.2 H; 
R.sub.1 is 
##STR47## 
R.sub.20 is 
##STR48## 
wherein ring C is benzo; R.sub.3 is 
--CO--R.sub.13, or 
##STR49## 
most preferably R.sub.3 is any one of 1), 2) or 3) as follows: 1) 
--CO--Ar.sub.2, 2) --CO--R.sub.9 where R.sub.9 is C.sub.3-6 alkyl 
substituted with two Ar.sub.1 groups or one Ar.sub.1 group itself 
substituted with an Ar.sub.1 group, --C.sub.1-2 --Ar.sub.1, --Cl, 
--CH.sub.3, or --CF.sub.3, or 3) --(CH.sub.2).sub.1,2 --T.sub.1 --R.sub.9 
where T.sub.1 is --O-- or --S-- and R.sub.9 is C.sub.1-2 alkyl substituted 
with two Ar.sub.1 groups or one Ar.sub.1 group itself substituted with an 
Ar.sub.1 group, C.sub.1-2 --Ar.sub.1, --Cl, --CH.sub.3, or --CF.sub.3 ; 
R.sub.4 is --H or --R.sub.9 ; 
T.sub.1 is 
--O--, 
--S--, 
--CO--, 
--O--CO--, or 
--SO.sub.2 --; 
when R.sub.1 is (a), (b), (k), or (m), R.sub.5 is preferably --Ar.sub.1 or 
C.sub.1-4 --Ar.sub.1 ; 
when R.sub.1 is (c), (e), (f), (o), or (r), R.sub.5 is preferably 
--SO.sub.2 --Ar.sub.1, --SO.sub.2 --R.sub.9, or --CO--C.sub.1-4 --Ar.sub.1 
; 
R.sub.7 is --H and R.sub.6 is C.sub.1-4 --Ar.sub.1 ; 
R.sub.10 is --H or a C.sub.1-3 straight or branched alkyl group; 
R.sub.13 is --Ar.sub.2 ; 
Ar.sub.1 is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, 
benzothienyl, benzoxazolyl, 2-indanyl, or indolyl; 
Ar.sub.2 is preferably substituted with --Ar.sub.1, or --C.sub.1-4 
--Ar.sub.1 ; 
Ar.sub.3 is phenyl, thiophene, thiazole, pyridine, or oxazole; and 
Q.sub.1 is --R.sub.9 or --(CH.sub.2).sub.1,2 --T.sub.1 --(CH.sub.2).sub.1-3 
--Ar.sub.1 where T.sub.1 is --O-- or --S--. 
In connection with this continuation-in-part, we now prefer the compounds 
of embodiment B of this invention which employ formula .alpha., wherein: 
X.sub.1 is --CH; 
g is 0; 
J is --H; 
m is 0 or 1 and T is --CO--CO.sub.2 H, or any bioisosteric replacement for 
--CO.sub.2 H; or 
m is 1 and T is --CO.sub.2 H; 
R.sub.1 is selected from the group consisting of the following formulae, in 
which any ring may optionally be singly or multiply substituted at any 
carbon by Q.sub.1, at any nitrogen by R.sub.5, or at any atom by .dbd.O, 
--OH, --CO.sub.2 H, or halogen, and wherein (e) is optionally benzofused: 
##STR50## 
R.sub.20 is 
##STR51## 
and c is 1; ring C is benzo optionally substituted with --C.sub.1-3 alkyl, 
--O--C.sub.1-3 alkyl, --Cl, --F or --CF.sub.3 ; 
R.sub.3 is: 
--CO--R.sub.13, or 
##STR52## 
more preferably R.sub.3 is any one of 1), 2) or 3) as follows: 1) 
--CO--Ar.sub.2 ; 2) --CO--R.sub.9 where R.sub.9 is C.sub.1-5 alkyl 
substituted with an Ar.sub.1 ; or 3) --CH.sub.2 --T.sub.1 --R.sub.9 where 
T.sub.1 is --O-- or --S-- and R.sub.9 is C.sub.1-2 alkyl substituted with 
one Ar.sub.1 group; 
R.sub.4 is --H or --R.sub.9 ; 
T.sub.1 is: 
--O--, 
--S--, 
--CO--, 
--O--CO--, or 
--SO.sub.2 --; 
when R.sub.1 is (a) or (b), R.sub.5 is preferably --H, and 
when R.sub.1 is (c), (e), (f), (o), (r), (w), (x) or (y), R.sub.5 is 
preferably: 
--CO--Ar.sub.1 
--SO.sub.2 --Ar.sub.1, 
--CO--NH.sub.2, 
--CO--NH--Ar.sub.1 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, or 
--CO--NH--R.sub.9, 
R.sub.7 is --H and R.sub.6 is 
--H, 
--R.sub.9 or 
--Ar.sub.1 ; 
R.sub.9 is C.sub.1-6 straight or branched alkyl group optionally 
substituted with .dbd.O and optionally substituted with --Ar.sub.1 ; 
R.sub.10 is --H or a C.sub.1-3 straight or branched alkyl group; 
R.sub.13 is: 
--H, 
--R.sub.9, 
--Ar.sub.2, or 
--CH.sub.2 --T.sub.1 --R.sub.9, 
more preferably where --Ar.sub.2 is (hh) and where (hh) is optionally 
substituted singly or multiply with --C.sub.1-6 alkyl, --O--C.sub.1-6 
alkyl, --NH--C.sub.1-6 alkyl, --N--(C.sub.1-6 alkyl).sub.2, --S--C.sub.1-6 
alkyl, --Cl, --F, --CF.sub.3, or 
##STR53## 
Ar.sub.1 is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, 
benzothienyl, benzoxazolyl, 2-indanyl, or indolyl substituted with 
--O--C.sub.1-3 alkyl, --NH--C.sub.1-3 alkyl, --N--(C.sub.1-3 alkyl).sub.2, 
--Cl, --F, --CF.sub.3, --C.sub.1-3 alkyl, or 
##STR54## 
preferably where Ar.sub.2 is: 
##STR55## 
each X is independently selected from the group consisting of .dbd.N-- and 
.dbd.CH--; 
each X.sub.2 is independently selected from the group consisting of --O--, 
--CH.sub.2 --, --NH--, --S--, --SO--, and --SO.sub.2 --; 
each X.sub.5 is independently selected from the group consisting of 
##STR56## 
X.sub.6 is 
##STR57## 
and Z is C.dbd.O; 
provided that when 
R.sub.1 is (f), 
R.sub.6 is an .alpha.-amino acid side chain residue, and 
R.sub.7 is --H, 
then (aa1) and (aa2) must be substituted with Q.sub.1 ; 
also provided that when 
R.sub.1 is (o), 
g is 0, 
J is --H, 
m is 1, 
R.sub.6 is an .alpha.-amino acid side chain residue, 
R.sub.7 is --H, 
X.sub.2 is --CH.sub.2 --, 
X.sub.5 is 
##STR58## 
X.sub.6 is 
##STR59## 
and R.sub.3 is 
##STR60## 
or --CO--R.sub.13, when 
R.sub.13 is: 
--CH.sub.2 --O--CO--Ar.sub.1, 
--CH.sub.2 --S--CO--Ar.sub.1, 
--CH.sub.2 --O--Ar.sub.1, 
--CH.sub.2 --S--Ar.sub.1, or 
--R.sub.4 when --R.sub.4 is --H; 
then the ring of the R.sub.1 (o) group must be substituted with Q.sub.1 or 
benzofused; and 
provided that when 
R.sub.1 is (w), 
g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H, 
X.sub.2 is O, 
R.sub.5 is benzyloxycarbonyl, and 
ring C is benzo, 
then R.sub.3 cannot be --CO--R.sub.13 when: 
R.sub.13 is --CH.sub.2 --O--Ar.sub.1 and 
Ar.sub.1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, 
wherein the phenyl is optionally substituted with a chlorine atom; 
or when R.sub.13 is --CH.sub.2 --O--CO--Ar.sub.1, wherein Ar.sub.1 is 
2,6-dichlorophenyl. 
A preferred form of R.sub.13 is --CH.sub.2 --O--R.sub.9, wherein R.sub.9 is 
a C.sub.1-6 straight or branched alkyl group optionally substituted with 
.dbd.O and optionally substituted with Ar.sub.1 ; 
another preferred form of R.sub.13 is CH.sub.2 --S--R.sub.9, wherein 
R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
substituted with Ar.sub.1 ; 
another preferred form of R.sub.13 is CH.sub.2 --O--R.sub.9 wherein R.sub.9 
is a C.sub.1-6 straight or branched alkyl group optionally substituted 
with Ar.sub.1 ; 
another preferred form of R.sub.13 is H. 
A more preferred form of the R.sub.1 group (a) is: 
##STR61## 
optionally substituted with Q.sub.1, wherein R.sub.5 is --H; 
R.sub.7 is --H; and 
Z is C.dbd.O; 
a more preferred form of the R.sub.1 group (b) is: 
##STR62## 
optionally substituted with Q.sub.1, wherein R.sub.5 is --H; 
R.sub.7 is --H; and 
Z is C.dbd.O; 
more preferred forms of the R.sub.1 group (c) are: 
##STR63## 
provided that when R.sub.1 is (c1), g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H, 
X is N, 
R.sub.5 is benzyloxycarbonyl, and 
R.sub.6 is --H, 
then R.sub.3 cannot be --CO--R.sub.13 when 
R.sub.13 is --CH.sub.2 --O--Ar.sub.1 and 
Ar.sub.1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl wherein the phenyl is 
optionally substituted with a chlorine atom; or when 
R.sub.13 is --CH.sub.2 --O--CO--Ar.sub.1, wherein 
Ar.sub.1 is 2,6-dichlorophenyl, 
and wherein the 2-position of the scaffold ring is substituted with 
para-fluoro-phenyl; 
more preferred forms of the R.sub.1 group (e) are: 
##STR64## 
wherein c is 2; and 
##STR65## 
which is optionally benzofused, wherein c is 1 or 2; 
provided that when R.sub.1 is (e4), 
g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H, 
R.sub.5 is benzyloxycarbonyl, and 
c is 1, 
then R.sub.3 cannot be --CO--R.sub.13 when 
R.sub.13 is --CH.sub.2 --O--Ar.sub.1 and 
Ar.sub.1 is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl wherein the phenyl is 
optionally substituted with a chlorine atom; or when 
R.sub.13 is --CH.sub.2 --O--CO--Ar.sub.1, wherein 
Ar.sub.1 is 2,6-dichlorophenyl, 
and wherein the 2-position of the scaffold ring is substituted with 
para-fluoro-phenyl; and 
also provided that when 
R.sub.1 is (e7), 
g is 0, 
J is --H, 
m is 1, 
T is --CO.sub.2 H, --CO--NH--OH, or a bioisosteric replacement for 
--CO.sub.2 H, 
R.sub.5 is a protective group for the N atom of an .alpha.-amino acid side 
chain residue, and 
each c is 1, 
then R.sub.3 cannot be --CO--R.sub.13 when R.sub.13 is: 
--CH.sub.2 --O--CO--Ar.sub.1, 
--CH.sub.2 --S--CO--Ar.sub.1, 
--CH.sub.2 --O--Ar.sub.1, or 
--CH.sub.2 --S--Ar.sub.1. 
a more preferred form of the R.sub.1 group (f) is 
##STR66## 
a more preferred form of the R.sub.1 group (g) is: 
##STR67## 
wherein R.sub.20 is (aa1) optionally substituted singly or multiply with 
Q.sub.1 ; and 
Z is C.dbd.O; 
a more preferred form of the R.sub.1 group (h) is: 
##STR68## 
wherein R.sub.20 is (aa1) optionally substituted singly or multiply with 
Q.sub.1 ; and 
Z is C.dbd.O; 
more preferred forms of the R.sub.1 group (o) are: 
##STR69## 
wherein d is 1 or 2; and 
##STR70## 
more preferred forms of the R.sub.1 group (r) are: 
##STR71## 
optionally substituted with Q.sub.1 ; a more preferred form of the R.sub.1 
group (w) is: 
##STR72## 
wherein X.sub.2 is: 
--NH--, 
--S--, 
--O--, or 
--SO.sub.2 --; 
optionally substituted with R.sub.5 or Q.sub.1 at X.sub.2 when X.sub.2 is 
--N--; and 
ring C is benzo substituted with --C.sub.1-3 alkyl, --O--C.sub.1-3 alkyl, 
--Cl, --F or --CF.sub.3. 
When R.sub.1 is: 
##STR73## 
preferred compounds of this invention include but are not limited to: 
##STR74## 
A preferred compound of embodiment B of this invention employs formula 
.alpha., wherein the R.sub.1 is: 
##STR75## 
Preferred compounds of this embodiment include but are not limited to: 
##STR76## 
When R.sub.1 is: 
##STR77## 
preferred compounds of this invention include but are not limited to: 
##STR78## 
A preferred compound of embodiment B of this invention employs formula 
.alpha., wherein: 
R.sub.1 is: 
##STR79## 
and c is 2; m is 1; 
T is --CO.sub.2 H; and 
R.sub.3 is --CO--R.sub.13. 
Preferred compounds of this embodiment include but are not limited to: 
##STR80## 
When R.sub.1 is: 
##STR81## 
preferred compounds of this invention include but are not limited to: 
##STR82## 
When R.sub.1 is: 
##STR83## 
preferred compounds of this invention include but are not limited to: 
##STR84## 
When R.sub.1 is: 
##STR85## 
preferred compounds of this invention include but are not limited to: 
##STR86## 
A preferred compound of embodiment B of this invention employs formula 
.alpha., wherein: 
R.sub.1 is: 
##STR87## 
X.sub.2 is --NH--; m is 1; 
T is --CO.sub.2 H; 
R.sub.3 is --CO--R.sub.13. 
Preferred compounds of this embodiment include but are not limited to: 
##STR88## 
When R.sub.1 is: 
##STR89## 
optionally substituted with Q.sub.1 ; preferred compounds of embodiment B 
of this invention include but are not limited to: 
##STR90## 
When R.sub.1 is: 
##STR91## 
preferred compounds of this invention include but are not limited to: 
##STR92## 
The ICE inhibitors of another embodiment (C) of this invention are 
represented by the formula .sigma.: 
##STR93## 
wherein the ring is optionally substituted with one or more R groups, 
preferably 0, 1 or 2; and wherein: 
R.sub.1 is R.sub.5 --(A).sub.p --; 
R.sub.5 is selected from the group consisting of: 
--H, 
--Ar.sub.1, 
--CO--Ar.sub.1, 
--SO.sub.2 --Ar.sub.1, 
--R.sub.9, 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, 
##STR94## 
each A is independently selected from the group consisiting of any 
.alpha.-amino acid; 
p is 0, 1, 2, 3 or 4; 
Y is: 
--O--, 
--S-- or 
--NH; 
R is: 
--H, 
--O--C.sub.1-6 alkyl, 
--NH(C.sub.1-6 alkyl), 
--N(C.sub.1-6 alkyl).sub.2, 
--S--C.sub.1-6 alkyl, 
--C.sub.1-6 alkyl, or 
--Q.sub.2 ; 
each R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
singly or multiply substituted by --OH, --F, or .dbd.O and optionally 
substituted with one or two Ar.sub.1 groups; 
each R.sub.10 is independently selected from the group consisting of --H or 
a C.sub.1-6 straight or branched alkyl group; 
each T.sub.1 is independently selected from the group consisting of: 
--CH.dbd.CH--, 
--O--, 
--S--, 
--SO--, 
--SO.sub.2 --, 
--NR.sub.10 --, 
--NR.sub.10 --CO--, 
--CO--, 
--O--CO--, 
--CO--O--, 
--CO--NR.sub.10 --, 
--O--CO--NR.sub.10 --, 
--NR.sub.10 --CO--O--, 
--NR.sub.10 --CO--NR.sub.10 --, 
--SO.sub.2 --NR.sub.10 --, 
--NR.sub.10 --SO.sub.2 --, and 
--NR.sub.10 --SO.sub.2 --NR.sub.10 --, 
each Ar.sub.1 is a cyclic group independently selected from the set 
consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms 
and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 
15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being 
optionally benzofused, and a heterocycle group containing between 5 and 15 
ring atoms and between 1 and 3 rings, said heterocycle group containing at 
least one heteroatom group selected from --O--, --S--, --SO--, --SO.sub.2 
--, .dbd.N--, and --NH--, said heterocycle group optionally containing one 
or more double bonds, said heterocycle group optionally comprising one or 
more aromatic rings, and said cyclic group optionally being singly or 
multiply substituted by: --NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, 
--NO.sub.2, --CN, .dbd.O, --OH, -perfluoro C.sub.1-3 alkyl, 
##STR95## 
or --Q.sub.1 ; each Q.sub.1 is independently selected from the group 
consisting of: 
--Ar.sub.1, 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9 ; 
each Q.sub.2 is independently selected from the group consisting of --OH, 
--NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, --NO.sub.2, --CN, 
--CF.sub.3, and 
##STR96## 
provided that when --Ar.sub.1 is substituted with a Q.sub.1 group which 
comprises one or more additional --Ar.sub.1 groups, said additional 
--Ar.sub.1 groups are not substituted with Q.sub.1. 
Preferred compounds of embodiment C of this invention include but are not 
limited to: 
##STR97## 
Preferred compounds of embodiment C of this invention are also those in 
which each A is independently selected from the group consisting of the 
.alpha.-amino acids: 
alanine, 
histidine, 
lysine, 
phenylalanine, 
proline, 
tyrosine, 
valine, 
leucine, 
isoleucine, 
glutamine, 
methionine, 
homoproline, 
3-(2-thienyl)alanine, and 
3-(3-thienyl)alanine. 
The ICE inhibitors of another embodiment (D) of this invention are 
represented by the formula .pi.: 
##STR98## 
wherein: R.sub.1 is R.sub.5 --(A).sub.p --; 
each T.sub.1 is independently selected from the group consisting of: 
--CH.dbd.CH--, 
--O--, 
--S--, 
--SO--, 
--SO.sub.2 --, 
--NR.sub.10 --, 
--NR.sub.10 --CO--, 
--CO--, 
--O--CO--, 
--CO--O--, 
--CO--NR.sub.10 --, 
--O--CO--NR.sub.10 --, 
--NR.sub.10 --CO--O--, 
--NR.sub.10 --CO--NR.sub.10 --, 
--SO.sub.2 --NR.sub.10 --, 
--NR.sub.10 --SO.sub.2 --, and 
--NR.sub.10 --SO.sub.2 --NR.sub.10 --; 
R.sub.5 is selected from the group consisting of: 
--H, 
--Ar.sub.1, 
--CO--Ar.sub.1, 
--SO.sub.2 --Ar.sub.1, 
--R.sub.9, 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, 
##STR99## 
each A is independently selected from the group consisiting of any 
.alpha.-amino acid; 
p is 0, 1, 2, 3 or 4; 
each R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
singly or multiply substituted by --OH, --F, or .dbd.O and optionally 
substituted with an Ar.sub.1 group; 
each R.sub.10 is independently selected from the group consisting of --H or 
a C.sub.1-6 straight or branched alkyl group; 
Ar.sub.1 is a cyclic group independently selected from the set consisting 
of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 
1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon 
atoms and between 1 and 3 rings, said cycloalkyl group being optionally 
benzofused, and a heterocycle group containing between 5 and 15 ring atoms 
and between 1 and 3 rings, said heterocycle group containing at least one 
heteroatom group selected from --O--, --S--, --SO--, --SO.sub.2 --, 
.dbd.N--, and --NH--, said heterocycle group optionally containing one or 
more double bonds, said heterocycle group optionally comprising one or 
more aromatic rings, and said cyclic group optionally being singly or 
multiply substituted by --NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, 
--NO.sub.2, --CH, .dbd.O, --OH, -perfluoro C.sub.1-3 alkyl, or 
##STR100## 
Preferred compounds of embodiment D of this invention are those in which 
R.sub.9 is a C.sub.1-4 straight or branched alkyl substituted with 
Ar.sub.1 when Ar.sub.1 is phenyl. 
Preferred compounds of embodiment D of this invention include but are not 
limited to: 
##STR101## 
Preferred compounds of embodiment D of this invention are also those in 
which A is independently selected from the group consisting of the 
.alpha.-amino acids: 
alanine, 
histidine, 
lysine, 
phenylalanine, 
proline, 
tyrosine, 
valine, 
leucine, 
isoleucine, 
glutamine, 
methionine, 
homoproline, 
3-(2-thienyl)alanine, and 
3-(3-thienyl)alanine. 
The ICE inhibitors of another embodiment (E) of this invention are 
represented by formula .gamma.: 
##STR102## 
wherein: m is 0, 1, or 2; 
T is --CO.sub.2 H, or any bioisosteric replacement for --CO.sub.2 H, 
R.sub.3 is 
--CN, 
--COR.sub.13, or 
##STR103## 
R.sub.5 is selected from the group consisting of: --H, 
--Ar.sub.1, 
--CO--Ar.sub.1, 
--SO.sub.2 --Ar.sub.1, 
--R.sub.9, 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, 
##STR104## 
each A is independently selected from the group consisting of any 
.alpha.-amino acid; 
p is 2 or 3; 
each R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
singly or multiply substituted by --OH, --F, or .dbd.O and optionally 
substituted with one Ar.sub.1 group; 
each T.sub.1 is independently selected from the group consisting of: 
--CH.dbd.CH--, 
--O--, 
--S--, 
--SO--, 
--SO.sub.2 --, 
--NR.sub.10 --, 
--NR.sub.10 --CO--, 
--CO--, 
--O--CO--, 
--CO--O--, 
--CO--NR.sub.10 --, 
--O--CO--NR.sub.10 --, 
--NR.sub.10 --CO--O--, 
--NR.sub.10 --CO--NR.sub.10 --, 
--SO.sub.2 --NR.sub.10 --, 
--NR.sub.10 --SO.sub.2 --, and 
--NR.sub.10 --SO.sub.2 --NR.sub.10 --; 
each R.sub.10 is independently selected from the group consisting of --H or 
a --C.sub.1-6 straight or branched alkyl group; 
each R.sub.13 is independently selected from the group consisting of H, 
R.sub.9, Ar.sub.2, and CH.sub.2 T.sub.1 R.sub.9 ; 
each Ar.sub.1 is a cyclic group independently selected from the set 
consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms 
and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 
15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being 
optionally benzofused, and a heterocycle group containing between 5 and 15 
ring atoms and between 1 and 3 rings, said heterocycle group containing at 
least one heteroatom group selected from --O--, --S--, --SO--, --SO.sub.2 
--, .dbd.N--, and --NH--, said heterocycle group optionally containing one 
or more double bonds, said heterocycle group optionally comprising one or 
more aromatic rings, and said cyclic group optionally being singly or 
multiply substituted by --NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, 
--NO.sub.2, --CN, .dbd.O, --OH, -perfluoro C.sub.1-3 alkyl, 
##STR105## 
or --Q.sub.1 ; and each Ar.sub.2 is independently selected from the 
following group, in which any ring may optionally be singly or multiply 
substituted by --Q.sub.1 and --Q.sub.2 : 
##STR106## 
each Q.sub.1 is independently selected from the group consisting of: 
--Ar.sub.1 
--O--Ar.sub.1 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9 ; 
each Q.sub.2 is independently selected from the group consisting of --OH, 
--NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, --NO.sub.2, --CN, 
--CF.sub.3, and 
##STR107## 
provided that when --Ar.sub.1 is substituted with a Q.sub.1 group which 
comprises one or more additional --Ar.sub.1 groups, said additional 
--Ar.sub.1 groups are not substituted with Q.sub.1. 
Preferred compounds of embodiment E of this invention include but are not 
limited to: 
##STR108## 
Preferred compounds of embodiment E of this invention are also those in 
which A is independently selected from the group consisting the 
.alpha.-amino acids: 
alanine, 
histidine, 
lysine, 
phenylalanine, 
proline, 
tyrosine, 
valine, 
leucine, 
isoleucine, 
glutamine, 
methionine, 
homoproline, 
3-(2-thienyl)alanine, and 
3-(3-thienyl)alanine. 
The ICE inhibitors of another embodiment (F) of this invention are 
represented by formula .delta.: 
##STR109## 
wherein: R.sub.1 is R.sub.5 --(A).sub.p --; 
R.sub.5 is selected from the group consisting of: 
--H, 
--Ar.sub.1, 
--CO--Ar.sub.1, 
--SO.sub.2 --Ar.sub.1, 
--R.sub.9, 
--CO--R.sub.9, 
--CO--O--R.sub.9, 
--SO.sub.2 --R.sub.9, 
##STR110## 
each A is independently selected from the group consisting of any 
.alpha.-amino acid; 
p is 0, 1, 2, 3 or 4; 
each R.sub.9 is a C.sub.1-6 straight or branched alkyl group optionally 
singly or multiply substituted by --OH, --F, or .dbd.O and optionally 
substituted with one Ar.sub.1 group; 
each R.sub.10 is independently selected from the group consisting of --H or 
a C.sub.1-6 straight or branched alkyl group; 
each T.sub.1 is independently selected from the group consisting of: 
--CH.dbd.CH--, 
--O--, 
--S--, 
--SO--, 
each Ar.sub.1 is a cyclic group independently selected from the set 
consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms 
and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 
15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being 
optionally benzofused, and a heterocycle group containing between 5 and 15 
ring atoms and between 1 and 3 rings, said heterocycle group containing at 
least one heteroatom group selected from --O--, --S--, --SO--, --SO.sub.2 
--, .dbd.N--, and --NH--, said heterocycle group optionally containing one 
or more double bonds, said heterocycle group optionally comprising one or 
more aromatic rings, and said cyclic group optionally being singly or 
multiply substituted by --NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, 
--NO.sub.2, --CN, .dbd.O, --OH, -perfluoro C.sub.1-3 alkyl, 
##STR111## 
or --Q.sub.1 ; and each Ar.sub.2 is independently selected from the 
following group, in which any ring may optionally be singly or multiply 
substituted by --Q.sub.1 and --Q.sub.2 : 
##STR112## 
each Q.sub.1 is independently selected from the group consisting of: 
--Ar.sub.1 
--O--Ar.sub.1 
--R.sub.9, 
--T.sub.1 --R.sub.9, and 
--(CH.sub.2).sub.1,2,3 --T.sub.1 --R.sub.9 ; 
each Q.sub.2 is independently selected from the group consisting of --OH, 
--NH.sub.2, --CO.sub.2 H, --Cl, --F, --Br, --I, --NO.sub.2, --CN, 
--CF.sub.3, and 
##STR113## 
provided that when --Ar.sub.1 is substituted with a Q.sub.1 group which 
comprises one or more additional --Ar.sub.1 groups, said additional 
--Ar.sub.1 groups are not substituted with Q.sub.1 ; 
each X is independently selected from the group consisting of .dbd.N--, and 
.dbd.CH--; and 
each Y is independently selected from the group consisting of --O--, --S--, 
and --NH. 
Preferred compounds of embodiment F of this invention include but are not 
limited to: 
##STR114## 
Preferred compounds of embodiment F of this invention are also those in 
which A is independently selected from the group consisting the 
.alpha.-amino acids: 
alanine, 
histidine, 
lysine, 
phenylalanine, 
proline, 
tyrosine, 
valine, 
leucine, 
isoleucine, 
glutamine, 
methionine, 
homoproline, 
3-(2-thienyl)alanine, and 
3-(3-thienyl)alanine. 
The compounds of this invention having a molecular weight of less than or 
equal to about 700 Daltons, and more preferably between about 400 and 600 
Daltons, are preferred. These preferred compounds may be readily absorbed 
by the bloodstream of patients upon oral administration. This oral 
availability makes such compounds excellent agents for orally-administered 
treatment and prevention regimens against IL-1 mediated diseases. 
The ICE inhibitors of this invention may be synthesized using conventional 
techniques. Advantageously, these compounds are conveniently synthesized 
from readily available starting materials. 
The compounds of this invention are among the most readily synthesized ICE 
inhibitors known. Previously described ICE inhibitors often contain four 
or more chiral centers and numerous peptide linkages. The relative ease 
with which the compounds of this invention can be synthesized represents 
an enormous advantage in the large scale production of these compounds. 
It should be understood that the compounds of this invention may exist in 
various equilibrium forms, depending on conditions including choice of 
solvent, pH, and others known to the practitioner skilled in the art. All 
such forms of these compounds are expressly included in the present 
invention. In particular, many of the compounds of this invention, 
especially those which contain aldehyde or ketone groups in R.sub.3 and 
carboxylic acid groups in T, may take hemi-ketal (or hemi-acetal) or 
hydrated forms, as depicted below: 
##STR115## 
Depending on the choice of solvent and other conditions known to the 
practitioner skilled in the art, compounds of this invention may also take 
acyloxy ketal, acyloxy acetal, ketal or acetal form: 
##STR116## 
In addition, it should be understood that the equilibrium forms of the 
compounds of this invention may include tautomeric forms. All such forms 
of these compounds are expressly included in the present invention. 
It should be understood that the compounds of this invention may be 
modified by appropriate functionalities to enhance selective biological 
properties. Such modifications are known in the art and include those 
which increase biological penetration into a given biological system 
(e.g., blood, lymphatic system, central nervous system), increase oral 
availability, increase solubility to allow administration by injection, 
alter metabolism and alter rate of excretion. In addition, the compounds 
may be altered to pro-drug form such that the desired compound is created 
in the body of the patient as the result of the action of metabolic or 
other biochemical processes on the pro-drug. Some examples of pro-drug 
forms include ketal, acetal, oxime, and hydrazone forms of compounds which 
contain ketone or aldehyde groups, especially where they occur in the 
R.sub.3 group of the compounds of this invention. 
The compounds of this invention are excellent ligands for ICE. Accordingly, 
these compounds are capable of targeting and inhibiting events in IL-1 
mediated diseases, such as the conversion of precursor IL-1.beta. to 
mature IL-1.beta. and, thus, the ultimate activity of that protein in 
inflammatory diseases, autoimmune diseases and neurodegenerative diseases. 
For example, the compounds of this invention inhibit the conversion of 
precursor IL-1.beta. to mature IL-1.beta. by inhibiting ICE. Because ICE 
is essential for the production of mature IL-1, inhibition of that enzyme 
effectively blocks initiation of IL-1 mediated physiological effects and 
symptoms, such as inflammation, by inhibiting the production of mature 
IL-1. Thus, by inhibiting IL-L1.beta. precursor activity, the compounds of 
this invention effectively function as IL-1 inhibitors. 
The compounds of this invention may be employed in a conventional manner 
for the treatment of diseases which are mediated by IL-1. Such methods of 
treatment, their dosage levels and requirements may be selected by those 
of ordinary skill in the art from available methods and techniques. For 
example, a compound of this invention may be combined with a 
pharmaceutically acceptable adjuvant for administration to a patient 
suffering from an IL-1 mediated disease in a pharmaceutically acceptable 
manner and in an amount effective to lessen the severity of that disease. 
Alternatively, the compounds of this invention may be used in compositions 
and methods for is treating or protecting individuals against IL-1 
mediated diseases over extended periods of time. The compounds may be 
employed in such compositions either alone or together with other 
compounds of this invention in a manner consistent with the conventional 
utilization of ICE inhibitors in pharmaceutical compositions. For example, 
a compound of this invention may be combined with pharmaceutically 
acceptable adjuvants conventionally employed in vaccines and administered 
in prophylactically effective amounts to protect individuals over an 
extended period time against IL-1 mediated diseases. 
The compounds of this invention may also be co-administered with other ICE 
inhibitors to increase the effect of therapy or prophylaxis against 
various IL-1-mediated diseases. 
In addition, the compounds of this invention may be used in combination 
either conventional anti-inflammatory agents or with matrix 
metalloprotease inhibitors, lipoxygenase inhibitors and antagonists of 
cytokines other than IL-1.beta.. 
The compounds of this invention can also be administered in combination 
with immunomodulators (e.g., bropirimine, anti-human alpha interferon 
antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, 
diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) or 
with prostaglandins, to prevent or combat IL-1-mediated disease symptoms 
such as inflammation. 
When the compounds of this invention are administered in combination 
therapies with other agents, they may be administered sequentially or 
concurrently to the patient. Alternatively, pharmaceutical or prophylactic 
compositions according to this invention may be comprised of a combination 
of an ICE inhibitor of this invention and another therapeutic or 
prophylactic agent. 
Pharmaceutical compositions of this invention comprise any of the compounds 
of the present invention, and pharmaceutically acceptable salts thereof, 
with any pharmaceutically acceptable carrier, adjuvant or vehicle. 
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be 
used in the pharmaceutical compositions of this invention include, but are 
not limited to, ion exchangers, alumina, aluminum stearate, lecithin, 
serum proteins, such as human serum albumin, buffer substances such as 
phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride 
mixtures of saturated vegetable fatty acids, water, salts or electrolytes, 
such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen 
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium 
trisilicate, polyvinyl pyrrolidone, cellulose-based substances, 
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, 
polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool 
fat. 
The pharmaceutical compositions of this invention may be administered 
orally, parenterally, by inhalation spray, topically, rectally, nasally, 
buccally, vaginally or via an implanted reservoir. We prefer oral 
administration. The pharmaceutical compositions of this invention may 
contain any conventional non-toxic pharmaceutically-acceptable carriers, 
adjuvants or vehicles. The term parenteral as used herein includes 
subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, 
intrasynovial, intrasternal, intrathecal, intralesional and intracranial 
injection or infusion techniques. 
The pharmaceutical compositions may be in the form of a sterile injectable 
preparation, for example, as a sterile injectable aqueous or oleaginous 
suspension. This suspension may be formulated according to techniques 
known in the art using suitable dispersing or wetting agents (such as, for 
example, Tween 80) and suspending agents. The sterile injectable 
preparation may also be a sterile injectable solution or suspension in a 
non-toxic parenterally-acceptable diluent or solvent, for example, as a 
solution in 1,3-butanediol. Among the acceptable vehicles and solvents 
that may be employed are mannitol, water, Ringer's solution and isotonic 
sodium chloride solution. In addition, sterile, fixed oils are 
conventionally employed as a solvent or suspending medium. For this 
purpose, any bland fixed oil may be employed including synthetic mono- or 
diglycerides. Fatty acids, such as oleic acid and its glyceride 
derivatives are useful in the preparation of injectables, as are natural 
pharmaceutically-acceptable oils, such as olive oil or castor oil, 
especially in their polyoxyethylated versions. These oil solutions or 
suspensions may also contain a long-chain alcohol diluent or dispersant 
such as Ph. Helv or a similar alcohol. 
The pharmaceutical compositions of this invention may be orally 
administered in any orally acceptable dosage form including, but not 
limited to, capsules, tablets, and aqueous suspensions and solutions. In 
the case of tablets for oral use, carriers which are commonly used include 
lactose and corn starch. Lubricating agents, such as magnesium stearate, 
are also typically added. For oral administration in a capsule form, 
useful diluents include lactose and dried corn starch. When aqueous 
suspensions are administered orally, the active ingredient is combined 
with emulsifying and suspending agents. If desired, certain sweetening 
and/or flavoring and/or coloring agents may be added. 
The pharmaceutical compositions of this invention may also be administered 
in the form of suppositories for rectal administration. These compositions 
can be prepared by mixing a compound of this invention with a suitable 
non-irritating excipient which is solid at room temperature but liquid at 
the rectal temperature and therefore will melt in the rectum to release 
the active components. Such materials include, but are not limited to, 
cocoa butter, beeswax and polyethylene glycols. 
Topical administration of the pharmaceutical compositions of this invention 
is especially useful when the desired treatment involves areas or organs 
readily accessible by topical application. For application topically to 
the skin, the pharmaceutical composition should be formulated with a 
suitable ointment containing the active components suspended or dissolved 
in a carrier. Carriers for topical administration of the compounds of this 
invention include, but are not limited to, mineral oil, liquid petroleum, 
white petroleum, propylene glycol, polyoxyethylene polyoxypropylene 
compound, emulsifying wax and water. Alternatively, the pharmaceutical 
composition can be formulated with a suitable lotion or cream containing 
the active compound suspended or dissolved in a carrier. Suitable carriers 
include, but are not limited to, mineral oil, sorbitan monostearate, 
polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, 
benzyl alcohol and water. The pharmaceutical compositions of this 
invention may also be topically applied to the lower intestinal tract by 
rectal suppository formulation or in a suitable enema formulation. 
Topically-transdermal patches are also included in this invention. 
The pharmaceutical compositions of this invention may be administered by 
nasal aerosol or inhalation. Such compositions are prepared according to 
techniques well-known in the art of pharmaceutical formulation and may be 
prepared as solutions in saline, employing benzyl alcohol or other 
suitable preservatives, absorption promoters to enhance bioavailability, 
fluorocarbons, and/or other solubilizing or dispersing agents known in the 
art. 
The IL-1 mediated diseases which may be treated or prevented by the 
compounds of this invention include, but are not limited to, inflammatory 
diseases, autoimmune diseases and neurodegenerative diseases. 
Inflammatory diseases which may be treated or prevented include, for 
example, septic shock, septicemia, and adult respiratory distress 
syndrome. Target autoimmune diseases include, for example, rheumatoid, 
arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, 
Graves' disease, autoimmune gastritis, insulin-dependent diabetes 
mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, 
thrombocytopenia, chronic active hepatitis, myasthenia gravis and multiple 
sclerosis. And target neurodegenerative diseases include, for example, 
amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, 
and primary lateral sclerosis. The ICE inhibitors of this invention may 
also be used to promote wound healing. And the ICE inhibitors of this 
invention may be used to treat infectious diseases. 
Although this invention focuses on the use of the compounds disclosed 
herein for preventing and treating IL-1-mediated diseases, the compounds 
of this invention can also be used as inhibitory agents for other cysteine 
proteases. 
The compounds of this invention are also useful as commercial reagents 
which effectively bind to ICE or other cysteine proteases. As commercial 
reagents, the compounds of this invention, and their derivatives, may be 
used to block proteolysis of a target peptide or may be derivatized to 
bind to a stable resin as a tethered substrate for affinity chromatography 
applications. These and other uses which characterize commercial cysteine 
protease inhibitors will be evident to those of ordinary skill in the art. 
In order that this invention be more fully understood, the following 
examples are set forth. These examples are for the purpose of illustration 
only and are not to be construed as limiting the scope of the invention in 
any way.