100454

Dcc. 4,2003

US 2003/0225147 Al

I HIAZOLt UliN/AMlDK DIKIYAHYLS AND PHARIM ACFUTICAI. COMPOSITIONS FOR INHIUrilNG CELL PROLIFERATION, AND MF.THOnS FOR THFIR USF.

CROSS-RLI l.RLNCES IX) R LI A liii) APPLICA110NS

[U001] Tbis applicatiou clairns the bcnctit of U.S. Provi-sionjl Application Serial No. 60/3(0,679, lilcd Jul. 6, 2001, and U.S. Provi.\ional Application Serial No. 60/305,274, fikd Jul. 13, 2001, which are hereby incorporaled herein by relcrcnce in iheir cnlirelies.

MLI DOI- IIIL IN VLN IION

[U002J This invcntion relates to compounds willi {4-ami-nothiazol-2-ylaminc>}-bciizamidc uuclci that dcmoustratc anii-prolifcrativc actieiry such as a mitu mor activitv, io pro-ccsscs for preparing thesc compounds and io pbarmaccuric.il composilions conlaining such compounds. The invenlion also relates to the therapetitie or propbylactic usc of such compounds and compositions, and to melhods of treating cauccr, viral. microbial, aud/or parasitic colouizatioa-infcc-lion, as wcII as olher discasc States associated with unwanted ccllular proliferation. by adruinistering cffcetivc amounrs of such compounds.

BACKGROUND OF THE INVENTION

[0003]    Celi proliferatiou occurs iu response to various sliinuli and may slcai from dc-rcgiilalion of the celi division cyclc (or ccii cycle), Ok proccss by which ccILs multiply and dividc. llypctpK>lifcialivc discasc States, iaduding cancci. are charactcrizcd by cclls rainpautly wiuding through tbc ccii cyclc with uncomrollcd vigor duc to, for cxamplc, damage to the genes that dircctly or iudircctly rcgulatc progressiou through the cyclc. Thus, agents that modulatc the ccii cyclc. and thus hypcrpnolifcratiou, cotild be uscd to treat various discasc States associated with uucoutrollcd or unwauted ccii proliferation. In additiou to canccr chcmo-thcrapcutic agents, ccii cyclc inhibitors are also proposcd as anliparasilics(sec Cray cl al., Curr. Mcd. Chem., 6,859-875 (1999)) aud rcccntly dcmonstratcd as potential aotivirals (sec Schang et al.,./. Ylrol.. 74. 2107-2120 (2000)). More-ovcr. the applic.ibility of antiprolifcrativc agents may be cxpandcd to treating cardiowiscular maladics such as artc-riosclcrosis or rcslcuosis (sec Braun-Dullacus et al., Circu-larion. 98,82-S9 (1998)), and States of iudaniinatiou, such as arthrilis (sec Taniguchi cl al., Nulurc Mcii, 5, 760-767(1999)) or psoriasis.

[0004]    Mechanisms of ccii proliferation are under aclivc imesligalioc al ccllular and molccular lcvcls. At lhc ccllular lcvel, dcrcgulaiion of sigualiug pathways, loss of ccii cyclc Controls, unbridlcd .tngiogenesis and slimulalion of inflam-matory pathways an: under scrutiny. whilc ai the ruolccular lcvel, thesc pniccsscs are modulaled by varinus prolcins, among which protein kinases are promiucut suspeets. Ovcr-all abatement of proliferation may also rcsult from pro-grammed celi death.orapoptosis, which is also regulatcd via multiplc pathways. somc involviug protcolytic cnzymc protę ins.

[0005]    Among lhc candidalc regulatory prolcins, protein kinases are a family of cn/.ymcs that calaly/c phosphoryla-lion of lhc hydroxyl group of spcciOc lyrosinc, senne or threonine residues iu protcins. TYpicaliy, such phosphoryla-lior dramalically perturbs lhc funclion of lhc protein, and thus protein kinases are pivotnl in the rcgulation of a widc varicty of ccllular proccsscs.

[0006]    Cyclin-dependcnl kinases (CI)Ks) are scrinc-threonine protein kinases that play critical roles in regulatiug the trausitions be twe en differeut phases of the ccll-cyclc, such as the progression Irom a quiescenl stage in G, (the gap bctwccn mitosis aud the ouset of DNA rcplicatiou for a ncw round of celi division) to S (the |>eriod of aetive DNA synthesis). or the progression from G. to M phasc. in which activc mitosis and ccll-divLsion occurs. (Sec. c g., the arlicles compiled in Science, 274, 1643-1677 (1996); and Ann. Rcv. Celi Dcv. Biol.. 13, 261-291 (1997)). CDK

complcscs are formed Ihrough associalion of a regulatory

cyclin sulntnit (c.g.. cyclin A. BI, B2, Dl. D2. D3, and E) and a calalylic kinasc subunil (c.g., <’I)KI, (’I)K2, <*I)K4, C’DK5. and CDK6). As lhc namc iraplies. lhc CUKs display an absolulc dcpcndcncc on lhc cyclin subunil in order to phusphorylatc Ihcir tatgel substr.itcs, and diDcrcnt kina.se/ cyclin pairs funclion to rcgulatc progression through specific phases of lhc ccll-cyclc.

[0007]    Aherralions in this conlrtd system, parlicularly lhosc that affccl the fmictioii of CDK4 aiKl CDK2. have bccu implicaled in lhc advanccmcnl of cclls to lhc highly pruł i f-erative State cliaractcristic of maliguaucics, parlicularly familia 1 mclauomas. esophageal carcinomas, and panereatie canccrs (sec, c.g.. Hall et al.Adr. Ca/icer Kes., 68, 67-108 (1996); Kamb. Trends in Cenefics, 11. 136-14(1 (1995); Kamb et al., Science, 264, 436-44(1 (1994)).

[0008]    Bccausc C DK ł may scrvc as a generał activator of ccii division in most cclls and cotnplcxcs of CDK4/cyclin D and CDKl cyclin E goveru the carly G1 phasc of the celi cyclc, CDK4 or CDK2 inhibitors may be used as auii-prolifcrative agents. Also. the pivotal roles of cyclin E/ODK2 and cyclin B/CDKI in lhc Gl.S phasc and <i2IM transitions. rcspectńcly. offer additiouol targets for tbera-pculic intcrvcnlion in suppressing dcrcgulatcd ccii cycle prrłgrossion.

[0009]    A large nnmbcr of stnall moleeulc ATP-sitc antago-nists have been identified xs CDK inhibitors (see, Webster, h.xp. Opin. Inve\1. Dmgs, 7, 865-887 (I998); Skwer cl al., Curr. Opin. Drug Disc. Dev., 2. 274-285(1999); Gray et al.. Curr. Mcd. Client., 6,859-875 (1999); Siclccki cl al.,./. Mcd. Chem., 43, 1-18 (2000); Cicws cl ul., Curr. Opin. Chem. Hioi, 4. 47-53 (2000); Buolamwini, Curr. 1‘liann. I)cs., 6, 379-392 (2000); and Kosania cl al., hxp. Ojńn. iher. Cal., 10, 215-230 (2000)).

[0010]    In addilion Io lhc protein kinases idenlilied abovc, many olher protein kinases have been considcred to be therapetitie targcis, aixl mimcrous publicatinns disclosc inhibilors of kinasc aclivily, as rcvie\ved in the following: Mc Mahoń et al ., Curr. O/fin. Drug Disc, Dew, 1, 131-146 (1998); Slrawn cl al., ixp. Opin. Invc.si. Dnifpt, 7, 55.3-573

(1998) ; Adams et al., Curr. Opin. Drug Disc. Dew, 2,96-109

(1999) ; Slover cl al., Curr. Opin. Dntg Disc. Dcv, 2, 274-285 (1999); lolcdo cl al., Curr. Mcd Chan., 6, 775-805 (1999); and Gareia-Lchcvcrria cl al., Mcd. Kes. Ker., 20, 28-57 (2000).