CA2161980A1 - Substituted methylenedioxy¬3',4':6,7|indolizino-¬1,2-b|quinolinones - Google Patents

Abstract

Antiviral substituted methylenedioxyindolizino[1,2-b]quinolinones, compositions comprising such compounds, and a method of treating viral infection by using such compounds are disclosed herein.

Description

~AJO 94/25465 2 1 6 1 9 8 0 PCT/US94/04866 SUBSTll UTED METHYLENEDIOXY[3',4':6,7]INDOLIZINO-[ 1 ,2-b]QUINOLINONES

This patent appliç~tion is a col.~;n--~tiQn-in-part of U.S. Serial No.
08/057,133, filed on May 3, 1993 by Pendrak et al.

SCOPF OF T~F. INYF.~TION
This invention relates to antiviral cc,.l.younds, pha~ r~i~ll;cal c~ osilions thereof, and a method of treating viral il~f~lions. More specifically, this invention 10 relates to certain indoli7inot1,2-b]~llinolinyl derivatives which have antiviral activity.

RA~KGROUND OF T~F. INVF~TION

Certain 1H-pyrano[3',4':6,7]in~loli7ino[1,2-b]qllino!inolles are known to have 15 CylOlu3~iC and antiviral activity. C~n~ ecin is an example of one such col~.~u"d.
It is a water-incol~lble, ~iyl~lo~ic AlkAloi(l produced by (`A.~,)loll.r~A ~ ;nAIA trees in~ P,nollc to China and Notl~o~hs "fQ~,da trees in(1i~PIlollc to India.
Cs~...ptoll~ and its close coT~g~nPrs are known to inhibit eukaryotic topoi~,..~,.rce I. The CylOlC)~iC and ~nl;l...oor activity of c~,~ oll.ec;.- and its close congPll~rs is due to this inhibition of eukaryotic topoicc~ Ase I (Cancer Res. 1988, 48, 1722;Molec. Phannacol. 1988, 34, 755). Co-l-~uullds that are related in structure to ç~ cin but do not inhibit e~k~yolic tOpOi~o~ .ase I are not Cy~ Aic to l~."...Ali~n cells and have no ~ activity (J. Med. Chem. 1988, 32, 715;
Cancer Res. 1989, 49, 1465; Cancer Pes. 1989, 49, 4358).
.~ oll.ecin has been shown to have an effect on viruses by a ~ of inve tig~tors in labo,alo,y settin~. Although c~,-l~loll.ecin has ~ or ~ c~
ansiviral activity in in vitro tissue cult,ure ~y~t~,llls, call~tolllecin and its close analogs that have a hy~ ,Aylactone moiety cannot be considered as useful in vivo antiviral agents be~ e they inhibit --,~ n topoiso"l~ se I, inhibit host cell DNA
30 replic~ti~ n, and are ~;y~l~JAic to ~A.~n~ n cells. I~u-!~ u~" C~l~ iS not c~pc~t~ ~ to be attractive for drug development as an antiviral agent beCauSe ofcc~~ hle dose-limi*ng lOAiCily, unpreAict~kle lu~iCily, poor ~ leoll~ so~ i and/or ~ cc~l~hle shelf life stability.
There is a need for new antiviral agents. Some s~lbs*tnteA lH-3~ pyrano[3',4':6,7]in~oli7in~[1,2-b]qllinolinones that lack the E-ring a-hydroxy lactone moiety of c~l.~ll-~in have been shown to be non-.;yl~lc"ic to ~ n cells and to lack A~ ol~ activity (Ann. Rev. Pharmcol. Toxicol. 1977, 17, 117; J.
Med. Chem. 1989, 32, 71~). This is because these co~ .u-lds do not contain the 2 1 6 1 9 8 0 PCT/US94/04866 ~
cs~ l structural features required tO inhibit eukaIyotic topoisomerase I. But it has been found that certain 7-ethyl-7-hydroxy-7,8,11,13-tetrahydro-10H-dioxolo[4,5g]pyrano[3',4':6,7]indoli7ino[1,2-b]qllinolinone-8,11-diones (hereinafter "methyl~n~Aioxyin~ no[1,2-b]q-lino!inones") lacking the hydroxylactone moiety S do have antiviral activity without the undesir~ble fealu es of c~l-yLothecin. As such they are useful for treating viral infections.

SUMMARY OF T~F INVF~.~TION

In a first aspect, the present invention provides a method for treating viral ;--fcel;nl-~, which method COIll~liSGS s~lmini~tering to an i..rc~l~ host in need thereof an effective amount of a collll ou-ld of Forrnula I, or a ph~ G~ lly acceptable salt thereof, alone or in combination with a ca~ier, diluent or exçil.;c --t R"

~ CH3 R (I) Wl~

R is =O, -OH, and OR1;
R1 is -CoR4, or-P(O)(OH)R5 wll~,.~,ill:

R3 is -H or lower allyl;

R4 is -CR3R6R7;

-(CH2)nCH2R7 (where n=0-3);

-(CH2)nCH2COOH (where n=0-3);

-NR9R10;

~IO 94/25465 2 1 6 1 9 8 0 PCTIUS94/04866 -NH(CH2)nCH2R7 (where n = 1-3); and -NH(CH2)nCH2COOH (where n = 0-3);

RS is OH or CH2NH2;

R6 is H or the side chain of any naturally occuring a-amino acid;

+ N/ =~ X - N/~ N3N~
R7 is-NR9Rl0 ~ ~N where X is any ~ e~ 1y ~çcept~hl~ anion;

R8 is lower alkyl;

R9 and R10 are infle~entlP ntly se1~clcA from the group conci~ting of -H, -Cl 6 alkyl, and R9 and R10 taken together to forrn a 5-7 m~mh~red salulalcd ~t~ ;yclic ring cor~ .;n~ the ni~o~.l on which R9 and R10 are s~ ut~A: and Rll is -CH2R12, wl,~

-N O, -N NCH3,-OH
R12 iS -N(CH3)2 \ J --~
In another aspect, this invention relates to novel co.l.pounds of Formula I, and ~h~....~ce~ 11y acceptable salts thereof.
In yet another aspect, this h~,e"L~Il relates to a co...po~;l;Qn comrri~in~ a novel c~ po~ 1 of Fonnula I in Cc~ bin~l;Q~ with an acceptable carrier, excipient or diluent, particularly a ph~ lty a~ cept~ble carrier, r~cil)k nt or diluent.

DFTAn FT) DF..~CRIPTION OF THF INVF.NTION

nefinitions The terms below, defined as follows, are used in describing the present 5 invention throughout this appli~tion.
lirh~tiC" iS intçn~erl tO include s~,tul~led and unsaturated radicals. This inclu~les normal and branched chains, satulated or mono or poly unsaluu~ted chains where both double and triple bonds may be present in any combin~tion The phrases"lower aL~cyl" and "Cl 6 aL~cyl" refer to and mean an aL~cyl group of 1 to 6 carbon 10 atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower aL~cyl-O-. "Halo" means fluoro, chloro, bromo or iodo. "Acyl" means the radical having a termin~l carbonyl carbon.
The phrase "5-7 I..~ .ll~ .~,d 5~ t~1 heterocyclic ring cont~ining the nil.~/gen" is in~çn-l~ to include 5?/tU" -~l rings such as piperi~line, py~rolidine, 15 morph~line, ~ ;"c, and N-aL~cyl ~i~.~le.
Salts of any sort may be made from these co...pounds, provided there is a acidic group present or a sllfficitontly basic ni~logcn. Particularly ~ ;Çc.l~d are the ph~ ;r~lly acceptaWe salts of the instant comyoL.nds. These latter salts arethose which are açcep~hle in thcir application to a pharm~reutir~l use. By that it is 20 meant that the salt will retain the biological activity of the parent COlllpOU ld and the salt will not have Uul~Wald or d~letçrious effects in its ~pplicntion and use in treating e.A ~.~
ph~ ;ç~lly acceptable salts are p-~d in a s~nd~-l lllann~i. The parent co,~uund in a sllit~le solvent is reacted with an excess of an organic or25 illol~,~U~iC acid, in the case of acid ~d-lition salts of a base moiety, or an excess of organic or inul~ic base in the case where there is an acid group. R~.~s~ e acids are hydrochlûric acid, hyJlu~u~.lic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or mrth~neslllfonic acid. C~tionir salts are readily ~Jl~i from metal bases such as sodium, pot~sillm, c~lrillm, m~ c~ , zinc, 30 copper or the like and amlllonia. Organic bases include the mono or ~ ub~ d ~mineS, ethyl,on~ min~ ;ne, amino acids, caffeine, and the like.

~0 94/25465 2 1 6 1 9 g O PCT/US94/04866 Here and throughout this application, the ring system of the colllpoullds of the present invention are numbered according to Formula II.

~<

II

If a chiral center or another farm of an isomeric center is created by some cc,l..h~ ;oll of substih~ent~, in a co~ )ou.ld of the present invention, all forms of such isomer(s) are inten~e~ to be covered herein. Inventive col,l~ounds cot.~i~;..;n~ a 10 chiral center may be used as a racemic llfixlulG or the ll~ixLunG may be S~J~al~d and an individual e--A~ - may be used alone.
The present invention provides a methoA for the L~e~ nt of viral infe caused by certain DNA viruses col-~ g ~r1mini~tering to an inf~tud animal, preferably a ...~....,.~1, most preferably a human, in need thereof an effective amount 15 of a co...~ of Formula I as dc.scribeA hereinabove, or a ph~ c~ ~I;c~lly ~cceptable salt thereof, alone or in cc,. . ~ tion with a calTier, ex~il)ienl or diluent.
The present invention also provides cc,l"~,ounds, and l~h~ c~ lly acceptable salts thereof, which exhibit antiviral activity, said cc~ v~ having the ~llu~;lulc ~ s~ .~t~ by Formula I hereinabove.
More ~ ec;r~plly~ these c~.. l.ou~.-ls and the present mPtho~ are espec;~lly useful in treating the following pathogens in hnm~n~
He~pes Simpl~Y virus types 1 and 2 (HSV-1 and HSV-2);
Cyt~ 1nvirus (CMV);
Varicella Zoster Virus (VZV);
No nn~ccept~ble toY~ico1Ogical effects are c,~l.ect~ when col"~ounds of the present invention are ~ ~d in accor~ce with the present invention.
A ~cf~ d m~thorl for treating viral infection~ acculding to the present invention uses the following c~n~l~oullds of Formula I:
7-Acetyl-8-methyklioxc~lQ[4~5-g]inrlQli7inQ[l~2-b]quinolin-9(l 1H)-one;
(+)-7-(l-Hydroxyethyl)-8-methyldioxolo[4,~-g]in-1. 1i7ino[1,2-b]quinolin-9(l 1H)-one;
(i)-7-[1(~- . ;- ~oa~ ~Iyl)oxy]ethyl]-8-methyldioxolo[4,5-g]in~lo1i7ino[1,2-b~quinolin-9(1 1H)-one hy~ if luoro~et~te;

WO 94/25465 2 1 6 1 9 8 0 PCT/US94l04866 ~
7-Acetyl-12-dimethy~ .o.~ hyl-8-methyldioxolo t4,5-8] intloli7ino t1.2-b]quinolin-9(llH)-one; and 7-Acetyl-12-hy~ y~ hy~1-8-methyldioxolo [4,5-g] incloli7ino [1,2-b]
quinolin-9(1 lH)-one.
S F~,Çe.l~,d compounds of the present invention include:
7-Acetyl-8-methyldioxolo[4,5-g]inrlcli7.ino[1,2-b]quinolin-9(1 1H)-one;
(+)-7-(l-Hydl~,A~ hyl)-8-methyldioxolo[4,5-g]in(lQli7inl [1,2-b]quinolin-9(1 lH)-one;
(i)-7-[l(Aminoacetyl)oxy]ethyl]-8-methyldioxolo[4,5-g]indoli7ino[1,2-b]quinolin-9(1 lH`J-one hydl~.~inuoroacet~t~;
7-Acetyl-12-dimethyl~. . .;n.,. ~ l1-yl-8-methyldioxolo [4,5-g] in~loli7ino [1,2-b]quinolin-9(llH)-one; and 7-Acetyl-12-hyd~ cyllle~lly-1-8-methyldioxolo [4,5-g] jnflc)li7.ino [1,2-b]
nlin-9(1 lH)-one.
The ccln~ullds of the present invention can be ~ ,d by the following m~tllof3s There are several mP.tho lc for ~ Uillg these colll~ùnds. One generic process C;Q~ ;~S ~ lg a 1-keto in~ioli7in~o adduct and then co.~lel-~ g this fr~gmP.nt with the a~ ~pl;ate ~b~ minobe.n7~kle.hyde or A.,.;..o~h~ ...c.
20 Star~ng m~t~ri~lc are co. -~ ;ially available or can be made by pnblichçA m-o.thoflc.
The~ ions~ cesare i~ .,.t~ bySchemesI-m. Co,-.--~ llyavailable 2-pynolidone 1 can be aLkylated with dimethyl sulfate to give ether 2 which can be con~r-n~e~ with ~c~ rA;f~ ylate to give in(lo!i7ine 3. Methylation of 3 with methyl iodide at ambient t~ , in the inert solvent produced 4, which can be hydluly~d with an a lu~us base to give 5 followed by deca~ ylation to produce 6.T,;llA~;~n of 6 with N-ph~nyll-; 11 ;u~irle in DMF in the presence of base, likeLt,1,l2lyl~illc, can give 7, which can be reacted via Heck reaction with n-butylvinylether in the pl~_sel-ce of p~lls dinm catalyst and base to give 8. Hydl~,ly~is of 8 with acid, like 3N HC1, can give 9 which can be ~lut~;t~d as a ketal using ethyl~ne~lycol and hydrochlorirle gas to give 10. Co~ ou-ld 10 can be ()Yi-2i7~
using Davis reagent and base to give alcohol 11 which can be further oyir2i7~d with pyri~lir~ nrl~l~Jlvcl~ a~ in methylene chlori-le to give k~,ton~-ketal 12. FrieAls2nder con~el~.c~l;on of compound 12 with arninop;p~ 1 13 in the l,r~s~,nc~ of p ~ ej~lfonic acid in toluene and subseq~lent hydrolysis with acid, like 3N HC1,3~ can give the tide compound 14 (Scheme II). ~mino~çetol,hl"one 20 can be pr~aled in four steps by first ni~ting methylen~Ait xyacetophenone 15 with nitric acid to give colll~uond 16 which can be l,l~,l..;l-A~A with bromine in dioxane to produce cu~ uund 17. Reaction of 17 with hydrazine 18 in açetQ~ ;le can give cc,ll~ound ~vo 94,2~46~ 2 1 6 1 9 8 0 PCTIUS94/04866 19 which can be reduced with nickel boride to give amine 20. Conden~tion of cc.lll~ul.d 12 and 20 as described previously can give the title compound 21 (Sçh~me II). Reaction of 17 with with sodium acetate in dimethyl~, . . .~ e produced co~ound 22 (Scheme III). Reduction of 22 with nickel boride can give 5 cc,~,p~.und 23 which can be conrlçn~e~l with coll-yo~ d 12 and hydrolysed as l~scrihe~ previously to produce the title col.l~)oulld 24.
.

SCHEME I

O OH

H 45~C Et3N J ~CO2Et Mel / NaH ~CO2Et ~CO2H OH
11 . T ¦I trichlorophenol \,~

THF, rt o~N~ MeOH/THF O~N~

oSO2CF3 ~OC4H9 ~
n-Butylvinylether Tf2NPh/ Et3N ~ Pd(oAc)2ldppp ~ ~ 3N HCI X `3 DMF, rt O N~ Et3N/ DMF O N~ AcOH O N~

<-- 2~N~ \/ 0~ 0--OH OH ~ LDA,-78C ~ PCC ~

HCI, rt o~N~ THF ~ N~H CH2CI2 ~ N~= O

21 61 ~80 ~10 94/25465 PCT/US94/04866 SCHEME ll S <o ~CHO

PTSA / toluene < ~N--~

0 12 0 2. 3N HCI / AcOH 14 --5=O

5O~ HNO3 O~ Br2 <O~ ,Br O 0-40C NO dioxane NO2 20~N~N_ \ Ni2B O ~N

25CH3CN O 19 NO2 MeOH / HCI NH2 <O ~

1 . O~ O N

PTSA / toluene < ~N
2. 3N HCl /ACOH N

~0 _9 _ WO 94/25465 2 1 6 1 9 8 0 PCT/US94/04866 ~

O O
o ~,)~ Br NaOAc O ~ ~O~ Ni2B

O--~NO2 DMF, 67C o NO2 MeOH / HCI

\0 1~

1. o N\ >=O OH
O 12 f <o ~qJ~~ PTSA/toluene <~ ~
--~NH2 2. 3N HCI / AcOH O ~ />_ 23 24 ~
/~cO

~o 94/25465 2 1 6 1 9 8 0 PCT/US94/04866 The assay used to test the compounds of the present invention for antiviral activity is well-known. A gçne~li7~ desc.;p~ion of the assay follows.
Well plates are seeded with the ap~)l~liate cells at a concentration of lx105 cells per well sncFen-leA in 0.5 mL of Earle's l!~inim-lm F.csenti~l Medium (EMEM) S cn~ ;llg 10% fetal bovine serum (FBS) and antibiotic and antimycot* solntio~
After the cells are 80-90% confluent (24 hours), old l l ~er~ U~ is removed and washed with Hank's l)ur~ d saline sohltisn (HBSS). Cells are then ill~ul.,d for 1 hour at 37C with 100-200 plaque forming units per well of a herpes simrlex ViTUS S-lcpentled in 250 mL HBSS. Following adsorption, the following are added:
10 A) 250 mL/well 2 x EMEM col~l~ill;ng Human IgG (Sigma ~htomir~l Co., St.
Louis, Mo.) (ca. 0.1 mg/mL);
B) 250 mL/well EMEM co~ ng 10% FBS and antibiotic/antimycotic solntiQn;
and C) 250 mL/well HBSS cor~t~ining a~lo~,liately diluted c~ pound.
After 24-48 hours (best time ~Ctt~ . . .ined by observation of plaques under a i.;l.~scopc), old .. ~.l;.. is a~hdt~,d off. Each well is stained with a selPct~ stain sollltil?n (0.5% crystal violet in MeOH:H20 7:3) and then rinsed with water, airdried, and the plaques are counted. C~lllpound effectiveness is evaluated in terms of int plaque rednction as cc,lllpalecl to u~ a~cd, i"r~ controls.
This assay can be used to test compound activity against many other viruses besides herpes ~;"~pl~ ~ by simply lllodiryil~g the cell type used in the first step to match the virus being tested, and otherwise following the l,lvcedul~ ~u~ ed above.
Other cell types which can be used in this assay include mouse ...~.-...-~.y tumor cells, human lung fibroblasts, sheep choqioplexus cells, and green monkey kidney cells.Altern~tively, other assays can be used to dete .. ;~.e the antiviral activity of the present cc.lllpoullds. Such assays include the following types: cell count, clollGg~,nic, cylu~a~lic effect, dish-colony form~tion, microtiter-growth inhihition, thymidine il~c~ lion and yield reduction. Each of these assays is well-known andis available either from the l;~ ..." or from a cc,.~ ial testing lab.
The present invention provides ph~rrn~reutir~l c~lllpo~;';on~ pl~ ,d from the colllpoul~ds of Formula I. These cc,lllposilions have both a human and vet~ ~y utility, and co.. 'l" ;~e an eYciri~nt or carrier which is ~cept~ble for the intenrl~A
phi., . .~ 1 end use and at least one inventive com~()ulld. For eY~mrle, if a v~,t~,lh~aly use is int~n~leA~ the carrier may be a liquid, or spray, or may be form~ tPA
35 in a solid, non-degrade~ble or d~ de~ble form for insertion in the rumen. SelecteA
excipients and carriers may be employed to prepare colllpo~itions accept~ble or adaptable for hllm~nc use.

WO 94/25465 2 1 6 1 9 8 0 PCT/US94104866 ~
An effective amount of the pharm~euti~l c~ osi~ions of the present invention may be cont~in~A in one emboAim.ont, such as in a single pill, cars--le, or pre~ .,d intravenous dose or pre-filled syringe for injection. Alternatively, as is r~ "ly the case, the cc,111l,osilion will be prepared in individual dose forms where S one unit, such as a pill, will contain a sub-optimal dose but the user will be instructed to take two or more unit doses per tre~tm~o~t When the composition is presented as a cream, it will contain a discrete amount of drug and the user will apply some amount of the cream one or more times until the disease is in remission or has been effectively treated. Co1-cenl-ates for later dilution by the end user may also be 10 ~ d, for in.~t~nce for intravenous (IV) form~ tion.~ and multi-dose injectable formnl~ti~)n~, CalTiers or Ailllent~ co~ )lated for use in these compositions are gen.o,r~lly known in the 1,h~ ~ . n~e~ll ;c~l formulary arts. Reference to useful materials can be found in well known comril~tion~ such as Remin~on's Ph~rm~ l Sciences.
lS Mack P~bli~hin~ Co., Easton, Pa.
The nature of the cc,111posilion and the pharm~entic~l carrier or diluent will, of course, depend upon the int~n-l~A route of ~Amini~lration~ for eY~mrle whell1er by intravenous and ;"I.,....i.c~;..l~r injeclion, lJ~,nte1~lly, topically, orally, or by inh~l~tir~n For~nt~ A.. ,;.. ;~ .l;onthel,h~.~n~reutic~lco.. ~ ;I;onwillbeinthe form of a sterile injectable liquid such as an arnpule or an aqueous or nonaqueous liquid ~
For topical ~A. - .;-~;~1.; l ;0l~ the l.h~ l C4~ ~ l-o~;~;nr~ will be in the form of a cream, Oili~ . nt, linim~nt, lotion, paste, spray or drops s~it~ble for 25 ~A- ~ ;on to the skin, eye, ear, nose or gçnit~
For oral ~A . .;ni~ l ;ol~ the pharm~reutic~l con~osi~ion will be in the form ofa tablet, c~rsule, ~uwd~, pellet, atroche, 107çnge, sy~up, liquid, or emnlcion The ~h~ ul;~l carrier employed may be, for eY~mrle~ either a solid or liquid. When the ph~rm~ne~-tir~l cc,111~)o~iLion is employed in the form of a soh-tion 30 or ~ e~ ;on~ eY~mpl~s of ~p~ iate ph~rm~entic~l ca~iers or r1illl1ont~ in~hlf~e:
for a lu~us systems, water; for non-a~lu~,ous ~st~ ; eth~nol, glycerin, propylene glycol, olive oil, corn oil, collo~-~e~A oil, peanut oil, sesame oil, liquid ~ rr;.-~, and ~lu~,S thereof with water, for solid systems: lactose, terra alba, sucrose, talc, gelatin, agar, peictin, acacia, m~ Si....~ stearate, stearic acid, kaolin and m~nnitol;
35 and for aerosol systems: dichlorodifluor~ ne, chlorotrifluoroethane and CCII~ S:;~1 carbon rlioYi~1e Also, in addition to the pharm~e.~ltic~l carrier ordiluent, the instant cc,~ o~iLions may include other ingredients such as st~hili7ers, ~ntioXi~nt~ preservatives, hl~ir~nt~, suspending agents, viscosity m~ifiers and the ~O 94/25465 2 1 6 1 ~ 8 0 PCT/US94/04866 like, provided that the ~Cl(lition~l ingredients do not have a den;...~l-t~l effect on the thl .. p~.l;r action of the instant comrositions. Similarly, the carrier or diluent may include time delay m~teri~l well known to the art, such as glyceryl monostearate or glyceryl di~a.~le alone or with a wax, ethyl( çlllllose~ hydroxypropylmethylcelll.lose, 5 methylm~th~rrylate and the like.
A wide variety of ph~rm~celltic~l forms can be employed. Thus, if a solid carrier is used, the ~ ion can be t~bleted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The ~llo~ t of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram. If a 10 liquid carrier is used, the ~ ;on will be in the form of a syrup, em~ ion, soft gelatin c~rsule, sterile injectable solution or ~ pen~io~ in an ampule or vial or non~ue~us liquid sll~pen~ n To obtain a stable water soluble dose form, a ph~rm~reutir~lly ~rcept~hle salt of the compound of Formula I is dissolved in anr l~,eo..~ soll-tion of an organic or inorganic acid or base. If a soluble salt form is not 15 available, the co~ ound of Forrnula I may be dissolved in a s~it~ble co-solvent o cu~h~ n~ thereo FY~mrl.os of such snit~hle cosolvents inr,lu(le, but are not limited to, ~lr,QhrJl, propylene glycol, polyethylene glycol 300, polys~,ll,ate 80, glycerin and the like in co.~ce~.l.nl;ol-~ ranging from 0-60% of the total volume.
It will be appl~,ciat~,d that the actual piere~ os~ges of the con~ounds 20 used in the conl~,o~ Jn~ of this invention will vary accol.ling to the particular cc,...~l . being used, the particular COlll~)OSiliOn fo~n~ t~A, the mode of ;on and the particular site, host and disease being treated. It is t~ l~e~t~
that these CO~ JU~ S will bc active in the co~.~c nt. ~ l ;on ranges of two co....-~ ial antiviral drugs, Cytovene (~nrirlovir) and Zovirax (acyclovir). The latter is 25 ..~ d in 200 mg c~rs~llçs with instructions for treating herpes simplex viral in~iLiolls by taking one capsule every 4 hours, but not to exceed 5 c~ps~les per day.

FXAMP~ .F.~

In the following sylllhllic eY~mples, t~ ,la~ul~ is in degrees C-entig~lç
(C). Unless c,~ vise in~liC~tÇ~, all of the starting m~t~ were Ob!;1;~ l from co.. ,.~;ial sources. Without further elaboration, it is believed that one skilled in the art can, using the ~,~,c~-g des~,liplion, udlize the present invention to its fullest extent. These F.Y~mpl.os are given to illustrate the invention, not to limit its scope.
35 Re~ ce is made to the claims for what is reserved to the inventors hereunder.

WO 94/25465 2 1 6 1 9 8 ~ PCT/US94/04866 ~
F,xAMPT~F~ 1 alion of 7-Acety1-8-rn~thyldioxolo r4 ~ l indolizino rl ~-b 1 quinolin-9(11H~-one.

5 lA) 2-Methoxy-~yrroline 2-Pyrrolidone (850 g, 760 rnL, 10 mol; Aldrich) was added dropwise, over a period of two hours, to a stirred sollltio~ of dimethyl sulfate (1260 g, 945 rnL, 10 mol;
Aldrich) under an argon atrnosphere, causing the tc ~ A~ c to rise to 45C. When~lition was complete the clear llliAlul~ was stirred for 16h at 60C. It was then 10 poured onto ice and c~tnr~terl K2C03, and extracted with ether (2 X lL). The c~ mbined organic phase was washed with brine, dried (Na2S04), and solvent removed on the rotary e~,apo atO~, keeping the heating bath at 20C. The residual liquid was rlictill~l under vacuum into a chilled receiver to yield, after a small forerun 635 g (64%) of colorless liquid, b.p. 35 C / 15 Torr: 1 NMR (400 MHz, CDC13) ~ 3.8 (s, 3H, OCH3), 3.65 (t, 2H, CH2-N)~ 2.45 (t, 2H, CH2-N)~ 2.1 (m, 2H, -CH2-)-lB) 7-IIy(l.u~-8-etho~ yl-2 ~-dihyrlro-lH-indoli7in-5-one Thc llliAIul~ of co,ll~ound of Example l(A) (100 g, 100 mL, 1 mol) and 1,3-diethyl ~c~t~ Ai~ ylate (202 g, 182 mL, 1.5 mol, Aldrich) alone with 20 Il;ell-ylal",nc (10 mL) was kept at room l~ c-nt~re for 1.5 weeks. The crystals foImed were s~ - A by filtr~tion and washed with petroleum ether and ethyl etherto give off white solid 94 g (41%), m.p. 131 C: 1 NMR (400 MHz, CDC13) ~ 5.8 (s,lH, olefin), 4.4 (m, 3H, ethyl ester), 4.15 (t, 2H, CH2-NCO), 3.5 (t, 2H, CH2-olefin), 2.25 (m, 2H, -CH2-), 1.4 (t, 3H, ethyl ester).
lC) 7-IIy-ln~y 8 cll.o,~ .l,u.~l-6-methyl-2 ~-dihydro-lH-indoli7in-5-one To a sol~ltion of cc,lll~ound of Example l(B) (10 g, 45 mmol) in dry TH~
(500 mL) under an argon ~I ..o~h- . ~, was added NaH (2 g, 49 mmol, 60%
~lispt~r~iQn). The r~snlting mi~Lul~ was stirred at room le.~ lul~ for 10 min.
30 Methyl iodide (2.8 m~ ., 45 mmol) was added and IlliXIUlC stirred at room le for 96h. Solvent was e~,ayul~t~d and residue purified by flash column cl~ alc,~al~hy (silica, 0-2% .n. ~ nol CH2C12) to give white solid 5.7 g (s4%) NMR (400 MHz, CDC13) ~ 11.4 (s, lH, OH), 4.4 (m, 3H, ethyl ester), 4.15 (t, 2H, CH2-NCO), 3.5 (t, 2H, CH2-olefin), 2.25 (m, 2H, -CH2-), 2.01 (s, 3H, CH3), 1.4 35 (t, 3H, ethyl ester) lD) 7-IIy~l . u~y-8-c&llJo~y-6-methyl-2.3-dihydro- lH-indolizin-5-one ~o 94/25465 2 1 6 1 9 8 0 PCT/US94/04866 To a sollltic-n of co,l,~,uu,,d of Example l(C) (1.2 g, 5 mmol) in mPth~nol (30 mL), T~F (20 mL) and H2O (20 mL) was added LiOH (lg, 25 mrnol) and n~lu~c stirred at room Ic,~ lure for 56h. Solvent was removed in vacuum. The reslllting llfixlulc was diluted with H20 and acidified to (PH~5) with 3N HCl. The S ~lC~ d solid was filtered and washed with H20 and dried in vacuum to give tan solid 0.8 g (76%): 1 NMR (400 MHz, CD30D) ~ 4.23 (m, 2H, CH2-NCO), 3.5 (t, 2H, CH2-olefin), 2.35 (m, 2H, -CH2-), 1.95 (s, 3H, CH3).

lE) 7-hy~lroxy-6-methyl-2 ~-dihydro-indoli7in-5-one The cc"ll~ound of FY~mple l(D) (0.8 g, 3.75 mmol) and 2,4,6-trichlc lu~henol (6 g) were heated at 220C until evolution of carbon dioxide slu~l,ed.
The resulting ll~i~lulc was cooled to room l~ nnc and diluted with ethyl ether.
The l~lcci~ ted solid was filtered and dried to give solid 0.62 g (98%): 1 NMR (400 MHz, CD30D) ~ 6.1 (s, lH, pyridyl), 4.23 (m, 2H, CH2-Nco)~ 3.5 (t, 2H, CH2-olefin), 2.35 (m, 2H, -CH2-), 1.95 (s, 3H, CH3).

lF) TlilluG~u~ ei,lllfûnic acid-6-methyl-5-oxo-1 ~ -tetr~l~ydro-indoli7in-7-yl-ester To the solntion of co...l)uu~ of Example 1(E) (5 g, 30 mmol) in DME (100 rnL) was adided ~ llyl~ le (12.6 rnL, 90 mmol) alone with N-phenyll~ifluulu...~ e~
20 (16 g, 45 rnmol). The reslll~ing Illi~lul~, was stiIred at room le~ .a~ul~ for lh. Solvent was removed in vacuum and residue purified by flash column c~"u",alography (silica, 50-100%
EtOAc: h~ es) to give tan solid 6.15 g (68%): 1 NMR (400 MHz, CDC13) ~ 6.15 (s, lH, pyridyl), 4.16 (t, 2H, -CH2), 3.13 (t, 2H, -CH2-), 2.24 (m, 2H, -CH2), 2.13 (s, 3H, CH3).

25 lG) 7-(1-Rutoxy-vinyl)-6-methyl-? ~-dihydro-lH-indolizin-5-one To the solution of co"l~uund of Example l(F) (6.15 g, 20 mmol) in DMF
(100 m~ ,) was added triethylamine (5.5 mL, 40 rnmol) alone with n-butyl vinylether (10.3 rnL, 80 mmol). To the resnlting ll~lule was added Pd(OAc)2 (0.27 g, 1.2 mmol) alone with 1,3-bis(.lil~hcnylpho~l"l,o)p~pane (0.49 g, 1.2 mmol). The 30 res -l~ing l~ , was stirreed at 60C for Sh. Solvent was removed in vacuum and residue purified by flash column cl"ulllaLography (silica, 3~60% EtOAc: hexane) to give oil 5 g (89%): 1 NMR (400 MHz, CDC13) o 6.15 (s, lH, pyridyl), 4.35 (d, lH,olefin), 4.16 (m, 3H, -CH2; olefine), 3.79 (t, 2H, CH2-O), 3.1 (T, 2H, -CH2-), 2.2 (m, SH, -CH3; -CH2-), 1.72 (m, 2H, alkyl), 1.48 (m, 2H, alkyl), 0.95 (t, 3H, alkyl).
lH) 7-Ac~ etyl-6-methyl-~ ~-dihydro- lH-indolizin-5-onç
To the solution of compound of Example 1 (G) (5 g, 20 mmol) in glacial acetic acid (10 mL) was added 3N HCl (3 mL) and the reaction ~l,ixlu,e was stirred WO 94/25465 2 1 6 1 9 8 0 PCT/US94/04866 ~
at room ~"l~.dLule for lh. Solvent was removed in vacuum and residue lP~l in EtOAc, washed with 5% NaHCO3, NaCl, dried (Na2S04). Solvent was removed in vacuum and residue purified by flash column cLull,aLc,graphy (silica, 40-100% EtOAc: hexane and 0-5% mPth~nol CH2C12) to give solid 2.3 g (52%).
m.p. 101-102C.

lI) ~Me~yl-7-(2-~n~t~yl-rl ~l-dioxolan-2yl)-2 ~-dihydro-lH-indolizin-~-one HCl gas was bubled in to the solution of cc,ll~oul-d of Example l(H) (2 g, 10.4 mmol) in ethelyneglycol (50 mL) at 0C. The res~llting solution was alowed to warm-up to room Lemp~ ture and stired at room lc.ll~ ture for 14h. The res~llting Ul~. was poored in to the solution NH40H and ice. The mixture was ~ ct~d with CH2C12, washed with H2O, NaCl and dried (Na2SO4). Solvent was removed in vacuum and residue p-lrifiPA by flash column cl,lwli~lography (silica, 0-5%
ol CH2C12) to give solid 2.13 g (86%). 1 NMR (400 MHz, CDCl3) ~ 6.37 (s, lH, pyridyl), 4.14 (t, 2H, -CH2-), 4.02 (m, 2H, ketal), 3.73 (m, 2H, ketal), 3.04 (t, 2H, -CH2-), 2.27 (s, 3H, -CH3), 2.16 (m, 2H, -CH2-), 1.61 (s, 3H, -CH3).

l-I~ ~-6-Tn~tllyl-7-(2-methyl-rl ~l-dioxol~n-2yl)-2 ~-dihy-lro-lH-lnl;,;.~-5-onc To the sollltion of diisul,lo~lamine (1.89 rnL, 13.6 mmol) in TH~ (20 rnL) at -78C was added n-butyllithillm (5.4 rnL, 13.6 mmol) and the resulting l~ ul~ was st~red at -78C for 10 rnin. The solution of cc,m~K,ulld of Example l(I) (2.13g, 9 rnmol) in THF (100 mL) was added via ~rl~lition funnel and the reslllting ,r.i,~ G was stirred at -78C for 10 min. Davis reagent (3.54 g, 18 mmol) in THF (20 mL) was added at once and the resl~l*ng llliX.IUl~, was stirred at -78C for lh. Saturated solution of NH4Cl (20 mL) was added at -78C and the res~lltin~ was ~cte~ with CH2C12. Aqueous layer was aci~lifi~ with 3N HCl and ex~çted with with CH2Cl~. The colnhin~ organic fractions were washed with H20, brine and dried (Na2S04). Solvent was removed in vacuum and residue p--rifieA by flashcolurnn cl~l.-Alo~hy (silica, 0-7% .. f ~ ol CH2C12) to give foam 1.16 g (51%). 1 NMR (400 MHz, CDCl3) ~ 6.66 (s, lH, pyridyl), 5.21 (br s, lH, -CH-OH), 4.14 (m, lH, -CH2-), 4.04 (br s, lH, -OH), 3.99 (m, 3H, ketal, -CH2-), 3.73(m, 2H, ketal), 2.46 (m, lH, -CH2-), 2.27 (s, 3H, -CH3), 2.16 (m, lH, -CH2-), 1.61 (s, 3H,-CH3).
lK) 6-Me~yl-7-(2-methyl-rl ~l-dioxolan-2yl)-~ ~-dihydro-lH-indolizin-l ~-dione To the solntion of compound of Flc~mple l(J) (l.lg, 4.3 mmol) in CH2cl2 (100 mL) was added pyTi(~ llllrhloroclllumal~; (1.89 g, 8.7 mmol) and the resul~ng ~O 94/25465 2 1 6 1 9 8 0 PCT/US94/04866 Lul~, was stiIred at room t~ cl~ture for 12h. The ~ tul~ was diluted with CH2C12 and the resl~lting residue was filtered through the bed of celite. Solvent was removed in vacuum and residue purified by flash column ~ ,ul~ .dphy (silica, 0-3% m.oth~nol: CH2C12) to give foam 0.8 g (74%). lH NMR (400 MHz, CDC13):
S o 7.20 (s, lH, pyridyl), 4.28 (br s, 2H, -CH2-), 4.07 (br s, 2H, ketal), 3.73 (br s, 2H, ketal), 2.89 (br s, 2H, -CH2-), 2.42 (s, 3H, -CH3), 1.61 (s, 3H, -CH3).

lL) 7-Acety1-8-Tn~tllyldioxolo r4~-g 1 intloli7ino rl ~-b 1 ~uinolin-9(1 lH)-oneTo the sollltion of compound of Example l(K) (O.lg, 0.4 mmol) in toluene (10 mL) was added ~lfinopi~)~i}lal (73 mg, 0.44mmol) alone with p-tol~lerlesulfoni~ei(l (2mg, catalyst). The reslllting llli~lule was refluxed uner Dean-Stark trap for 12h. The ~ ule was cooled and diluted with hexane and Et2O. The precipitated tan solid was filtered and dried in vacuo to give ketal 65mg (43%). lH NMR (400 MHz, CDC13): ~ 8.1 (s, lH, 12-quinolyl), 7.57 (s, lH, 13-quinolyl), 7.48 (s, lH, 4-quinolyl), 7.14 (s, lH, 6-pyridyl), 6.18 (s, 2H, O-CH2-O), 5.19 (s, 2H, l l-CH2-), 4.09 (m, 2H, ketal), 3.84 (m, 2H, ketal), 2.45 (s, 3H, -CH3), 1.72 (s, 3H, -CH3).
To the ketal above (65 mg, 0.17 mmol) in glacial acetic acid (5 mL) was added 3N HCl (1 mL). The reslllting lll~lul`e was heated at 70C for lh. The llliAlU~i was diluted with H20 and eYtr~cte~ with CH2C12. The oragnic layer was washed with brine and dried (Na2SO4). Solvent was removed in vacuo to give yellow solid 28 mg (SO~o). lH NMR (400 MHz, CDC13+ CD30D): ~ 8.23 (s, lH, 12-quinolyl), 7.49 (s, lH, 13-quinolyl), 7.35 (s, lH, 4-quinolyl), 7.19 (s, lH, ~
pyndyl), 6.20 (s, 2H, O-CH2-O), 5.23 (s, 2H, l l-CH2-), 2.64 (s, 3H, -CH3), 2.32 (s, 3H, -CH3); Anal. (ClgH14N204. 0.5 H20) calcd.: C, 66.47; H, 4.40; N, 8.16 found: C, 66.41; H 4.20; N, 8.14. m.p >300C.

WO 94/25465 2 1 6 1 9 8 0 PCTIUS94/04866 ~
F.X~MP~.F. 2 P~cyI~Lioll of 7-Acetyl-12-dimethylaminomethyl-8-methyldioxolo r4~ indoli7ino rl ~-b l ~linolin-9(1 lH)-one.

5 2A) 1-(2-- itro-~hellyl)et~none To the cooled 65% HNO3 (200 mL) was added 3,4-MethyleneAiox~aceto~hc ~OI~F
(41 g, 0.25 mol; Aldrich) and the res--lting Ini~UlG was stirred at 40C for lh with the evolution of heat. When the evolution of the heat ceased the ll~ ulc was poured into the ice. The water was ~1sc~nteA and the resulting gum was ~ uldtcd with meth~nc)l. The product soliAifi~ and filtered to give solid 40g (76%). 1H NMR (400 MHz, CDCl3):ô 7.55 (s, lH, aromatic), 6.76 (s, lH, aromatic), 6.19 (s, 2H, O-CH2-O), 2.56 (s, 3H, -CH3); m.p 112C.

2B) '~-Rrom~ -nitTo-ghenyl)ethanone To the solution of co~ A of Example 2(A) (10 g, 47.8 mmol) in ~liox~n~
(30 mL) was added dr~ise the solntion of blullline (2.5 mL, 48.3 mmol) in ;o~ e (100 mL) via the ~Arlition funnel. The resnlting IIJixLulc was stirred at room t~ for 4h. Solvent was removed in vacuum and Illixlure was diluted with Et2O, washed with 5% NaHCO3, H2O, brine and dried (Na2SO4). Solvent was 20 removed in vacuum and residue purified by flash column cluu.--~log.,~l~hy (silica, 0-60% Et20: hexane) to give lacl ylllatoly solid 8g (58%). lH NMR (400 MHz, CDCl3): ~ 7.62 (s, lH, aromatic), 6.84 (s, lH, aromatic), 6.22 (s, 2H, O-CH2-0),4.23 (s, 2H, CH2Br).

25 2C) N'-benz~ line-N.N-(limr^thyl-~yrlr~7ine To the soll~tiQn of ben7~1~1ehyde (5 g, 47 mmol; Aldrich) in ethanol (250 mL) at 10C was added dropwise N,N-dimethylhy&~ e (5.37 mL, 70.6 mmol; Aldrich) in ethanol (50 mL). The resnlting ~ ule was allowed to warm up to r~om and was stirred at room l~.n~ dture for 30 min, and then refluxed for 30 20h. Solvent was removed in vacuum and res~l*ng nu~luuc was diluted with H20,e,~ cl~d with Et20. Organic layer was washed with brine and dried (Na2S04).
Solvent was removed in vacuum to give light yellow oil 5.2 g (74%). lH NMR (400 MHz, CDCl3): ô 7.6 (m, 2H, aromatic), 7.3 (m, 2H, aromatic), 7.2 (m, 3H, aromatic;
CH=N), 2.95 (s, 6H, dill~elhylamino).

~0 94l25465 PCT/US94/04866 2D) ~-nim~tllyl~mino-l-(2-nitro-~henyl)-eth~nnne To the solution of co~llyollnd of Example 2(B) (0.5 g, 1.73 mmol) in CH3CN
(5 rnL) was added comyou,ld of Exarnple 2(C) (0.26 g, 1.73 mmol) and the res~ ing mi~lul~e was allowed to stand at room temperature for 24h. The product y~ iyi~ted and filtered to give solid 126 mg (25%). lH NMR (4J0 MHz, CDC13+CD30D):
7.65 (s, lH, aromatic), 7.19 (s, lH, aromatic), 6.27 (s, 2H, O-CH2-O), 4.67 (s, 2H, CH2N+(CH3)2), 3.09 (s, 6H, dimethylamino+).

2E) 1-(2-Amino-l~henyl)-2-dimethylamino-ethanone To the sol~ltio~ of con,youlld of Example 2(D) (0.126 g, 0.38 mmol) in o] (5 rnL) was added lN HCl (3 mL) alone with Ni2B (200 mg) and the res~ ing lllixlul~ was heated at 60C for lh. The Illi~ul~ was diluted with H20 and c~ act~,d with EtOAc. The nr~g~ni-~. layer was washed with brine and dried (Na2SO4). Solvent was removed in vacuum to give solid 76 mg (90%). lH NMR
(400 MHz, CDC13): S 7.28 (s, lH, ~ull~aLic), 6.45 (br s, 2H, -NH2), 6.13 (s, lH,aromatic), 5.9 (s, 2H, O-CH2-O), 3.52 (s, 2H, CH2N(CH3)2), 2.34 (s, 6H, dil~lllyla~illo).
2P) 7-Acetyl-l~-flim~ minometllyl-8-metl~yldioxolo r4 ~-~ 1 indoli7i~o rl ~-b 1 q~linrllin-9(l lH~-one ~O~ "~ of FY ~ ylf. l(K) (71 mg, 0.28 mmol) and coll~yuund of FY~mrle 2~E) (71 mg; 0.31 mmol) were reacted following the ylvc~lul~ of Example l(L).
Solvent was e~,ayul~ed and residue purified by flash column cLv...~ hy (silica, 0-10% m~th~nol- CH2a2) tO give ketal as yellow solid 25 mg (25%). lH NMR
(400 MHz, CDC13): o 7.61 (s, lH, quinolyl), 7.49 (s, lH, quinolyl), 7.45 (s, lH
pyridyl), 6.15 (s, 2H, O-CH2-0), 5.23 (s, 2H, 11-CH2), 4.07 (m, 2H, ketal), 3.82(m, 2H, ketal), 3.80 (s, 2H, CH2N(CH3)2), 2.45 (s, 3H, -CH3), 2.29 (s, 6H, dimethylamino), 1.71 (s, 3H, -CH3).
The ketal above was hydrolyzed following the ylvc~lule of Fy~mrle l(L).
The resnlting residue was lyophilized to give solid 12 mg (65%). lH NMR (400 MHz, D2O): o 7.4 (s, lH, quinolyl), 7.2 (s, lH, quinolyl), 7.01 (s, lH pyridyl), 6.3 (s, 2H, O-CH2-O), 5.18 (s, 2H, ll-CH2), 3.65 (s, 2H, CH2N(CH3)2), 2.98 (s, 6H, di~ yl~l~no+)2.66 (s, 3H,-CH3),, 2.17 (s, 3H, -CH3).

W094/25~5 2 1 6 1 q 8 0 PCT~S94/0~66 ~
F.X~MPT.F.3 P~r~ ;on of7-Acetyl-12-hy-lroY~ymethyl-8-methyldioxolor4~-~1indoli7inorl~-b inolin-9(1 lH)-one.
3A) Ar~tic acid-2-(2-nitro-~henyl)-2-oxo-ethyl ester To the solution of co.ll~ound of Ex~mrle 2(B) (0.5 g, 1.73 mmol) in DMF
(10 mL) was added sodium acetate (0.43 g, 5.19 mmol) and the resulting l~ Lule was heated at 67C for lh. The resulting ~l~ix~ufe was diluted with H20 and aeL~,d with EtOAc, washed with brine and dried (Na2S04). The solution was trit~ t-oA with hexane and l)lecil)il;~ted solid was filterd to give 0.32 g (74%). lH
NMR (400 MHz, CDC13): ~ 7.58 (s, lH, aromatic), 7.84 (s, lH, aromatic), 6.2 (s, 2H, O-CH2-O), 4.92 (s, 2H, CH2-OAc), 2.06 (s, 3H, -CH3).
3B) A~rtic acid-2-(2-~mino-~henyl)-2-oxo-et~yl ester Cc,llJ~oul.d of F.Y~mrle 3(A) (0.3 g, 1.2 mmol) was reduced following the ~vc~lulci of FY~mrle 2(E) to give foam 0.24 g (92%). lHNMR (400 MHz, CDC13): ~ 6.89 (s, lH, aromatic), 6.43 (br s, 2H, -NH2), 6.17 (s, lH, aromatic),5.91 (s, 2H, O-CH2-O), 5.17 (s, 2H, CH2-OAc), 2.23 (s, 3H, -CH3).
3C) 7-Acetyl-12-l~ yl-8-methyldioxolo r4-S-~ 1 in~loli7.ino rl.2-innlin-9(1lH)-one ~..q~ou~ of FY.~mrlel(K) (50 mg, 0.2 mmol) and colll~ nd of Example 3(}3) (50 mg; 0.22 mmol) were reacted following ~e procedure of Fy~mrle llL).
The ~r~ l~ solid was filtered to give ketal 45 mg (50%). lHNMR (400 MHz, CDC13): ~ 7.50 (s, lH, quinolyl), 7.30 (s, lH, quinolyl), 7.15 (s, lH pyridyl), 6.20 (s, 2H, O-CH2-O), 5.5 (s, 2H, -CH2Ac), 5.30 (s, 2H, 1 l-CH2), 4.07 (m, 2H, ketal), 3.82 (m, 2H, ketal), 2.50 (s, 3H, -CH3), 2.20 (s, 3H, -CH3), 1.71 (s, 3H, -CH3).
The ketal above (40 mg, 0.1 mmol) was hydrolyzed following the ~
of FY~mrl.o l(L) to give solid 30 mg (65%). lHNMR (400 MHz, DMSOd6): ~ 7.50 (s, lH, quinolyl), 7.40 (s, lH, quinolyl), 7.20 (s, lH pyridyl), 6.25 (s, 2H, O-CH2-O), 5.4 (s, 2H, -CH2Ac), 5.17 (s, 2H, 11-CH2), 2.55 (s, 3H, -CH3), 2.20 (s, 3H, -CH3).
F.XA~p~F.4 f+)-7-(1-~.l~ yl)-8-Tn~--tllyldioxolo r4 ~-~ l indolizino rl .2-b 1 ~uinolin-9(l lH)-one.

4A) (+)-7-(1-Hydro~yethvl)-8-methyldioxolo r4.s-g 1 indolizino rl.2-b 1 quinolin-9(1 lH)-one.
To the solution of 7-Acetyl-8-methyldioxolo [4,5-g ] indoli7ino [1,2-b ]

~O 94/2~465 2 1 6 1 9 8 0 PCT/US94/04866 qllinolin-9(1 lH) one (2 mg, Symol) in a IlliAlulG of MeOH (0.2 mL), CH2c~2 (0-6mL) and THF (0.2 mL) was added a single portion of sodium borohydride (2 mg, SS
ymol). After stining at room ~e~ ,c.~tul~ for l.Sh, the solvent was removed in vacuum. The res--lting residue was treated with 10% aqueous NH4Cl (150 yL) and 5 allowed to stand at 4C overnight. The solid which was formed was collected byfiltr~tion, washed sp~ringly with H20 and dried to give yellow solid 1.7 mg, (89%):
lH NMR (400 MHz, CDC13): o 8.2 (s, lH, 12-quinolyl), 7.4 (s, lH, 13-quinolyl), 7.12 (s, lH, 4-quinolyl), 7.1 (s, lH, 6-pyridyl), 6.15 (s, 2H, O-CH2-O), 5.2 (s, 2H, 11-CH2-), 4.89 (m, lH, CHOH), 2.3 (s, 3H, Methyl)l.S (d, 3H, aliphatic).
FX~,MpJ.F. 5 (+)-7-rl(A.~ oacel~yl)oxylethyll-8-methyldioxolo r4 ~ 1 indolizino rl ~-b innljn-9(1 lH)-one ~ydlU~lif1~1lua~

15 5A) (+)-7-rl-rrrr(l~l-nim~tylethoxy~rbonyll~minolacetylloxylethyll-8 m~th~yldioxolo r4 ~-~1 in-1olizino rl.2-b 1 ~uinolin-9(1 lH)-one.
To a ~ .C n!l of (t-l~uluAyc~l~onyl)glycine (2 mg, 10 ymol) in CH2C12 (2 mL) under an argon ~I...n~l.f .~, was added 1,3-dicyclohexylcall~oA;;..~;Ae (2 mg, 10 ~mol). After stirnng at room t~ atul~; for 0.5 h, (i)-7-(1-IIyLux~elllyl)-8-methyldioxolo [4,5-g ] inf~oli7ino [1,2-b ] quinolin-9(1 lH)-one.(2 mg, 5 ymol) was added, followed by 1 mg of 4-dimethylallJil.u~,ylidine. The reslllting lllixlul~, was stired at room te.l~tul~, overnight, then was ffltered. The filtrate was washed ,~cce~ ely wit`h 25% &lucous NaHCO3 (2 mL), 0.1 N HCl (2 mL) and H20 (2 rnL), dried (Na2S04). The solid residue was purified by flash column cl~ o~rhy (silica, 0-3% .. ~ .. ol: CH2C12) to give the title colll~oulld 2.5 mg, (75%): lH NMR (400 MHz, CDC13): ~ 8.2 (s, lH, 12-quinolyl), 7.4 (s, lH, 13-quinolyl), 7.12 (s, lH, 4-quinolyl), 7.1 (s, lH, 6-pyridyl), 6.15 (s, 2H, O-CH2-O), 5.89 (m, lH, CHOH), 5.2 (s, 2H, ll-CH2-), 5.03 (br s, lH, NH),4.14-3.94 (m, 2H, CH2-NCO), 2.3 (s, 3H, Methyl), 1.44 (s, 9H, t-Bu), 1.5 (d, 3H, ~lirh~tic).
5B) (+)-7-rlfA...;.-n~ yl)oxylethyll-8-methyJdioxolo r4~ 1 indolizino rl.2-b 1 inolin-9(l lH~-one IIy.l. uLI in--roacrt~tr To a stirring ~ ,&n~:on of (:t)-7-[1-[[[[(1,1-Dimetylethoxy)call~nyl]arnino]
acetyl]oxy]ethyl]-8-methyldioxolo [4,5-g ] indoli7.ino [1,2-b ] quinolin-9(1 lH)-one (2.5mg, 4 ymol) in 1,3-~ .o~y~nLe"c (2 mL) under an argon ~I~.. os~k.,.~, was added l~inuuluac~.lic acid (2 mL). After stirring for l.S h at room ~ c"~u~e~ the "~u,~, was conre ~ ed under reduced ~es~ulG. The residue was dissolved in H20, extracted with Et20, filtered and lyophilized to afford the title colllpound as a WO 94/2546~ PCT/US94/04866 pale yellow solid 1.8 mg, (79%): lH NMR (400MHz, CD30D) ~ 8.12 (s, lH, 12-quinolyl), 7.45 (s, lH, 13-quinolyl), 7.13 (s, lH, 4-quinolyl), 7.16 (s, lH, 6-pyridyl), 6.15 (s, 2H, O-CH2-O), 5.89 (m, lH, CHOH), 5.1 (s, 2H, 11-CH2-), 4.02 (br s, 2H,CH2N), 2.25 (s, 3H, Methyl), 1.4 (d, 3H, aliphatic).
s F.X~MPT F. 6 Pt..~l~teli1l Cc"~ o~ilion To prepare a ~,~ent~,.al ph~ euLical com~osition of this invention suitable for ~lmini~tration by injection, 100 mg of a water soluble salt of a compound of10 Formula I is rnixed with 10 ml of 0.9% sterile saline, and the mixture is incol~,ulat~d into a dosage unit form sllit~ble for ~tlmini~tration by injection.

F.XAMpT.F. 7 0~1 CC~ i~il~
To 1~ an oral ph~n~ce~ltiral collll.osi~ion of this invention, 100 mg of a col~ û~d of Formula I is mixed with 750 mg of lactose, and the llliAlUl~ is ted into an oral dosage unit form, such as a hard gelatin c~psllle, which is ,leforo~ l...;n;~ ;on

Claims (15)

We claim

1. A method for treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier, diluent or excipient (I) wherein:

R is =O, -OH, and OR1;

R1 is OCOR4, or OP(O)(OH)R5 wherein:

R3 is -H or lower alkyl;

R4 is -CR3R6R7;

-(CH2)nCH2R7 (where n=0-3);

-(CH2)nCH2COOH (where n=0-3);

-NR9R10;

-NH(CH2)nCH2R7 (where n = 1-3); and -NH(CH2)nCH2COOH (where n = 0-3);

R5 is OH or CH2NH2;

R6 is H or the side chain of any naturally occuring .alpha.-amino acid;

, , R7 is NR9R10, , where X is any pharmaceutically acceptable anion;

R8 is lower alkyl;

R9 and R10 are independently selected from the group consisting of -H, -C1-6 alkyl, and R9 and R10 taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen on which R9 and R10 are substituted and R11 is -CH2R12, wherein:

R12 is -N(CH3)2

2. The method of claim 1 wherein said compound is selected from the group consisting of:
7-Acetyl-8-methyldioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)-one;
()-7-(1-Hydroxyethyl)-8-methyldioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)-one;
()-7-[1(Aminoacetyl)oxy]ethyl]-8-methyldioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)-one hydrotrifluracetate;
7-Acetyl-12-dimethylaminomethyl-8-methyldioxolo [4,5-g] indolizino [1,2-b]quinolin-9(11H)-one; and 7-Acetyl-12-hydroxymethyl-8-methyldioxolo[4,5-g] indolizino [1,2-b]
qninolin-9(11H)-one.

3. The method of claim 2 wherein said compound is 7-acetyl-8-methyldioxolo[4,5g]indolizino[1,2-b]quinolin-9(11H)-one.

4. The method of claim 2 wherein said compound is 7-acetyl-12 dimethylaminomethyl-8-methyldioxolo [4,5-g] indolizino [1,2-b]quinolin-9(11H)-one.

5. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:
R is =O, -OH, and OR1 R1 is OCOR4, or OP(O)(OH)R5 wherein:

R3 is -H or lower alkyl;

R4 is -CR3R6R7;

-(CH2)nCH2R7 (where n=0-3);

-(CH2)nCH2COOH (where n=0-3);

-O(CH2)nCH2COOH (where n = 0-3);

-NR9R10;

-NH(CH2)nCH2R7 (where n = 1-3); and -NH(CH2)nCH2COOH (where n = 0-3);

R5 is OH or CH2NH2;

R6 is H or the side chain of any naturally occuring .alpha.-amino acid;

where X is any pharmaceutically acceptable anion;

R7 is NR9R10, , , where X is any pharmaceutically acceptable anion;

R8 is lower alkyl;

R9 and R10 are independently selected from the group consisting of -H, -C1-6 alkyl, and R9 and R10 taken together to form a 5-7 memhered saturated heterocyclic ring containing the nitrogen on which R9 and R10 are substituted: and R11 is-CH2R12, wherein:

R12 is -N(CH3)2

6. The compoundof claim 5 wherein said compound is selected from the group consisting of:
7-Acetyl-8-methyldioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)-one;
()-7-(1-Hydroxyethyl)-8-medtyldioxolo[4,5-g]indolizino[1,2-b]quijolin-9(11H)-one;
()-7-[1(Aminoacetyl)oxy]ethyl)-8-methykldioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)-one hydrotrifluracetate;
7-Acetyl-12-dimethylaminomethyl-8-methyldioxolo[4,5-g]indolizino [1,2-b]qninolin-9(11H)-one; and 7-Acetyl-12-hydroxymethyl-8-methyldioxolo [4,5-g]indolizino[1,2-b]
quinolin-9(11H)-one.

7. The compound of claim 6 wherein said compound is 7-acetyl-8-methyldioxolo[4,5g]indolizino[1,2-b]quinolin-9(11)-one.

8. The compound of claim 6 wherein said compound is 7-acetyl-12-dimethylaminomethyl-8-methyldioxolo [4,5-g] indolizino [1,2-b]quinolin-9(11H)-one.

9. A formulation comprising a compound of claim 5 in admixture with a carrieror excipient.

10. The formulation of claim 9 wherein said carrier or excipient is a pharmaceutically acceptable carrier or excipient.

11. The method of claim 1 wherein the viral infection is caused by a herpesvirus.

12. The method of claim 11 wherein said virus is herpes simplex type 1 and said infected host is a mammal.

13. The method of claim 11 wherein said virus is herpes simplex type 2 and said infected host is a mammal.

14. The method of claim 1 wherein said viral infection is caused by cytomegalovirus and said infected host is a mammal.

15. The method of claim 1 wherein said viral infection is caused by varicella zoster virus and said infected host is a mammal.