MXPA96006192A

MXPA96006192A - Inhibitors of lactama biciclica de la enzima queconvierte la interleucina-1-b

Info

Publication number: MXPA96006192A
Application number: MXPA/A/1996/006192A
Authority: MX
Inventors: E Dolle Roland; J Schmidt Stanley; V Chaturvedula Prasad; Morganross Tina
Original assignee: Sterling Winthrop Inc
Priority date: 1994-06-08
Filing date: 1995-06-07
Publication date: 1998-10-30

Abstract

The present invention relates to the compounds, compositions and methods for inhibiting the activity of the interleukin-1a protease, having the formula A, wherein Y = (a) or (b) or (c), Z = several lactams bicycles with a nitroge upper bridge

Description

BLEICHIC LACTAMA INHIBITORS OF ENZYME BECOMING INTERLEUCINE-1-BETA BACKGROUND OF THE INVENTION The present invention relates to a series of 5 novel bicyclic derivatives, which show an inhibition in vi tro and in vivo of the enzyme that converts interleukin-lß, to compositions containing the novel bicyclic derivatives and to methods of therapeutic use.

• - * More particularly, the inhibitors that convert the Interleukin-lβ described in this invention comprise the novel bicyclic derivatives of a-substituted methyl aldehydes and acetones, which have particular utility in the treatment of inflammatory and immune-based diseases of the lung, central nervous system and connective tissues. REPORTED DEVELOPMENTS Interleukin lß (IL-lß) protease (also known as the enzyme that converts interleukin-lβ or ICE) is the enzyme responsible for the processing of biologically inactive 31kD precursor IL-lß 20 to a biologically active 17 kD form (Kostura, MJ; Tocci, MJ; Limjuco, G .; Chin, J .; Cameron, P .; Hillman, AG; Chartrain, NA; Schmidt, JA, Proc. Nat. Acad. Sci., (1989), 6 , 5227-5231 and Black, RA; Kronheim, SR; Sleath, PR, FEBS Let. (1989), 247 386 391). In addition to acting as an early response of the body to injuries and infections, including rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, sepsis, acute and chronic myelogenous leukemia and osteoporosis (Dinarello, CA; olff, SM, New Engl. Med., (1993), 328, 106). An IL-1β receptor antagonist which occurs naturally to demonstrate the intervention of IL-1β in a number of human diseases and animal models has been used (Hannu, CH, Wilcox, CJ, Arend, WP, Joslin, GG, Dripps, DJ, Heimdal, PL, Armes, LG, Sommer, A., Eisenberg, SP, Thompson, RC, Nature, (1990), 343, 336-340, Eisenberg, SP, Evans, RJ, Arend, WP, Verderber, E Brewer, MT; Hannum, CH; Thompson, RC, Nature (1990), 343; 342-346; Ohlsson, K .; Bjork, P .; Bergenfeldt, M .; Hageman, R .; Thompson, RC, Nature , (1990), 348, 550,552, akabayashi, G. FASEB, (1991), 338.343, Pacifici, R., et al., Proc. Nati, Acad. Sci. (1989), 06, 2398-2402 and Yamamoto, I ., et al. Cancer Rsh (1989), 49, 4242-4246). The specific role of IL-1β in inflammation and immunomodulation is supported by the recent observation that vaccine viruses use an ICE inhibitor to suppress the inflammatory response of their host (Ray, CA, et al, Cell, (1992). ), 69, 597-604). The importance of these observations is well recognized by those with experience in the technique and several workers have proposed and demonstrated in vivo the usefulness of the inhibitors in the modification of certain disease states indirectly caused by IL-1β. Some have suggested the development and therapeutic use of a small molecule inhibitor in the formation of mature IL-1β. (See, for example, Miller, DK, et al., "The Antiinflammatory Drugs, Annals of the New York Academy of Sciences, Vol. 696, ppl33 -148, 1993) The following review of the current state of the art in ICE investigations also supports such utility of ICE inhibitors: 1) Patent WO 9309135, published on May 11, 1993, teaches that acetone Aryloxymethyl and arylaxymethyl of peptide-based aspartic acid are potent inhibitors of ICE in vitro These compounds also specifically inhibit ICE in whole cells (in vivo) for their ability to inhibit the formation of IL-1β in whole cells. These ICE inhibitors also prove useful in reducing fever and inflammation / swelling in rats 2) Patients with Lyme disease sometimes develop Lyme arthritis B. Burgdorferi the causative agent of Lyme disease Lyme, is a potent inducer of the synthesis of IL-1 by mononuclear cells. Miller, et al., (Miller, L.C., Lynch, E.A., Isa, S., Logan, J.W., Dinarello, C.A .; and Steere, A.C., "" Balance of synovial.

Fluid IL-1β and IL-1 Antagonist Receptor and Recovery from Lyme Arthritis "(Receptor Antagonist Balance of IL-1β and IL-1 in Synovial Fluid and Recovery of Lyme Arthritis), Lancet (1993) 341, 146-148) show that in patients who • '*' quickly recovered from Lyme Arthritis, the balance in the synovial fluid of IL-1β and IL-1 was in favor of IL-ra. When the balance changed in favor of the IL-1, it took a significantly longer period of time to resolve the disease. The conclusion was that the excess of IL-lra blocks the effects of IL-lβ in the patients studied. 15 3) The IL-1 receptor antagonist, Antril (Synergen), has a significant anti-inflammatory activity in patients with active rheumatoid arthritis. In a study that varies the dose of Phase II from multiple centers, 175 patients received subcutaneous doses of antril to 20 mg, 70 mg and 200 mg. It was found that the antagonist is more effective when taken daily. After three weeks of daily treatment, the patients showed a decrease in joint swelling and decreased activity of the disease. A second Phase II clinical trial was scheduled at the beginning of 1994 (Scrip, NO 1873, 1993). 4) IL-1 is present in tissues affected in ulcerative colitis in humans. In animal models of the disease, IL-1B levels correlate with several diseases. In the model, the administration of IL-lra reduced tissue necrosis and the number of inflammatory cells in the colon. See, Cominelli, F .; Nast, C.C .; Clark, B.D .; Schindler, R .; Llerena, R .; Eysselein, V.E .; Thompson, R.C .; and Dinarello, C.A .; ?, Interleukin-l Gene Expression, Synthesis, and Effect of Specific IL-1 Receptor Blockade in Rabbit Immune Complex Colitis "(Expression, Synthesis, and Effect of Interleukin-1 Gene on Blocking the Specific IL-1 Receptor in Colitis Complex Immune of Rabbits), J. Clin. Investigations (1990) Vol. 86, pp. 972-980 5) The IL-1 receptor antagonist, Antril (Synergen), possesses a significant anti-inflammatory activity in patients with rheumatoid arthritis In a study that varies the dose of Phase II in multiple centers, 175 patients received subcutaneous doses of Antril 20 mg, 70 mg and 200 mg seven times, three times and once a week. When taken daily, after three weeks of daily treatment, the patients showed a decrease in joint swelling and decreased activity of the disease (Scrip, NO 1873, 1993) 6) The IL-lra suppressed the joint effect in the PG-AP model S of arthritis in rats. See Schwab, J.H .; Anderle, S.K .; Brown, R.R .; Dalldorf, F.G .; and Thompson, RC, "Pro- and Anti-Inflammatory Roles of Interelukin-1 in Recurrence of Bacterial Cell Wall-Induced Arthritis in Rats" (Anti-Inflammatory Papers and that Prevent Inflammation of Interleukin-1 in the Recurrence of Induced Arthritis through the Bacterial Cell Wall in Rats), Infect. Immun., (1991) 59, 4436-4442. 7) IL-lra was shown to be effective in an open classification human rheumatoid arthritis test. See, Lebsack, M.E .; Paul, C.C .; Bloedow, C.C .; Burch, F.X .; Sack, M.A.; Chase, W., and Catalano, M.A. "Subcutaneous IL-1 Antagonist Receptor in Patients with Rheumatoid Arthritis" (Subcutaneous IL-1 Receptor Antagonist in Patients with Rheumatoid Arthritis), Arth. Rheum. (1991), 34; 545. 8) The soluble IL-1 receptor significantly reduces the allergic reaction of the last cutaneous phase clinically. This was demonstrated in a study with double blind placebo controlled randomized prospects in 15 allergic subjects. See, Mullarkey, M.F .; et al., "Human Cutaneous Allergic Late-Phase Response is Inhibited by Soluble IL-1 Receptor" The Ultimate-Phase Allergic Skin Response is Inhibited by the Soluble IL-1 Receptor), J. De immunology, (1994) 152; 2033-2041. 9) IL-1 appears to be an autocrine growth factor for the proliferation of chronic myelogenous leukemia cells. Both IL-lra and sIL-lR inhibit the growth of the colony in cells removed from patients with leukemia. See Estrov, Z.; Kurzrock, R .; Wetzler, M .; Kantarjian, H .; Blake, M .; Harris, D .; Gutterman, J.U .; and Talpaz, M., "Suppression of Chronic Myelogenous Leukemia Colony Growth by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors: a Novel Application for Inhibitors of IL-1 Activity" (Suppression of the Growth of the Colony of Chronic Myelogenous Leukemia by Interleukin-1 Receptor Antagonist (IL-1) and Solubles IL-1 Receptors: a Novel Application for Inhibitors of IL-1 Activity), Blood (1991), 1%, 1476-1484. 10) as in number 6) above, but for acute myelogenous leukemia instead of chronic myelogenous leukemia. See, Estrov, Z .; Kurzrock, R .; Estey, E .; Wetzler, M .; Ferrajoli, A .; Harris, D .; Blake, M .; Gutterman, J.U .; and Talpaz, M., "Inhibition of Acute Myelogenous Leukemia Blast Proliferation by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors" (Inhibition of Explosive Proliferation of Acute Myelogenous Leukemia by the Interleukin Receptor Antagonist- 1 (IL-1) and the Solubles IL-1 Receptors), Blood (1992), 79 '1938-1945. The IL-1 receptor antagonist Antril (Synergen) possesses significant anti-inflammatory activity in patients with active rheumatoid arthritis. In a study that varies the dose of Phase II in multiple centers, 175 patients received subcutaneous doses of Antril of 20 mg, 70 mg and 200 mg. It was found that the antagonist is more effective when taken daily. After three weeks of daily treatment, the patients showed a decrease in joint swelling and decreased activity of the disease. A second Phase II clinical trial was scheduled to begin in 1994 (Scrip, NO 1873, 1993). As an effective therapy has been fully developed commercially for the treatment of inflammatory diseases indirectly caused by the IL-lß. Accordingly, there is a need for effective therapeutic agents in the treatment and prevention of these diseases. BRIEF DESCRIPTION OF THE INVENTION We describe in the present invention inhibitors of ICE that are not peptide-based, specifically where the fused bicyclic lactam peptidomimetics serve as recognition elements for ICE. One of the classes of the most potent ICE inhibitors described in the literature is the tripeptide i, Z-Val-Ala-Asp-CH2-X (Figure 1: wherein X = 2,6-dichlorobenzoyloxy; Dolle RE, et al. ., J. Med. Chem. (1994), 37, 563) and the related tripeptides described by Thornberry (Thornberry, NA, et al., Biochemistry (1994), 33, 3934). A well-known disadvantage of peptide-based inhibitors is their potential to be extensively metabolized by the body and to be poorly bioavailable when administered orally. In contrast, a significant advantage of the peptidomimetic-based inhibitors compared to their peptide counterparts is that the metabolism and in vivo excretion of such peptidomimetic agents is greatly attenuated, thus leading to increased oral bioavailability of these compounds in animals and animals. Human (Humphrey, MJ and Ringrose, PS, "Peptides and Related Drugs: a Review of their Absorption, Metabolism and Excretion". {Peptides and Related Drugs: a Review of their Absorption, Metabolism and Excretion), Drug Metabolism Reviews, ( 1986), 17, 283-310; Plattner, J.J. and Norbeck, D.W., "Obstacles to Drug Development from Peptide Leads", Drug Discovery Technologies, (1990), Chapter 5, 92-126, C.R. Clark and W.H. Moos, eds .; Horwood: Chichester, U.K.).

For this reason the researchers look for peptidomimetics to act as substitutes for the peptides portion of the pharmaceutically active agents. The bicyclic (7-6) -fused lactam present in Structure ii) is such a peptidomimetic for the peptide portion P3-P2 (Val-Ala) of inhibitor i (Structure i). In addition, the bicyclic system (7-6) fused is linked to the angles α, 0 around the amide P3-P2 amide bonded in a fixed conformation. Accordingly, this invention relates to the discovery of a favorable bioactive conformation with ICE. The bicyclic lactam iii (Structures iii-xii) is a rigid system with angles?, 0. The rigidity of the system has been confirmed by X-ray crystallography (Attwodd, MR; et al., J. Chem. Soc., Perking Trans. I (1986), 1011-1019). The angle ? It has been set at 163.9 °. Logically, by virtue of the rigid bicyclic nature of the fused ring system, any other bicyclic lactam (7,6) derivative or an analogue of iii will have angles α, 0 approximately those found in iii and the bioactive conformation necessary for a link with a high affinity with ICE, as shown in ii. For this reason we declare that any of the lactam (7, 6) -bicyclic or related (8,6) -, (7,5) - and (8,5) -bicyclic rings and their derivatives and analogues will have potential the property of acting as a substitute for iii. So, when incorporated into an ICE inhibitor, these peptidomimetics will be active against the enzyme. Examples of lactam rings iv-xii, whose synthesis is described in the art and which represent the derivatives and analogs of ii are presented in Structures iii-xii. In addition, the stereochemistry around the carbon atoms to which the functional groups of -NH- and -CO- are fixed as shown in Structures iii-xii will be "S" to achieve maximum potency against ICE. That is, both functional groups of -NH- and -CO- will be above and on the same surface of the bicyclic lactam ring. STRUCTURE I ICE inhibitor based on peptides (Dolle, R.E., et al., J. Med. Chem. (1994), 37, 563) STRUCTURE ii ICE Inhibitor based on Lactam (7, 6) -Bicyclic (the invention) STRUCTURE iii-xii The lactam (7, 6) -bicyclic peptidomimetic iii and the bicyclic lactam-related peptidomimetics iv-xii: 111 In accordance with the present invention, there is provided a compound of the formula (A) or its pharmaceutically acceptable salt: Z-N-Y H (A) wherein and when R2 = 0H, then Y can also be equal- where n = 0, 1 R1 = H or deuterium; R2 = OR4 or NHOH; R 4 = H, alkyl, cycloalkyl, aralkyl; R3 = H, (CRßRβ) 0-6CF3, (CR8R9) 0-6CF2CF3, (CRsRβ) o- "COOR5, (CR8-R9) o- 6CONR6R7, CF2 (CHβR9) 0-6aryl, CF2 (CR8R9) 0-6heteroaryl , CF2 (CR8R9) 0-ßalkyl, CHN2CH2R10, COR5: wherein R5 = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R6 and R7 are independently selected from H, alkyl, cycloalkyl, aryl aralkyl, heteroaryl, heteroaralkyl and wherein R6 and R7 taken together may be a 3-, 4-, 5-, 6- or 7-membered carbocyclic ring. R8 and R9 independently are H or alkyl; ? o = alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl / H, halo, SRS, SRSR6, 0 (CO) or -aryl, 0 (CO) 0-? Heteroaryl, R11 and R12 are optionally selected from H, OH, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, aroxy, aralkyloxy, heteroaroxi, heteroaralkyloxy; R 13 = H, alkyl, aryl, aralkyl; R14 and R15 are optionally selected from H, alkyl, aryl or when R14 is taken and RX5 together is an aryl ring; X1 = O, S, NR28 wherein R28 = H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R16 = H, Cl, alkyl, (CR8R9) or -aryl; R17 and R18 independently are H or alkyl; X2 = CH2, O, NR28; R19 = H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; R "= H, alkyl, CF3, CF2, CF3, COORB, CONR" "rR7 ', cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and wherein R21 = H or alkyl; R22, R23, R24, R25, R26 and R27 independently are selected from H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and R29; and wherein R -2 * and R together may be aryl or heteroaryl; X3 = O, S; > 29 = F, Cl, CF3, CF2CF3, (CF2) 0-3-H, COOR 5 °, wherein R30 and R31 are optionally selected from R6 and R7, (CR8R9) 2-6 '-o where q = 0, 1 m = 0, 1, 2, 3; o = 0, 1, 2; X4 = H, alkylthio; R33 and R34 are optionally H, alkyl, aryl or when taken together, R33 and R34 are aryl, heteroaryl or a double bond; R3S and R3ß are optionally an oxygen atom or do not bind; R37 = H, alkyl; R38 = independently is selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R * ° -S02, R41-CO, R0o0-CO, R51NR5-C0; wherein R40 = Rs or HNR5; R41 = alkenyl, aralkenyl, heteroaralkenyl, alkynyl, aralkynyl, heteroaralkynyl, R42-0C0R5, R43-C0R5, R42-NR47C (= NR6) R5, R42-NR47 (= NR6) NR5, R42-SR5, R2-S (CR8R9) ? - "COOR47, R42-S (CR8R9)? - 6C00NR7R48, R2-OR5, R42-0 (CR? R9)? -6COOR47, R42-0 (CR8R9) x. 6COONR47R48, R4 -NR5S02R6, R43-R44, R3-RS, R43-R46, R43-NR7R48, R42-OH, R3-CF3; wherein R42 = (CRVJ and R43 = (CR8R9) 0-6; ? = H, alkyl, - (CH 2) 0 - «- cycloalkyl; - (CH2) 0-. 3 - (CH2) o- < J & / aryl heteroaryl, aralkyl, heteroaralkyl, - (CH2) 2_6R49; where p = 1-4; R49 = alkoxy, CH2F, CHF2, CF3, CF2CF3, OH, COOR47, CONR47R48; or NR7R48; wherein R48 is independently H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, CH2CH20-alkyl and C (0) -R49; R47 is independently H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; and when R47 and R48 are taken together, they can be equal to a ring with five, six or seven members, of the type: where p = l-4 and n = 0-l; R49 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; R 46, wherein p-1-4; R50 and R51 = independently is selected from alkyl, R43-cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R42-alkenyl, R2-heteroaralkenyl, R42-alkynyl, R42-aralkynyl, R ^ -heteroaralkynyl R43-R46, R4-R49, R52-R45, R42-COOR47, R "-CONR47, R2-CONR47R48, RS2-0C0Rs, R52-C0R5, R52-NR47C (NRβ) R5, RS2-NR47 (= NR6) NR5, R52-SR5, R52-S (CR8R9)? -βC00R47, R52-S (CR8R9)? -6COONR47R48, RS2-OR5, RS2 -0 (CR8R9)? -6COOR47, R52-S (CR8R9) i-6COONR * 7R48, R52-NRsS02R6, R52-R44, R52-NR7R48, where R82 - (CR8R9) 2.6; As used herein, the term "pharmaceutically acceptable salts" includes the acid and the base addition salts. The term "acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically undesirable or otherwise undesirable, formed with organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malinic acid, succinic acid, fumaric acid, tartaric acid, acid citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term "base addition salts" includes those derived from inorganic bases, such as the salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like.

Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable non-toxic organic bases include the primary, secondary and tertiary amine salts, substituted amines including the naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, usin, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine , glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine. The following terms are used as above and throughout the description, unless otherwise indicated, it will be understood to have the following meanings: "Alkyl" is defined as a saturated aliphatic hydrocarbon which may be straight or branched chain. Preferred groups have not more than 12 carbon atoms and can be methyl, ethyl, propyl, and so on, and the structural isomers of propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl. "Cycloalkyl" is defined as a saturated cyclic hydrocarbon containing at least 3 to 8 carbon atoms. Preferred groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Aryl" is defined as a phenyl or naphthyl ring or a substituted phenyl or naphthyl ring wherein one or more hydrogen atoms have been replaced by the same substituents or different substituents, selected from R43-R5, R43-CN , R3-N02, R43-halo, R2-OR5, R43-R38, R43-NR5OH, R3-CF3, R43-CF2CF3, R43-C00R5, R3-CONR6R7, R43-CF2 (CRβR9) or-β-heteroaryl , R3-CF2 (CR8R9) 0- "aryl, R3-CF2 (CR8R9) 0-6aril ?, R43-C0N 7R48, R3-C0N30R31, R42-NR5R38, R43-P (0) (OH) (OR5 ), alkenyl, aralkenyl, heteroaralkenyl, alkynyl, aralkynyl heteroaralkynyl, R43-S02Rs, R3-S02NR6R7, R43-NRsS? 2R53, R43-NR5S02R53, R43-S02-R42-C00R47, R43-S02-R42-C0NR6R7, R3 -0C0R5, R43-CORs, R43-NR47C (= NR6) R5, R43-NR47C (= NR6) R5, R43-S-R43-R5, R3-SR2-COOR47, R43-0-R42-C00R47, R43 -SR 2-C0NR47R48, R3-0-R3-R5, R3-0-R52-R45, R3-S-R5 -0-R46, R43-S-R82-R45, R3-S-R4β , R43-R45, R43-R46, wherein RS3 = alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroalkyl.

"Heteroaryl" is defined as an unsubstituted or optionally substituted monocyclic or bicyclic ring system of about 5 to 12 carbon atoms and wherein each monocyclic ring may possess 0 to heteroatoms, and each bicyclic ring may possess about 0 to 5 selected heteroatoms of N, 0 and S provided that the atoms are not adjacent oxygen and / or sulfur atoms and wherein the substituents, numbered from 0 to 5 can be located at any appropriate position in the ring system and are optionally selected from the substituents listed for those described for the aril. Examples of such monocyclic and bicyclic ring systems, which by no means limit the scope of the present invention, including benzofuran, benzothiophenol, indole, benzopyrazole, coumarin, isoquinoline, pyrrole, tifen, furan, thiazole, imidazole, pyrazole, triazole , quinoline, pyrimidine, pyridine, pyridone, pyrazine, pyridazine, isothiazole, isoxazole and tetrazole. "Aralkyl" refers to an alkyl group substituted by an aryl radical. For example, benzyl. "Heteroaralkyl" refers to an alkyl group substituted by a heteroaryl radical. For example, (4-pyridyl) methyl.

"Alkoxy" refers to an atom of 0 substituted by an alkyl radical. For example, methoxy, ethoxy, phenoxy, benzyloxy. "Halo" means iodine, bromine, chlorine and fluorine. The designation "(CRßR9) 2-4 refers to an alkyl bond composed of at least 2 carbon atoms, but is not greater than 4 carbon atoms, wherein said carbon atoms are independently substituted with the radicals described by R8. and R9 Examples of such linkages include, but are not limited to ethyl, propyl, butyl, 2-methylethyl- (MeHCCH2) and 2,2-dimethylethyl (Me2CCH2-). "Aroxy" refers to an O-atom substituted by an aryl radical For example, phenoxy "Heteroaroxi" refers to an O atom substituted by a heteroaryl radical, eg pyridinyloxy "Alkenyl" refers to an unsaturated hydrocarbon which may be straight or branched chain, and has one or more double bonds The preferred groups have no more than 12 carbon atoms and can be ethenyl, propenyl, hexadienyl, and so on and their structural isomers. "Alkynyl" refers to an unsaturated hydrocarbon which can be a chain straight or branched, and t It has one or more triple links. Preferred groups dye no more than 12 carbon atoms and can be ethyl, propynyl, 4-methylpentinyl and so on and their structural isomers. "Aralkenyl and heteroaralkenyl" refers to an alkenyl group substituted by an aryl or heteroaryl ring. For example, ArCH = CH-, ArCH2CH2CH2HC = C-, CH3CH2CH (Ar) CH2CH2CH = CH-, and so on. "Aralkynyl and heteroaralkynyl" refers to an alkynyl group substituted by an aryl or heteroaryl ring. For example, ArC = C-, ArCH2CH2CH2D = C-, and so on. The present invention also relates to a pharmaceutical composition and to a method of treating disease states or disorders indirectly caused by the IL-1β protease in a mammal in need of such treatment comprising the administration of IL protease inhibitors. -lß of Formula (I) as the active agent. These disease states and disorders include: infectious diseases, such as meningitis and salpingitis, septic shock, respiratory diseases, inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis, and reperfusion injury, underlying diseases immune, such as hypersensitivity, auto-immune diseases, such as multiple sclerosis; diseases of the bones, and certain tumors and leukemias. The present invention has particular utility in modulating the processing of IL-1β for the treatment of rheumatoid arthritis. The levels of IL-lß are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1β stimulates the synthesis of enzymes that are considered to be involved in inflammation, such as collagenase and PLA2, and produces a joint destruction, which is very similar to rheumatoid arthritis after intra-articular injection in animals. . In the practice of the present invention an effective amount of a compound of the invention or its pharmaceutical composition is administered to the subject in need of such treatment, or who so desires. These compounds or compositions may be administered by any route of a variety of routes depending on the specific end use, including orally, parenterally (including subcutaneous, intra-articular, intramuscular and intravenous administration), rectally, buccally (including sublingual, transdermal administration) or intranasal entity). The most appropriate route in any given case will depend on the use, the particular active ingredient, and the subject involved. The compound or composition can also be administered by means of a controlled release patch implant or injection formulations as described more fully herein. In general, for the uses described in the present invention, it is expedient to administer the active ingredient in approximate amounts of 0.1 and 100 mg / kg of body weight, more preferably from 0.1 to 30 mg / kg of body weight for human therapy, the active ingredient will preferably be administered in a range of approximately 0.1 to 20-50 mg / kg / per day. This administration can be achieved by a simple administration, by the distribution of several applications, or by a slow release in order to achieve the most effective results. When administered as a single dose, the most preferred administration will be in the range of about 0.1 mg / kg to 10 mg / kg. The exact dose and regimen for administration of these compounds and compositions will necessarily depend on the needs of the individual subject being treated, the type of treatment and the degree of disease or need. In general, parenteral administration requires lower dosage than other methods of administration that are more dependent on absorption. An additional aspect of the present invention relates to pharmaceutical compositions comprising an active ingredient as a compound "of the present invention in a mixture with a non-toxic pharmaceutically acceptable carrier. As mentioned above, such compositions can be prepared to be used for administration. parenteral (subcutaneous, intra-articular, intramuscular or intravenous), particularly in the form of liquid solutions or suspensions, for oral or buccal administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, drops or nasal sprays. When administered orally (or rectally) the compounds will generally be formulated in a unit dosage form, such as tablets, capsules, suppositories or capsules. Such formulations typically include a solid, semi-solid or liquid carrier or diluent. Diluents and exemplary vehicles are lactose, dextrose, sucrose, sorbitol, mannitol, aginates, tragacanths, gelatin, syrup, methylcellulose, polyoxyethylene sorbitan onolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc and magnesium stearate. The compositions can be prepared by any of the methods well known in the pharmaceutical art, for example as described in Remington Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985. Formulations for parenteral administration may contain as common excipients sterile water or saline, alkylene glycols, such as propylene glycols, polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Examples of vehicles for parenteral administration include water, aqueous vehicles such as saline substances, Ringer's solution, dextrose solution, and Hank's solution and non-aqueous vehicles such as stable oils (such as corn, cottonseed, peanut, and sesame seeds). , ethyl oleate and isopropyl myristate. Sterile saline is a preferred vehicle and the compounds are sufficiently soluble in water to form a solution for all foreseeable needs. The vehicle may contain minor amounts of additives, such as substances that increase solubility, isotonicity and chemical stability, for example, antioxidants, stabilizers and preservatives. For oral administration, the formula can be improved by the addition of bile salts, and also by the addition of acicarnitins (Am. J. Physiol 251: 332 (1986)). The nasal administration formulations can be solid and contain as excipients, for example, lactose or dextran, or they can be aqueous or oily solutions for administration in the form of nose drops or a dosed spray. For buccal administration typical excipients include sugar, calcium stearate, magnesium stearate, starch previously formed in gelatin, and the like. When formulated for nasal administration, uptake through the nasal mucosal membrane is enhanced by surfactant acids, for example, such as glycocholic acid, cholic acid, taurocholic acid, ethocolic acid, deoxycholic acid, chenodeoxycholic acid, dehydrocholic acid, glycodeoxy-colic acid, and the like. (See, B.H. Vickery, "LHRH and its Therapeutic Applications and Analogous Contraception", Pt. 2, B.H. Vickery and J.S. Nester, Eds., MTP Press, Lancaster, UK 1987). DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are prepared by using the general synthetic methods as described in Schemes 1, 2, 3, 4 and 5. The a-bromomethyl acetone of Z-asparatic acid (Scheme 1); Formula 1; Z = benxyloxycarbonyl) is treated with an alcohol or a carboxylic acid in the presence of KF using DMF as a solvent to provide the methyl acetones of a-substituted Z-aspartic acid (Formula 2). The preparation of bromide (Formula 1) and its conversion to the compounds of Formula 2 is achieved using the method described by A. Krantz, et al., (Biochemistry, (1991), 30, 4678-4687). Subsequently, the group Z is removed to generate an N-terminal amine (Formula 3) under hydrogenolytic conditions. The reagents and typical conditions used to carry out the hydrogenolytic removal of the Z group are a hydrogen gas, pressure and room temperature, 5% palladium on carbon as the catalyst in an alcohol solvent, for example, methanol optionally containing two equivalents of hydrochloric acid. It is not necessary to purify the free amine of intermediates (or the hydrochloric salt if hydrochloric acid is used in hydrogenolysis), although this material needs to be dried and free of alcohol for the subsequent binding reaction to proceed with good production. The amine (Formula 3) thus obtained is then condensed with the bicyclic carboxylic acid (Formula 4) to produce the intermediates of Formula 5. First it is necessary to activate the bicyclic carboxylic acid as an acid chloride or a mixed anhydride and then react with the free amine (or the hydrochloric salt) in the presence of an organic base, for example, N-methylmorpholine. Alternatively, linking the bicyclic carboxylic acid with the intermediate amine is carried out using reagents that bind the amine and conditions used in the binding chemistry of the peptides ("The Practice of Peptide Synthesis" (The Practice of Peptide Synthesis) , M. Bodanszky, Springer, Verlag, NY, 1984, The Peptides Vol 1-3, E. Gross and J. Meienhofer, Eds. Academic Press, NY, 1981). The remaining synthetic transformation to generate the ICE inhibitors is the hydrolysis of the t-butyl ester function. This is carried out by exposing the t-butyl ester (Formula 5) to 25% of a solution of trifluoroacetic acid (TFA) in methylene chloride at 25 ° C. Deesterification is usually completed in 3 hours. Removal of the volatile TFA and the organic solvent provides the aspartic acid (Formula 6). The product of the reaction is quantitative in most of the examples, which provides a starting material of t-butyl ester which is of high purity. The purification, if required, can be performed by recrystallization or chromatographic techniques, which are well known to those skilled in the art. The concentration of TFA can vary from 5% to 100%, and other organic solvents such as chloroform can be used. A three-mole anhydride hydrochloric acid solution in ethyl acetate can also be used in place of TFA-methylene chloride solution with equal efficiency. Scheme 2 summarizes the synthesis of the aldehyde containing bicycles. The starting material for its synthesis is aspartyl semicarbazone (Formula). The group Z is removed by means of the normal hydrogenation conditions to produce the corresponding amine (Formula 8) This is then linked to the bicyclic carboxylic acid (Formula 4) using the analogous binding conditions as described above. A double deprotection is required to release the beta carboxylic acid (trifluoroacetic acid) and the alpha aldehyde (37% aqueous formaldehyde, acetic acid, methanol) producing the compounds of Formula 10. Scheme 3 summarizes an alternative synthetic method to introduce the R38 groups into the bicyclic amino function which further increases the scope of the invention. Bicycles either as their amines of aspartic acid, free acids or esters containing a group Z (Formula 11) can be subjected to the hydrogenolysis conditions (similar to those described above) to produce the corresponding amino bicycles (conditions analogous to used to link Formula 3 and 4, as described in Scheme 1 above), or sulfonyl chlorides or isocyanates to provide R38 containing bicyclic lactams with a structural diversity in R38. The bicyclic lactam of Formula 4 (Scheme 4) was prepared using the known methods, see: Attwood, et al., CA200 (17): 139158j CA, "Bicyclic Carboxylic Acids and their Alkyl and Aralkyl Esters" (Bicyclic Carboxylic Acids and its Esters of Alkyl and Aralkyl), Gb-13850 820512; and GB 83-5505 839228; Hassall, C.H., et al .; J. Chem. Soc. Perkin I, 1451-1454, (1979) and Hale, K. J., et al; Tetrahedron Letters (1992), 33 7613-7616. The ester was tested with hydrazine under normal conditions (See Green, T.W .; "Protective Groups in Organic Synthesis"; John Wiley &Sons, 1981) to give us the free amine (Formula 15) in high yield. This material reacted with the benzyloxycarbonyl chloride and then with TFA also using the normal conditions (Formula 15-> Formula 16 - Formula 4). The details for these series are provided below. In Scheme 5, the synthesis of other bicyclic lactam derivatives is presented. The bicyclic lactams of Formulas 17-26 are known in the art. For the synthesis of Formula 17, 18 and 199, see (Hoffmann's patent La Roche); for the synthesis of formula 20, see Flynn, G.A .; et al., J. Amer. Chem. Soc. (1987), 109, 7914-1915; for the synthesis of the compound of formula 21, see Robl, J.A .; et al., J. Amer. Chem. Soc, (1994), 116, 2348-2355; for the synthesis of the compounds of formula 22-24 see, Robl, J.A. Tetrahedron Letters, (1994), 35, 393-396; for the synthesis of the compounds of formulas 25 and 26, see Wyvratt, MJ, et al., in "Peptides Structure and Function", Proceeding of the Eight American Symposium (Proceedings of the Eighth Conference American on Peptides), Eds. V.J. Hruby and D.H. Rich, pages 551-554, 1983 and Wyvratt, Matthew J., Jr. (Merck and Co., Inc.) S. African ZA 85 07,527 (C1.C07D), May 28, 1986, Application of the U.S.A. 655,818 from October 1, 1984. By analogy with the chemistry presented in Schemes 1-4, practitioners skilled in the art will quickly see that Formulas 17-26 can be transformed into bicyclic lactam inhibitors of the Formulas 27 classes. -36. The phthaloyl protection group in the amino group can be treated with hydrazine analogues in the transformation of Formula 14? Formula 15 in Scheme 4. Effectively such a transformation is reported by Formulas 17-26 in the literature (see previous list of references) This will produce a free amine or its salt that can be treated with PhCH20C0Cl or any reactive group to produce R38 - which contains the inhibitors as in formulas 28-37. As for the hydrolysis of the ester function in Formulas 17-26, TFA may be used for cases where the esters are t-butyl esters, an aqueous hydroxide anion may be used to effect hydrolysis. After the ester is hydrolyzed with the corresponding acid, the acid functionality in turn is used in the linkage with the aspartic acid derivatives (analogs to Formula 4? 5 (Scheme 1) and Formula 4 -> 9 ( Scheme 2) producing the compounds of the type described by the formulas SCHEME 1 Formula 2 Formula 1 H2; Pd / C; xtococí H-mßtllmorfolina Formula 'Formula 4 Formula 6 Formula 5 SCHEME 2 Formula 7 Formula 8 Formula 4 SCHEME 3 Formula 13 SCHEME 4 PhCH2OCOCI SCHEME 5 The following bicyclic ring systems are known in the literature and by analogy with Schemes 1, 2, 3 and 4, the following classes of compounds can be prepared.

SCHEME 5 (Continued) ' Formula 28 Formula 29 Formula 30 25 SCHEME 5 (Continue ¬ Formula 33 Formula 35 5 SCHEME 5 (Continued) where .COOtBu .c CoOcOtBu = OH, OtBu, Orne, Oet, X. COCHjX, N- NNHCONH, Z = PhCH20C0- (benzyloxycarbonyl); X = 0 (CO) 0-? Aryl, O (CO) o -heteroaryl, where the aryl, heteroaryl, X1, X2, X3? R38 are as previously described. SYNTHESIS OF INTERMEDIARIES OF FORMULAS 16 AND 4 A suspension of (1S, 9S) -t-butyloctahydro-10-oxo-9-phthalimido-6H-pyridazino [1, 2-a] [1,2] diazepine-1-carboxylate (Formula 14: 4.13 g, 10 mmol ) in ethanol (4.13 ml) was treated with hydrazine hydrate (1.1 g, 22 mmol). After the mixture has been stirred for 1 h. at room temperature, the solvents were evaporated and the residue was azeotroped with toluene. It was 2M aqueous acetic acid (41.3 ml) and the mixture was stirred for 3 h and then filtered.

The filtrate was basified with anhydrous sodium carbonate and 100 ml of dichloromethane were added. Then anhydrous sodium carbonate (1.59 g, 15 mmol) and benzyl chloroformate (2.14 ml, 15 mmol) were added at room temperature and the reaction mixture was stirred for 3 hours. The organic phase was separated, dried (Na2SO4) and the product (Formula 16) was purified by evaporative chromatography using 50% ethyl acetate-hexane.

To a stirred solution of t-butyl ester (Formula 16: 3.88 g, 9 mmol) in methylene chloride (30 ml) was added trifluoroacetic acid (50 ml) and continuous stirring for 5 hours. The solvents were evaporated and twice azeotroped with toluene (30 ml) to provide the product (Formula 4) in almost the quantitative product. Mass Spectrum: 376 (M + H) The following further illustrates the compounds of the present invention. EXAMPLE 1 Acid 5- (1-4-chlorofenyl) -3-trifluoromethyl) pyrazoloxymethyl acid acetonide [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazine [1, 2a] [ l, 2] diazepine-l-formmoyl] -L-aspartic Part A: Compound 1 (1.25 g, 3.3 mmol) was dissolved in THF (20 ml). The solution was cooled to -15 ° C and N-ethylmorpholine (440 uL, 4 mmol) was added followed by ethyl chloroformate (342 uL, 3.6 mmol). After stirring for 15 minutes at -15 ° C, and warmed to room temperature for 1 hour. Ethyl acetate (200 ml) was added and the solution was washed with water (100 ml) and saturated bicarbonate (50 ml) and dried over Na2SO4. Chromatography on silica gel was eluted with a gradient of EtOAc-hexane (10-70%) to yield 1.5 g (58%) of the bound product.

Part B: Compound 3 (1 g, 1.29 mmol) was dissolved in 200 ml of absolute ethanol. To this was added 6 N HCl (2.1 ml, 2.58 mmole) and Pd black (100 mg). The solution was reduced in Paar vibrator (2.10 kg / cm2 (30 psi) H2) for 4 hours. TLC (70% EtOAc / hexane) showed an Rf decrease of 0.75 to 0.00. The Pd was filtered and the solvent was evaporated to provide a quantitative product of the hydrochloric salt of amine 4. 1 Example 1 Part C: A 4 (1.18 g, 1.68 mmol) in methylene chloride (40 ml at 0 ° C) was added (456 mg, 252 mmol). Subsequently, N-methylmorpholine (920 uL, 8.4 mmol) was added along with dimethylaminopyridine (20 mg). The resulting mixture was stirred 30 minutes at 0 ° C and 1 hour at 25 ° C. The reaction mixture was washed with saturated bicarbonate. Purification by chromatographic elution of silica gel with a gradient of MeOH / methylene chloride (2-10% MeOH) yielded 1.5 g (76%) of the acylated product 6. This material was then treated with 255 of a solution of TFA in CH2C12 to provide the objective compound employing the conditions described for the preparation of Formula 4. Mass Spectrum: 776 (M + H) EXAMPLE 2 Aldehyde of [9-benzyloxycarbonylamino) octahydro-6, 10-dioxo-6h-pyridazino [l, 2a] [1,2] diazipine-l-formmoyl] -L-aspartic acid i Part A: H-Asp (OtBu) semicarbazone 7 (269 mg, 1.17 mmol), diazepine acid 1 (504 mg, 1.35 mmol, 1.1 eq), benzotriazole-1 were placed in a 200 ml round bottom flask. li-oxitris (dimethylamino) phosphonium hexafluorophosphate (BOP) (672 mg, 1.52 mmol, 1.3 eq), HOBT (206 mg, 1.52 mmol, 1.3 eq) together with anhydrous DMF (60 ml). Then, disopropylethylamine (0.8 ml, 4.68 mmol, 4 eq) was added. The reaction mixture was stirred overnight at 25 ° C and then the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO3 (saturated), H2O (3x), and brine. The organic layer was dried with NaSO4, filtered and the solvent evaporated to yield white crystals (395 mg, 57%). Mass spectrum: M / z 558 (M + H) Example 2 Part B: In a round bottom flask, 2.0 moles of 8 were added together with 70 ml of 25% trifluoroacetic acid in dichloromethane. After stirring for 2 hours, the solvents were removed in vacuo to provide a semi-solid residue. The residue was taken up in 30 ml of MeOH to which 9 ml of each ice cold HOAc and 37% aqueous formaldehyde was added. The mixture was stirred for 2 hours and 50 ml of water was added. The MeOH was removed in vacuo and the diluted aqueous solution was added with water and extracted with EtOAc. Further processing and purification by silica gel chromatography afforded the aldehyde of Example 2 in 50% ca produced completely from L. Mass Spectrum: m / z 475 (M + H) Using the methodology described for the preparation of Example 1 and 2 and with reference to Schemes 1, 2 and 3, the following compounds were prepared. EXAMPLE 3 Acetone 2,6-dichlorobenzoyloxymethyl acid [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum : m / z 677 (M + H) EXAMPLE 4 Acetone of 5- (1-phenyl-3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarbonylamino) octahydro-6, 10-dioxo-6H-pyridine-dazinofl, 2a] [1,2] diazepine-l-formmoyl] - L-aspartic Mass spectrum: m / z 715 (M + H) EXAMPLE 5 Acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l acetyl -formoil] -L-aspartic Mass Spectrum: m / z 749 (M + H) EXAMPLE 6 Acetone of 5- (1- (2-pyridinyl) -3-trifluoromethyl) pyrazoloxy-methyl [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine- acetone l-formmoyl] -L-aspartic Mass Spectrum: m / z 716 (M + H) EXAMPLE 7 Acetone of 5- (1- (4-chlorophenyl) -3-trif luoromethyl) pyrazoloxy-ethyl acid [9-benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1,2-] [1,2] diazepine -l-formmoyl] -L-aspartic Mass Spectrum: m / z 719 (M + H) EXAMPLE 8 Acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9- (4-carboxymethylthio) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [l] acetone , 2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 809 (M + H) Acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9- (4-carboxyethylthio) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1, 2a | , 2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 823 (M + H) EXAMPLE 10 Acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9-isobutyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine- acetone lf ormoil] -L-aspartic Mass Spectrum: m / z 715 (M + H) EXAMPLE 11 Acetone of 2,6- dichlorobenzoyloxymethyl acid [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridin-dazin [1,2-] [1,2] diazepine-l-formmoyl] -L -aspartic Mass spectrum: m / z 705 (M + H) EXAMPLE 12 Acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) -pyrazol-oxymethyl of [9- (4-carboxyethylmethyl) benzoylamino) octa-hydro-6,10-dioxo-6H-pyridazino [l, 2a] acetone ] [1, 2] diazepine-l-formmoyl] - L-aspartic Mass Spectrum: m / z 791 (M + H) EXAMPLE 13 Acetone 2,6- dichlorobenzoyloxymethyl acid [9- (4-N-morpholinomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridine-zino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 746 (M + H) EXAMPLE 14 Acetone of 2,6-dichlorobenzoyloxymethyl acid [9- (N- [4- (N-methylpiperazino) methyl] benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1,2-] [1,2] diazepine- l-formmoyl] -L-aspartic Mass Spectrum: m / z 759 (M + H) EXAMPLE 15 Acetone of 2,6- dichlorobenzoyloxymethyl acid [9- (4- (N- (2-methyl) imidazolylmethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1,2-] [1,2] diazepine- l-formmoyl] -L-aspartic Mass Spectrum: m / z 742 (M + H) EXAMPLE 16 Acetone 2,6-dichlorobenzoyloxymethyl acid [9- (5-benzimidazoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1, 2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 687 (M + H) EXAMPLE 17 Acetone 2,6-dichlorobenzoyloxymethyl acid [9- (5-benthiazoylamino) octahydro-6, 10-dioxo-6H-pyridazinofl, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid Mass Spectrum: m / z 688 (M + H) EXAMPLE 18 Acetone 2,6-dichlorobenzoyloxymethyl acid [9- (N-carboethoxy-5-benthiazoylamino) benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1,2 a] [1,2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 760 (M + H) EXAMPLE 19 Acetone 2,6-dichlorobenzoyloxymethyl acid [9- (N-carboethoxy-5-benzimidazolamino) octahydro-6, 10-dioxo-6H-pyridin-dazinofl, 2a] [1,2] diazepine-l-formmoyl] -L -aspartic Mass Spectrum: m / z 759 (M + H) EXAMPLE 20 Acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9- (4-carboxypropyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [] 1, 2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 805 (M + H) EXAMPLE 21 [9-Benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid aldehyde Mass Spectrum: m / z 446 (M + H) EXAMPLE 22 [9- (4-Carboxymethoxy) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid aldehyde Mass spectrum: m / z 519 (M + H) EXAMPLE 23 Acetone 2,6-dichlorobenzoyloxymethyl acid [9-benzyloxycarbonylamino) octahydro-6, 10-oxo-6H-pyridazino [1,2a] [1,2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 663 (M + H) EXAMPLE 24 Acetone of 5- (1- (4-chloro-2-pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl acid [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 750 (M + H) EXAMPLE 25 Acetone of 5- (1- (2-pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl [9- (4-dimethylaminomethyl) benzoylamino) octahi-dro-6,10-dioxo-6H-pyridazino [1, 2a] acetone ] [1, 2] diazepine-l-formmoyl] -L-aspartic Mass Spectrum: m / z 743 (M + H) EXAMPLE 26 [9- (2-Fluorobenzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid aldehyde Mass Spectrum: m / z 463 (M + H) EXAMPLE 27 Acid aldehyde [9- (2-pyridinolamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic Acid mass: m / z 5446 (M + H) EXAMPLE 28 [9- (4-Methylpiperazino) methyl] benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid aldehyde Mass Spectrum: m / z 557 (M + H) IN VITRO TEST The second inactivation ratios were obtained by using the enzymatic assay described in Dolle, RE.; et al., J. Med. Chem. (1994), 37, 563. Note that the aldehydes of Examples 2, 21, 22 and 26.28 are irreversible inhibitors and show slow kinetic elements. In the case of these irreversible inhibitors, the in vitro assay was modified to obtain the reversible K ± * as follows: The Ki * values for the reversible inhibitors were determined by pre-incubation of ICE with various concentrations of the inhibitor at 10 mM. HEPES (a common laboratory stabilizer at a pH of 7.5), 25% glycerol, 1 mM dithiothreitol for 30 minutes at 37 ° C in a polystyrene 96 well plate. The activity of the remaining ICE was measured by adding 10 uM methylcoumarin of Succinyl-Tyrosine-Valine-Alinaine Aspartic acid (Bachem Bioscience, Inc.) and the increase in fluorescence at 37 ° C was monitored using a plate reader of fluorescence Fluorskan II. The Ki * was calculated from a 1 / v piece as compared to I as previously described (Morrison, JF and Cleland, W. (1983) Biochemistry 22, 5507- 5513. The compounds of Examples 1, 3-20 and 23-25 possess the inhibition of the protease IL-lß (kob »/ [I] = >; 10,000 M_1s "x) while compounds 2, 21, 22 and 26-28 also have the inhibition of IL-lß protease (Ki * = <10 μM) IN VIVO TEST Inhibition was determined in vivo (IC50) as follows: Human monocytes were isolated from heparinized leukophoresis units through Biological Specialty Corporation (Lansdale, PA) Monocytes were purified by Ficoll-Hupaque gradient centrifugation.

(Pharmacia Fine Chemicals, Piscataway, NJ) and more than 95% of the pure monocyte populations were obtained by centrifugal purification or elutriation. The assay was carried out on duplicate samples of freshly isolated human monocytes, cultured in suspension at 37 ° C and gently turned in conical bottom polypropylene tubes (Sardstedt Inc., Princeton, NJ). Human monocytes at a concentration of 5 x 10 6 cells / ml were resuspended in 1 ml of RPMI 1640 (a common tissue stabilizer from MA Bioproducts, Waikersville, MD) containing 1% fetal calf serum (FCS). ) (HyClone, Logan UT) and 50 μg / ml gentamicin (Gibco, Grand Island, NY). The cells were treated either with a compound of the invention (ie, test compounds) or without an inhibitor (control compound, typically 0.03% DMSO) for 15 minutes and then activated with 0.01% stable Staphylococcus aureus (The Enzyme Center, from Malden, MA) for 1 hour. The cells were then centrifuged and resuspended in 1 ml of cysteine, the methionine-free RPMI medium containing 1% dialyzed FCS (Hyclone). The cells were pretreated with a test compound or control compound for 15 minutes after which, 0.01% stable S. aureus plus 100 μCi of the Tran 35-S classification (ICN, Irvine, CA) was added and the cells were incubated at 37 ° C for 1 hour. After incubation, the cells were centrifuged, washed once in the phosphate stabilizing saline and resuspended in 1 ml of RPMI containing 1% fetal calf serum. The cells were again pre-treated with a test or control compound for 15 minutes and then 0.01% S. aureus was added for 2 hours. At the end of the incubation, the cells were centrifuged and the supernatants stored for immunoprecipitation. The cells were washed once in the phosphate stabilizing saline then lysed in RIPA, a stabilizer from the continuous cell medium containing 2 mM phenylmethylsulfonyl fluoride, 10 mM iodoacetate, 1 μg / ml pepstatin A, 1 μg / ml of leupeptin and 0.5 of aprotinin from TIU. For immunoprecipitations, an equal volume of of dry milk in a RIPA stabilizer plus 50 μl of resuspended protein Sepharose A CL-4B (Pharmacia, from Piscataway, New York) were added to the supernatants and 1 ml of 4% dry milk containing Sepharose A from protein CL-4b in the samples and cell lysates under agitation for 30 minutes at 4 ° C. The beads were then centrifuged, the samples transferred to the new tubes and incubated overnight with 40 μg of the rabbit anti-human IL-1 polyclonal antibody (Genzyme, Cambridge, MA). The IL-lβ proteins were then precipitated with 70 μl of protein Sepharose A, resuspended in 60 μl of the SDS sample stabilizer and run in 15% SGD-PAGE gels. Autoradiography was carried out on dry gels and the amount of radioactivity (count per minute, cpm) was quantified using a Betascope 603 analyzer. DATA ANALYSIS In the pulsed monocyte extraction assay, each test parameter was run through duplicate. The data was collected from a Betascope analyzer using a personal computer, then transferred to the VAX system to calculate the standard deviation and the mean cpm of the mean. When testing compounds were evaluated, the percentage inhibition of mature IL-lβ was calculated as follows: 100 x [1- (cells treated with stimuli + the test compound - unstimulated cells) / (cells treated with stimuli + test compounds - unstimulated cells)] This percentage in the inhibition values were then used to calculate the IC5o value for each compound. Since the pulsed-extraction assay of human monocytes employs primary cells from different donors, each test compound ran in 2.3 separate experiments, using monocytes from 2-3 different donors.

Claims

For examples 1-25, the IC50 in vivo was from < 10 μM. NOVELTY OF THE INVENTION Having described the invention as above, the content of the following is considered to be our property. CLAIMS 1. A compound of the formula (A) or its pharmaceutically acceptable salt: Z-N-Y H (A) wherein and when R2 = 0H, then Y can also be equal to where n = 0, 1 R1 = H or deuterium; R2 = OR4 or NHOH; R * = H, alkyl, cycloalkyl, aralkyl; R3 = H, (CRβR) 0-6CF3, (CRβR9) or -6CF2CF3, (CR8R9) 0-ßC00R5, (CR8-R9) 0-6CONR6R7, CF2 (CHβR9) or -6aryl, CF2 (CR8R9) 0-6heteroaryl, CF2 (CR8R9) 0-ßalkyl, CHN2CH2R10, C0R5: wherein R5 = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R6 and R7 are independently selected from H, alkyl, cycloalkyl, aryl aralkyl, heteroaryl, heteroaralkyl and wherein R6 and R7 taken together may be a 3-, 4-, 5-, 6- or 7-membered carbocyclic ring. R8 and R9 independently are H or alkyl; R10 = alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, H, halo, SR5, SR5R6, O (CO) 0-? Aryl, O (CO) o -heteroaryl, R11 and R12 are optionally selected from H, OH, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, aroxy, aralkyloxy, heteroaroxi, heteroaralkyloxy; R 13 = H, alkyl, aryl, aralkyl; R 14 and R 15 are optionally selected from H, alkyl, aryl or when R 14 and R 15 are taken together is an aryl ring; X1 = O, S, NR28 wherein R2B = H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R16 = H, Cl, alkyl, (CR8R9) 0-6aryl; R17 and R18 independently are H or alkyl; X2 = CH2, O, NR28; R19 = H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; R20 = H, alkyl, CF3, CF2CF3, COOR5, CONR6R7, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and wherein R21 = H or alkyl; R22, R23, R24, R25, R26 and R27 independently are selected from H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and R29; and wherein R24 and R25 are taken together can be aryl or heteroaryl; X3 = 0, S; > 29 = F, Cl, CF3, CF2CF3, (CF2) 0-3-H, C00Ra, CONR30R31, where R > 30 and R > 31 are optionally selected from R and R, (CR8R -O z = where q = 0, 1 m = 0, 1, 2, 3; o = 0, 1, 2; X4 = H, alkylthio; R33 and R34 are optionally H, alkyl, aryl or when taken together, R33 and R34 are aryl, heteroaryl or a double bond; R35 and R36 are optionally an oxygen atom or do not bind; R37 = H, alkyl; R3B = independently is selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R0-S02, R41-C0, R500- CO, R51NR5-C0; wherein R40 = R5 or HNR5; R41 = alkenyl, aralkenyl, heteroaralkenyl, alkynyl, aralkynyl, heteroaralkynyl, R42-0C0Rd, R3-COR5, R42- NR7C (= NR6) R5, R42-NR7 (= NR6) NR5, R42-SR5, R42-S (CR8R9) ? -6C00R47, R42- S (CR8R9)? 6COONR47R48, R42-OR5, R42-0 (CR8R9)! -6C00R47, R42-0 (CR8R9) x_ 6COONR47R48, R42-NR5S02R6, R3-R44, R3-R45, R43-R46, R43-NR7R48, R42-OH, R43-CF3; where R42 = (CRßR9)? -7 and R43 = (CR8R9) 0-6 f R = H, alkyl, - (CH 2) 0 - «- cycloalkyl; ~ (CH2) 0- .43 , aryl, heteroaryl, aralkyl, heteroaryl, - (CH2) 2-6R49; where p = 1-4; R49 = alkoxy, CH2F, CHF2, CF3, CF2CF3, OH, COOR47, CONR47R48; or NR47R48; wherein R48 is independently H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, CH2CH20-alkyl and C (0) -R49; R47 is independently H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; and when R47 and R48 are taken together, they can be equal to a ring with five, six or seven members, of the type: where p = l-4 and n = 0-l; R49 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; where p-1-4; R50 and R51 = independently is selected from alkyl, R43-cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R42-alkenyl, R42-heteroaralkenyl, R42-alkynyl, R42-aralkynyl, R5"2 -heteroaralkynyl R 43_ -nR46, t R342_ -rR) 49, t R >; 5ß2z -_? R-, 4"5, t R, 4 € 2Z.-COOR47, R42-CONR47, R 2-CONR 7R48, R52-0C0R5, R52-C0Rs, R52-NR> 4" 7C, ( NR? 6ß) R > 5 °, n R52 - »NtrR > 4"7? _" COOR, R -S (CR8R9)? _6COONR47R48, RS2-0R5, RS2-0 (CR8R9)? -6COOR47, R? 2-S (CR8R9)! -6COONR47R4?, R52-NR5S02R6, R52-R44, R52 -NR47R48, wherein R92 = (CR8R9) 2-6, 2. The compound according to claim 1, wherein: R2 = OR4 R3 = H, COR5, COOR5, CONR6R7, CF2 (CR8R9) 0-ßayl, CF2 (CR8R9) 0-β -heteroaryl, CF2 (CR8R9) 0-6alkyl, CHN2, CH2R10 3. The compound according to claim 2, wherein: R10 is = alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, 0 ( C0) o -aryl, 0 (C0) o-aheteroaryl, 4. The compound according to claim 3, wherein: R10 = halo, 0 (CO) 0-? Aryl, O (CO) o -heteroaryl, OPIOJR ^ R12, wherein R11 and R12 = alkyl, aralkyl and aryl; R19 = aryl; R20 = alkyl, CF3, CF2CF3, COOR8, CONR6R7; R22 = aryl, aralkyl, heteroaryl and heteroaralkyl. 5. The compound according to claim 1, wherein: where X3 = O; q = 0, 1; = 1, 2; o = 1; R33 and R34 are H when taken together can be an aryl or a double bond and when R37 = H. 6. The compound according to claim 2, wherein: where X3 = 0; q = 0, 1; m = 1, 2; o = 1; R33 and R34 are H when taken together can be an aryl or a double bond and when R37 = H. The compound according to claim 3, wherein where X3 = 0; q = 0, 1; m = 1, 2; o = 1; R33 and R34 are H when taken together can be an aryl or a double bond and when R37 = H. The compound of claim 4, wherein where X3 = O; q = 0, 1; m = 1, 2; o = 1; R33 and R34 are H when taken together can be an aryl or a double bond and when R37 = H. 9. The compound according to claim 2, wherein: R 4 = H, alkyl; R > 1i9 = aryl; R, 2"0" alkyl, CF3 and CF2CF3; R "= H where X3 = O; q = 0, 1; m = 1, 2; o = 1; R33 and R34 are H when taken together can be an aryl or a double bond and when R37 = H. The compound according to claim 9, wherein m = 1.2; X3 = O; q = O,. 11. The compound according to claim 9 wherein: X3 = O; m = 1.2; q = O, 1. 12. The compound according to the claim 9, where: X3 = 0; m = 1.2; q = 0, 1 13. The compound according to claim 10, wherein: R4 = H, alkyl; n = 0; R3 = H, CH2-halo, CH2-0C0-aryl, and wherein R21 = H, alkyl. The compound according to claim 13, wherein: X3 = 0; m = 1.2; q = 0, 1. 15. The compound according to the claim 13, where: X3 = O; m = 1.2; q = 0, 1. 16. The compound according to claim 1 selected from the group consisting of: acetone of 2,6-dichlorobenzoyloxymethyl acid [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l] , 2a] [1,2] diazepine-l-for-moyl] -L-aspartic acid, 2,6-dichlorobenzoyloxymethyl acetone [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6,10-dioxo-6H- acetone pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-dichlorobenzoyloxymethyl acetone [9- (N- [4-methylpiperazine] methyl] benzoylamino) octahydro- 6,10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid 2,6-dichlorobenzoyloxymethyl acetone [9- (4- (N-methylpiperazi- nylmethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1,2-] [1,2] diazepine-1-formmoyl] -L-aspartic acid 2,6-dichloro-benzoyloxymethyl acetone [9-] (4- (N- (2-methyl) imidazolylmethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1,2-] [1,2] dia-zepine-1-formmoyl] -L-aspartic acid. The compound according to claim 1, selected from the group consisting of: [9- (5-benzimidazoylamino) oc-tahydro-6,10-dioxo-6H-pyridazino [2,6-dichlorobenzoyloxymethyl] acetone [l] , 2a] [1,2] diazepine-l-for-moyl] -L-aspartic acid, 2-6-dichlorobenzoyloxymethyl acetone [9- (5-benthiazoylamino) octahydro-6,10-dioxo-6H-pyrida- zino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-dichlorobenzoyloxymethyl acetone [9- (N-carboethoxy-5-ben-triazoylamino) octahydro-6, 10 -dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-dichloroben-zoyloxymethyl acetone [9- (N-carboethoxy-5-benzimidazoylamino)] octahydro-6, 10-dioxo-6H-pyridazino [1,2 a] [1,2] diazepine-l-for-moyl] -L-aspartic acid 2,6-dichlorobenzoyloxymethyl acetic acid [9-benzyloxycarbonylamino) octahydro- 6, 10-oxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid. 18. The compound according to claim 1 selected from the group consisting of: 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone of [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6 acid , 10-dioxo-6H-pyr-dazino [1,2,2] [1,2] diazepine-l-formmoyl] -L-aspartic acid, acetone 5- (1-phenyl-3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarbonylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formyl] -L-aspartic acid , acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl of [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l acetone -formoyl] -L-aspartic acid, acetone of 5- (l- (2-pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarbonylamins) octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [ 1, 2] diazepine-1-formmoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone of [9-benzoylamino) octahydro-6,10-dioxo-6H- acetone pyridazino [l, 2a] [l, 2] dia-zepine-1-f ormoyl] -L-aspartic acid. 19. The compound according to claim 1 selected from the group consisting of: acetone of 5- (1- (4-chlorofenyl) -3-trif luoromethyl (pyrazoloxymethyl of [9- (4-carboxymethylthio) benzoylamino) octahydro acid -6, 10-dioxo-6H-pyridine-zino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) acetone) pyrazoloxymethyl [9- (4-carboxyethylthio) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid acetone of 5- ( 1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9-isobutyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L acid -aspartic, acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acid [9- (4-carboxyethylbenzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [l , 2] diazepine-lf ormoyl] -L-aspartic acid, acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl of [9-carboxypropyl) benzoylamino) octahydro- 6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-lf ormoyl] -L-aspartic acid, 5- (1- (4-chloro-2-pyridinyl) -3-trif luoromethyl acetone ) [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-lf ormoyl] -L-aspartic acid pyrazooxymethyl acetone of 5- (1- (2- pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl [9- (4-dimethylaminomethyl) benzoyl-amino) octa-hydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] ] -L-aspartic. 20. The compound according to the claim 1, selected from the group consisting of [9-benzyloxycarbonylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid aldehyde, aldehyde [9-benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid, [9- (4-carboxymethoxy) benzoylamino acid aldehyde ) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid [9- (2-fluorobenzoylamino) octahydro-6, 10- dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid [9- (2-pyridinoylamino) octahydro-6,10-dioxo-6H-pyridazinodehyde [l] , 2a] [1, 2] diazepine-l-formmoyl] -L-aspartic acid and [9- (N- (4-methylpiperazino) methyl] benzoylamino) octahydro-6, 10-dioxodehyde acid -6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid. A pharmaceutical composition for inhibiting the interleukin-lβ protease comprising the compound of the formula (A) defined in claim 1 in a pharmaceutically acceptable carrier. 22. A pharmaceutically composition comprising the compound defined in any of claims 2-15 in a pharmaceutically acceptable carrier. 23. A pharmaceutical composition comprising the compound according to claim 1, acetone of 2,6-dichlorobenzoyloxymethyl [9-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] acetone. ] diazepine-l-for-moyl] -L-aspartic acid, 2-6-dichlorobenzoyloxymethyl acetone [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [ l, 2] diazepine-l-formmoyl] -L-aspartic acid, 2-6-dichlorobenzoyloxymethyl acetone [9- (4- (N-morpholinomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridine-zine [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic, acetone of 2,6-dichlorobenzoyloxymethyl acid [9- (N- (4-methylpiperazino) methyl] octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepamine l-formoyl] -L-aspartic acid acetone of 2,6-dichlorobenzoyl-oxymethyl acid [9- (4- (N- (2-methyl) imidazolylmethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [ 1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid 24. A pharmaceutical composition comprising the compound according to claim 1, selected from the group consisting of the group consisting of acetone of 2, 6-Dichlorobenzoyloxymethyl [9- (5-be? Cimidazoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-for-moyl] -L-aspartic acid, acetone of 2,6-dichlorobenzoyloxymethyl [9-bentriazoylamino) octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-acetone [9- (N-carboethoxy-5-benzene-zoilamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diaze-pina-l-formmoyl] -L-dichlorobenzoyloxymethyl acid aspart co, acetone of 2,6-dichlorobenzoyl-oxymethyl acid [9- (N-carboethoxy-5-benzimidazoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l- for-moil] -L-aspartic acid, 2-6-dichlorobenzoyloxymethyl acetic acid [9-benzyloxycarbonylamino) octahydro-6, 10-oxo-6H-pyridine-zino [l, 2a] [1,2] diazepine-l- formoil] -L-aspartic. 25. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of: 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone of [9- (4-dimethylamino- methyl) benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1, 2] diazepine-l-formmoyl] -L-aspartic acid, 5- (l-phenyl-3-trifluoromethyl) pyrazoloxymethyl acetone of [9-benzyloxycarbo-nylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [l, 2] diaze-pina-l-formmoyl] -L-aspartic acid, acetone of 5- (1-) (4-Chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarboxy-nyla) -hydrohydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diaze-pina-l-formmoyl] -L-aspartic acid acetone of 5- (1- (2-pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarbo-nylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l] acid , 2] diazepi-na-l-formmoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone [9-benzoylamino) oc-tahi dro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-for-moyl] -L-aspartic acid. 26. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of: 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone of [9- (4-carboxymethyl- tiltio) benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, acetone of 5- (1- (4-chlorophenyl) -3 -trifluoromethyl) pyrazoloxymethyl [9- (4-carboxyethylthio) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diaze? ina-l-formmoyl] -L- Aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetic acid [9-isobutyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridine-zine [1, 2a] [1,2] diazepine-l-formoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone of [9- (4-carboxyethylbenzoylamino) octahydro-6,10-dioxo-6H-pyridine -zino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acid acetone [9-carbo] xypropyl) benzoylamino) octahydro-6, 10-dioxo-6H-pyridine-zinofl, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 5- (1- (4-chloro-2-acetone pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl [9-benzyloxycarbonylamino) octahydro-6, 10-dioxo-6H-pyridin-dazinofl, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, acetone 5- (1- (2-pyridinyl) -3-trifluoromethyl) pyrazoloxymethyl [9- (4-dimethylaminomethyl) benzoylamino) octa-hydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid. 27. A pharmaceutical composition comprising the compound according to claim 1, selected from the group consisting of [9-benzyloxycarbonylamino) octahydro-6 acid aldehyde., 10-dioxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, [9-benzoylamino) octahydro-6,10-dioxo-6H-pyridazinodehyde [] , 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid [9- (4-carboxymethoxy) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [] , 2] diazepine-l-formmoyl] -L-aspartic acid [9- (2-fluorobenzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-aldehyde formoyl] -L-aspartic acid [9- (2-pyridinoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] acid aldehyde [1, 2] diazepine-l-formoyl] -L-aspartic acid and [9- (N- (4-methylpiperazino) methyl] benzoylamino) octahydro-6, 10-dioxodehyde acid -6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid. 28. A method for inhibiting the activity of interleukin-lb protease in a mammal in need of treatment for inflammatory diseases and immune-based diseases of the lung, central nervous system and connective tissue, which comprises administering to said mammals an effective amount inhibiting interleukin-lb of a composition comprising a compound of the formula (a) or its pharmaceutically acceptable salt: ZNY H (A) wherein and when R2 = 0H, then Y can also be equal to where n = 0, 1 R1 = H or deuterium; R2 = OR4 or NHOH; R 4 = H, alkyl, cycloalkyl, aralkyl; R3 = H, (CR8R9) 0-6CF3, (CR8R9) 0-6CF2CF3, (CR8R9) o-ßCOOR5, (CRβ-R9) 0-6CONR6R7, CF2 (CH8R9) 0-6aril, CF2 (CR8R9) o-β -heteroaryl, CF2 (CR8R9) 0- "alkyl, CHN2CH2R10, C0R5: wherein R5 = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R6 and R7 are independently selected from H, alkyl, cycloalkyl, aryl aralkyl, heteroaryl, heteroaralkyl and wherein R6 and R7 taken together may be a 3-, 4-, 5-, 6- or 7-membered carbocyclic ring. R8 and R9 independently are H or alkyl; R10 = alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, H, halo, SR5, SRSR6, O (CO) or -aryl, O (CO) o -heteroaryl, 0P (0) R "R12, R11 and R12 are optionally selected from H, OH, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, aroxy, aralkyloxy, heteroaroxi, heteroaralkyloxy; R 13 = H, alkyl, aryl, aralkyl; R 14 and R 1 S are optionally selected from H, alkyl, aryl or when R 14 and R 15 are taken together is an aryl ring; X1 = O, S, NR28 wherein R28 = H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R16 = H, Cl, alkyl, (CR8R9) 0-p-aryl; R17 and R18 independently are H or alkyl; X2 = CH2, O, NR28; R = H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; R20 = H, alkyl, CF3, CF2, CF3, COOR5, CONR6R7, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and wherein R21 = H or alkyl; R22, R23, R24, R2S, R26 and R27 independently are selected from H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and R29; and wherein R24 and R25 are taken together can be aryl or heteroaryl; X3 = 0, S; R29 = F, Cl, CF3, CF2CF3, (CF2) 0-3-H, COOR5, C0NR30R31, where R30 and R31 are optionally selected from R6 and R7, (CRßR9) 2. • N (CR1 ßD »l - - * - i (CR8R! 2-í O '. q = 0, 1 m = 0, 1, 2, 3; o = 0, 1, 2; X4 = H, alkylthio; R33 and R34 are optionally H, alkyl, aryl or when taken together, R33 and R34 are aryl, heteroaryl or a double bond; R35 and R36 are optionally an oxygen atom or do not bind; R37 = H, alkyl; R38 = independently is selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R40-S02, R41-CO, R500- CO, R51NR5-C0; where R '"= R ° or HNR °; R41 = alkenyl, aralkenyl, heteroaralkenyl, alkynyl, aralkynyl, heteroaralkynyl, R42-0C0R5, R43-COR5, R42-NR47C (= NR6) RS, R2-NR47 (= NR6) NR5, R42-SR5, R42-S (CR8R9) ? -6C00R47, R42-S (CR? R9)? 6COONR47R48, R4 -OR5, R42-0 (CR8R9)? - "COOR47, R2-0 (CR8R9) i-" COONR47R48, R -NR5S02R6, R43-R44, R43- R45, R3-R46, R3-NR7R4β, R42-OH, R43-CF3; wherein R42 = (CR) ^ and R43 = (CR8R9) 0-β; R "= H, alkyl, - (CH 2) o-4-cycloalkyl; - (CH 2) - F - (CH2) o-4 i aryl heteroaryl, aralkyl, heteroaralkyl, - (CH2) 2.6R49; where p = 1-4; R49 = alkoxy, CH2F, CHF2, CF3, CF2CF3, OH, COOR47, C0NR7R48; or NR7R48; wherein R48 is independently H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, CH2CH20-alkyl and C (0) -R49; R47 is independently H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; and when R47 and R48 are taken together, they can be equal to a ring with five, six or seven members, of the type: where p = l-4 and n = 0-l; R49 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; r ~ \ 545 - N if X -N ^ s R "= 'in don e p-1-4; R50 and R51 = independently is selected from alkyl, R43-cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R2-alkenyl, R2-heteroaralkenyl, R42-alkynyl, R42-aralkynyl, R2-heteroaralkynyl R3-R46, R-R49, R52 -R45, R42-COOR47, R2-CONR47, R -CONR47R48, R52-OCOR5, R52-C0R5, R52-NR7C (NR6) R5, R52-NR47 (= NR6) NR5, R52-SR5, R52-S (CR8R9) ? _ «COOR47, R52-S (CR8R9)? - 6COONR47R48, R52-0Rs, RS2-0 (CR8R9) x-« C00R47, R52-S (CRβR9) 2-6C00NR47R48, R52-NR5S02Rβ, R52-R44, R52- NR47R48, where R52 = (CR8R9) 2.β; 29. A method for inhibiting the activity of the interleukin-1β protease in a mammal in need of treatment for inflammatory and lung-based diseases of the lung, central nervous system and connective tissue, which comprises administering to said mammals an effective amount inhibitor of interleukin-lβ of a composition comprising a compound defined in any of claims 2-15. 30. A method for inhibiting the activity of interleukin-1β protease in a mammal in need of treatment for inflammatory and immune-based diseases of the lung, central nervous system and connective tissue, comprising administering to said mammals an effective amount inhibitor of interleukin-1β of a composition comprising a compound selected from the group consisting of: [6-benzyloxycarbonylamino) octahydro-6,10-dioxo-6H-pyridazino [2,6-dichlorobenzoyloxymethyl] acetone [1, 2a] [l] , 2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-dichlorobenzoyloxymethyl acetone [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [ l, 2] dia-zepine-l-formmoyl] -L-aspartic acid, 2,6-dichloro-benzoyloxymethyl acetone [9- (4- (N-morpholinomethyl) benzoylamino) octahydro-6, 10-dioxo-6H -pyridazino [1, 2a] [1,2] diazepine-1-formmoyl] -L-aspartic acid, 2,6-dichlorobenzoyloxymethyl acetone [9- (N- [4-methylpiperazino] m] ethyl] benzoylamino) octahi-dro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-d-chlorobenzoyloxymethyl acid acetone [ 9- (N- [4-methylpiperazino) methyl] benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1,2,2] [1,2] diazepine-l-formmoyl-J-L-aspartic acid, 2,6-acetone [9- (4- (N- (2-ethyl) imidazolylmethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] - dichlorobenzoyloxymethyl acid L-aspartic. 31. A method for inhibiting the activity of the interleukin-1β protease in a mammal in need of treatment for inflammatory and immune-based diseases of the lung, central nervous system and connective tissue, which comprises administering to said mammals an effective amount inhibitory of interleukin-1β of a composition comprising a compound selected from the group consisting of: [9- (5-benzimidazoylamino) octahydro-6,10-dioxo-6H-pyridazino [6,2-dichlorobenzoyloxymethyl] acetone [1, 2a] ] [1,2] diazepine-l-for-moyl] -L-aspartic acid acetone of [9- (5-bentriazoylamino) octa-hydro-6,10-dioxo-6H-pyridazino [2,6-dichlorobenzoyloxymethyl] acetone [ l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-dichlorobenzoyloxymethyl acetone [9- (N-carboethoxy-5-bentriazoylamino) octahydro-6, 10-dioxo-6H acetone] -pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 2-6-dichlorobenzoyloxymethyl acetone [9- (N-carboethoxy-5-benzimidazoylamino) octa] Hydro-6, 10-dioxo-6H-pyridazino [1,2-] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 2,6-dichloro-benzoyloxymethyl acetone [9-benzyloxycarbonylamino) octahydro- 6, 10-oxo-6H-pyridazino [1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid. 32. A method for inhibiting the activity of the interleukin-1β protease in a mammal in need of treatment for inflammatory and immune-based diseases of the lung, central nervous system and connective tissue, which comprises administering to said mammals an effective amount inhibitory of interleukin-lβ of a composition comprising a compound selected from the group consisting of: 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetone of [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] diaze-pina-l-formmoyl] -L-aspartic acid, 5- (1-phenyl-3-trifluoromethyl) pyrazoloxymethyl acid acetone [9-] benzyloxycarbonyl-amino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-acetone -tri-fluoromethyl) pyrazoloxymethyl of [9-benzyloxycarbonyl-amino) octahydro-6,10-dioxo-6H-pyridazino [1,2 a] [1,2] diazepine-l-formmoyl] -L-aspartic acid acetone; - (1- (2-pyridinyl) -3-tri-fluoromethyl) pyrazoloxymethyl [9-benzyloxycarbonyl-amino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l -formoyl] -L-aspartic acid, acetone of 5- (1- (4-chlorophenyl) -3-tri-fluoromethyl) pyrazoloxymethyl [9-benzoylamino) octa-hydro-6,10-dioxo-6H-? iridazino acid acetone [ 1, 2a] [1,2] diazepine-l-formmoyl] -L-aspartic acid. 33. A method for inhibiting the activity of the interleukin-1β protease in a mammal in need of treatment for inflammatory and immune-based diseases of the lung, central nervous system and connective tissue, which comprises administering to said mammals an effective amount inhibitor of interleukin-lβ of a composition comprising a compound selected from the group consisting of: 5- (1- (4-chlorophenyl) -3-trifluoro-methydropyrazoloxymethyl acid [9- (4-carboxymethylthio) benzoylamino) octahydro- 6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] dia-zepine-l-formmoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) acetone ) [9- (4-carboxy-ethylthio) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid pyrazooxymethyl acetone 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl [9-isobutyloxycarbonylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-l-formmoyl] -L-aspá Arctic, acetone of 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acid [9- (4-carboxyethylbenzoylamino) octahydro-6,10-dioxo-6H-pyridazino [1, 2a] [1,2] ] diazepine-l-formoyl] -L-aspartic acid, 5- (1- (4-chlorophenyl) -3-trifluoromethyl) pyrazoloxymethyl acetic acid [9-carboxypropyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazine [1, 2a] [1,2] diazepine-1-formmoyl] -L-aspartic acid, acetone of 5- (1- (4-chloro-2-pyridinyl) -3-trifluoromethyl) pyrazoloxyethyl acid [9-] benzyloxycarbonylamino) octahydro-6, 10-dioxo-6H-pyr-dazino [1,2,2] [1,2] diazepine-l-formmoyl] -L-aspartic acid, 5- (1- (2-pyridinyl) -acetone) trifluoromethyl) pyrazoloxymethyl [9- (4-dimethylaminomethyl) benzoylamino) octahydro-6,10-dioxo-6H-pyridazino [l, 2a] [1,2] diazepine-1-formmoyl] -L-aspartic acid. 34. A method for inhibiting the activity of the interleukin-1β protease in a mammal in need of treatment for inflammatory and immune-based diseases of the lung, central nervous system and connective tissue, which comprises administering to said mammals an amount Effective interleukin-lβ inhibitory composition of a composition comprising a compound selected from the group consisting of: [9-benzyloxycarbonylamino-n-octahydro-6,10-dioxo-6H-pyridazino] [1, 2] acid aldehyde [1, 2] diazepine-l-formmoyl] -L-aspartic acid [9-benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [l, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid aldehyde , [9- (4-carboxymethoxy) benzoylamino) octahydro-6, 10-dioxo-6H-pyridazino [1, 2a] [1,2] dia-zepine-l-formmoyl] -L-aspartic acid aldehyde, aldehyde [9- (2-fluorobenzoylamino) octahydro-6, 10-dioxo-6H-pyridazinofl, 2a] [l, 2] diazepine-l-formmoyl] -L-aspartic acid, [9- (2-pyridinoylamino) acid aldehyde octahydro- 6, 10-dioxo-6H-pyridazino [1,2-] [1,2] diazepine-l-formmoyl] -L-aspartic acid and [9- (N- (4-methylpiperazino) methyl] benzoylamino) octahydro- 6, 10-dioxo-6H-pyridazinofl, 2a] [1,2] diazepine-lf ormoyl] -L-aspartic acid.