COMBINATION TREATMENT WITH IL-1RA AND DIARYL SULPHONYL UREA COMPOUNDS

Abstract: The invention relates to methods and compositions for treating and preventing interleukin 1 (IL-1) mediated disease states. The methods and compositions use an interleukin 1 receptor antagonist (IL-1ra) polypeptide or variant thereof in combination with a non-steroidal IL-1 processing and release inhibiting agent.

Description: COMBINATION TREATMENT WITH IL-1RA AND DIARY SU PHONYL UREA COMPOUNDS COMBINATION TREATMENT WITH IL-1 RA AND COMPOUNDS THAT INHIBIT IL-1 PROCESSING AND RELEASE Background of the Invention Interleukin 1 refers to two proteins (IL1α and IL1 β, also referred to as IL-1a and IL-1 b, respectively) which play a key role early in the inflammatory response {for a review see C A Dinarello, Blood, 87 2095-2147 (1996) and references therein} Both proteins are made as 31 kDal intracellular precursor proteins which are cleaved and secreted to yield mature carboxy-terminal 17 kDal fragments which are biologically active In the case of IL-1 β, this cleavage involves an intracellular cysteine protease, known as ICE, which is required to release the active fragment from the inactive precursor The precursor of IL-1α is active These two proteins act by binding to cell surface receptors found on almost all cell types and triggering a range of responses either alone or in concert with other secreted factors These range from effects on proliferation (e g of fibroblasts, T cells), apoptosis (e g A375 melanoma cells), cytokine induction (e g of tumor necrosis factor, "TNF", IL1 , IL8), receptor activation (e g E-selectin), eicosanoid production (e g PGE2) and the secretion of degradative enzymes (e g collagenase) To achieve this, IL-1 activates transcription factors such as NF-κB and AP-1 , Several of the activities of IL-1 action on target cells are believed to be mediated through activation of kinase cascades that have also been associated with cellular stresses, such as the stress activated MAP kinases JNK/SAPK and p38 A third member of the IL-1 family was subsequently discovered which acts as a natural antagonist of IL-1 α and IL-1 β by binding to the IL-1 receptor but not transducing an intracellular signal or a biological response The protein was called IL-1 ra (for IL-1 receptor antagonist) Therapies involving the administration of IL-1 ra proteins have been described in various patents and publications as detailed below None of these descriptions, however, provide any suggestion of the combination of an IL-1 ra protein and an IL-1 processing and release inhibiting agent It has now been discovered that the combination of an IL-1ra polypeptide and an IL-1 processing and release inhibiting agent of the present invention provides a synergistic benefit over the individual agents, alone The combinations of the present invention therefore enables effective therapeutic doses of an IL-1 ra that are significantly reduced in comparison to what is required in the absence of the IL-1 processing and release inhibiting agent, and the combination is also significantly more effective than is administration of an IL-1 processing and release inhibiting agent alone or than the IL-1 processing and release inhibiting agent alone Canadian Patent Application No 2039458 discloses treatment of inflammatory diseases using IL-1 ra United States Patent No. 5,508,262 describes a treatment of acute pancreatitis using IL-1ra. PCT publication WO 97/28828 discloses treatments of IL-1 mediated disease using IL-1 ra and variants in a controlled-release polymer matrix. PCT publication WO 99/11292 describes gene therapies for treating arthritis that inter alia, involve directed expression in a patient of IL-1 ra. United States Patent Nos. 5,880,096, 5,861 ,476, 5,786,331 , 5,767,234, 5,608,035 and PCT publication WO 95/20973 describe peptides and compounds that bind to the IL-1 receptor. In particular, these patents describe small peptides (1 to 40 amino acids and molecular weights of less than 3 kD) for use in treating various diseases. Canadian patent application 2,039,458 describes methods of treatment of IL-1 mediated diseases by administering IL-1ra. In particular, this application describes treatment of various inflammatory conditions, preferably septic shock by administering IL-1 ra parenterally. PCT publication WO 93/21946 describes combination therapies for conditions that are mediated by both IL-1 and TNF. The therapies use IL-1 inhibitors, and especially IL-1ra, in combination with a TNF inhibitor. PCT publication WO 97/28828 discloses pharmaceutical compositions comprising IL- 1 ra polypeptides and controlled-release polymers. PCT publication WO 98/24477 discloses various combination therapies using IL-1ra polypeptides along with a wide variety of agents. In particular, this publication is directed to combinations of IL-1ra and methotrexate, although there is disclosure of various other anti- inflammatory agents such as leflunomide. Methotrexate, leflunomide and the like are not IL-1 processing and release inhibiting agents, but may influence the IL-1 axis because they are known to elicit their effects through a supression of cell division. Where cell division is suppressed, the number of cells available to produce cytokines may be reduced, and thus the amount of IL-1 in the system my be reduced. Many studies using IL-1ra, soluble IL-1 R, derived from the intracellular domain of the type I IL-1 R, antibodies to IL-1α or β, and transgenic knockouts of these genes have shown conclusively that the IL-1 ' s play a key role in a number of pathophysiologies (see C. A. Dinarello, Blood 87:2095-2147 (1996) for a review). For example, IL-1ra has been shown to be effective in animal models of septic shock, rheumatoid arthritis, graft versus host disease, stroke, cardiac ischemia, and is currently in clinical trials for some of these indications. See Ohlsson et al., 1990, "lnterleukin-1 receptor antagonist reduced mortality from endotoxin shock", Nature 348:550-551 ; Aiura et al., 1991 , "lnterleukin-1 receptor antagonist blocks hypotension in rabbit model of gram-positive septic shock", Cytokine 4:498; Fischer et al., 1991 , "A comparison between effects of interleukin-1α administration and sublethal endotoxemia in primates", Am. J. Physiol. 261 :R444; Waage and Espevik, 1988, "lnterleukin-1 potentiates the lethal effect of tumor necrosis factor/cachectin in mice", J. Exp. Med. 1678:1987; Fischer et al., "interleukin-1 Receptor Blockade Improves Survival and Hemodynamic Performance in E. coli Septic Shock . . . ", J. Clin. Invest. 89:1551-1557; Granowitz et al., 1992, "Pharmacokinetics, Safety, Immunomodulatory Effects of Human Recombinant interleukin-1 Receptor Antagonist in Healthy Humans", Cytokine 4(5):353-360; Bloedow et al., 1992, "Intravenous Disposition of lnterleukin-1 Receptor Antagonist in Healthy Volunteers", Amer. Soc. Clin. Pharm. and Therapeutics, Orlando, Florida (Abstract). Moreover, IL-1α and β have shown some potential as hematopoietic stem cell stimulators with potential as radio- and chemo-protectants. Inflammatory diseases such as rheumatoid arthritis are characterized by an excessive production of cytokines that promote and/or maintain the inflammatory state. Prominent among them are IL-1 (both the α and β forms) and tumor necrosis factor α (TNFa) (Dinarello, C.A., Blood 87:2095-2147 (1996); Aggarwal, B.B. and Natarajan, K., Eur Cytokine Netw. 7:93-124 (1996); Ushio, S. et al. J. Immunol. 156:4274-4279 (1996)). After release from producing cells, these cytokines bind to specific receptors on target cells to initiate cytokine signaling cascades. As a result of their importance in the disease process, therapeutic approaches aimed at regulating production and/or activity of these cytokines are desirable. Most cytokines are secreted from cells via the constitutive secretory apparatus composed of the rough endoplasmic reticulum and Golgi apparatus, but IL-1 is exported by an untypical route (Rubartelli, A. et al. EMBO J. 9:1503-1510 (1990)). The need for a non-traditional export pathway is a consequence of the synthesis of IL-1 as a polypeptide lacking signal sequences (Auron, P.E. et al. Proc. Natl. Acad. Sci. USA 81 :7907-7911 (1984); March, C.J. et al. Nature 315:641-647 (1985); Ushio, S. et al. J. Immunol. 156:4274-4279 (1996)). This signal or leader sequence typically is found at the amino terminus of polypeptides which are destined to be released from the cell (von Heijne, G. J. Membrane Biol. 115:195-201 (1990)). A signal sequence serves as a molecular address to direct newly synthesized polypeptides into the endoplasmic reticulum. Because newly synthesized IL-1 (prolL-1 ) and IL-18 (prolL-18) lack this sequence, they accumulate within the cytoplasmic compartment of the producing cell. In addition to their co-localization, prolL-1b and prolL-18 also must be processed by the protease caspase I (Thornberry, N.A. et al. Nature 356:768-774 (1992); Ghayur, T. et al. Nature 360:619-623 (1997)); this cleavage generates biologically active, mature forms of the cytokines competent to bind to target cell receptors. ProlL-1a does not share this requirement for proteolytic activation (Moseley, B. et al. J. Biol. Chem. 262:2941-2944 (1987). Other polypeptides exported by similar non-traditional routes include: Mif-related protein (MRP) 8/14 (Rammes, A. et al. J. Biol. Chem. 272:9496-9502 (1997)), basic fibroblast growth factor (Abraham, J.A. Science 233: 545-548 (1986)), galectins (Cleves, A.E. et al. J. Cell Biol. 133:1017-1026 (1997)), a form of the IL-1 receptor antagonist (Haskill, S. et al. Proc. Natl. Acad. Sci. USA 88:3681-3685 (1991 )), thioredoxin (Rubartelli, A. et al. J. Biol. Chem. 267:24161-24164 (1992)), and several virally-encoded polypeptides including VP22 and Tat (Ensoli, B. et al. J. Virol. 67:277-287 (1993)); Elliott, G. and OOHare, P. Cell 88:223-233 (1997)). Lipopolysaccharide (LPS)-treated monocytes and macrophages produce large quantities of prolL-1b, but the release of mature cytokine is inefficient in the absence of a secondary stimulus (Hogquist, K.A. et al. J. Immunol. 147:2181-2186 (1991 )); Perregaux, D. et al. J. Immunol. 149:1294-1303 (1992)). Both proteolytic maturation of prolL-1b and the release of mature cytokine are enhanced by treating LPS-activated cells with any of a number of different stimuli including: extracellular ATP, cytolytic T-cells, high concentrations of LPS, ionophore-like molecules, toxins, hypotonic stress, and mechanical stress (Hogquist, K.A. et al. Proc. Natl. Acad. Sci. USA 88:8485-8489 (1991 ); Perregaux, D. and Gabel, CA. J. Biol. Chem. 269:15195-15203 (1994); Walev, I. et al. Eur Mol. Biol. Org. J. 14:1607-1614 (1995); Bhakdi, S. et al. J. Clin. Invest. 85:1746-1753 (1990); Chin, J. and Kostura, M.J. J. Immunol. 151 :5574-5585 (1993)). Importantly, stimulus-coupled cytokine posttranslational processing is sensitive to pharmacological intervention. Thus, a variety of non-selective anion transport inhibitors can block stimulus-coupled posttranslational processing of prolL-1 b (Laliberte, R. et al. J. Immunol. 153:2168-2179 (1994); Perregaux, et al. J. Immunol. 157:57-64 (1996); Perregaux et al. J. Immunol. 160:2469-2477 (1998)). These agents are effective inhibitors of IL-1 posttranslational processing independent of the nature of the activating stimulus. Moreover, their inhibitory effect is manifested as a complete suppression in the externalization of both IL-1 a and IL-1 b. A series of agents diarylsulfonylureas ("DASUs") has been identified as potent inhibitors of stimulus-coupled posttranslational processing. These compounds are described and claimed in PCT application WO 98/32733 filed December 29, 1997, which entered the United States national stage as Application Serial No. 09/341 ,782 on August 16, 1999, the entire disclosure of which is hereby incorporated by reference for all purposes. Because IL-1 is an important mediator of inflammation and inhibitor of its function provide therapeutic relief in animal models of disease (Cominelli, F. et al. J. Clin. Invest. 86:972-980 (1990); Akeson, A.L. et al. J. Biol. Chem. 271 :30517-30523 (1996); Caron, J.P. et al. Arthritis Rheum. 39:1535-1544 (1996); Okamura, H. et al. Nature 378:88-91 (1995); Rothwell, N. J. Clin. Invest. 100:2648-2652 (1997)), agents that disrupt the process of stimulus-coupled posttranslational processing will be useful for the treatment in man and animals of disorders that are sustained by inflammatory mediators. These include rheumatoid arthritis, osteoarthritis, asthma, inflammatory bowel disease, ulcerative colitis, neurodegeneration, atherosclerosis, and psoriasis. The activities of interleukin-1 are many. Subcutaneous injection of IL-1 leads to fever, sleepiness, anorexia, generalized myalgias, arthralgias, headache, and, on increasing exposure, hypotension. Margination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN) is also observed. IL-1 also stimulates chondrocytes to release matrix metalloproteases, resulting in the degradation of cartilage matrix. Accordingly, disease states that may be treated or prevented by the combination of an IL-1 processing and release inhibiting agent and an IL-1ra polypeptide include, but are not limited to, inappropriate host responses to infectious diseases where active infection exists at any body site, such as septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases which may be responsive to combinations of IL-1 ra polypeptides and IL-1 processing and release inhibiting agents of include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. Combinations of IL-1 ra polypeptides and IL-1 processing and release inhibiting agents of may also be useful in the treatment of bone and cartilage resorption as well as diseases resulting in excess deposition of extracellular matrix. Such diseases include osteoporosis, periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis and keloid formation. Combinations of IL-1ra polypeptides and IL-1 processing and release inhibiting agents of may also be useful in treatment of certain tumors which produce IL-1 as an autocrine growth factor and in preventing the cachexia associated with certain tumors. Combinations of IL-1 ra polypeptides and IL-1 processing and release inhibiting agents of may also be useful in the treatment of neuronal diseases with an inflammatory component, including, but not limited to Alzheimer's disease, stroke, depression and percussion injury. Combinations of IL-1 ra polypeptides and IL-1 processing and release inhibiting agents may also be useful in treating cardiovascular diseases in which recruitment of monocytes into the subendothelial space plays a role, such as the development of atherosclerotic plaques. IL-1ra polypeptides, to be effective in treatment of IL-1 mediated disease states, must be resident in body fluids at relatively high concentrations for sustained periods of time because even small amounts of IL-1 that reach the IL-1 receptor are sufficient to initiate a cascade of other cytokines and inflammatory mediators. Sustaining high concentrations of peptide therapeutic agents is difficult due to problems in passage from the gut to the bloodstream and even for intravenous administration, due to elimination of the peptides by endogenous proteases. Because IL-1 processing and release inhibiting agents reduce production of IL-1 by over 90 %, the amount of lL-1 ra polypeptides needed to treat effectively an IL-1 mediated disease state is greatly reduced. Likewise, IL-1 processing and release agents may exhibit toxicity that limit the available dosages. When the two types of agents are combined, the synergy of reducing the production of IL-1 by the processing and release inhibitor along with antagonism of the IL-1 receptor by the IL-1 ra leads to great reduction in the needed dosages of both agents. Summary of the Invention The present invention provides methods and compositions for the treatment of IL-1 mediated disease states. In particular, the invention provides a method for treating or preventing IL-1 mediated disease states comprising adjunctively administering to a mammal in need of such treatment effective amounts of an IL-1 ra polypeptide or variant thereof and a non-steroidal IL-1 processing and release inhibiting agent. The invention also provides for compositions comprising an IL-1 ra polypeptide or variant thereof and a non-steroidal IL-1 processing and release inhibiting agent. Methotrexate, leflunomide and the like are not IL-1 processing and release inhibiting agents, but may influence the IL-1 axis because they are known to elicit their effects through a supression of cell division. Where cell division is suppressed, the number of cells available to produce cytokines may be reduced, and thus the amount of IL-1 in the system my be reduced. Preferably, the methods and compositions of the present invention employ an IL-1 processing and release inhibiting agent selected from the group consisting of inhibitors of ICE, inhibitors of caspase, and inhibitors of IL-1 posttranslational processing. More preferably, the IL-1 processing and release inhibiting agent is an inhibitor of IL-1 posttranslational processing. Particularly preferred inhibitors of IL-1 posttranslational processing are inhibitors of IL-1 stimulus-coupled posttranslational processing, and more particularly, anion transport inhibitors, and diuretics such as thiazides and ethacrynic acid. A particularly preferred diuretic is ethacrynic acid. IL-1 processing and release inhibiting agents that are preferred are those that have IC 50 values of less than 50 μM, more preferably less than 1 μM, and most preferably less than 100 nM A particularly preferred class of IL-1 processing and release inhibiting agents that are useful in the methods and compositions of the present invention are diarylsulfonylureas. Preferred diarylsulfonylureas are compounds of formula I I or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently a group of formula II wherein the broken lines ( — ) represent optional double bonds; n is 0, 1 , 2 or 3; A, B, D, E and G are each independently oxygen, sulfur, nitrogen or CR 5 R 6 wherein R 5 and R 6 are each independently selected from (1) hydrogen, (2) (d-C 6 )alkyl optionally substituted by one or two groups selected from (d-C 6 )alkylamino, (d-CβJalkylthio, (d- C 6 )alkoxy, hydroxy, cyano, perfluoro(Cι-C 6 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 - C 10 )arylamino, (C 6 -C 10 )arylthio, (C 6 -C 10 )aryloxy wherein the aryl group is optionally substituted by (Cι-C 6 )alkoxy, (d-C 6 )acyl, carboxy, hydroxy or halo; (C 5 -C 9 )heteroarylamino, (C 5 - C 9 )heteroarylthio, (C 5 -C 9 )heteroaryloxy, (C 6 -C o)aryl(C 6 -C 10 )aryl, (C 3 -C 6 )cycloalkyl, hydroxy, piperazinyl, (Ce-doJary Ci-C δ Jalkoxy, (C 5 -C 9 )heteroaryl(d-C 6 )alkoxy, (C 1 -C 6 )acylamino, (d- C 6 )acylthio, (d-C 6 )acyloxy, (d-C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (d-C 6 )alkylsulfonyl, (C 6 - C 0 )arylsulfonyl, amino, (d-C 6 )alkylannino or ((C 1 -C 6 )alkyl) 2 amino; (3) halo, (4) cyano, (5) amino, (6) hydroxy, (7) perfluoro(C 1 -C 6 )alkyl, (8) perfluoro(C 1 -C 6 )alkoxy, (9) (C 2 -C 6 )alkenyl, (10) carboxy(C 2 -C 6 )alkenyl, (11 ) (C 2 -C 6 )alkynyl, (12) (C C 6 )alkylamino, (13) ((d- C 6 )alkyl) 2 amino, (14) (C 1 -C 6 )alkylsulfonylamido, (15) (Cι-C 6 )alkylsulfinyl, (16) (d- C 6 )alkylsulfonyl, (17) aminosulfonyl, (18) (d-d alkylaminosulfonyl, (19) ((d- C 6 )alkyl) 2 aminosulfonyl, (20) (d-C 6 )alkylthio, (21 ) (d-C 6 )alkoxy, (22) perfluoro(C 1 -C 6 )alkyl, (23) (C 6 -C 10 )aryl, (24) (C 5 -C 9 )heteroaryl, (25) (C 6 -C 10 )arylamino, (26) (C 6 -C 10 )arylthio, (27) (Ce-doJary^d-CeJalkoxy, (28) (C 5 -C 9 )heteroarylamino, (29) (C 5 -C 9 )heteroarylthio, (30) (C 5 - C 9 )heteroaryloxy, (31) (C 3 -C 6 )cycloalkyl, (32) (d-CβJalky hydroxymethylene), (33) piperidyl, (34) pyridinyl, (35) thienyl, (36) furanyl, (37) (d-C 6 )alkylpiperidyl, (38) (d-C 6 )acylamino, (39) (C C 6 )acylthio, (40) (d-C 6 )acyloxy, (41 ) R 7 (d-C 6 )alkyl wherein R 7 is (C^CeJacylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (d-C 6 )alkylpiperazino, (Cβ-CioJary Ci- C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(C C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (d-C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (CrCeJalkylpiperidy C^CβJalkyl, (Ce-CioJarylpiperidy d-CeJalkyl, (C 5 - C 9 )heteroarylpiperidyl(CrC 6 )alkyl or (d-C 6 )acylpiperidyl; (42) or a group of formula III wherein s is 0 to 6; t is 0 or 1 ; X is oxygen or NR 8 wherein R 8 is hydrogen, (C C 6 )alkyl or (C 3 -C 7 )cycloalkyl(d- C 6 )alkyl; Y is hydrogen, hydroxy, (d-C 6 )alkyl optionally substituted by halo, hydroxy or cyano; (d-C 6 )alkoxy, cyano, (C 2 -C 6 )alkynyl, (C 6 -Cι 0 )aryl wherein the aryl group is optionally substituted by halo, hydroxy, carboxy, (d-C 6 )alkyl, (d-C 6 )alkoxy, perfluoro(d-C 6 )alkyl, (d- C 6 )alkoxy(Cι-C 6 )alkyl or NR 9 R 10 ; wherein R 9 and R 10 are each independently selected from the group consisting of hydrogen and (d-C 6 )alkyl optionally substituted by (d- C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl, (C 5 - C 9 )heteroaryl or (C 3 -C 6 )cycloalkyl; piperidyl, (d-C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (d-C-eJacylpiperidyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 3 -C 6 )cycloalkyl, R 11 (C 2 -C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 11 )(C 1 -C 6 )alkyl wherein R 11 is hydroxy, (d-C 6 )acyloxy, (d- C 6 )alkoxy, piperazino, (d-C 6 )acylamino, (C C 6 )alkylthio, (C 6 -C 10 )arylthio, (d-C 6 )alkylsulfinyl, (C 6 -Cιo)arylsulfinyl, (d-C 6 )alkylsulfoxyl, (C 6 -C 10 )arylsulfoxyl, amino, (d-C 6 )alkylamino, ((C C 6 )alkyl) 2 amino, (d-C 6 )acylpiperazino, (d-C 6 )alkylpiperazino, (C 6 -C 10 )aryl(C 1 - C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(d-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 12 (d-C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 12 )(C 1 -C 6 )alkyl wherein R 12 is piperidyl or (d-C 6 )alkylpiperidyl; and CH(R 13 )COR 14 wherein R 14 is as defined below and R 13 is hydrogen, (C 1 -C 6 )alkyl, (Ce-C^Jary d-CeJalkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl, (d- C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 6 - (d-CeJalkylsulfony d-CeJalkyl, (Ce-doJarylsulfony d-d alkyl, hydroxy(d-C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((C C 6 )alkylamino) 2 (C C 6 )alkyl, R 15 R 16 NCO(d-C 6 )alkyl or R 15 OCO(d-C 6 )alkyl wherein R 15 and R 6 are each independently selected from the group consisting of hydrogen, (CτC 6 )alkyl, (C 6 - C 10 )aryl(d-C 6 )alkyl and (C 5 -C 9 )heteroaryl(C C 6 )alkyl; and R 14 is R 17 0 or R 17 R 18 N wherein R 17 and R 18 are each independently selected from the group consisting of hydrogen, (d- C 6 )alkyl, (C 6 -C 10 )aryl(d-C 6 )alkyl and (C 5 -C 9 )heteroaryl(d-C 6 )alkyl; (43) or a group of formula IV wherein u is 0, 1 or 2; R ,19 is hydrogen, (d-C 6 )alkyl or perfluoro(Cι-C 6 )alkyl; FC is hydrogen, (d-C 6 )alkyl, (d-C 6 )carboxyalkyl or (Ce-doJary d-CeJalkyl. (44) or a group of formula V wherein a is 0, 1 or 2; b is 0 or 1 ; c is 1 , 2 or 3; d is 0 or 1 ; e is 0, 1 or 2; J and L are each independently oxygen or sulfur; R 21 is hydrogen, hydroxy, fluoro, (d-C β )alkyl, (d-C 6 )alkoxy, halo(d-C 6 )alkyl, amino, (d-C 6 )acylamino or NR 26 R 27 wherein R 26 and R 27 are each independently selected from hydrogen, (d-C 6 )alkyl or (C 6 -C 10 )aryl; and R 22 is hydrogen, (d-C 6 )alkyl optionally substituted by hydroxy, halo, (Cι-C 6 )alkylthio, (C CeJalkylsulfinyl or (d-C 6 )alkylsulfonyl; or in fomula II when n is 1 and B and D are both CR 5 , the two R 5 groups may be taken together with the carbons to which they are attached to form a group of formula VI wherein the broken lines represent optional double bonds; m is 0 or 1 ; and T, U, V and W are each independently oxygen, sulfur, CO, nitrogen or CR 5 0 R6 , wherein R 5 and R 6 are as defined above; or when A and B are both CR 5 , or when n is 1 and B and D are both CR 5 , or when D and E are both CR 5 , or when E and G are both CR 5 , the two R 5 groups may be taken together with the adjacent carbons to which they are attached to form a (C 5 -C 6 )cycloalkyl group optionally substituted by hydroxy or a benzo group. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, L , salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 , 1 '-methylene-bis-(2-hydroxy-3- naphthoate)]salts. The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations ( j^., potassium and sodium) and alkaline earth metal cations (ejj., calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. An embodiment of the compounds of formula I requires that R 2 must be aromatic. Another embodiment of the compounds of formula I requires the groups of formulas II and VI not have two oxygens, two sulfurs or an oxygen and sulfur defined in adjacent positions. Another embodiment of the compounds of formula I requires that either a or e is 0, the other must be 1. Another embodiment of the compounds of formula I requires that when b and d are 1 , the sum of a, c and e cannot be 6 or 7. Another embodiment of the compounds of formula I requires that when A, B, D, E, G, T, U, V and W represent an sp 2 carbon, R 6 does not exist. Preferred diarylsulfonyl ureas have an IC 50 values of less than 50 μM, and more preferably, less than 1 μM, and most preferably less than 100 nM. More preferred diarylsulfonylureas useful for the methods and compositions of the present invention are compounds of formula I wherein R 1 is a group of formula II wherein the broken lines represent double bonds; n is 0 or 1 ; A is CR 5 wherein R 5 is hydrogen or halo; B and E are both independently CR 5 wherein R 5 is (1 ) hydrogen, (2) cyano, (3) halo, (4) (d-C 6 )alkyl optionally substituted by one or two hydroxy; (5) (C 3 - C 7 )cycloalkylaminosulfonyl, (6) (d-C^alkylaminosulfonyl, (7) a group of formula III wherein s is 0; t is 0; and Y is hydrogen, (d-C 6 )alkyl optionally substituted by halo; or (d-C 6 )alkoxy(Cι- C 6 )alkyl I;; (8) a group of formula V wherein a is 0 or 1 ; b is 0 or 1 ; c is 1 or 2; d is 0 or 1 ; e is 0 or 1 ; J and L are each independently oxygen or sulfur; R 2 is hydrogen, hydroxy or (d-C 6 )alkyl optionally substituted by halo; and R 22 is hydrogen or (d-C 6 )alkyl optionally substituted by hydroxy, halo, (d C 6 )alkylthio, (d-C 6 )alkylsulfinyl or (d-C 6 )alkylsulfonyl; or (9) a group of formula IV wherein u is 0 or 1 ; R 19 is (d-C 6 )alkyl or trifluoromethyl; and ,20 R is hydrogen; D is CR 5 wherein R 5 is hydrogen, (d-C 6 )alkyl or halo; G is CR 5 wherein R 5 is oxygen, sulfur or CR 5 wherein R 5 is hydrogen or halo. Other preferred diarylsulfonylureas useful in the methods and compositions of the present invention are compounds of formula I wherein R 2 is a group of formula II wherein the broken lines represent optional double bonds; n is 1 ; A is CR 5 wherein R 5 is halo or (d-C 6 )alkyl; B is CR 5 wherein R 5 is hydrogen or halo; D is CR 5 wherein R 5 is hydrogen, halo, cyano or a group of formula wherein s is 0; t is 0; and Y is NH 2 ; E is CR 5 wherein R 5 is hydrogen or halo; and G is CR 5 wherein R 5 is halo or (C C 6 )alkyl; or when A and B, or E and G, are both CR 5 , the two R 5 groups may be taken together with the adjacent carbons to which they are attached to form a (C 5 -C 6 )cycloalkyl group. Additional preferred diarylsulfonylureas useful for the methods and compositions of the present invention are compounds of formula I with R 1 a group of formula II wherein the broken lines represent double bonds; n is 1 ; A is CR 5 wherein R 5 is hydrogen or halo; B and D are both CR 5 and the two R 5 groups are taken together with the carbons to which they are attached to form a group of formula VI wherein the broken lines represent double bonds; m is 0; T is oxygen, nitrogen or CR 5 wherein R 5 is hydrogen; U is CO or CR 5 wherein R 5 is hydrogen; and W is nitrogen or CR 5 wherein R 5 is hydrogen. Other preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 2 is a group of formula II wherein the broken lines represent optional double bonds; n is 1 ; A is CR 5 wherein R 5 is halo or (d-C 6 )alkyl; B is CR 5 wherein R 5 is hydrogen or halo; D is CR 5 wherein R 5 is hydrogen, halo, cyano or a group of formula wherein s is 0; t is 0; and Y is NH 2 ; E is CR 5 wherein R 5 is hydrogen or halo; and G is CR 5 wherein R 5 is halo or (d-C 6 )alkyl. Other preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 2 is a group of formula II wherein the broken lines represent optional double bonds; n is 1 ; and A and B, or E and G, are both CR 5 , and the two R 5 groups taken together with the adjacent carbons to which they are attached form a (C 5 -C 6 )cycloalkyl group. Particularly preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 2 is a group of formula Other preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 1 is a group of formula II wherein the broken lines represent double bonds; n is 0 or 1 ; A is CR 5 wherein R 5 is hydrogen or halo; and B and E are both independently CR 5 wherein R 5 is hydrogen, cyano, halo, (d- C 6 )alkyl optionally substituted by one or two hydroxy; (C 3 -C 7 )cycloalkylaminosulfonyl, (d- C 6 )alkylaminosulfonyl, a group of formula III wherein s is 0; t is O; or a group of formula IV wherein u is 0 or 1 ; R 19 is (d-C 6 )alkyl or trifluoromethyl; and R 20 is hydrogen; D is CR 5 wherein R 5 is hydrogen, (d-C 6 )alkyl or halo; G is CR 5 wherein R 5 is oxygen, sulfur or CR 5 wherein R 5 is hydrogen or halo. Other preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 1 is a group of formula II wherein the broken lines represent double bonds; n is 0; A is oxygen; and B, E and G are each independently CR 5 wherein R 5 is hydrogen, cyano, halo, (Ci- C 6 )alkyl optionally substituted by one or two hydroxy; (C 3 -C 7 )cycloalkylaminosulfonyl, (C C 6 )alkylaminosulfonyl, a group of formula III wherein s is 0; t is O; or a group of formula IV wherein u is 0 or 1 ; R 19 is (C C 6 )alkyl or trifluoromethyl; and R 20 is hydrogen. More preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 1 is a group of formula II wherein the broken lines represent double bonds; n is 0; A is oxygen; and B, E and G are each independently CR 5 wherein R 5 is hydrogen, cyano, halo, (d- C 6 )alkyl optionally substituted by one or two hydroxy; (C 3 -C 7 )cycloalkylaminosulfonyl, (d- C 6 )alkylaminosulfonyl (most preferably wherein B and G are each independently CR 5 wherein R 5 is hydrogen). Other preferred diarylsulfonyl ureas of formula I useful in the methods and compositions of the present invention are those in which R 2 is a group of formula II wherein the broken lines represent optional double bonds; n is 1 ; A is CR 5 wherein R 5 is halo or (d-C 6 )alkyl; B is CR 5 wherein R 5 is hydrogen or halo; D is CR 5 wherein R 5 is hydrogen, halo, cyano or a group of formula wherein s is 0; t is 0; and Y is NH 2 ; E is CR 5 wherein R 5 is hydrogen or halo; and G is CR 5 wherein R 5 is halo or (d-C 6 )alkyl; or when A and B, or E and G, are both CR 5 , the two R 5 groups may be taken together with the adjacent carbons to which they are attached to form a (C 5 -C 6 )cycloalkyl group. Particular species of diarylsulfonylureas that are useful in the compositions and methods of the present invention may be selected from the group consisting of 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2- sulfonyl]-urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea; 1 -(1 ,2,3, 5,6,7-Hexahydro-4-aza-s-indacen-8-yl)-3-[4-(1-hydroxy-1 -methyl-ethyl )-furan- 2-sulfonyl]-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonyl]- urea; 1 -(1 ,2, 3,5,6, 7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiopheπe- 2-sulfonyl]-urea; 1 -(4-[1 ,3]Dioxolan-2-yl-furan-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)- urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea; 1-(4-Acetyl-thiophene-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1 -(1 H-Benzoimidazole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1 -(1 ,2,3, 5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene- 2-sulfonyl]-urea; 1-(8-Chloro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)- furan-2-sulfonyl]-urea; 1-(4-Acetyl-furan-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(8-Fluoro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)- furan-2-sulfonyl]-urea; 1 -(4-Fluoro-2,6-diisopropyl-phenyl)-3-[3-(1 -hydroxy-1 -methyl-ethyl)-benzenesulfonyl]- urea; 1-(6-Fluoro-1 H-benzoimidazole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)- urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(1 H-indole-6-sulfonyl)-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1 H-indole-6-sulfonyl)-urea; 1-[1 ,2,3,5,6,7-Hexahydro-s-indacen-u-yl)-3-(1 H-indole-6-sulfonyl)-urea; 1-(5-Fluoro-1 H-indole-6-sulfonyl)-3-(1 ,2,3,5,6,7-hexanhydro-5-indacen-4-yl)-urea; 1-[4-Chloro-2,6-diisopropyl-phenyl]-3-[2-fluoro-5-(2-methyl-(1 ,3)dioxolan-2-yl)- benzenesulfonyl]-urea; 3-[3-[4-Chloro-2,6-diisopropyl-phenyl]-ureidosulfonyl]-N-methyl-benzenesulfonamide; 1 -[2-Fluoro-5-(2-methyl-(1 ,3)dioxolan-2-yl)benzenesulfonyl]-3-1 ,2,3,5,6,7-hexahydro- indacen-4-yl)-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]-urea; 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]-urea; and 3-[3-(1 ,2,3,5,6J-Hexahydro-S-indacen-4-yl)-ureidosulfonyl]-N-methyl- benzenesulfonamide. Particularly preferred species among those diarylsulfonylureas useful in the compositions and methods of the present invention are 1 -(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy- 1 -methyl-ethyl )-furan-2- sulfonyl]-urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea; 4-Chloro-2,6-diisopropyl-phenyl-3-[4-(1-hydroxy-1 -methyl-ethyl )-furan-2-sulfonyl]- urea; 1 ,2,3,5,6,7-Hexahydro-4-aza-s-indacen-8-yl-3-[4-(1 -hydroxy- 1 -methyl-ethyl)-furan-2- sulfonyl]-urea; 8-Chloro-1 , 2,3, 5,6,7-hexahydro-s-indacen-4-yl-3-[4-(1-hydroxy-1 -methyl-ethyl )-furan- 2-sulfonyl]-urea; 8-Fluoro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl-3-[4-(1 -hydroxy-1 -methyl-ethyl)-furan- 2-sulfonyl]-urea; and 4-Fluoro-2,6-diisopropyl-pheπyl-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]- urea. Another class of IL-1 processing and release inhibitors useful in the methods and compositions of the present invention are inhibitors of ICE. In particular, preferred inhibitors of ICE are compounds and pharmaceutically acceptable salts thereof selected from the group consisting of wherein g, J, m, R-i, R 3 , T and X, are as defined in United States Patent No. 5,847,135; wherein g, m, R 1t R 3 , T and X, are as defined in United States Patent No. 5,656,627; wherein R 30 , R 3 ι and R 32 are as defined in United States Patent No. 5,656,627; wherein Y 4 , R,, R 13 , T 5 and X 7 are as defined in United States Patent No. 5,656,627; wherein R 13 , R 16 , T 5 and Z, are as defined in United States Patent No. 5,656,627; wherein m, R,, R 3 , and R 15 are as defined in United States Patent No. 5,874,424; (7) wherein n is 0-2; AA is independently L-valine or L-alanine; R is selected from the group consisting of N-[4-(N,N-dimethylaminomethyl)]benzoyl, N-benzyloxycarbonyl, N-methyl-N-[4-(pyridyl)methyl], N-[4-(pyridyl)methyl]carbonyl, N-3-(piperidinopropionyl), N-[4-(morpholinoethoxy)benzoyl, N-2-(quinuclidinyl)carbonyl, N-(3-pyridyl)methoxy carbonyl, N-(2-pyridyl)methoxy carbonyl, N-methyl-N-benzyl carbonyl, N-methyl-N-[2-(4-pyridyl)ethyl]carbonyl, and N-(N-phenylpiperazino)carbonyl; and Re , R 9 and R 10 are each independently hydrogen, lower alkyl, halo substituted methyl, carbalkoxy, benzyl, phenyl, or phenyl mono or disubstituted with fluoro, nitro, methoxy, chloro, trifluoromethyl or methanesulfonyl; (8) or a pharmaceutically acceptable salt thereof thereof, wherein R 1t R 2 , R 3 , X 1 f X 2 , and X 3 are as defined in United States Patent No. 5,866,545; R— N χ (9) R2 or a pharmaceutically acceptable salt thereof wherein Y is CO or S0 2 ; R-i is independently selected from alkyl, haloalkyl and alkoxyalkyl; R 2 is H, alkyl, (CH 2 )-alkenyl, aralkyl, heteroaralkyl, carboxyalkyl, cyanoalkyl, aryl, heteroaryl; and R 3 is H, alkyl, (CH 2 )-alkenyl, aralkyl, heteroaralkyl, aryl, heteraryl; wherein AA 1 f AA 2 , AA 3 , R^ and Y are as defined in United States Patent No. 5,434,248; and the pharmaceutically acceptable base salts thereof wherein A 1 is L-Pro-NR 1 R 2 or --NR 1 R 2 , where R 1 and R 2 are independently selected from the group consisting of hydrogen, d -C 6 alkyl and benzyl; or R 1 and R 2 are taken together with the nitrogen to which they are attached and form wherein n is an integer from 2 to 6; A 2 is selected from the group consisting of L-His, L-Cys, L-Cys(Me), L-Phe, L-Phe-R 3, L-Val, L-Ala, L-lle, L-Leu and L-Tyr; A 3 is selected from the group consisting of L-Val, L-Leu, L-lle, L-Tyr, L-Phe and L-Phe- R 3 ; A 4 is selected from the group consisting of a covalent bond, L-Phe, L-Phe-R 3 ' L-Tyr, and L-Leu; wherein R 3 is attached to the aromatic ring of the phenylalanine and for each occurrence is selected from the group consisting of d -C 6 alkyl, d -C 6 alkoxy, benzyl, fluoro, trifluoromethyl and chloro; and Q 1 is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, R 4 CO and phenylcarbonyl, wherein R 4 is hydrogen, Ci -C 6 alkyl or benzyl; (12) wherein Y, R, R^ and R 9 , are as defined in United States Patent No. 5,716,929; wherein R 1 -R 5 , are as defined in United States Patent No. 5,843,904; wherein R, R, and R 2 , are as defined in United States Patent No. 5,744,451 ; (15) wherein A, n, R^R,, and Z are as defined in United States Patent No. 5,462,939; H -(AA)— N Y (16) wherein AA, n, R-i , and Y are as defined in United States Patent No. 5,843,905; wherein R R 3 are as defined in United States Patent No. 5,565,430; H Z — N- (18) wherein Z, N and Y are as defined in United States Patent No. 5,639,745; (19) an inhibitor as described in United States Patent No. 5,756,466 comprising (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; wherein the first and second hydrogen bonding moieties of (a), the first and second moderately hydrophobic moieties of (b), and the electronegative moiety of (c) are capable of forming said hydrogen bonds of (a), said associations with the separate binding pockets of (b) and said hydrogen bonds or salt bridges of (c), respectively, with said backbone atoms, binding pockets or residues of ICE at the same time; and wherein when said inhibitor is bound to ICE, at least two of the following four conditions d) through g) are met: d) one of said moderately hydrophobic moieties associates with the P2 binding pocket of ICE, in such a way that: 1 ) 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 A and about 12.5 A; 2) 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 A and about 12 A; and 3) 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 A and about 9.5 A; e) one of said moderately hydrophobic moieties associates with the P3 binding pocket of ICE in such a way that: 1 ) 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 A and about 9.5 A; 2) 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 A and about 11 A; and 3) 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 A and about 13 A; f) one of said moderately hydrophobic moieties associates with the P4 binding pocket of ICE in such a way that: 1 ) 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 A and about 7.5 A; 2) 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 A and about 8.5 A; and 3) 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 A and about 11 A; and g) one of said moderately hydrophobic moieties associates with the P' binding pocket of ICE in such a way that: 1 ) 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 A and about 16 A; 2) 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 A and about 15 A; and 3) 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 A and about 12 A, wherein the first and the second hydrogen bonding moieties comprise a polysubstituted cyclic group having between three and seven substituents, and wherein the moderately hydrophobic moiety being capable of associating with the P4 binding pocket is not 4-(dimethylaminomethyl)phenyl, benzyl, phenyl, 4-(carboxymethylthio)phenyl, 4-(carboxyethylthio)phenyl, isobutyl, 4-(carboxyethyl)phenyl, 4-(N-morpholinomethyl)phenyl, 4-((N-methylpiperazino)methyl)phenyl, 4-(N-(2-methyl)imidazolylmethyl)phenyl, 5-benzimidazole, 5-benztriazole, N-carboethoxy-5-benztriazole, N-carboethoxy-5-benzimidazole, 4-carboxypropylphenyl, 4-carboxymethoxyphenyl, 2-fluorophenyl, isopropyl or 5-thiomethylphenyl; (20) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1 , 6-dihydro-1 -pyrimidinyl-acetoyl}-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone; [5,670,494] (21 ) N-{2-(5-thiomethyl-benzoylamino-6-oxo-2-(4-fluorophenyl)-1 , 6-dihyro-1 -pyrimidinyl) acetoyl}-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone; (22) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1 , 6-dihydro-1 -pyrimidinyl)acetoyl}-L-aspartic acid diphenylphosphinoxymethyl ketone; (23) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl-1 , 6-dihydro- 1 -pyrimidinyl)acetoyl}-L-aspartic acid 5-(1 -(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone (24) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1 , 6-dihydro-1 -pyrimidinyl)acetoyl}-L-aspartic acid 5-(3-pheny)coumarinyloxymethyl ketone; (25) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1 , 6-dihydro-1 -pyrimidinyl)acetoyl}-L-aspartic acid 5-(1-phenyl-3-fluoromethyl)-pyrazoloxymethyl ketone; (26) N-{2-(5-isopropyloxycarbonylamino-6-oxo-2-phenyl-1 ,6-dihydro-1 -pyrimidinyl) acetoyl}-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone; (27) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(3-pyridinyl)-1 , 6-dihydro-1 -pyrimidinyl)acetoyl}-L-aspartic acid 5-(1 -phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone; (28) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1 ,6-dihydro-1 -pyrimidinyl) acetoyl}-L-aspartic acid 5-(1 -phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone; (29) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-methyl-1 , 6-dihydro-1 -pyrimidinyl)-acetoyl}-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone; (30) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1 ,6-dihydro-1 -pyrimidinyl) acetoyl}-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone; (31 ) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1 ,6-dihydro-1 -pyrimidinyl) acetoyl}-L-aspartic acid 5-( 1 -(4-chlorophenyl-3-trifluoromethyl)pyrazoloxymethyl ketone; (32) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1 ,6-dihydro-1 -pyrimidinyl) acetoyl}-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone; (33) N-{2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1 ,6-dihydro-1 -pyrimidiny I) acetoyl}-L-aspartic acid aldehyde; (34) gamma-pyrone-3-acetic acid; and (35) a fused-bicyclic lactam selected from the group consisting of [9- Benzyloxycarbonylamino)octahydro-6, 10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1 -formoyl]- L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, [9-(4- Dimethylaminomethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2] diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, [9-(N-[4- Methylpiperazino)methyl]benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a] [1 ,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, [9-(4-(N- Methylpiperazinylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a] [1 ,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyl-oxymethyl ketone, [9-(4-(N-(2- Methyl)imidazolylmethyl)benzoyloamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a] [1 ,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, [9-(5- Benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L- aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, [9-(5-Bentriazoylamino) octahydro-6,10- dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1 -formoyl]-L-aspartic acid 2,6- dichlorobenzoyloxymethyl ketone, [9-(N-Carboethoxy-5-bentriazoylamino) octahydro-6,10- dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1 -formoyl]-L-aspartic acid 2,6- dichlorobenzoyloxymethyl ketone, [9-(N-Carboethoxy-5-benzimidazoylamino) octahydro-6,10- dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L-aspartic acid 2,6- dichlorobenzoyloxymethyl ketone, [9-Benzyloxycarbonylamino)octahydro-10-oxo-6H- pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, [9-(4-Dimethylaminomethyl)benzoylamino)octahydro-6, 10-dioxo-6H- pyridazino[1 ,2a][1 ,2] diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3- thfluoromethyl) pyrazoloxymethyl ketone, [9-Benzyloxycarbonylamino)octahydro-6,10-dioxo- 6H-pyridazino[1 ,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl) pyrazoloxymethyl ketone, [9-Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H- pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3- trifluoromethyl)pyrazoloxymethyl ketone, [9-Benzyloxycarbonylamino)octahydro-6, 10-dioxo- 6H-pyridazino[1 ,2a][1 ,2]diazepine-1 -formoyl]-L-aspartic acid 5-(1 -(2-pyridinyl)-3- trifluoromethyl)pyrazoloxymethyl ketone, [9-Benzoylamino)octahydro-6, 10-dioxo-6H- pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3- trifluoromethyl)pyrazoloxymethyl ketone, [9-(4-Carboxymethylthio)benzoylamino)octahydro- 6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2] diazepine-1-formoyl]-L-aspartic acid 5-(1-(4- chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone, [9-(4- carboxyethylthio)benzoylamino)octahydro-6,10-dioxo-6H-pyridazinot1 ,2a][1 ,2]diazepine-1- formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone, [9- lsobutyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1- formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone, 9-(4- Carboxyethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1- formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)-pyrazoloxymethyl ketone, [9- (4-Carboxypropyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1- formoyi]-L-aspartic acid 5-(1-(4-chlorophenyl)-3trifluoromethyl)pyrazoloxymethyl ketone, [9- Benzyloxycarbonylamino)octahydro-6, 10-dioxo-6H-pyridazino[1 ,2a][1 ,2]dia zepine-1 -formoyl]- L-aspartic acid 5-(1-(4-chloro-2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone, [9-(4- Dimethylaminomethyl)benzoylamino)octahydro-6, 10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine- 1-form oyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone; [9- benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a][1 ,2]dia zepine-1 -formoyl]- L-aspartic acid aldehyde, [9-Benzoylamino)octahydro-6,10-dioxo-6H- pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L-aspartic acid aldehyde, [9-(4- Carboxymethoxy)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1 ,2a] [1 ,2]diazepine-1- formoyl]-L-aspartic acid aldehyde, [9-(2-Fluorobenzoylamiπo) octahydro-6,10-dioxo-6H- pyridazino[1 ,2a][1 ,2]diazepine-1-formoyl]-L-aspartic acid aldehyde, [9-(2- Pyridinoylamino)octahydro-6, 10-dioxo-6H-pyridazino[1 ,2a][1 ,2]diazepine-1 -formoyl]-L-aspartic acid aldehyde and [9-(N-[4-Methylpiperazino)methyl]benzoylamino)octahydro-6,10-dioxo-6H- pyridazino[1 ,2a][1 ,2]diazepine-1 -formoyl]-L-aspartic acid aldehyde. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula 1-35. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, Lα, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1 '-methyiene-bis-(2-hydroxy-3- naphthoate)]salts. The invention also relates to base addition salts of formulae 1-35. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula 1-35 that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. A preferred ICE inhibitor useful in the compositions and methods of the present invention is Vertex VX740, whose synthesis and activity are described in detail in United States Patent No. 5,874,424. VX740 has the structure: The United States patents mentioned in the preceding paragraphs are all incorporated by reference in their entireties for all purposes as if full set forth herein. The methods and compositions of the present invention are directed toward treatment and prophylaxis of IL-1 mediated disease states in mammals. While any mammal that suffers from IL-1 mediated disease states may be treated using the compositions and methods of the present invention, preferably, the mammal is human. Accordingly, for the compositions and methods of the present invention, the preferred IL-1ra polypeptide is human IL-1ra. While the methods and compostions of the present invention are useful for treatment of any IL-1 mediated disease state, preferably, the IL-1 mediated disease state is selected from the group consisting of cytokine-mediated brain diseases such as Alzheimers disease; inflammatory diseases such as acute or chronic inflammation and rheumatoid arthritis; cartillage degenerative diseases such as osteoarthritis; connective tissue diseases such as scleroderma or fibrosing lung diseases such as interstitial pulmonary fibrosis; inflammatory bowel disease; inflammatory eye diseases such as iritis and uveitis; auto-immune diseases; meningitis; salpingitis; septic shock; disseminated intravascular coagulation; adult respiratory distress syndrome; cholangitis; colitis; encephalitis; endocarditis; glomerulonephritis; hepatitis; myocarditis; pancreatitis; pericarditis; reperfusion injury; vasculitis; acute and delayed hypersensitivity; graft rejection; graft-versus-host disease; periodonate diseases, cirrhosis, systemic sclerosis, keloid formation, tumors which produce IL-1 as an autocrine growth factor, cachexia, percussion injury, depression, atherosclerosis and osteoporosis. Disease states for which the methods and compositions are particularly useful are autoimmune diseases, and particularly, autoimune diseases selected from the group consisting of Type 1 diabetes mellitus and multiple sclerosis. The present invention also provides pharmaceutical compositions comprising an IL-1 ra polypeptide or variant thereof, a non-steroidal IL-1 processing and release inhibiting agent, and one or more ingredients selected from the group consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a wetting agent, a buffering agent, an emulsifying agent, and a binding agent. The present invention also provides a kit comprising in one or more containers an IL- 1 ra polypeptide or variant thereof and a non-steroidal IL-1 processing and release inhibiting agent. Definitions "IL-1 processing and release inhibiting agent" refers to any substance that prevents the post-translational processing and release of IL-1 cytokines such as by preventing cleavage of the 31 kDal pro-cytokines that are precursors to the carboxy-terminal 17 kDal mature cytokines, or by preventing release of the mature cytokines into the cellular and/or extracellular fluids. Examples of such inhibitors are inhibitors of ICE, inhibitors of caspase, and inhibitors of IL-1 posttranslational processing. "Polypeptide" refers to any peptide or protein comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. "Polypeptide" refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. "Polypeptides" include amino acid sequences modified either by natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched and branched cyclic polypeptides may result from post-translation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. See, for instance, PROTEINS-STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, N.Y., 1993 and Wold, F., Posttranslational Protein Modifications: Perspectives and Prospects, pgs. 1-12 in POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, N.Y., 1983; Seifter et al., "Analysis for protein modifications and nonprotein cofactors", Meth Enzymol (1990) 182:626-646 and Rattan et al., "Protein Synthesis: Posttranslational Modifications and Aging", Ann NY Acad Sci (1992) 663:48-62. "Variant" as the term is used herein, is a polypeptide that differs from a reference polypeptide but retains essential properties. A typical variant of a polypeptide differs in amino acid sequence from another, reference polypeptide. Generally, differences are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical. A variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. A variant of a polypeptide may be naturally occurring or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis. "Identity" is a measure of the identity of nucleotide sequences or amino acid sequences. In general, the sequences are aligned so that the highest order match is obtained. "Identity" per se has an art-recognized meaning and can be calculated using published techniques. See, e.g.: (COMPUTATIONAL MOLECULAR BIOLOGY; Lesk, A. M., ed., Oxford University Press, N.Y., 1988; BIOCOMPUTING: INFORMATICS AND GENOME PROJECTS, Smith, D. W., ed., Academic Press, N.Y., 1993; COMPUTER ANALYSIS OF SEQUENCE DATA, PART I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, N.J., 1994; SEQUENCE ANALYSIS IN MOLECULAR BIOLOGY, von Heinje, G., Academic Press, 1987; and SEQUENCE ANALYSIS PRIMER, Gribskov, M. and Devereux, J., eds., M Stockton Press, N.Y., 1991 ). While there exist a number of methods to measure identity between two polynucleotide or polypeptide sequences, the term "identity" is well known to skilled artisans (Carillo, H., and Upton, D., SIAM J Applied Math (1988) 48:1073). Methods commonly employed to determine identity or similarity between two sequences include, but are not limited to, those disclosed in Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo, H., and Upton, D., SIAM J Applied Math (1988) 48:1073. Methods to determine identity and similarity are codified in computer programs. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, GCS program package (Devereux, J., et al., Nucleic Acids Research (1984) 12 (1 ):387), BLASTP, BLASTN, FASTA (Atschul, S. F. et al., J Molec Biol (1990) 215:403). "Adjunctively administering" means administering a first agent and while that agent is becoming active or still active, administering a second agent; either of the two agents may be the first to be administered, and the two agent ' s may be administered simultaneously. For example, adjunctively administering an IL-1ra polypeptide and an IL-1 processing and release inhibiting agent to a mammal may be accomplished by first administering the IL-1ra polypeptide, and then before or within the time that the IL-1 ra polypeptide reaches its maximum concentration in the body fluids of the mammal, administering an IL-1 processing and release inhibiting agent, or by first administering the IL-1 processing and release inhibiting agent and then administering the IL-1ra polypeptide, or by administering the IL-1ra polypeptide together with the IL-1 processing and release inhibiting agent. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above. The term "cycloalkyl", as used herein, includes (C 3 -C 14 ) mono-, bi- and tri-cyclic saturated hydrocarbon compounds, optionally substituted by 1 to 2 substituents selected from the group consisting of hydroxy, fluoro, chloro, trifluoromethyl, (Cι-C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (d-C 6 )alkyl. Preferably, cycloalky is substituted with hydroxy. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (d-C 6 )alkoxy, (C β -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (d-C 6 )alkyl. The term "heteroaryl", especially (C 5 -C 9 ), as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound (e.g., 5 to 9 membered mono or bicyclic ring containing one or more heteroatoms) by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (d-C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (d-C 6 )alkyl. The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms "alkyl" or "aryl" are as defined above. The term "acyloxy", as used herein, includes O-acyl groups wherein "acyl" is defined above. "Incorporation by reference" as used herein means incorporation not only of the text and graphics of the reference, but also the preferences, genera, subgenera, and specific embodiments of the reference. Detailed Description of the Preferred Embodiments The present invention is directed to methods and compositions using combinations of IL-1 processing and release inhibiting agents and IL-1 ra polypeptides. These combinations provide an unexpected synergy due to the fact that the processing and release inhibitors reduce the production of IL-1 by more than 90 percent which permits the antagonism by IL-1ra to effectively block the inflammatory cascade. The IL-1 processing and release inhibiting agents that are useful in the combinations of the present invention are described above. Particularly useful among the IL-1 processing and release inhibiting agents for the present methods and compositions are diarylsulfonyl urea (DASU) compounds. Related to these DASU compounds are DASU binding proteins (DBPs) that mediate the cytokine inhibitory activity of these agents. DBPs may be used to screen for structurally unique drugs that disrupt stimulus-coupled posttranslational processing. Compounds that bind to the DBPs also may be used as therapeutics in the treatment of inflammatory disorders. DBPs are described in United States Provisional Patent Application No. 60/098,448, filed August 31 , 1998, which is incorporated herein by reference for all purposes as if fully set forth. Particular I L- 1 ra polypeptides useful in the combination of the invention are described below, as are details regarding the preparation of the diarylsulfonylureas that are the preferred IL-1 processing and release inhibiting agents for the present invention. One skilled in the art will recognize that the synergistic effect from the combination of an IL-1 processing and release inhibiting agent and an IL-1 ra polypeptide will be found with any combination of any substance that inhibits the processing and release of IL-1 cytokines with any IL-1 ra polypeptide as defined above. Thus, the methods and compositions of the present invention are not limited to the species described below. Polypeptides Useful in the Invention IL-1ra polypeptides and analogs are well known in the art, and those skilled in the art understand how to make and use them for treatment of disease. The polypeptides useful in the present invention include but are not limited to those described in the following references. United States Patent Nos. 5,872,095, 5,874,561 and 5,824,549 describe methods of treating diseases using IL-1 receptor antagonist proteins and methods for generating IL-1 receptor antagonist proteins. United States Patent Nos. 5,872,095, 5,874,561 and 5,824,549 are hereby incorporated by reference in their entirety for all purposes as if fully set forth herein. United States Patent No. 5,874,561 describes various IL-1 receptor antagonist proteins, as well as methods for making them and therapeutic methods using them. United States Patent No. 5,874,561 is hereby incorporated by reference in its entirety for all purposes as if fully set forth herein. United States Patent No. 5,455,330 describes a particular class of IL-1 receptor antagonist proteins, as well as methods for making them and therapeutic methods using them. United States Patent No. 5,455,330 is hereby incorporated by reference in its entirety for all purposes as if fully set forth herein. United States Patent No. 5,075,022 describes the structure, properties and methods of making IL-1 ra, and in particular, its corresponding DNA sequence. United States Patent No. 5,075,022 is hereby incorporated by reference in its entirety for all purposes as if fully set forth herein. Preferred polypeptides that are useful in the present invention include the polypeptide of SEQ ID NO:2 of United States Patent No. 5,863,769 which is incorporated herein by reference in its entirety for all purposes as if fully set forth herein. Particularly preferred are the mature IL-1ra beta polypeptide described therein, which differs from the ordinary human IL-1 RA in that it incorparates a N-terminal methionein. Moreover, polypeptides are useful which have at least 80% identity to the polypeptide of SEQ ID NO:2 of United States Patent No. 5,863,769 or the relevant portion and more preferably at least 85% identity, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO:2 of United States Patent No. 5,863,769. Useful IL-1ra beta polypeptides may be in the form of the "mature" protein or may be a part of a larger protein such as a fusion protein. It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification such as multiple histidine residues, or an additional sequence for stability during recombinant production. Thus, the polypeptides particularly useful in the present invention include polypeptides having an amino acid sequence at least identical to that of SEQ ID NO:2 of United States Patent No. 5,863,769 or fragments thereof with at least 80% identity to the corresponding fragment of SEQ ID NO:2 of United States Patent No. 5,863,769. Preferably, all of these polypeptides retain the biological activity of the IL-1ra beta, including antigenic activity. Included in this group are variants of the defined sequence and fragments. Preferred variants are those that vary from the referents by conservative amino acid substitutions - i.e., those that substitute a residue with another of like characteristics. Typical such substitutions are among Ala, Val, Leu and lie; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gin; and among the basic residues Lys and Arg; or aromatic residues Phe and Tyr. Particularly preferred are variants in which several, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination. The IL-1ra beta polypeptides that are particularly useful in the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art. Other preferred polypeptides useful in the present invention also include IL-1ra polypeptides as described above and additionally conjugated with one or more polymeric moieties that protect the IL-1ra polypeptide from enzymatic degradation that may take place in the gut of an animal, in the blood serum or other extracellular environment of an animal, or within the cells of an animal. Preferred polymeric moieties useful for conjugating 11-1 ra for the present invention are so-called linear and branched pegylation reagents such as those described in United States Patent Nos. 5,681 ,811 and 5,932,462, both of which are incorporated herein by reference in their entireties for all purposes as if fully set forth herein. Pegylated IL-1 ra is described, as well, in PCT publication WO 97/28828. Methods for conjugating polymeric moieties to proteins are well known in the art, and are described, for example, in the patents set forth above in this paragraph, as well as in Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications J. M. Harris, Ed., Plenum, NY, 1992. Diarylsulfonyl Urea Inhibitors Useful in the Invention The following reaction Schemes illustrate the preparation of the diarylsulfonylureas described above and preferred in the methods and compositions of the present invention. Unless otherwise indicated n, A, B, D, E and G in the reaction Schemes and the discussion that follow are defined as above. The following preparations and examples are illustrative of the compounds useful in the present invention, and should in no way be taken to limit the scope of the invention; those skilled in the art can readily appreciate the possible routine variations available for the chemistry described, below, and thus the present invention contemplates any such variation. Preparation A Preparation B XII XIV XI XIII Preparation C Preparation D XVI XVIII XV XVII Scheme 1 VIII In reaction 1 of Preparation A, the compound of formula XII is converted to the corresponding isocyanate compound of formula XI by reacting XII with triphosgene in the presence of a base, such as triethylamine, diisopropylethylamine or 1 ,8- diazabicyclo[5.4.0]undec-7-ene, and a aprotic solvent, such as tetrahydrofuran, benzene or methylene chloride. The mixture is stirred and heated to reflux for a time period between about 1 hour to about 3 hours, preferably about 2 hours. In reaction 1 of Preparation B, the compound of formula XIV is converted to the corresponding sulfonamide compound of formula XIII by adding an alkyllithium, such as n- butyl, sec-butyl or tert-butyl lithium, to a stirred solution of XIV in a polar solvent, such as tetrahydrofuran, at a temperature between about -70°C to about -85°C, preferably about -78°C. After approximately 15 minutes, liquified sulfur dioxide is added to the reaction mixture so formed, stirred at approximately -78°C for 5 minutes and then warmed to room temperature for a time period between about 1 hour to about 3 hours, preferably about 2 hours. The mixture is then (a) concentrated in vacuo, and treated with either a chlorinating reagent, such as N-chloro-succinimide in a polar solvent, such as methylene chloride, followed by treatment with gasous or aqueous ammonia or (b) treated with hydroxylamine o- sulfonic acid in water in the presence of a buffer, such as sodium acetate. In reaction 1 of Preparation C, the compound of formula XVI is converted to the corresponding sulfonamide compound of formula XV by adding a solution of sodium nitrate in water to a stirred solution of XVI in a mixture acetic acid and hydrochloric acid. Acetic acid saturated with sulfur dioxide gas is then added followed by cuprous chloride. The reaction mixture so formed is stirred at a temperature between about -10°C to about 10°C, preferably about 0°C, for a time period between about 1 hour to about 3 hours, preferably about 2 hours. The resulting sulfonyl chloride is then treated with gasous or aqueous ammonia bubbled through a solution of the sulfonyl chloride in an aprotic solvent, such as methylene chloride or ether. In reaction 1 of Preparation D, the compound of formula XVIII is converted to the corresponding sulfonamide compound of formula XVII by reacting XVIII with chlorosulfonic acid in a polar aprotic solvent, such as chloroform at a temperature between about -10°C to about 10°C, preferably about 0°C. The reaction mixture so formed is warmed to approximately 60°C. After a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours, the reaction mixture is once again cooled to a temperature approximately 0°C and poured onto ice. The resulting sulfonyl chloride is then treated with gasseous or aqueous ammonia bubbled through a solution of the sulfonyl chloride n an aprotic solvent such as methylene chloride or ether. In reaction 1 of Scheme 1 , the isocyanate compound of formula X and the sulfonamide compound of formula IX are converted to the corresponding sulfonyl urea compound of formula VII by reacting IX and X in the presence of a base, such as sodium hydride, sodium hydroxide, triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene, and a polar solvent, such as tetrahydrofuran, acetone or dimethylformamide. The reaction mixture so formed is heated to reflux for a time period between about 10 hours to about 14 hours, preferably about 12 hours. Preferred furan hydroxyisopropylfuransulfonyl urea compouinds useful in the present invention may be prepared according to Reaction Scheme 1 above, using furan sulfonamides prepared according to Reaction Scheme 2, below. R 1 in Scheme 2 is (d-C 6 ) alkyl. Scheme 2 Bectrophilic sulfonating agent Chlorinating agent and acid scavenger in inert solvent Arrination reagent in inert solvent Methyl Grignard reagent in inert solvent XIX The ester in step (a) is treated with an electrophilic sulfonating agent to form a sulfonic acid compound. Using chlorosulfonic acid and methylene chloride, a portion of the sulfonic acid is crystallized from the reaction mixture. The sulfonic acid compound in step (a) can be isolated as a salt in high purity. The isolated sulfonic acid from step (a) can be converted to sulfonyl chloride compound in step (b) with a chlorinating agent and an acid scavenger. In a one pot procedure, steps (a) and (b) are carried out without isolating the sulfonic acid compound: for example, the ester in methylene chloride is treated with chlorosulfonic acid at ice bath temperature and then stirred, for instance for 48 hours, to complete formation of the sulfonic acid compound; the reaction is then recooled to less then about 0°C, pyridine is added, followed by phosphorous pentachloride. After stirring, for instance overnight, at room temperature the sulfonyl chloride product shown in step (b) can be isolated as an oil. The primary sulfonamide product in step (c) can be formed under Schotten-Baumann conditions with an aminating agent in aqueous acetone. The sulfonamide may then be treated in step (d) with excess Grignard reagent in an inert solvent to form the desired hydroxyisopropyl furan sulfonamide Compound XIX. Compound XIX can be used as an intermediate, with an isocyanate compound, RNCO, as illustrated in Reaction Scheme 1 , to form sulfonyl urea derivatives that are particularly preferred useful processing and release inhibitors useful in the methods and compositions of the present invention. The isocyanate substituent R is decribed in U.S. Patent Application serial no. 60/036,979 which is herein incorporated by reference and can be among the following. 4-Chloro-2,6-diisopropyl-phenyl, 1 ,2,3, 5,6, 7-Hexahydro-s-indacen-4-yl, 1 ,2,3,5,6,7-Hexahydro-4-aza-s-indacen-8-yl, 8-Chloro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl, 8-Fluoro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl, 4-Fluoro-2,6-diisopropyl-phenyl, and 2,6-Diisopropyl-phenyl. The coupling of isocyanate X with sulfonamide XIX requires the presence of a base to deprotonate the sulfonamide. Sodium methoxide and triethylamine can be used in an organic solvent such as tetrahydrofuran or isopropyl alcohol, preferably tetrahydrofuran. An alternative to the isocyanate process is based on a process where di-t-butyl dicarborate and catalytic dimethyl-aminopyridine was used to prepare sterically hindered phenylisocyanates in situ. This is shown in Example 137, below. The compounds of the formula I and 1-35 which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I or 1-35 from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, Le^, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1 ,1 '- methylene-bis-(2-hydroxy-3-naphthoate)] salts. Those compounds of the formula I or 1-35 which are also acidic in nature, e.g., where R 5 includes a COOH or tetrazole moiety, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I or 1- 35. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields. The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, M S, 18 F, and 36 CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 1 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula I or the ICE inhibitors 1-35. This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of matrix metalloproteinases or the inhibition of mammalian reprolysin comprising administering prodrugs of compounds of the formula I or the ICE inhibitors 1-35. Compounds of formula I or the ICE inhibitors 1-35 having free amino, amido, hydroxy, hydroxamic acid, sulfonamide or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded Inhibition of ATP Induced Release of IL-1 B Mononuclear cells are purified from 100 ml of blood isolated using LSM (Organon Teknika). The heparinized blood (1.5 ml of 1000 units/ml heparin for injectin from Apotheconis added to each 50 ml syringe) is diluted with 20 ml of Medium (RMI 1640, 5% FBS, 1% pen/strep, 25 mM HEPES, pH 7.3). 30 ml of the diluted blood is layered over 15 ml of LSM (Organon Teknika) in a 50 ml conical polypropylene centrifuge tube. The tubes are centrifuged at 1200 rpm for 30 minutes in benchtop Sorvall centrifuge at room temperature. The mononuclear cells, located at the interface of the plasma and LSM, are removed, diluted with Medium to achieve a final volume of 50 ml, and collected by centrifugation as above. The supernatant is discarded and the cell pellet is washed 2 times with 50 ml of medium. A 10 μl sample of the suspended cells is taken before the second wash for counting; based on this count the washed cells are diluted with medium to a final concentration of 2.0 x 106 cells/ml. 0.1 ml of the cell suspension is added to each well of 96 well plates. The monocytes are allowed to adhere for 2 hours, then non-adherent cells are removed by aspiration and the attached cells are washed twice with 100 μl f Medium. 100 μl of Medium is added to each well, and the cells are incubated overnight at 37EC in a 5% carbon dioxide incubator. The following day, 25 μl of 50 ng/ml LPS (in Medium) is added to each well and the cells are activated for 2 hours at 37°C. Test agent solutions are prepared as follows. IL-1 processing and release inhibitors are diluted with dimethyl sulfoxide to a final concentration of 10 mM. From this stock solution IL-1 processing and release inhibitors are first diluted 1 :50 [5 μl of 10 mM stock + 245 μl Chase Medium (RPMI 1640, 25 mM Hepes, pH 6.9, 1 % FBS, 1% pen/strep, 10 ng/ml LPS and 5 mM sodium bicarbonate] to a concentration of 200 μM. A second dilution is prepared by adding 10 μl of the 200 μM IL-1 processing and release inhibitor solution to 90 μl of Chase Medium containing various concentrations of IL-1 ra polypeptides, yielding a final concentration of 20 μM diarylsulfonylurea; the dimethyl sulfoxide concentration at this point is 0.2%. The concentrations of IL-1 ra polypeptides in Chase medium combined with 10 μl of the 200 μM IL-1 processing and release inhibitor solution are varied from 1.1 μg/ml to 110 μg/ml to yield approximate concentrations of IL-1ra in the test agent solutions of from 1 to 100 μg/ml. The LPS-activated monocytes are washed once with 100 μl of Chase Medium then 100 μl of Chase Medium (containing 0.2% dimethyl sulfoxide) is added to each well. 0.011 ml of the test agent solutions are added to the appropriate wells, and the monocytes are incubated for 30 minutes at 37 C C. At this point 2 mM ATP is introduced by adding 12 μl of a 20mM stock solution (previously adjusted to pH 7.2 with sodium hydroxide) and the cells are inccubated for an additional 3 hours at 37°C. The 96-well plates are centrifuged for 10 minutes at 2000 rpm in a Sorvall benchtop centrifuge to remove cells and cell debris. A 90 μl aliquot of each supernatant is removed and transferred to a 96 well round bottom plate and this plate is centrifuged a second time to ensure that all cell debris is removed. 30 μl of the resulting supernatant is added to a well of an IL-1 β ELISA plate that also contains 70 μl of PBS, 1 % FBS. The ELISA plate is incubated overnight at 4°C. The ELISA (R&D Systems) is run following the kit kirections. Data Calculation and Analysis: The amount of IL-1 β immunoreactivity in the Chase medium samples is calculated as the percent control, which equals one hundred times the quotient of the difference between optical density at 450 nm of the test compound well and the optical density at 450 nm of the Reagent Blank wells on the ELISA, and the difference between the optical density at 450 nm of the cells that were treated with 0.2% dimethyl sulfoxide only and the optical density at 450 nm of the Reagent Blank wells: % control = {(X-B) / (TOT-B)} x 100, where X = OD450 nm of test compound well; B = OD450 of Reagent Blank wells on the ELISA; TOT = OD450 of cells that were treated with 0.2% dimethyl sulfoxide only. Using the methods described above, test agent solutions may be prepared containing human recombinant IL-1ra and 20 μM of 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2- sulfonyl]-urea and1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]- urea. Blood-based cytokine production assay Blood was collected from normal volunteers and RA patients in heparin-containing vaccutainer tubes; these samples could be stored on ice for up to 4 hr with no adverse effect on assay performance. 75 μl of blood was placed into an individual well of a 96-well plate and diluted with 75 μl of RPMI 1640 medium containing 20 mM Hepes, pH 7.3. The diluted blood samples then were incubated for 2 hours in the absence or presence of LPS (100 ng/ml; E. coli serotype 055:B5; Sigma Chemicals; St. Louis, MO) at 37°C in a 5% C0 2 environment. After this incubation, ATP was introduced as a secretion stimulus (by addition of 10 μl of a solution of 100 mM ATP in 20 mM Hepes, pH 7), and the mixtures were incubated at 37°C for an additional 2 hours. The 96-well plates then were centrifuged at 700 x g for 10 minutes, and the resulting plasma samples were harvested; these samples were stored at -20°C. Test agents to be assessed as IL-1 processing and release inhibitors were dissolved in DMSO at various concentrations and diluted into the blood samples just prior to the addition of LPS; the final concentration of DMSO vehicle in all samples was 0.2%. Each condition was assayed in a minimum of triplicate wells. Plasma supernantants were analyzed in the following ELISAs: IL-1b (R&D Systems, Minneapolis, MN); IL-18 (MBL, Nagoya, Japan); TNFα (R&D Systems). The assays were performed following the manufacturer' s specifications, and absolute cytokine levels were calculated based on comparison to assay performance in the presence of known quantities of recombinant cytokine standards. Whole blood IC 50 values for the IL-1 processing and release inhibiting agents are determined from this test as the blood plasma concentration at which the absolute cytokine levels were reduced down to 50% of the levels of the controls run without any of the IL-1 processing and release inhibiting agents present. The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. Suppositories generally contain the active ingredients in the range of 0.5% to 10% by weight; oral formulations preferably contain 10% to 70% active ingredients. Standard methods for the procedures described in the following example, or suitable alternative procedures, are provided in widely recognized manuals of molecular biology such as, for example, Sambrook et al., Molecular Cloning, Second Edition, Cold Spring Harbor Laboratory Press (1987) and Ausabel et al., Current Protocols in Molecular Biology, Greene Publishing Associates/Wiley Interscience, New York (1990). All chemicals were either analytical grade or USP grade. An animal model of rheumatoid arthritis induced by an adjuvant was used to investigate the combination therapy of an IL-1 inhibitor and 1-(1 , 2,3,5,6, 7-Hexahydro-s- indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-. Male Lewis rats (Charles River, Portage, Ml) (5 per group) weighing at least 200g were cannulated with jugular catheters and allowed to recover for several days. They were then placed in infusion cages and acclimated for a week prior to initiating adjuvant injections. On day 0, all treated rats were injected with 100 μl of Freunds Complete Adjuvant (Sigma Chemical Co., St. Louis, MO) to which a synthetic adjuvant, N, N-dioctyldecyldecyl-N', N-bis (2-hydroxy-ethyl) propanediamine, 75 mg/ml, was added. On days 0-14 1 -(1 ,2,3, 5,6,7- Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea in 1 % carboxymethylcellulose (Sigma) treatment was started and orally administered (15 mg/kg). On day 8, treatment with E. coli-derived human recombinant IL-1 receptor antagonist (prepared generally in accordance with the teachings of U.S. Patent No. 5,075,222, rhulL-1 ra) formulated in a pharmaceutical composition (10 millimolar sodium citrate, 140 millimolar sodium chloride, 0.5 millimolar EDTA, 0.1% polysorbate (w/w) in water, pH 6.5) was administered by continuous IV infusion (5mg/kg/hr) to one group of rats being treated with both Freunds Complete Adjuvant and methotrexate and to another group of rats being treated with Freunds Complete Adjuvant alone. Body weights were taken on day 0 and every other day from day 8 to termination on day 15. Caliper measurements and clinical scoring were done on day 8 and every other day until termination. At this time the animals' body, paw and spleen weights were determined. Rats treated with rhu-IL-1ra alone exhibited a 57% inhibition of arthritis (paw swelling), no significant benefit on splenomegaly and 25% inhibition of body weight change. The combination therapy provided a surprising degree of inhibition of arthritis and a surprising benefit on splenomegaly and a surprising inhibition of body weight change. The invention provides methods of treatment (and prophylaxis) by administration to a subject of an effective amount of an IL-1 ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent. The subject is preferably an animal, including but not limited to animals such as cows, pigs, chickens, primates, etc., and is preferably a mammal, and most preferably human. Various delivery systems are known and can be used to administer IL-1ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent, e.g., encapsulation in liposomes, microparticles, microcapsules, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The IL-1ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). A preferred delvery system for the IL-1ra polypeptide is a subcutaneous pump. Adjunctive administration of the IL-1 processing and release inhibiting agent will lead to a reduced need for the IL-1 ra polypeptide which may manifest itself as a need for less frequent dosing than for the IL-1 ra polypeptide alone. The IL-1 ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent may be administered together with other biologically active agents. Preferred biologically active agents for administration in combination with the IL-1 ra and IL-1 processing and release inihibitting agents are NSAIDs, especially COX-2 selective inhibitors (e.g. Celebrex, Valdecoxib and Vioxx), and matrix metalloproteases. Administration can be systemic or local. In addition, it may be desirable to introduce an IL-1ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. In a specific embodiment, it may be desirable to administer the IL-1ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Thus, the present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of IL-1 ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent and a pharmaceutically acceptable carrier or excipient. Such a carrier includes but is not limited to saline, buffered saline, dextrose, water, glycerol, and combinations thereof. The carrier and composition can be sterile. The formulation should suit the mode of administration. The pharmaceutical composition, if desired, can also contain wetting or emulsifying agents, or pH buffering agents. The pharmaceutical composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The pharmaceutical composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc., and should include a means (e.g. coating, inclusion in a liposome, etc.) that prevents digestion of the domains by stomach enzymes. In one embodiment, the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, pharmaceutical compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the pharmaceutical composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the pharmaceutical composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the pharmaceutical composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. The IL-1ra polypeptide in conjuction and IL-1 processing and release inhibiting agent may also be derivatized so as to immobilize them, for example, on a biologically-inert non- polymeric or polymeric support. Non-limiting examples of such supports include functionalized polystyrene or other polymeric beads, fibers, sheets, etc, and functionalized cellulosic materials such as paper, cotton thread, and the like. Immobilization may involve covalent attachment to the support, or inclusion, adsorption or absorption on or into a porous, non-porous or swellable support. Such immobilization permits easy introduction of the compounds to a specific site by administering the compound on the support, and also provides for easy later removal by removal of the support. The support may be the same support used in the solid-state synthesis described above, where the cleavage step has been omitted. Preferably, the support is a functionalized polystyrene. The IL-1 ra polypeptide in conjuction with an IL-1 processing and release inhibiting agent may also be formulated for transdermal and transmucosal administration. One of ordinary skill would understand that there are numerous technologies available for carrying out such transdermal and transmucosal administration. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. The present invention is illustrated by the following examples, but it is not limited to the details thereof. PREPARATION A 3-Tert-butylsulfamoyl-benzenesulfonyl chloride A solution of 1.46 grams (20 mmole) of t-butylamine and 2.02 grams (20 mmole) of triethylamine in tetrahydrofuran was added dropwise to a solution of 5.5 grams (20 mmole) of 1 ,3-benzenedisulfonyl chloride in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified on silica gel eluting with methylene chloride to give 3.86 grams of the titled compound as an oil. PREPARATION B Benzene-1 ,3-disulfonic acid tert-butyl-amide methylamide 5 ml of a 33% solution of methylamine in ethanol was added to a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred for 2 hours. The ethyl acetate layer was separated and concentrated in vacuo. The residue was purified on silica gel eluting 5% methanol in dichloromethane to give 1.32 grams of the titled compound as a white solid. PREPARATION C Benzene-1 ,3-disulfonic acid tert-butyl-amide dimethylamide Dimethylamine gas was allowed to bubble for 3 minutes into a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. Water was added and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to a solid which was triturated with hexane/isopropyl ether to give 1.59 grams of the titled compound, m.p. 100- 102°C. PREPARATION D Benzene-1 ,3-disulfonic acid amide tert-butyl amide 20 ml of concentrated ammonium hydroxide was added to a solution of 1 gram (3.2 mmole) 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. It was stirred vigorously for 8 hours. The ethyl acetate layer was separated dried over magnesium sulfate in vacuo to give 320 mg of the titled compound as a white solid, m.p. 151-154°C. PREPARATION E Benzene-1 ,3-disulfonic acid tert-butyl-amide cyclopropylamide A mixture of 5 ml of cyclopropylamine and 10 ml of water was added to a solution of 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to an oil which crystallized from isopropyl ether to give 839 mg of the titled compound as a solid. PREPARATION F Benzene-1 ,3-disulfonic acid tert-butyl-amide cyclobutylamide Using a procedure similar to that described in Preparation E, 4 ml of cyclobutylamine was added to 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride to give 813 mg of the titled compound. PREPARATION G Benzene-1 , 3-disulfonic acid amide methylamide A solution of 1.3 grams (4.3 mmole) of benzene-1 ,3-disulfonic acid tert- butylamidemethylamide in 15 ml of trifluoroacetic acid containing 1 drop of anisole was stirred at room temperature for 12 hours. The trifluoroacetic acid was evaporated in vacuo and the residue triturated with methylene chloride to give 330 mg of the titled compound, mp: 124- 126°C. The titled compounds of Preparations H-J were prepared by a method analogous to that described in Preparation G using the starting material indicated. PREPARATION H Benzene-1 ,3-disulfonic acid amide dimethylamide Benzene-1 , 3-disulfonic acid tert-butyl-amide dimethylamide. mp: 166-167°C. PREPARATION I Benzene-1 , 3-disulfonic acid amide cyclopropylamide Benzene-1 , 3-disulfonic acid tert-butyl amide cyclopropylamide. mp: 120-121 °C. PREPARATION J Benzene-1 , 3-disulfonic acid amide cyclobutylamide Benzene-1 , 3-disulfonic acid tert-butyl-amide cyclobutylamide. mp: 128-130°C. PREPARATION K 3-Methylsulfanyl-benzenesulfonamide A solution of 1.6M n-butyllithium (12.5 ml, 20 mmol) in hexane was added to a solution of m-bromothioanisole (4.06 grams, 20 mmol). The solution so formed was stirred at -78°C for 3 hours. Sulfur dioxide was then bubbled into the reaction until it was acidic. The reaction was allowed to warm to room temperature overnight. A solution of N- chlorosuccinimde (2.4 grams, 78 mmol) in methylene chloride was added and after stirring for 1 hour at room temperature, the tetrahydrofuran was evaporated. The residue was slurried in methylene chloride and filtered. The filtrate was mixed with concentrated ammonium hydroxide and stirred at room temperature for 1 hour. The methylene chloride layer was dried and evaporated. The residue was triturated with methylene chloride to give 1.5 grams of the titled compound, mp: 126-127°C. PREPARATION L 3-Methanesulfinyl-benzenesulfonamide A mixture of 3-methylsulfanyl-benzenesulfonamide (406 mg, 2 mmol) and N- chlorosuccinimide (268 mg, 2 mmol) in methanol was stirred at room temperature for 8 hours. The methanol was evaporated and the residue was slurried with methylene chloride and filtered. The filtrate was evaporated to give 250 mg of the titled compound as a white solid. PREPARATION M 3-Methanesulfonyl-benzenesulfonamide To a solution of 3-methylsulfanylbenzenesulfonamide (500 mg, 2.5 mmol) in acetone was added an aqueous solution of OXONE (3.2 grams, 5 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was evaporated to dryness in vacuo. The residue was triturated with acetone and filtered. The filtrated was evaporated to give 460 mg of the titled compound. PREPARATION N 1 -(3-Bromo-phenyl)-cyclobutanol To a solution of 1 ,3-dibromo-benzene (2.36 grams, 10 mmol) in tetrahydrofuran at -78°C was added a 1.6M solution of n-butyllithium (6.3 ml, 10 mmol) in hexane and stirred for 4 hours. Cydobutanone (700 mg, 10 mmol) was then added in one portion. After stirring for 2 hours at -78°C, the reaction was quenched with 2N hydrochloric acid. The reaction was warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2.5 grams of crude product which was purified on silica gel eluting with 50% methylene chloride in hexane to give 1.5 grams of the titled compound. PREPARATION O 3-(1-Hydroxy-cyclobutyl)-benzenesulfonamide A 1.6M solution of n-butyllithium (8 ml, 12.8 mmol) in hexane was added to a solution of 1-(3-bromo-phenyl)-cyclobutanol (1.44 grams, 6.4 mmol) in tetrahydrofuran at -78 C C. After 30 minutes, at the reaction was allowed to warm to 0°C. Sulfur dioxide was bubbled into the reaction mixture and stirred for an additional 30 minutes. The tetrahydrofuran was evaporated and an aqueous solution of sodium acetate (4.1 grams, 50 mmol) and of hydroxylamine-sulfonic acid (1.85 grams, 16 mmol) was added. After stirring at room temperature for 2 hours, the reaction was acidified with 2N hydrochloric acid then extracted with ethyl acetate. The ethyl acetate was dried over sodium sulfate and evaporated. The residue was purified on silica gel with dichloromethane/ether to give 70 mg of the titled compound. PREPARATION P 1 -(3-Bromophenyl)-cyclopentanol Using a procedure similar to that of Preparation N, from 2.36 grams of 1,3- dibromobenzene, 6.3 ml of 1.6M n-butyllithium and 840 mg of cyclopentanone, there was obtained 1.56 grams of 1-(3-bromophenyl)-cyclopentanol as an oil. PREPARATION Q 3-(1-Hydroxy-cyclopentyl)-6-benzenesulfonamide Using a procedure similar to that of Preparation O, from 1.5 grams of 1-(3-bromo- phenyl)-cyclopentanol, 7.9 ml of 1.6M n-butyllithium, 1.85 grams of hydroxylamine-0-sulfonic acid and 4.1 grams of NaOAc, there was obtained 220 mg of 3-(1-hydroxy-cyclopentyl)- benzenesulfonamide as a white solid from dichloromethane. mp: 146-148°C. PREPARATION R 1 -(3-Bromophenyl)-cyclohexanol Using a procedure similar to that of Preparation N, from 20 grams (85 mmole) of 1 ,3- dibromobenzene, 53 ml of 1.6M n-butyllithium in hexane and 8.3 grams of cyclohexanone, there was obtained 4.9 grams of 1-(3-bromophenyl)-cyclohexanol as a white solid. PREPARATION S 3-(1-hydroxy-cyclohexyl)-benzenesulfonamide A 1.6M solution of n-butyllithium (12.35 ml, 19.8 mmol) in hexane was added to a solution of 1-(3-bromophenyl)-cyclohexanol (2.4 grams, 9.4 mmol) in tetrahydrofuran at -78°C. The reaction was stirred for 1 hour, then sulfur dioxide was bubbled into the solution until it was acidic to wet pH paper. The reaction was allowed to warm to room temperature over 12 hours. N-chlorosuccinimide (1.38 grams, 10.3 mmole), dissolved in dichloromethane was added and the reaction stirred for 2 hours. The tetrahydrofuran was evaporated and the residue slurried with methylene chloride and filtered. The filtrate was evaporated to 2.1 grams of 3-(1-hydroxy-cyclohexyl)-benzenesulfonyl chloride as a brown oil. This was dissolved in methylene chloride and added dropwise to 20 ml of liquid ammonia. The ammonia was allowed to evaporated and the residue purified on silica gel with dichloromethane/methanol to give 250 mg of the title compound as a white solid. The titled compounds of Preparations T-V were prepared by a method analogous to that described in Preparation K using the starting material indicated. PREPARATION T 3-(2-Methyl-[1 ,3]dioxolan-2-yl)-benzenesulfonamide 2-(3-Bromophenyl)-2-methyl-[1 ,3]dioxolane. mp: 96-98°C. PREPARATION U 3-[1 ,3]Dioxolan-2-yl-benzenesulfonamide 2-(3-Bromophenyl)-[1 ,3]-dioxolane. mp: 55-58°C. PREPARATION V 2-Fluoro-5-(2-methyl-[1 ,3]dioxolan-2-yl)-benzenesulfonamide 2-[3-Bromo-4-fluorophenyi]-2-methyl-[1 ,3]-dioxolane. mp: 149-150°C. PREPARATION W [2-[4-bromo-2-nitro-phenyl)-vinyl]-dimethyl amine A solution of 27 grams (.125 moles) of 4-bromo-1-methyl-2-nitrobenzene and 1 ml (.31 moles of N,N-dimethylformamide dimethyl acetal in 120 ml of DMF was heated at 80° for 2 hours. After cooling, the reaction was poured onto water and extracted with ethylacetate. Then was dried over sodium sulfate and evaporated to give 36 grams of the titled compound as a purple solid. PREPARATION X Acetic acid [2-(4-Bromo-2-nitro-phenyl)-ethylidene-hydrazide A solution of 36 grams of crude [2-[4-bromo-2-nitro-phenyl)-vinyl]-dimethyl amine in 75 ml of dimethylformamide was cooled to 0°C. A solution of 26 grams of semicarbazide hydrochloride in 200 ml of water was added. 20 ml of concentrated hydrochloric acid was then added. The resulting solution was allowed to warm to room temperature. A tan precipitate was filtered, washed with water and dried. PREPARATION Y 6-Bromo-1 H-indole A solution of 375 grams of iron (II) sulfate heptahydrate in 700 ml of water was added to a suspension of 35 grams of crude acetic acid [2-(4-bromo-2-nitrophenyl)-ethylidene- hydrazide 300 ml of concentrated ammonium hydroxyide. The mechanically stirred mixture was heated to reflux for 4 hours, then cooled and filtered. The precipitate was triturated several times with hot ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give 18 grams of the titled compound. PREPARATION Z 1 H-lndole-6-sulfonic acid amide To a suspension of 3.5 (.03 moles) of 35% KH in mineral oil in ether at 0°C was added dropwise a solution of 6.0 grams (.03 moles) of 6-bromo-1 H-indole. After stirring for 1 hour, the light yellow solution was colled to -78°C. 36.5 ml (.06 moles) of a 1.7M solution of t- btyl lighium in pentane was added dropwise. After stirring for 1 hour at -78°C, S0 2 (g) was bubbled into the solution during 5 minutes. The reaction was allowed to warm to room temperature overnight. A solution of 4.1 grams (.03 moles) of N-chlorosuccinimide was added in one portion. After stirring for 1 hour, the reaction was filtered to remove succinimide and the filtrate evaporated to a yellow solid. This was dissolved in tetrahydrofuran and added to 20 ml of liquid ammonia. The reaction was allowed to warm to room temperature. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to give 1.4 grams of the titled compound. PREPARATION AA 5-Fluoro-2,3-dihydro-1 H-indole A solution of 6.8 grams (.05 moles) of 5-fluoro-1 H-indole in 50 ml of ether was cooled to 0°C under nitrogen. 507 ml of a 0.15M solution of zinc borohydride in ether was added dropwise. The reaction was allowed to stir for 48 hours. The reaction was quenched with dilute hydrochloric acid. The pH was adjusted to 8.0 with dilute sodium hydroxide. The ether layer was seperated, dried and evaporated to give 7 grams of the titled compound. PREPARATION BB 1-(5-Fluoro-2,3-dihydro-indol-yl)-ethanone Acetyl chloride (3 ml) was added dropwise to a solution of 7 grams of crude 5-fluoro- 2,3-dihydro-1 H-indole and 3 ml of triethylamine in 100 ml of CH 2 CI 2 at 0°C. After two hours, the reaction was diluted with water. The methylene chloride layer was seperated, dried and evaporated to afford 7.3 grams of crude product which was purified on silica gel eluting with hexane/ethyl acetate to give 3.3 grams of the titled compound. PREPARATION CC 1-Acetyl-5-fluoro-2,3-dihydro-1 H-indole-6-sulfonic acid amide Chlorosulfonic acid (35 ml) was cooled to 0°C under nitrogen. 3 grams (.016 moles) of 1-(5-fluoro-2,3-dihydro-indol-yl)-ethanone was added in portions. The reaction was heated a 50°C for 3 hours, cooled and poured onto ice. The resulting white precipitate was filtered off and dissovled in methylene chloride. A solution of concentrated ammonium hydroxide was added and the mixture stirred at room temperature for 1 hour. The volitiles were evaporated in vacuo and dilute hydrochloric acid was added. The precipitate was filtered and washed with water to give 3.6 grams of the titled compound. PREPARATION DD 5-Fluoro-2,3-dihydro-1 H-indole-6-sulfonic acid amide A mixture of 3.6 grams of 1-Acetyl-5-fluoro-2,3-dihydro-1 H-indole-6-sulfonic acid amide and 30 ml of 2N sodium hydroxide was heated at 100°C for 3 hours. The reaction was cooled and the pH was adjusted to 7.0 with acetic acid. The resulting precipitate was filtered to give 3.0 grams of the titled compound. PREPARATION EE 5-Fluoro-1 H-indole-6-sulfonic acid amide A mixture of 3 grams of mangenese dioxide and 3 grams of 5-fluoro-2,3-dihydro-1 H- indole-6-sulfonic acid amide in 30 ml of dioxane was heated at 50°C overnight. The reaction was filtered and the filtrate was evaporated to afford crude product which was purified on silica gel eluting with methylene chloride/ethyl acetate to give 1.1 grams of the titled compound. Mp: 181-182°C. PREPARATION FF 2-(3-Bromophenyl)-propan-2-ol To a stirred solution of methylmagnesium bromide (60 mL of a 3.0 M solution in diethyl ether) at 0°C was added dropwise a solution of 3-bromoacetophenone (29.8 grams) in 75 mL of diethyl ether. Once the addition was complete, the mixture was stirred for 0.5 hours and poured into water. The aqueous phase was acidified with 1 M hydrochloric acid and extracted with three portions of diethyl ether. The combined ether layers were washed with saturated sodium bicarbonate, concentrated to afford 30.4 grams of the title compound. H NMR δ 7.72 (br s, 1), 7.49 (d, 1 , J = 7.8), 7.37 (d, 1 , J = 7.9), 7.25 (dd, 1 , J = 7.8, 7.9), 4.19 (s, 1 ), 1.50 (br s, 6). PREPARATION GG 2-(3-Aminosulfonylphenyl)-propan-2-ol To a stirred solution of 2-(3-bromophenyl)-propan-2-ol (30 grams) in tetrahydrofuran (1.5 L) at -78°C was added methyllithium (110 mL of a 1.4 M solution in diethyl ether). The solution was stirred at -78°C for 15 minutes, then butyllithium (61 mL of a 2.5 M solution in hexane) was added. The solution was stirred for 15 minutes at -78°C at which point a slurry formed. To this slurry was added liquified sulfur dioxide (approximately 5 equivalents) in one portion. The slurry was stirred at -78°C for 5 minutes, then warmed to room temperature and stirred for an additional two hours. The mixture was concentrated in vacuo to afford a yellow solid which was taken up in water (418 mL). Sodium acetate (190 grams) and hydroxylamine O-sulfonic acid (47.3 grams) were added to the aqueous solution, and the solution was stirred overnight. The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography (2:1 ethyl acetate/hexane) gave 27 grams of the title compound, m.p. 107.2-108.2°C. PREPARATION HH 4-Chloro-2,6-diisopropyaniline To a stirred solution of 2,6-diisopropylaniline (47 grams) in N,N-dimethylformamide (886 mL) was added N-chlorosuccinimide (37.3 grams) and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 L) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with 6:1 hexane/methylene chloride to afford 32 grams of the title compound. H NMR δ 7.02 (s, 2), 3.71 (br s, 2), 2.91 (qq, 2, J = 6.9 Hz), 1.27 (d, 6, J = 6.9 Hz), 1.27 (d, 6, J = 6.9 Hz). PREPARATION II 4-Chloro-2,6-diisopropylphenylisocyanate To a stirred solution of 4-chloro-2,6-diisopropylaniline (32 grams) and triethylamine (7.8 mL) in tetrahydrofuran (505 mL) was added triphosgene (14.9 grams). The mixture was refluxed for two hours with stirring. The tetrahydrofuran was then revolved in vacuo and the resulting oil was taken up in pentane and filtered through silica gel to afford 33.3 grams of the product. 1 H NMR δ 7.18 (s, 2), 3.22 (qq, 2, J = 7.1 Hz), 1.25 (d, 6, J = 7.1 Hz), 1.25 (d, 6, J = 7.1 Hz). PREPARATION JJ 2-[3-[[[(4-Chloro-2,6-diisopropylphenylamino)amino)carbonyl]amino1sulfonyl]phenyl]- propan-2-ol To a stirred solution of 2-(3-aminosulfonylphenyl)-propan-2-ol (26.5 grams) in tetrahydrofuran was added sodium hydride (5.2 grams of a 60% dispersion in mineral oil) in several portions. Once hydrogen evolution had subsided, 4-chloro-2,6- diisopropylphenylisocyanate (30.8 grams) was added in one portion, and the resulting mixture was heated to reflux for twelve hours. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting foam was dissolved in water, made basic with 1 N sodium hydroxide and extracted with two portions of 1 :1 ether/hexane. The aqueous layer was acidified with 1 N hydrochloric acid, and the resulting white solid was filtered, washed with water and dried. This afforded 50 grams of a white solid which was recrystallized from wet ethyl acetate/hexane afforded the title compound, melting point 160.5-162.0°C. PREPARATION KK 5-Nitroisopthaloyl chloride To a stirred solution of 5-nitroisopthalic acid (10 grams) in methylene chloride (943 mL) was added oxalyl chloride (12.3 mL) and N,N-dimethylforamide (1 drop). The reaction mixture was stirred at room temperature overnight. Removal of the solvent in vacuo afforded 10.63 grams of the title compound. 1 H NMR δ 9.17 (s, 2), 9.07 (s, 1). PREPARATION LL 3,5-Diacetylnitrobenzene Magnesium turnings (2.27 grams) were stirred with ethanol (12 mL) and carbon tetrachloride (1 drop). Once hydrogen evolution was complete, diethyl malonate (15.18 grams) in diethyl ether (30 mL) was added and the mixture was refluxed until all of the magnesium was consumed. 5-Nitroisopthaloyl chloride (10 grams) in tetrahydrofuran (29 mL) was added to the mixture and reflux was continued for an additional 16 hours. The mixture was cooled in an ice bath and acidified with 10% sulfuric acid. The aqueous phase was extracted with ethyl acetate and the organic phase was concentrated in vacuo. The oily residue was taken up in acetic acid (72 mL) and water (14 mL) and sulfuric acid (4 mL) was added. The mixture was vigorously refluxed for 12 hours, then cooled in an ice bath. The mixture was neutralized with 3M sodium hydroxide and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 7.54 grams of the title compound. 1 H NMR δ 8.90 (s, 2), 886 (s, 1 ), 2.78 (s, 6). PREPARATION MM 3,5-Diacetylaniline To a stirred solution of tin (II) chloride dihydrate (32.87 grams) in concentrated hydrochloric acid (93 mL) at 50°C was added 3,5-diacetylnitrobenzene (7.54 grams). The heat was removed immediately and an exotherm occurred. The mixture was stirred for 5 minutes, cooled with an ice bath, and neutralized with saturated potassium carbonate solution. The aqueous phase was extracted with several portions of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3.01 grams of the title compound. 1 H NMR δ 7.77 (s, 1 ), 7.48 (s, 2), 5.16 (br s, 2), 2.55 (s, 6). PREPARATION NN 3,5-Diacetylbenzenesulfonamide To a stirred solution of 3,5-diacetylaniline (3.00 grams) in a mixture of acetic acid (17 (mL) and hydrochloric acid (5.7 mL) was added a solution of sodium nitrate (1.27 grams) in 2.1 mL of water. The solution was stirred for 20 minutes. 14 mL of acetic acid was saturated with sulfur dioxide gas, and this mixture was added to the reaction, followed by cuprous chloride (0.63 grams). Significant foaming occurred. The reaction mixture was stirred for one hour, diluted with water, and extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with water, and concentrated. The resulting oil was taken up in diethyl ether, and ammonia gas was bubbled through the solution. The resulting slurry was filtered, and the solid was taken up in acetone and filtered to remove ammonium chloride. Removal of the acetone in vacuo afforded 1.48 grams of the title compound, m.p. 179.2-180.7°C. PREPARATION OO 1-[3-[[[(4-Chloro-2,6-diisopropylphenylamino)carbonyl]amino]sulfonyl]-5- acetylphenyl]-ethan-1 -one The title compound was prepared as described in method A from 3,5- diacetylbenzenesulfonamide (0.35 grams), 4-chloro-2,6-diisopropylphenylisocyanate (0.37 grams), sodium hydride (0.06 grams of a 60% dispersion in mineral oil), in tetrahydrofuran (4 mL). This afforded 0.28 grams of the title compound, m.p. 201.9-203.4°C. PREPARATION PP 3-Chloro-1 -indan-5-yl-propan-1 -one To a stirred solution of indane (300 grams) and 3-chloropropionoyl chloride (323 grams) in methylene chloride (2L) at 0°C was added aluminum chloride (376 grams) over a period of 3 hours. Once the addition was complete, the cooling bath was removed and the mixture was warmed to room temperature and stirred until hydrogen chloride evolution ceased. The reaction was quenched by pouring onto a mixture of 3.5 kg of ice and 700 mL of concentrated hydrochloric acid. The layers were separated, and the aqueous phase was extracted with methylene chloride. The combined methylene chloride layers were washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to afford 282 grams of a yellow solid, m.p. 63.5-65.1°C. PREPARATION QQ 3,5,6,7-Tetrahydro-2H-s-indacen-1-one Concentrated sulfuric acid (550 mL) was added dropwise, with stirring over a time period of 2 hours to 137 grams of 3-chloro-1-indan-5-yl-propan-1-one. The resulting thick black solution was heated to 90°C until hydrogen chloride evolution ceased (usually 1-4 hours). The mixture was then cooled to room temperature and poured onto 5 kg of ice. The resulting slurry was stirred overnight and filtered. The solid was washed with water until the water ran clear through the filter. The tan solid was then dried in vacuo and recrystallized from hexane to afford 90 grams of the title compound, m.p. 72.4-74.8 c C. PREPARATION RR 1 , 2,3,5,6, 7-Hexahydro-s-indacene A mixture of 3,5,6,7-tetrahydro-2H-s-indacen-1-one (90 grams), ethanol (1 L), 10% palladium on carbon (1-2 grams) and concentrated hydrochloric acid (50 mL) was hydrogenated on a Parr shaker at room temperature until hydrogen uptake ceased. The mixture was filtered through a Celite pad. The pad was washed with 1 L diethyl ether. The filtrate was diluted with water and the organic phase was separated. The aqueous phase was extracted with 1 L of ether, and the combined ether extracts were washed with water, saturated sodium bicarbonate solution and brine. The ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting pale yellow solid was recrystallized from methanol to afford 61 grams of the title compound as colorless crystals, m.p. 56.6-58.5°C. PREPARATION SS 1 -(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-ethanone To a stirred solution of 1 , 2,3,5,6, 7-hexahydro-s-indacene (30 grams) and acetyl chloride (14.2 mL) in 120 mL of benzene at 0°C was added 30 grams of aluminum chloride over a period of 1 hour. The cooling bath was removed and the solution was warmed to room temperature and stirred for 4 hours. The deep red mixture was then poured onto a mixture of 270 grams of ice and 50 mL of concentrated hydrochloric acid. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford an orange solid which was recrystallized from hexane to give 34 grams of the title compound, m.p. 69.1-76.1°C. PREPARATION TT 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-ethanone oxide A mixture of 1-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-ethanone (33 grams), ethanol (250 mL) hydroxylamine hydrochloride (58.5 grams) and pyridine (80 mL) was heated to reflux for a period of 12 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was then treated with 500 mL of water and extracted with chloroform-methanol. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 32 grams of the title compound as a mixture of E and Z isomers, 178.6-182.3°C. PREPARATION UU N-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-acetamide A mixture of 1 -(1 ,2,3, 5,6, 7-hexahydro-s-indacen-4-yl)-ethanone oxime (85 grams) in 270 mL of trifluoroacetic acid was added dropwise to a stirred refluxing solution of 90 mL of trifluoroacetic acid over a period of 1/2 hour. The resulting purple solution was then refluxed for 1 hour. The solution was cooled to room temperature and the trifluoroacetic acid was removed in vacuo. The dark solid was triturated with ethyl acetate/hexanes to afford 83 grams of a grey solid which was used without further purification, m.p. 257.4-259.1°C. PREPARATION W 1 ,2,3,5,6,7-Hexahydro-s-indacen-4-ylamine A slurry of N-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-acetamide (110 grams) in YY mL of 25% sulfuric acid was treated with enough ethanol to make a solution (ca YY mL). The resulting solution was heated to reflux for a period of 2 days. The resulting black solution was treated with charcoal at reflux, filtered hot and cooled to 0°C. The solution was then cautiously neutralized with 20% sodium hydroxide solution. The resulting slurry was then filtered and washed with water until the filtrate ran neutral. The tan solid was then isolated and dried in vacuo to give 80 grams of the title compound, m.p. 94.5-96.6°C, which was used without further purification. If necessary, the title compound can be recrystallized from methanol to afford a white solid. PREPARATION WW 1 ,2,3,5,6,7-Hexahydro-s-indacene To a stirred solution of 1 ,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (77 grams) in tetrahydrofuran (1.5 L) and triethylamine (68.3 mL) was added triphosgene (43.9 grams) in one portion. The mixture was heated to reflux for 2 hour, then cooled to room temperature. The tetrahydrofuran was removed under reduced pressure, and the residue was taken up in pentane and filtered through a plug of silica gel. Removal of the pentane in vacuo afforded 80 grams of a white solid, m.p. 35.0-36.2°C. PREPARATION XX 3-(1-Hydroxy-1 -methyl )ethylfuran To a stirred solution of 24.97 mL of methyl magnesium bromide (3M solution in diethyl ether) at 0°C was added 4.82 mL of ethyl 3-furoate in diethyl ether. The mixture was heated gently using a warm water bath for 30 minutes. Upon completion, the mixture was poured into ice water, carefully acidified using a buffered solution, and extracted with diethyl ether. The ether extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The tertiary alcohol furan was purified using flash column chromatography with 6:1 hexane/ethyl acetate. Recovery: 2.89 grams (64%). 1 H NMR (400 MHz, Acetone-d 6 ) δ 1.45 (s, 3H), 1.46 (s, 3H), 3.89 (br s, 1 H), 6.45 (br s, 1 H), 7.41 (br s, 1 H), 7.42 (br s, 1 H). PREPARATION YY 2-Aminosulfonyl-3-(1-hydroxy-1 -methyl )ethylfuran To a stirred mixture of 2.89 grams of tertiary alcohol furan in THF at -78°C was added 17.19 mL of methyl lithium (1.4M solution in diethyl ether) followed 5 minutes later by 18.51 mL of sec-butyl lithium (1.3M solution in cyclohexanes). The mixture continued to stir at - 78°C for 40 minutes and 5.02 mL of liquid S0 2 was added. The temperature was maintained at -78°C for 5 minutes and was then warmed to room temperature with continued stirring for 2 hours. The THF was then removed in vacuo and the lithium sulfinate was dissolved in 76.4 mL of water followed by addition of 7.78 grams of hydroxylamine o-sulfonic acid and 31 grams of sodium acetate. This mixture stirred at room temperature overnight and was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The sulfonamide was purified using flash column chromatography with 2:1 hexane/ethyl acetate. Recovery: 1.91 grams (41%) m.p. 110.1-111.6°C. PREPARATION ZZ 3-(1-Hydroxy-1-methyl)ethylthiophene To a stirred solution of 3.17 mL of methyl magnesium bromide (3M solution in diethyl ether) at 0°C was added 1 gram of 3-acetylthiophene in diethyl ether. The mixture was then allowed to stir for 30 minutes while warming to room temperature. Upon completion, the mixture was poured into ice water, acidified, and extracted with diethyl ether. The ether extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. Recovery: 800 mg (71%) 1 H NMR (400 MHz, Acetone-d 6 ) δ 1.50 (s, 6H), 4.00 (br s, 1H), 7.15 (dd, 1H, J=1.4, 5), 7.23 (m, 1 H), 7.33 (dd, 1 H, J=3.1 , 5). PREPARATION AAA 2-Aminosulfonyl-3-(1 -hydroxy-1 -methyQethylthiophene To a stirred mixture of 800 mg of tertiary alcohol thiophene in THF at 78°C was added 4.22 mL of methyllithium (1.4M solution in diethyl ether) followed 5 minutes later by 4.55 mL of sec-butyl lithium (1.3M solution in cyclohexanes). The mixture continued to stir at -78°C for 40 minutes and 1.23 mL of liquid S0 2 was added. The temperature was maintained at -78°C for 5 minutes and was then warmed to room temperture with continued stirring for 2 hours. The THF was then removed in vacuo and the lithium sulfinate was dissolved in 19 mL of water followed by addition of 1.9 grams of hydroxylamine o-sulfonic acid and 7.66 grams of sodium acetate. This mixture stirred at room temperature overnight and as extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The sulfonamide was purified using flash column chromatography with 2:1 hexane/ethyl acetate. Recovery: 600 mg (48%) m.p. 114.3- 115.1°C. EXAMPLE 1 1 -(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1 -hydroxy- 1 -methylethyQ-benzenesulfonyl]- urea To a stirred solution of 2-(3-aminosulfonylphenyl)-propan-2-ol (26.5 grams) in tetrahydrofuran was added sodium hydride (5.2 grams of a 60% dispersion in mineral oil) in several portions. Once hydrogen evolution had subsided, 4-chloro-2,6- dissopropylphenylisocyanate (30.8 grams) was added in one portion, and the resulting mixture was heated to reflux for twelve hours. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting foam was dissolved in water, made basic with 1 N sodium hydroxide and extracted with two portions of a 1 :1 ration of ether/hexane. The aqueous layer was acidified with 1 N hydrochloric acid, and the resulting white solid was filtered, washed with water and dried. This afforded 50 grams of a white solid which was recrystallized from wet ethyl acetate/hexane afforded the title compound, melting point 160.5-162.0°C. The titled compounds of Example 2-130 were prepared by a method analogous to that described in Example 1 using the reagents indicated. EXAMPLE 2 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxycyclopentyl)-benzenesulfonyl]- urea 3-1 -Hydroxycyclopentyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 155°C. EXAMPLE 3 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-methylsulfamoyl-benzenesulfonyl]-urea 3-Methylsulfamoyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 125-128°C. EXAMPLE 4 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-dimethylsulfamoyl-benzenesulfonyl]-urea 3-Dimethylsulfamoyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 101-106°C. EXAMPLE 5 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-cyclopropylsulfamoyl-benzenesulfonyl]-urea 3-Cyclopropylsulfamoyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 170-174°C. EXAMPLE 6 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-cyclobutylsulfamoyl-benzenesulfonyl]-urea 3-Cyclobutylsulfamoyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 140-143°C. EXAMPLE 7 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-methylsulfanyl-benzenesulfonyl]-urea 3-Methylsulfanyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 125-126°C. EXAMPLE 8 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-methanesulfinyl-benzenesulfonyl]-urea 3-Methylsulfιnyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 226-227°C. EXAMPLE 9 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-methanesulfonyl-benzenesulfonyl]-urea 3-Methylsulfonyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: °C. EXAMPLE 10 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxycyclobutyl)-benzenesulfonyl]-urea 3-1-Hydroxycyclobutyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 155-157°C. EXAMPLE 11 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxycyclopentyl)-benzenesulfonyl]- urea 3-1-Hydroxycyclopentyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 155°C. EXAMPLE 12 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxycyclohexyl)-benzenesulfonyl]-urea 3-1-Hydroxycyclohexyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 1 2-176°C. EXAMPLE 13 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(2-methyl-[1 ,3]dioxolan-2-yl)- benzenesulfonyl]-urea 3-(2-Methyl-[1 ,3]dioxolan-2-yl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 155-157°C. EXAMPLE 14 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(3-[1 ,3]dioxolan-2-yl-benzenesulfonyl3-urea 3-([1 ,3]Dioxolan-2-yl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 145-147°C. EXAMPLE 15 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(2-fluoro-5-(2-methyl-[1 ,3]-dioxolan-2-yl)- benzenesulfonyl]-urea 3-(2-Fluoro-5-(2-methyl-[1 ,3]dioxolan-2-yl)-benzenesulfonamide; 4-Chloro-2,6- diisopropyl-phenyl isocyanate. mp: 168-170°C. EXAMPLE 16 1 -[2-Fluoro-5-(2-methyl-(1 ,3)-dioxolan-2-yl)benzenesulfonyl]-3-(1 ,2,3,5,6,7- hexahydro-5-indacen-4-yl)urea EXAMPLE 17 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[1 H-indole-6-sulfonyl]-urea 3-(1 H-indole-6-sulfonamide)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 220-221°C. EXAMPLE 18 1-(1 ,2,3,5,6,7-Hexahydro-5-indacen-4-yl)-3-[1 H-indole-6-sulfonyl]-urea EXAMPLE 19 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1 H-indole-6-sulfonyl]-urea 3-(5-Fluoro-1 H-indole-6-sulfonamide)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl- phenyl isocyanate. mp: 226-227°C. EXAMPLE 20 1 -[5-Fluoro-1 H-indole-6-sulfonyl]-3-(1 ,2,3,5,6J-hexahydro-5-indacen-4-yl)urea EXAMPLE 21 l-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(l-hydroxy-ethyl)-5- trifluoromethyl-benzenesulfonyl]-urea 3-(1-Hydroxy-ethyl)-5-trifluoromethyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl- phenyl isocyanate. mp: 168.9-170.0°C. EXAMPLE 22 1-(3-Acetyl-5-trifluoromethyl-benzenesulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)- urea 3-Acetyl-5-trifluoromethyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 157.4-158.9°C. EXAMPLE 23 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-4-methyl-benzenesulfonyl]- urea 3-(1-Hydroxy-ethyl)-4-methyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 155.2-158.2°C. EXAMPLE 24 1-(3-Acetyl-4-methyl-benzenesulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 3-Acetyl-4-methyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 152.5-154.6°C. EXAMPLE 25 1-[3,5-Bis-(1-hydroxy-ethyl)-benzenesulfonyl]-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 3,5-Bis-(1-hydroxy-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 175.3-176.8°C. EXAMPLE 26 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-5-iodo-benzenesulfonyl]- urea 3-(1-Hydroxy-ethyl)-5-iodo-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 184.4-186.6°C. EXAMPLE 27 1-(3-Acetyl-5-iodo-benzenesulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 3-Acetyl-5-iodo-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 187.6-188.9°C. EXAMPLE 28 l-(4-Chloro-2,6-diisopropyl-phenyl)-3-[4-fluoro-3-(l-hydroxy-ethyl)- benzenesulfonyl]-urea 4-Fluoro-3-(1-hydroxy-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 149.7-151.8°C. EXAMPLE 29 1-(3-Acetyl-4-fluoro-benzenesulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 3-Acetyl-4-fluoro-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 171.8-173.4°C. EXAMPLE 30 1-(4-Acetyl-thiophene-2-sulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 4-Acetyl-thiophene-2-sulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 169.7-171.8°C. EXAMPLE 31 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[4-(1-hydroxy-ethyl)-thiophene-2-sulfonyl]-urea 4-(1-Hydroxy-ethyl)-thiophene-2-sulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 164.5-166.6°C. EXAMPLE 32 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(2-hydroxyimino-propyl)-benzenesulfonyl]- urea 3-(2-Hydroxyimino-propyl)-benzenesulfonyl; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 153.8-156.7°C. EXAMPLE 33 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(2-hydroxy-propyl)-benzenesulfonyl]-urea 3-(2-Hydroxy-propyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 148.7-149.9°C. EXAMPLE 34 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(2-oxo-propyl)-benzenesulfonyl]-urea 3-(2-Oxo-propyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 154.8-156.6°C. EXAMPLE 35 1-(2,6-Diisopropyl-phenyl)-3-(3-propionyl-benzenesulfonyl)-urea 3-Propionyl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 151.7- 152.8°C. EXAMPLE 36 1-(3-Acetyl-4-methoxy-benzenesulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 3-Acetyl-4-methoxy-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 214.2-215.1°C. EXAMPLE 37 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-4-methoxy- benzenesulfonyl]-urea 3-(1-Hydroxy-ethyl)-4-methoxy-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 164.9-166.1°C. EXAMPLE 38 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-propyl)-benzenesulfonyl]-urea 3-(1-Hydroxy-propyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 218.4-220.3°C. EXAMPLE 39 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(3-propionyl-benzenesulfonyl)-urea 3-Propionyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 149.1-152.2°C. EXAMPLE 40 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyl]-urea 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 151.8-154.3°C. EXAMPLE 41 1-(5-Acetyl-2-methoxy-benzenesulfonyl)-3-(4-bromo-2,6-diisopropyl-phenyl)-urea 5-Acetyl-2-methoxy-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 185.1-186.5°C. EXAMPLE 42 1-(5-Acetyl-2-methoxy-benzenesulfonyl)-3-(2,6-diisopropyl-phenyl)-urea 5-Acetyl-2-methoxy-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 199.7-201.3°C. EXAMPLE 43 1-(3-Acetyl-benzenesulfonyl)-3-(4-chloro-2,6-diisopropyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 163.1-165.6°C. EXAMPLE 44 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxyimino-ethyl)-benzenesulfonyl]- urea 3-(1-Hydroxyimino-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 158.4-160.0°C. EXAMPLE 45 1-(4-Bromo-2,6-diisopropyl-phenyl)-3-(6-methyl-1 ,1-dioxo-1-thiochroman-7-sulfonyl)- urea 6-Methyl-1 ,1-dioxo-1-thiochroman-7-sulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 250.4-251.9°C. EXAMPLE 46 1-(2,6-Diisopropyl-phenyl)-3-(6-methyl-1 ,1-dioxo-1-thiochroman-7-sulfonyl)-urea 6-Methyl-1 ,1-dioxo-1-thiochroman-7-sulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 242.7-245.2°C. EXAMPLE 47 1-(2,6-Diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyl]-urea 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 122.6-124.0°C. EXAMPLE 48 1-(4-Bromo-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyll-urea 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 142.5-144.80°C. EXAMPLE 49 1-(3-Acetyl-benzenesulfonyl)-3-(4-bromo-2,6-diisopropyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 231.4-233.6°C. EXAMPLE 50 1-(3-Acetyl-4-hydroxy-benzenesulfonyl)-3-(2,6-diisopropyl-phenyl)-urea 3-Acetyl-4-hydroxy-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 196.6-198.90°C. EXAMPLE 51 1-(3-Acetyl-4-methoxy-benzenesulfonyl)-3-(2,6-diisopropyl-phenyl)-urea 3-Acetyl-4-methoxy-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 203.4-205.7°C. EXAMPLE 52 1-(3-Acetyl-benzenesulfonyl)-3-(2-sec-butyl-6-ethyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 2-sec-Butyl-6-ethyl-phenyl isocyanate. mp: 136.3- 138.9°C. EXAMPLE 53 1-(3-Acetyl-benzenesulfonyl)-3-(2-isopropyl-6-methyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 2-lsopropyl-6-methyl-phenyl isocyanate. mp: 136.8- 138.9°C. EXAMPLE 54 1-(3-Acetyl-benzenesulfonyl)-3-(2-tert-butyl-6-methyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 2-tert-Butyl-6-methyl-phenyl isocyanate. mp: 155.4- 157.7°C. EXAMPLE 55 1-(3-Acetyl-benzenesulfonyl)-3-(2-ethyl-6-isopropyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 2-Ethyl-6-isopropyl-phenyl isocyanate. mp: 127.1- 128.5°C. EXAMPLE 56 1-(3-Acetyl-benzenesulfonyl)-3-(2,6-diisopropyl-phenyl)-urea 3-Acetyl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 151.6- 153.5°C. EXAMPLE 57 1-(4-Acetyl-2,6-diisopropyl-phenyl)-3-(3,5-diacetyl-benzenesulfonyl)-urea 3,5-Diacetyl-benzeπesulfonamide; 4-Acetyl-2,6-diisopropyl-phenyl isocyanate. mp: 154.0-156.40°C. EXAMPLE 58 4-[3-(3,5-Diacetyl-benzenesulfonyl)-ureido]-3,5-diisopropyl-benzamide 3,5-Diacetyl-benzenesulfonamide; 4-lsocyanato-3,5-diisopropyl-benzamide. mp: 198.5-199.8°C. EXAMPLE 59 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)- benzenesulfonyl]-urea 3-(2,2,2-Trifluoro-1 -hydroxy-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl- phenyl isocyanate. mp: 129.6-131.5°C. EXAMPLE 60 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(3-trifluoroacetyl-benzenesulfonyl)-urea 3-Trifluoroacetyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 88.4-89.1 °C. EXAMPLE 61 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-2-methoxy-ethyl)- benzenesulfonyl]-urea 3-(1-Hydroxy-2-methoxy-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 108.7-109.2°C. EXAMPLE 62 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(3-methoxyacetyl-benzenesulfonyl)-urea 3-Methoxyacetyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 121.2-122.1°C. EXAMPLE 63 4-[3-[3-(1-Hydroxy-ethyl)-benzenesulfonyl]-ureido]-3,5-diisopropyl-benzamide 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 4-lsocyanato-3,5-diisopropyl-benzamide. mp: 204.6-205.9°C. EXAMPLE 64 1-(4-Cyano-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyl]-urea 3-(1 -Hydroxy-ethyl)-benzenesulfonamide; 4-Cyano-2,6-diisopropyl-phenyl isocyanate. mp: 191.3-194.0°C. EXAMPLE 65 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1-hydroxy-2-methyl-propyl)- benzenesulfonyl]-urea 3-(1-Hydroxy-2-methyl-propyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 152.3-153.0°C. EXAMPLE 66 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(3-isobutyryl-benzenesulfonyl)-urea 3-lsobutyryl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 170.2-171.4°C. EXAMPLE 67 1-(2,6-Diisopropyl-4-thiophen-3-yl-phenyl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyl]- urea 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-4-thiophen-3-yl-phenyl isocyanate. mp: 137.0-139.4°C. EXAMPLE 68 1-(2,6-Diisopropyl-4-thiophen-2-yl-phenyl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyl]- urea 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-4-thiophen-2-yl-phenyl isocyanate. mp: 98.4-99.9 c C. EXAMPLE 69 1-(3,5-Diisopropyl-biphenyl-4-yl)-3-[3-(1-hydroxy-ethyl)-benzenesulfonyl]-urea 3-(1-Hydroxy-ethyl)-benzenesulfonamide; 4-lsocyanato-3,5-diisopropyl-biphenyl. mp: 127.4-128.6°C. EXAMPLE 70 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(8-hydroxy-5,6,7,8-tetrahydro-naphthalene-2- sulfonyl)-urea 8-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 4-Chloro-2,6-diisopropyl- phenyl isocyanate. mp: 136.8-138.2°C. EXAMPLE 71 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(8-oxo-5,6,7,8-tetrahydro-naphthalene-2- sulfonyl)-urea δ-Oxo-5,6,7, 8-tetrahydro-naphthalene-2-sulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 180.0-182.4°C. EXAMPLE 72 l-(4-Chloro-2,6-diisopropyl-phenyl)-3-(8-hydroxyimino-5,6,7,8-tetrahydro- naphthalene-2-sulfonyl)-urea 8-Hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 4-Chloro-2,6- diisopropyl-phenyl isocyanate. mp: 162.5-164.2°C. EXAMPLE 73 1 -(4-Bromo-2,6-diisopropyl-phenyl)-3-(8-hydroxy-5,6,7,8-tetrahydro-naphthalene-2- sulfonyl)-urea 8-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 4-Bromo-2,6-diisopropyl- phenyl isocyanate. mp: 164.0-165.8°C. EXAMPLE 74 1 -(2,6-Diisopropyl-phenyl )-3-(8-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)- urea 8-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 120.0-122.6°C. EXAMPLE 75 1-(2,6-Diisopropyl-phenyl)-3-(8-hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2- sulfonyl)-urea 8-Hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 2,6-Diisopropyl- phenyl isocyanate. mp: 139.2-140.0°C. EXAMPLE 76 1-(4-Bromo-2,6-diisopropyl-phenyl)-3-(8-hydroxyimino-5,6,7,8-tetrahydro- naphthalene-2-sulfonyl)-urea 8-Hydroxyimino-5,6,7,8-tetrahydro-naphthalene-2 -sulfonamide; 4-Bromo-2,6- diisopropyl-phenyl isocyanate. mp: 168.6-169.2°C. EXAMPLE 77 1-(4-Bromo-2,6-diisopropyl-phenyl)-3-(8-oxo-5,6,7,8-tetrahydro-naphthalene-2- sulfonyl)-urea 8-Oxo-5,6, 7, 8-tetrahydro-naphthalene-2-sulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 208.0-208.8°C. EXAMPLE 78 1-(2,6-Diisopropyl-phenyl)-3-(8-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-urea 8-Oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 197.4-198.0°C. EXAMPLE 79 3-[3-(4-Bromo-2,6-diisopropyl-phenyl)-ureidosulfonyl3-benzamide 3-Sulfonamido-benzamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 180.0- 180.6°C. EXAMPLE 80 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1 ,2-dihydroxy-ethyl)-benzenesulfonyl]-urea 3-(1 ,2-Dihydroxy-ethyl)-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 169.7-171.2°C. EXAMPLE 81 3-[3-(2,6-Diisopropyl-phenyl)-ureidosulfonyl]-benzamide 3-Sulfonamido-benzamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 182.3-184.1°C. EXAMPLE 82 3-[3-(4-Bromo-2,6-diisopropyl-phenyl)-ureidosulfonyl]-N-methyl-benzamide 3-Sulfonamido-N-methyl-benzamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 243.8-245.1 °C. EXAMPLE 83 3-[3-(2,6-Diisopropyl-phenyl)-ureidosulfonyl]-N-methyl-benzamide 3-Sulfonamido-N-methyl-benzamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 236.2- 237.2°C. EXAMPLE 84 1-(5-Acetyl-2-bromo-benzenesulfonyl)-3-(4-bromo-2,6-diisopropyl-phenyl)-urea 5-Acetyl-2-bromo-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 177.2-179.1 °C. EXAMPLE 85 1-[2-Chloro-5-(1-hydroxy-ethyl)-benzenesulfonyl]-3-(2,6-diisopropyl-phenyl)-urea 2-Chloro-5-(1-hydroxy-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 154.0-156.0°C. EXAMPLE 86 1-[2-Chloro-5-(1-hydroxy-ethyl)-benzenesulfonyl]-3-(4-bromo-2,6-diisopropyl-phenyl)- urea 2-Chloro-5-(1 -hydroxy-ethyl)-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 144.3-146.2°C. EXAMPLE 87 1-[2-Chloro-5-(1-hydroxyimino-ethyl)-benzenesulfonyl]-3-(2,6-diisopropyl-phenyl)- urea 2-Chloro-5-(1-hydroxyimino-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 156.6-158.0°C. EXAMPLE 88 1-[2-Chloro-5-(1-hydroxyimino-ethyl)-benzenesulfonyl]-3-(4-bromo-2,6-diisopropyl- phenyl)-urea 2-Chloro-5-(1-hydroxyimino-ethyl)-benzenesulfonamide; 4-Bromo-2,6-diisopropyl- phenyl isocyanate. mp: 185.0-186.2°C. EXAMPLE 89 1-(5-Acetyl-2-chloro-benzenesulfonyl)-3-(2,6-diisopropyl-phenyl)-urea 5-Acetyl-2-chloro-benzenesulfoπamide; 2,6-Diisopropyl-phenyl isocyanate. mp 180.7-182.3°C. EXAMPLE 90 1-(5-Acetyl-2-chloro-benzenesulfonyl)-3-(4-bromo-2,6-diisopropyl-phenyl)-urea 5-Acetyl-2-chloro-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 175.2-176.5°C. EXAMPLE 91 3-[3-(2,6-Diisopropyl-phenyl)-ureidosulfonyl]-N,N-dimethyl-benzamide 3-Sulfonamido-N,N-dimethyl-benzamide; 2,6-Diisopropyl-phenyl isocyanate. mp 211.8-212.6°C. EXAMPLE 92 3-[3-(4-Bromo-2,6-diisopropyl-phenyl)-ureidosulfonyl]-N,N-dimethyl-benzamide 3-Sulfonamido-N,N-dimethyl-benzamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 225.7-227.6°C. EXAMPLE 93 1-(2,6-Diisopropyl-phenyl)-3-(3-formyl-benzenesulfonyl)-urea 3-Formyl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 108.3- 109.0°C. EXAMPLE 94 1-(2,6-Diisopropyl(hydroxyimino-methyl)-benzenesulfonyl]-urea 3-(Hydroxyimino-methyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 107.0-108.1°C. EXAMPLE 95 1-(2,6-Diisopropyl-phenyl)-3-[3-(1-methoxyimino-ethyl)-benzenesulfonyl]-urea 3-(1 -Methoxyimino-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 164.9-165.9°C. EXAMPLE 96 1-[3-(1-Benzyloxyimino-ethyl)-benzenesulfonyl]-3-(2,6-diisopropyl-phenyl)-urea 3-(1-Benzyloxyimino-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 136.5-139.0°C. EXAMPLE 97 1-(2,6-Diisopropyl-phenyl)-3-[3-(1-ethoxyimino-ethyl)-benzenesulfonyl]-urea 3-(1 -Ethoxyimino-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 156.9-158.4°C. EXAMPLE 98 (1-{3-[3-(2,6-Diisopropyl-phenyl)-ureidosulfonyl]-phenyl}-ethylideneaminooxy)-acetic acid 3-Sulfonamido-phenyl-(1 -ethylideneaminooxy)-acetic acid; 2,6-Diisopropyl-phenyl isocyanate. mp: 107.1-107.7°C. EXAMPLE 99 1-(2,6-Diisopropyl-phenyl)-3-[3-(1-hydroxyimino-ethyl)-benzenesulfonyl]-urea 3-(1-Hydroxyimino-ethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 131.0-132.6°C. EXAMPLE 100 1-(2,6-Diisopropyl-phenyl)-3-(3-methanesulfonyl-benzenesulfonyl)-urea 3-Methanesulfonyl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 99.5-100.6°C. EXAMPLE 101 1-(2,6-Diisopropyl-phenyl)-3-(3-methanesulfιnyl-benzenesulfonyl)-urea 3-Methanesulfinyl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 217.4-221.0°C. EXAMPLE 102 3-[3-(2,6-Diisopropyl-phenyl)-ureidosulfonyl]-benzenesulfonamide 3-Sulfonamido-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 131.4- 133.5°C. EXAMPLE 103 1-(4-Bromo-2,6-diisopropyl-phenyl)-3-(3-formyl-benzenesulfonyl)-urea 3-Formyl-benzenesulfonamide; 4-Bromo-2,6-diisopropyl-phenyl isocyanate. mp: 127.2-128.6°C. EXAMPLE 104 1-[3-(2-Acetyl-phenoxymethyl)-benzenesulfonyl]-3-(2,6-diisopropyl-phenyl)-urea 3-(2-Acetyl-phenoxymethyl)-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 124.2-125°C. EXAMPLE 105 1-[3-(1-Amino-ethyl)-benzenesulfonyl]-3-(2,6-diisopropyl-phenyl)-urea hydrochloride 3-(1-Amino-ethyl)-benzenesulfonamide hydrochloride; 2,6-Diisopropyl-phenyl isocyanate. mp: 210.6-212.9°C. EXAMPLE 106 1-(2,6-Diisopropyl-phenyl)-3-(3-furan-2-yl-benzenesulfonyl)-urea 3-Furan-2-yl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 196.6- 198.0°C. EXAMPLE 107 1-(2,6-Diisopropyl-phenyl)-3-(4-furan-2-yl-benzenesulfonyl)-urea 4-Furan-2-yl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 201.5- 202.7°C. EXAMPLE 108 1 -(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxyimino-ethyl)-thiophene-2- sulfonyl]-urea 4-(1 -Hydroxyimino-ethyl)-thiophene-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7- hexahydro-s-indacene. mp: 261.8-266.1°C. EXAMPLE 109 1-(4-Acetyl-thiophene-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea 4-Acetyl-thiophene-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s-indacene. mp: 270.2-272.3°C. EXAMPLE 110 1 -(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[5-(1 -hydroxy- 1 -methyl-ethyl)-thiophene- 3-sulfonyl]-urea 5-(1-Hydroxy-1-methyl-ethyl)-thiophene-3-sulfonamide; 4-lsocyanato-1 , 2,3, 5,6,7- hexahydro-s-indacene. mp: 149.5-154.8°C. EXAMPLE 111 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene-2-sulfonyl]-urea 4-(1 -Hydroxy- 1 -methyl-ethyl)-thiophene-2-sulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp = 124.6-127.4°C. EXAMPLE 112 1-(2,6-Diisopropyl-phenyl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]-urea 4-(1-Hydroxy-1-methyl-ethyl)-furan-2-sulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 121.3-126.4°C. EXAMPLE 113 1-(1 ,2,3,5,6J-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene- 2-sulfonylj-urea 4-(1 -Hydroxy-1 -methyl-ethyl)-thiophene-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7- hexahydro-s-indacene. mp: 133.1-134.0°C. EXAMPLE 114 1 -(1 ,2,3, 5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2- sulfonyl]-urea 4-(1 -Hydroxy-1 -methyl-ethyl)-furan-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7- hexahydro-s-indacene. mp: 153.8-154 °C. EXAMPLE 115 1 -(8-Chloro-1 ,2, 3, 5,6, 7-hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)- furan-2-sulfonyl]-urea 4-(1 -Hydroxy-1 -methyl-ethyl)-furan-2 -sulfonamide; 4-Chloro-8-isocyanato-1 ,2,3,5,6,7- hexahydro-s-indacene. mp: 163.7°C (decomposed). EXAMPLE 116 1-(4-Formyl-furan-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea 4-Formyl-furan-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s-indacene. mp: 281.3-284.1 °C. EXAMPLE 1 17 1 -(1 ,2, 3,5,6, 7-Hexahydro-s-indacen-4-yl)-3-(4-hydroxymethyl-thiophene-2-sulfonyl)- urea 4-Hydroxymethyl-thiophene-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s- indacene. mp: 273.9-275.8°C. EXAMPLE 118 1-(4-Formyl-thiophene-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea 4-Formyl-thiophene-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s-indacene. mp: 146.3-148.9°C. EXAMPLE 119 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[4-(1-hydroxyimino-ethyl)-thiophene-2-sulfonyl]- urea 4-(1-Hydroxyimino-ethyl)-thiophene-2-sulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 184.7-187.8°C. EXAMPLE 120 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[5-(1 -hydroxy-1 -methyl-ethyl)-furan-2-sulfonyl]- urea 5-(1 -Hydroxy-1 -methyl-ethyl)-furan-2-sulfonamide; 4-Chloro-2,6-diisopropyi-phenyl isocyanate. mp: 1 16.0-117.9°C. EXAMPLE 121 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-furan-2-sulfonyl]- urea 4-(1 -Hydroxy-1 -methyl-ethyl)-furan-2-sulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 127.4-129.2°C. EXAMPLE 122 l-(4-Chloro-2,6-diisopropyl-phenyl)-3-[4-(l-hydroxy-l-methyl-ethyl)- thiophene-2-sulfonyll-urea 4-(1 -Hydroxy-1 -methyl-ethyl)-thiophene-2-sulfonamide; 4-Chloro-2,6-diisopropyl- phenyl isocyanate. mp: 131.2-133.6°C. EXAMPLE 123 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[5-(1 -hydroxy-1 -methyl-ethyl)-thiophene-2- sulfonyl]-urea, sodium salt 5-(1 -Hydroxy-1 -methyl-ethyl)-thiophene-2-sulfonamide; 4-Chloro-2,6-diisopropyl- phenyl isocyanate. mp: 270.3-271.9°C. EXAMPLE 124 1-(4-[1 ,3]Dioxolan-2-yl-thiophene-2-sulfonyl)-3-(1 ,2,3,5,6J-hexahydro-s-indacen-4- yl)-urea 4-[1 ,3]Dioxolan-2-yl-thiophene-2 -sulfonamide; 4-lsocyanato-1 ,2,3,5,6, 7-hexahydro-s- indacene. mp: 224.7-226.6°C. EXAMPLE 125 1-(4-[1 ,3]Dioxolan-2-yl-furan-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)- urea 4-[1 ,3]Dioxolan-2-yl-furan-2-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s- indacene. mp: 183.5°C (decomposition). EXAMPLE 126 1 -[3-(4,5-Dihydro-1 H-imidazol-2-yl)-benzenesulfonyl]-3-(1 ,2,3,5,6,7-hexahydro-s- indacen-4-yl)-urea 3-(4,5-Dihydro-1 H-imidazol-2-yl)-benzenesulfonamide; 4-lsocyanato-1 ,2,3,5,6,7- hexahydro-s-indacene. mp: 241.0 C C (decomposition). EXAMPLE 127 1-(1 H-Benzoimidazole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea 1 H-Benzoimidazole-5-sulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s-indacene. mp: 239.0°C (decomposition). EXAMPLE 128 1 -(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[3-(1 -hydroxyimino-ethyl)- benzenesulfonyl]-urea 3-(1 -Hydroxyimino-ethyl)-benzenesulfonamide; 4-lsocyanato-1 ,2,3,5,6,7-hexahydro- s-indacene. mp: 249.8°C (decomposition). EXAMPLE 129 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-tert-butylsulfamoyl-benzenesulfonyl]urea Benzene-1 ,3-disulfonic acid amide tert-butyl-amide; 5-Chloro-2-isocyanto-1 ,3- diisopropyl-benzene. EXAMPLE 130 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-sulfamoyl-benzenesulfonyl]-urea Using a procedure similar to that of Preparation G, from 200 mg (0.38 mmole) of 1-(4- chloro-2,6-diisopropyl-phenyl)-3-[3-tert-butylsulfamoyl-benezenesulfonyl]-urea, there was obtained 92 mg of the titled compound as a white solid, mp: 172-177°C. EXAMPLE 131 Ethyl 2-(chlorosulfonyl)-4-furoate: In a four necked one liter flask with mechanical stirring and a nitrogen atmosphere was placed ethyl 3-furoate (50g, 0.357 moles) and methylene chloride (500 ml). This was cooled to -10°C and chlorosulfonic acid (24.92 ml, 0.375 moles) was added dropwise over five minutes. The temperature rose to -€°C. The cooling bath was removed and the reaction was allowed to warm slowly to room temperature. The reaction was stirred for 72 hours at which time it consisted of a green solution with a white solid slurry. This was cooled to -10°C and pyridine (31.7 ml, 0.393 moles) was added dropwise. This caused an exotherm which was controlled by the rate of addition with the temperature below 0 C C. After this addition, the reaction was a thick slurry. After cooling to -8°C, phosphorous pentachloride (PCI S ) (81.74g, 0.393 moles) was added in 15 g portions over a ten minute period. After stirring for 30 minutes cold, the bath was removed and the reaction was allowed to warm to room temperature. The mixture was stirred overnight. The reaction mixture was transferred to an addition funnel and added dropwise to water(IL) with stirring at room temperature. During the addition, the temperature rose to 38°C due to the hydrolysis of (POCI 3 ). The addition took 1.5 hours and the mixture was stirred for 45 minutes to assure complete hydrolysis. The layers were separated and the aqueous layer was extracted with methylene chloride (75 ml). The combined organics were washed with water and dried over sodium sulfate. The solution was filtered and evaporated in vacuo. to provide the sulfonyl chloride as an oil, 67.8 g, 80% yield. This was suitable as is for use in the next reaction. 1 HNMR of Ethyl 2-(chlorosulfonyl)-4-furoate (CDCI 3 , 400 MHZ) δ 8.21 (s, 1 ), 7.59 (s, 1 ), 4.35 (q, 2), 1.36 (t, 3), 13 CMR (CDC1 3 , 400 MHZ) δ 160.5, 151.4, 150.7, 121.6, 118.1 , 61.7, 14.2. EXAMPLE 132 Ethyl 4-furoate-2-sulfonic acid: Ethyl 3-furoate (13.5 ml, 0.1 moles) was dissolved in methylene chloride (150 ml) and stirred under nitrogen while being cooled to -10°C. Chlorosulfonic acid (8.3 ml, 0.125 moles) in methylene chloride (25 ml) was added dropwise over 15 minutes. The reaction was warmed to room temperature and stirred overnight. The precipitated, white solid was collected under nitrogen and washed with fresh methylene chloride. This was transferred rapidly to a round bottom flask (the material was hygroscopic) and dried under high vacuum. The yield of hygroscopic white solid was 14.1 g, 64%. When this material was dissolved in ethyl acetate and dried over sodium sulfate, the sodium salt was isolated as a white solid, mp 220°C (sinters) 245-248°C (dec.) IR (DRIFTS) 3507, 3459, 3155, 3127, 1731 , 1712, 1262, 1231 , 1205 CM "1 ). 1 HMR (D 2 0, 300 MHZ) δ 8.19 (s, 1 ), 7.10 (s, 1 ), 4.27 (q, 2), 1.30 (t,3). 13 CMR (D 2 0, 300 MHZ) δ 164.4, 152.9, 149.8, 119.6, 110.5, 62.2, 13.4. Analysis Calcd for C 7 H 7 0 6 SNa 0.5 H20: C, 33.46; H, 3.21 ; S, 12.76; Na, 9.15. Found: C, 33.77; H, 3.00; Na, 8.97; S, 12.49. EXAMPLE 133 Ethyl 4-furoate-2-sulfonic acid (0.5 g, 2.77 mmoles) was added to (4 ml) pyridine under nitrogen. The sulfonic acid dissolved and then a precipitate formed. The slurry was diluted with ether (18 ml) and stirred. The solid salt was collected, washed with ether and dried. The yield of the pyridinium salt was 0.6 g, 91 %, mp 145 -146°C IR (DRIFTS) 1726, 1289,1259, 1198, 1170, 1134, 1028 CM "1 , 1 HMR (D 2 0, 300 MHz) δ 8.70 (d, 2), 8.54 (t, 1 ), 8.11 (s, 1 ), 7.99 (t, 2), 6.99 (s, 1 ), 4.20 (q, 2), 1.23 (t, 3). 13 CMR (D 2 0, 400 Mhz) δ 167.0, 156.0, 152.4, 150.0, 143.9, 130.3, 122.3, 113.1 , 64.9, 16.2. Analysis Calcd for C 12 H 13 Nθ 6 S: C, 48.15 H, 4.38; N, 4.68; S, 10.71. Found: C, 48.07; H, 4.33; N, 4.70; S, 10.71. EXAMPLE 134 Ethyl 2-(sulfonamide)-4-furoate: Ammonium bicarbonate (89.93 g, 1.137 moles) was dissolved in water (1.5 L). This caused the temperature to fall to 17.5°C. This was stirred while a solution of sulfonyl chloride (67.8 g, 0.284 moles) in acetone (500 ml) was added dropwise over 16 minutes. During the addition, the temperature rose to 25°C. After 65 minutes, thin layer chromatography (tic) indicated that the reaction was complete (silica gel, 4:1 hexanes: ethyl acetate). Ethyl acetate (500 ml) was added and the pH was lowered to 2.0 with cone, hydrochloric acid (HCl) added dropwise (appr. 53 ml). The layers were separated and the aqueous layer was saturated with sodium chloride (NaCI) and extracted with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The extract was concentrated to about 175 ml and passed through a pad of silica gel which was washed thoroughly with ethyl acetate (final volume 650 ml). The ethyl acetate was removed in vacuo and the residue was taken up in hot ethyl acetate (150 ml) and filtered to remove a haze. This was concentrated to ca. 100 ml and hexanes (250 ml) was added dropwise. The resulting slurry was stirred for 30 minutes, then collected and washed with hexanes/ethyl acetate (4:1 ). The sulfonamide was air dried. 39.9 g, 64% yield, mp 131-132.5°C. IR (DRIFTS) 3340, 3261 , 3150, 1697, 1579, 1561 , 1364, 1219, 1195 cm "1 . 1 HNMR (DMSO-d6, 300 MHz) δ 8.62 (s, 1 ), 7.94 (s, 2, NH 2 ), 4.25 (q, 2), 1.27 (t, 3). 13 CMR (DMSO-d 6 , 300 MHz) δ 161.7, 153.9, 150.8, 120.0, 112.0, 61.2, 14.5. Analysis Calcd for C7H9NO5S: C, 38.35; H, 4.14; N, 6.39; S, 14.62. Found: C, 38.42; H, 4.08; N, 6.31 ; S, 14.70. EXAMPLE 135 4-(1 -Hydroxy-1 -methyl -ethyl)-furan-2-sulfonamide: The sulfonamide ester of Example IV (25 g, 0.114 moles) was dissolved in dry tetrahydrofuran (1 L) under nitrogen. The solution was cooled to -10°C and stirred while methyl magnesium chloride (171 ml, 3 M in tetrahydrofuran) was added dropwise over 5 minutes to give a clear solution. The cooling bath was removed and the reaction allowed to warm to room temperature. During the warm-up the reaction mixture thickened and then became more fluid. After six hours TLC showed that reaction was complete. The reaction was cooled to -5°C and treated with a solution of ammonium chloride (137.4 g in 700 ml of water). The initial quench caused some exotherm and gas emission during the first 50 ml. The remaining solution was added quickly. After the quench was complete, a clear solution resulted. Ethyl acetate (500 ml) was added and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (500 ml). The combined organics were washed with brine and dried over sodium sulfate. The solution was filtered and concentrated to low volume. Isopropyl ether(IPE) was added and the solution was concentrated again. During the process, the product was an oil, then solidified. More IPE was added and the slurry was stirred 3 hours. The solid was collected and the filtrate was evaporated to a solid. The solid from the filtrate was triturated with methylene chloride to provide more of the desired product which was combined with the IPE solid and triturated with methylene chloride to afford the sulfonamide alcohol 4-(1-hydroxyl-1-methyl-ethyl-)furan-2-sulfonamide as a solid, 19.98 g, 85% yield, mp 92 (sintered) 99.5-101.5°C. 1 HNMR (DMSO-d6, 300 Mhz) δ 151.7, 140.3, 136.6, 112.1 , 66.6, 31.0. Analysis Calcd for C 7 H H NO 4 S: C, 40.96; H, 5.40; N.6.82; S, 15.62. Found: C, 40.73; H, 5.14; N, 6.82; S, 15.53. 4-Acetyl-furan-2-sulfonamide: From the filtrates of this reaction were isolated small amounts of 4-acetyl-furan-2- sulfonamide as a by product, mp 135-6°C. IR (DRIFTS) 333, 3228, 3144, 1671 , 1572, 1355, 1177, 1129 cm '1 . 1 HNMR (DMSO-d6, 300 MHz) δ 8.77 (s, 1 ) 7.93 (s, 2), 7.13 (s, 1 ), 2.44 (s, 3). 13 CMR (DMSO " -d 6 , 400 MHz) δ 192.3, 151.5, 128.2, 110.8, 28.3. Analysis Calcd for C 6 H 7 N0 4 S: C, 38.09; H, 3.73; N, 7.40: S. 16.95. Found: C, 38.30; H, 3.63; N, 7.36; S, 16.94. EXAMPLE 136 Sodium salt of 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl- ethyl)-furan-2-sulfonyl]-urea; The sulfonamide (5 g, 0.0244 mole) was dissolved in tetrahydrofuran (THF) (50 ml) under nitrogen atmosphere. Solid sodium methoxide (1.32 g, 0.0244 mole) was added in one portion. This caused a suspension to form and the color turned to light brown (a small amount of an oily solid is sometimes seen at this point). This mixture was stirred for several hours. The isocyanate (4.77 g, 0.0244 mole) was added as an neat oil. The sodium salt suspension mostly went into solution as the isocyanate was added and a new precipitate formed. After thirty minutes, the reaction still contained a little gummy solids from the sodium methoxide addition. The reaction mixture was heated to reflux for four hours, was cooled to room temperature and the crude sodium salt of substituted sulfonyl urea derivatives of U.S. Patent Application 60/036,979 was collected and washed with fresh THF. The solids were dried under nitrogen and then under high vacuum. The crude weight was 10.66 g, > 100%. NMR showed this was the THF solvate. The crude sodium salt (5 g, 0.0106 mole) was dissolved in hot isopropanol (100 ml). The solution was filtered through celite and the celite cake was washed with hot isopropanol (2 X 40 ml). The filtrate was concentrated to 30 -35 ml and the solids which precipitated were granulated for 30 minutes at room temperature, then cooled in an ice water bath. The solids were collected and washed with cold isopropanol. After drying in vacuo, the solids weighed 4.9 g. NMR in D20 gave a clear solution and showed the presence of the isopropanol solvate. EXAMPLE 137 Alternative preparation of sodium salt of 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3- [4-(1 -hydroxy-1 -methyl-ethyl)-furan-2-sulfonyl]-urea; A 500 ml three necked flask was equipped with a magnetic stirrer, a thermometer, and two addition funnels. To the flask under a nitrogen atmosphere was added dry acetonitrile (100 ml), di-t-butyl dicarbonate (30.52 g, 0.14 mole). A solution of dimethylaminopyridine (1.83 g, 0.015 mole) in acetonitrile (25 ml) was added over 3.5 minutes. A slight exotherm of 2 degrees was seen. After stirring for two minutes, a solution of 4-amino-s-hydrindacene (17.1 g, 0.0988 mole) in acetontrile (100 ml) was added over six minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 25 minutes. This mixture was added to a slurry of the preformed sodium salt of 4-(1-Hydroxy-1-methyl-ethyl)-furan-2-sulfonamide (23.3 g, 0.098 mole; prepared by addition of one equiv. of sodium methoide to the sulfonamide in methanol solution followed by evaporation) in acetontrile (50 ml). The intiial reaction flask was washed with 2 x 40 of acetontrile to aid the complete transfer. The combined reaction mixture was stirred at room temperature overnight. The reaction mixture was heated to a gentle reflux for 1.5 hours to help insure complete reaction. The reaction slurry was cooled to room temperature and the solids collected and washed with acetonitrile and dried in vacuo to give 30.4 g of crude sodium salt. The sodium salt was triturated with ethyl acetate and recovered by filtration. The sodium salt (10.25 g, 0.02213 mole, corrected for ethyl acetate content) was dissolved in water (150 ml) and treated with a small amount of Darco. The solution was filtered through a millipore filter. The aqueous filtrate was acidified with 2N HCl to precipitate the free sulfonylurea. The product was collected by filtration, washed with water and dried in dried. The yield was 8.33 g, 81%. EXAMPLE 138 Synthesis of [ 14 C]-1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[2-fluoro-5- oxiranylbenzenesulfonyl]-urea and [ 14 C]-1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[2-fluoro- 5-oxiranylbenzenesulfonyl]-urea; [ 14 C]-labeled derivatives were prepared by coupling 2-fluoro-5-oxiranyl- benzenesulfonamide with [ 1 C]4-isocyanato-1 ,2,3,5,6,7-hexahydro-5-indacene and [ 1 C]-5- chloro-2-isocyanato-1 ,3-diisopropyl-benzene using sodium hydride in tetrahydrofuran. The labeled isocyanates were prepared by reaction of 14 C-phosgene with either 4-chloro-2,6- diisopropyl-phenylamine or 1 ,2,3, 5,6, 7-hexahydro-5-indacen-4-ylamine and triethylamine in tetrahydrofuran or toluene as shown in Scheme 1. The synthesis of 2-fluoro-5-oxiranyl-benzenesulfonamide is is accomplished using a Dean-Stark distillation of a toluene solution of commercially available 1 -(3-bromo-4-fluoro- phenyl)-ethanone I, ethylene glycol and a trace of p-toluenesulfonic acid to give 2-(3-bromo-4- fluoro-phenyl)-2-methyl-(1 ,3)dioxolane. Successive treatment of 2-(3-bromo-4-fluoro-phenyl)- 2-rπethyl-(1 ,3)dioxolane with n-butyllithium in tetrahydrofuran at -78°C, sulfur dioxide, N- chlorosuccinimide in dichloromethane and aqueous ammonium hydroxide gave 2-fluoro-5-(2- methyl-[1 ,3]dioxolan-2-yl)-benzenesulfonamide. Bromination of 2-fluoro-5-(2-methyl- [1 ,3]dioxolan-2-yl)-benzenesulfonamide with phenyltrimethylammonium tribromide in acetronitrile gave 5-(2-bromomethyl-[1 ,3]dioxolan-2-yl)-2-fluoro-benzenesulfonamide which was treated with aqueous hydrochloric acid in dioxane to give 5-bromoacetyl-2-fluoro- benzenesulfonamide. Reduction of 5-bromoacetyl-2-fluoro-benzenesulfonamide with sodium borohydride in methanol, followed by treatment with dilute sodium hydroxide gave the desired product. EXAMPLE 139 2-(3-Bromo-4-fluoro-phenyl)-2-methyl-(1 ,3)dioxolane . A solution of 25 g (0.115 mole) of 1 -(3-bromo-4-fluoro-phenyl)-ethanone (Fluorochem), 20 mL (0.345 mole) of ethylene glycol and a trace of p-toluenesulfonic acid in 200 mL of toluene was heated at reflux for 12 hours with Dean-Stark separation of water. The reaction was cooled to room temperature, washed with a dilute sodium bicarbonate solution, dried over Na 2 S0 and the solvent was evaporated to give 30 g of the desired product (100%) as an oil (TLC:CH 2 CI 2 single spot material R, 0.040). 1 H-N R (300 MHz DMSO-D 6 ) d: (1.52, s, 3H), (3.67, m, 2H), (3.95, m, 2H), (7.34, m, 1 H), (7.40, m, 1 H), 7.63, m, 1 H). EXAMPLE 140 2-Fluoro-5(2-methyl-[1 ,3]dioxolan-2-yl)-benzenesulfonamide. n-BuLi [1.6 M in hexane, 50 mL (0.08 mole)] was added dropwise to a solution of 20.88 g (0.08 mole) of 2-(3- bromo-4-fluoro-phenyl)-2-methyl-(1 ,3)dioxolane in 200 mL tetrahydrofuran at -78°C. After stirring for 2 hrs at -78°C, S0 2 was bubbled in for 15 minutes. The reaction was allowed to warm to room temperature and stirred overnight. A solution of 10.8 g (0.08 mole) of NCS in 150 mL of CH 2 CI 2 was added and the reaction stirred for 1 hour. The volatiles were evaporated in vacuo, and the brown residue was slurried with CH 2 CI 2 and filtered. The filtrate was treated with 200 mL of 30% NH 4 OH and stirred for 3 hours. The CH 2 CI 2 layer was separated, dried over Na 2 S0 4 and evaporated. The residue was triturated with CH 2 CI 2 and filtered to give 8.1 g ofthe desired product (77%); mp 149-150°C (TLC: CH 2 CI 2 /MeOH::9/1 single-spot material R, 0.5). 1 H NMR (300 MHz, DMSO-D 6 ) d: (1.60, s, 3H), (3.70, m, 2H). (4.05, m, 2H), (7.41 , t, 1 H), (7.71 , broad s, 3H), (7.84, dd, 1 H). EXAMPLE 141 5-(2-bromomethyl-[1 ,3]dioxolan-2-yl)-2-fluoro-benzenesulfonamide. A solution of 8.4 g (0.0225 mole) of phenyltrimethylammonium tribromide in 20 mL of CH 3 CN was added dropwise to a solution of 5.2 g (0.022 mole) 2-flυoro-5(2-methyl-[1 ,3]dioxolan-2-yl)- benzenesulfonamide in 100 mL of CH 3 CN. The reaction was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo. The residue was dissolved in EtOAc, washed with water, dried over Na 2 S0 and evaporated. The residue was purified by column chromatography on silica gel eluting with CH 2 CI 2 /Et 2 0::9/1 to give 4.6 g of the desired product (62%) as an oil (CH 2 CI 2 /Et 2 0::9/1 single-spot material R f 0.30). 1 H NMR (300 MHz CDCI 3 ) d: (3.68, s, 2H), (3.80,m , 2H), (4.21 , m, 2H), 5.15, broad s, 2H), (7.26, t, 1 H), (7.75, m, 1 H), 8.15, dd, 1 H). EXAMPLE 142 5-Bromoacetyl-2-fluoro-benzenesulfonamide. A solution of 1.5 g (4.4 mmol) of 5-(2- bromomethyl-[1 ,3]dioxolan-2-yl)-2-fluoro-benzenesulfonamide in 50 mL of dioxane and 10 mL of 2N HCl was heated at reflux for 5 hours then cooled to room temperature. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc, washed with H 2 0, and dried over Na 2 S0 4 . The residue was purified by column chromatography on silica gel eluting with EtOAc to give 900 mg of material which was recrystallized from MeOAc to give 700 mg of the desired product (54%); mp 153-158°C (TLC: CH 2 CI 2 /Et 2 0::7/3 single-spot material R f 0.60) 1 H NMR (300 MHz DMSO-D 6 d: (5.20, s 2H), (7.63, t, 1 H), (7.86, broad s, 2H), (8.32, m, 2H). EXAMPLE 143 2-Fluoro-5-oxiranyl-benzenesulfonamide. A solution of 0.5 g (1.7 mmol) of 5- bromoacetyl-2-fluoro-benzenesulfonamide in 20 mL MeOH was cooled to 0°C. NaBH 26 mg (0.67 mmol) was added and the reaction was stirred at 0°C for 15 minutes. 4 mL of 1 N NaOH was added and the reaction was stirred at 0°C for 4 hours. The reaction was adjusted to pH 6 by addition of dilute HCl. The volatiles were evaporated and the residue dissolved in EtOAc, washed with H 2 0, dried over Na 2 S0 4 and evaporated. The product was purified by column chromatography on silica gel eluting with CH 2 CI 2 /MeOH::9/1 to give 180 mg of the desired product (48%); mp 100-103°C (TLC:CH 2 CI 2 /MeOH::9/1 single-spot material R f 0.65). 1 H-NMR (300 MHz DMSO-D 6 ) d: (2.82, m, 1 H), (3.14, m, 1 H), (4.06, m, 1 H), (7.40, t, 1 H), (7.56, m, 1 H), (7.66, m, 3H). EXAMPLE 144 4-Chloro-2-isocyanato-1 ,3-diisopropyl-benzene (non-labeled). To a solution of 8.9 g (0.042 mole) of 4-chloro-2,6-diisopropyl-phenylamine (which is prepared in quantitative yield by treatment of commercially available 2,6-diisopropylamine with N-chlorosuccinimide and N.N-dimethylformamide) and 4.66 g (0.046 mole) of triethylamine in 125 mL of tetrahydrofuran was added 23.8 mL (0.046 mole) of a 1.93 M solution of phosgene in toluene. The reaction was stirred at room temperature for 15 minutes, then at 70°C for 15 minutes. The solvents were evaporated in vacuo. The residue was dissolved in hexane and purified on a plug of silica gel eluting with 10% CH 2 CI 2 /hexane to give 9.45 g of the desired product (95%) as an oil (TLC:Hex/ CH 2 CI 2 ::2/1 single spot material R f 0.70). 1 H-NMR (300 MHz CDCI 3 ) d: (1.20, d, 12H), (3.19, septet, 2H), (7.06, s, 2H). (2.13, t, 4H), (2.85, m, 8H), (6.93, s, 1 H). EXAMPLE 145 4-lsocyanato-1 ,2,3,5,6,7-hexahydro-s-indacene (non-labeled). To a solution of 1.77 g (0.01 mole) of 1 ,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (Vejdelek et al. Coll. Czech Chem. Comm. 42: 3094 (1977) and 1.11 g (0.011 mole) of triethylamine in 25 mL of tetrahydrofuran was added 5.7 mLv(0.011 mole) of a 1.93 M solution of phosgene in toluene. The reaction was stirred at room temperature for 15 minutes and at 70 C C for 15 minutes. The solvents were evaporated in vacuo. The residue was dissolved in hexane and purified on a plug of silica gel eluting with 10% CH 2 CI 2 /hexane to give 1.79 g of the desired product (90%); mp 40- 41 °C (TLC:Hex/ CH 2 CI 2 ::2/1 single-spot material R f 0.70). 1 H-NMR (300 MHz CDCI 3 ) d: (2.13, t, 4H), (2.85, m, 8H), (6.93, s, 1 H). EXAMPLE 146 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[2-fluoro-5-oxiranylbenzene-sulfonyl]-urea (non- labeled). Sodium hydride [60% dispersion in mineral oil, 23 mg (0.57 mmol)] was added to a solution of 113 mg (0.52 mmol) of 2-fluoro-5-oxiranyl-benzenesulfonamide and 136 mg (0.57 mmol) of 4-chloro-2-isocyanato-1 ,3-diisopropyl-benzene in 10 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the solvent was evaporated in vacuo. The residue was acidified with 2N HCl, then extracted with EtOAc. The EtOAc layer was dried over Na 2 S0 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with CH 2 CI 2 /MeOH::9/1 to give 190 mg of the desired product (81%); mp 126-130°C (TLC:CH 2 CI 2 /MeOH::9/1 single-spot material R, .70). 1 H-NMR (300 MHz DMSO- D 6 ) d: (0.97, m, 12H), (2.76, m, 1 H), (2.93, m, 1 H), (3.10, m, 1 H), (4.05, m, 1 H), (7.04, s, 2H), (7.35, m, 1 H), (7.50, m, 1 H), (7.77, m, 2H). EXAMPLE 147 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[2-fluoro-5-oxiranyl-benzenesulfonyl]-urea (non-labeled). Sodium hydride [60% dispersion in mineral oil, 30 mg (0.75 mmol)] was added to a solution of 148 mg (0.68 mmol) of 2-fluoro-5-oxiranyl-benzenesulfonamide and 150 mg (0.75 mmol) of 4-isocyanato-1 ,2,3,5,6,7-hexahydro-s-indacene. After stirring at room temperature for 12 hours, the solvent was evaporated in vacuo. The residue was acidified with 2N HCl, then extracted with EtOAc. The EtOAc layer was dried over Na 2 S0 4 and evaporated in vacuo. The residue was triturated with hexane and filtered to give 210 mg of the desired product (75%); mp 97-102°C (TLC:CH 2 CI 2 /MeOH::9/1 single-spot material R f .65). 1 H-NMR (300 MHz DMSO-D 6 ) d: (1.96, m, 4H), (2.47, m, 4H), (2.74, m, 5H), (3.11 , m, 1 H), (4.06, m, 1 H), (6.90, s, 1 H), (7.49, t, 1 H), (7.61 , m, 1 H), (7.78, dd, 1 H), (8.05, s, 1 H). EXAMPLE 148 [ 14 C]4-Chloro-2-isocyanato-1 ,3-diisopropyl-benzene. 4-Chloro-2,6-diisopropyl- phenylamine hydrochloride (0.045 g, 0.18 mmol, 2 eq) was dispersed in ether, and triethylamine (57 mL, 0.41 mmol, 4.5 eq) was added. The solution was filtered through a cotton plug, and most of the ether evaporated in vacuo. The residual clear colorless oil was taken up in dry toluene (3 mL) and fitted to a vacuum manifold. The solution was degassed, cooled in a liquid nitrogen bath and evacuated. An ampoule containing [ 14 C]phosgene gas (5 mCi at 55 mCi/mmol) was fitted to the manifold, and the system evacuated. The manifold was then isolated from the pump, the ampoule broken, and the [ 14 C]phosgene allowed to vacuum transfer into the cooled reaction vessel. After 20 minutes, the cold bath was removed, and the reaction mixture warmed to room temperature. It was then backflushed with nitrogen and heated to 80°C for one hour, after which time, no starting material remained (radio-TLC). The mixture was cooled to room temperature, and concentrated in vacuo. The yellow oil was filtered through a small plug of silica gel (hexanes) to give 5 mCi of [ 14 C]5- chloro-2-isocyanto-1 ,3-diisopropylbenzene, >99% radiochemically pure by radio-TLC (hexanes). EXAMPLE 149 [ 14 C]4-isocyanto-1 ,2,3,5,6,7-hexahydro-s-indacene. [ 14 C]Phosgene (35 mCi at 57 mCi/mmol) as a solution in toluene (35 mL) was cooled to 0°C, and triethylamine (0.50 mL, 3.6 mmol, 6 eq) and 1 ,2,3,5,6,7-hexahydro-5-indacen-4-ylamine (0.17 g, 0.1 mmol, 1.6 eq) were added as a solution in toluene (2 mL). After 15 minutes, the reaction was removed from the ice bath and let warm to room temperature over 30 minutes after which time radio-TLC analysis indicated desired product was present in 93%. The reaction mixture was concentrated in vacuo, and filtered through a plug of silica gel (hexanes). Significant white radioactive solid formed which did not dissolve in the hexanes. Concentration of the filtrate gave 9 mCi of [ 14 C]4-isocyanto-1 ,2,3,5,6,7-hexahydro-5-indacene, which was >99% pure by radio-TLC (hexanes). EXAMPLE 150 [ 14 C]-1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]-urea. The [ 1 C]5-chloro-2-isocyanto-1 ,3-diisopropylbenzene (1.08 mCi at 55 mCi/mmol) and 2- fluoro-5-oxiranylbenzenesulfonamide (95 mg, 0.022 mmol, 1.1 eq) were dissolved in freshly distilled tetrahydrofuran and sodium hydride (2 mg) was added. After 5 minutes, radio-TLC indicated complete reaction. The reaction mixture was concentrated in vacuo, dissolved in water (5 mL) and extracted with ether. The aqueous was then acidified with 2N HCl, and extracted with ethyl acetate. The combined ethyl acetate layers were dried, filtered, concentrated and the residue chromatographed (silica gel, EtOAc) to give 0.84 mCi of the desired compound (>99% pure radio-TLC, EtOAc). EXAMPLE 151 [ 14 C]-1 -(1 ,2,3, 5,6,7-Hexahydro-s-indacen-4-yl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]- urea. [ 1 C]4-lsocyanto-1 ,2,3,5,6,7-hexahydro-5-indacene (0.9 mCi at 57 mCi/mmol) was dissolved in tetrahydrofuran (5 mL), and 2-fluoro-5-oxiranylbenzenesulfonamide (4.2 mg, 0.19 mmol, 1.2 eq) was added, followed by sodium hydride (2 mg). After 15 minutes, no starting material remained by radio-TLC. The reaction mixture was concentrated in vacuo, and the residue was dispersed in 0.2 M HCl (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried, filtered, concentrated and the residue chromatographed (EtOAc) to give 0.58 mCi of the desired compound (>99% pure by radio-TLC, EtOAc). ICE Inhibitors Useful in the Invention United States Patent Nos. 5,656,627, 5,847,135, 5,756,466, 5,716,929 and 5,874,424 disclose several classes of ICE inhibitor compounds characterized by hydrogen-bonding, hydrophobic, and electronegative moieties configured so as to bind to the ICE receptor site. These patents disclose generic combinations of the particular ICE inhibitors with inhibitors and antagonists of cytokines, but does not disclose or suggest the combination of an ICE and IL-1ra that provides the unexpected synergy of the compositions and methods of the present invention. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising IL-1ra and one or more ICE inhibitor compounds of United States Patent Nos. 5,656,627, 5,847,135, 5,756,466, 5,716,929 and 5,874,424. United States Patent Nos. 5,656,627, 5,847,135, 5,756,466, 5,716,929 and 5,874,424 are incorporated herein by reference in their entireties for all purposes as if fully set forth herein. United States Patent No. 5,585,357 discloses a class of substituted pyrazole ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,585,357. United States Patent No. 5,585,357 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United States Patent 5,434,248 discloses a class of peptidyl aldehyde ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,434,248. United States Patent No. 5,434,248 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United States Patent Nos. 5,462,939 and 5,585,486 disclose a class of peptidic ketone ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent Nos.5,462,939 and 5,585,486. United States Patent Nos. 5,462,939 and 5,585,486 are incorporated herein by reference in their entireties for all purposes as if fully set forth. United states patent 5,411 ,985 discloses gamma-pyrone-3-acetic acid as an ICE inhibitor. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1 ra and gamma-pyrone-3-acetic acid. United States Patent No. 5,411 ,985 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,834,514 discloses a class of halomethyl amides as ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,834,514. United States Patent No. 5,834,514 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,739,279 discloses a class of peptidyl derivatives of 4-amino-2,2-difluoro-8-oxo-1 ,6-hexanedioic acid as ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1 ra and one or more ICE inhibitor compounds of United States Patent No. 5,739,279. United States Patent No. 5,739,279 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,843,904 discloses a class of peptidyl ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,843,904. United States Patent No. 5,843,904 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,670,494 discloses a class of substituted pyrimidine ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,670,494. United States Patent No. 5,670,494 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,744,451 discloses a class of substituted glutamic acid ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,744,451. United States Patent No. 5,744,451 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,843,905 discloses a class of substituted glutamic acid ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent No. 5,843,905. United States Patent No. 5,843,905 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United states patent 5,565,430 discloses a class of azaaspartic acid analogs as ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1 ra and one or more ICE inhibitor compounds of United States Patent No. 5,565,430. United States Patent No. 5,565,430 is incorporated herein by reference in its entirety for all purposes as if fully set forth. United States Patent Nos. 5,552,400 and 5,639,745 disclose a class of fused-bicyclic lactam ICE inhibitors. One embodiment of the present invention provides for compositions and methods of treatment using compositions comprising an IL-1ra and one or more ICE inhibitor compounds of United States Patent Nos.5,552,400 and 5,639,745. United States Patent Nos. 5,552,400 and 5,639,745 are incorporated herein by reference in their entireties for all purposes as if fully set forth. IL-1 polypeptides, such as the soluble form of IL-1ra beta polypeptides, and agonists and antagonist peptides, may be formulated in combination with an IL-1 processing and release inhibiting agent and a suitable pharmaceutical carrier. Such formulations comprise a therapeutically effective amount of the polypeptide and IL-1 processing and release inhibiting agent, and a pharmaceutically acceptable carrier or excipient. Such carriers include but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. Formulation should suit the mode of administration, and is well within the skill of the art. The invention further relates to pharmaceutical packs and kits comprising one or more containers filled with one or more of the ingredients of the aforementioned compositions of the invention. Preferred forms of systemic administration of the pharmaceutical compositions include injection, typically by subcutaneous injection. Other injection routes, such as intravenous, intramuscular, or intraperitoneal, can be used. Alternative means for systemic administration include transmucosal and transdermal administration using penetrants such as bile salts or fusidic acids or other detergents. In addition, if properly formulated in enteric or encapsulated formulations, oral administration may also be possible. Administration of these compounds may also be topical and/or localized, in the form of salves, pastes, gels and the like. Preferably, the IL-1ra is administered by subcutaneous injection while the IL-1 processing and release inhibitting agent is administered orally. For subcutaneous injection, a preferred pharmaceutical composition consists of IL-1ra in sterile water at a pH of 6.5, and containing sodium chloride, sodium citrate, polysorbate 80, disodium edtate, and citric acid. For intravenous injection, the IL-1 ra is preferably in a 10mM citrate buffer, with EDTA and sodium chloride. The dosage range required depends on the choice of IL-1 ra polypeptide and IL-1 processing and releasing inhibitor, the route of administration, the nature of the formulation, the nature of the subject's condition, and the judgment of the attending practitioner. Suitable once or twice twice-daily dosages for the IL-1 ra polypeptides, however, are in the range of 1-1000 μg/kg of subject in combination with 50-1200 mg of of an IL-1 processing and release inhibiting agent. Wide variations in the needed dosage, however, are to be expected in view of the variety of compounds available and the differing efficiencies of various routes of administration. Adjunctive administration, of the IL-1 processing and release inhibting agent will reduce the amount of IL-1ra polypeptide needed by an amount in the range of 50-90 % of that required in the absence of the IL-1 processing and release inhibting agent. Oral administration would be expected to require higher dosages than administration by intravenous injection. Variations in these dosage levels can be made using standard empirical routines for optimization, as is well understood in the art. Compositions comprising IL-1ra polypeptides and IL-1 processing and release agents can be administered in a wide variety of dosage forms. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purpose. Solid compositions of a similar type may also be employed as filters in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient in usually prepared. Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Thus, one preferred embodiment of the invention provides a pharmaceutical composition comprising an IL-1 ra polypeptide or variant thereof, a non-steroidal IL-1 processing and release inhibiting agent, and one or more ingredients selected from the group consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a wetting agent, a buffering agent, an emulsifying agent, and a binding agent. In another preferred embodiment, a kit is provided comprising in one or more containers an IL-1ra polypeptide or variant thereof and a non-steroidal IL-1 processing and release inhibiting agent. (1) INFORMATION FOR SEQ ID NO 2 of United States Patent No. 5,863,769: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 169 amino acids (B) TYPE: amino acid (C) STRANDEDNESS : single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO 2 of United States Patent No. 5,863,769: MetArgGlyThrProGlyAspAlaAspGlyGlyGlyArgAlaValTyr 1 5 10 15 GlnSerMetCysLysProIleThrGlyThrlleAsnAspLeuAsnGln 20 25 30 GlnValTrpThrLeuGlnGlyGlnAsnLeuValAlaValProArgSer 35 40 45 AspSerValThrProValThrValAlaVallleThrCysLysTyrPro 50 55 60 GluAlaLeuGluGlnGlyArgGlyAspProIleTyrLeuGlylleGln 65 70 75 80 AsnProGluMetCysLeuTyrCysGluLysValGlyGluGlnProThr 85 90 95 LeuGlnLeuLysGluGlnLysIleMetAspLeuTyrGlyGlnProGl 100 105 110 ProValLysProPheLeuPheTyrArgAlaLysThrGlyArgThrSer 115 120 125 ThrLeuGluSerValAlaPheProAspTrpPhelleAlaSerSerLys 130 135 140 ArgAspGlnProIlelleLeuThrSerGluLeuGlyLysSerTyrAsn 145 150 155 160 ThrAlaPheGluLeuAsnlleAsnAsp 165

Claims: CLAIMS 1. A method for treating or preventing IL-1 mediated disease states comprising adjunctively administering to a mammal in need of such treatment effective amounts of an IL- 1 ra polypeptide or variant thereof and a non-steroidal IL-1 processing and release inhibiting > agent. 2. The method according to claim 1 , wherein the IL-1 processing and release inhibitor is a diarylsulfonylurea. 3. The method according to claim 1 , wherein the IL-1 processing and release inhibitor is a diarylsulfonylurea of formula I R NH NH I or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently a group of formula II wherein the broken lines ( — ) represent optional double bonds; n is 0, 1 , 2 or 3; A, B, D, E and G are each independently oxygen, sulfur, nitrogen or CR 5 R 6 wherein R 5 and R 6 are each independently selected from (1 ) hydrogen, (2) (d-C 6 )alkyl optionally substituted by one or two groups selected from (d-C 6 )alkylamino, (d-C 6 )alkylthio, (d- C 6 )alkoxy, hydroxy, cyano, perfluoro(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 - C 10 )arylamino, (C 6 -C 10 )arylthio, (C 6 -C 10 )aryloxy wherein the aryl group is optionally substituted by (d-C 6 )alkoxy, (C 1 -C 6 )acyl, carboxy, hydroxy or halo; (C 5 -C 9 )heteroarylamino, (C 5 - C 9 )heteroarylthio, (C 5 -C 9 )heteroaryloxy, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 3 -C 6 )cycloalkyl, hydroxy, piperazinyl, (C 5 -C 9 )heteroaryl(d-C 6 )alkoxy, (d-C 6 )acylamino, (C r C 6 )acylthio, (d-C 6 )acyloxy, (d-C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfιnyl, (d-C 6 )alkylsulfonyl, (C 6 - C 10 )arylsulfonyl, amino, (d-C 6 )alkylamino or ((Cι-C 6 )alkyl) 2 amino; (3) halo, (4) cyano, (5) amino, (6) hydroxy, (7) perfluoro(C 1 -C 6 )alkyl, (8) perfluoro(C 1 -C 6 )alkoxy, (9) (C 2 -C 6 )alkenyl, (10) carboxy(C 2 -C 6 )alkenyl, (11 ) (C 2 -C 6 )alkynyl, (12) (d-C 6 )alkylamino, (13) ((d- C 6 )alkyl) 2 amino, (14) (d-C 6 )alkylsulfonylamido, (15) (d-C 6 )alkylsulfinyl, (16) (d- C 6 )alkylsulfonyl, (17) aminosulfonyl, (18) (d-C 6 )alkylaminosulfonyl, (19) ((d- C 6 )alkyl) 2 aminosulfonyl, (20) (d-C 6 )alkylthio, (21 ) (C C 6 )alkoxy, (22) perfluoro(d-C 6 )alkyl, (23) (C 6 -C 10 )aryl, (24) (C 5 -C 9 )heteroaryl, (25) (C 6 -C 10 )arylamino, (26) (C 6 -C 10 )arylthio, (27) (Ce-doJary d-CeJalkoxy, (28) (C 5 -C 9 )heteroarylamino, (29) (C 5 -C 9 )heteroarylthio, (30) (C 5 - C 9 )heteroaryloxy, (31 ) (C 3 -C 6 )cycloalkyl, (32) (d-C 6 )alkyl(hydroxymethylene), (33) piperidyl, (34) pyridinyl, (35) thienyl, (36) furanyl, (37) (C C 6 )alkylpiperidyl, (38) (d-C 6 )acylamino, (39) (d-C 6 )acylthio, (40) (d-C 6 )acyloxy, (41 ) R 7 (C C 6 )alkyl wherein R 7 is (C C β )acylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (d-C 6 )alkylpiperazino, (Cβ-Cu ary d- C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(d-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (d-C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (d-Ce^lkylpiperidyKd-Cejalkyl, (Ce-doJarylpiperidy d-CeJalkyl, (C 5 - C 9 )heteroarylpiperidyl(d-C 6 )alkyl or (d-C 6 )acylpiperidyl; (42) or a group of formula III wherein s is 0 to 6; t is O or 1 ; X is oxygen or NR 8 wherein R 8 is hydrogen, (d-C 6 )alkyl or (C 3 -C 7 )cycloalkyl(d- Cβ)alkyl; Y is hydrogen, hydroxy, (d-C 6 )alkyl optionally substituted by halo, hydroxy or cyano; (d-CβJalkoxy, cyano, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl wherein the aryl group is optionally substituted by halo, hydroxy, carboxy, (d-C 6 )alkyl, (Cι-C 6 )alkoxy, perfluoro(C 1 -C 6 )alkyl, (d- C 6 )aikoxy(d-C 6 )alkyl or NR 9 R 10 ; wherein R 9 and R 10 are each independently selected from the group consisting of hydrogen and (d-C 6 )alkyl optionally substituted by (d- C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl, (C 5 - C 9 )heteroaryl or (C 3 -C 6 )cycloalkyl; piperidyl, (d-C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (d-C 6 )acylpiperidyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 3 -C 6 )cycloalkyl, R 11 (C 2 -C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 11 )(C 1 -C β )alkyl wherein R 11 is hydroxy, (d-C 6 )acyloxy, (d- C 6 )alkoxy, piperazino, (d-C 6 )acylamino, (d-C 6 )alkylthio, (C 6 -C 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (d-C 6 )alkylsulfoxyl, (C 6 -C 10 )arylsulfoxyl, amino, (d-C 6 )alkylamino, ((d- C 6 )alkyl) 2 amino, (C^CeJacylpiperazino, (d-C 6 )alkylpiperazino, (Cβ-doJary d- C 6 )alkylpiperazino, (Cs-CgJheteroary C T -CeJalkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 12 (d-C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 12 )(C 1 -C 6 )alkyl wherein R 12 is piperidyl or (C C 6 )alkylpiperidyl; and CH(R 13 )COR 14 wherein R 14 is as defined below and R 13 is hydrogen, (d-C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (Cs-CgJheteroary C CeJalkyl, (d- C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 -C 10 )arylthio(C 1 -C 6 )alkyl, (d-CeJalkylsulfiny d-CeJalkyl, (C 6 - doJarylsulfiny C CeJalkyl, (C CeJalkylsulfony d-CeJalkyl, (C 6 -do)arylsulfonyl(d-C 6 )alkyl, hydroxy(d-C 6 )alkyl, amino(C 1 -C 6 )alkyl, ((d- C f alkylamino d-CβJalkyl, R 15 R 16 NCO(d-C 6 )alkyl or R 15 OCO(d-C 6 )alkyl wherein R 15 and R 16 are each independently selected from the group consisting of hydrogen, (d-C 6 )alkyl, (C 6 - C 10 )aryl(d-C 6 )alkyl and (C 5 -C 9 )heteroaryl(d-C 6 )alkyl; and R 14 is R u O or R 17 R 18 N wherein R 17 and R 18 are each independently selected from the group consisting of hydrogen, (d- C 6 )alkyl, (Ce-doJary d-C alkyl and (C 5 -Cg)heteroaryl(d-C 6 )alkyl; (43) or a group of formula IV wherein u is 0, 1 or 2; R 19 is hydrogen, (d-C 6 )alkyl or perfluoro(d-C 6 )alkyl; R 20 is hydrogen, (d-C 6 )alkyl, (d-C 6 )carboxyalkyl or (Ce-dc^ary d-d alkyl; (44) or a group of formula V wherein a is 0, 1 or 2; b is 0 or 1 ; c is 1 , 2 or 3; d is 0 or 1 ; e is 0, 1 or 2; J and L are each independently oxygen or sulfur; R 21 is hydrogen, hydroxy, fluoro, (d-C 6 )alkyl, (d-C 6 )alkoxy, halo(C 1 -C 6 )alkyl, amino, (d-C 6 )acylamino or NR 26 R 27 wherein R 26 and R 27 are each independently selected from hydrogen, (d-C 6 )alkyl or (C 6 -C 10 )aryl; and R 22 is hydrogen, (Cι-C 6 )alkyl optionally substituted by hydroxy, halo, (d-C 6 )alkylthio, (d-C 6 )alkylsulfιnyl or (d-C 6 )alkylsulfonyl; oorr iinn ffoommuullaa IIII wwhheenn nn iiss 11 aanndd B and D are both CR 5 , the two R 5 groups may be taken together with the carbons to which they are attached to form a group of formula VI wherein the broken lines represent optional double bonds; m is 0 or 1 ; and T, U, V and W are each independently oxygen, sulfur, CO, nitrogen or CR 5o R6 , wherein R 5 and R 6 are as defined above; or when A and B are both CR 5 , or when n is 1 and B and D are both CR 5 , or when D and E are both CR 5 , or when E and G are both CR 5 , the two R 5 groups may be taken together with the adjacent carbons to which they are attached to form a (C 5 -C 6 )cycloalkyl group optionally substituted by hydroxy or a benzo group. 4. The method according to claim 3, wherein R 2 is a group of formula II wherein the broken lines represent optional double bonds; n is 1 ; A is CR 5 wherein R 5 is halo or (d-C 6 )alkyl; B is CR 5 wherein R 5 is hydrogen or halo; D is CR 5 wherein R 5 is hydrogen, halo, cyano or a group of formula wherein s is 0; t is 0; and Y is NH 2 ; E is CR 5 wherein R 5 is hydrogen or halo; and G is CR 5 wherein R 5 is halo or (C C 6 )alkyl. 5. The method according to claim 3, wherein R 2 is a group of formula 6. The method according to claim 3, wherein R is a group of formula II wherein the broken lines represent double bonds; n is 0; A is oxygen; and B, E and G are each independently CR 5 wherein R 5 is hydrogen, cyano, halo, (d- C 6 )alkyl optionally substituted by one or two hydroxy; (C 3 -C 7 )cycloalkylaminosulfonyl, (d- C 6 )alkylaminosulfonyl, a group of formula III wherein s is 0; t is O; or a group of formula IV wherein u is 0 or 1 ; R 19 is (d-C 6 )alkyl or trifluoromethyl; and R 20 is hydrogen. 7. The method according to claim 1 wherein the IL-1 processing and release inhibiting agent is a compound selected from the group consisting of 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-furan-2- sulfonyl]-urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-furan-2-sulfonyl]-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1 -hydroxy-1 -methyl-ethyl)-benzenesulfonyl]- urea; 1 -(1 ,2,3, 5,6, 7-Hexahydro-4-aza-s-indacen-8-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan- 2-sulfonyl]-urea; 1 -(1 ,2, 3, 5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl )-thiophene- 2-sulfonyl]-urea; 1-(4-[1 ,3]Dioxolan-2-yl-furan-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)- urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-thiophene-2-sulfonyl]-urea; 1-(4-Acetyl-thiophene-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(1 H-Benzoimidazole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(1 , 2,3, 5,6, 7-Hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-thiophene- 2-sulfonyl]-urea; 1-(8-Chloro-1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)- furan-2-sulfonyl]-urea; 1-(4-Acetyl-furan-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(8-Fluoro-1 ,2,3, 5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)- furan-2-sulfonyl]-urea; 1-(4-Fluoro-2,6-diisopropyl-phenyl)-3-[3-(1 -hydroxy-1 -methyl-ethyl)-benzenesulfonyl]- urea; 1-(6-Fluoro-1 H-benzoimidazole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)- urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(1 H-indole-6-sulfonyl)-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1 H-indole-6-sulfonyl)-urea; 1 -[1 ,2,3,5,6,7-Hexahydro-s-indacen-u-yl)-3-(1 H-indole-6-sulfonyl)-urea; 1-(5-Fluoro-1 H-indole-6-sulfonyl)-3-(1 ,2,3,5,6,7-hexanhydro-5-indacen-4-yl)-urea; 1-[4-Chloro-2,6-diisopropyl-phenyl]-3-[2-fluoro-5-(2-methyl-(1 ,3)dioxolan-2-yl)- benzenesulfonyl]-urea; 3-[3-[4-Chloro-2,6-diisopropyl-phenyl]-ureidosulfonyl]-N-methyl-benzenesulfonamide; 1-[2-Fluoro-5-(2-methyl-(1 ,3)dioxolan-2-yl)benzenesulfonyl]-3-1 ,2,3,5,6J-hexahydro- indacen-4-yl)-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]-urea; 1-(1 ,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]-urea; and 3-[3-(1 ,2,3,5,6,7-Hexahydro-S-indacen-4-yl)-ureidosulfonyl]-N-methyl- benzenesulfonamide. 8. The method according to claim 5, wherein the IL-1 ra polypeptide is human recombinant IL-1 ra corresponding to SEQ ID NO 2 of United States Patent No. 5,863,769. 9. The method according to claim 8, wherein the inhibitor of ICE is Vertex VX740 having the formula or a pharmaceutically acceptable salt thereof. 10. A composition comprising an IL-1 RA polypeptide or variant thereof thereof and a non-steroidal IL-1 processing and release inhibiting agent. 11. The composition according to claim 10, wherein the non-steroidal IL-1 processing and release inhibiting agent is a diarylsulfonylurea. 12. The composition according to claim 11 , wherein the diarylsulfonylurea has a structure of formula I X. / NH ' NH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently a group of formula II wherein the broken lines ( ) represent optional double bonds; n is 0, 1 , 2 or 3; A, B, D, E and G are each independently oxygen, sulfur, nitrogen or CR 3 5° n R6° wherein R 5 and R 6 are each independently selected from (1 ) hydrogen, (2) (d-C 6 )alkyl optionally substituted by one or two groups selected from (d-CeJalkylamino, (d-CβJalkylthio, (d- C 6 )alkoxy, hydroxy, cyano, perfluoro(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 - C 10 )arylamino, (C 6 -C 10 )arylthio, (C 6 -C 10 )aryloxy wherein the aryl group is optionally substituted by (d-C 6 )alkoxy, (d-C 6 )acyl, carboxy, hydroxy or halo; (C 5 -C 9 )heteroarylamino, (C 5 - C 9 )heteroarylthio, (C 5 -C 9 )heteroaryloxy, (C 6 -d 0 )aryl(C 6 -C 10 )aryl, (C 3 -C 6 )cycloalkyl, hydroxy, piperazinyl, (C 6 -C o)aryl(C 1 -C 6 )alkoxy, (Cs-Cgjheteroarylfd-Cgjalkoxy, (d-CβJacylamino, (C C 6 )acylthio, (d-C 6 )acyloxy, (d-C 6 )alkylsulfinyl, (C 6 -C 10 )aryisulfιnyl, (d-C 6 )alkylsulfonyl, (C 6 - do)arylsulfonyl, amino, (d-C 6 )alkylamino or ((d-C 6 )alkyl) 2 amino; (3) halo, (4) cyano, (5) amino, (6) hydroxy, (7) perfluoro(C 1 -C 6 )alkyl, (8) perfluoro(C 1 -C 6 )alkoxy, (9) (C 2 -C 6 )alkenyl, (10) carboxy(C 2 -C 6 )alkenyl, (11) (C 2 -C 6 )alkynyl, (12) (d-C 6 )alkylamino, (13) ((d- C 6 )alkyl) 2 amino, (14) (d-C 6 )alkylsulfonylamido, (15) (d-C 6 )alkylsulfinyl, (16) (d- C 6 )alkylsulfonyl, (17) aminosulfonyl, (18) (d-d alkylaminosulfonyl, (19) ((d- C 6 )alkyl) 2 aminosulfonyl, (20) (d-C 6 )alkylthio, (21 ) (d-C 6 )alkoxy, (22) perfluorofd-d alkyl, (23) (C β -C,o)aryl, (24) (C 5 -C 9 )heteroaryl, (25) (C 6 -C 10 )arylamino, (26) (C 6 -C 10 )arylthio, (27) (Ce-doJary d-Ce alkoxy, (28) (C 5 -C 9 )heteroarylamino, (29) (C 5 -C 9 )heteroarylthio, (30) (C 5 - C 9 )heteroaryloxy, (31) (C 3 -C 6 )cycloalkyl, (32) (d-C 6 )alkyl(hydroxymethylene), (33) piperidyl, (34) pyridinyl, (35) thienyl, (36) furanyl, (37) (d-C 6 )alkylpiperidyl, (38) (d-C 6 )acylamino, (39) (d-C 6 )acylthio, (40) (d-C 6 )acyloxy, (41 ) R 7 (d-C 6 )alkyl wherein R 7 is (d-C 6 )acylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (Cι-C 6 )alkylpiperazino, (C 6 -C 10 )aryl(d- C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(d-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (d-C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (d-CeJalkylpiperidy d-CeJalkyl, (C 6 -C 10 )arylpiperidyl(d-C 6 )alkyl, (C 5 - CgJheteroarylpiperidy Ci-CeJalkyl or (d-C 6 )acylpiperidyl; (42) or a group of formula III wherein s is 0 to 6; t is 0 or 1 ; X is oxygen or NR 8 wherein R 8 is hydrogen, (d-C β )alkyl or (C 3 -C 7 )cycloalkyl(Cι- Cβ)alkyl; Y is hydrogen, hydroxy, (d-C 6 )alkyl optionally substituted by halo, hydroxy or cyano; (d-C 6 )alkoxy, cyano, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl wherein the aryl group is optionally substituted by halo, hydroxy, carboxy, (d-C 6 )alkyl, (d-C 6 )alkoxy, perfluoro(d-C 6 )alkyl, (C-,- C 6 )alkoxy(d-C 6 )alkyl or NR 9 R 1 °; wherein R 9 and R 10 are each independently selected from the group consisting of hydrogen and (d-C 6 )alkyl optionally substituted by (d- C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl, (C 5 - C 9 )heteroaryl or (C 3 -C 6 )cycloalkyl; piperidyl, (d-C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (d-C 6 )acylpiperidyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 3 -C 6 )cycloalkyl, R 11 (C 2 -C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 11 )(C 1 -C 6 )alkyl wherein R 11 is hydroxy, (d-C 6 )acyloxy, (d- C 6 )alkoxy, piperazino, (d-C 6 )acylamino, (d-C 6 )alkylthio, (C 6 -C 0 )arylthio, (d-C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfιnyl, (d-C 6 )alkyisulfoxyl, (C 6 -C 10 )arylsulfoxyl, amino, (d-C 6 )alkylamino, ((d- C 6 )alkyl) 2 amino, (d-C 6 )acylpiperazino, (d-C 6 )alkylpiperazino, (Ce-dojary^d- C 6 )alkylpiperazino, (C 5 -C 9 )heteroaryl(d-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 12 (d-C 6 )alkyl, (C 1 -C 5 )alkyl(CHR 12 )(C 1 -C 6 )alkyl wherein R 12 is piperidyl or (d-C 6 )alkylpiperidyl; and CH(R 13 )COR 14 wherein R 14 is as defined below and R 13 is hydrogen, (d-C 6 )alkyl, (C 6 -C 10 )aryl(d-C 6 )alkyl, (Cs-CgJheteroary d-CeJalkyl, (C,- C 6 )alkylthio(C 1 -C 6 )alkyl, (Ce-doJarylthiofd-CeJslkyl, (d-CeJalkylsulfiny d-CeJalkyl, (C 6 - C 10 )arylsulfinyl(C C 6 )alkyl, (d-CeJalkylsulfony d-CeJalkyl, hydroxy(d-C 6 )alkyl, amino(C 1 -C 6 )alkyl, (d-d alkylaminofd-d slkyl, ((d- Ce)alkylamino) 2 (d-C 6 )alkyl, R 15 R 16 NCO(d-C 6 )alkyl or R 15 OCO(d-C 6 )alkyl wherein R 15 and R 16 are each independently selected from the group consisting of hydrogen, (d-C 6 )alkyl, (C 6 - C 10 )3ryl(d-C 6 )3lkyl and (C 5 -C 9 )heteroaryl(d-C 6 )alkyl; and R 14 is R 17 0 or R 17 R 18 N wherein R 17 and R 18 are each independently selected from the group consisting of hydrogen, (d- C 6 )alkyl, (C 6 -C 10 )aryl(d-C 6 )3lkyl and (C 5 -Cg)heteroaryl(d-C 6 )3lkyl; (43) or 3 group of formula IV wherein u is 0, 1 or 2; R 19 is hydrogen, (d-C 6 )alkyl or perfluoro(d-C 6 )alkyl; R 20 is hydrogen, (d-C 6 )alkyl, (C C 6 )carboxyalkyl or (Ce-doϊary d-CeJalkyI; (44) or a group of formula V wherein a is 0, 1 or 2; b is 0 or 1 ; c is 1 , 2 or 3; d is 0 or 1 ; e is O, 1 or 2; J and L are each independently oxygen or sulfur; R 21 is hydrogen, hydroxy, fluoro, (d-C 6 )alkyl, (d-C 6 )alkoxy, halo(d-C 6 )alkyl, amino, (d-C 6 )acylamino or NR 26 R 27 wherein R 26 and R 27 are each independently selected from hydrogen, (d-C 6 )alkyl or (C 6 -C 10 )aryl; and R 22 is hydrogen, (d-C 6 )alkyl optionally substituted by hydroxy, halo, (C C 6 )alkylthio, (Cι-C 6 )alkylsulfinyl or (d-C 6 )alkylsulfonyl; or in fomula II when n is 1 and B and D are both CR 5 , the two R 5 groups may be taken together with the carbons to which they are sttached to form a group of formula VI wherein the broken lines represent optional double bonds; m is 0 or 1 ; and T, U, V and W are each independently oxygen, sulfur, CO, nitrogen or CR 5r R- 6 . wherein R 5 and R 6 are as defined above; or when A and B, or when n is 1 and B and D, or D and E, or E and G, are both CR 5 , the two R 5 groups may be taken together with the adjacent carbons to which they are attached to form a (C 5 -C 6 )cycloalkyl group optionally substituted by hydroxy or a benzo group. 13. The composition according to claim 12, wherein R 2 is a group of formula II wherein the broken lines represent optional double bonds; n is 1; A is CR 5 wherein R 5 is halo or (C C 6 )alkyl; B is CR 5 wherein R 5 is hydrogen or halo; D is CR 5 wherein R 5 is hydrogen, halo, cyano or a group of formula wherein s is 0; t is 0; and Y is NH 2 ; E is CR 5 wherein R 5 is hydrogen or halo; and G is CR 5 wherein R 5 is halo or (C C 6 )alkyl. 14. The composition according to claim 12, wherein the diarylsulfonylurea is 3 compound selected from the group consisting of 1 -(1 ,2,3, 5,6,7-Hexahydro-s-ind3cen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-fur3n-2- sulfonyl]-urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-furan-2-sulfonyl]-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-(1 -hydroxy-1 -methyl-ethyl )-benzenesulfonyl]- urea; 1-(1 ,2,3,5,6,7-Hexahydro-4-az3-s-ind3cen-8-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-fur3n- 2-sulfonyl]-ure3; 1-(1 ,2,3,5,6,7-Hex3hydro-s-ind3cen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-thiophene- 2-sulfonyl]-ure3; 1 -(4-[1 ,3]Dioxol3n-2-yl-fur3n-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)- urea; 1-(2,6-Diisopropyl-phenyl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-thiophene-2-sulfonyl]-urea; 1-(4-Acetyl-thiophene-2-sulfonyl)-3-(1, 2,3,5, 6,7-hex3hydro-s-indacen-4-yl)-urea; 1 -(1 H-Benzoimid3zole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1 -(1 ,2,3, 5,6,7-Hexahydro-s-ind3cen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)-thiophene- 2-sulfonyl]-ures; 1-(8-Chloro-1 ,2,3,5,6,7-hex3hydro-s-ind3cen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl)- furan-2-sulfonyl]-urea; 1-(4-Acetyl-fur3n-2-sulfonyl)-3-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; 1-(8-Fluoro-1,2,3,5,6,7-hex3hydro-s-indacen-4-yl)-3-[4-(1 -hydroxy-1 -methyl-ethyl )- fur3n-2-sulfonyl]-ure3; 1-(4-Fluoro-2,6-diisopropyl-phenyl)-3-[3-(1 -hydroxy-1 -methyl-ethyl)-benzenesulfonyl]- urea; 1 -(6-Fluoro-1 H-benzoimidazole-5-sulfonyl)-3-(1 ,2,3,5,6,7-hex3hydro-s-ind3cen-4-yl)- ures; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(1 H-indole-6-sulfonyl)-ure3; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-(5-fluoro-1 H-indole-6-sulfonyl)-ure3; 1 -[1 ,2,3,5,6,7-Hex3hydro-s-ind3cen-u-yl)-3-(1 H-indole-6-sulfonyl)-ure3; 1 -(5-Fluoro-1 H-indole-6-sulfonyl)-3-(1 ,2,3,5,6,7-hex3nhydro-5-indacen-4-yl)-ure3; 1 -[4-Chloro-2,6-diisopropyl-phenyl]-3-[2-fluoro-5-(2-methyl-(1 ,3)dioxolan-2-yl)- benzenesulfonyl]-urea; 3-[3-[4-Chloro-2,6-diisopropyl-phenyl]-ureidosulfonyl]-N-methyl-benzenesulfonamide; 1 -[2-Fluoro-5-(2-methyl-(1 ,3)dioxolan-2-yl)benzenesulfonyl]-3-1 ,2,3,5,6,7-hexahydro- indacen-4-yl)-urea; 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[2-fluoro-5-oxir3nylbenzenesulfonyl]-ure3; 1-(1 ,2,3,5,6,7-Hex3hydro-s-indacen-4-yl)-3-[2-fluoro-5-oxiranylbenzenesulfonyl]-urea; and 3-[3-(1 ,2,3,5,6,7-Hexahydro-S-indacen-4-yl)-ureidosulfonyl]-N-methyl- benzenesulfonamide. 15. The composition according to claim 10, wherein the inhibitor of ICE is Vertex having the formula or a pharmaceutically acceptsble salt thereof.

Inventors: DOMBROSKI MARK ANTHONY, LITTMAN BRUCE HENRY, WOODWORTH THASIA LOUISE GOODWI, DOMBROSKI, MARK, ANTHONY, LITTMAN, BRUCE, HENRY, WOODWORTH, THASIA, LOUISE, GOODWIN
Applicants: DOMBROSKI MARK ANTHONY, LITTMAN BRUCE HENRY, PFIZER PROD INC, WOODWORTH THASIA LOUISE GOODWI, DOMBROSKI, MARK, ANTHONY, LITTMAN, BRUCE, HENRY, PFIZER PRODUCTS INC., WOODWORTH, THASIA, LOUISE, GOODWIN
Application year: 2000
Main classification: A61K38
IPC codes: A61K31, A61K38, A61K45, A61P19, A61P29, A61P43