100452

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US 6,359,145 BI

IMIDAZOI.F. COMPOUNDS

Iłiis applicalit.n is a 371 of WT Jm«M.W Jul. 22, 1999.

lliC IINICAl. lilii I)

This inccntion relaks to uovcl imidazolc compounds having pharmacological acmity, to a proccss for thcir produ ction aud to a pharmaecutical composition contaiuing tlić same.

BAC KC.ROUND .ART

Adenosinc (Ado) is an endogcnnus purine nuclcosklc relcascd by cells as pan of ihc normal metabolit machinery. Ark) bas wi<ie v«iricty of biologie.*I activitics. namcly potcut anliinflanimalory and imniunosuppressive properlies prn-tcctivc effeets in cardiovascular aud ccrcbrocascular ischcmia, atilicorvulsanl eflccls and modulation clTccls of plakiet aggregalion. lipolysis. glycogcncsis, blood llow and neurolrunsmission. Ado shows the biologie*] aclivitics byli ind ing lo its ieecplors .inchorcd in the cdi membranę. Thcrcforc. it is tbc bcucficial trcauucnt for many discascs to pcildrm the phannacułogRal clcvaiion of cMuecllular Ado cooccnrratioas.

Adenosinc dcamina.sc (ADA) cataly/cs an c.sscmially irrcvcrsiblc dcamination of adenosinc or dcoxvadenosinc to inosinc or dcoxyinosiuc, respectivcly. In the last 10 ycars. ADA. wbieb was considcrcd to be cytosolie, bas bccn fouud on the ccii surfacc of many cells. TTws. blookiug ADA acłivily wilh specilic inhibitor is the polciil \vav lo clevaic Ario conccutratious in biological Systems and tbc bcacfici.il Irealrrcnl for many discascs.

Sonic compounds have knowrt lo havc inhibitory aelivily of ADA (J. Mcd. Chem. 27, 274-278, 1984; ibid. 31, 390-393, 1988; ibid. 34, 1187-1192, 1991; ibid. 35, 4180-4184. 1992; ibid. 37, 305-308. 1994; ibid. 37, 3844-3849, 1994; and W098.02166).

Knowu imidazolc conipounds with pharmaecutical activ-ily olher Iban ADA inhibitory aclivily are dcscribcd in U.S. Rat. No. 4.451.478 and W097/26883.

Furthcrmorc. somc imidazolc dcrivativcs baving ADA inhibilory aclmly havc bccn rcporlctl, for cxampk\ as dcscribcd in Dmg Dcvclopcmcut Research 28, 253-258. 1993.

DISCI.OSURI2 Ol MIL INVLNTION

"Iłiis invcnlion rclalcs lo novcl imida/ole compounds, which havc plurmacculicai activity such as ADA inhibiiiog adivily, to a proccss for their produclion. lo a pharniaceu-lical composilion cuntaining the same aud lo a usc llicicof.

One objęci of lhi.s invenlion is lo pnividc the novel imidazolc corupouuds, wbieh havc an ADA iuhibilmg adiv-ity.

Anotber objcct of this invcntion is to providc a proccss for produetion of rbc imidazolc compounds.

A further olijcct of this invcntion is to pro\'idc a płiarma-ceuiical composition containing tbc imidazolc eompound as an activc ingredient.

Slfll further objęci of this invenlion is lo providc a usc of tbc imidazolc eompound lor uiauufacruring a mcdicamcut for trealing or prcvęnling various discascs, or a melhod of trealing or prevenling various discascs by adminislcring the imida/ole eompound in an efl"eclivc aniounl lo clcvalc adenosinc coneenlralion.

7

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"Ibc imida/ole compounds of this invenlion can be rep-resented by tbc following formula 0):

Oj

whercin R^ł is hydrogen. hydroxy, prnlecled hydroxy, or aryl optionally substiruted with suiUblc substitucnt(s);

R³ is hydrogeu or lowcr alkyl;

R⁵ is hydroxy or protecled hydroxy;

R⁴ is cyano, (bulroxy)imino.miino(lo\vct)alkyl, curboxy, protcctcd cart>oxy. bctcrocyclic group optionally sub-sliUUod with amino, or carbamoyl optionally subsii-tiitcd witb .suitablc substituent(s); and

—A— is —0— or —O—0—, whercin 0 is single hond or lowcr ulkylene. providcd ihal when K^: is lowcr alkyl. then R¹ is hydroxy, protcctcd hvdroxy.or aryl optionally sulssti-luled wilh suilable subsiiluent(s), ils prodtug, «*r their salt.

Ihc eompound (I), ils prodtug, or ibcii salt can be prepared by the following processes. In the following formulac, compounds may be prtslrugs or iheir salls.

t*Iv)U.SX 1

(tu;    (tv)    (ij

whercin R¹. R', R\ R⁴. and A re cach as dclincd abovc, aud X is bytlroxy or a lcaviug group, providcd that R³ is not hydroxy.

In this proccss the eompound (I) ean lic pmduced by reacting tlve eompound (IV), where X is hydroxy, wilh alkanesulfonyl chloride (i.e., methanesulfonyl ehloridc, ele.) or arylsulfonyl ehloridc (i.e., loluencsulfonyl chloride, cle.) in the ptesenee of a base such as triclhylamine or pyridine in a solvcnl such as dichloromclhanc, chloroform. Iclrahydrofuran, or dielhyl elher fmm 0° (1. lo room temperaturę Lor aboul 1 bo nr and rcaeling ihe rcsulling sulfoualc with the eompound (III) in ihc prcscncc of a basc such as studium hydtidc, polussium icri-buioxidc, or polassium ear-bonatc in a sohent such as dimcthyllormamidc (DMF) from room temperaturę to 100° C. for 5 to 100 hours. Altcrnativciy, tbc compoiitKl (III) can bc rcactcd with tbc eompound (IV) iu tbc prcscncc of a basc such as sodium mcthoxidc. potassium tcr-buioxidc. or sodium hydridc to givc the eompound (D-

"Ihc eompound (I) whercin K⁴ is hydroxy ean be ohlaincd

by the following proccss: