CA2139836A1 - Iracil derivatives as enzyme inhibitors - Google Patents

Iracil derivatives as enzyme inhibitors

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Publication number
CA2139836A1
CA2139836A1 CA002139836A CA2139836A CA2139836A1 CA 2139836 A1 CA2139836 A1 CA 2139836A1 CA 002139836 A CA002139836 A CA 002139836A CA 2139836 A CA2139836 A CA 2139836A CA 2139836 A1 CA2139836 A1 CA 2139836A1
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Prior art keywords
compound
formula
uracil
methyl
benzyl
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French (fr)
Inventor
James L. Kelley
David P. Baccanari, Sr.
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Wellcome Foundation Ltd
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel uracil derivatives of formula (I) and esters and prodrugs thereof wherein R1 is H, C1-8 straight or branched-chain alkyl, C2-6 alkenyl, or (C1-3 alkyl-C3-6 cycloalkyl-C1-3 alkyl) optionally substituted by 1 or 2 substituents selected from-OR8 or -NR8R9 (wherein R8 and R9 are the same or different and are selected from H, C1-6 straight or branched-chain alkyl, and aralkyl); or a-CH2ZR10,-ZCH2R10, or CH2ZR10aZR10 group (wherein R10a is selected from C1-6 straight or branched-chain alkylene and R10 is selected from C1-6 straight or branched chain alkyl) each of R10a and R10 being optionally substituted by 1 or 2 substituents independently selected from-OR8 and-NR8R9(wherein R8 and R9 are as defined above) and Z is select-ed from O,S,-CH2O-,or-CH2S-); R2 is selected from O or S; R3 is selected from O, S, -SO, -SO2, -NR8, C=O, or -C1-6 straight or branched-chain alkyl; R4 is selected from H, C1-4 straight or branched-chain alkyl, halogen,-OR11 (wherein R11 is C1-4 straight or branched-chain alkyl optionally substituted by halogen, aryl, C3-6 cycloalkyl, (C1-3 alkyl-C3-6 cycloalkyl), C2-6alkenyl or C2-6alkynyl), methylenedioxy, -CX3 (wherein X is halogen), NO2, or CN; R5 is selected from H, halogen or -OR11; R6 is selected from H, or Y-Ar-R7(m) (wherein Y is selected from O, S, -SO, -SO2, -NR8, C = O, or -C1-6 straight or branched-chain alkyl, Ar is phenyl or naphthyl, m is 1-3 and R7 is selected from R8,-CO2R8,-COR8,-CONR8R9,R8aOR8 (wherein R8a is selected from C1-6 straight or branched-chain alkyl, and aralkyl),-CN,-CX3 (wherein X is halogen),-OR8, OCX3 (wherein X is halogen),-SR8,-SO2R8,-OR8aO-(when m= 1),-NO2,-NR8R9,-NHCOR8,-NHSO2R8,fluoro,chloro, bromo, or iodo, or a combination thereof); provided that when R1 is H,CH2OCH2CH20H or CH2OCH(CH2OH)2, R2 is O, R3 is -CH2 then R4, R5 and R6 are other than -OCH3, -OCH2CH3, -OCH2Ph, or -O-iso-propyl, pharmaceutical composi-tions containing them, their uses in medicine and the preparation of such compounds are disclosed.

Description

~ 3983~
~0 94/01414 - 1 - PCI'/GB93/01443 URACIL DERIVATIVES AS ENZYME INHIBITORS

The present invention relates to certain enzyme inhibitors which are especially useful for co-~mini~tration with other therapeutic compounds such as antiviral compounds in order to provide an improved therapeutic effect including reduction in toxic side-effects.

A therapeutic nucleoside that has been found to have a particularly beneficial clinical effect against a spectrum of conditions associated with Human rmml~nodeficiency Virus (HIV) infections such as Acquired Tmm-~ne Deficiency Syndrome (AIDS), AIDS-related complex (ARC) and asymptomatic infections, is the compound 3'-azido-3'-deoxythymidine(AZT) having the approved name zidovudine. This compound at low doses is generally very well tolerated by patients and is now widely used in the treatment of HIV infections. However, in certain patients treated with zidovudine, some h~m~tological suppression inc.il~-ling ~n~mi~ and neutropenia may be observed, presumably arising from a certain limited level of toxicity of zidovudine observed towards stem cells. Other less commonly observed side-effects have beendescribed such as myopathy which may be related to intr~cell~ r activity of zidovudine.

Recently, it has been found that uridine and cytidine could reverse the toxic effect of zidovudine in vitro(Sommadosi, et al., Antimicrobial Agents Chemo., 1987, 31:453-454). However, uridine is toxic to humans when given via continuous infusion in vivo.
When uridine is ~mini~t~red to a patient in an intermittent schedule, it is rapidly ;"~led from the plasma(van Groeniger, et al., 1986, Cancer Tle~ lr~l1 Rept.
70:745-750).

US patent 4,874,602 describes the use of 5-benzylacyclouridine(BAU) for the reduction of the severity of anernia in~-lced by the a~mini~tration of zidovudine. This compound has been described as an inhibitor of the enzyme uridine phosphorylase which is responsible for the cleavage of uridine to uracil(Niedzwicki, et al., Biochem.
Ph~lllacol., 1982, 31:1857-1861). Several derivatives of BAU have been shown to be superior to BAU in their ability to inhibit uridine phosphorylase(Naguib, et. al., Biochem. Ph~rm~col. 1987, 36:2195-2201). Certain 5-benzyl barbituate compounds have been desclil.ed as uridine phosphorylase inhibitors which are useful for red~1cing
2 1 3 9 8 3 6 -2 - PCr/GB93/01443 the toxicity and anemia indllced by antiviral drugs, such as AZT, as well as forpot~nti~ting anticancer drugs and combatting their host-toxicity(PCT Publication No.
3 15). Furthermore, benzyloxy derivatives of BAU have been reported to decrease the bone marrow toxicity of pyrimidine nucleoside analogs, such as AZT(published under WO 89/09603, October 19, 1989, PCT/US89/01528). Recently issued US Patent 5,077,280 discloses a tre~tment for AIDS-type dice~cec in which a pyrimidine nucleoside compound, such as AZT, and a uridine phosphorylase inhibitor are co-~1minict~red either cimlllt~neously or sequentially to treat the viral infection and protect or rescue uninfected cells in the af~licted subject.

It has now been found that a class of uracil derivatives are potent inhibitors of the uridine phosphorylase enzyrne. Accordingly the present invention provides a compound of formula (I) ~' I

wherein R1 is H, Cl 8 straight or branched-chain allyl, C2 6 alKenyl, or (Cl 3 alkyl-C3-6 cycloalkyl-C1 3 alKyl) optionally substituted by 1 or 2 substi~ ntc selected from oR8 or -NR8R9(wherein R8 and R9 are the same or ~lifre~ and are selected from H, Cl 6 straight or 'ul~lched-chain alkyl, and aralkyl); or a -CH2ZR10, -ZCH2R10, or CH2ZR10aZR10 group(wherein Rl0a is selected from Cl 6 straight or b,~1clled-chain alkylene and R10 is selecte~l from C1 6 straight or branched chain alkyl) each of RlOa and R10 being optionally substituted by 1 or 2 substitl~nt~ in~epPnrl~ntly s~-lected from oR8 and -NR8R9(wherein R8 and R9 are as defined above) and Z is s~lected from O, S, -CH2O-, or -CH2S-); R2 is s~lected from O or S; R3 is selected from O, S, -SO, -S02, NR8, C=O, or -Cl 6 straight or blancl1ed-chain alkyl(e.g.,-CH2-); R4 is s~lected from H, Cl~ straight or bl~1clled-chain alkyl, halogen, -213~83~
~0 94/01414 - 3 - - . i c PCr/GB93/01443 OR11(wherein Rl1 is C1 4 straight or branched-chain alkyl optionally substituted by halogen, aryl, C3 6 cycloalkyl, (C1 3 alkyl-C3 6 cycloalkyl), C2 6 alkenyl or C2 6 alkynyl), methylenedioxy, -CX3(wherein X is halogen, preferably fluoro), NO2, or CN;
R5 is selected from H, halogen or oRl 1; R6 is selected from H, or Y-Ar-R7(m)(wherein Y is selected from O, S, -SO, -SO2, -NR8, C=O, or -Cl 6 straight or branched-chain alkyl(e.g., -CH2), Ar is phenyl or naphthyl, m is 1-3 and R7 is selected from R8, -CO2R8, -COR8, -CONR8R9, R8aOR8(wherein R8a is selected from Cl 6 straight or branched-chain alkyl, and aralkyl), -CN, -CX3(wherein X is halogen, e.g., fluoro), -oR8, OCX3(wherein ~ is halogen, e.g., fluoro), -SR8, -SO7R8, -OR8aO-(when m=l), -NO ~, -NR8R9, -NHCOR8, -NHS02R8, fluoro, chloro, bromo or iodo, or a combination thereof); and esters and prodrugs thereof (incl~l-iins~ amino acid esters, e.g., valyl or iso-leucyl) of the alcohols; provided that when Rl is H, CH2OCH2CH2OH or CH2OCH(CH2OH)2, R2 is O, R3 is -CH2, then R4, R5 and R6 are other than -OCH3, -OCH2CH3 -OCH2Ph, or -O-iso-propyl.

P-er~lled compounds of formula (I) are those of formula (IA) and esters and prodrugs thereof ~
(IA) r 1,. ~.

~D
C~t" ~
wherein R10b is a C2 3 straight or branched chain alkyl group substituted by one or two hydroxyl groups; R4a is H or oR1 la wherein R1 la is a C3 5 straight or branched chain allyl group optionally substituted by fluoro; and R6a is H or -O-Ar-R7a wherein Ar is phenyl and R7a is fluoro, chloro or cyano; provided that one but not both of R4a andR6aisH.

The compounds of formula (IA) and esters and prodrugs thereof, wherein Rl0b is CH2CH2OH, CH(CH2OH)2, and R4a is -OCH2CH2CH3, or -OCH(CH3)CH2CH3 and R6a is H are more ~lert;.led compounds of the invention.

The compounds of formula (LA) and esters and prodrugs thereof, wherein wherein RlOb is CH2CH20H, CH(CH20H)2 R4a is H and R6a is -0-Ar-R7a wherein Ar is
4 21 3 9 8 3 ~ - ~ - PCr/GB93/01443 ~

phenyl and R7a is H, fluoro, chloro or cyano are a further ~.~rt ., ed group of compounds of the invention.

The compounds of formula (IA) and esters and prodrugs thereof, wherein R10b is CH2CH2OH or -CH(CH2OH)2, R4a is H, and R6a is is -O-Ar-R7a wherein Ar is phenyl and R7a is 3-fluoro, 3-chloro or 3-cyano are most p.c;fe.,ed compounds of the mventlon.

It will be appreciated by the skilled practicioner that the arnino acid esters of the compounds of the present invention can be in the D, L, or DL configuration with the L
configuration p, ere" ed.

Accol dh~g to the present invention, the compounds of formula (I) or (IA), or prodrugs thereof, may be in the form of their pharm,.ce~ltically acceptable addition salts, which are preferably non-toxic base salts and include ammonium salts, alkali metal salts such as those of sodium and pot,..ccillm, alkaline earth metal salts such as those of calcium and m~gn~cillm salts with organic bases such as dicyclohexylamine and N-methyl-D-gl~lt~mine~ and salts with amino acids such as arginine and Iysine.

Preferably the compounds of the present invention are in the non-salt form.

Prodrugs of the uracil derivatives defined hereinbefore are compounds which may be metabolised in vivo to give the corresponding uracil derivatives. These prodrugs may or may not have activity in their own right but will normally have some activity. Such prodrugs may possess substitu~ntc on the unsubstituted N-3 of the compounds of formula I such as -COR8, -CSR8, -CONR8R8, -COOR8, -CH3, -CH(CH3)2, -CR8R8OCR8R8OCOR8(wheleill R8 is as defined h~ l)t;fu~e), -C02CH2Ph, or -CH~R8b(wherein R8b is -OCOR8, -OCSR8, -oR8, -OCO(CH2)nNR8R8, -OPO3=, OSO3~, -OC(O)(CH2)nCO ~R8, -OCR8R80H, -NR8R8, NR8COR8(wherein R8 is as defined hereinbefore and n=l~). In addition, compounds of formula I in which the -OH functionality of Rl is replaced by -OR9a(wherein R9a is selected from C1 6 straight or bl~lcl1ed-chain alkyl, and arallyl)may also act as prodrugs, -COR8, -CSR8, -COCR8R8NR8R8, -CSCR8R8NR8R8, -CR8R80COR8, -S020R8, -PO(OR8)2 or -PS(OR8)2(wherein R8 is as defined herei.~berole).

2~83~
5 PCr/GB93/01443 Particularly plefe,led compounds offormula I in accordance with the invention are:
1 -((2-hydroxyethoxy)methyl)-5-(3 -propoxybenzyl)uracil, I -((2-hydro-xyethoxy)methyl)-5-(3 -sec-butoxybenzyl)uracil, I -((2-hydroxyethoxy)methyl)-5-(3 -phenoxybenzyl)uracil, 1 -((2-hydroxyethoxy)methyl-5 -(3 -(3 -fluorophenoxy)benzyl)uracil, 1-((2-hydroxyethoxy)methyl)-5-(3-(3-chlorophenoxy)benzyl)uracil and I -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3-cyanophenoxy)benzyl)uracil.

The most pler~ d compounds offormula I in accordance with the invention are:
I -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-phenoxybenzyl)uracil, I -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl)uracil, I -((2-hydroxy- 1 -(hydroxyrnethyl)ethoxy)methyl)-5-(3-(4-fluorophenoxy)benzyl)uracil, I -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3-chlorophenoxy)benzyl)uracil and 1 -((2-hydroxyethoxy)methyl)-5-(3 -(3 -cyanophenoxy)benzyl)uracil.

Other p,erel,ed compounds include:
1 -((2-hydroxy- 1 -(hydl uxyl~ethyl)ethoxy)methyl)-5-(3-propoxybenzyl)uracil, I -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-chlorobenzyl)uracil, 2-((5-(3 -chlorobenzyl)- 1,2,3 ,4-tetrahydro-2,4-dioxo- 1 -pyrimidinyl)methoxy)ethyl acetate, 5-(3-chlorobenzyl)- 1 -((2-hydro-xyethoxy)methyl)uracil, 5-(3-chlorobenzyl)- 1 -(4-hydroxybutyl)uracil, I -((2-hydro,~y~Llloxy~methyl)-5-(3 -allyloxybenzyl)uracil, I -((2-hydroxyethoxy)methyl)-5-(3 -(3-fluol op, opu~y)benzyl)uracil, I -((2-hydro-xyethoxy)methyl)-5 -(3 -sec-butoxybenzyl)uracil, 1-((2-hydroxyethoxy)methyl)-5-(3,5-difluorobenzyl)uracil, 1 -((2-hydl o~ye~ oxy)methyl)-5-(3-trifluorollle~hoxyberlzyl)uracil, 1 -((2-hydroxyethoxy)methyl)-5-(3-(4-fluo, ophel1oxy)benzyl)uracil, 3 -(3 -(2-fluorophenoxy)phenyl)propionate, 1-((2-hydroxyethoxy)methyl)-5-(3-(4-chlorophenoxy)benzyl) uracil, 1-((2-hyd,oAyeLlloxy)methyl)-5-(3-(4-methoxyphenoxy)benzyl) uracil, 1 -((2-Hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3 -trifluol o",GLl,yll.henoxy)benzyl)uracil, 1-((2-hydluAyeLllo~y)methyl)-5-(3-(3-methoxyphenoxy)benzyl) uracil, WO 94/01414 2 ~ 3 ~ ~ 3 6 6 - PCr/GB93/01443 ~

1 -((2-Hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3-methoxyphenoxy)benzyl)uracil, 1-((2-hydroxyethoxy)methyl)-5-(3-(4-cyanophenoxy)benzyl)uracil, 1 -((2-Hydroxy- 1 -(hydro~y~elllyl)ethoxy)methyl)-5-(3-(4-cyanophenoxy)benzyl)uracil, 1 -((2-hydroxyethoxy)methyl)-5-(3-(4-trifluol o",~;Lhylphenoxy)benzyl)uracil, 1 -((2-Hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(4-trifluoromethylphenoxy)benzyl)uracil, 1 -((2-hydroxyethoxy)methyl)-S -(3 -(4-methylphenoxy)benzyl)uracil, 1 -((2-Hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(4-methylphenoxy)benzyl)uracil, 1 -((2-hydroxyethoxy)methyl)-5 -(3 -(3 -methylphenoxy)benzyl)uracil, 1 -((2-Hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3-methylphenoxy)benzyl)uracil, 1 -((2-hydroxy- 1 -(aminomethyl)ethoxy)methyl)-5-(3-phenoxybenzyl)uracil, 1 -((2-aminoethoxy)methyl)-5 -(3 -phenoxybenzyl)uracil, 1 -((2-hydroxy- 1-(aminomethyl)ethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl)uracil, 1 -((2-aminoethoxy)methyl)-5 -(3 -(3 -fluorophenoxy)benzyl)uracil, 1 -((2-hydroxy(ethylthio))methyl)-5 -(3 -phenoxybenzyl)uracil, 1 -((2-hydl oxy(ethylthio))ethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl)uracil, 1-((2-hydroxyethoxy)methyl)-5-(3-isobutoxybenzyl)uracil and 1-((2 -l,ydro~yeLhoxy)methyl)-5 -(3 -butoxybenzyl)uracil .

The compounds of the present invention are useful for the inhibition of the enzyme uridine phosphorylase in m~mm~l~(e.g., humans) in need of such enzyme inhibitionwhich comprises ~mini~t~ring to a m,-mm~l in need thereof an effective amount of a compound of the invention or a pharm~ceutic~l composition co"~ g a said compound in combination with one or more pharm~ceut~ ly acceptable carriers.

The present invention is thus based on the use of compounds of formula I in colnbinalion with pyrimidine nucleosides such as zidovudine and reducing the cellular toxicity of the pyrimidine nucleoside, such as the stem cell and h~m~tological toxicity.

According to the present invention therefore we provide a uridine phosphorylase il,hibiLor, of formula (I) or a prodrug thereof, for use in m~-licine especially in Wo 94/01414 ~ PCr/GB93/01443 combination with pyrimidine nucleosides such as zidovudine for the reduction of pyrimidine nucleoside(e.g.,zidovudine) in~lced toxicity in m~mm~lc(e.g., humans).

In another aspect of the present invention, there is provided a treatment for AIDS-type rlice~ces in which a pyrimidine nucleoside analogue, such as zidovudine, and a uridine phosphorylase inhibitor of the invention are co-~tlminictered either cimlllt~neously or sequentially to protect or rescue uninfected cells from the toxic effects of thepyrimidine nucleoside in a ...~....,.~I(e.g., a human) requiring such treatment.
AlDS-type ~ice~ces are defined herein as Acquired Immune Deficiency Disease(AlDS), AIDS-related complex(ARC), asy",pto",a~ic ~V infections, as well as any disease which causes a deficiency in the immune system.

Pyrimidine nucleoside analogues which are useful according to the present invention include, for eAalllplc, 3'-azido-3'-deoxythymidine(AZT); 3'-azido-2',3'-dideoxyuridine(AZddU);
2',3'-dideoxycytidin-2'-ene; 3'-deoxy-3'deoxythymidin-2-ene; and other related compounds.

The compounds of the present invention are not restricted to use for the reduction of zidovudine toxicity. Acco,din~,ly, the compounds of the present invention can beutilized to inhibit the enzyme uridine phosphorylase in a ..,,..."..~I(e.g., a human) when such enzyme inhibition is desired. Therefore, other uses of the compounds of theinvention which rely on the inhibition of uridine phosphorylase are also ~nco,~ cced by the present invention. Such uses include: t~nh~nring the ~ntitllmor activity of halogenaLed pyrimi~in~C(e.g.~ 5-fluoro-2'-deoxyuridine, S-fiuorouridine and 5-fluorouracil) and &~Lineopla~Lic pyrimidine nucleosides(e.g., 5-fluoro-2'-deoxyuridine~FdUrd), 5-trifluol c lll~;Lhyldeoxyuridine(TFT), and 5-bromovinyldeoxyuridine(BVdU)) which are subject to degradation by uridine phosphorylase. The uridine phosphorylase inhibitors of the present invention are useful for redllcin~ the toxicity of ~lh~eopla tic pyrimidine nucleosides as well as for pot~ the efflcacy of ~lLi,leoplastic drugs.

The compounds of the inventi~n can be ~-I...;.~;clP-ed to a ,..~ 1 either prior to, during or subsequent to ~I...;.~;cl.~lion of the antineoplastic agent. The compounds WO 94/01414 213 ~ 8 3 ~ 8 - PCr/GB93/01443 ~

are preferably ~minict~red prior to ~minictration of the all~h1eoplastic agent to inhibit the uridine phosphorylase enzyme and thereby prevent the degradation of the all~hleoplastic agent.
The compounds of the present invention can also be used in the tre~tm~nt of nervous disorders(e.g., schizophrenia and Parkinson's disease) and in the Lle~ of ~ice~ces in which increased levels of uridine are beneficial.

In a further aspect, the present invention provides a uracil derivative as hereinbefore defined for use in the m~nllf~r,t-~re of a medicament for use in reducing zidovudine in~uced toxicity or pot~nti~rint~ the antitumor effects of antineoplastic pyrimidine nucleosides, or in the treatment of nervous disorders and diseases in which increased levels of uridine are beneficial.

The present invention further provides:

a) a colllbhl~ion of a uridine phosphorylase inhibitor, as shown in figure I, and zidovudine or a pharm~ceutically acceptable salt or ester thereof;

b) a coll~ ation of a uridine phosphorylase inhibitor, as shown in figure I, and 5-fluorouracil;

c) a method for the treiqtm~nt or prophylaxis of an ~V infection in a .~A~
inr.~ ing a human, which comprises ~minictering to the said ",~."".~1 an effective anti-H[V amount of zidovudine or a pharm~ceutically acceptable salt or ester thereof in co--,bin~ion with an effective uridine phosphorylase inhibiting amount of a compound of figure I as defined hereinbefore.

d) a method for the ~re~ or prophylaxis of tumors in a m~mm~l, in~ ing a human, which comprises ~11mini~t~ring to the said .. ~.. ~1 an effective anti-tumor amount of S-fluorouracil in colnl,ill~ion with an effective uridine phosphorylase inhibi~ing amount of a compound of figure I as defined hereinbefore.

~3~3~
~0 94/01414 9 PCr/GB93/01443 Zidovudine(or a pharm,.~e~.tically acceptable salt or ester thereof) or an antineoplastic pyrimidine nucleoside, and the said uridine phosphorylase inhibitor may be employed in co",bh,~Lion in accordance with the invention by ~tlmini~tration of the components of the combination to an ap~r~,p,iate subject either concomiL~,lly, for example in a unitary pharm,.ce~ltical formulation, or, more preferably, separately, or sequentially within a sufficient time period whereby the desired therapeutic effect of the combination is achieved.

Zidovudine may be ~rlmini~tered per se or in the form of a pharm,.ceutically acceptable salt, e.g., an alkali metal salt such as sodium or pot,.c~ m an alkaline earth salt or ammonium salt. The mono-, di- or triphosphates of zidovudine or their pharmaceutically acceptable base salts(i.e., alkali metal, alkaline earth or ammonium salt) can also be substituted for zidovudine in the co"lbi"aLion described by this inventlon.

Zidovudine or a pharm~celltic~lly acceptable salt or ester thereof and the uridine phosphorylase inhibitor of formula I may be ~minictered respectively for therapy by any suitable route incl~ing oral, rectal, nasal, topical (in~lllrling buccal andsublingual), vaginal and parenteral (inclu~ling subcutaneous, intrS~m--scul~r, intravenous and intradermal). It will be app~c~iaLed that the p~erclled route will vary with the condition and age of the recipient, the nature of the infection and other clinical factors.

A suitable dose of zidovudine or a pharn ~ce~ltically acceptable salt or ester thereof is in the range of 5 to 250 mg per kilogram body weight of the recipient per day, preferably in the range of S to 40 mg per kilogram body weight per day and most plcrc,~bly in the range of S to 10 mg per kilogram body weight per day in cG~billaLion with each of the a~ore",e"Lioned uridine phosphorylase inhibitors of formula I. The desired dose is preferably p.cscl.Led as two, three, four, five, six or more sub-doses ~imini~tered at app,o~ -iate intervals throught the day. These sub-doses may be ?~riminict~red in unit dosage forms, for example, cor,~ g 10 to 1500 mg, prcrc.~bly 20 to 1000 mg, and most p.erc.~bly 50 to 700 mg of active ingredient per unit dosage form.

Er.~c~h~c~ls with 3'-azido-3'-deo~LyLllyll idine(zidovudine) suggest that a dose should be a-lminict~o-red to achieve peak plasma conccllLl ~Lions of the active compound of from WO 94/01414 21~ ~ 8 3 6 PCr/GB93/01443 ~

about 1 to about 75 uM(the abbreviation uM is used herein as micromolar), preferably about 2 to 50 uM, most preferably about 3 to about 30 uM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally ~minictçred as a bolus cont~ininp about 1 to about 100 mg/kg of the active ingredient(the abbreviation "mg/kg" is well understood by one of ordinary skill in the art). Desirable blood levels may be m~int~ined by a continuous infusion to provide about 0.01 to about 5.0 mgAcg/hour or by intermittent infusions co"l;~ ;ng about 0.4 to about 15 mg/kg ofthe active ingredient.

The antineoplastic pyrimidine nucleosides of the present invention are those which are known in the art and are ~minictered according to procedures known by one skilled in the art of treating antineoplastic disease. Particularly pl e~ d antineoplastic pyrimidine nucleosides used in accordance with the present invention include but are not limited to: 5-fluoro-2'-deoxyuridine, 5-fluorouridine, 5-fluorouracil, 5-fluoro-2'-deoxyuridine(FdUrd), 5-trifluoromethyldeoxyuridine(TFT), and 5-bromovinyldeoxyuridine(BVdU)). The antineoplastic pyrirnidine nucleosides of thepresent invention are readily available to the skilled practicioner in the art.

The uridine phosphorylase inhibitor of formula I may be ~-lmini~tered in a dosage in the range of 1 to 300 mg per kilogram body weight of the recipient per day, preferably in the range of 3 to 100 mg per kilogram body weight per day, most pl~r~l~bly in the range of 5 to 30 mg per kilogram body weight per day in col"binalion with zidovudine or the antiviral pyrimidine nucleoside analogs or antineoplastic pyrimidine nucleosides described hereinbefore. Unless otherwise in~ic~te~, all weights of active ingredients are c~lc~ ted as the parent free base compound of formula I; for salts thereof the figures would be increased ,~,vpo, lionally.

The desired dose is pr~r~,~bly p,~;se"~ed as one, two or more sub-doses ~rlmini.~t~red at approp,iaLe intervals throughout the day. These sub-doses may be ~i....n;~lç.ed in unit dosage forms for ~Aalllple co..li.;..;.~g 1 to 200 mg, p,cre,~bly 10 to 200 mg, most preferably 10 to 100 mg of a compound of formula I.

Zidovudine and the uridine phosphorylase inhibitor are employed in an dpplop,iaLe ratio wl,c. ~y the above-mentioned toxic effects of zidovudine are reduced or obviated VO 94/01414 2 1~ 9 ~ 3 ~ pcr/GB93/0l443 without significant reduction of the therapeutic effect of zidovudine or the antiviral pyrimidine nucleosides.
In a similar manner to that described above for zidovudine, other antiviral pyrimidine nucleosides hereinbefore described, are used in co.l,bh1a~ion with the uridine phosphorylase inhibitor to reduce the toxic effects of the antiviral pyrimidine nucleosides without significant reduction of the therapeutic effect of the antiviral pyrimidine nucleosides.

The antineoplastic pyrimidine nucleosides described hereinbefore and the uridinephosphorylase inhibitor are employed in an appropriate ratio whereby the above-mentioned ~nSitl~mnr effects of the antineoplastic pyrimidine nucleoside are enhanced or increased.

Zidovudine and the uridine phosphorylase inhibitor are preferably ~lmini~tered in a pharm~ce~ltical forrnulation, either in a single pharm~ceutical formulation co,.~ ;"g both components or in separate pharm~se~ltical formulation each co~ ;llg one of the components of the col,lbhla~ions.

The present invention thus in~ des as a further feature a pharrn~ce--tical formulation comprising a uridine phosphorylase inhibitor of formula I optionally in eolllbillaLion with zidovudine together with at least one pharm~e~1tically accep~ablc carrier or excîplent.

Each carrier must be "pharm~se~ltis~lly acceptable" in the sense of being co,l"t)a~ible with the other ingredients of the formulation and not injurious to the patient.
Formulations include those adapted for oral, rectal, nasal, topical (inr.~ in~ buccal and sublingual), vaginal and parenteral (in~ l1ing subcutaneous, intr~ml~sc -l~r, intravenous and intradermal) a-lmini~tration. The formulations may conveniently be presented in unit dosage form and may be plep~ed by any methods well known in the art of pharmacy. Such methods include the step of blin~ g into association the active ingredient with the carrier which con~ti~1tes one or more accesso~y ingredients. In general, the form--l~tic)n~ are prepared by ul,i~lll,ly and i..~ ly brin~ng intoassociation the active ingredient with liquid carriers or finely divided solid carriers or both, and then if nece~ y shaping the product.

WO 94/01414 213 9 8 3 ~ 12 - PCr/GB93/01443 Formulations of the present invention adapted for oral arlminictration may be presented as discrete units such as capsules, cachets or tablets each cont~ining a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by coln~"cssion or molding, optionally with one or more accessory ingredients. Colll~ressed tablets may be prepared by coln~les~ing in asuitable m~rhine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, tli~integrant (e.g., sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or di~,~)e.~ g agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be form~ ted so as to provide controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.

Formulations for topical arl,.,;";~ ion in the mouth include 1O7en~es comprising the active ingredient in a flavored basis, usually sucrose and acacia or tr~g~r;~nth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes colllyli~ g the active ingredient in a suitable liquid carrier.

Compositions for transdermal arl~";";~ lion may be delivered by passive diffusion or by electrically-~cci~ted ~ SI)O1L~ for example, iontophoresis (see, for example,Pharm~celltic~l Research ~(6), 318, (1986)) and may take the form of an optionally buffered aqueous solution of a compound of formula I.

Formulations for rectal ~(lmini~tration may be presented as a suppository with asuitable base comprising for example cocoa butter or a salicylate.

~9~6 WO 94/01414 - 13 - PCr/GB93/01443 Formulation for vaginal ~rlmini~tration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations CO~ .it~ SJ in addition to the active ingredient such carriers as are known in the art to be app,up,iate Formulations for parenteral ~lminictration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intt?n-led recipient;
and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed cor,Lain~ for example, ampoules and vials, and may be stored in a freeze-dried (Iyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, imme~ .teIy prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

P~t;fe"ed unit dosage formulations are those cor.l~ ;.-g a daily dose or unit, daily sub-dose, as herein above recited, or an applupliate fraction thereof, of an active ingredient.

Zidovudine is 3'-azido-3'-deoxythymidine(AZT) and is commercially available under the tr~d~n,.me RETROVIR~) from Burroughs Wellcome Co., Research Triangle Park, North Carolina, USA. It is an antiviral compound active against human immlmodeficiency virus(HIV) and is approved for the tre~tment of H[V infection in both children and adults. The pie~al~ion of zidovudine has been disclosed(Horowitz J.P. et al., J. Org. Chem. 29: 2076(1964) and Glinski R.P. et al., ibid. 38: 4299(1973)) and its synthesis and use in the ~ of AIDS and AIDS-related complex has been disclosed in U.S. Patent No. 4,724,232(1988) which is incorporated in its entirety herein by rt;rerence. Zidovudine is well known in the art.

WO94/01414 213 9 8 3 ~ 14 - PCr/GB93/01443 Compounds of formula (I) may be prepared by hydrolysis of the corresponding compound of formula (II) (n) G~ ~
wherein R~ to R6 are as hereinbefore defined and Q is NH2, oRl3 or SR13 wherein R13 is Cl 6 straight or branched chain alkyl group to give a compound of formula (I) where Rl is H, and therea~er optionally converted to a compound of formula (I) wherein R1 is other than H.

When Q is SH, the compound of formula (II) may exist in tautomeric form.

The hydrolysis of a compound of formula (II) may suitably be carried out with inorganic or organic acids (for example glacial acetic acid/aqueous chloroacetic acid, 20% hydrochloric acid/aqueous sodium nitrite or sulphuric acid), with an aqueousalkali (for example 20% sodium hydroxide), or when Q is SH and the compound is in the tautomeric form, with an organic peroxide and an organic alcohol (for example hydrogen peroxide/tert-butanol), and at a tw~pt;laLLIre of 0-250C and preferably 20-150C (for example the reflux temperature).

The conversion to a compound of formula (I) wherein R1 is other than H may be carried out by the reaction of a compound of formula (I) where R1 is H with a silylating agent, for example, Ll;lllt;Lllylsilyl chloride, bis(Lli-l-~;Lhylsilyl)~cet~mi~e or h ~ elllyl~licil~7~ne either neat or in a suitable inert solvent, for example, 1,2-dichloroethane or dichloro...~ e at a temperature of b~lween 0-150 C (plerel~bly the reflux te-~el~ re) and then further reachng the ;~le~ c.li~te ~en~ilaled with XRl(wherein X is a leaving group, for ~x~mple, halogen(plt:re,ably chloro or bromo) or acyloxy, and R1 is as defined hereinbefore other than H) at a tel,lpe~ re of between 0-150 C (p,erelably at ambient tell.~ al,lre). A glycosidic bond forrning ~0 94/01414 PCI/GB93/01443 catalyst(e.g., trifluoromethane sulfonic acid, 4-tol~nes-llfonic acid, stannic chloride or triethylamine) can be added to f~cilit~te the rate of reaction.

Alternatively, the conversion can be effected by reacting an excess of the compound of formula (I) where R1 is H with XR1(wherein X is a leaving group, for example, halogen(preferably chloro or bromo~ or acyloxy, and Rl is as defined hereinbefore other than H) in an inert organic solvent(e.g., DMF, DMSO) in the presence of a base(e.g., K 7CO3, NaHCO3 or NaH) at a temperature of between 0-150 C.

Compounds of formula XR1 can be obtained by methods well-known to those skilled in the art.

Compounds offormula I wherein Rl contains at least one -OH or -NH2 moiety can beconverted by the hydrolysis of a compound of formula III

~3~ R~

BYC~ f~
wherein R2, R3, R4, RS, and R6 are as he-ehlbero,e define~1 B is that portion of R1 other than -OH or -NH2, Y is O or NH and R12 is C1-6 straight or branched-chain alkyl, C6Hs or substituted aryl, with ammonia gas or an organic amine(for example, methylamine, dil~eLllylamine). The reaction will generally be carried out with stirring in an organic solvent such as an organic alcohol, e.g., meth~nol or ethanol, at a temperature between 0-150 C., preferably ~nbi~.,L tel-.~)e~ re; or by tre~tmPnt with a metal alkoxide(e.g., sodium etho~i~ie) in water or alcohol; or by L.e~ l with an illo,ga~,ic base(e.g., a metal hydroxide such as NaOH or KOH) in H20 or alkanol solvent(e.g., meth~nol); or by Lle..l".~"l with alcohol(e.g., ethanol) in the presence of potassium c~l,onaLe; or by hydrolysis with aqueous acid(e.g., lN hydrochloric acid) optionally with an organic cosolvent such as tetrahydrofuran. The reaction ten.l)e.~L~lre may conveniently be between 0-150 C. and ple~é-~bly at ambient tt...pe. ~L.Ire.

WO 94/01414 21 3 ~ 16 PCr/GB93/01443 Alternatively, the target hydroxy compounds may be formed from the intermetli,-te O-benzyl ethers by llea~ ;llL with hydrogen in an organic alcohol solvent(e.g., ethanol) in the presence of a catalyst(e.g., p~ lm) Alternatively, the target hydroxy compounds may be forrned from the O-trimethylsilyl ether intermediate by hydrolysis with neat or aqueous organic alcohol(e.g., ethanol) under acidic or neutral conditions.

Compounds of forrnula III can be prepared by reacting a compound of forrnula (I)where Rl is H with XBYCOR12(wherein X, B, Y and R12 are as previously defined) by the methods described herein for the pl~al~Lion of compounds of formula I by replacing XRl with XBYCORl-.

Compounds of formula XBYCOR12 can be obtained by methods well-known to those skilled in the art.

It will be appreciated by one of ordinary skill in the art that the esters depicted in formula III are prodrugs as defined hereinbefore and thereby constitute a further aspect of this invention.

The compounds of formula m are also hydrolysed by any of the standard methods ofhydrolysis of carboxylic acid esters such as those described in, e.g., J. March,Advanced Organic Chemistry, 2nd edit., 349-353, McGraw-Hill, N.Y., 1977.

Compounds of forrnula (II~ can be prepared by reacting an ester as depicted by forrnula (I~

R

(rv) ~398~;6 (wherein R4, R~ and R6 are as defined hereinbefore and R14 is C1 6 straight or branched chain alkyl; preferably R14 is ethyl) dissolved in a suitable inert solvent such as tetrahydrofuran with a non-nucleophilic base~e.g., lithium diisopropylamide, sodium, sodium hydride or potassium tert-butoxide) at a t~ pe.dture of -100-25 C.(preferably -78 C). The resulting anionic interme~ te is then reacted with an alkyl formate(preferably ethyl formate) at a temperature of-78-25 C(~r~ dbly -30 C).The resulting anionic salt of the alpha-formyl ester is then reacted with a ureaderivative, such as thiourea, ~ nilline, O-a&ylisourea or S-alkylisothiourea at a temperature of-78-25 C.

Alternatively, the illt~l",ç~ te anionic salts may be O-alkylated using an al3cylatin~
agent(e.g., methyl iodide or dimethyl sulfate) to generate an enol ether which is reacted with thiourea~ guanidine, O-a&ylisourea or S-alkylisothiourea Compounds of forrnula (IV) can be obtained by methods well-known to those skilled in the art.

The following Exarnples illustrate the prcsent invention.

Example I
Preparation of l-(f2-hvdroxyethoxy)methvl~-5-(3-~ropoxvbenzyl)uracil A. Preparation of (E)-ethvl 3-(3-hydroxvphenvl)-2-propenoate This compound was prepared ~y the following modified method of Stodola, J. Or~.
Chem., 1964, _9 2490. A solution of (E)-3-(3-hydroxyphenyl)-2-propenoic acid (Aldrich) (100.00 g, 609 rnmoles) and 1.0 M ethereal hydrochloric acid (100 rnl) in absolute ethanol (1000 ml) was refiuxed with stirrin~ under nitro~en for 48 hours. The ethanol was removed tn vacuo, and the residue dissolved in ethyl acetate (600 ml) and washed with a saturated aqueous sodium bicarbonate solution (2 x 400 rnl). The washes were back-extracted with ethyl acetate (2 x 100 ml) and the combined extracts washed with water ~;00 ml) and brine (400 rnl), dried over anhydrcus sodium sulfate and filtered.

A~lENDE~ SHE~

WO 94/01414 213 ~ 8 3 ~ PCI/GB93/01443 ~

The filtrate was evaporated in vacuo to give 113.55 g (97%) of ethyl 3-(3-hydroxyphenyl)-2-propenoate as a brown waxy solid, which was used without further purification; tlc, dichlorometh~ne B . P, epa, ~Lion of ethyl 3-(3-hydroxyphenyl)propanoate This compound was prepared by the following modification of the previously reported method of J.M. Bruce, D. Creed and H. Dawes, J. Chem. Soc. C.
1971, 3749-3756.

A mixture of (E)-ethyl 3-(3-hydroxyphenyl)-2-propenoate (30.0 g, 156 mmoles), platinum oxide hydrate (0.25 g, 1.1 mmoles) and 95% ethanol (150 ml) was shaken in the presence of hydrogen at 2-3 atmospheres for 18 hours. The catalyst was removed by filtration through Celite, and the filtrate was evaporated in vacuo to give 26.72 g (89%) of ethyl 3-(3-hydroxy-phenyl)propanoate as a brown oil, which was used without further purification;
tlc, dichlorometh~ne.

C. P~e~a~Lion of ethyl 3-(3-propoxyphenyl)propionate A mixture of ethyl 3-(3-hydroxyphenyl)prop~no~te (18.0 g, 92.7mmoles), bromopropane (11.4 g, 92.7 mmoles), potassium carbonate (20.0 g, 144.7 mmoles), potassium iodide (18.5 g, 111.4 mmoles) and acetone (300 ml) was refluxed with stiITing under a calcium chloride drying tube for 48 hours.
The cooled m-ixture was filtered, and the solids washed with diethyl ether (3 x 50 ml). The filtrate and washings were co,llbined, and the solvents removed in vacuo. The residue was taken up in diethyl ether, washed s~lccçeeively with water (200 ml), 0.5 N sodium hydroxide (150 ml), water (lOO ml) and brine (100 ml). The extracts were dried over anhydrous m~ s;~,. sulfate, filtered and evaporated invacuo to give 17.1 g (78%) of ethyl 3-(3-propoxy-phenyl)propionate as a brown oil. Part of the product was purified by flash cl~olllaLography on Silica Gel 60. The colurnn was eluted with hP~n~s:e~hyl acetate (1: 1) to give an analytically pure sample.

2~3~836 I~NO 94/01414 . , PCr/GB93/01443 D. Preparation of 1 ~2-dihydro-5-(3-propoxvbenzyl)-2-thioxo-4(3H)-pvrimidinone A solution of ethyl 3-(3-propoxyphenyl)propionate (2.00 g, 8.5 mmoles) in tetrahydrofuran (3 ml) was added eo a solution of lithium diisopropylarnine [This salt was prepared from diisopropylamine (1.42 ml, 10.0 mmoles~ and n-butyl lithium (5 ml of a 2 M pentane solution, 10.0 mmoles)] in tetra-hydrofuran (7 ml), cooled to -78C under nitrogen. The solution wzs stilTed for 1.5 hours while the temperature was allowed to rise to -60C. The solution was cooled to -78C, ethyl formate (0.8 ml, 10.0 mmoles) added, and stirring continued for 2.5 hours while the solution warmed to -30C. Af[er re-cooling to -78C, thiourea (0.76 g, 10.0 mmoles) was added in one portion, and the res~lltinE suspension allowed to warm to ambient temperature. Ethanol (15 ml) was added, and the solution was refluxed under nitrogen for 18 hours. The ethanol was removed in vacuo, and the residue was partitioned between dichlorometh~ne:water (75 ml:l25 ml). The layers were separated, and the aqueous layer was washed with additional dichloromethane (2 x 100 ml). The organic washes were combined and back-extracted with 0.5 N sodium hydroxide. The combined aqueous layers were cooled in an ice bath, and the pH was adjusted to 4 with conce"~ ed hydrochloric acid. The light brown precirit~te was collected on a filter, washed several times with water and diethyl ether, and dried under a vacuum at ambient temperature for 18 hours to give 1.24 g (53%) of 1,2-dihydro-5-(3-propo~cybe-~yl)-2-thioxo-4 (3H)-pyrimidinone, mp 183-185C. Recryst~ tion from act;Loni~,ile gave 0.53 g of an analytically pure sample.

E. ~ep~alion of 5-(3-~"opo~ybenz,vl)uracil A suspension of 1,2-dihydro-5-(3-propoxybenzyl)-2-thioxo-4(3H) _~yl;~ e (0.350g, 1.3mmol~) in glacial acetic acid (5 ml) and 20%
aqueous chloroacetic acid (5 ml) was refiuxed with stirring for 18 hours. After cooling to ambient temperature and then in an ice bath, the mixture was f~ltered, and the solids were washed with water and diethyl ether and dried in a WO 94/01414 2 ~ ~ ~ 8 3 ~ 20 - PCr/GB93/01443 vacuum oven at 80C for 18 hours to give 0.28 g (85%) of 5-(3-propoxybenzyl) uracil as an off-white solid, mp 247-249C.

F. Preparation of 1-((2-acetoxyethoxy)methyl)-5-(3-propoxybenzyl)uracil 1/2 hydrate Bis(trimethylsilyl)acet~mide (0.85 ml, 3.4 mmoles) was added to a stirred suspension of 5-(3-propoxybenzyl)uracil (0.50 g, 1.9 mmoles) in dichloro-ethane (20 ml) under nitrogen. The mixture was refluxed with stirring for 35 min~ltec, and the resultant solution cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (0.327 g, 1.7 mmoles), see below for ple~ ion, in acetonitrile (3 ml) was added to the cooled solution and the r~s~-lt~nt solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours. The volatiles were removed in vacuo, and the residual oil introduced onto a column of Silica Gel 60 wetted with dichlorometh~ne.
The column was eluted with dichlorometh~ne:methanol (30:1), and the fractions cont~inin~ product were combined. The solvents were removed in vacuo to give 0.63 g (83%) of 1-((2-acetoxyethoxy)methyl)-5-(3-propoxybenzyl)uracil 1/2 hydrate as a light yellow oil; tlc, dichloro-methane mPth~nol (19: 1); uv (0.1 N hydrochloric acid + 10% me,th~nol): ImaX
266 nm (e. 10100); (pH 7 buffer + 10% meth~nol): ImaX 266 nm (e 9500);
(0.1 N sodium hydroxide + 10% methanol): ImaX 267 nm (e 7200).

Ple~al~ion of (2-acetoxyethoxy)methyl bromide (Robins, M.I. and Hatfield, P.W., Can. J. Chem., 1982, ~Q 547). Freshly distilled acetyl bromide (13.0 g, 106 mmol) was stirred m~gnetically with cooling in an ice bath while 7.4 g (100 mmol) of 1,3-dioxolane was added slowly. A rapid exothermic reaction occurred giving q~ ve conversion to the title compound (as judged by 1H
NMR). Vacuum ~lictill~tion of this material gave 17.4 g (88%) of product, bp 58-60C/0.1 Torr.

~t 3~83;~
~WO 94/01414 - 21 - PCr/GB93/01443 G. P-~pal~Lion of 1-((2-hydroxyethoxy)methyl)-5-(3-propoxybenzyl)uracil 1/4 hydrate A solution of 0.30 g (0.8 mmoles) of 1-((2-acetoxyethoxy)methyl)-5-(3-propoxybenzyl)uracil in meth~nol (250 ml) saturated with ammonia gas was stirred in a stoppered flask for 18 hours at ambient temperature. The meth~nol was removed in vacuo, and the residue was recryst~lli7ed from dichlorometh~ne / hexane:one drop water to give 0.19 g (70%~ of 1-((2-hydroxy-ethoxy)methyl)-5-(3-propoxybenzyl)uracil 1/4 hydrate as a white solid m.p. 85-87C; uv (0.1 N hydrochloric acid + 10% mPth~nol): ImaX
266 nm (e9800); (0.1 N sodium hydroxide + 10% meth~nol): ImaX 265 nm (e 10900); NMR (DMSO-d6): d 7.62 (s, lH, H-6), 6.94 (m, 4H, ArH), 5.06 (s, 2H, NCH2O), 4.68 (s, lH, OH), 3.86 (t, 2H, J=6.5 Hz, OCH2), 3.47 (s, 6H, CH2Ar and (CH2)2), 1.71 (dq, 2H, J=6.5 Hz and 7.4 Hz, CCH2C), 0.94 (t, 3H, J=7.4 Hz, CH3); ms: m/e 335.
Anal. Calcd. for C17H22N2Os 1/4 H2O: C, 60.25; H, 6.69; N, 8.27.
Found: C, 60.23; H, 6.70; N, 8.21.

Example 2 Ple~ ion of 1 -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-propoxybenzyl)uracil A) P~ )~alion of 2-((1.2.3.4-tetrahydro-2.4-dioxo-5-(3-propoxybenzyl)- 1 -pyrimidinyl)methoxy)-1.3-propanediyl ~ cet~te This compound was prepared in an analogous manner to that of Example lF
with the repl~cemPnt of 0.327g of (2-acetoxyethoxy) methyl bromide in Example lF with 0.51 g of (2-acetoxy-(1-acetoxy-methyl)ethoxy)methyl brornide (see below for plep~aLion). The clhc-l,alography fractions were spin e~alJo-~Led in vacuo to give 0.83 g ~98%) of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3 -propo~ybel~yl)- 1 -pyrimidinyl)methoxy)- 1,3-propalle-diyl et~te as a clear oil; tlc, dichloro-meth~ne ~ .ol (19.:1).

WO 94/01414 21 3 ~ ~ 3 6 22 - PCr/GB93/01443 t2-acetoxy-(1-acetoxy-methyl)ethoxy)methyl bromide This compound was made by the same method as that described for 2-(bromomethoxy)- 1,3-propanediyl dibPn7o~te, referred to in Exarnple 4A~
with the repl~cPm~nt of sodium benzoate with an equimolar arnount of sodium acetate.

B. Preparation of I -(f2-hvdroxv- 1 -(hydroxymethvl)ethoxy)methyl)-5-(3 -propoxybenzyl) uracil This compound was ~ a~ed in an analogous manner to that of Example lG with the replacement of 0.30 g of 1-((2-acetoxyethoxy)methyl)-S- (3-propoxybenzyl) uracilwith 0.73 g of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3-propoxybenzyl)-1-pyrimidinyl) methoxy)-1,3-propanediyl ~ cet~te. The meth~nol was removed in vacuo, and the residue was chromatographed on silica Gel 60, eluting with dichlorometh~ne:
meth~nol (19: 1) to give 0.44 g of a waxy solid which was washed with water to give 0.14 g (24%) of 1-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-5-(3-propo~benzyl)uracil as a white solid, mp 101-102C.

Exarnple 3 Preparation of 1-((2-hyd~o~yt;lhoxy)methyl)-5-(3-phenoxybenzyl)uracil A. Plepa,~Lion of (E)-3-(3-phenoxyphenyl)-2-,~,upe"oic acid A solution of 3-pheno~yl,~l,,; lrlehyde (Aldrich) (25.0 g, 126 mmol), malonic acid (26.2 g, 252 mmol) and piperidine (2.0 ml, 20 mmol) in pyridine (S0 ml) was stirred in an oil bath heated at 90C for 18 h. After cooling to ambient t~,~"pt;l~ re, the solution was poured into cold water (1 L). The pH of the aqueous mixture was adjusted to pH 2 with co"ce"L~Ied hydrochloric acid.
The solids which formed were collected by suction filtration, washed with water, and lec,y~l~lli7ed from aceLon.L.;le/water to give 24.18g (80%) of (E)-3-(3-phenoxyphenyl)-2-propenoic acid as a white solid: mp 111-113C;
tlc, meth~nol: dichlo,o..,~ ne (1: 19).

213~83~
~WO 94/01414 - 23 - PCI/GB93/01443 B. Preparation of fE)-ethyl 3-(3-phenoxy)phenyl-2-propenoate A solution of (E)-3-(3-phenoxyphenyl)-2-propenoic acid (14.51 g, 60.4 mmoles) and 1.0 M ethereal hydrochloric acid (40 ml) in absolute ethanol (150 ml) was refluxed with stirring under nitrogen for 24 hours. The ethanol was removed in vacuo and the residue taken up in ethyl acetate (150 ml) and washed with a saturated aqueous sodium bicarbonate solution (2 x 75 ml). The washes were back-extracted with ethyl acetate (50 ml) and the combined extracts washed with brine, dried over anhydrous sodium sulfate and filtered.
The filtrate was evaporated invacuo to give 15.31 g (94%) of (E)-ethyl 3-(3-phenoxy)-2-propenoate as a yellow oil, which was used without further purification.

C. Pl epal ~lion of ethyl 3-(3-phenoxyphenyl)l)l opanoate A mixture of (E)-ethyl 3-(3-phenoxyphenyl)-2-propenoate (15.2 g, 56.7 mmoles), platinum oxide hydrate (0.10 g, 0.44 mmoles) and 95% ethanol (60 ml) was shaken in the plesellce of hydrogen at 2-3 atmospheres for 18 hours. The catalyst was removed by filtration through Celite and the ethanol removed from the filtrate invacuo to give 13.87g (90%) of ethyl 3-(3-phenoxyphenyl) propanoate as an orange oil, which was used without further purification; tlc, dichlolul,.~Lh~e: hexane (1:1).

D. P~e~ ion of 1~2-dihydro-5-(3-phenoxybenzyl)-2-thioxo-4~3H)-pyrimidinone A solution of ethyl 3-~3-phenoxyphenyl)~lul~no~te (10.90 g, 33.0 mmoles) and ethyl formate (5.33 g, 72.0 mmoles) in diethyl ether (75 ml) was added dropwise with stirring to a solution of potassium tert-b~ltoxide (1 M in tetrahydrofuran, 81.4 ml, 81.4 mmoles) in diethyl ether (225 ml) cooled in an ice bath under nitrogen. The solution was stirred at ambient te.llpel~ re for 18 hours, and the solvent was removed in vacuo. The residue was treated with 2-propanol (100 ml) and thiourea (6.18 g, 66.0 mrnoles) and the res--lting WO 94/01414 213 ~ 8 3 ~ PCI/GB93/01443 ~

mixture was refluxed for 5 hours under nitrogen. The solvent was removed in vacuo, and the solid residue was washed with cold diethyl ether, dissolved incold water, and the pH was adjusted to 4 with glacial acetic acid. The beige precipitate was collected on a filter, washed several times with water and diethyl ether, and dried under a vacuum at ambient temperature for 18 hours to give 7.97 g (78%) of 1,2-dihydro-5-(3-phenoxybenzyl)-2-thioxo-4 (3H)-pyrimidinone, mp 195-197C (dec.). Recryst~lli7~tion of 0.85 g from acetonitrile gave 0.36 g of an analytically pure sample; tlc, dichloromethane:
methanol (19:1); uv (0.1 N hydrochloric acid 10% meth~nol): I 276 nm (e 24400); (pH 7 buffer ~ 10% methanol): 1 275 nm (e 22500); (0.1 N sodium hydroxide + 10% methanol): 1 262 nm ~e 17700); sh 307 nm (e 9500).

E. Preparation of 5-(3-phenoxybenzyl) uracil A suspension of 1,2-dihydro-5-(3-phenoxybenzyl)-2-thioxo4(3H)-pyrimidinone (7.97 g, 25.7 mmoles) in glacial acetic acid (140 ml) and 20%
aqueous chloroacetic acid (140 ml) was refluxed with stirring for 6 hours.
After cooling to ambient temperature and then in an ice bath, the mixture was filtered, and the solids were washed with water and diethyl ether and dried in avacuum oven at 70C for 18 hours to give 6.46 g (85%) of 5-(3-phenoxybenzyl)uracil as an off-white solid, mp 281-283C.
Recryst~11i7~tion of 0.410 g from acetic acid/water gave 0.208 g of an analytically pure sample; tlc, dichloro-meth~ne: meth~nol (19: 1), uv (0.1 N
hydrochloric acid + 10% meth~nol): I 268 nm (e 24000), sh 296 nm (e 11600);
(pH 7 buffer + 10% meth~nol): I 267 nm (e 16600), sh 300 nm (e 6500); (0.1 N sodium hydroxide + 1û% meth~nol): 1 279 nm (e 8300), sh 291 nm (e 7500) F. P,el)a-~Lion of 1-((2-acetoxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil 1/4 hydrate Bis(trimethylsilyl)~cet~mi~1e (8.24m1, 32.5 m~noles) was added to a stirred suspension of 5-(3-phenoxybenzyl)uracil (5.435 g, 18.5 ~nmoles) in 1,2-dichloroethane (95 m1) under nitrogen. The mixture was refluxed with 213~36 ~0 94/01414 - 25 - PCI/GB93/01443 stirring for 3 hours, the heat removed and the solution that formed cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (3.15 g, 16.0 m~noles) in acetonitrile (15 m1) was added to the cooled solution, the resulting solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours. The solvents were removed in vacuo and the residual oil introduced onto a column of Silica Gel 60 wetted with dichlorometh~ne. The column was eluted with dichlorometh~ne: 2-propanol (100: 1), and the fractions cont~inin~ product were combined. The solvents were removed in vacuo, and the residue was dissolved in dichloromethane (150 ml) and washed with water (3 X 75 ml) and brine. The dichloro".cLhAne solution was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give S .301 g (80%) of I -((2-acetoxyethoxy)methyl)-5-(3-propoxy-benzyl)uracil _1/4 hydrate as a clear oil; tlc, dichlorometh~ne: methAnt~l (19 :1); uv (0.1 N hydrochloric acid + 10% methanol): 1 266 nm (e 11800); (pH 7 buffer + 10% meth~nol): 1 266 nm (e 10800); (0.1 N sodium hydroxide + 10%
methanol): 1 265 nm (e 8800).

G. P,~ Lion of 1-((2-hydroxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil A solution of 8.40 g (20.3 mmoles) of 1-((2-acetoxyethoxy)methyl)-5-(3-phen-oxybenzyl)uracil in meth~nol (300 rnl) saturated with ammonia gas was stirred in a stoppered flask for 24 hours at ambient temperature. The methanol was removed in vacuo, and the residue was washed with water and diethyl ether and dried in a vacuum oven at 80C to give 5.532 g (74 %) of 1-((2-hydroxy-ethoxy)methyl)-5-(3-phenoxybenzyl)uracil as a white solid, mp 93-95C; uv (0.1 N hydrochloric acid + 10% ,.,elhA~ol): I 266 nm (e 12000); (pH 7 buffer + 10% meth~nol): I 266 nrn (e 11800); (0.1 N sodium hydroxide + 10%
meth~nol): 1 265 n n (e 8700); NMR (DMSO-d6): d 11.40 (s, lH, NH), 7.65 (s, lH, H-6), 6.94 (m, 9H, ArH), 5.09 (s, 2H, NCH20), 4.68 (s, lH, OH), 3.49 (s, 6H, CH~Ar and (CH2)2); ms: m/e 369.
Anal. Calcd. for C20H20N2os: C,65.20; H, 5.47; N, 7.61.
Found: C, 65.25; H, 5.51; N, 7.62.

WO 94/01414 2 ~ 3 9 8 3 6 26 - PCI/GB93/01443 Example 4 P~ a.~lion of I-(t2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)5-(3 phenoxybenzyl)uracil A. Preparation of 2-((1 ~2,3.4-tetrahydro-2,4-dioxo-5-(3-phenoxybenzyl)- 1 -pynmidinyl)methoxy)-1.3-propanediyl dibenzoate This compound was prepared in an analogous manner to that of Example 3F
with 9.10 g of 2-(bromomethoxy)-1,3-propanediyl dibenzoate (see below for preparation). The ~,hlo.na~ography fractions were spin evaporated in vacuo to give 10.09 g of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3-phenoxybenzyl)-1-pyrimidinyl)methoxy)-1,3-~ropallediyl dibenzoate as a white solid, which was used without further purification.

P,e~ ion of 2-(bromomethoxy)-1.3-~-opallediyl dibenzoate This compound was made by the following method of Be~lch~mr. et al., J.
Med. Chem., 1988, 31, 144.
1.3-Dichloro-2-(methoxymethoxy)prol)alle. To a solution of S00 g (3.88 mol) of 1,3-dichloro-2-propanol (2), 780 mL of chloroform, and 780 mL of dh~l~Llloxy.l.eth~ne was added 330g (2.32mol) of phosphorus pentoxide, portion wise, with vigorous stirring, with the t~ e.a~lre IllA;~lAil~ed at 40-45C. The mixture was then stirred at ambient ~ w~ re for 18 h. The supelll~ was (lec~nted and washed once with water, once with 10% aqueous sodium bicarbonate, and once more with water. The organic layer was dried (sodium sulfate) and e~pol~Le in vacuo to give 569 g (85%) of a pale amber liquid, which was of sufficient purity for use.

2-(Metho~y...eLlloxy)-1.3-p,c.pallediyl dibenzoate. A mixture of 181.1 g (1.04mol) of 1,3-dichloro-2-(methoxymethoxy)propane, 3453.0g (3.14mol) of sodium ben7O~tç, 20mL (O.lmol) of 15-crown-5 ether, and 2.5L of dh~ lylr~ A~ e was refluxed with stirring for 2 days. The cooled reaction mixture was filtered and the pl~ e washed with ether. The conlbined washings and filtrate were flash e~pol~Led, and the residue was triturated with ~13~
~0 94/01414 - 27 - . ~ , PCr/GB93/01443 ether. the ethereal extracts were washed with water, dried (sodium sulfate), and evaporated to yield 341 g (95%) of a dark brown oil.

2-(Acetoxymethoxy)-1.3-propanediyl dibenzoate. A solution of 143 g (0.415 mol) of 2-(Methoxymethoxy)-1,3-propanediyl dibenzoate in 55 mL
(0.581 mol) of acetic anhydride and 14.3 rnL (0.12 mol) of boron trifluoride etherate was stirred at 0C for 2 h. The solution was poured into 800 rnL of ice and water cont~ining 60 g of sodium bicarbonate. The oily mixture was extracted with three 600-mL portions of ether. The ethereal extracts were washed once with 10% aqueous sodium bicarbonate solution and twice with water and dried over sodium sulfate. The solvent was removed in vacuo to give 154 g (99%) of 2-(acetoxymethoxy)-1,3-propanediyl dibenzoate, which was of sufficient purity for further use.

'7-(Bromomethoxy)-l.3-propanediyl dibenzoate. A mixture of 15 g (0.04 mol) of 2-(acetoxymethoxy)-1,3-propanediyl dibenzoate, 70 mL of dry dichloromethane, and 17 ~nL of bromotrimethylsilane was gently refluxed for 18 h. The solution was evaporated in vacuo to give the target compound, 2-(Bromomethoxy)-1,3-plopallediyl dibçn7:o~t~, as a light arnber oil in q~.~ntit~tive yield.

B. 1-((2-hydroxy-1-~hydroxymethyl)ethoxy)methyl)-5-(3-phenoxybenzyl)uracil This compound was p-epa ed in an analogous manner to that of Example 3G
with the repl~cem.ont of 8.40 g of 1-((2-aceLo,~e.lloxy)methyl)-5-(3-phenoxybenzyl)uracil and 300 mL of meth~nol saturated with ammonia gas in Exarnple 3G with 9.25 g of 2-((1, ,3,4-tetrahydro-2,4-dioxo-5-(3-phenoxy-benzyl)-1-pyrimidinyl)methoxy) -1, 3-propanediyl dib~ll,.oa~e and 200 mL of 40% aqueous methyl amine, respectively. The mixture was sealed in a bomb and heated at 80C for 5 days. Since the reaction was h~co...~.lete, the solventwas removed in vacuo, the residue was taken up in MeOH (100 mL), and sodium methoxide (0.70 g, 0.013 mmoles) was added. The mixture was refiuxed for 18hours, cooled in an ice bath, and neutralized with 1.0M
ethereal hydrochloric acid. The white pre~ e which forrned was collected by filtration, washed with water and diethyl ether, re~i~y~ ed from meth~nol~

W O 94/01414 2 1 3 9 8 3 ~ - 28- PC~r/G B93/01443 and dried in vacuum oven at 80C to give 1.921 g (32%) of 1-((2-hydroxy-1-(hydroxymethyl)-ethoxy)methyl)-5-(3-phenoxybenzyl)uracil as a white solid, mp 139-141C; uv (0.1 N hydrochloric acid + 10% methanol): I
266 nm (e 10800); (pH 7 buffer + 10% methanol): 1 266 nm (e 10100); (0.1 N
sodium hydroxide + 10% meth~nol): 1 265 nrn ( 8100): NMR (DMSO-d6): d 11.35 (s, lH, NH, 7.67 (s, lH, H-6), 711 (m, 9X ArH), 5.17 (s, 2H, NCH20), 4.62 (t, 2H, OH), 3.58 (s, 2H, CH2Ar), 3.42 (m, 5H, CH and CH20H); ms:
~rJe 399 Anal. Calcd. for C21H ~2N206: C, 6~.30; H, 5.57; N, 7.03.
Found: C, 63.28; H, 5.60; N, 7.06.

Example 5 Plepa,~Lion of 1-((2-hydroxyethoxy)methyl)-5-(3-(3-fluoropropoxy)benzyl)uracil A. P, ~al~lion of ethyl 3-(3-(3-fluoropropoxy)phenyl)-2-propanoate A mixture of ethyl 3-(3-hydroxyphenyl)-2-propanoate (7.77 g, 40.0 mrnoles), I-bromo-3-fluoloplopalle (7.1 g, 50.4 mmoles), pot~c.ci--m carbonate (8.3 g, 60.0 mmoles), potassium iodide (8.3 g, 50.0 mmoles) and acetone (150 ml) was refluxed with stirring under a calcium chloride drying tube for 48 hours.
The mixture was le~,ha,~,ed with additional potassium carbonate (8.0 g, 57.9 mmoles) and refluxed for 18 hours. The cooled mLxture was filtered and the solids washed with ethyl acetate (3 x 50 ml). The filtrate and washings were combined and the solvents removed in vacuo. The residue was purified by flash chrc,llalography on Silica Gel 60 eluting with heY~nes: ethyl acetate (98: 2) to give 8.95 g (88%) of ethyl 3-(3-(3-fluoropropoxy)phenyl)-2-prop~no~te as a pale yellow oil.

B. P~ Lionof I .2-dihydro-5-(3 -(3 -fluol opl opo~ybenzyl)-2-thioxo-4(3H)-pyrimidinone A solution of ethyl 3-(3-(3-fluoloplopo~y)phenyl)-2-prop~n-~te (1.83 g, 7.2 mmoles) in tetrahydrofuran (3 ml) was added to a soll-tion of lithium di~soplopylamine freshly pl~ ed from diisopl.~pylamine (1.2 ml, 8.6 mmoles) and n-butyl lithium (3.4ml of a 2.5 M hexane solution, 8.6 mmoles), in 213~83 ~
~WO 94/01414 PCr/GB93/01443 tetrahydrofuran (7 ml), cooled to -78C under nitrogen. The solution was stirred for 2.0 hours while the temperature was allowed to rise to -55C. The solution was cooled to -78C, ethyl formate (0.68 ml, 8.6 mrnoles) added, and stirnng continued for ''.0 hours while the solution warmed to -60C. After recooling to -78C, thiourea (0.65 g, 8.6 rnmoles) was added in one portion and the res-~lting suspension allowed to warrn to ambient temperature. Ethanol (30 ml) was added, and the solution was refluxed under nitrogen for 6 hours.
The ethanol was removed in vacuo~ and the residue was partitioned between dichloromethane: water (50 ml: 100 ml). The layers were separated, and the aqueous layer was washed with additional dichloromethane (2 x 50 ml). The aqueous solution was cooled in an ice bath, and the pH was ~djllsted to 3 with concentrated hydrochloric acid. The preci~ d~e was collected on a filter, washed several times with water and diethyl ether, and dried under a vacuum at ambient temperature for 18 hours to give 0.84 g (39%) of crude 1,2-dihydro-5-(3 -(3-fluoropropoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone which was used in the next step without further purification. Recryst~11i7~tion of 0.33 g from acetonitrile gave 0.17 g of an analytically pure sample, mp 166-167C; tlc, dichlorometh~ne: meth~nol (19: 1).

C. P~ epa- aLion of 5-(3-t3-fluolo~), opoxy)benzyl)uracil A suspension of 1,2-dihydro-5-(3-(3-fluo~oprcJpoxy)benzyl)-2-thioxo-4(3H) -pyrimidinone (0.50 g, 1.6 mmoles) in glacial acetic acid (8 rnl) and 20%
aqueous chloroacetic acid (8 ml) was refluxed with stirring for 6 hours. A~er cooling to ambient te~ )cldL~Ire and then in an ice bath, the mixture was filtered, and the solids were washed with water and diethyl ether and dried in avacuum oven at 80C for 18 hours to give 0.392 g (88%) of 5-(3-(3-fluo~upl~,po~y)benzyl)uracil as a white solid, mp = 240-242C, tlc, dichloror,.t;lh~ne: meth~nol (19: 1).

D. P, e;p~ dlion of - 1 -((2-acelo~y~lllo~y)methyl)-5-(3-(3-fluo, upr~po~sy)benzyl)uraci -Bis(trimethylsilyl)~cet~mide (2.05 ml, 8.4 mmoles) was added to a stirred suspension of 5-(3-(3-fluo,op,-~poxy)benzyl)uracil (1.30 g, 4.7 mmoles) in WO 94/01414 ~ 13 ~ ~ ~ 6 30 PCr/GB93/01443 dichloroethane (45 ml) under nitrogen. The mixture was refluxed with stirring for 35 minlltec, the heat removed, and the solution which formed cooled in an ice bath. A solution of (2-acetoxyethoxy3methyl bromide (0.81 g, 4.1 mmoles) in acetonitrile (5 m1) was added to the cooled solution and the res~ ing~
solution allowed to warm to ambient temperature and stirred under nitro~en for 18 hours. The solvents were removed in vacuo and the residual oil introduced onto a column of Silica Gel 60 wetted with dichlorometh~ne The column was eluted with dichloromethane: meth~nol (99:1), and the fractions containing product were combined and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water (2 x 50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated invacuo to give 1.10 g (59%) of 1-((2-acetoxyethoxy)methyl)-5-(3-(3-fluoropropoxy)benzyl)uracil as a clear oil; tlc, dichlo~o,.,~ ne: methanol (19:1).

E. Preparation of 1 -((2-hydroxyethoxy)methyl)-5-(3-(3-fluo, o~), opoxy)benzyl)uracil A solution of 1 -((2-acetoxyethoxy)methyl)-5-(3-(3-fluol O~)l opoxy)benzyl) uracil (1.05 g, 2.7 mmoles) in meth~nol (100 ml) saturated with ammonia gas was stirred in a stoppered flask for 18 hours at ambient te-"~e,~ re. The methanol was removed in vacuo, and the residue was recryst~ili7ed from 2-propanol: hexane and dried in a vacuum oven at 48C to give 0.725 g (77 %) of 1-((2-hydroxy-ethoxy)methyl)-5-(3-(3-fluolopropoxy)- benzyl)uracil as a white solid, mp 78-82C; uv (0.1 N l~ydlocllloric acid + 10% meth~nol): I
266 nm (e 11600); (pH 7 buffer + 10% ,,,~ ol): I 266 nm (e 11500); (0.1 N
sodium hydroxide + 10% ,,,PIIl~l~ol): I 268 nm (e 7600); NMR (DMSO-d6):
d 11.40 (s, 1H, NH), 7.65 (s, lH, H-6), 6.94 (m, 4H, ArH), 5.09 (s, 2H, NCH20), 4.68 (s, lH, OH), 4.72 (t, lH, CHF), 4.49 (t, 1H~ CHF), 4.03 (t, 2H, OCH2), 3.49 (s, 6H, CH2Ar and (CH2)2), 2.10 (m, 2H, CH2C_2CH2);
ms: m/e 353.
Anal. Calcd. for C17H21N2OsF: C,57.94; H, 6.01; N, 7.95.
Found: C, 58.03; H, 5.99; N, 7.89.

~39~
~0 94/01414 - 31 - PCr/GB93/01443 Example 6 Pl ~)~ alion of I -((2-hyd, u~yelhoxy)methyl)-5-(3-sec-butoxybenzyl)uracil A. PlepalaLion of ethyl 3-(3-sec-butûxyphenyl)-2-propanoate A mixture of ethyl 3-(3-hydroxyphenyl)-2-propanoate (9.0 g, 46.4 mmoles), 2-bromobutane (lO.Oml, 61.0mmoles), potassium carbonate (17.0 g, 123.0 mrnoles), potassium iodide (10.0 g, 60.2 mrnoles) and acetone (200 ml) was refluxed with stirring under a calcium chloride drying tube for 5 days. The mixture was l~;cll~,ed with additional potassium carbonate (8.3 g, 60.0 mmoles) and 2-bromobutane (10.0 ml, 61.0 mmoles) and refluxed for 48 hours. The cooled mixture was filtered and the solids washed with ethyl acetate (3 x 75 ml). The filtrate and washings were combined and the solvents removed in vacuo. The residue was purified by flash chromatography on Silica Gel 60 eluting with hexanes: ethyl acetate (98:2) to give 8.93 g (77%) of ethyl 3-(3-sec-butoxyphenyl)-2-propanoate as a yellow oil.

B. P, e,~a, alion of 1.2-dihydro-5-(3-sec-butoxybenzyl)-2-thioxo4(3H)-pyrimidinone A solution of ethyl 3-(3-sec-butoxyphenyl)-2-propanoate (4.0 g, 16.0 mrnoles) in tetrahydrofuran (7 ml) was added to a solution of lithium diisopropylamine freshly prepared from diisopropylarnine (2.75 ml, 19.4 mmoles) and n-butyl lithium (7.75 ml of a 2.5 M hexane solution, 19.4 mmoles), in tetrahydrofuran (15 ml), cooled to -78C under nitrogen. The solution was stirred for 1.5 hours while the teln,~)e~aLIlre was allowed to rise to -65C. The solution was cooled to -78C, ethyl fo""dLe (1.6 ml, 20.0 mmoles) added, and stirring continued for 2.0 hours while the solution warmed to -60C. After recooling to -78C, thiourea (1.47 g, 19.4 mrnoles) was added in one portion and the res.~lting suspension allowed to warm to arnbient telllpe~aLIlre. Ethanol (15 ml) was added, and the sol-.tion was refiuxed under nitrogen for 6 hours. The ethanol was removed in vacuo, and the residue was taken up in dichloro~e~l~AI-e (150 ml). The suspension was extracted with water (3 x 50) and 0.5 N sodium hydroxide (2 x 50 ml). The ~queo~C extracts were colllbined, cooled in an ice bath, and the pH was AdJ..cted to 3.5 with WO 94/01414 213 ~ 8 3 ~ 32 - PCI/GB93/01443 concentrated hydrochloric acid. The orange, sticky p, t~ ate was recrystallized from methanol/water to give 1.20 g (26%) of 1,2-dihydro-5-(3-sec-butoxy-benzyl)-2-thioxo~(3H)-pyrimidinone, mp 1'77-1 30C.

C. Preparation of 5-(3-sec-butoxybenzvl)uracil A suspension of 1,~-dihydro-5-(3-sec-butoxybenzyl)-2-thioxo-4(3H)-pyrimidinone (0.60 g, 2.0mmoles) in glacial acetic acid (lOml) and 20%
aqueous chloroacetic acid (lOml) was refluxed with stirring for 18 hours.
After cooling to ambient temperature and then in an ice bath~ the mixture was filtered, and the solids were washed with water and diethyl ether and dried in avacuum oven at 80C for 18 hours to give 0.13 g (24%) of 5-(3-sec-butoxybenzyl)uracil as a white solid, mp 213-215C.

D. P-e~a,dLion of 1-(~2-acetoxyethoxy)methyl)-5-(3-sec-butoxybenzyl)uracil Bis(trimethylsilyl)acet~mide (1.4 ml, 5.6 mmoles) was added to a stirred suspension of 5-(3-sec-butoxybenzyl)uracil (0.875 g, 3.2 mmoles) in dichloroethane (35 rnl) under nitrogen. The mixture was refluxed with stirring for 35 minl~tes~ the heat removed, and the solution which formed cooled in an ice bath. A solution of (2-ace~o~yelllu~y)methyl bromide (0.55 g, 2.8 mmoles) in acetonitrile (5 ml) was added to the cooled solution and the resl-lting solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours. The solvents were removed in vacuo and the residual oil introduced onto a column of Silica Gel 60 wetted with dichlo~o."e~ e The column was eluted with dichlo-o...~ e: ",~lh~-~ol (99: 1), and the fractions co.~ g product were combined and evaporated in vacuo. The residue was dissolved in dichlolo.n~ e, washed with water (2 x 75 ml) and brine (75 ml), dried over anhydrous m~n~ m sulfate, filtered and evaporated in vacuo to give 0.80 g (64%) of 1-((2-acetoxy-ethoxy)methyl~-5-(3-sec-butoxy-benzyl)uracil as a clear oil; tlc, dichlorom~th~ne: meth~nol (19:1).

~13983~
~WO 94/01414 33 PCr/GB93/01443 E. Preparation of l-((2^hydroxyethoxy)methyl)-5-(3-sec-butoxybenzyl)uracil A solution of 1-((2-acetoxyethoxy)methyl)-5-(3-sec-butoxybenzyl)uracil (0.80 g, 2.0 rnînoles) in meth~nQI (100 ml) saturated with ammonia gas was stirred in a stoppered flask for 18 hours at ambient temperature. The methanol was removed in vacuo, and the residue was cryst~11i7-oci from 2-propanol: hexane and dried in a vacuum oven at 48C to give 0.48 g (67 %) of 1-((2-hydroxy-ethoxy)methyl)-5-(3-sec-butoxybenzyl)uracil as a white solid, mp 82-86C; uv (0.1 N hydrochloric acid + 10% methanol): I ''66 nm (e 10800); (pH 7 buffer + 10% methanol): 1 266 nm (e 10800); (0.1 N sodium hydroxide + 10%
methanol): 1 266 nm (e 7500); NMR (DMSO-d6). d 11.39 (s, lH, NH), 7.67 (s, lH, H-6), 6.96 (m, 4H, ArH), 5.10 (s, 2H, NCH70), 4.69 (s, lH, OH), 4.33 (m, lH, OCH), 3.50 (s, 6H, CH2Ar and (CH2)2), 1.60 (m, 2H, CH2CH3), 1.21 (d, 3H, OCHCH3), 0.85 (t, 3H, CH2CH3); ms: m/e 349.
Anal. Calcd. for ClgH24N20s: C,62.05; H, 6 94; N, 8 04 Found: C, 61.90; H, 6.93; N, 7.97.

Example 7 Preparation of 1-((2-hydroxyethoxy)methvl-5-(3-(3-fluorophenoxy)benzyl)uracil A. Pl e~al ~lion of 3-bromo-3'-fluorodiphenyl ether A solution of 3-fluorophenol (Aldrich) (8.2~g, 74mmol) and 25% NaOMe in meth~nol (Aldrich) (18.5rnL, 81mmol) was stirred for 3 hours at ambient temperature. The solution was concentrated in vacuo to a tan solid. The phenoxide was dissolved in N-methyl-2-pyrrolidinone (Aldrich) (SOmL) and heated in a 180C oil bath. 1-Bromo-3-fluorobenzene (Aldrich) (12.95g, 74mmol) was added and the mixture was stirred for 24 hours at 180C. After cooling to room tel~ tl~LLIre, the reaction mixture was diluted with H20 (IOOmL) and extracted with dichlol~ e (2 x lOOmL). The organic layer was concentrated to dryness invacuo~ redissolved in diethyl ether (lOOmL), washed with H20 (lOOmL), saLu~Led NaHC03 (lOOmL), dried over Na2S04, filtered and concentrated invacuo to a brown oil (12.Sg). The oil was chrQmatographed on Silica Gel 60 using hexane. The fractions co.~ ;..g only WO94/01414 21 3 ~ ~ 3 ~ 34- PCI/GB93/01443 3-bromo-3'-fluorodiphenyl ether were combined and conce.~ ted in vacuo to give 8.42g (43%) of a clear, colorless oil.

B. Preparation of ethyl 3-(3-(3-fluorophenoxy)phenyl)acrylate A mixture of 3-bromo-3'-fluorodiphenyl ether (5.30g, 19.8mrnol), ethyl acrylate (Aldrich) (2.48g, 24.8mrnol), triethylamine (Kodak) (7.51g, 24.8rnrnol), p~ m (II) acetate (Aldrich) (44.5mg, O.~mrnol), tri-o-tolylphosphine (Aldrich) (244mg, 0.8rnrnol), and acetonitrile (20mL) were added to a heavy-glass walled bottle, flushed with nitrogen, sealed and heated in a 100C oil bath for 5 hours. Cold 0.1N HCI (40mL) was added to the cooled reaction mixture. The lower layer was collected and concentrated in vacuo to a dark-green oil and cl~-ol"atographed on Silica Gel 60 with 0-3% ethyl acetate/hexanes as eluent. The fractions co..~ only ethyl 3-(3-(3-fluorophenoxy)phenyl)acrylate were combined and concentrated in vacuo to give 4.48g (79%) of a clear, colorless oil.

C. Preparation of ethyl 3-(3-(3-fluorophenoxy)phenyl)propionate To a solution of ethyl 3-(3-(3-fluorophenoxy)phenyl)acrylate (6.33g, 22mmol) and absolute EtOH (lOOrnL) was added platinum oxide hydrate (E.M. Science) (lOOmg, 0.44rnmol). The mixture was shaken on a Parr al)p~L-ls under hydrogen atmosphere (30psi) for 6 hours. The mixture was filtered to remove the catalyst and conce~ Led in vacuo to give 5.91g (93%) of a clear, colorless oil.

D. P. ~ aLion of 1.2-dihydro-5-(3-(3-fluorophenoxy)benzy1)-2-thioxo-4(3H)-pyrirnidinone A solution of ethyl 3-(3-(3-fluolophenoxy)phenyl propionate (5.51 g, 19.0 mmoles) and ethyl forrnate (3.07 g, 41.4 mmoles) in diethyl ether (35 mL) was added dropwise with stirring to a soh~tion of potassium tert-butoxide (1 M
in T~, 47.0 mL, 47.0 mmoles) in diethyl ether (125 rnL) cooled in an ice bath under nitrogen. The solution was stirred at ambient temperature for 18 hours, and the solvent was removed in vacuo. The residue was dissolved in 2-propanol ~13~83~
~WO 94/01414 PCr/GB93/01443 (50 mL), thiourea (2.89 g, 38.0 rnmoles) was added, and the mixture was refluxed under nitrogen for 5 hours. The solvent was removed in vacuo, and the solid residue was washed with cold diethyl ether, dissolved in cold water, and the pH was adjusted to 4 with glacial acetic acid. The beige precipitate was collected on a filter, washed several times with water and diethyl ether, and dried under a vacuum at ambient temperature for 18 hours to give 3.Z9 g (53%) of 1,2-dihydro-5-(3 -(3 -fluorophenoxy)-benzyl)-2-thioxo-4(3 H)-pyrimidinone, mp 170-172C (dec.). Recryst~lli7~tion of 0.40 g from methanol gave 0.20 g of an anaiytically pure sample.

E. Preparation of 5-(3-~3-fluorophenoxy)benzyl) uracil A suspension of 1,2-dihydro-5-(3-(3-fluo~ ol~henoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone (2.70 g, 8.2 mmoles) in glacial acetic acid (40 mL) and 20%
aqueous chloroacetic acid (40 mL) was refluxed with stirring for 6 hours. A~er cooling to ambient temperature and then in an ice bath, the mixture was filtered, and the solids were washed with water and ether and dried in a vacuum oven at 80C for 18 hours to give 2.34 g (91%) of 5-(3-(3-fluorophenoxy)benzyl) uracil as an off-white solid, mp 243-245C. Recryst~11i7~tion of 0.400 g from acetic acid-water gave 0.161 g of an analytically pure sample.

F. Ple~ Lion of 1-((2-ac~L~yeLhoxy)methyl)-5-(3-(3-fluorophenoxy)-benzyl)uracil Bis(trimethylsilyl)~cet~mide (1.38 mL, 5.6 mmoles) was added to a stirred suspension of 5-(3-(3-fluoropheno~y)benzyl)uracil (1.00 g, 3.2 mmoles) in dichloroethane (35 mL) undN nitrogen. The mixture was refluxed with stirring for 1 hour, the heat was removed, and the solution which for ned was cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (0.55 g, 2.8 mmoles) in ~cetonitrile (4 mL) was added to the cooled solution, and the rçc~liting solution allowed to warm to ~nl)ie..l temperature and stirred under nitrogen for 18 hours. The solvents were removed in vacuo, and the residue was dissolved in dichloromçth~ne (75 mL) and washed with water (3 X 25 mL) and brine. The solvents were removed in vacuo~ and the residual oil was introduced onto a column of Silica Gel 60 wetted with dichlolo..~ ne. The column was WO 94/01414 213 9 8 3 B 36 - PCr/GB93/01443 eluted with dichloromethane: 2-propanol (100: 2), and the fractions cont~ininP
product were combined. The solvents were removed in vacuo to give 0.58 g (48%) of 1-((2-acetoxyethoxy)methyl)-5-(3- (3-fluorophenoxy)benzyl)uracil as a clear oil.

G. Preparation of 1-((2-hydroxyethoxy)methyl)-5-(3-(3-fluorophenoxy)-benzyl)uracil A solution of 0.53 g (1.2 rnrnoles) of 1-((2-acetoxYethoxy)methyl)-5-(3-(3-fluorophenoxv)benz~Yl)uracil in methanol (75 mL) saturated with ammonia gas was stirred in a stoppered flask for 24 hours at ambient temperature. The methanol was removed in vacuo, and the residue was recryst~lli7ed from 2-propanol: hexane and dried in a vacuum oven at 80C to give 0.282 g (74%) of 1-((2-hydroxyethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl)uracil as a white solid, mp 98-100C; NMR (DMSO-d6): d 11.40 (s, lH, NH), 7.69 (s, lH, H-6), 7.11 (m, 8H, ArH), 5.08 (s, 2H, NCH2O), 4.68 (s, lH, OH), 3.54 (s, 2H, CH~Ar), 3.49 (s, 4H, (CH2)2); ms: rn/e 387.
Anal. Calcd. for C20HlgFN2Os: C, 62.17; H, 4.96; N, 7.25.
Found: C, 62.01; H, 5.00; N, 7.16.

Example 8 Ple~ Lion of I -((2-hYdroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl)uracil A. P,e~ Lion of 2-((1.2.3.4-tetrahydro-2.4-dioxo-5-(3-(3-fluorophenoxy)benzyl)- 1 -pyrimidinyl)methoxy)- 1.3 -propanediyl dibenzoate 1 /4 hydrate Bis(~ ,cLhylsilyl)~cet~mi~e (1.30 mL, 5.3 mmoles) was added to a stirred ~u~l)ell~ion of 5-(3-(3-fluorophenoxy)benzyl)uracil (0.937 g, 3.0 mmoles) in dichloroethane (35 mL) under nitrogen. The mixture was refiuxed with stirring for 35 ...;...~les, and the resultant solution cooled in an ice bath. A solution of 2-(bl~,l.,o",t;llloxy)-1,3-~ ediyl dil,el~oaLe (0.76 g, 2.0 mmoles) in ac~lol~illile (i mL) was added to the cooled solution, and the resultant solution ~sa~
~WO 94/01414 PCr/GB93/01443 was allowed to warm to ambient temperature and stirred under nitrogen for 18 hours. The solvents were removed in vacuo, and the residue was dissolved in dichloromethane (75 mL) and washed with water (3 X 25 mL) and brine. The volatiles were removed in vacuo, and the residual oil was introduced onto a column of Silica Gel 60 wetted with dichloromethane. The column was eluted with dichloromethane: 2-propanol (50: 1), the fractions cont~inin~g product were combined, and the solvents were removed in vacuo to give 0.77 g (41%) of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3-(3-fluorophenoxy)benzyl)- 1-pyrimidinyl)methoxy)-1,3-propanediyl dibenzoate _1/4 hydrate as a white solid, mp 158-161C.

B. Preparation of 1-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-5-(3-r3-fluoro-phenoxy)benzyl)uracil A solution of 0.68 g (1.1 mmoles) of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3 -(3 -fluoro-phenoxy)benzyl)- 1 -pyrimidinyl)methoxy)- 1 ,3-propanediyl dibenzoate in methanol (75 mL) saturated with ammonia gas was stirred in a stoppered flask for 24 hours at ambient temperature. The methanol was removed in vacuo, and the residue was dissolved in ethyl acetate and extracted with 0.3 N sodium hydroxide (4 x ''5 m'l ). The combined aqueous extracts were cooled in an ice bath, neutralized with lN hydrochloric acid, and extractedwith ethyl acetate (3 x 50 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. Trituration ofthe residual oil with cold dichlolo",~ e (20 mL) gave 0.161 (36%) of 1 -((2-hydroxy- 1 -(hy~ y~ Llly-l)ethoxy)methyl)-5-(3-(3-fluorophenoxy)benzyl) uracil as a white solid, mp 122-123C. .

WO 94/01414 ~ 1 ~ 9 8 3 ~ 38 - PCr/GB93/01443 J~

Example 9 Preparation of I -((2-hydroxy- 1 -~hydroxymethyl)ethoxy)methyl)-5-(3-(4-fluorophenoxy)benzyl)uracil A. P, epal ~lion of 2-((1 7~3.4-tetrahydro-2.4-dioxo-5-(3 -(4-fluorophenoxy)-benzyl)-l- pyrimidinyl)methoxy)-1.3-propanediyl dibenzoate Bis(trimethylsilyl)~cet~mi~e (1.30 mL, 5.3 m--moles) was added to a stirred suspension of 5-(3-(4-fluorophenoxy)benzyl)uracil (0.937 g, 3.0 mmoles) in dichloroethane (35 mL) under nitrogen. The mixture was refluxed with stirring for 45 minlltes, and the resultant solution cooled in an ice bath. A solution of2-(bromomethoxy)-1,3-plopanediyl dibenzoate (0.76 g, 2.0 mmoles) in acetonitrile (4 mL) was added to the cooled solution, and the resultant solutionwas allowed to warm to ambient temperature and stirred under nitrogen for 18 hours. The solvents were removed in vacuo, and the residue was dissolved in dichloromethane (75 mL) and washed with water (3 X ?S mL) and brine. The volatiles were removed in vacuo~ and the residual oil introduced onto a column of Silica Gel 60 wetted with dichlorometh~n~. The column was eluted with dichlorometh~ne: 2-propanol (50: 1), the fractions co.,li.;..;.~g product were combined, and the solvents were removed in vacuo to give 0.853 g (45%) of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3 -(4-fluorophenoxy)benzyl)- 1 -pyrimidinyl)methoxy)-1,3-plopallediyl dibenzoate as a white solid, mp 155-158C.

B. Preparation of 1-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-5-(3-(4-fluoro-phenoxv)benzyl)uracil A solution of 0.77 g (1.2 mmoles) of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3-(4-fluorophenoxy)benzyl)- l-pyrimidinyl)methoxy)- 1,3-1~l c,panedi~1 dibenzoate in meth~nol (75 mL) saturated with a,~ olfia gas was stirred in a stoppered flask for 24 hours at ambient te~ Lure. The meth~nol was removed in vacuo, and the residue was dissolved in ethyl acetate and extracted with 0.1 N sodium hydroxide (6 x 15 mL). The.col.lbh~ed aqueous extracts were allowed to stand at arnbient tcn~ re for 30 rninutes and diluted with water. The ~ iL~Le ~VO 94/01414 PCI/GB93/01443 which forrned was collected by filtration, washed with water, and dried in a vacuum oven at 100C for 18 hours to give 0.168 g (33%) of I -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(4-fluorophenoxy)benzyl) uracil as a white solid, mp 147-148C, NMR (DMSO-d6): s 11.35 (s, IH, NH), 7.65 (s, IH, H-6), 7.03 (m, 8H, ArH), 5.17 (s, 2H, NCH~O), 4.63 (t, 2H, OH), 3.58 (s, 2H, CH2Ar), 3.36 (m, SH, CH and "(CH20H)); ms: m/e 417.
Anal. Calcd. for C21H21FN206: C, 60.57; H, 5.08; N, 6.73.
Found: C, 60.46; H, S.11; N, 6.64.

Example 10 Pie~alaLion of 1-((2-hydroxyethoxy)methyl)-5-(3-(2-fluorophenoxy)benzyl) uracil A. PlepalaLion of ethyl 3-(3-(2-fluorophenoxy)phenyl)propionate This compound was plepared from 2-fluorophenol (Aldrich) in an analogous manner to that of Examples 7A to 7C with the repl~cPmçnt of ethyl 3-(3-(3-fluorophenoxy)phenyl)acrylate with ethyl 3-(3-(2-fluorophenoxy) phenyl) acrylate (3.20g, 11.2mmol). The filtrate was concentrated in vacuo and ch~ aLoglaphed on Silica Gel 60 using 5% EtOAc/hexanes. The fractions cont~ining only ethyl 3-(3-(2-fluorophenoxy) phenyl)propionate were combined and conc~"L, aLed to give 1.16g (36%) of a clear, colorless oil.

B. Preparation of 1.2-dihydro-5-(3-(2-fluorophenoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone A solution of ethyl 3-(3-(2-fluorophenoxy)phenyl propionate (11.95 g, 41.4 mmoles) and ethyl fo"-lale (6.62 g, 89.3 mmoles) in diethyl ether (80 ml) was added dropwise with stirring to a solution of potassium tert- butoxide (1 M in THF, 102.0 ml, 102.0 mmoles) in diethyl ether (200 ml) cooled in an ice bath under nitrogen. The solution was stirred at arnbient telllpelaLule for 18 hours,and the solvent was removed in vacuo. The residue was dissolved in 2-propanol (100 ml), llhoult;a (6.30 g, 82.8 mmoles) was added, and the mixture was refluxed under nitrogen for 5 hours. The solvent was removed in vacuo, and the solid residue was washed with cold diethyl ether, dissolved in cold water, and the pH was ~djllsted to 4 with glacial acetic acid. The beige pl~i~iLa~e was collected WO 94/01414 2 1 3 ~ 8 3 6 - ~ - PCr/GB93/01443 ~

on a filter washed several times with water and diethyl ether and dried under a vacuum at 70C for 18 hours to give 7.92 g (58%) of 1 2-dihydro-5-(3-(2-fluorophenoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone mp 210-213C (dec.).
Recryst~lli7~tion of 0.40 g from meth~nol gave 0.28 g of an analytically pure sample.

C. Preparation of 5-(3-(2-fluorophenoxy)benzyl) uracil A suspension of 1 2-dihydro-5-(3-(2-fluorophenoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone (7.515 g 22.9 mmoles) in glacial acetic acid (110 ml) and 20%
aqueous chloroacetic acid (110 ml) was refluxed with stirring for 5 hours. A~er cooling to ambient temperature and then in an ice bath the mixture was filtered and the solids were washed with water and ether and dried in a vacuum oven at 80C for 18 hours to give 6.45 g (90%) of 5-(3-(2-fluorophenoxy)benzyl) uracil as an off-white solid mp = 266-268C.

D. Preparation of 1-((2-acetoxyethoxy)methyl)-5-(3-(2-fluorophenoxy)benzyl) uracil Bis(trimethylsilyl)~cet~mide (2.8 ml, 11.4 mmoles) was added to a stirred suspension of 5-(3-(2-fluorophenoxy)benzyl) uracil (2.0 g, 6.4 mmoles) in dichloroethane (65 ml) under nitrogen. The mixture was refluxed with stirring for 1.5 hours the heat removed and the solution which formed cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (1.2 g 6.1 mmoles) in acetonitrile (8 ml) was added to the cooled solution and the resulting solution allowed to warm to ambient te-"pe,~ re and stirred under nitrogen for 18 hours.
The solvents were removed in Y~2 and the residue was dissolved in dichloromethane (50 ml) and washed with water (3 X 25 ml) and brine. The solvents were removed in vacuo and the residual oil introduced onto a column of Silica Gel 60 wetted with dichloro~ e The column was eluted with dichlo,u-"~ e: 2-propanol (100: 1), and the fractions Col~fA;~ g product were con~ined and evaporated in vacuo to give 2.16 g (83%) of 1-((2-ace~o~yt:Llloxy)methyl)-5-(3-(2-fiuorophenoxy)benzyl) uracil as a sticky yellow ~3~83~
~WO 94/01414 ~1 PCI/GB93/01443 oil, which was used without further purification; tlc, dichloro.llt;Ll,ane: methanol-(19:1).

E. Preparation of l-f(2-hydroxyethoxy)methyl)-5-(3-(2-fluorophenoxy)benzyl) uracil A solution of 2.13 g (5.0 mmoles) of 1-((2-acetoxyethoxy)methyl)-5-(3-(2-fluorophenoxy)benzyl) uracil in methanol (60 ml) saturated with ammonia gas was stirred in a stoppered flask for '~4 hours at ambient temperature. The methanol was removed in vacuo, and the residue was recryst, lli7~d from 2-propanol and dried in a vacuum oven at 70C to give 0.96 g (50 %) of 1-((2-hydroxyethoxy)methyl)-5-(3-('~-fluorophenoxy)benzyl)uracil as a white solid, mp 107-108C; NMR (DMSO-d6): d 11.40 (s, lH, NH), 7.68 (s, lH, H-6), 7.07 (m, 8H, ArH), 5.08 (s, '~H, NCH20), 4.67 ~m, lH, OH), 3.52 (s, 2H, CH2Ar), 3.48 (s, 4H, (CH2)2); ms: m~e 387.
Anal. Calcd. for C20HlgFN2os: C, 62.17; H, 4.96, N, 7.25.
Found: C, 62.29; H, 5.01; N, 7.26.

Example 1 1 Pl~ al~Lion of 1-((2-hydroxyethoxy)methyl)-5-(3-(3-chlorophenoxy)benzyl) uracil A. Pl el~al dLion of ethyl 3-(3-(3-chlorophenoxy)phenyl)acr,vlate This compound was prepared in an analogous manner to that of Example 7A
and 7B with the repl~c~ment of 3-fiuorophenol with 3-chlorophenol (Aldrich) (lO.Og, 77.8mmd). The cL,ul"alography fractions that cont~ine~l only ethyl 3-(3-(3-chlûrophenoxy)phenyl)acrylate were coll,bhled and cûnce,,l,dLed in vacuo to give 14.40g (79%) of a clear, colorless oil.

B. Pl e~ dlion of ethyl 3-(3-(3-chlorophenoxy)phenyl)propionate To a solution of ethyl 3-(3-(3-chloropheno~y)phenyl)acrylate (14.4g, 48mmol) and absolute EtOH (lOOmL) was added platinum oxide hydrate (E.M. Science) (o.sog~ ~ ~mmol) The mixture was stirred under hydrogen atmosphere at ambient pressure until hydrogen uptake stopped (approx. 1.11). The mixture WO 94/01414 213 9 8 ~ ~ PCI/GB93/01443 ~
-~2 -was filtered to remove the catalyst and concentrated in vacuo. The oil was chromatographed on Silica Gel 60 with 10% EtOAclhexanes. The fractions cont~inin~; only ethyl 3-(3-(3-chlorophenoxy)phenyl)propionate were combined and concentrated in vacuo to give 12.7g (87%) of a clear, colorless oil.

C. Preparation of 1.2-dihydro-5-(3-(3-chlorophenoxy)berlzyl)-2-thioxo-4(3H)-pyrimidinone A solution of ethyl 3-(3-(3-chlorophenoxy)phenyl propionate (12.40 ~, 40.7 mmoles) and ethyl formate (6.60 g, 88.8 mmoles) in diethyl ether (90 rnl) was added dropwise with stirring to a solution of potassium tert-butoxide (1 M in TE~, 102.0 ml, 102.0 mmoles) in diethyl ether (210 rnl) cooled in an ice bath under nitrogen. The solution was stirred at ambient temperature for 18 hours, and the solvent was removed in vacuo. The residue was dissolved in 2-propanol (100 ml), thiourea (6.20 g, 81.4 mmoles) was added, and the mixture was refluxed under nitrogen for 5 hours. The solvent was removed in vacuo, and the solid residue was washed with cold diethyl ether, dissolved in cold water, and the pH was adjusted to 4 with glacial acetic acid. The beige p,e~ ;lale was collected on a filter, washed several times with water and diethyl ether, and dried under a vacuum at 70C for 18 hours to give 7.64 g (54%) of 1,2-dihydro-5-(3-(3-chlorophenoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone, mp 163-165C (dec.).
Recryst~lli7~tion of 0.39 g from meth~nc)l gave 0.265 g of an analytically pure sample.

D. P, epa, alion of 5-(3-(3-chlorophenoxy)benzyl) uracil A suspension of 1,2-dihydro-5-(3-(3 -chlol ophenoxy)benzyl)-2-thioxo~(3H)-pyrimidinone (6.40 g, 18.6 mmoles) in glacial acetic acid (90 ml) and 20%
aqueous chloroacetic acid (90 ml) was refluxed with stirring for 18 hours. Aftercooling to ambient te-"pt;-~l-lre and then in an ice bath, the mixture was filtered, and the solids were washed with water and ether and dried in a vacuum oven at 80C for 18 hours to give 5.39 g (88%) of 5-(3-(3-chlo-oph~,.lu~y)benzyl) uracilas an off-white solid, mp 209-211C.

213~83~
~0 94/01414 PCI/GB93/01443 E. Preparation of 1-((2-acetoxvethoxy)methyl)-5-(3-(3-chlorophenoxy)benzyl) uracil Bis(trimethylsilyl)acet~mide (2.6 ml, 10.6 mmoles) was added to a stirred suspension of 5-(3-(3-chlorophenoxy)benzyl) uracil (2.0 g, 6.0 mmoles) in dichloroethane (65 ml) under nitrogen. The mixture was re~uxed with stirring for 1.5 hours, the heat removed, and the solution which formed cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl bromide (0.95 g, 4.8 mmoles) in acetonitrile (8 ml) was added to the cooled solution and the resulting solution allowed to warm to ambient temperature and stirred under nitrogen for 18 hours.
The solvents were removed _ vacuo, and the residue was dissolved in dichloromethane (100 ml) and washed with water (3 ~ 25 ml) and brine. The solvents were removed in vacuo and the residual oil introduced onto a column of Silica Gel 60 wetted with dichloromethane. The column was eluted with dichloromethane: 2-propanol (100: 1), and the fractions corS~ g product were combined and evaporated in vacuo to give 1.61 g (74%) of 1-((2-acetoxyethoxy)methyl)-5-(3-(3-chlorophenoxy)ben_yl) uracil as a clear oil, whichwas used without further purification; tlc, dichlorometh~ne: meth~nol (19: 1).

F. P, el)al aLion of I -((2-Lydl o~yellloxy)methyl)-5-(3-(3-chlorophenoxy)benzyl) uracil A solution of 1.60 g (3.6 mrnoles) of 1-((2-acetoxyethoxy)methyl)-5-(3-(3-chlorophenoxy)ben_yl) uracil in meth~nol (150 ml) saturated with ammonia gas was stirred in a alol)peled fiask for 24 hours at ambient tellly~ re. The methanol was removed in vacuo, and the residue was re~;,yal~lli7e~ from 2-propanol: hexane and dried in a vacuum oven at 70C to give 1.27 g (88%) of 1-((2-hydl u~yt:lhu~y)methyl)-5-(3-(3-chlol vphello~y)benzyl) uracil as a white solid, mp = 118-120C; NMR (DMSO-d6): d 11.30 (s,lH, NH), 7.71 (s, lH, H-6), 7.16 (rn, 8H, ArH), 5.10 (s, 2H, NCH20), 4.71 (m, lH, OH), 3.56 (s, 2H, CH2Ar), 3.50 (s, 4H, (CH2)2); ms: mle 403 (M+).
Anal. Calcd. for C20HlgClN2O5: C, 59.63; H, 4.75; N, 6.96.
Found: C, 59.661; H, 4.77; N, 6.91.

WO 94/01414 ~ 1 3 9 8 3 ~ PCr/GB93/01443 Example 12 Preparation of l-(( 7-hvdroxyethoxv~methyl)-5-(3-(3-cyanophenoxy)benzyl)uracil A. Preparation of 3-bromo-3'-cyanodiphenyl ether 3-Cyanophenol ~AIdrich) (19.06 g, 160 mmoles) was added to a solution of sodium (3.90 g, 170 mmoles) in meth~nQI (140 ml). The solution was stirred for 18 hours at ambient te~ )eldL~Ire, and the methanol was removed in vacuo .
The phenoxide was dissolved in N-methyl-2-pyrrolidinone (Aldrich) (100 ml) and heated in a 175C oil bath. I-Bromo-3-fluorobenzene (Aldrich) (28.0 g, 160 mmoles) was added, and the solution was stirred for 3 days at 170-180C.
After cooling to ambient temperature, the mixture was diluted with water (400 rnl) and extracted with dichlorometh~ne (3 x 150 ml). The co"lbhled extracts were concel,Ll~Led in vacuo, and the residue was dissolved in diethyl ether (300ml). The ether solution was washed with water (3 x 150 ml) and brine (150 ml) and concen~ ed in vacuo. The residue was chromatographed on Silica Gel 60 eluting with hexane. The fractions cont~inin~ product were combined and evaporated in vacuo to give 20.10 g (46%) of crude 3-bromo-3'-cyanodiphenyl ether as a clear oil which was used without further purification.

B. Pl~;i,al~Lion of (E)-ethyl 3-(3-(3-cyanophenoxv)phenyl)acrylate This compound was pl~l)~ed in an analogous manner to that of Example 14B
with the repi~clom~nt of 3-bromo-3'-fluorodiphenyl ether with 3-bromo-3'-cyanodiphenyl ether (19.0 g, 69.3 mmoles). The chlu"latography fractions cont~inin~ product were combined and evaporated in vacuo to give 18.38 g (90%) of (E)-ethyl 3-(3-(3-cyanophenoxy)phenyl)acrylate as a yellow oil.

C. ~le~)a,~Lion of ethyl 3-(3-(3-cyanophenoxy)phenyl)propionate A mixture of (E)-ethyl 3-(3-(3-cyanophenoxy)phenyl)acrylate (0.75 g, 2.6 mmoles), 10% p~ riillm-carbon (0.200 g) and 95% ethanol (170 ml) was shaken in the presence of hydrogen at 2-3 atmospheres for four hours. The catalyst was removed by f~ltration through Celite, and the ethanol was removed 213~83 6 ~0 94/01414 PCI/GB93/01443 -~5 -from the filtrate in vacuo. The residue was cl~o.l,atographed on Silica Gel 60, eluting with hexane: ethyl acetate (9: 1), and the fractions cont~ining product with Rf=0.5 in hexane . ethyl acetate (19: 1) were combined and evaporated _ vacuo to give 0.54 g (70%) of ethyl 3-(3-(3-cyanophenoxy)phenyl)propionate as a clear oil.

D. Pl~,va~a~ion of l~-dihvdro-5-(3-(3-cyanophenoxy)benzyl)-2-thioxo-4(3H)-pvrimidinone A solution of ethyl 3-(3-(3-cyanophenoxy)phenyl propionate (7.52 g, 25.5 mmoles) and ethyl formate (4.17 g, 56.3 mmoles) in diethyl ether (50 ml) was added dropwise with stirring to a solution of potassium tert- butoxide (I M in THF, 64.0 ml, 64.0 mmoles) in diethyl ether (165 ml) cooled in an ice bath under nitrogen. The solution was stirred at arnbient temperature for 18 hours, and the solvent was removed in vacuo. The residue was dissolved in 2-propanol (65 ml), thiourea (3.92 g, 51.5 mmoles) was added, and the mixture was refluxed under nitrogen for 5 hours. The solvent was removed in vacuo, and the solid residue was washed with cold diethyl ether, dissolved in cold water, and the pH was adjusted to 4 with glacial acetic acid. The yellow sticky solid was washed several times with water and diethyl ether to give 7.20 g (84%) of crude 1,2-dihydro-5-(3-(3-cyanophenoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone which was used without further purification. Recry~t~lli7~tion of 1.00 g from meth~nol followed by trituration with acelolfillile gave 0.14 g of 1,2-dihydro-5-(3-(3-cyanophenoxy)benzyl)-2-thioxo-4(3H)-pyrimidinone; mp 203-205C.

E. P,epa, dLion of 5-(3-(3-cyanophenoxy)benzyl) uracil A suspension of 1,2-dihydro-5-(3-(3-cyanophenoxy)benzyl)-2-thioxo-4(3H)-pyri~nidinone (6.00 g, 17.9 mmoles) in glacial acetic acid (100 ml) and 20%
aqueous chloroaGetic acid (100 ml) was refluxed with stirring for 18 hours.
After cooling to arnbient telll~eldLLIre and then in an ice bath, the mixture was filtered, and the solids were washed with water and ether and dried in a vacuum oven at 80C for 3 days to give 3.05 g (53%) of 5-(3-(3-cyanophenoxy)benzyl) WO 94/01414 ~ 8 ~ ~ -46 - PCI/GB93/01443 uracil as a beige solid which was used without further purification, mp 179-1 85C.

F. Pl~pa,aLion of 1-((2-acetoxyethoxy)methyl)-5-(3-(3 cyanophenoxy)benzyl)uracil Bis(trimethylsilyl)~cet~rnide (2.80 rnl, 11.3 rnrnoles) was added to a stirred suspension of 5-(3-(3-cyanophenoxy)benzyl)uracil (2.00 g, 5.5 mmoles) in dichloroethane (65 ml) under nitrogen. The mixture was refluxed with stirring for 1 hour, the heat was removed, and the solution which forrned was cooled in an ice bath. A solution of (2-acetoxyethoxy)methyl brornide (0.84 g, 4.2 mrnoles) in acetonitrile (7 ml) was added to the cooled solution, and the resl~lting solution was allowed to warm to ambient tenll,el~L~lre and stirred under nitrogen for 18 hours. The solvents were removed in vacuo~ and the residue was dissolved in dichlorometh~ne (150 ml) and washed with water (3 X
50 ml) and brine. The solvents were removed in vacuo, and the residual oil was introduced onto a column of Silica Gel 60 wetted with dichloromethane. The column was eluted with dichloromethane: 2-propanol (100: 2), and the fractions conl~ product were combined. The solvents were removed in vacuo to give 1.76 g (64%) of 1-((2-acetoxyethoxy)methyl)-5-(3-(3-cyanophenoxy)benzyl)uracil as a clear oil which was used without further purification.

G. Ple~)a,~ion of 1-((2-hydroxy~lhoxy)methyl)-5-(3-(3 cyanophenoxy)benzyl)uracil A solution of 1.74 g (4 mmoles) of 1-((2-acetoxyethoxy)metho-xy)-5-(3-(3-cyanophenoxy)benzyl)uracil in meth~n~l (150 ml) saturated with ammonia gas was stirred in a stoppered flask for 24 hours at ambient temperature. The meth~nol was removed in vacuo, and the residue was r~ily~lli7ed from 2-~lopaQol and dried in a vacuum oven at 80C to give 0.97 g (62 %) of 1-((2-hy~ yt;llloxy)methyl)-5-(3-(3-cyanophenoxy)benzyl)uracil as a white solid, mp 115-117C.
--~139~3 ~
0 94/01414 PCr/GB93/01443 - l7 --Example 13 Preparation of 1-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-5-(3-(3-chlorophenoxy)benzyl)-uracil A. Pl epa- ~lion of 2-((1,2.3 ~4-tetrahydro-2~4-dioxo-5-(3-(3 -chlorophenoxy)ben_yl)-l-pyrimidinyl)methoxy)-1~3-propanediyl dibenzoate This compound was prepared in an analogous manner to that of Example 12F
with the repl~cPment of 0.95 g of (2-acetoxyethoxy)methyl bromide in Exarnple 19F with 1.89 g of 2-(bromomethoxy)-1,3-propanediyl dibenzoate.
The chrol,latography fractions were spin evaporated in vacuo to give 2.42 g of a clear oil. Trituration with acetonitrile gave 1.94 g (50%) of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3-(3-chlorophenoxy)ben_yl)- 1 -pyrimidinyl)methoxy)-1,3-propanediyl dibenzoate as a white solid; mp 147-148C.

B. Preparation of 1-((2-hydroxy-1-(hydroxymethyl)ethox,v)methyl)-5-(3-(3-chlorophenoxv)-ben_yl)uracil This compound was prepared in an analogous manner to that of Example 12G
with the replacement of 1.60 g of 1-((2-acetoxyethoxy)methyl)-5-(3-(3-chlorophenoxy)benzyl)uracil in Example 19G with 1.82 g of 2-((1,2,3,4-tetrahydro-2,4-dioxo-5-(3-(3-chlorophenoxy)ben_yl)- 1 -pyrimidinyl~methoxy)-1,3-propanediyl diben70ztte. The meth~nol was removed in vacuo, and the residue was dissolved in ethyl acetate (100 ml) and extracted with 0.3 N
NaOH (5 x 50 ml). The aqueous extracts were cooled in an ice bath, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (3 x 100 ml). The organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was le~i.y~llt7ed from dichloro.,~ llal1e and dried in a vacuum for 3 days to give 0.366 g (30 %) of 1-((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(3 -chlorophenoxy)benzyl)uracil as a white solid, mp 118-119C; uv (0.1 N
hydrochloric acid + 10% m~.th~nol): l max 266 nm (I 11600);(pH 7 buffer +
10% I--e~ nol) l max 267 nm (I 10100); (0.1 N sodium hydroxide + 10%
ol): 1 max 266 nm (I 8300); nmr (DMSO-d6): d 11.35 (s, lH, NH), WO 94/01414 2 1~3;9 8t3 ~ PCI/GB93/01443 7.67 (s, lH, H-6), 7 11 (m, 8X ArH), 5.17 (s, H, NCH2O), 4.62 (t, 2H, OH), 3.58 (s, 2H, CH2Ar), 3.42 (m, 5H, CH and CH2OH); ms: m/e 433 (M+).
Anal. Calcd. for C21H21CIN206: C, 58.27; H, 4.89; N, 6.47; Cl, 8.19.
Found: C, 58.19; H, 4.85; N, 6.44; Cl, 8.29.

Example 14 A. Pl epa, ~Lion of ~-(3-chlorobenzyl)- 1 -(4-hydroxvbutyl)uracil A suspension of 5-(3-chlorobenzyl)uracil (3.00 g, 12.7 mmoles), bromobutyl acetate (0.61 ml, 4.2 mmoles) and cesium carbonate (4.14 g, 12.7 mmoles) was heated with stirring at 80-90C for 1.5 hours. Aflcer cooling to ambient temperature, the cesium carbonate was removed by filtration and washed with dichloromethane. The filtrate and washings were combined and evaporated in vacuo to give a beige solid. Chromatography on Silica Gel 60, eluting with dichlorometh~ne meth~n~l (33:1), gave 0.56 g of a clear oil which was shown by tlc analysis to be a rnixture of three products. The oil was refluxed in a solution of sodium methoxide (0.086 g, 1.6 mmoles) and meth~nol (10 ml) for 1.5 hours under nitrogen. AfLer cooling to ambient temperature, the meth~nQI
was removed invacuo and the residue chromatographed on Silica Gel60 eluting with dichlo-~",~ e meth~nol (33:1). One pure fraction was obtained which, a~er evaporation in vacuo. gave 0.110g of 5-(3-chlorobenzyl-1-(4-hydroxybutyl)uracil as a white solid, mp 125-127C; tlc, dichloromethane:methanol (33:1), uv (0.1 N hydrochloric acid + 10%
mP~th~nol) Imax 274 r~n (e 10400); (pH 7 buffer + 10% meth,.nol) Imax 274 nm (e 9800); (0.1 N sodium hydroxide + 10% meth~nol) ImaX 272 nrn (e 7100); NMR (DMSO-d6): d 7.18 (m, 4H, Ar), 6.88 (s, lH, H-6), 3.71 (m, 4H, NCH~ and CH20), 3.62 (s, 2H, CH2Ar), 1.68 (m, 5H, CCH2C 2C and OH);
ms: m/e 309 (M+).
Anal. Calcd. for C1sH17N2O3Cl: C, 58.35; H, 5.55; N, 9.07.
Found: C, 58.31; H, 5.60; N, 9.06.

~YO 94/01414 2 1 3 9 8 3 ~ PCr/GB93/01443 ~9 The following compounds of formula (I) were also made by methods analogous to, or adapted from that described in Example 1.
Example No.
., 5-(3-chlorobenzyl)-1-((2-hydroxyethoxy) methyl)uracil from l-((2-acetoxyethoxy)methyl)-S -(3 -chlorobenzyl)uracil .
mpt: 157 - 159C

16 1 -((2-hydroxy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-chlorobenzyl)uracil from 2-((5-(3-chlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo- 1 -pyrimidinyl)-methoxv)- 1,3-propanediyl dipivalate.

Colourless Oil.
NMR (DMSO - d6): d 11.33 (s, lH, NH), 7.71 (s, lH, H-6), 7.25 (m, 4H, ArH), 5.16 (s, 2H, NCH2 O), 4.61 (t, 2H, OH), 3.52 (s, 2H, CH2 Ar), 3.42 (m, 5H, CH and C_2OH).

17 1-((2-hydroxyethoxy)methyl)-5-(3-allyloxybenzyl)uracil from 1-((2-acetoxyethoxy)methyl)-5 -(3 -allyloxybenzyl)uracil.
mpt: 89 - 93C

18 1 -((3 -hydroxypropoxy)methyl)-5-(3 -propoxybenzyl)uracil from 1 -((3 -acetoxypropoxy)methyl)-5-(3 -propoxybenzyl)uracil.

Clear Oil.
NMR (DMSO-d6): d 8.25 (s,1H, NH), 7.30(s, lH, H-6), 7.10 (m, 4H, ArH), 5.08 (s, 2H, NCH2O), 3.91 (t, 2H, ArOC_2), 3.66 (m, 5H, C_ 2 Ar and OH and NCH2OCH2), 1.78 (m, 4H, 2(0C_2CH2)), 1.04(t,3H,CH3).

19 1 -((2-h-ydro~yeLlloxy)methyl)-5-(3,5-difluorobenzyl)uracil from I -((2- acetoxy ethoxy)methyl-5-(3,5-difluorobenzyl)uracil.
mpt: 138- 139C

WO 94/01414 2 13 ~ ~ 3 6 PCI/GB93/01443 1-((2-hydroxyethoxy)methyl)-5-(3-trifluoromethoxy)benzyl)uracil from 1 -((2-acetoxyethoxy)methyl)-5-(3 -trifluoromethoxy)benzyl)uracil.
mpt: 92 - 93C

21 1-((2-hydroxyethoxy)methyl)-5-(3-(4-fluorophenoxy)benzyl)uracil from 1 -((2-acetoxyethoxy)methyl)-5-(3 -(4-fluorophenoxy)benzyl)uracil.
mpt: 106 - 109C

22 1-((2-hydroxyethoxy)methyl)-5-(3-(3-methoxyphenoxy)benzyl)uracil from 1-((2-acetoxyethoxy)methyl)-5-(3-(3-methoxyphenoxy)benzyl) uracil.
mpt: 98- 102C

23 1 -((2-hydl oxy~lhoxy)methyl)-5-(3-(3-trifluoromethylphenoxy)benzyl) uracil from 1-((2-acetoxy ethoxy)methyl)-5-(3-(3-trifluoromethyl phenoxy)benzyl)uracil .
mpt: 103- 105C

24 1-((2-hydroxyethoxy)methyl)-5-(3-(3-methylphenoxy)benzyl)uracil from 1 -((2-acetoxyethoxy)methyl)-5-(3 -(3 -methylphenoxy)benzyl)uracil .
mpt: 110-111C

1-((2-l.ydroxyelho-xy)methyl)-5-(3-isobutoxybenxyl)uracil from 1-((2-aceLoxyt;Lhoxy)methyl)-5 -(3 -isobutoxybenzyl)uracil .
mpt: 95 - 97C

26 1-((2-l~ydlo~y~ho~y)methyl)-5-(3-butoxybenzyl)uracil from 1-((2-acc;~ yeLhoxy)methyl)-5-(3-b~ ybe~yl)uracil.
NMR (DMSO - d6): d 11.25 (s, lH, NH), 7.63 (s, lH, H-6), 6.95 (m, 4H, ArH), 5.08 (s, 2H, NCH2O), 4.67 (t, lH, OH), 3.91 (t, 2H, ArOCH2), 3.49 (m, 6H, CH2Ar and (CH2)2), 1.67 (m, 2H, Ar OCH2C_2)~ 1.43 (m, 2H, CH2 CH3), 0.92 (t, 3H, CH3).

213~3~
~0 94/01414 : PCI/GB93/01443 - 51 -27 1 -((2-hydroxy- 1-(hydroxymethyl)ethoxy)methyl-5-(3-(3-fluoropropoxy)benzyl)uracil from 2-((1,2,3,4 - tetrahydro-2, 4 - dioxo-5-(3-(3-fluoropropoxy)benzyl)- 1 -pyrimidinyl)methoxy)- I ,3-propanediyl dibenzoate.
mpt: 99- 101C

Example ~8 In-vitro Inhibition of Uridine Phosphorylase Method Preparation of enzyme-- Fresh livers, obtained from female CD-1 mice under Fluothane or carbon dioxide anesthesia, were weighed then homogenized in ice cold (3:1, v/w) 20 mM potassium phosphate buffer pH 8, lmM EDTA, 1 mM
mercaptoethanol. The homogenate was centrifuged at lO0000 x g for l hour at 4 C, and the supel.lata~lL was used as the enzyme source.

Enzyme inhibition studies-- Assays were con~l-ctecl in 20 mM potassium phosphate buffer, pH 8, 1 mM EDTA, l mM dithiothreitol co,.~ ;"g 170 mM
[2-14C] uridine (7 mCi/mmole), various arnounts of inhibitor or buffer and 20 mL of enzyme in a final volume of 60 mL. The reaction was carried out for 30 minllteS 37C then termin~ted by boiling for 1 minute. P~ ed proteins were removed by centrifugation, and SmL of the supelna~ l were spotted on silica gel thin layer chrolll~lography sheets (with fluorescence indicator) thatwere prea~olled with 5 mL of a mixture of 10 mM each uracil and uridine. The plates were developed in chlororc,l", ",eli,~nol:acetic acid (90:5:5), and uridine and uracil were detected by W ~ n~hing The pyrimitlines areas were cut out and counted by liquid scint~ tion in 5rnl of Ready Safe (Recl~m~n). The cpm (velocity) of the inhibitor co.l~ samples were colll~uared to those of the control, and percent inhibition values were calc~ ted Plots of percentage of inhibition versus the logarithm of inhibitor concentration were used to =

WO 94/01414 2 L 3 ~3 8 3 6 s2 - PCI/GB93/01443 calculate the ICso values (the concentration of inhibitor needed to give a 50% reduction of the enzyme reaction rate) shown below.

Compound of example: IC50 mM
~0.05 2 0.06 3 cO.05 4 <0.05 0.068
6 ~0.05
7 <0.05
8 <0.05
9 <0.05 0.063 1 1 <0.05 12 <0.05 13 <0.05 14 0.43 0.3 16 0.11 The following Examples illustrate pharm~ceutical formulations in which the "Active .Ingredient" is a compound of formula I, preferably:
=

1 -((2-hydroxy- 1 -(h~d, uAyll~ llyl) thoxy)methyl)-(3 -phenoxybenzyl)uracil, I -((2-hydroxy- 1 -(hydroxyrnethyl)ethoxy)methyl)-5-(3-(3-fluol opllelloAy)benzyl)uracil, 1 -((2-hydl UAy- 1 -(hydroxymethyl)ethoxy)methyl)-5-(3-(4-fiuo. ophe.~Ay)benzyl)uracil 1 -((2-hydroxy- 1 -(hydl oAy-"ethyl)ethoxy)methyl)-5-(3-(3-chlorophenoAy)benzyl)uracil or 1 -((2-hydl ~kyethoxy)methyl)-5-(3-(3-cy~lûphenoAy)benzyl)uracil.

21 3~3~
~0 94/01414 PCI/GB93/01443 Example 29 Tablet Fo~nulations The following formulations 29A, 29B and 29C are prepared by wet granulation of the ingredients (except the m~unesillm stearate) with a solution of the povidone followed by drying of the granules, addition of the magnesium stearate and compression.

Formulation 29A mg/tablet mg/tablet Active ingredient 100 10 Lactose, B.P. 200 60 Povidone, B.P. 20 10 Sodium starch glycollate 20 10 Magnesium stearate 10 10 Formulation 29B mg/tablet mg/tablet Active ingredient 100 10 Lactose, B.P. 150 60 AvicelPH lOl 50 25 Povidone, B.P. 15 10 Sodium starch glycollate 20 10 Magnesium stearate 15 5 Formulation 29C mg/tablet Active ingredient 100 Lactose, B.P. 200 Starch 40 Povidone, B.P. 6 l~gnesi-~m stearate 4 The following formulation 29D is prepared by direct coml),ession of the ~rimi~e(l ingredients. The lactose used is of the direct collll)les~ion type.

WO 94/01414 21 3 9 ~ 3 6 PCI/GB93/01443 Formulation 29Dmg/tablet Active ingredient 100 Lactose 1 50 Avicel PH 101 100 The following formulation 29E is a controlled release tablet and is prepared by wet granulation of the ingredients (except magnesium stearate) with a solution of the povidone, followed by drying of the granules, addition of the magnesium stearate and CO~ eSSiOII.

Formulation 29E mg/tablet Active ingredient 100 Hydroxypropylmethylcellulose 1 00 (Methocel K4M Premium) Lactose, B.P. 50 Povidone, B.P. 30 M~gn~sillm stearate 20 Example 30 Capsule Formulations The following formulations 30A and 30B are l,-epared by admixing the unco""),essed ingredients and filling into a two-part hard gelatin capsule.

Forrnulation 30Amg/capsule Active ingredient 10 Lactose, B.P. 250 Sodium starch glycollate25 l~gn~ci-lm stearate 5 213~36 0 94/01414 PC~r/G B93/01443 Formulation 30B mg/capsule Active ingredient 100 Pregel.-tini7ed starchNF15 250 For nulation 30C mglcapsule Active ingredient 10 Macrogol 4000, B.P. 340 The Macrogol 4000, B.P. is melted and the active ingredient dispersed therein. The thoroughly mixed melt is then filled into a two-part hard gelatin capsule.

Exarnple 3 1 Injectable Formulation Active ingredient lOOmg Sterile, pyrogen free phosphate buffer (pH 7.0), q.s. to lOml .

The active ingredient is dissolved in most of the phosphate buffer ~35~0C), then made up to volume and filtered through a sterile micropore filter into a 10 ml arnber glass vial (type 1) and sealed with a sterile closure and overseal.

WO 94/01414 2 13 ~ 8 3 ~ 56 - PCr/GB93/01443 Example 32 Suppository Formulation mg/suppositorv Active ingredient, 63 m* 100 Hard fat, B.P. (Witepsol HlS-Dynamit Nobel) 1700 *The active ingredient is used as a powder wherein at least 90% of the particles are of 63 m or less. The symbol "m" as used herein means micron.

One-fifth of the Witepsol H15 is melted in a steamjac~ted pan at 45C maximum.
The active ingredient is sifced through a 200 m sieve and added to the molten base with mixing, using a silverson fitted with a cutting head, until a smooth dispersion is achieved. ~;"l~i";"g the mixhlre at 45C, the ,~ Witepsol HlS is added to the suspension and stirred to ensure a homogeneous mix. The entire suspension ispassed through a 250 m stainless steel screen and, with continuous stirring, is allowed to cool to about 40C. At a temperature of 38C to 40C, 1.80 g of the mixture is filled into suitable plastic moulds. The suppositories are allowed to cool to room temperature.

Claims (23)

1) A compound of formula (IA) (IA) and esters and prodrugs thereof wherein R10b is C2-3 straight or branched chain alkyl group substituted by one or two hydroxyl groups; R4a is H or OR11a wherein R11a is a C3-5 straight or branched chain alkyl group optionally substituted by fluoro; and R6a is H or -O-Ar-R7a wherein Ar is phenyl and R7a is fluoro, chloro or cyano; provided that one but not both of R4a and R6a is H.
2) A compound of formula (IA) according to Claim 1 and esters and prodrugs thereof wherein R10b is -CH2CH2OH or CH(CH20H)2, R4a is -OR11a is-OCH2CH2CH3 or -OCH(CH3)CH2CH3 and R6a is H.
3) A compound of formula (IA) according to Claim 1 and esters and prodrugs thereof wherein R10b is CH2CH2OH or CH(CH2OH)2, R4a is H and R6a is-O-Ar-R7a wherein Ar is phenyl and R7a is H, fluoro, chloro or cyano.
4) A compound of formula (IA) according to Claim 1 and esters and prodrugs thereof wherein R10b is CH2CH20H or CH(CH20H)2, R4a is H and R6a is -O-Ar-R7a wherein Ar is phenyl and R7a is 3-fluoro, 3-chloro or 3-cyano.
5) A compound of formula (IA) for use in medicine.
6) A compound of formula (IA) for use as a uridine phosphorylase inhibitor.
7) A compound of formula (IA) for use in reducing the cellular toxicity associated with the administration of a pyrimidine nucleoside.
8) A compound of formula (IA) for use in reducing the toxicity of neoplastic pyrimidine nucleosides and/or potentiating the efficacy of anti-neoplastic drugs.
9) A compound of formula (IA) for use in the treatment of nervous disorders and conditions in which increased levels or uridine are beneficial.
10) Use of a compound of formula (IA) in the manufacture of a medicament for reducing the cellular toxicity associated with the administration of a pyrimidine nucleoside.
11) Use of a compound of formula (IA) in the manufacture of a medicament for reducing the toxicity and /or potentiating the efficacy of antineoplastic drugs.
12) Use of a compound of formula (IA) in the manufacture of a a medicament for the treatment and /or prophylaxis of nervous disorders and conditions in which increased levels of uridine are beneficial.
13) A method of reducing the cellular toxicity associated with the administration of a pyrimidine nucleoside which comprises the administration of a pharmaceutically effective amount of a compound of formula (IA)
14) A method of reducing the toxicity and/or potentiating the efficacy of an antineoplastic drug which comprises the administration of a therapeutically effective amount of a compound of formula (IA)
15) A method of treatment and/or prophylaxis of nervous disorders and conditions in which increased levels of uridine are beneficial which comprises the administration of a therapeutically effective amount of a compound of formula (IA).
16) A method of treatment and/or prophylaxis of AIDS-type diseases which comprises the simultaneous or sequential administration of a pyrimidine nucleoside and a compound of formula (IA).
17) A method of treatment and/or prophylaxis of an HIV infection in a mammal which comprises the administration of an effective amount of zidovudine or a pharmaceutically acceptable ester or salt thereof in combination with an effective amount of a compound of formula (IA).
18) A method of treatment and/or prophylaxis of tumours in a mammal which comprises the administration of an effective amount of 5-fluorouracil in combination with an effective amount of compound of formula (IA).
19) A compound of formula (IA) in combination with a pyrimidine nucleoside or anti-neoplastic agent.
20) A compound of formula (IA) in combination with a pyrimidine nucleoside according to Claim 18 wherein the pyrimidine nucleoside is zidovudine.
21) A compound of formula (IA) in combination with an anti-neoplastic agent according to Claim 18 wherein the anti-neoplastic agent is 5-fluorouracil.
22) A pharmaceutical formulation comprising a compound of formula (IA) and optionally containing a pyrimidine nucleoside or antineopiastic agent together with at least one pharmaceutically acceptable carrier or excipient therefor.
23) A process for the preparation of a compound of formula (IA) which comprises a) the hydrolysis of a compound of formula (II) (II) wherein R4a and R6a are as hereinbefore defined and Q is NH2, OR13 or SR13 wherein R13 is C1-6 straight or branched chain alkyl, and thereafter attaching a group CH2OR10b wherein R10b is as hereinbefore defined;

b) the hydrolysis of a compound of formula (III) (III) wherein R4a and R6a are as hereinbefore defined, B is that portion of CH2OR10b other than -OH, Y is O and R12 is a C1-6 straight or branched-chain alkyl group, C6H5 or substituted aryl group;

c) by hydrolysis of the O-timethylsilyl ether with neat or aqueous organic alcohol;

d) from O-benzyl ethers by treatment with hydrogen in an organic alcohol solvent in the presence of a catalyst.
CA002139836A 1992-07-10 1993-07-09 Iracil derivatives as enzyme inhibitors Abandoned CA2139836A1 (en)

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GB929214720A GB9214720D0 (en) 1992-07-10 1992-07-10 Enzyme inhibitors
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GB9214720D0 (en) 1992-08-19
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ZA934970B (en) 1995-01-09

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