GB2129425A

GB2129425A - 5-halovinyl-2'-deoxyuridine derivatives

Info

Publication number: GB2129425A
Application number: GB08324813A
Authority: GB
Inventors: David Ian Carter Scopes; Paul Ravenscroft; Roger Frank Newton; Richard Clive Cookson
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1982-09-17
Filing date: 1983-09-16
Publication date: 1984-05-16
Also published as: EP0104066A3; HK84190A; AU601583B2; CA1271199C; ES8506751A1; DK422183A; NZ205619A; MX9203234A; IE55921B1; GB8324813D0; CZ402691A3; DK422183D0; EP0104066A2; DK160271C; CA1257595A; ES532056A0; ES8502978A1; EP0104066B1; US4564618A; GB2129425B

Abstract

Compounds of general formula (I):wherein R is a chlorine, bromine or Iodine atom and physiologically acceptable salts thereof with bases of use as antiviral agents.

Description

1 GB 2 129 425 A 1

SPECIFICATION 5-H alovi nVI-21-deoxyu rid ine derivatives

This invention relates to new uracil derivatives having antiviral activity.

Deoxyuridine derivatives such as 2'-deoxy-5-iodouridine (Prussoff and Goz: Handbook of Experimental Pharmacology, Part 11 of Antineoplastic and Immunosuppressive Agents, SpringerVerlag, New York 1975, pages 272-347) and 2'-deoxy-5-vinyluridine (Cheng Lat at, Antimicrobial Agents and Chemotherapy 10, 1, 119-122 (1976) have been found to possess antiviral activity. The activity of these compounds, however, is not very specific. British Patent Specification No. 1,601,020 discloses E-5-(2-bromo and iodo-vinyl)-2-deoxyuridine which are described as having selective antiviral activity against herpes simplex viruses. There is a need, however, for compounds with better and more selective antiviral activity.

We have now found a small group of uracil derivatives which have improved selective activity against viruses, especially Herpetoviridae.

Thus, the invention provides compounds of the general formula (0:

0 RN j.' 0 N R (1) wherein R is a chlorine, bromine or iodine atom and physiologically acceptable salts thereof with bases. In particular, salts with alkali metals such as sodium and potassium may be mentioned. In the compounds of formula (1) the halovinyi group is in the E-configuration and the pyrimidine ring is in the P-configuration relative to the cyclopentane ring. 20 It is to be understood that the present invention encompasses the individual (+) and (-) isomeric 20 forms of the compounds of formula (1) as well as wholly or partially racemic mixtures of such isomers. On account of their structural similarity to naturally occurring compounds such as thymidine, the 1 R,3S-hydroxy-4R-hydroxymethyl-cyclopentyI isomers are of particular interest. It will be further understood that the invention includes within its scope biological precursors of the compounds of formula (1) and their physiologically acceptable salts with bases, e.g. metabolically 25 labile esters which are converted in vivo into the parent compound.

The compounds according to the invention may exist in tautomeric forms, for example in the form OH N NO R0 R and it will be understood that such tautomeric forms are included within the scope of the invention.

Initially we found that compounds according to the invention were extremely effective substrates 30 for thymidine kinase produced by herpes simplex virus type 1 and herpes simplex virus type 2, thus strongly suggesting that the compounds would have selective activity against strains of herpes viruses, for example, herpes simplex viruses. (J. C. Drach, Annual Reports in Medicinal Chemistry, 15, 1980, 149-161). Further work has indeed confirmed that these compounds are potent selective antiviral agents.

It should be noted that the compounds of formula (1) lack the glycosidic bond which forms a site for both chemical and biological cleavage in the compounds of GB-A-1,601, 020. Stability against glycosidic cleavage is, of course, a valuable feature in compounds for in vivo use.

In view of their antiviral activity, the compounds of formula (1) and their physiologically acceptable salts with bases recommend themselves for the treatment of a variety of diseases caused 40 2 GB 2 129 425 A 2 by the Herpetoviridae, particularly herpes simplex viruses, in human beings and animals. Such diseases include stomatitis and skin eruptions, shingles, encephalitis, eye and genital herpes infections.

The invention accordingly provides compounds of formula (1) and their physiologically acceptable salts with bases for use in the therapy or prophylaxis of Herpetoviridae, e.g. herpes simplex, infections 5 in a human or animal subject.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising at least one compound of formula (1) or a physiologically acceptable salt thereof with a base adapted for use in human or veterinary medicine. Such compositions may be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The compositions may optionally further contain one or more other therapeutic agents which may if desired be a different antiviral agent.

Thus, the compounds according to the invention may be formulated for oral, buccal, parenteral, topical or rectal administration.

Tablets and capsules for oral administration may contain conventional excipients such as 15 binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, sugar, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations maybe in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan 25 mono oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates for sorbic acid. The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the compositions may take the form of tablets or lozenges formulated 30 in conventional manner.

The compounds according to the invention may also be formulated for injection and may be presented in unit dose form in ampoules or in multidose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.

Alternatively, the active ingredient maybe in powder form for constitution with a suitable vehicle, e.g.

sterile, pyrogen-free water, before use.

For topical administration the compounds according to the invention may be formulated as ointments, creams, lotions, powders, pessaries, sprays, aerosols or drops (e.g. eye or nose drops).

Ointments and creams may for example, be formulated with an aqueous or oily base with the addition 40 of suitable thickening and/or gelling agents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil. Thickening agents which may be used include soft paraffin, aluminium stearate, cetosteary] alcohol, polyethylene glycols, hydrogenated lanolins and beeswax.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or 45 more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Powders may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, sol ubi lising agents or suspending agents.

Aerosol sprays are conveniently delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

The pharmaceutical composition according to the invention may also contain other active ingredients such an antimicrobial agents, or preservatives.

The compositions may contain from 0.1 %-99% of the active material. For topical administration, for example, the composition will generally contain from 0. 1 % to 10%, more preferably 0.5% to 5% of the active material.

For topical administration the daily dosage as employed for adult human treatment will range from 0.1 mg to 100 mg, preferably 0.5 mg to 10 mg. However, it will be appreciated that extensive 60 skin infections may require the use of higher doses.

For systemic administration the daily dosage as employed for adult human treatment will range from 50 mg to 5 g, preferably 100 mg to 2 g, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient. When the compositions comprise dosage units, each unit will preferably contain 25rng-2 g of active ingredient, 65 W 1h 1 1 3 GB 2 129 425 A 3 for example 50 mg to 500 mg. For serious infections the compounds may be administered by intravenous infusion using, for example 0.1 to 10 mg/kg/hr of the active ingredient.

The compounds of formula (1) according to the invention may be prepared by treatment of a compound of formula (11):

OR' 1 0, , N R30 ', J -COH NI (11) R20 or a salt thereof (where R', R' and R', which may be the same or different, represent hydrogen atoms or protecting groups) with a halogenating agent followed where necessary by removal of any protecting groups as described hereinafter.

The reaction is conveniently effected in a medium such as water; an alcohol, e.g. methanol or ethanoi; a halogenated hydrocarbon, e.g. chloroform or carbon tetrachloride; or a substituted amide, 10 e.g. N,N-dimethylformarnicle, and at a temperature in the range of 01 to + 1 001C, preferably +300 to +700C.

Suitable reagents for the halogenation include an N-halo amide or imide such as N-bromosuccinimide, N-chlorosuccinimide, Modosuccinimide, Nbromophthalimide, N-bromoacetamide, N- bromocaprolactam or 1,3-dibromo5,5-dimethyi-hydantoin. Alternatively, molecular halogen, e.g. iodinechloride, chlorine or bromine, may be used.

In aqueous media the treatment of a compound of formula (11) with a halogenating agent is conveniently carried out in the presence of a base such as potassium acetate.

When the compound of formula (11) is used in the form of a salt the salt may be formed with an inorganic or organic base. Suitable salts include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium salts; or organic base salts, e.g. triethylamine or pyridine salts.

Where W, R' or R' represents a protecting group, it may be any conventional protecting group, for example, as described in 'Protective Groups in Organic Chemistry', Ed. J. F. W. McOmie (Plenum Press, 1973). Examples of suitable protecting groups are alkyl groups such as methyl, tbutyl or methoxymethyl; aralkyi groups such as benzyi, diphenyimethyl or triph enyl m ethyl; heterocyclic groups 25 such as tetra hyd ropyra nyi; acyl groups such as acetyl and sily] groups such as trialkyl silyl groups, e.g. trimethyisilyl.

The protecting groups may be removed by using conventional techniques to yield a compound of formula (1). Thus, for example, an alkyl, aryi, silyl or heterocyclic group may be removed by solvolysis, e.g. hydrolysis under acidic or basic conditions, and an aralkyl group maybe cleaved with a boron trihalide e.g. boron trichloride in a solvent such as methylene chloride and at low temperature.

The compounds of formula (11) may be prepared by deprotection of the carboxyl group of a compound of formula (Ill):

ORI C02 R 4.

N 1 Q N R30 2 1 _ Rle rill) (where R', R' and R' are as previously defined and R' represents a carboxyl protecting group).

R 4 may be any conventional carboxyl protecting group such as an alkyl group, e.g. methyl or ethyl, or an aralkyl group, e.g. benzyl. The group R 4 may be cleaved by conventional means, e.g. by hydrolysis under basic conditions (using for example aqueous sodium hydroxide). The deprotection will generally be effected in the temperature range 0 to +501C. If desired, removal of the protecting group R 4 may 40 also be accompanied by removal of any protecting groups W, R' or R' where present.

4 GB 2 129 425 A 4 The compounds of formula (111) may be prepared by reaction of a compound of formula (IV):

OR1 N 1 RgX a-1--L N (IV) R 30 R20 "Z" (where R', R' and R' are as previously defined and X is an anion e.g. chloride ion) with an ester of acrylic acid:

CH,=CHCO,R 4 5 (where R' is as previously defined).

The reaction is conveniently carried out in the presence of a transition metal complex such as dilithium palladium tetrachloride in a solvent such as an alcohol e.g. methanol; acetonitrile; or water and at a temperature in the range 0 to +500C.

The compounds of formula (IV) may be prepared by reaction of a compound of formula (V): 10 OR' N 0 J, N R 3 0"" R20 1 (V) (where R', R' and R 3 are as previously defined) with a mercury salt HgX, (where X is as previously defined).

The mercury salt may be, for example, mercuric acetate or a mercuric halide, e.g. mercuric chloride. If desired, the anion X in compounds of formula (IV) may be changed after reaction of a compound of formula (V) with a mercury salt. For example, a compound of formula (IV) in which X represents an acetate ion may be converted into a compound of formula (IV) in which X represents a chloride ion by reaction with sodium chloride.

The reaction is conveniently carried out in a solvent such as water, acetonitrile or an alcohol, e.g.

methanol at a temperature in the range 0 to +1000C.

The compounds of formula (V) may be prepared by reduction of a compound of formula (VI):

OR I N C 0 OHYJ R 0 1 (VI) (where R' and R 2 are as previous defined) followed where required by introduction of a protecting group R 3.

Suitable reducing agents for this reaction include alkali metal or alkaline earth metal borohydrides, such as sodium borohydride, or hydrogen in the presence of a catalyst, such as palladium J GB 2 129 425 A 5 on charcoal. This reaction is conveniently carried out in an organic solvent such as an alcohol, e.g. methanol or ethanol, or an ether, e.g. tetrahydrofuran, at a temperature of, for example, -20 to +800C. Where it is desired to introduce a protecting group R 3 this may be effected by conventional methods. 5 Where RI in the compounds of formula (V) thus produced represents a protecting group it may be 5 convenient at this stage to remove the protecting group, for example by hydrolysis under acidic conditions using e.g. hydrochloric acid in aqueous methanol. The compounds of formula (VI) may be prepared by hydrolysis of a compound of formula (VI I):

OR 1 N 1 c- -" N W;% CH - t^1 R z 0 1 (Vil) (where R' and R' are as previously defined and R5 represents a substituent derived from an alcohol or 10 diol R501-1) under acidic conditions.

The group R' may be, for example, a C,-, alkyl group, e.g. a methyl group, or an aralkyl group, e.g. a benzyl group. Alternatively, the acetal grouping (RIO),CH- can be derived from a diol such that it has the structure:

/"- 0 \ (CH2)n CH- 15 \I-,-- 0 / where n is, for example, 2 or 3.

Suitable acids include organic and inorganic acids such as acetic, trifluoroacetic, hydrochloric and sulphuric acids. The reaction may be effected at any temperature in the range 0 to 1 001C.

The compounds of formula (VII) may be prepared by cyclisation of a compound of formula (Vili):

R6 OR' HN 0) 2 CH 0 R 2 0 IS':' "I r, N (Viii) (where W, R 2 and R5 are as previously defined and R' represents a leaving group). Suitable leaving groups R' include a C,-, alkoxy group, e.g. a methoxy or ethoxy group, a sulphonyloxy group, e.g. a methanesulphonyloxy or toluene-p-sulphonyloxy group, or a halogen atom, e. g. a chlorine or bromine atom.

The cyclisation is effected by treatment of a compound of formula (V] II) with a base such as 25 ammonia, triethylamine, pyridine or sodium carbonate. The reaction may be carried out in any suitable solvent such as water, an alcohol, e.g. methanol, or a halogenated hydrocarbon, e.g. methylene chloride, at a temperature in the range 0 to + 1 OWC. It will be appreciated that where R' represents hydrogen, the compounds of formula (VIII) may exist in the alternative keto form.

The compounds of formula (VIII) may be prepared by acyiation of a compound of formula (IX): 30 (R 6 0)zCV W wz 1 R'D 0 (IX) (where R 2 and R5 are as previously defined) with an acylating agent of formula N:

6 GB 2 129 425 A 6 0 Rb "^ R (X) (where R' is as previously defined and R' represents a readily displaceable atom or group). R' may be, for example, a halogen atom such as chlorine or bromine, a sulphonyloxy group such as methanesulphonyloxy or toluene-p-suiphonyloxy or an acyloxy group, i.e. such that the compound of formula (X) 5 is a mixed anhydride, formed, for example, from an alkyl haloformate such as ethyl chloroform ate.

The acylation may be effected in a solvent such as a ketone, e.g. acetone; a halogenated hydrocarbon, e.g. chloroform; an ester, e.g. ethyl acetate; and mixtures of such solvents, at a temperature in the range -20 to + 501C. When R represents a halogen atom, the reaction may conveniently be carried out in the presence of an acid binding agent such as pyridine, triethylamine or 10 sodium bicarbonate.

The compounds of formula (IX) may be prepared, for example, by a Curtius reaction. Thus, the compounds of formula (K) may be obtained, by amination of the intermediate isocyanate generated, e.g. by conventional methods, from a compound of formula (XW 2, R 0 (R - 9 0)z c CO. N3 (XI) where R 2 and R' are as previously defined.

The amination may be effected by using gaseous ammonia or a solution of ammonia in a solvent such as a hydrocarbon, e.g. benzene or toluene, or a halogenated hydrocarbon, e.g. chloroform.

The reaction is conveniently carried out in an organic solvent such as an ether, e.g. tetrahydrofuran; an amide, e.g. N,N-dimethylformarnide; a halogenated hydrocarbon, e.g. chloroform; or a 20 hydrocarbon, e.g. benzene and at a temperature of, for example, -20 to +501C.

The compound_s of formula (Xl) may be prepared by reaction of a compound of formula (Xli):

(R 5 0)7CH COR 5 R 2 0 (m) (where R' and R' are as previously defined and R' represents a hydroxyl group or a readily displaceable atom or group) or when R' represents a hydroxyl group, a salt thereof, with a source of azide.

The readily displaceable atom or group R' may be as previously defined for R'.

When R' represents an hydroxyl group the source of azide is preferably an acyl azide, for example, a phosphorus azide such as diphenylphosphoryl azide. When R' represents a readily displaceable atom or group, e.g. a chlorine atom, the source of azide may be, for example, an alkali metal or alkaline earth metal azide such as sodium azide.

The reaction is conveniently carried out in an organic solvent such as an ether, e.g. tetrahydro furan; an amide, e.g. N,N-dimethylformarnide; a halogenated hydrocarbon, e.g. chloroform; or a hydrocarbon, e.g. benzene, and at a temperature in the range 0 to + 1 500C, preferably 50 to 1 OOOC, conveniently under an atmosphere of an inert gas, such as nitrogen.

Salts of compounds of formula (X11) may be formed with inorganic or organic bases. Suitable salts include a mine salts such as triethyla mine, alkali metal salts, such as sodium and alkaline earth metal 35 salts such as calcium.

The compounds of formula (X11) where R' is a readily displaceable atom or group may be prepared from the corresponding compounds where R' is a hydroxyl group by standard means.

The compounds of formula (X11) may be prepared by deprotection of a compound of formula (Xlil):

(R 5 0) 2. CH CO R? R 2 0 (where R 2 and R 5 are as previously defined and R' represents a protecting group).

WII) 7 GB 2 129 425 A 7 R' may be any conventional protecting group such as an alkyl group, e.g. a methoxymethyl group, or an aralkyl group, e.g. a benzyl, diphenyimethyl or triphenyimethyl group.

The deprotection may be effected, for example, by hydrolysis, e.g. under basic conditions. Suitable bases include potassium carbonate and sodium bicarbonate.

The reaction may be carried out in an aqueous reaction medium such as water; an aqueous alcohol, e.g. aqueous methanol; or an aqueous ketone, e. g. aqueous acetone, at a temperature in the range 0 to + 1 OWC.

The compounds of formula (XIII) may be prepared by reduction of a compound of formula (XIV):

(R 0) CH RO 0 (where R', R5 and R9 are as previously defined).

-1 1 A C02 - R9- N (Xly) The reduction may be carried out using hydrogen in the presence of a metal catalyst such as palladium, platinum, platinum oxide, rhodium or Raney nickel, which may be supported on, for example, charcoal, or a homogeneous catalyst such as tris triphenylphosphine rhodium chloride may be used.

The reduction may be carried out in an organic solvent-such as an alcohol, e.g. ethanol; an ester, 15 e.g. ethyl acetate or an ether, e.g. tetrahydrofuran, at a temperature in the range 0-to 1 OWC.

The compounds of formula (XIV) may be prepared by treatment of a compound of formula (XV):

0).Z CH C91;H i 6 - 0 X (XV) (where R' is as previously defined) or a salt thereof with a base, followed by reaction of the intermediate thus produced with a reagent capable of introducin g the protecting groups R 2 and R'.

Suitable bases for the reaction include alkyl lithium, e.g. n-butyl lithium, alkali metal hydrides, e.g.

sodium hydride and lithium diisopropylamide/hexamethylphosphbramide. Suitable reagents for the introduction of the protecting groups RI and R' are, for example, alkyl and aralkyl halides such as methoxymethyl chloride and benzyl bromide.

When the compound of formula (XV) is in the form of a salt, it may be any suitable inorganic or 25 organic base salt such as an alkali metal, e.g. sodium, alkaline. earth metal, e.g. calcium, or amine, e.g.

triethylamine, salt.

The reaction is conveniently carried out in an organic solvent such as an ether, e.g. tetrahydro furan, or a hydrocarbon, e.g. benzene, at a temperature of -50 to +801C, preferably 0 to +501C.

The compounds of formula (XV) may be prepared by reaction of the compound of formula (XVI): 30 CHO CO-, H I'Cl 0 0 X (XVI) or a salt thereof with an alcohol or diol R'OH (where R' is as previously defined) or by transacetalisation.

In the reaction of the compound of formula (XVI) with R'OH, the alcohol or diol will generally serve also as the reaction solvent, but a co-solvent such as a hydrocarbon, e.g. benzene or pentane, 35 may be used if desired.

The transacetalisation may be carried out using an acetal such as 2,2dimethoxypropane.

The source of protons in this reaction may be, for example, a mineral or organic acid such as hydrochloric, sulphuric or acetic acid, or a cationic exchangp resin such as Dowex 50GM. The reaction is conveniently carried out in the temperature range -20 to +501C.

The compounds of formula (XVI) may be prepared by ozonolysis of a compound of formula (XVII):

8 GB 2 129 425 A 8 0 - 0 H 0 i OR' H (XVII) (where W' represents a trihydrocarbylsilyl group).

Ozonolysis is preferably effected with ozone in the presence of an organic solvent such a& an alcohol, e.g. methanol, and/or a halogenated hydrocarbon e.g. dichforomethane, and at a low temperature, e.g. -100 to OOC, conveniently at about -801C. When the ozonolysis is completed the intermediate ozonide may be converted into a compound of formula (XVI) by the addition of a mild reducing agent such as methyl sulphide and allowing the temperature to rise.

The trihydrocarbyl silyl group W' may be, for example, a trialkyl, triaryl or triaralkyl sily] group, such as trimethyl silyl, t-butyl dimethyl silVI, triphenyl silyl or tribenzy] sily].

The compounds of formula (XVI I) may be prepared by the reaction of the compound of formula (XVl 10:

\ 0 0 0 5 IA 9 with a base followed by reaction with a silyiating agent.

(XVIII) The base may be, for example, an alkali metal hydride such as sodium hydride, an alkyl lithium such as n-butyl lithium, or lithium diisopropylamide. The silylating agent may, for example, be a 15 trihydrocarbyl silyl halide, e.g. trihydrocarbyl silyl chloride or a trihydrocarbyl silyl sulphonate, e.g. trihydrocarbyl silyl triflate.

The reaction is preferably effected in an organic solvent such as a hydrocarbon, e.g. benzene, or an ether, e.g. tetra hydrofuran, at a temperature in the range -100 to +501C, advantageously -80 to +200C.

The compounds of formula (V) wherein R' and R' each represents a protecting group may alternatively be prepared by reacting compounds of formula (M), R 3a 0 Z R 2 a,, (XIX) (where R 2a and R 3a represent protecting groups as previously defined in relation to R' and R 3 and Z 25 represents a leaving group) with a compound of formula (XX):

0 R 1 J.) 0 j, H (where R' is as previously defined) or a base salt thereof.

(XX) The reaction may be effected in an organic solvent such as for example a sulphoxide e.g.

dimethyisulphoxide, an amide such as dimethylformamide, an ether e.g. tetrahydrofuran or water. The reaction is generally carried out at a temperature in the range 01 to 1 201C e.g. 301-1 OOOC and in 30 the presence of an organic or inorganic base such as sodium or potassium hydride, carbonate or bicarbonate or triethylamine. The leaving group represented by Z may, for example be a halogen atom e.g. Cl, Br or an acyloxy group such as a hydrocarbyisulphonyloxy group e. g. methanesulphonyloxy or p toluenesulphonyloxy.

Compounds of formula (M) may be prepared by treatment of compounds of formula (XXI): 35 J 1 9 GB 2 129 425 A 9 R 3a, 0 R 2a 0 (m) (where R 21 and R" are as previously defined) with a reagent serving to introduce the desired group Z.

Thus, for example, a halogen atom may be introduced by halide ion displacement or using an oxyhalicle reagent such as thionyl chloride. Alternatively an acyloxy group Z may be introduced by reaction with an appropriate acyl halide such as e.g. tosyl chloride. The reaction may, if desired, be carried out in the 5 presence of a base e.g. pyridine or triethylamine and is conveniently effected in a medium such as water; an alcohol e.g. methanol or ethanol; a halogenated hydrocarbon e.g. chloroform, or carbon tetrachloride; or a substituted amide e.g. N,N-dimethylformamide, or a ketone e.g. acetone.

Temperatures are generally in the range -201C to +701C e.g. OOC to +500C. Alternatively, the base itself maybe the solvent.

Compounds of formula (XXI) may be prepared by deprotecting compounds of formula (XXII):

R 3a 0 OR R 2a (XXII) (where R 21 and R3a are as previously defined and W' represents a protecting group such as those described in relation to R 2 and R 3). It will be appreciated that the group W' should be one which can be selectively removed, for example a trialkylsilyl group such as a dimethyltertiarybutylsilyl group. Such a 15 group may be removed by reaction with tetraalkylammonium halides e.g. tetra-n-butylammonium fluoride or with hydrogen fluoride in aqueous acetonitflie. The reaction may conveniently be carried out in solvents such as ethers, e.g. tetrahydrofuran and at a temperature in the range -500C to +501C e.g.

-201)C to +200C.

Compounds of formula (XXII) may be prepared by the introduction of hydroxyl protecting groups 20

R and R 3@ into a compound of formula (XXIII):

OR (XXIII) (where R" is as previously defined).

Introduction of the hydroxyl protecting groups R" and R" may be carried out according to any appropriate conventional method. Suitable reagents for the introduction of protecting groups include 25 alkyl and aralkyl halides such as methoxmethyl chloride and benzyl bromide. The reaction isoptionally carried out in the presence of a base such as diisopropylethyla mine and in organic solvents such as ethers e.g. tetrahydrofuran, hydrocarbons e.g. benzene, halogenated hydrocarbons e.g. clichloro methane. The reaction may be carried out in the temperature range -500C to +500C e.g. -200C to +200C.

Compounds of formula (XXIII) may be prepared by ozonolysis of compounds of formula (XXIV) =10 OR (XXIV) (where R" is as previously defined) followed by the reduction of the products formed therefrom with an alkali metal borohydricle such as sodium borohydride. The reaction may be carried out in organic solvents such as an alcohol e.g. methanol, halogenated hydrocarbons e.g. dichloromethane; ethers e.9- 35 tetrahydrofuran or mixtures thereof and at a temperature in the range - 70'C to +501C.

Compounds of formula (XXIV) may be prepared from compounds of formula (XXV):

0 i 'F I OR (XXV) (where R" is as previously defined) using a Grignard reagent capable of introducing a vinyl group, for example vinyl magnesium bromide. The reaction may conveniently be carried out in the presence of a 40 catalyst such as cuprous iodide and in an organic solvent such as a halogenated hydrocarbon e.g.

dichloromethane; and ether e.g. tetrahydrofuran or mixtures thereof and at a temperature in the range -700C to +500C.

GB 2 129 425 A 10 Compounds of formula (XXV) may be prepared from the known compound of formula (XXVI):

0 ON (XXVI) by reaction with a reagent serving to introduce the protecting group R".

The reaction may be carried out in the presence of a coupling agent such as an imidazole and in an organic solvent such as an amide for example dimethylformamide and at a temperature in the range 5 -501C to +501C for example -200C to +200C.

According to an alternative embodiment of the invention the compounds of formula (1) may be obtained by reacting compounds of formula (XXVII):

oR, N (XXVII) H (where Rand R' areas previously defined) or abase salt thereof with a compound of formula (XIX) as 10 defined above. The reaction is analogous to that described above to obtain compounds of formula (V) by reaction of compounds of formula (XIX) with compounds of formula (XX). The preferred conditions are as described for that reaction. The reaction is followed, where necessary by removal of any protecting groups as described hereinbefore.

Alternatively the compounds of formula (XIX) may be prepared in situ by treatment of a compound of formula (XXI) with a dialkylazodicarboxylate, e.g. diethylazodicarboxylate, and a tertiary phosphine e.g. trip henyl phosph i ne in a solvent such as tetrahydrofuran or acetonitrile.

Mixtures of isomers may be separated at any convenient stage of the synthesis, for example, either before or after removal of protecting groups. Thus the desired epimer may, where necessary, be separated from the corresponding epimer by conventional means, for example, by fractional crystallisation and/or chromatography. Optically active isomers of the compounds of the invention may be obtained by resolution of the racemic mixtures using conventional means; see for example 'Stereochemistry of Carbon Compounds'by E. L. Eliel (MeGraw Hill, 1962) and'Tables of Resolving Agents'by S. H. Wilen.

The compounds of formula (1) may be converted into their salts with bases according to conventional methods by reaction with an appropriate base.

The compounds of formulae (11), (111), (N), (V1), (V11), (Vill), (K), (X[), (Xli), (X111), (XIV), (XV) (XVI) WIX), (XXI), (XXII), WX111), (XXIA and (XW are novel compounds, useful as intermediates for the preparation of compounds of formula (1), and they, together with processes for their preparation, constitute further features of the invention. Of these novel intermediates, the compounds of formulae 30 (11), (111), OV) and (V1) and (V10 are closely related chemically and all fall within the general formula (A):

R R A 0 B R: \ Y N R 0 where R' and R' are as defined previously and either R A represents a group (A) C0 2 H or /--V C02 R4 /__=7/ - or a group HgX and R' represents a group -CH20RI, orR A represents hydrogen and R' represents a 35 group -CHO or -CH-(R 5 0)2 (in which X, R', R' and R 5 are as previously defined).

The compounds of formulae (V110, OX), (M), (X11) and (X110 are also closely related chemically and all fall within the general formula (B):

(R 5 0)2 CH 41 R c R 2 A (B) 11 GB 2 129 425 A 11 where R 2 and R 5 are as defined previously and R' represents a group of formula R 6 OR 1 -FIN NH 2 -y o r -HN---1 f,' N 0 0 or -CON, or -COR' or -C0211' (in which R', R' and R' are as defined previously).

The intermediates of formulae (XIX), (XXI), M10, Mill), and MIV) are further closely related 5 chemically and may be expressed as having the formula (Q R D &ill R F R E' (C) where either R' represents a hydroxymethyl group and R E represents a hydroxyl group or P' represents a protected hydroxymethyl group and R' represents a protected hydroxyl group or R E represents a hydroxyl group and R D represents an ethenyl group and R' represents a hydroxyi or protected hydroxyl group or a group Z as defined above with the proviso that either R' represents a protected hydroxymethyl group and R E represents a protected hydroxyl group or R' represents a protected hydroxyl group. - The following examples illustrate the invention. Temperatures are in 'C. The nomenclature used is in accordance with the Chemical Abstracts system.

Solutions were dried by use of magnesium sulphate. Flash column chromatography was carried 151 out over silica using the method described by W. E. Still et a]. J. Org. Chem. 1978, 14, 2923.

Intermediate 1 (3a(x,4p,7a(x)-( )-5-[[(1,1 -Di methyl ethyl) d i methyisi lyll -oxy]-3a, 4,7,7atetrahydro-2,2 dimethyl-4,7-methano-1,3-benzodioxole A solution of lithium diisopropylamide was prepared by treating diisopropylamin'e (10.5 9) in dry 20 THF (90 mi), cooled to -151 under nitrogen, with n-butyl lithium (61.2 mi, 1.7M solution in hexane).

After stirring for 10 min at ca -101 to -200, the solution was cooled to 700 and a solution of (3aa,4p,7p,7aa)-( )-tetrahydro-2,2-dimethyi-4,7-methano-1,3-benzodioxol-5(4 H)-one (15.8 g) in dryTHF (40 mi) was added dropwise over 15 min keeping the temperature lower than -650. The solution was stirred at -700 for 0.75h, hexamethylphosphoramide (13 mi) was added, followed by tbutyidimethyisilyl chloride (14.2 9) in dry pentane (11 mi). The mixture was allowed to warm up to room temperature over 2h, poured into pentane (300 mi) and the organic phase washed with water (1 x 100 mi, 1 x40 mO. The solution was dried and concentrated to afford crude title compound as an oil. Kugelrolir distillation gave pure title compound as a yellow oil (21. 6 g).

r (CDC13 5.36 (IH, d, =CH-), 5.54, 5.65 (21-11, AB doublet rn, H-5, H-6), 8.51, 8.61 (6H, 2xs, 30 2xMe).

Intermediate 2 (3aa,4a,6aa)-( )-6-(Dimethoxymethyi)tetrahydro-2,2-dimethyi-4aHcyclopenta-1,3-dioxole-4- carboxylic acid Oxygenated ozone was bubbled through a solution of Intermediate 1 (20.0 g) in dry methanol 35 (190 mi) and dry methylene chloride (60 mi) at -701 until a blue colouration appeared. Dimethyl sulphide (14 ml) was added and the reaction mixture slowly allowed to reach room temperature. The solvents were evaporated and the residue taken up in 2,2-dimethoxypropane (190 mi) and dry methanol (10 mi). After cooling to 00, Dowex 5OW-X8[H-] (9 g) was added and the reaction mixture stirred at 01 for 3 days. The resin was removed byfiltration and the solvents evaporated in vacuo. The 40 residue was purified by flash chromatography, eluting with methanol- methylene chloride Q:97), to give the title compound (10.4 g) as a solid, m.p. 82-83.5 0.

Intermediate 3 (3p,4a)-( )-Methoxyrnethyi-4-(dimethoxymethyi)-3(mothoxymethoxy)-1 -cyclopentene-l - carboxylate A solution of lithium diisopropylamide was prepared by treating diisopropylamine (17.2 9) in dry THF (250 mi), cooled to -201 under nitrogen, with n-buty ' 1 fithium (99 mi, 1.7M solution in hexane). The mixture was cooled to ca. -651 and stirred for a further 0.5h, A solution of Intermediate 2 (10.4 g) in dry THF was added dropwise over 20 min, keeping the temperature -601. The solution was then allowed to slowly warm to room temperature and stirring continued for 1. 5h. Methoxymethyl chloride 50 (18.44 g) was added and the reaction mixture allowed to stir at room temperature for 1 8h. The THF was evaporated in vacuo and the residue was partitioned between diethyl ether (400 mi) and water (50 mi). The organic phase was washed with saturated ammonium chloride solution (30 ml), saturated sodium bicarbonate solution (50 mi) and dried. Removal of the solvent gave the title compound as an oil (11.8 g).

12 GB 2 129 425 A 12 T (CDCI,) 2.25 (1 H, -CH), 4.67 (2H, C02CHOMe), 5.16-5.34 (3H, m, CCH0ChIZOMe), 5.66 (1 bl, d, CH(OMe),), 6.5 0, 6.5 9 (12 H, 4xs, 4xO M e); i,,,,a,, (liq. film) 1720,1640 em-'.

Intermediate 4 (3p.4t,)-( )-Methoxymethyi-3-(dimethoxymethyl)-4(methoxymethoxy)-1-eyclope ntanecarboxylate Intermediate 3 (17.6 g) and 5% palladium on charcoal (5.5 g) in ethanol (300 mi) was stirred under a hydrogen atmosphere for 4 hours and the reaction mixture was then filtered. The catalyst was washed with ethanol (300 mi) and the combined filtrate and washings were evaporated under reduced pressure to give the title compound (16 g) as a mixture of epimers. T (CDCI,) 4.75 (2H, CO, CH20Me), 5.35 (2H, CHOCH20Me), 5.70-6.00 (1 H, m, CCH 0_), 6.55, 6.60 (12H, 4xS, 4xOMe); i,max (CCI,) 1745 em-'.

Intermediate 5 20 (3p,4(y)-( )-3-(Dimethoxymethyi)-4-(methoxymethoxy)-1cyclopentane-carboxylic acid Potassium carbonate (40 g) was added to a solution of Intermediate 4 (16 g) in methanol (100 ml) and water (200 mi) and the reaction mixture was stirred for approximately 16 hours. The solution was washed with methylene chloride (150 mi) and the aqueous phase was acidified with 2N HCI (320 mi) and extracted with methylene chloride (3x300 mi). The organic layer was dried and concentrated to give the title compound (8.2 g) as a mixture of epimers. (CDCI,) 1.0-3. 0 (1 H, br, CO,H) 53-5.4 (2H, m, MeoC2), 5.87, 5.96 (1 H, m, c CH-0), 6.65 (9H, 3s, 3xOMe) 7.00, 7.18 (1 H, m, CH2CO2H).

Intermediate 6 (3p,4cy)-( )N-[[[3-(Dimethoxymethyi)-4(methoxymethoxy)cyclopentyi]aminolca rbonyll-3- ethoxy-2-propenamide To Intermediate 5 (2.8 g) and triethylamine (1.7 mi) in dry benzene (50 mi) under a nitrogen atmosphere was added diphenylphosphoryl azide (3.1 g) and the resulting solution refluxed for 1.25 hours. Ammonia gas was then bubbled through the solution at 50 to 101 for 40 minutes. The solvent was completely removed, the residue taken up in chloroform (50 mi) and pyridine (2.25 mi) was added.

The solution was cooled (ice bath), P-ethoxyacryloyi chloride (2.25 mO added, and the mixture stirred at room temperature. After 48 hours, more acid chloride (2.25 mi) was added and stirring continued for a further 12 hours. Water (30 mi) was added, the aqueous layer was extracted with chloroform (30 mi) 40 and the combined organic layers washed with 5% aqueous potassium hydrogen sulphate (30 mi, 15 mi) and aqueous sodium bicarbonate (50 mi) and dried. Evaporation of the solvent afforded an oil, which was purified by flash column chromatography eluting with 5% methanol/m ethylene chloride to give the title compound (2.23 g) as a mixture of epimers.

T (CDCI,) 2.37 (1 H, d, -CH=CHOEt), 5.31 (1 H, d, -CH=CHOEt), t,max (CC], ), 1680,1620, 45 1545 em.

Analysis found: C, 53.47; H, 7.83; N, 7.66% C16H28N207 requires: C, 53.32; H, 7.83; N, 7.77%.

Intermediate 7 ( )-1-[(3j.)',4ci)-3-(Dimethoxymethyi)-4-(methoxymethoxy)cYciOPentyll-2,4 (1 H, 3H) pyrimidinedione Intermediate 6 (2.23 g) was refluxed in 0.88 aq. ammonia (150 mi) for 2 hours and the solvent removed below 401 under reduced pressure. The residue was partitioned between methylene chloride (50 mi) and saturated aqueous sodium bicarbonate (30 mi). The aqueous layer was extracted with methylene chloride (2x25 mi), the combined organic layers dried and the solvent removed by 55 z 4 1; 13 GB 2 129 425 A 13 evaporation under reduced pressure to yield the title compound (1.57 9) as a mixture of epimers. A small portion of the product was purified by flash column chromatography eluting with 5% methanol/methylene chlorode.

-c (D20) 2.40, 2.67 (1 H, cl, H-6) 4.25, 4.26 (1 H, cl, H-5), 4.85 (1 H, m, HA').

Intermediate 8 - ( )-1 -[(3p,4a)-3-(Hydroxymethyi)-4-(methoxymethoxy)cyclopentyl]-2,4 (1 H, 3H) pyrimidinedione Intermediate 7 (2.05 g) was heated in 80% aq. acetic acid (50 mi) for 15 minutes at 80-850. The solution was diluted with benzene (200 mi) and the benzene removed at room temperature under reduced pressure. Toluene (200 mi, 100 mi) was twice added and removed at 25-301 under reduced 10 pressure. The residue was dissolved in dry methanol (25 mi) and ethanol (5 mi), and sodium borohydride (380 mg) added at 01. The mixture was stirred for fifteen minutes at room temperature, acetone (1 mi) added, and the solvent removed under reduced pressure. The residue was dissolved in dry methanol (20 mi) and trifluoroacetic acid (ca. 0.6 ml) added to acidify the solution (pH 2). Removal of the solvent under reduced pressure and purification of the product by flash column chromatography 15 eluting with 10% methanol/methylene chloride gave the title compound (1.3 g) as a mixture of epimers.

T (CDC'3) 2.43, 2.7 (1 H, cl, H-6), 4.25, 4.26 (1 H, d, H-5), 4.75 (1 H, m, H-1% Intermediate 9 ( )-1-[(3p,4a)-3-Hydroxy-4-(hydroxymethyi)cyclopentyll-2,4(1H,3H)pyrimidined ione A solution of Intermediate 8 (1.3 g) in methanol (30 mi) containing conc. Hydrochloric acid (0.5 ml) was refluxed for 25 minutes. The solution was neutralised with 2N sodium hydroxide followed by saturated aqueous sodium bicarbonate and the solvent removed below 400 under reduced pressure. Ethanol (30 mO was twice added and removed. The residue was taken up in ethanol (3x20 mi), filtered and concentrated. Flash column chromatography eluting with 20% methanol/methylene chloride gave 25 the title compound (700 mg) as a mixture of epimers.

c (D,O) 2.14, 2.27 (1 H, d, H-6), 4.10, 4.13 (1 H, cl, H-5), 5.00, 5.10 (1 H, m, H-1% Intermediate 10 ( )-Chloro-[1,2,3,4-tetrahydro-1 -[(30,4a)-3-hydroxy-4- (hydroxymethyl)cyclopentyll-2,4-dioxo5-pyrimidinyll-mercury To Intermediate 9 (400 mg) in water (1.5 ml) was added mercuric acetate (595 mg) in water (4.5 ml) and the solution stirred at 500 for 4h. Sodium chloride (256 mg) in water (1 ml) was added at 40' and the reaction mixture cooled (ice bath). Filtration of the solid, followed by drying at 601 in vacuo, afforded the title compound as a white solid which was used directly in the next stage.

Intermediate 11 ( )-(E)-Ethyi-3-[1,2,3,4-tetrahydro-1 -[(3p,4a)-3-hydroxy4-(hydroxymethyi)cyclopentyll-2,4dioxo-5-pyrimidinyll-2-propenoate Intermediate 10 (390 mg), ethyl acrylate (0.75 ml) and dilithium palladium tetrachloriode (0.1 M solution in methanol, 8.7 mi) were stirred for 1 6h under nitrogen. The reaction mixture was filtered, the precipitate washed with warm methanol (20 mi), and hydrogen sulphide gas bubbled through the combined methanol filtrate and washings to precipitate mercuric sulphide. The resulting mixture was filtered through Hyflo and the solvent removed in vacuo. Water (5 mi) was added, and then removed in vacuo at 30'. The residue was purified by flash bliromatography eluting with chloroform-ethanol (6:1) to give the title compound (195 mg).

(['H,,] DMSO) (Mixture of epimers) 1.56,130 (1 H, s, H-6), 2.54,2.61 (1 H, cl, CH=CHC02Et), 45 3.08, 3.14 (1 H, cl, =CHC02Et).

Intermediate 12 ( )-(E)-3-[1,2,3,4-Tetrahydro-l-[(3p,4a)-3-hydroxy-4(hydroxymethyi)cyclopen ty11-2,4-dioxo-5pyrimidinyll-2-propenoic acid Intermediate 11 (180 mg) in 0.5N aqueous sodium hydroxide (2.5 mi) was stirred at room 50 temperature for 4h. Dowex 50G-X8 cation exchange resin was added until the solution had pH4. The resin was filtered off and the filtrate evaporated in vacuo at 30-351) to give the title compound as an off-white solid (131 mg).

r (['Hj DMSO) (Mixture of epimers) 1.70,1.86 (1 H, s, H-6),2.80, 286 (1 H, d, CH=CHC021-1), 3.23, 3.34 (1 H, cl, =CHC02H). 55 Intermediate 13 (1 -Di methylethyl)d i methyl si ly 11 oxy]-6-oxa bicyclo [3, 1 01 hexa ne A solution of (1 cv,3p,5a)-( )-3-hydroxy-6-oxabicyclo[3,1,Olhexane (2.5 9) in dry DMF (25 mi) was treated with imidazole (3.40 g), the solution cooled to 01 under N, and t-butyidimethyisilyl chloride 14 GB 2 129 425 A 14 (4.15 g) added. The solution was stirred at 00 for 10 minutes, allowed to warm up to room temperature and stirring continued for a further 18 hours. The mixture was poured into water (150 mi) and extracted with pentane (2 x 150 mi). The organic phase was washed with water (2x 150 mi), dried and concentrated to afford the crude product as a colourless oil. The latter was purified by flash chromatography, elution with 7% ROAp/hexane affording the title compound as a colourless mobile oil 5 (3.9 g).

(CDCI,) 5.56 (1 H, ABX, CHOSi), 0 6.52 (2H, s,CH - CH), 7.86-8.08 (4H,ABX, CHO, 9.1 (9 H, s, C Me), 9.96 (61-1, s, Me).

Intermediate 14 (1 a,2p,4a),-( )-4-[[(1,1Dimethylethyl)dimethyisilylloxy]-2-ethenylcyclopentano I A stirred suspension of cuprous iodide (190 mg) in dry THF (10 mi) at -300 under N2 was treated dropwise with a solution of vinyimagnesium bromide (1M inTHF, 10 mi) causing a greyish coloured 15 suspension to form. The latter was stirred at -300 for 15 minutes and then a solution of Intermediate 13 (1.50 g) in dry THF (5 mi) added dropwise. The resulting dark coloured solution was stirred at -301 for 15 minutes, the mixture allowed to slowly warm to 01 (ca. 0.5h) and then stirred for a further 2 hours. The reaction was quenched by pouring into saturated NH4C1 solution (100 mi) and extracted %0 with ether (2x 100 mi). The combined organic extracts were washed with further saturated NI-14C1 solution (100 mi), dried and concentrated to afford the crude product as a pale yellow oil. The latter was purified by flash chromatography, elution with 8% ROAp/hexane yielding the title compound as a colourless oil (1.25 g).

Analysis found: C, 64.54; H, 11.07% C,^602Si requires: C, 64.40; H, 10.81%.

Intermediate 15 (la,2p,4p)-( )-[[(1,1-Dimethylethyi)dimethyisilylloxy]-2hydroxylcyclopentan emethanoI Oxygenated ozone was bubbled through a solution of Intermediate 14 (6.68 g) in dry methanol (100 mi) and dichloromethane (50 mi) cooled to -701 until a deep blue colouration appeared. Sodium borohydride (1.05 g) was then quickly added in one portion and stirring at -701 continued for 30 minutes. Further sodium borohydride (1.05 g) was then added, the mixture allowed to slowly warm to room temperature (ca. 1 hr) and then stirred for a further 30 minutes. The solvents were evaporated and the residue partitioned between dichloromethane (250 m]) and saturated ammonium chloride solution (250 mi). The aqueous layer was further extracted with dichloromethane (1 x250 mi), the combined organics dried and concentrated to afford the crude product as an opaque viscous oil. The 35 latter was purified by flash chromatography, elution with 5% Me0H/CHCl, yielding the title compound as a. viscous colourless oil (5.34 g).

Analysis found: C, 52.94; H, 10.89% C1,1-1,,0,Si. 0.1 H,0 requires: C, 58.06; H, 10.64%.

Intermediate 16 (1 1 -Di methylethyOdi methyl [[4-(methoxymethoxy)-3 [(methoxym ethoxy) methyll] cycl opentyll oxylsi lane To a solution of Intermediate 15 (5.0 g), and N,N-diisopropylethylarnine (7.87 g, 10.6 mi) in dry dichloromethane (100 mi), cooled to 0' under nitrogen, was added ch loromethy 1 methyl ether (90%:

5.44 g, 5.19 mi), dropwise over 10 minutes. The mixture was stirred at 0' for 5 minutes, allowed to 45 warm up to room temperature and stirring continued overnight. The solution was washed with water (100 mi), the aqueous layer extracted with further dichloromethane (1 x50 mi) and the combined organic layers dried. Concentration afforded the crude product as an orange oil which was purified by flash chromatography, elution with 10% EtOAc/hexane yielding the title compound as a colourless mobile oil (5.1 g).

Analysis found: C, 57.51; H, 10.75% C1,1-1,,0,Si requires: C, 5 7.44; H, 10.55%.

Intermediate 17 (1 (Y,3a,4p)-( )-3-(Methoxymethoxy)-4-[(methoxym ethoxy) m ethyl] cyclope nta nol A solution of Intermediate 16 (5.0 g) in THF (150 mi), stirred and cooled to 00, was treated with 55 Z 1 i Z GB 2 129 425 A 15 tetra-n-butylammonium fluoride (1 M in THF, 16 mi). The solution was allowed to warm up to room temperature and stirred for a further 4 hours. The mixture was concentrated to ca. 30 mi and subjected to flash chromatography. Elution with EtOAc/hexane (M) afforded the title compoundas a pale yellow oil (3.2 g).

(CDC13) 5.24-5.4 (41-1, 2,,AB, OCH20)15.67 (1 H, m, CHOCH2),5.9 (1 H, m, CHOH), 6.4-6.7 5 (81-1, m+2s, 0Me, C1-1,0), 7.45 (1 H, m, CHCH20) 7.6 (1 H, cl, OH), 7.9-8. 4 (41-1, m, 2xCH2) Intermediate 18 (1 a, 3a.4p)-( )-3-(Methoxymethoxy-4- Urnethoxymethoxy) m ethyl] cyclopentanol, 4 methylbenzenesulphonate A mixture of Intermediate 17 (1 g), paratoluenesulphonyl chloride (0.96 g) and dry pyridine (20 10 mi) was stirred at room temperature overnight. The pyridine was removed in vacuo at 351, the residue taken up in dichloromethane (50 mi) and the solution washedwith copper (11) sulphate solution (3x50 mi). The organic phase was dried and concentrated to afford the crude product as a yellow oil. The latter was purified by flash chromatography. Elution with ROAc/hexane (1, 1) afforded the title compound as a colourless oil (1. 18 g).

Analysis found: C, 54.68; H, 6.57% C17H2607S requires: C, 54.52; H, 6.99%.

Intermediate 19 (1 a,3p,4a)-( )-1 -[3-(Methoxym ethoxy)-4[(methoxymethoxy) methyl] cyclopentyll -2,4-0 1-11,31-11)20 pyrimidinedione A mixture of Intermediate 18 (374 mg), finely ground anhydrous potassium carbonate (414 mg) and uracil (336 mg) in dry DMSO (5 mi) was stirred under nitrogen at 901 for 15 hours. The resulting dark coloured solution was poured into brine (ca. 50 mi) and the mixture extracted with dichloro methane (3x30 mi). The organic phase was washed with brine (1 x50 m]), dried and concentrated to afford the crude product as a yellow oil. The latter was purified by flash chromatography. Elution with 25 5-8% Me0H/CH2C12 afforded the title compound as a pale yellow oil (138 rng).

T(CDCI,)1.13(1H,brs,NH),2.68(1H,d,N-CH=CH),4.25(1H,d,N-CH=CH),4.88(1H, quin., H-1 1), 5.35 (41-1, s, OCH,O), 5.88 (1 H, dt, CH-O-CH2 53-5.46 (2H, m, C1-1,0), 6.62 (61-1, s, 0Me).

Intermediate 20 a,3p,4a)-( )-1 -[3-Hydroxy-4-(hydroxymethyi)cyclopentyll-2,4-(1 H,3H)- pyrimidinedione A mixture of Intermediate 19 and p-toluenesulphonic acid (1.40 9) in methanol (100 mi), was heated under gentle reflux on a steam bath for 1 hour. The solution was cooled, stirred and treated with R8050 polyvinyl pyridine resin (Reilly Corporation) until pH6 was attained (ca. 2 g resin). Filtration and concentration yielded the crude product as a pale yellow oil. The latter was purified by flash chromatography. Elution with 15% Me0H/CH2C12 afforded the title compound as a white crystalline powder (1.1 g) m.p. 159-1621.

Example 1 ( )-(E)-5-(2-Bromoethenyi)-1 -[0 a,3p,4a)-3-hydroxy-4-(hydroxymethyi)- cyclopentyi]-2,4- (1 H,3H)-pyrimidinedione Intermediate 12 (110 mg) and potassium acetate (77 mg) in water (5 mi) were heated to 60'. N bromosuccinimide (69.5 mg) was added in small portions over 5 min and the clear solution stirred at 600 for 10 min and then at room temperature for 2h. The solvent was removed and the residue purified by column chromatography, eluting with chloroformethanol (M), to give the title compound (10 mg).

(CD,OD) 2.24 (1 H, s, H-6), 2.66 (1 H, d, CH=CHBr), 3.19 (1 H, d, CH=CH13r, 4.93 (1 H, m, H-1% 5.81 (1 H, m, 1-1-3% 6.2-6.4 (2H, m, H-W, 511).

Example 2 ( )-(E)-5-(2-Bromoethenyi)-1 -[(1 a,3p,4a)-3-hydroxy-4-(hydroxymethyi)- cyclopentyll-2,4(1H,3H)-pyrimidinedione A mixture of Intermediate 18 (374 mg), (E)-5-(2-bromovinyi)uracil (326 mg) and finely ground anhydrous potassium carbonate (207 mg) was stirred in dry DMSO (5 mi) at 900 under nitrogen for 4h.

The dark coloured mixure was poured into water (50 mi) and extracted with dichloromethane (3x25 mi). The combined organic phases were washed with brine (50 ml), dried and concentrated to afford a yellow oil. The latter was purified by flash chromatography eluting with 2% methanol/ dichloromethane to give crude ( )-(E)-5-(2-bromoethenyl)-1 -[(1 a,3p,4a)3-methoxymethoxy-4 [(methoxymethoxy)methyilcyclopentyll-2,4-(1 H,3H)-pyrimidinedione (42 mg) which was taken up in methanol (5 mi), para-toluenesulphonic acid (50 mg) was added and the solution refluxed for 1 h. The 16 GB 2 129 425 A 16 mixture was neutralised by the addition of R8050 polyvinyl pyridine resin (Reffly Corporation) and subsequently evaporated onto flash silica (ca 1 g). The latter was applied to a flash chromatography column eluting with 10% methanol/dichloromethane to yield the title compound (11 mg). m.p. 1791839d).

Examples of pharmaceutical formulations Example A Oral Capsule Product of Example 1 or 2 Sodium starch glycollate (Explotab) Microcrystal line cellulose (Avicel PH) Magnesium stearate Capsule fill weight Per capsule 125.00 mg 12.5 mg 110.0 mg 2.5 mg 250.0 mg Make a pre-blend of the magnesium stearate, sodium starch glycollate and a portion of the active compound and pass through a 250 pm screen. Then blend with the microcrystalline cellulose and the remaining active compound. Fill the blend into two-piece hard gelatin capsule shells to a target fill weight of 2 50 mg per capsule.

Topical cream Example B

Product of Example 1 or 2 Chlorocresol Cetosteary] alcohol White soft paraffin Liquid paraffin Cetomacrogol 1000 Disodium hydrogen phosphate Sodium dihydrogen phosphate (dihydrate) Sodium hydroxide or phosphoric acid Distilled water Quantities for 1 kg 209 '1.0 g 72 g 1509 60 g 18 g 2.0 g 1.0 g to pH 7.0 to 1.00 kg Heat 650 mi water and dissolve the chlorocresol and phosphates. Take 100 m] of the solution, dissolve 2.5 g cetomacrogol 1000 and cool. Disperse the milled drug in the solution using a high shear 30 mixer. Melt the cetostearyl alcohol, white soft paraffin, liquid paraffin and the remainder of the cetomacrogol 1000 together and mix with the remainder of the aqueous phase at not more than 650C.

Stir until cool. Add the drug slurry to the aqueous cream base with stirring. Check the pH and adjust to pH 7.0 with a solution of phosphoric acid or sodium hydroxide as appropriate. Make up to volume with water and stir. Fill into lacquered aluminium tubes at a fill weight of 30 g and seal.

Eye ointment 2 j Z Example C

Product of Example 1 or 2 White soft paraffin Liquid paraffin Quantities for 1 kg 309 770 g 200 g Strain the paraffins and sterilise by heating at 1 501C for 1 hour and cool. Disperse the sterile milled drug aseptically in the liquid paraffin. To the molten white soft paraffin add the drug slurry and stir until set. When cool, fill into sterile tin eye ointment tubes at a fill weight of 3.0 9 and seal.

17 GB 2 129 425 A 17

Claims

1. Compounds of general formula (I):

0 HN 0 N HO YGI R (1) no wherein R is a chlorine, bromine or iodine atom and physiologically acceptable salts thereof with bases.

2. E-5-(2-bromoethenyl)- 1 -[(1 a,3p,4a)-3-hydroxy-4(hydroxymethyl)cyciopentyll-2,4-(1 1-1,3 H)- 5 pyrimidinedione.

3. Compounds as claimed in claim 1 or claim 2 in (+) or (-) isomeric form.

4. Compounds as claimed in claim 1 or claim 2 having a 1 R, 3S, 4R configuration in the cyclopentane ring.

5. Compounds as claimed in any preceding claim for use as antiviral agents.

6. Pharmaceutical compositions comprising, as active ingredient, at least one compound as defined in claim 1 in association with a physiologically acceptable carrier or exciplent.

7. A process for the preparation of compounds as defined in claim 1 which comprises:

A. treating a compound of formula (I]): - OR' N 0 N R 3o -CO2H (II) 3 (where W, R' and R, which may be the same or different, represent hydrogen atoms or protecting groups) or a salt thereof with a halogenating agent, or B. reacting a compound of formula (XW 0:

OR 1 105r N 1 0 1-- N ' H (XXVI I) (where R is as defined in claim 1 and R' is as defined above) or salt thereof with a compound of formula 20 WX), R 3a 0 z R 2 a():Z (XIX) (where R 2a and R", which may be the same or different, represent protecting groups and Z represents a leaving group), followed where necessary by removal of any protecting groups and/or by conversion of 25 a compound of formula (1) into a physiologically acceptable salt thereof with abase.

8. A process as claimed in claim 7A wherein the compound of formula (11) is obtained by reaction of a compound of formula (V) 18 GB 2 129 425 A 18 OR 1 N -)l 1 0 N R 3 0""yj R20 (V) (where R1, R 2 and R 3 are as defined in claim 7) with a mercury salt HgX, (where X is an anion) to give a compound of formula OV):

OR' N Hgx R30 (IV) R20 1 (where W, R' and R' areas defined in claim 7 and X isas defined above) which compound is reacted 5 with an ester of acrylic acid of formula:

CH2=CHCO,R 4 (where R' represents a carboxyl protecting group) to form a compound of formula (H0:

ORI CO? R4.

N N R3 0 RZ 0 (III) (where W, R' and R' are as defined in claim 7 and R 4 is as defined above) which compound of formula 10 (111) is subjected to deprotection to yield the compound of formula (11).

9. Compounds of formula W:

N R A j, 1 0 R B N R 2 0 where R' and R' are as defined in claim 7 and either RA represents a group (A) Col R or,=:y C02 R 4 19 GB 2 129 425 A 19 or a group HqX (in which X and R' are as defined in claim 8) and R' represents a group -CH,OR3 (in which R' is as defined in claim 7) or R A represents hydrogen and R' represents a group -CHO or -CH(R 5 0)2 (in which R' represents a substituent derived from an alcohol or diol RIOH).

10. Compounds of formula (B) (R 5 0)2CH 41 RC R 2 'Z (B) where R 2 is as defined in claim 7, R5 is as defined in claim 9 and Rc represents a group of formula R 6 OR 1 -HN NH or 2 -HN,IrN 0 0 or -CON, or -CORI or _C02RI (in which R' is as defined in claim 7, R' represents a leaving group, R 8 represents a hydroxyl group or a 10 readily displaceable atom or group and R represents a protecting group).

11. Compounds of formula (C) R D '410 il)l R F R EZ (C) where either R' represents a hydroxymethyl group and R E represents a hydroxyl group or R' represents a protected hydroxymethyl group and R' represents a protected hydroxyl group or R E represents a hydroxyl group and R' represents an ethenyl group and R' represents a hydroxyl or protected hydroxyl 15 group or a group Z as defined in claim 7 with the proviso that either R represents a protected hydroxymethyl group and R E represents a protected hydroxyl group or R' represents a protected hydroxyl group.

12. Compounds of formula (XIV):

W C02 R r I RO (XIV) where R' is as defined in claim 7, R 5 is as defined in claim 9 and R' is as defined in claim 10.

13. Compounds of formula e( '04G COZH 0 ""::O where R' represents a group CHO or a group (R10),CH- in which R' is as defined in claim 9.

14. Compounds as claimed in any one of claims 9, 10, 11, 12 and 13 as herein specifically 25 disclosed in any one of the Examples.

15. A process for preparation of compounds as claimed in claim 1 substantially as herein described.

16. A process preparation of compounds as claimed in claim 1 substantially as herein described with reference to the Examples.

17. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 7, 8, 15 and 16.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.