DK200600313A - Treating type 2 diabetes or metabolic syndrome with an interleukin 1beta inhibitor or an interleukin 1beta synthesis or release inhibitor - Google Patents

Description

TREATING TYPE 2 DIABETES OR METABOLIC SYNDROME WITH AN INTERLEUKIN 1|3 INHIBITOR OR AN INTERLEUKIN Ip SYNTHESIS OR RELEASE INHIBITOR

FIELD OF INVENTION

[0001] The presem invention relates to treating type 2 diabetes by administering a compound that inhibits (a) IL-Ιβ, (b) (he synthesis oriL-Ip, (c) the release of IL-Ιβ. The present invention also relates to treating metabolic syndrome by administering a compound that inhibits (a) IL-Ιβ, (b) the synthesis of IL- Ip, (c) the release oflL-Ιβ.

BACKGROUND OF INVENTION

[0002] Type 2 diabetes is characterised by insulin resistance and impaired beta cell function, which includes impaired first phase insulin release, reduced beta cell pulse mass and insulin deficiency (Donath & Halban, Diabetologia 2004, 47,531-589.) This results in hyperglycemia that often is associated with the metabolic syndrome characterised by dyslipidcmia, obesity, and hypertension. In the UKPDS study, it was found that beta cell function by the time of diagnosis qf type 2 diabetes already is impaired, and that it continues to decline in spite of treatment. In time, loss of beta cell function will be accompanied and partly caused by a loss of beta cell mass, presumably due to apoptosis. (Butler, ct al, Diabetes 2003,52,102-110.) The decline in beta cell function mid less of beta cell mass could be caused hy endoplasmic stress, by chronic hyperglycemia, (glucotoxicity), chronic hyperlipidemia (lipotoxicity), oxidative stress, beta amyloid fibrils, certain cytokines and atlipokines, and a combination o: these and other factors (Rhodes Science 2005, 307,380-384).

[0003] It has been found that high concentrations of glucose or lipids, ns well as human beta amyloid peptide, certain cytokines like IL-Ιβ and certain adipokincs like Icpiin, impair the function of rodent and human beta cells and cause apoptosis upon incubation in vitro. (See, Maerller, et. al. J. CHn. !r\WM. 2002, //Λ, 851-860; Maedler, et. al. Diabetes 2004,53, 1706-1713; Ritzel, ct. al. Diabeiw 2003,52, 1701-1708; Butler, et. al, Dieb&es 2003,52,2304-2314 and Maodlcr, oral. Proc. Natl, Acad, Sci, U.S.A. 2004, /0/,8138-8143.) Incubation ol'hnman islets in the presence of high glucose concentrations or of leptin induces release of IL-Ιβ to cause apoptosis of the beta cells. Neutralising the effect oflL-Ιβ with a soluble H.-l receptor antagonist (ILRa) has been shown to ameliorate the glucotoxicity and to protect from the deleterious effects oflcptin, (See. Maedler, et. al. J. Gin. Invest. 2002, 110, 851-860; Maedler, et. al. Diabetes 2004, S3,1706-1713; Proc. Nad. Acad. Sci. U.S.A. 2004,101, 8138-8143; and, WO 04/002512.) EL-φ acts oil IL-lfJ receptors on the beta cells and induces i;AS expression, which subsequently cause apoptosis. Activation of the nuclear factor Kappa β (ΝΤκΙΪ) is required for TL-1 (3 induced FAS expression and apoptosis, NFkB transcription factors arc composed of homo- and heterodimers of the Rel family oiDNA-binding proteins. (Karin st al. Nut Rei1 Drug Discov 2004,3,17 26.) A key role of these Iran scrip lion factors is to induce and coordinate the expression uf a broad spectrum of pro-inflammatory genes including cytokines, chcmokincs. interferons, MffC proteins, growth factors, and cell adhesion molecules, NFkB is normally retained in the cytoplasm by IkD; however, upon cellular activation, TkR is pliosphorylatcd by an b;B kinase (IKK) and is subsequently degraded. Free NFkB then translocates to the nucleus where it mediates pro-inflammatory gene expression. There are three classical IkB's: ΙκΒα, ΙκΒβ, and IkBe; all require the phosphorylation of two key serine residues before they can be degraded. Two major enzymes appear to be responsible for IkB phosphorylation: JKK-1 and IKK-2, Dominant-negative fDK) versions of either IKK-1 or IKK-2 (where ΑΎΡ binding is disabled by the mutation of a key kinase domain residue) were found to suppress the activation of NFkB by TNF-a, IL-lb, LPS, and CD3/CD28 crosslinking; importantly IKK-2 DN was found to be e. far more potent inhibitor Lhan IK.K-1 1)N. Furthermore, the generation of TKK-1 and IKK-2 deficient mice has established the requirement of IKK-2 for activation of ΝΙ'κΙϊ by pro-in flam mat ury stimuli and reinforced the dominant role οΓΪΚΚ-2 suggested by biochemical data. Indeed it was demonstrated that 1KK-1 was dispensable for Μ·'κΒ activation by these stimuli.

[0004] Anli-inflammatory salicylic acids have an anlidiabctic effect in humans, (Yuan, et. al. Science 2001, 293,1673-1677.) It furthermore has been found that signalling pathways leading to ΙΚΚβ and Nlncll are activated in insulin responsive tissues of obese and high fat fed animals, It is therefore hypothesized that I KK.fi/ NFkB, which is part of the signalling pathway leading to the anti-inflammatory effects of salicylic acid, is part of Ihe molecular mechanism leading to insulin resistance, (Yuan, el. al. Science 2001,293,1673-1677.)

Activation of ΙΚΚβ/ NFkB is in part mediated, through activation of interleukin receptors by c.g" IL-Ιβ and 1L6. (Braddock, el. ah Nat RevDmgDiscov 2004,3, 330-339.) 100051 IL-Ιβ is a 17 kDa. protein derived from the 31 kDapro-IL-lp through cleavage by tile 1L-1 [3-converting enzyme (ICE or caspase-l). (Braddock. et. a(. Na t Rev Drug Disco v 2004,3,330-339.) Several signalling pathways regulate the transcriptional upregulalion of pro-LL-1 β including 1L-1 β itself via NFkB, TNFa, and Toll-like receptor ligands, such as lipopolysacchnridc (LPS). Inhibitors of ICE will reduce LPS induced IL-Ιβ release. It has been found that ICE is present in rat islets, (Karlsen, et. al. J. Clin. Endocrinol Mctab 21100, ¢3, 830-836.) f(100(i| Certain chemical entities, e.g., sulphonyliireas, have furthermore been found to inhibit LPS induced IL-ίβ release, possibly through a mechanism that involves glutathione S-transferase (GST), (Braddock, el. a), Nat Rev Drug Discov 2004,3, 330-339.) These arc called Cytokine-Release Inhibitory Drugs (CRIDs).

[00071 In view of the above, it would appear beneficial to treat type 2 diabetes or metabolic syndrome by cither inhibiting IL-Ιβ itselfot inhibiting the synthesis or release of IL-1 β. It would therefore also be desirable to treat type 2 diabetes or metabolic syndrome with an ICE inhibitor, a cytokine-release inhibitor, an IKK-2 inhibitor, or a combination thereof.

SUMMARY OF THE INVENTION

[0008] III an aspect, the present invention provides a novel method of treating type 2 diabetes by administering a compound that inhibits (a) IL-I β, (b) the synthesis οΓΙΙ^Ιβ, or (c) the release of IL· I β.

[0009] In an aspect, the present invention provides a novel method of beating metabolic syndrome by administering a compound I hat inhibits (ii)IL-lp, (b) the synthesis ofIL-Ιβ, (c) the release of TL-1 β.

[0010] In another aspect, the present invention provides a compound that inhibits (a) IL-Ιβ, (h) the synthesis oflf.-ΐβ, or (c) the release nf II.-1 β for use in therapy.

[0011] Tn another aspect, the present invention provides a compound that inhibits (a) IL-1 ji, (b) the synthesis ofJL-1 β, or (c) the release of IL-1 [i for the manufacture of a medicament for the treatment of type 2 diabetes.

[00121 in another aspect, the present invention provides a compound that inhibits (a) 1L-1(1, (b) the synthesis of IL-Ιβ, or (c) the release of IL-1 β for the manufacture of a medicament tor the treatment of metabolic syndrome, [0013] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds that inhibits (a) IL-Ιβ, (b) the- synthesis ofIL-Ιβ, or(c)the release ol'IL-1 β or pharmaceutically acceptable salts thereof, should be effective for treating type 2 diabetes or metabolic syndrume. DESCRIPTION OF THE INVENTION1 10014] In an embodiment, the present invention provides a method of treating type 2 diabetes, comprising: administering a compound tout inhibits (a) IL-Ιβ, (b) the synthesis of 1L-1 β, or (c) the release ofIL-Ιβ, provided that the compound is other than p yrrol i di n edi thi ocarbam ale.

[0015] In a preferred embodiment, the compound is selected from an lCt, inhibitor, a cytokine-release inhibitor, and an IKK-2 inhibitor.

[0016] In another preferred embodiment, the compound is an ICE inhibitor.

[0017] In another preferred embodiment, the ICE inhibitor is a peptide inhibitor.

[0018] In another preferred embodiment, the peptide is:

or a pharmaceutically acceptable salt form thereof.

[0014)] In another preferred embodiment, the ICE inhibitor is a peptidomemetic.

[0020] In another preferred embodiment, the popti do trim otic is sclented from the group:

or a pharmaceutically acceptable salt form thereof.

[0021] in anoLher preferred embodiment, the compound is a cytokine-rdease inhibitor.

[0022] In another preferred embodiment, the cytokine-release inhibitor is selected from:

or a pharmaceutically acceptable salt form thereof.

[002?I In another preferred embodiment, the cytokine release inhibitor is selected from: [00241 1 -(4-Chloro-2,6-diisopropyl-phcnyl)-3-[3-(l -hydroxy-1 -methylcthyl)-benzenesul fony Γ -urea; [0023] 1 -(4-Chloro-2,6-diisopn>pyl-phenyl)-3-[3-(l-hydroxycydopcntyrj-benzenes ulfon yf-urea, [0026] l-(4-Chloro-2!6-diisopropyl-phenyl)-3-[3-riethy!siilfamoyl-benzenesi]lfonyr-iirea; |(I027[ I-(4-Chloro-2,6-diisopropyT-pfienyl)-3-[3-dimetfiy!$ii(fainoyi-bcn7,encsuifonYJ]- urea; [0028] 1 -(4-Chloro-2,6-di isopropyl-phenyl)-3-[3-cyclopropylsulfamoy[-benzenesul fbnyj]-urea, [0029] l-(4-Chloro-2/j-diisopropyl'pliejiyl)'3-[3-cyclobutylsulfainoyl-beiizenesii]foiiyl]-urca; |0030] l-(4-Chloro-2,6-diisopropyl-pheny1)-3-P-methylsulfanyl.ben?encsulfonyl]-urea; [00311 I -(4-Chloro-2,G-diisopropyl-phcnyl)-3-[3-mclhancsidfinyl-bcnz:enc3ulfonyl]-urca: 100321 l-(i-Chloro-2.6-diisopropyl-pheny1)-3-[3-Tnelhanesi:lfonyl-benzenesulfonylJ-titea; [OOJ3J I - (4-Chloro -2,6-dii sopropyl-ph cny 1) -3 [ 3-(1 -h ydroxycycbbu cy 1) -benzen esu I fon yl ] -urea; [0034] 1 -(4-Oiloro-2}0-diisopropy1-phenyl)-3-[3-(l-hydroxycy&lopcntyl)-benzenesulfonyl]-urea; [0035] l-(4-Chloro-2,6-diisopropyl-pberiyt}-3-[3-(l-hydroxycyclohcxy 1) benz enesu Ifony 1] -urea; [0036| 1 - (4-CMo ro -2/)-dii sopropy l-p hcny 1) 3-[3 (2 mcthv1-[ 1,3]dioxo!an-2-y1)-bcnzuiiusulfoiiyl]-urea, [0037] 1 - (4- CMoro-2,6-dii sopropy l-p hcnyl) -3 -(3 - [ 1,3 jd ioxoIan-2-yi)-benzenesul i bny 1 ] -urea; [0038] l-(4-Chloro-2,6-diisopropyl-phenyl)-3-(2-iluoro-5-(2-tnethyl-[1.3]dioxcilati-2-yl)-benzen e su I fon y 11 - nr ea; [0039] l-[2-FlLioro-5-(2-mcthyl-(l,3)-dioxolan-2-yl)benzeiiesLilfonyl]-3-(l,2,3,5 76,7-b cxatiydno- 5 - i ndacen-4-yl }urea; [0040] 1 -(4-Chloro-2, ό-diisopro pyl-pheny1)-3-[ 1 H-indole-6-sul ferny l]-urea; [0041] 1 -(1,2,3,5,fi,7-Hexahydro-5-indacen-4-yi)-3-[lH~indole-6sulfoiiyll-urea; [0042] 1 -(4 -Chl oro- 2,6-di i sop ropy 1 -phenyl)- 3 -(5 -fluoro-1 H-indole-6-s ulibnyl] - urea; |00431 l-[5-Kluoro-1 H-indo]c-6-sulfonyl]-3-(l,2,3,5,0,7-liexahydro-5-indacen-4-yl)uiia; [0044J 1 -(4 -C h ] oro-2, fj-di isopropv 1-pheny I)- 3 -[ 3 -('1 - h y<irox y-ethy Γ) - 5 - Iri ti u.org m ethy I -benze n esul fo nyl ] -urea; [0045] 1 -{j-Acctyl-5 - Lriflu oromahyl-benzen sul fonyl )-3- (4-cli I om- 2,6 -diisopropyl -plienyl)-urea, [0046] l-(4-Chloro-2,G-diisøpiopyl-phenyl)-3-[3-(1-hydroxy-elhyl)-4-melliyl-benzen esu Ifon yl J - urea; j0047] 1 -(3 - Ac c L yl -4-r n«l ί I -bti ιΐϋΐ;ιΐϋ u.1 fonyl) -3 -(4-ch I oro-2,6-di i soprop y 1 -p hen y 1)-ure n; [00481 1 -[3,5-Bis-{ l-hydraxy-ethyl)-benzensul l'onyl]-3-(4-chloro-2,0-di isopropyl-phenyl)-urea; [0049] 1 -(4- Cb 1 o ro-236-di i sopmpyl -pbcny 1) -3 -[ 3- (1 -liv droxy-elliy 1)- 5 -iodo-benzenesul fonyl] -urca; |0050| l-(3-AceLyl-5-indn-benzensulfnny1)-3-(4-r3dorø-3/wiHsoprøpy1-phciiyl)-urea.; [0051] 1 -(4-Chluro-2,6-diisopropyl-pheiiyl)-3-[4-fluoro-3-( I -hydroxv-ethyl)-benzene sul fon yl J -urea; [0052] l-(3-Amyl-4-:liioro-benzcnsulfony])-3-(4-chlorO'2,G-diisopropyl-phenyl>urea; [00531 1 -(4- Acetyl -lhi ophcnc-2-sLilfonyl)-3 -(4-chlorø-2,6-di isopiopyl-phenyl) urea; [00541 1 -(4- C hloro- 2,6-d iisopropyl-ph«ny t)-3 - Γ 4-(1 - hydroxy-ethy I )-th io phene-2-snlfonylj'iirca; [0055] 1 -(4-ChbTO-2,6 d ii sopropy 1-pheny 1)-3 - [ 3 -(2 - livdrox yiinmo-prop y 1)-benzenesulfonylj-urea; [00561 1 -(4-Chloro-2,6-dhsoprøpyl-phenyl)-3-[3-(2-liydroxy-propy])-ben/ene:>ul ΓDnyl]- urea; [0057J l-(4-Cliloro-2,(5-diis<jpn>pyl-pheiiyl)-3-[3-(2-o'io-pi,opyl)'bejizenes ,jironyl]-ure^ [U058J 1 -(216-IJiisopn>py[-p[ienyl}-3-(3-piOpionyl-bsnzaiesu=ibiiyJ)-urca; [0059] l-(3-Acc:yl-4-methyoxy-ben7enesullbnyl)-3-(4-chlofo-2 >6-(liisopropyl-phcnyl)-urca; [0060] l'(4-Chloro-2,&-diisopropyl-phciiyl)-3-[3-(l-hydroxy-ethyl)-4-iiiethoxy· henzenesulfnrylj-iirea; [0061] l-(4-Chluro-2,6-diisopropyl-pheny[)-3-[3-(l-hydToxy-propyl)-bemzenesLilfonyIl- urea; [0062] l-(4-Ch!oro-2,6-diisopropyl-phenyl)-3-(3-piopionyI-beDzenesu]fonyl)-urea; 100631 t (4-Ch 1oro-2;6-dii soprop yl -phenyl)-3-[3-{ 1 -hydroxy-ethyl)-b enzenes ulfonyl] -uiea; [00641 1 - (5 - Acety 1'2-methox v-b enzeti sul fonyl) -3 -(4-bro mo-2,ti-di i sopropyl -p heny Γ)'ΐι rca; [0065] 1 - (5 - Ac-et yl-2-melhoxy-b enzen sul fony 1) -3 -(2,6-dii sopropy] -p h en yl)- trea; [0066] l-(3-Acctyl-bcrizcnsulforiylV3-{4-chloiO-2,6-diiaopiopyl-ph«iyl)-urca; |0067] 1 - (4-Cid o ro-2,6- d iisopr opyl-ph eri y 1 )-3 -[3- (i -hydroxyirnino-ethyl)-benzeiiesulfoiiyll-urea; [0068] l-(4-Bromo-2f6-diisopropyl'phenyl)-3-(6-melhyl-l,l-dioxo-l-thioclironnan-7-sulfonyl)-urea; [0069] 1 -(2,6-Diisopropyl-phcnyl)-(t>-methyl-l f 1 -dioxo-1 -thi ochroman-7 -su i fony I) -urea; [0070] l-(2,6-Diisopropyl-phcnyl)-3-[3-(l-hydiOxy-eLhyl)-benzenesulfonyl]-ureii; [0071] l-(4-l3romo-276-diisopropyl-pheiiyl)'3'[3'('l'hydroxy-e1hyl)-be*iietiesullbnylJ-urca; [0072] 1 -{3 - A cel yl-benzensul fonyl)-3-(4-brnmo-2/i-di i snpropyl -phenyl)-tirea; [0073] 1 (3 Acetyl 4 hydroxy-bcn?cusulfoiiyl)-3-(2.6-diisopropy!-phenyl)-urea; 100741 l -(3-Aceiy1-4-ineLht)xy-ben/en£ulibiiyl)-3-(2,<j-cliisopropyl-phenyl)-iirea; [0075] 1 -(3-Aceiyl-bcnzensu] lbnyl)-3-(2-sec-butyl-6-ethyl-pheriyl)-i»rea; [0076] 1-(3 -Acetyl-benzensul fo ny 1)-3 -(2-isopropyl- 6 -methyl-phenyl)-u rea; [0077] l-ii-Acetyl-benzensulfonylJ-S^-tert-butyl-G-inethyl-phenyli-urea; [0078J 1 - (3 - A cetyl-ben^ ensu I fo nyl)-3 -(2 -ethyl -6- i sop nop y I -p heny Π-urea; |0079| 1 -(3-Acetyl-bcnzcnsulfonyl)-3-(2.6-diisopropyl-phcnyl)-urca; [00S0] 1-(4-Acctyl-2,6-diisopropyl-plienyl)-3-(315-diacdy]-benzenesulfony])-urea; |008l] 4-[3-(3,5-Diacetyl-benzenesu:fony])-ureido]-3.5-diisopropyl-hen7.amide, [0082] l-(4-Chloro-2,6-diisopropyi phenyl)-3 [3-(2,2,2-11111110110-1-hydroxy-ethyl)-benzenesulfonylj -urea; 100831 1-(4- Chloro -2,6-d ii sopropyl-pheny I )-3 -(3 -Iriflu oroace:yl-benzene sul fonyl) - urea; [00 84] 1 -(4- Chloro -2,6-d u sopropyl-pheny] )-3 - [ 3-( 1-hydroxy-2 -medioxy-et hy 1) -benzenssulfonylj-utea; [0085] l-(4-Chloro-2t6-diisopropyJ-phcnyl>3-(3-mcthoxyacctyl-bcnzcncs i.ilfoiiyl)-urca; 10086| 4-[3-[3-(I-Hydroxy-ethyl)-ben2enesulforyl]-ureido]-3?5-<liisopropyl.benzainide; [OOS7| 1 -(4- Cyuno-2,6 -diisoprop yl-phcnvl)- 3-[3 - l-hydroxy-tthyl)-bcnzcn(:sidfony]]-un;a, [0088] l-(4-Chloro-2,6-diisopropyl-pheny])-3-[3-l-hydroxy-2-incthyl-propyl)· be nzen esn I fon y 1 ] -u rea; [0089] 1 -(4- Ch I oro-2t6-d u sopropy 1-pheny I )-3 -(3 -isob u lyryl-benzenesu I fony l) - u rea; [Q090| l-(2,6-Diisopropyl-4-lhiophen-3-y1-pheny1)-3-[3-l-hydroxy-elhyl)-benzen csu li o nylj-urea; 10091 ] l-(2,6-Diisopropy]-4-lliiophen-2-yl-plienyl)-3-[3-l-hydroxy-ethyl)-benzen esu I fo ny 1] -u rea; [0092] 1 -(3 (5-Diisopropyl-biplienyl-4-yl)-3-[3-( 1 -hydroxy-ethyl)-benzen5ulfonyl'|-urca; [0093] 1 -(4-Ch loro-2,6-d ii supropyl-phenyl )-3-(S-hydroxy-f ,6,7,8 - telrahydro-miphlhalene-2-sullbnyl)-urca; [0094] l-(4-Chloro-216-diisopropyl-phcnyl)-3-(£'Oxo-5,6 i71S-teirahydro-naphthalen.c-2-sulfonyI)-urea; [0095] l-(4-Chloro-2,6-diisopropyl-phenyl)-3-(S-hydTOxyimino-5,6 )7,8-(etrahydro-na phtl ialene-2 su 1 fo iiyl) - urea; [0096] l-{4-iiTomo-2,6-diisopropyl-phenyi)-3-(8-hydroxy-5,6,7,8-letrahydrc-naphihalene-2-sulfonyl)-urea; [0097] 1-(2,i-Diisopropyl-phcny^-i-ffi-hydroxy-i^^jfi-tBtrahydro-naphthalenc^-sulfonyl)-urea; [()0981 1 -(2,0-DnMpTopy]-pheny])-3-(5'hydrox>Tmim-5;6?7,S-Lclrahydro-nap1l thai ene-2-sultbiiyl)-nrca; [0099] l-fi-Bromo^fi-dnsopropyl-phenylJ-^-fB-hydroxyimino-S^jT^-tetraliydro-naphlhalcne-2-a ulibnyl)-urea; [00100] i-(4-Bromo-2,6-diiaopropyl-pheiiyl)-3-(8-oxo-5.6,7.8-tctrahydro-nap lithal ene*2 -s ulfonyl)- urea; [QG101] 1 -(2,6- Di i sopropy ] -pheny I) -3 -(8-o xo-5,6.7.8 -l clrahy dro - uapht h al ene-2- sulfonyl)-urea; [00102] 3-[3-(4-Broino-2,d-diisopropyl-phenyl)-umdosullbnyl]-hen7.aniide; [00103] 1 (4 Chloro-2,6-diisopiopyl phcnyl)-3-[3-(l ,2-dibydroxy-elhyli-benzenesulibnylj-urea; [00104] 3-[3-(2,6-DiisopTopyl-pheny])-ureidcsLlfonylJ-bcnza»nide; [00105] 3-[3-(4-Bromo-2,6-diiBcpropy]-pheuylJ-urcidosulfonyl3-K-meLhyl-beuzamidc; [001061 3-[3-(2f6-Diisopropyl-pheiiyl)-ureidosulfbnyll-N-metbyl-bcnzamidc; [00107] 1 -(5 - A cet yl- 2-bromo -benzenes ul fonyl) - 3-(4-b romo -2 ,S-d li sopropyl- phcnylt-urea; |00108] 1-[2-Chloro-5-(l-hydn>xy-elhyl)-bcnzcncsulfonyl]-3-(2,0-diisopTDpyl- phcnylj-urca; [00109] l -[2- Chlo ro -5-(1- hydnox y-et hyl)- benz ene sul fon yl]-3-{4-brom o-2,6 -d i i sopr o p y1. -plien y l) - uj ea; [00110] 1 - [2-Ch 1 oro-5-( 1 -h ydrox yi m i no-tith yJ )-b enzenes ll ] Ton y I ] -3 -(2.6-d;isopropyl-phcny1)-urea; [00111] 1 -[2-Chloro-5-(l-hydroxyimmo-ctliyl)-bcnzenesu]fbnyl]-3-(4-br<Hno-2,6-di isopropyl-phenyl)-urea; [00112] 1 -(5-Acelyl-2-ch1nro-bRnzenesi]1fonyl)-H2/i-diisnprapyl-p1icny1)-urca; [00113] 1 (5-Acctyl-2-chloTo-benzenesulfonyl)-3-(4-bromo-2,6-diisopropyl-phenylj-urca; [00114] 3-[3-(2, b-Diisopropyl-phciiylJ-ureidosulfonylJ -MfW-d imelhyl-benzamidc; |0Q115] 3-[3-(4-Bromo-2/i-tli isopropyl-phenyl)-Lireidosulfony^-NjN-dimethyl- benzamidc, |0QJ 16] 1 -(2,6-Diisopropy]-plienyl)-3-(5-formyI-benzenesulfonyl)-urea; (00117] 1 -(2,6- Π li sopropyl(hy Jioxyim ίπΰ-mct hyl) -btmzen e Su 1 fonyl] -urea; [001 18] l-(2,6-Diisopropyl-phenyl)-3-[3-(l-metlroxyiiTiiiio-ethyl)- bcnzcncsu lfonyl] -urea; |00119| l-[3-0-Rcnzy1oxyfoimo-ethyi)-bcnzenesiilfonyl]-3-(2,6-diisopropyl- phcnylj-urca: |001201 \ -(216-Dii5øpropyl-phcnyl)0-[3-{l-ethoxyimnio-cthyO-bcirøMcsulfoiiyl]- urca; [00121 ] 1 - {3 -[3-(2,i-Diisopmpyl-plienyl)-ureidosulfonyl]-pheiiyl} - ethy lid eneam i noox y)- accticac id; [00! 22] !-(2,6-Diisopropyl-phenyJ)-3-[3( 1 -hydrovyimiuo-ethyty-bejizenesulfonylJ- ur«; [00123] l-(2,6-Diigopropyl-plienylJ-3(3-nietlianesulfonyl-beiizeiiesuUbnylJ'UJ'ea; [001241 L-(2,G-Diisopropy1-phenyl)-3(3-methancsii]finyl-benzenesuironyl)-urea; J00125] 3-[3-(2.6-Diisopropyl-pheny])urddosu1fony1]-ben2enesulfonamide; [00126] 1 -(4-Broino-2,6-di isopropyl-phenyl)-3-(3-fbnnyl-benzeneswlfonyl)-urea3-Fonnyl-benzenesul fon am id c; [00127] 1 -[3-(2-Acelyl-phenoxymethy l)-henzenesul fonyl]-3(2/i-d i knpnopyt-phenyl)-urea; [00128] 1 - [ 31 -Am i no-t;il»y I) 1 fony I ]-3 (2 ,-6-d i i soprop yl -phen yl )- iirealiydiOchloride; [00129] 1 -(2,6-Dusopropyl-pheny [)-3-(3-foran-2-yl-benzcncsul fbny1)-urca; [00130] 1 -(2,6-Dii sopropyl-phcnyJ)-3-(4 - foran-2 yl-bcnze nesulfo ny] )-ui ea; [001311 l -(1 ?2,3,5,ti,7-Hexahydro-s-mdacen-4-y 1)-3-(4-( 1 -Hydroxyiniino-cthyl)- thiophene-2-su1fonyl]-iiiea; [00132] l-(4-Acety]-thiopheiie-2-sulfonyJ)-3-( 1,2,3,5,6,7-licxahydno-s-indaccn-4-yl)-urea; [00133] 1 -(1,2,3,5,6,7-Hexahydro-s-iiidaceii-4'yl)-3-[5-( ] -hydroxy- ] -mcthyl-ethyl)-ihiop hene-3 - s n lfony l ] -urea; [00134] 1 -(2,6-Diisopropyl-phenyl)-3-[4-(l -liydfoxy-1 -nurihy l-oihyl)-lli:opht:in:-2-sulfoiiyl]-iirca; [00133] l-(2,0-Piisopropy!-phenyl)-3-[4-(l-hydroxy-l-melhyl-cthyl)-furan-2- sulfonylj-urca; [00136] 1 -(1,2,3,5,6,7-Hcxahydro-s-indacen-4-yl)-3-[4-( 1 -hydroxy-1 -mcthyl-ethyl)- tliioplicnc-2-su!fonyl]-urea; [00137J 1 -(1,2,.1,5 ,6,7-1 icxahydro-s-indacen-4-yl)o-[4-(l -hydroxy-1 -methyl-cthyl)- furan-2-suiroryll-urca; [00138] l-fS-Chloro. 1,2.3,5,6,7-licx ahydro -s-m dac en-4-yl)- 3-[4-( 1 -hydroxy-l-mcrh}rl-othyl)-lljran-2-sifJibny)]-urca; [00139] 1 -(4-Formyl-fujan-2-su1fony1)-3 -(1,2,3,5,6,7-hexahydros-indac en-4-yl)-urea; [00140] l-(!,2,3,5,6,7-ilexahydro-5-indacen-4vl) 3 (4 -hydroxymcthyl-thioplicnc- l-sulibny^-Linja, |00141] l-(4-l'oiniyl-thiophene-2-SLilfoiiyl)-3-(l,2,3,5,6 s7-licxahydro-s-in(lacea- 4y[)-urea; [00142] 1 -(4-Chk>ro-2.6 -d ii sopropvl-phetiy 1)-3 -[4-( 1 -liydroxyimino-cthyl)-tiiiopheiie-2-sulfonyl |-urea; [00143] 1 -(4-Ch loro-2,6-d i i sop ropy 1-phenyl)-3-[ 5-( 1 -hydruxy-1 -melhyl-elhyl)-furaii-2-sulfon yI ] - urea; [00144] 1 -(4-Chloro-2,6'diisopropyl*plienyl}'3-[4-(1 -hydroxy-1 mcthyl-clhyl)-åir aii-2 -su lfonyl] -urea; 100145] 1 -(Ί-Ch 1 oro-2,6-diisopropy 1-pheny 1)-3 [4-(1 -hydroxy-1 mcthyl-cthyl)-

Uiiophuue-2 - s ulfuiiyl] -u rea; [0U146J 1 -(4-C; h 3 oto- 2 ,d-di i prop yl-pheny0-3-[5-(l -hydroxy-1 ) - th i oph ene-2 - sul fo nyl ] -ureasodi umsa It; [00147] 1 -(4-[ 1,3 JDioxo lan-2 -yl -t hiophcnc-2-su i fon y 1)-3-( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-urea; [00148] 1 -(4-[1 ,j]Dioxoliiri-2-y]-riiran-2-su] fnnyl)-3-(1,2,3,5,6,7 -hexahydro-s-indaccn 4 yl) urea; |001491 1 -[3 -(4,5 - Ui hydro-1 H-imidazol -2-y l)-benzenesulfonyl] -3-( 1,2,3,5,6,7- hexahydiO-s-indacen y 1)- urea; [00150] l-(lH-Benaoimidaaolc-5suironyL)-3-(1 ,2 ,3,5,6,7-hexah ydro-s-indacen-4- yl)-urea; [00151 ] 1-(1,2,3,5,6,7-Hexahydro-S-indacen-4-yl)-3-[3-( 1 -hydroxyimino-ethyl)- benzensiillbnylj-iirea; [00152] I -(4-C1 il o ro-2.6-di i sopropyl -phen yl )-3 - [ 3-lori-bulylsulfaitH) yl- bcnzeaesulfonyljurea; [001531 1 -(4-Cli loro -2?6-di i aopropyl-p hcnyl) -3-[ 3 - su L famoyl- ben zcncsu I fony 1] - urea; [00154[ or ti pharmaceutically acceptable salt farm thereof. 1001551 In another prefend embodiment, the compound is an KK-2 inhibitor, [00156] In another preferred embodiment, the KK-2 inhibitor is selected from:

or a pharmaceutically acceptable salt form thereof. 100157| In another preferred embodiment, die KK-2 inhibitor is selected from: |0015S| l-methyl-4-m ethyl aminobenzo[g]imida7o[l,2-a]quinoxalinc; [001591 l-inclhyl-4-(2-N-mcthyl£imirocthylaniiiio)beiizo[g]iniidazo[l,2- ajqumoxaline; |00160[ 1-ηιεώγΙ-4-™ε^γΐ3ΐπί^εηζο[§]ρνΓ:ιζοΙο[1,5-ο^ιιίη3Ζθ1ίη0; [001611 1 -iticihyl-4-{2-N-iiiclJiylainiiiocthylamino)bcnzo[g]pyrazolo[ 1,5- cjquinazoline; |00162| L-methyl'4-methylaminobenzo(g)imidazo(4,5-c)quinolinc; [00163] l-melhyl-4-(2-N-melhykminoethylammo)ben2o(g)imidazo(4,5- c)qu incline; [001641 l-methyl-4-(2-hydroxyeUiyl:miino)beiU!oLg]i]nidazoll,2-ajquinoxaJine; [00165| l-mcthyl-4-(2-piperidin-1 -yl- ethy kimino)b enzo[g] imidazo [1,2- a]quinoxaline; [00166] οτ ti pharmaceutically acceptable salt form thereof.

[00167] lu another preferred embodiment, the ΪΚΚ-2 inhibitor is selected from: [00168] 3-[(Anunoearbonyl)amino]-5-phenyl-2-thiophenecarboxariiLde; [00169] 3-[(Aminocarbonyl)aiTiina]-5-(3-chlorop]ienyl)-2-tliiopl]enecarboxaniide, [00170] 3 - [(Aminocarbon y l)am i η a ] -5 - (4- fl uorapheny l)-2-th i ophenecarbox amide; [00171] 3 - [(Aminocarbony l)amino J -5 - (4-chlorophcriy 1)-2 -thiophenecarbox amid e; [00172] 3'[(Amiiiocaiboiiyl)amino]-5-(4-isobi»tylplietiyl)-2-thiopheiiecarboxaiiiide; 100173] 3-|(Aiimiocarbonyi)aitiina]-')-(2-thienyl}-2-lhiophenecarbojiamidc; [00174] 3-[(Aminocarbonyl)amino]-5-(4-tnethoxyphcnyl)-2-thiophcnccarboxamide; |00175] 3-[(Aminocarbonyl)aiTiino]-5-(3-thienyl)-2-tliiophenecarbo7iamids; [00176] 3-[(Anunocarbonyl)ammø]-5-(3'hydroxypheriyl)-2-thiophcnecarboxamidc; [00177] 3-[(Am[nocarbony1)aininn]5-(2-ch1orophenyl)'2-thiaphenscai ,boxamide; [00178] 3-[(Aminocurbony])amino]-5-(2-methoxyphenyl)-2-thioplienecarbøxarnide; [00179] 3-[(Aminocarbonyl)amino]-5-{2-[2'(di:netliylaniino)cthoxy]phenyl}-2-ihiaphenecarboxamide; 100180] 3-[(Aminocarbonyl)amino]-5-{4-[2'(di:netliy1amino]cthoxy]pbcnyl}-2-

Ihiophcnccarboxaniid e; [00181] 3-[{Aiiiiiiocarbonyl)amiiiol-5-(3-methoxyphenylJ-2-tliioplienecarboxamide; [00182] 2-[(AixiinocaTbonyl)aminu]-5-phenyl-3-lhiopheii5carb{>xiimide; [00183] 3-[(Aniinocarboiiyl)aminc]-5 - {4-[2·( 1 -moipholiny l)diiox y ]phcny 1} -2-thiophenecarboxamide; [00184] 3 - [(Ami no c arbon y 1) ami tio]-5-{4[2-(l -py rro 1 id i tty V) etho x y ] pile nyl} -2 -th iophenecarboxam ide; [00185] 3-[(Aiiiiiiui:arboiiyl)aiiiiiiu]-5-{4-[2-(l-piperidiiiyl)L:llioxy]phetiyl}-2· thiophenecarboxamide; [00186] 3 - [(Aniinoc arbon y 1) amino]-5 - {4-[ 3 - (dimelhy 1 amino)propo x y ]pheny 1} -2-thicphenecarbox am ide; |0OI87| 3-[{Ammocarbonyl)amino]-5-{3-[2-(dimethylamim))eLhoxy]pbenyl}-2- tliicphenecarboxamide; [00188] 3-[(Aniinccarbonyl)amino]-5 - {3-[2-( 1 -morpholinyl}elhoxy]phenyl ] -2- thiophenecarbo xam ide; (00189] 3 - [ (Ami nocarbo tiyl)am πιο ] - 5 { 3 - [2-( 1 -pyrro lid i nyi)et hex y]phen yl} -2-thi aph en ecarbox am ide; [00190] 3 - [ CAmiuocarbonyl>ainino] -5-(3-2-(1 -pip eri d inyl)«th ox y] phe n yl}- 2 -thi ophcnccarbox arcii dc; [00191J 3-[(Aminociirbonyl)aniinoJ-5-{3-[3-(diiTislbylainino)prt.)poxy]pheny]}-2-thi ophcnecarbox amide; 100192 ] 3- [ (Ami nocarbonytjam i no] -5 - (2-[2-( 1 -morp ho li nyl )etbo xy] phenyl} -2- ihiu pi ua leuarbux timide; [00193] 3-[(Aminocarbonyl}aiiiinaJO'{2-[2-(l'-pyTrolidinyOelhoxy'lphenyl}-2-fhiophenecarboxamide; [00194] 3-[(Ammocarbonyl)aniino]-5 -{2-[2-(l-pipcndinyl)ahoxy]phenyl} -2-thiophenecarboxamide; [00195] 3-[(Aminocarbotiyl)amino]-5- (2-[3 -(dlmevhylami nojpropoxyjphcnyl -1.-thi oph en ecarbox am ide; [00196| 2-[(Aminocarbonyl)amiflo]4*mdhyl-5-(4-chlorophcnyl)-3- tbiophenecarboxamide; [00197| 2 - [ (Ami nocarbonyljam ino]-4-m elhy 1-5 -(4-methylphsny 1)-3 - t hio plici uxai'boxaiiiid e; [UU198| 2-[(Amincn;arbony])aiirtinc]-4-ethyJ-5-phtii]yl-3-lhiophfinecarboxamide; [00199| 2-[(Amiiiocarbonyl)animo]-4-methyl-5-(4-methoxypheny1)-3- ihiophcnccarboxamide; [00200] 2-[(Aininocarbonyl)amino]-4-rrdhyl-5-(4-fluoroptienyl)-3- thinphenecarhoxamide, [00201J 2-[(Aminocarbony1)amino] 4-methy1-5-(3 fluorophcnyl)· 3 ihi oph en ecarbox am ide; [00202] 2-l{Amlnocarbonyl)aminoJ-4-metbyl-5-(3-metboxyphenyl]-3-Ihiophenecarboxamide; [00203] 2-[(Aniinocarbo«yl)amino]-4-inethyl-5-(3-chloro-4-methoxyphenyl)-3-thiophenecarboxamide; [00204] 2-[(Aniinocarbonyl)amino]-4-mc0iyl-5-(2-chlorophcnyl)-3-thiophcnccarboxam idc; [00205] 2-[(Aminocarbonyl)amino]-4-niethyl-5'(3'CrifljoromethylpIjenyl)-3-thiophenecarboxamide; 1002061 2- [(Α ιτι i n oc strbon y l)aniicio]-4-mel hyl- 5-(3 -mctli y 1 -4-m cthoxyphcn y 1 )-3 ^ thtophenecarboxamidc; |00207| 2'[(Atninocarbonyl)ainino]4-meLhyl-5-(3,5-dimethoxyplicnyl)-3- thioplienecarboxamide, [002081 2- [(Λιπ irioi; arb un yl)amino] -4-1116 Lhyl-5-(2,3 -di melho x yphenyl )-3- thi ophen eearboxam ide; 100209] 2-[(AnHnocarbonyl)amino]-4-mdhyl-5-(4-iBOpropylphcnyl)-3-

Ihi ophen ecaiboxauiidc; [002101 2-[tAminocHrbonyl)ammo]-4-mcthyl-5-(3A5-trimcthoxyphcnyl)~3-

Ihiophenecarboxamide; [0O211J 2 - [(Am in ocarb on yl)aniino]-4-radhyl-5-(4-p ynd yl)- 3 -

Ihi ophenecarbo xamide, [00212] 2-[(Aniiitocafboiiyl)amino]-4-meihy!-5-(2-pvndy!)-3-thiophenecarboxamide; [00213] 2-[(Aiiiiitouirboilyl)amino]-5-[2-(5-melhoxypYridyl)]-4-methy1-3-I h iop ben ecaTbox amide; [00214] 2 - [{Aminocarbo ny l)amino] 4-mediy 1- 5-(4-pynmi d y 1)-3 -th iophenecarb ox am ide; [002151 2-](ArninocarbOTiyl)amino]4-metliyl-5-(2-pyrazinyl)'3- th iophcncca rb o* am i d c; [00216] 2-[(Aminocarbonyl) ami no] -4 - m etb yl-5- (3,4-d i chi o rophc tiyl)-3 -ih i ophenecarb o x-dm i de; [00217] 2 - [{Am inocarbonyl)ammo]4-iimhyl-5-(4-oyaTiophenyl)-3-thi ophen ecarbo xamide; 100218] 2 -[(Aminocarbonyl)ami no] 4-ni etb y 1 - 5-(4-hydioxypheny1)-3- thiophcnccarboxamide; [00219] 2-[(Aininocarbonyl)atnino]-4-methyl-5-(4-[2-(l pipcrid i nyl)cthoxy]pb eny 1) -3 -tli i ophcncc arbox amide; [00220| 2- [(Amin ocarbony 1) amino] 4 -m ethyl -5- (4- [ 2- (diethylamino)etlioxy]phenylj-3'thiophcnecarboxamidc; [00221] 2-[AmmocaTbonyl)amiiio] 4-mcthyl-5 (2 luryl)-3 thioplicnccarb ox amide; [00222] 2-[(Ainiiiooarboiiyl)anint)]4-lrifltion>Tnetliyl-,'j-phenyl-3-thiophenecaTb ox amide; [00223] 2-[(Aininocarbonyl)amino]-4-mcthyl-5 -(2 - (4 -m ethy Iliiiazolyl))-3- thiophcnccarboxamidc; [0022-41 2-[(Aminocafbony1)ami:io]'4-incthy1-S-phenyl-3-thiopheiiecarboxamidc: [00225] 2-[(AminocarbonyJ)amino]4-methyI-5-(3-mcthyf-isoxazo I-5-y))-3-thiophenecarbox amide; [00226] 2 - [ (Am i no c arbon y 1) am i πΰ] -5 - (4-cyunophcn y 1) -3 - thi ο μ hen ecarboxami de; [00217] 2-[ (Aminoc arbonyl) aminoj -5 - (4-tri fluoram ethylp henyl) -3 - tli iophenecarbox amide; [U0228] 2-[(AminocarbonytJamina]-5-(2,4-cjifluoroplienyl)-3- ihiophetiecarboxiiniide; [00229] 2 - [(Am i riocarbo ny1)am i n o ] -5-(2 -pyr i d y I) - 3 -t hioph cnccarbox amide; [00230] 2-[(Aniinocarbooyl)amino]-5-(3-pyridyl)-3-lhiophenecarboxamide; 1002.11 ] 2 - [(A mi rmcarbon y I )ami η n ] o -(4-p yri d >1) - 3-thioph en ecarboxam ide; [00232] 2-[(Aimnoearbonyl)ammu]-5-[5-(2-mqthi)>:yp)Tidyl]-3-thiophenecai'boxainid e; [00233] 2-[(Aminocarbonyl)amina]-5-[5-(2,4''dimcthoxypyrimidyl)]-3-ih i ophcriccarboxamid e; [00234] 2-[(AminocarbonyJ)amino]-5-(4-liydioxypheuyl)-3-tliioplietiecarboxaniJde, [002351 2'[(Aminocaibonyl)ainiiio]-5'(4-chlorophenyl)3-ihiophenscarboxamide; [00236] 2- [(Aminocarbony 1 )aniino]-5 -(4-melh an e sulpbo n y Iph eny 1) 3 -(hiophcnccarbo xamid c; [00237] 2-[(Aminocarbonyl)amino]-5-(2-(N-t-biitoxyi:arbotiyl)pytTOlyl)-3-thiopheneearboxamide; [00238] 2 -f (Ami nocar bon y I )ani i no]- 5 -(2 -(5 -c yano thi eny 1}) - 3 -thioplieuecaiboxamide; [00239] 2-[(AminoearboTiylJa.minu]-5-(3,5-dimcthyl-jsoxazol-4-yl)-3-ihiophenecarboxamide; |00240| 2-[(Atninocarbonyl)amino]-5-(3-fury])-3-(hiophcnccarboxamidc; [002411 2-[(Aminocarb(>nyl)amimil-5-(2-pynolyl)'3'thiophenecarboxainide; [002421 2-[(Aminrearhi>nyl)amino]-5-(5-pyrimidinyl)-3-ihiophenecarboxaniide; [00243] 2-[(Aminoearbonyl)amino]-5-(2-(5-chlorothicny1))-3- ihi uphen et arbo x am i de; f00244] 2 [(Aniinocarbonyl)ammo J-5- [2 -(5 -(ri fl uoromd hylpyridyl)] -3 - thiophcnecarboxamide; |00245] 2 [(Ami noc arbon yl )am ino]-5'[2-(5-b roniopyr idyl)] - 3 - thi ophcnccarboxåm id c; [00246] 2-[(Aminocarbonyl}amiiioJ'5-(2-(5 -cyano fii ryl))- 3-thi ophcnec arboxam id c; [00247] 2-[(Aminocarbony])amimi]-5-(4-[2-(l-pipen tliny])et]ioxy]phenyt)-3-th i opb en ccarbox am i de; [00248] 2 - [(Ami r 10 carbon y]) am inu] -5 -(4-[2-( 1-(2,2,6.6-letramethyl)piperidinyl)ethoxyJphenyl)-3-thu')phenecarhoxamide; [00249] 2-[(A mi nocarbo nyl) amino J-5 -(4- (thi azo 1-4- yl-methoxy)ph enyl) - 3-thiophenecarboxamide; [002501 2*[(Amiiiocarbonyl)iitiimo]-5-(4-[2-(dimelhylamint>)elh(ixy]phenyl)-3- thiophenecarboxamide; [00251] 2-[(Aminoearbonyl)amino]-5-(4-[2-(diahylammo)cthoxy]phciiyl)-3-thioplienecarboxaniide; (00252] 2-[(Aininocarbonyl)amino]-5-(4-[2-(l-TnoTpholinyl)elhoxy]plienyl)-.1-thiophenecarboxamide; 100253 ] 2 -[(Anii nocarboiiyljaniiiio] -5 -{2 -furyl)-3 - thioph enecarb o x am i de; ]U0254] 2-[( Am i nocarbon yl)am i n o j-5 -(2-(5 -methylfury] ))-3 -thiop hcnocarboxam ide; (00255] 5-[(Aminocarbonyl)atninoj-2-(3,5-dich!{>rophenyl)-I,3-oxazo]e-4- carboxamide; 100256] S-KAminocarbonyOaminol^^-triJluoromethylphcnyO-l^-oxaiole-^ carboxamido; [00257] 2-[{Aminothiocarbonyl)ainina-5-pheny]-3-thiophenccarbox am ide; [00258] or a pharmaceutically acceptable salt form thereof |00259] In another preferred embodiment, the present invention provides a method of treating metabolic syndrome, comprising: administering a compound that inhibits (a) fb) the synthesis of IL-ip, or (e) the release ofIL-Ιβ, provided that the compound is other than pyrrolidinedilhiocaibamate.

[002601 The references cited herein arc incorporated herein in their entirely.

[00261 ] It is preferred that the compounds that inhibit (a) 1L-1 (}, (b) the synthesis of IL-1[1, or (c) the release oflL-1 β have a molecular weight of less than about 500, 550, 600, 650, 700,750,800, 850, 900,950, or 10()0 grams per mole. More preferably, the molecular weight is between about 250,300, 350,400,450, 500, 550, and 600.

[002621 As used herein, 'treating" or "treatment" covers the treatment of a disease-state in a mammal, particularly in a human, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-slate hut has not yet been diagnosed as having it; (b) inhibiting the disease-state, c.g., arresting or slowing its development; and/or (c) relieving the disease-stale, e.g., causing regression of the disease stale ilsdf or some symptom(s) of the disease state. [00263] TC'E-inhibitors: Several inlerleukin-1 [3 converting enzyme (ICR, caspase-1) inhibitors have been described. These include peptide inhibitors and pcptidomimclics, [00264J Peptide inhibitors' The letrupeplide L-709,049 is a potent, reversible inhibitor oflCb with aKi of0.76±0.16 tiM, (Chapman, ct. al. Bioorg. Med. Chem. Lett. 1992,2,613-618.) This compound prevents secretion of biologically active IL-Ιβ in whole human blood.

[00265] Derivatives of this compound have been investigated by several groups. (Giegel, ct, al. Ann. Rep. Med. Chem. 2004, 23,183-192.) [00266] Ρ<φΐuiomimetivs; Peptidomiilietics have been derived from L - 709,049 in order to improve oral hioavai lability. This has resulted in a number of compounds, including compounds 1,2, and 3 (shown below). (Dolle, et. al. J. Med Chem 1997,40, 1941-1946 and WO 97/0022619.)

[IMJ267J Using structure based drug discovery a new series of ICE inhibitors has been identified. (Shahripour, et. al. Bioorg Med Chem 2002, JO, 3 1-40.) These,, however arc considerably weaker inhibitors in vitro with Ki values in the micronolar range (e.g,, compound 4 (shown above) with Ki=l ,6 μΜ), [()026¾] Cytokine-release inhibitory drugs (CWDs). Based on the finding (hat glibcncl amide inhibits the release of mature IL-Ιβ wilh an IC;o of 12 μΜ, whereas structurally related sulphonyl ureas like glipizide had no significant effect al concentrations up m 100 μΜ, several new sulphonyl ureas were identified by Pfizer, including CP-412,245 and CP-424,174, which block ATP-induecd IL-Ιβ release wilh IC5(t of 0.26 μΜ and 0.21 μΜ, respectively. (Ichikawa, el. al. J, Antibiot P'okvo) 2001,54, 703-70!) and WO 9832733.) The exact mechanism of action of CP-412,245 and CP-424,174 is not known, but it is assumed that it could involve interaction with glutathione S-iransfcrase (GST) omega 1-1.

[00269] A series of pyridiiie-2-carboxykles, including CJ-14877 and CJ-14897.

The compounds, which were isolated from fermentation broths, were able to inhibit LPS induced TNF-u and IL-Ιβ in human whole blood. (Ichikawa, et. al. J. Antlbioi (Tokyo) 2001, J4, 703-709,) [00270] Another natural product, LL-Z1271tt, isolated from the brolh of a fungus, has been shuwn lo inhibit production of IL-1 β m human blood in a dose dependent manner with an IC<o of 49 nM. When orally dosed at 50 mg/kg to mice challenged with 10 pg LPS per mouse, the compound inhibited IL-1 β production by 10O%, (Ichikawa, ct, al. Biochem. Biophys. Jies. Comm, 2001,286,697-700,) The precise mechanism is unknown, [002711 Several compounds have been shown lo inhibit NFkB either directly or indirectly by inhibiting e.g., IKK-2. (Baxter, ct, al, Bioorg, Med. Chem, Lett. 2004, 14, 2817-2822; Karin, et. al. Nat. Rev, Drug Discov. 2004,3.17-26; Kishore, cl. at.,/ Bid Cher» 200.1,278, 32861 -32871; and, Burke, et. al.,/ Biol Chem 2003,278,1450-1456.) [0Q272] Inhibitors of IKK-2: Selective active inhibitors of IKK-2 have previously been described. These include the i midaz;o( 1,2-a)qmnoxalinc BMS-345541 (Burke, ct. al, J. Biol Chem 2003,278,1450-1456 and USAN 03/0022898), thiophenecarboxamide SC-514 (Kishore, el. al../ Biol Chan 2003,278,32861-32871), compound 5 (Baxter, el, al. Bioorg. Med Chem. Lett. 2004, )4, 2817-2822 and WO 01/0058890), and compound 6. (Pahuiki, cl. aJ. Bioorg. Med. Client. Lett. 2003,13,4077-4080.) BM5-345541 and compounds 5 and 6 have been shown to be orally active.

UTILITY 14)0273J Inhibition of interleukin converting enzyme (ICE). Assays for measuring ability to inhibiL InLerlcukin converting enzyme in vitro have been described. (Ichikawa, eL. al. 1 Antiblot (Tokyo) 2001,54,697-702.) 100274] Inhibit it ion of release ofIL-l β. Assays for measuring release afIL-Ιβ from different tissues, e.g,, human blood, have been described, (Ichikawa, et, al. J Aniibioi (Tokyo) 2001,54,697-702 and Pcrrcgaux. ct. al. J. Pharmacol Exp Ther 2001, 299, 187-197.) [0027S] Inhibition of glucose induced beta cell death (apoptosis). Assays for measuring beta cell dealli/apoptosis induced by glucose have been described. (Maedler, et. al. J. Clin. Invest. 2002, 110, 851-860.) [002761 Preservation of beta cell function. Assays for measuring effects of compounds on function of human beta cells incubated in presence of high glucose has been described, (See, Maedler, et. al. Diabetes 2004, 53,1706-1713; Ritzel, et. al. J. Clin. Endocrinol Metab 2004,89, 795-805; and, Bjorklund, el. al. Diabetes 2000, 49, 1840-184S.) IUUZ77J Acute effects on beta cel!function in vivo. The acule effects of lest compounds on beta cells function in vivo can be determined using an oral glucose tolerance test. The same method can be used to characterize the duration of acdon of the compounds.

[00278] Anddiabettc effects. The antidiabetic effects of the compounds can be determined can be measured using standard pharmacological methods. This includes measuring effects of the compounds on blood glucose and HhAl c upon acute find sub-chronic administration to diabetic rats and mice, Such methods have been described [002791 Prevention of diabetes. Methods for measuring the ability of the compounds to prevent diabetes in preclinical models have been described. This includes measuring blood glucose, HbAlc, and glucose tolerance in e.g,, obese Zuckcr rats (Carr, ct. al. Diabetes 20(13,52,2513-2518) and in Psamiuoiuys Obeseus (Anis, cL. ah Diabelologiti 2004* 47, 1232-J244) to which the lest compounds have been administered.

[00280| In another embodiment of the present invention, the present compounds Eire administered in combination with one or more further active substances in any suitable ratios. When used in combination with one or more further active substances, the combination of compounds is preferably a synergistic combination. Synergy occurs when the died of the compounds when administered in combination is greater than the additive effect of the compounds when administered as a single agent. In general, a synergisuc effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Such further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, anti-obesity agents, antihypertensive agents, and agents for the treatment of complications resulting from or associated with diabetes, [00281] Suitable antidiabetic agents include insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycemic agents.

[00282] Suitable orally active hypoglycemic agents preferably include imidazulines, sulfonylureas, biguanides, meglitinides, oxad iazo lid inediones, (hiazolidincdioncs, insulin sensitizers, α-glucosidasc inhibitors, agents acting on Oic ATP-dcpcndenl potassium channel of the pancreatic p-cells e.g., potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which arc incorporated herein by reference, potassium channel openers, potassium channel blockers such as natsglinide or BTS-67582, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agnuron Pharmaceuticals, Inc.), all of which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-iV (dipeptidyl peptidase-IV) inhibitors, PTPasc (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconcogencsis and/or glycogcnolysis, glucose uptake modulators, GSK.-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, and PPAR (peroxisome prolifcraior-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069, [00283] in another embodiment of the present invention, the present compounds are administered in combination wich a sulphonyl urea, e.g, tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide, or glyburide.

[00284] In another embodiment of the present invention, the present compounds are administered ir. combination with a biguanide, e.g., metformin.

[00285] In another embodiment of the present invention, the present compounds are administered in combination with ameglitinide, e.g., rcpaglinidc or sena glinid e/naleglinide, [00286] In another embodiment of the present invention, the present compounds are administered in combination with a thiazoiidinedione insulin sensitizer, e.g., troglitazonc, ciglilazone, pioglilazone, rosiglilazons, isaglitazons, darglitazore, englitazone, CS- 011/Cl-l037,1' 174, the compounds disclosed in WO 97/41097 (ΠΕΪΡ-2344), WO 97/41119, WO 97/41120, WO 00/41121. and WO 98/45292 (Ur. Reddy's Research Foundation), which are incorporated herein by reference.

[00287] In another embodiment of the present invention, the present compounds may be administered in combination with an insulin sensitizer, e.g., GI262570, YM-440, MCC-555, JTT-5Q1, AR-H039242, KRP-297, GW-409544, CRR-16336, AR-H049020, LY510929, MBX-102, C LX-0940, GW-50I5I6, the compounds disclosed in WO 99/19313 (NN622/DRP-2725), WO 00/50434, WO 00/63191, WO 00/63192, WO 00/63193 (Ur. Reddy's Research Foundation), WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190, and WO 00/63189 (Novo Nordisk Ay'S), which are incorporated herein by reference.

[0(1288] In another embodiment of the present invention, the present compounds are administered in combination with an a-glucosidase inhibitor, e.g., voglibosc, cmiglitate, miglitol, oracarbose.

[00289] In another embodiment of the present invention, the present compounds are administered in combination with a glycogen pliosphorylase inhibitor, e.g., the compounds described in WO 97/09040 (Novo Nordisk A/S). 100290] In another embodiment of the present invention, the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the pancreatic β-cells, e.g., tolbutamide, glib end amide, glipizide, glicazidc, BTS-67582, or repaglinide.

[00291 ] In another embodiment of the present invention, the present compounds arc administered in combination with nateghmde.

[00292] In another embodiment of the present invention, the present compounds are administered in combination wiLh an anlihypcrlipideiiiie agent or a ailtilipidenlic agent, e.g., cholestyramine, colestipol, clofibrate, gemfibrozil, lovaslalin, pravastatin, simvastatin, probucol, or dextroihyroxine, [00293] Iu another embodiment, the compounds of the present invention may be administered in combination with one or more anti-obesity agents or appetite regulating agents. Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC3 (melanocciTlin 3) agonists, MC4 (melanocortm 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists. [33 adrenergic agonists such as CL-3ld243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSti (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK. (cholecystokinin) agonists, serotonin re uptake inhibitors (lluoxctinc, scroxat or cilalopram), serotonin and norepinephrine rcuptake inhibitors, 5ΗΊ' (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH {thyreotropin releasing homione) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitor's, PFAR modulators, RXR modulators, l'It β agonists, adrenergic CNS stimulating agents, AGRP (agouti related protein) inhibitors, H3 histamine antagonists such as those disclosed in WO 00/42023, WO 00/03208 and WO 0D/G48S4, which are incorporated herein by reference, cxctidin-4, GLP-1 agonists, ciliary neurotrophic factor, and oxynlomoduiin. KurtheT anti-obesity agents are bupropion (antidepressant), topirantatc (anticonvulsant), ecopipam (dopamine D1/D5 antagonist), and naltrexone (opioid antagonist).

[00294] In another embodiment of the present invention, the anti-obesity agent is leptin.

[00295] In another embodiment of the present invention, the anti-obesity agent is a serotonin and norepinephrine reuptake inhibitor, c.g,, sibutraminc, [00296] In another embodiment of the present invention, the anti-obesity agent is a lipase inhibitor, e.g., orlistat.

[00297] In another embodiment of the present, invention, the anti-nhesity agent is an adrenergic CNS stimulating agenl, e.g., dexamphetamine, amphetamine, phentermine, mazindol phendimetrazine, dicthylpropion, fenfluramine, oi dexfenfluramine, 1002981 In another embodiment of the present invention, the present compounds may be administered in combination with one or more anti hypertensive agents. Examples ofanlihypeilensive agents are β-blockers such as alpreuolol. atenolol, timolol, pindolol, propranolol andinetoproloi, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captapril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, fclcdipinc, nicardipine, isradipinc, nimodipinc, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Praaice of Pharmacy, 19lh Edition, Gemutro, Ed,, Mack Publishing Co., Easton, ΡΛ, 1995, [002991 In another embodiment of the present invention, the present compounds are administered in combination with insulin, insulin derivatives or insulin analogues. 100300] In another embodiment of (he present invention, the insulin is an insulin derivative is selected from the group consisting of B29-Nemiyi'istoy!-des(B30) human insulin, B I m i to yl -des(R30) human insulin, BiQ-hP-myristoyl human insulin, B29-Nc-pa]mitoyl human insulin, Β28-^-ιην[ΐ$Ιθν1 Lys®"8 Pro1*29 human insulin, B28-Ne-palmitoyl Lysnte Pro029 human insulin, B30-N^m>TistoyHhruaLysW(> human insulin, BiO-N^palmitoyl-Th^Lys1330 human insulin, B29-Nt-fN:-pulmitoyl-y-glutamyl)-des(B30) human insulin, B 29-N*-(N Ti thochol yl -γ-glu tam y 1) -d es(B 3 0) human insulin, B29-Nc-(a}-carboxyheptadecanoyl)-dc$(B30) human insulin and B29-Ne-(»-carboxyhcpta-decanoyl) human insulin.

[00301] In another embodiment of the present invention, the insulin derivative is B29-NT-rnyristoyl-dcs(B30) human insulin.

[00302] In another embodiment of the present invention, the insulin is an acid-stabilised insulin. The acid-stabilised insulin may be selected from analogues of human insulin having one of the following amino acid residue substitutions:

(1) A21G

(2) A2IG, B28K, B29P

(3) A2IG, B2$D

(4) A2!G,B28P

(5) A21C, B3JC,B29B (6) A2IG,desB27

(7) A21G.B9E <S) A21G. B9D (9) A21G, B10E insulin.

[01)303] In another embodiment of the present invention, the insulin is an insulin analogue. The insulin analogue maybe selected from the group consisting of: an analogue wherein position B28 is Asp, Lys, Leu. Val, or Ala and position B29 is Lys or Pro; des(B26-B30); des{B27); or, des(B30) human insulin.

[00304] Tn another embodiment the analogue is an analogue of human insulin wherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

[00305] In another embodiment the analogue is dcs(B3()) human insulin.

[00306] in anotiter embodiment the insulin analogue is an analogue of human insulin wherein position B28 is Asp.

[00307] In another embodiment the analogue is an analogue wherein position 133 is Lys and position B29 is Glu or Asp.

[00308] In another embodiment :hc Gl P-1 derivative to be employed in combination with a compound of the present invention refers to GLP-](l-37), exendin-4(1-39), insulinotropic fragments thereof, insulinotropic analogues thcreofand insulinotropic derivatives thereof. Insulinotropic fragments of GLP-Kl-37) are insulinotropic peptides for which the entire sequence can be found in the sequence of GLP-l (l -37) and where at least one terminal amino acid has been deleted. Examples of insulinotropic fragments of GLP-1(1 -37) arc GUM (7-37) wherein tho amino acid residues in positions 1-6 of GLP-l{l-37) have been deleted, and GLP-l(7-36) where the amino acid residues in position 1-6 and 37 ofGLP-l(]-37) have been deleted. Examples of insulinotropic fragments of excndin-4{ I -39) arc cxcridin4(i-38) and cxendm-4(l-31). The insulinotropic property of a compound may be determined by in vivo or in vitro assays well Known in the art, For instance, the compound may be administered to an animal and monitoring the insulin concentration over lime, insulinotropic analogues of Gl .P-1 (1 -37) and cxendin-4(l-39) refer to the respective molecules wherein one or more of the amino acids residues have been exchanged with other amino acid residues and/or tom which one or more amino acid residues have been deleted and/or from which one or more amino acid residues have been added with the proviso that said analogue cither is insulinotropic or is a prodrug of an insulinotropic compound. Examples of insulinotropic analogues of GUP-1 (1-37) arc e.g. Mets-GLP-1(7-37) wherein die alanine in position 8 has been replaced by methionine and the amino acid residues in position 1 to 6 have been deleted, and Arg^-GLP-1(7-37) wherein the valine in position 34 has been replaced with arginine and the amino acid residues in position 1 to 6 have been deleted. An example of an insulinotropic analogue of excndin-4(l -39) is Ser^AspJ-exendin-4{ 1 -39) wherein the amino acid residues in position 2 and 3 have been replaced with serine and aspartic, acid, respectively (this particular analogue also being known in the art as cxcndin-3),

Insulino tropic derivatives ofGLP-l(l-37), exendin-4(l-39) and analogues thcrcofare what the person skilled in the art considers to be derivatives of these peptides, i.e., having at least one substituent which is not present in the parent peptide molecule with the proviso that said derivative either is insulinotropic or is a pro drug of an insulinotropic compound. Examples of substituents are amides, carbohydrates, alkyl groups and lipophilic substituents. Examples of insulinotropic derivatives of GLP-1(1-37), cxenditl-4(1-39) and analogues thereof are GLP-l(7-36)-amidc, Axgf54, Lys^N'-iy-Glu/N'1-hcxadeciuioyl)))-GLP-1(7-37) and Tyr^-exendin-^l -3l)-amide. Further examples of GUM (1-37), eri.endin-4( 1-39)., insulinotropic fragments thereof, insulinotropic analogues thereof and insulinotropic derivatives thereof arc described in WO 98/08871. WO 99/43706, US 5424286, and WO 00/09666.

[00309] In another embodiment of the present invention, the present compounds arc administered in combination with more than one of the above-mentioned compounds, e.g. in combination wiih metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, rneLlbnniii and irogliLazuiic; insulin and a sulfonylurea; insulin aild metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc, [00310| It should be understood that any suitable combination of the compounds according lo the invention with diet und/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention. In another embodiment of the present invention, the pharmaceutical composition according to the present invention comprises c.g, a compound of the invention in combination with metformin and a sulphonyl urea such as glyburide; a compound of the invention in combination with a sulphonyl urea and acarbosc; nateglinidc and metformin; acarbosc and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin, insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.

PHARMACEUTICAL COMPOSITIONS 1003111 The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be form ulaicd with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

[00312| T he pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (includingbuccal and sublingual), tmnsdcrmal, intracistcmal, intiapcriloncal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) route, the crral route being preferred, the preferred route will depend on the general condition and age of the subj cct to be treated, the nature o f the condition to be Lroaled, and Iho active ingredient chosen.

[00313| Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include so lull oris, emulsions, aqueous or oily suspensions, syrups, and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions,dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in stadie injectable solutions or dispersions prior lo use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, omimcnls, cremes, gels, inhalants, dermal patches, implants, etc, [(10314] A typical oral dosage is in the range of from ahnut. 0,001 to about 10(1 mg'kg body weight per day, preferably from about 0,01 to about 50 mg/kg body weight peT day, and more preferred from about 0.05 to about i 0 mg/kgbody weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and genera! condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the an.

[00315] The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the ait. A typical unit dosage form for oral administration one or more times per day, such as 1 to 3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0,5 mg lo about 200 mg.

[00316] Fur parenteral routes such as intravenous, intrathecal, intramuscular, and similar administration, typically doses-arc in the order of about half the dose employed tor oral administration.

[00317] The compounds of this invention are general ly uti 1 ized as the free substance or as a pharmaceutically acceptable salt thereof. Examples arc an acid addition salt of a compound having Lhe utility of a free base and a base addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salt(s)" refers to non-toxic salts of the compounds of this invention which are generally prepared by reacting the Tree base with a suitable organic or inorganic acid or by reacting the free acid with a suitable organic or inorganic base. When a compound according to the present invention contains a free base, such salts are prepared in a conventional maimer by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a compound according to the present invention contains a free acid, such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation, such as sodium or ammonium ion. Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the present, invention and these form a further aspect of the present invention.

[00318] Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids, and the like. Representative examples of suitable organic adds include formic, acetic, trichloroacetic, Irifluoroacelic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelie, oxalic, picric, pyruvic, salicylic, succinic, methanesulforne, elhanesulTonic, tartaric, ascorbic, pamoic, bismcthylenc salicylic, ethanedi sulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobcnzoic, glutamic, bcnzencsulfonic, p-taluenesulfonic acids, and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1077,66,2. Examples of metal salts include lithium, sodium, potassium, magnesium salts, and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammoniiim, dimethylammonium, tri methyl ammonium, ethylammonium, hydroxyethylammonium, diethylan'.monium, butyliummomum, tclramcthy ] ammonium salts, and the like.

[003191 For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may he employed. Such aqueous solutions should be suitably buffered if necessary and the liquid cilucm first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperriloneal administration. T he sterile aqueous media employed are all readily available by standard techniques known lu those skilled in the tut.

[003201 Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil. phospholipids, fatly acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in tie art, such as glyceryl monostearale or glyceryl dislearatc, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the present invention and the pharmaceutically acceptable carriers arc then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy, [003211 formulations of the present invention suit able fur oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient, Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

[00322] Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the grou p consi sti ng of sweetening agent s, flavo ring a gents, co lo ring agents, and preserv i ng agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pliarniaccutically-acceptable excipients which are suitable ibr the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic add or talc. The tablets may be uncoated or they may be coaled by known techniques lo delay disintegration and absorption id the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265.874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.

[00323] Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a Soft gelatin capsules wherein the active ingredient is mixed with water ot an oil medium, for example peanut oil, liquid paraffin, or olive oil |t)0324| Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcelluluse, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, hcptadecacthyl-cncoxycctanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbilol monoolcatc, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleatc. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. (0()325] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, fur example araciiis oil, ulive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alchol. Sweetening agents such as those set forth above, and flavoring ngcnls may be added to provide a palatable οτλΙ preparation. These compositions may be preserved by the addition of an ami-oxidant such as ascorbic acid. [00326] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present.

[003271 The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatide*, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hcxitol anhydrides, for example sorbitan monoolcate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan itionoobatc, The emulsions may also contain sweetening ami flavoring agents.

[00328] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according Lo the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acccptablc diluent or solvent, Tor example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed arc water, Ringer's Solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in (he preparation of injectable*.

[00329] The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.

[00330] For topical use, creams, ointments, jellies, solutions of suspensions, etc·., containing the compounds of the present invention are contemplated. For Lhc purpose of this application, topical applications shall include mouth washes and gargles, [00331 ] The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stcarylaminc, or phosphatidylcholines, [00332] In addition, some of the compounds of the present invention may form solvates with water or common organic solvents, Such solvates are also encompassed within the scope of the present invention.

[003331 Thus, in a farther embodiment, there i s provided a pharmaceutical composition comprising a compound according 10 the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable earners, excipients, or diluents, [00334] If a solid carrier is used for oral administration, the preparation rrwy be tub letted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from abouL 25 mg lu about 1 g. If a liquid carrier is used, the preparation may be in (lie form of a syrup, emulsion, soil gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension ot solution, [003351 Λ typ ical t ablet that may be prop ared by conventional t ab le tting tcchniq ucs may contain:

Core: (1) Active compound {a3 lice compound or salt thereof) 5.0 mg (2) Lactosum Ph. Eur, 67,8 mg (3) Cellulose, microcryst. (Aviccl) 31.4 mg (4) Ambcrlite^JRPSS* 1.0 mg (5) Magnesii stearas Ph. Bur. q.s.

Coating: (ti) Ilydi'oxypropyl methylceliulose approx. 9 mg (7) Mywacell 9-40 T** approx. 0.9 mg (8) Polacrillin potassium NF, tablet disintegrant, Rohm and Haas, (9) Acyhied monoglyceride used as plasticizer for film coating.

[003361 ΓΓ desired, the pharmaceutical composition of the present invention may comprise a compound according to the present invention in combination with further acLive substances such as those previously described.

[00337] Whi le the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein without departing from the spirit and scope of the present invention, For example^ effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal bqi ng treated for type 2 diabetes. Likewise, the specific pharmacological responses observed may vary according to and depending on (he particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results arc contemplated in accordance with the objects and practices of the present invention.