EP1214087A1 - Behandlung mit kombinationen aus il1-ra und diarylsulfonylureaverbindungen - Google Patents

Behandlung mit kombinationen aus il1-ra und diarylsulfonylureaverbindungen

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Publication number
EP1214087A1
EP1214087A1 EP00951799A EP00951799A EP1214087A1 EP 1214087 A1 EP1214087 A1 EP 1214087A1 EP 00951799 A EP00951799 A EP 00951799A EP 00951799 A EP00951799 A EP 00951799A EP 1214087 A1 EP1214087 A1 EP 1214087A1
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EP
European Patent Office
Prior art keywords
alkyl
hydroxy
urea
diisopropyl
sulfonyl
Prior art date
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EP00951799A
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English (en)
French (fr)
Inventor
Bruce Henry c/o Pfizer Inc Central Res LITTMAN
Thasia Louise Goodwin Pfizer Inc. WOODWORTH
Mark Anthony Pfizer Inc DOMBROSKI
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Pfizer Products Inc
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Pfizer Products Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Interleukin 1 refers to two proteins (IL1 ⁇ and IL1 ⁇ , 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
  • 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
  • this cleavage involves an intracellular cysteine protease, known as ICE, which is required to release the active fragment from the inactive precursor
  • ICE intracellular cysteine protease
  • IL-1 activates transcription factors such as NF- ⁇ B and AP-1 .
  • 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.
  • Canadian patent application 2,039,458 describes methods of treatment of IL-1 mediated diseases by administering IL-1ra.
  • 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.
  • 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.
  • IL-1ra soluble IL-1 R
  • IL-1 ⁇ or ⁇ antibodies to IL-1 ⁇ or ⁇
  • 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).
  • 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.
  • Inflammatory diseases such as rheumatoid arthritis are characterized by an excessive production of cytokines that promote and/or maintain the inflammatory state.
  • cytokines Prominent among them are IL-1 (both the ⁇ and ⁇ forms) and tumor necrosis factor ⁇ (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.
  • 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.
  • 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.
  • 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.
  • LPS Lipopolysaccharide
  • LPS-activated cells 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.
  • 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.
  • 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.
  • interleukin-1 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.
  • PMN polymorphonuclear leukocytes
  • 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.
  • 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, glomerulonep
  • 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.
  • 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.
  • IL-1 processing and release agents may exhibit toxicity that limit the available dosages.
  • 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.
  • the present invention provides methods and compositions for the treatment of IL-1 mediated disease states.
  • 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.
  • 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.
  • 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 ⁇ M, more preferably less than 1 ⁇ M, 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
  • R 1 and R 2 are each independently a group of formula II
  • 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 ⁇ Jalkylthio, (d- C 6 )alkoxy, hydroxy, cyano, perfluoro(C ⁇ -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 (C ⁇ -C 6 )alkoxy, (d-C 6 )acyl, carboxy, hydroxy or halo; (C 5 -C 9 )heteroarylamino, (C 5 - C
  • 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 -C ⁇ 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(C ⁇ -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
  • u 0, 1 or 2;
  • R ,19 is hydrogen, (d-C 6 )alkyl or perfluoro(C ⁇ -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
  • J and L are each independently oxygen or sulfur
  • R 21 is hydrogen, hydroxy, fluoro, (d-C ⁇ )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, (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
  • 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.
  • pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nit
  • 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.
  • 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 ⁇ M, and more preferably, less than 1 ⁇ M, 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
  • n 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
  • Y is hydrogen, (d-C 6 )alkyl optionally substituted by halo; or (d-C 6 )alkoxy(C ⁇ - C 6 )alkyl I;; (8) a group of formula V
  • 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
  • u is 0 or 1 ;
  • R 19 is (d-C 6 )alkyl or trifluoromethyl
  • 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
  • n 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
  • Y is NH 2 ;
  • E is CR 5 wherein R 5 is hydrogen or halo
  • 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.
  • n 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.
  • 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
  • n 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
  • Y is NH 2 ;
  • E is CR 5 wherein R 5 is hydrogen or halo
  • G is CR 5 wherein R 5 is halo or (d-C 6 )alkyl.
  • 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
  • n 1 ;
  • 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.
  • 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
  • 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
  • n 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 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
  • 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
  • A is oxygen
  • 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
  • u is 0 or 1 ;
  • R 19 is (C C 6 )alkyl or trifluoromethyl; and R 20 is hydrogen.
  • 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).
  • 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
  • n 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
  • Y is NH 2 ;
  • E is CR 5 wherein R 5 is hydrogen or halo
  • 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.
  • 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;
  • 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;
  • IL-1 processing and release inhibitors useful in the methods and compositions of the present invention are inhibitors of ICE.
  • preferred inhibitors of ICE are compounds and pharmaceutically acceptable salts thereof selected from the group consisting of
  • R 30 , R 3 ⁇ 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;
  • R 13 , R 16 , T 5 and Z are as defined in United States Patent No. 5,656,627;
  • n 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,
  • 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;
  • 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-i is independently selected from alkyl, haloalkyl and alkoxyalkyl;
  • R 2 is H, alkyl, (CH 2 )-alkenyl, aralkyl, heteroaralkyl, carboxyalkyl, cyanoalkyl, aryl, heteroaryl;
  • R 3 is H, alkyl, (CH 2 )-alkenyl, aralkyl, heteroaralkyl, aryl, heteraryl;
  • AA 1 f AA 2 , AA 3 , R ⁇ and Y are as defined in United States Patent No. 5,434,248;
  • 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
  • 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, benzyloxycarbony
  • R 1 -R 5 are as defined in United States Patent No. 5,843,904;
  • R, R, and R 2 are as defined in United States Patent No. 5,744,451 ; (15)
  • R R 3 are as defined in United States Patent No. 5,565,430;
  • 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:
  • 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;
  • 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
  • one of said moderately hydrophobic moieties associates with the P4 binding pocket of ICE in such a way that:
  • 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
  • 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;
  • 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:
  • 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
  • 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
  • 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-
  • 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, 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 '-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.
  • VX740 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:
  • compositions and methods 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.
  • 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 ulceris 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 rejection; graft rejection; graft mediated brain diseases such as Alzheimers disease; inflammatory diseases such as
  • 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.
  • 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.
  • 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.
  • Variant 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.
  • 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.
  • 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.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkoxy includes O-alkyl groups wherein “alkyl” is defined above.
  • cycloalkyl 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, (C ⁇ -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (d-C 6 )alkyl.
  • substituents selected from the group consisting of hydroxy, fluoro, chloro, trifluoromethyl, (C ⁇ -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (d-C 6 )alkyl.
  • cycloalky is substituted with hydroxy.
  • aryl 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 ⁇ -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (d-C 6 )alkyl.
  • 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
  • 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.
  • acyloxy includes O-acyl groups wherein “acyl” is defined above.
  • incorporation by reference means incorporation not only of the text and graphics of the reference, but also the preferences, genera, subgenera, and specific embodiments of the reference.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • all of these polypeptides retain the biological activity of the IL-1ra beta, including antigenic activity.
  • variants of the defined sequence and fragments 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.
  • 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.
  • 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.
  • a base such as triethylamine, diisopropylethylamine or 1 ,8- diazabicyclo[5.4.0]undec-7-ene
  • a aprotic solvent such as tetrahydrofuran, benzene or methylene chloride.
  • 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.
  • an alkyllithium such as n- butyl, sec-butyl or tert-butyl lithium
  • a polar solvent such as tetrahydrofuran
  • 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.
  • a chlorinating reagent such as N-chloro-succinimide in a polar solvent, such as methylene chloride
  • 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.
  • an aprotic solvent such as methylene chloride or ether.
  • 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.
  • a polar aprotic solvent such as chloroform
  • the reaction mixture so formed is warmed to approximately 60°C.
  • 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.
  • 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.
  • a base such as sodium hydride, sodium hydroxide, triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • a polar solvent such as tetrahydrofuran, acetone or dimethylformamide.
  • 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.
  • Chlorinating agent and acid scavenger in inert solvent Chlorinating agent and acid scavenger in inert solvent
  • the ester in step (a) is treated with an electrophilic sulfonating agent to form a sulfonic acid compound.
  • an electrophilic sulfonating agent to form a sulfonic acid compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tart
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 ⁇ l f Medium.
  • 100 ⁇ l of Medium is added to each well, and the cells are incubated overnight at 37EC in a 5% carbon dioxide incubator.
  • 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 ⁇ l of 10 mM stock + 245 ⁇ l 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 ⁇ M.
  • a second dilution is prepared by adding 10 ⁇ l of the 200 ⁇ M IL-1 processing and release inhibitor solution to 90 ⁇ l of Chase Medium containing various concentrations of IL-1 ra polypeptides, yielding a final concentration of 20 ⁇ M diarylsulfonylurea; the dimethyl sulfoxide concentration at this point is 0.2%.
  • concentrations of IL-1 ra polypeptides in Chase medium combined with 10 ⁇ l of the 200 ⁇ M IL-1 processing and release inhibitor solution are varied from 1.1 ⁇ g/ml to 110 ⁇ g/ml to yield approximate concentrations of IL-1ra in the test agent solutions of from 1 to 100 ⁇ g/ml.
  • the LPS-activated monocytes are washed once with 100 ⁇ l of Chase Medium then 100 ⁇ l 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 ⁇ l 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 ⁇ l 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 ⁇ l of the resulting supernatant is added to a well of an IL-1 ⁇ ELISA plate that also contains 70 ⁇ l of PBS, 1 % FBS. The ELISA plate is incubated overnight at 4°C. The ELISA (R&D Systems) is run following the kit kirections.
  • test agent solutions may be prepared containing human recombinant IL-1ra and 20 ⁇ M 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.
  • LPS 100 ng/ml
  • E. coli serotype 055:B5 Sigma Chemicals; St. Louis, MO
  • ATP was introduced as a secretion stimulus (by addition of 10 ⁇ l 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); TNF ⁇ (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.
  • mice 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable 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 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.
  • the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • pharmaceutical compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • 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.
  • 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.
  • the pharmaceutical composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes.
  • 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.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • 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.
  • 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 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.
  • 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 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-cyclopropylsulfamoyl-benzenesulfonyl]-urea 3-Cyclopropylsulfamoyl-benzenesulfonamide; 4-Chloro-2,6-diisopropyl-phenyl isocyanate. mp: 170-174°C.
  • EXAMPLE 8 1-(4-Chloro-2,6-diisopropyl-phenyl)-3-[3-methanesulfinyl-benzenesulfonyl]-urea 3-Methylsulf ⁇ nyl-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 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
  • 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 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
  • 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
  • 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
  • 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 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 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 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-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-4-methoxy-benzenesulfonyl)-3-(2,6-diisopropyl-phenyl)-urea 3-A
  • EXAMPLE 58 4-[3-(3,5-Diacetyl-benzenesulfonyl)-ureido]-3,5-diisopropyl-benzamide 3,5-Diacetyl-benzenesulfonamide; 4-lsocyanato-3,5-diisopropyl-benzamide. mp:
  • 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 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 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 4-[3-[3-(1-Hy
  • 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-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-
  • 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
  • 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-(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-(2,6-Diisopropyl-pheny
  • 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-methanesulf ⁇ nyl-benzenesulfonyl)-urea 3-Methanesulfinyl-benzenesulfonamide; 2,6-Diisopropyl-phenyl isocyanate. mp: 217.4-221.0°C. EXAMPLE 102
  • 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
  • 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-(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-(2,6-Diisopropyl-phenyl
  • EXAMPLE 1 17 1 -(1 ,2, 3,5,6, 7-Hexahydro-s-indacen-4-yl)-3-(4-hydroxymethyl-thiophene-2-sulfonyl)- urea
  • 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
  • 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
  • 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 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.
  • NaCI sodium chloride
  • 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 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.
  • a 500 ml three necked flask was equipped with a magnetic stirrer, a thermometer, and two addition funnels.
  • 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.
  • a solution of 4-amino-s-hydrindacene (17.1 g, 0.0988 mole) in acetontrile (100 ml) was added over six minutes.
  • 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).
  • 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.
  • 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%.
  • [ 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.
  • [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 .
  • 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.
  • the reaction was stirred at room temperature for 15 minutes, then at 70°C for 15 minutes.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • IL-1 processing and release inhibiting agent e.g., IL-1 processing and release inhibiting agent, and a suitable pharmaceutical carrier.
  • suitable pharmaceutical carrier 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.
  • 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.
  • 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.
  • the IL-1ra is administered by subcutaneous injection while the IL-1 processing and release inhibitting agent is administered orally.
  • 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.
  • 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 ⁇ g/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.
  • 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.
  • 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.
  • 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.
  • 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.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • 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.
  • 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.
  • one preferred embodiment of the invention provides a pharmaceutical composition
  • 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.
  • 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.

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HK1257569A1 (zh) 2016-02-16 2019-10-25 The University Of Queensland 磺醯脲和相关化合物及其用途
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