GB2135992A - Substituted pyrimidines and processes for their preparation - Google Patents

Abstract

5-Trifluoromethyl pyrimidines of the formula:- <IMAGE> [wherein A represents the group -CO-NR<3>- or <IMAGE> (wherein R<3> represents a hydrogen atom, a glycosyl group or an optionally substituted C1-4 saturated or unsaturated, straight or branched chain, aliphatic hydrocarbyl group; n is 0, 1 or 2 and R<4> represents a C1-32 saturated or unsaturated, straight or branched, cyclic or acyclic aliphatic group or an araliphatic or heterocyclic substituted aliphatic group, a heterocyclic group or an aryl group which groups may if desired carry one or more substituents)] and where an acidic or basic group is present, the salts thereof; are of interest either in combating abnormal cell proliferation or as intermediates in the preparation of such compounds. The compounds of formula I may be prepared in good yield from the known compound 2-chloro-5- trifluoromethyl pyrimidine or an analogue thereof.

Description

SPECIFICATION Substituted pyrimidines and processes for their preparation The present invention relates to certain 1- or 2-substituted-5-trifluoromethyl pyrimidines and to processes for their preparation.

The 1- or 2-substituted-5-trifluoromethyl pyrimidines of the present invention are of interest either in combating cell proliferation or as intermediates in the preparation of such compounds. The compounds of the present invention have hitherto proved difficult to prepare by introduction of a trifluoromethyl group into a corresponding pyrimidine unsubstituted at the 5-position, whilst direct ring closure methods are generally rather inefficient. The present invention is thus based, at least in part, on the discovery that the 1- or 2su bstituted-5-trifluoromethyl pyri m idines of the present invention may be prepared good yield from a known compound 2-chloro5-trifluoromethyl pyrimidine or an analogue thereof as hereinafter described.

The present invention relates to 5-trifluoromethyl-pyrimidines of the formula:

[wherein A represents the group -CO-NR3or

(wherein R3 represents a hydrogen atom, a glycosyl group or a C14 saturated or unsaturated, straight or branched chain, aliphatic hydrocarbyl group optionally substituted by one or more substituents selected from halogen atoms, oxo groups and optionally substituted hydroxyl, mercapto, carboxyl, carboxamido, amino, carbocyclic aryl and heterocyclic groups, such heterocyclic groups being Cattached 3-9 membered, saturated, unsaturated or aromatic heterocyclic rings containing one or more hetero atoms selected from 0, N and S and optionally carrying a fused ring and/or optionally substituted by one or more substituents selected from halogen atoms and hydroxy, C14 alkoxy, amino, acylamino, nitro, oxo, C14 alkyl groups and monocyclic carbocyclic and heterocyclic aryl groups having 5-8 ring members; such a heterocyclic ring being saturated and having only a single heteroatom when there are 3 or 4 ring members; n is 0, 1 or 2 and R4 represents a C1 32 saturated or unsaturated, straight or branched, cyclic or acyclic aliphatic group or an araliphatic or heterocyclic substituted aliphatic group, a heterocyclic group or an aryl group which groups may if desired carry one or more substituents selected from halogen atoms and oxo, nitro, hydroxy, etherified hydroxy, esterified hydroxy, primary, secondary or tertiary amino, acylamino, etherified mercapto or -SO or -SO2 derivatives thereof and esterified phosphonic acid groups)] and where an acidic or basic group is present, the salts thereof; as well as to processes for their preparation.

Analogues of the pyrimidines of formula I having a halogen atom in the 5-position of the pyrimidine ring have been described in our British Patent No. 1,561,290 and in our European Patent Applications Nos.

81300031.2 and 81300098.1 and preferred definintions of R3 and R4 in formula I above are given in detail in relation to R3, -alk-Het and R3 in our above-mentioned British Patent and European Patent Applications Nos.

81300031.2 and 81300098.1 respectively.

Where R3 represents a glycosyl group such groups may include 5- and 6- carbon sugar derivatives, in particular glucofuranone derivatives. Such glycosyl groups are linked to the nitrogen atom at the 1-position of the glycosyl ring. The hydroxyl groups of the glycosyl group may, if desired, be protected e.g. by acylation for example as an acetoxy group or by acetonide formation, or may be replaced by an amino group which itself may be protected e.g. by acylation for example as an acetamido group. R3 may also, for example, represent an alkyl or alkylene group having 1 to 3, e.g. one, carbon atom optionally substituted as detailed above e.g. by phenyl.

In relation to the definition of R3 it will be appreciated that R3 may represent a C14 saturated or unsaturated straight or branched chain aliphatic hydrocarbyl group substituted by at least one optionally substituted amino group. The term "optionally substituted amino" as used herein includes primary, secondary and tertiary amino groups. The nitrogen atom of the amino group may therefore carry one or more C14 alkyl, or C610 aryl groups as in the methylamino, dimethylamino, or methylphenylamino group. Carbocyclic aryl substituents are conveniently phenyl groups. Acylamino groups, e.g. alkanoylamino, conveniently contain 1 to 4 carbon atoms, as in the acetylamino group.

In particular the term "optionally substituted amino" includes the grouping -ZRR4 defined in claim 1 of European Patent Application No. 82300106.0 (publication No.

0056319) and certain definitions of "optionally substituted amino" as used herein are exemplified by the preferred definitions of Z, R and R4 in this European Patent Application.

When an oxo group is situated on a carbon atom of a C14 alkyl group and that carbon atom carries an optionally substituted amino group (as herein defined) a corresponding optionally substituted amido group will be present. Thus for example R3 may represent a C14 hydrocarbyl (e.g. C14 alkyl especially methylene) group carrying such an optionally substituted amido group e.g. methylamido, methylphenylamido or dimethylamido group.

In relation to the definition of R3, heterocyclic groups may for example be unsaturated or aromatic heterocyclic rings optionally carrying a fused ring and/or optionally substituted. In general, such heterocyclic groups will have 4 or more ring members, advantageously not more than 7 ring members. Heterocyclic rings having 5 or 6 members are particularly preferred, 5-membered rings being especially suitable. In general, the heterocyclic group is preferably aromatic. Where the heterocyclic ring has another ring fused to it this may, for example, be a carbocyclic ring e.g. phenyl. In general, the heterocyclic ring preferably contains not more than two heteroatoms.

Where R3 represents a group which includes as a substituent a substituted hydroxyl, mercapto, carboxyl, carboxamido or amino moiety, the substituent (or, in the case of amino moieties, substituents) on said moieties may for example be an alkyl, alkenyl or alkynyl radical with 1-4 carbon atoms or a sugar.

Esterified carboxyl moieties may thus for example include ethoxycarbonyl moieties. Sugar residues will, for example, be present as substituents of hydroxyl or amino moieties.

Substituents on substituted hydroxyl, mercapto, SO or SO2 groups may also be C610 carbocyclic aromatic groups or heterocyclic groups containing 5-9 membered unsaturated or aromatic heterocyclic rings as described in European Patent Application No.

82300106.0 (publication No. 0056319).

Thus for example substituted hydroxyl groups may include optionally substituted phenoxy groups, for example halogen (e.g. chlorine) substituted phenoxy groups such as the pchlorophenoxy group.

With regard to compounds of formula I in which A represents the group

n is advantageously 1 or 2, but preferably 2.

In relation to the definition of R4 the term "aliphatic" includes as preferred groupings C1 8, more preferably C, 4, alkyl, alkenyl or alkynyl groups (for example ethyl), which may carry one or more substituents such as halogen, e.g. chlorine or iodine, oxo, amino, hydroxy, heterocyclic, etherified hydroxy, etherified mercapto, esterified hydroxy or mercapto groups. The term "aliphatic" also includes such radicals which comprise C38 cyclo-alkyl or -alkenyl groups which groups may, if desired, carry fused rings.

In relation to the definition of R4 the term "heterocyclic" as used herein preferably relates to groups having 3 to 9, advantageously 5 to 7, ring members and having one or more heteroatoms selected from oxygen, nitrogen or sulfur and optionally carrying a fused ring or carrying one or more hydrocarbon substituents such as aliphatic groups e.g. C14 alkyl groups, aromatic rings such as phenyl groups or further heterocyclic rings. The ring systems may be saturated or unsaturated, e.g.

aromatic. Examples of such groups include thienyl, furyl, 2,4-dihydro-1 H- 1 ,4-diazepinyl, epoxy, azetidinone, perhydroazocinyl and pyri midinyl groups optionally substituted by halogen e.g. chlorine. The term extends inter alia to saccharide residues, i.e. glycosyl groups, for example, furanosyl and pyranosyl derivatives e.g. glucofuranosyl or glucopyranosyl derivatives, including deoxy derivatives thereof the hydroxy groups of which may, if desired, be esterified, as in the 2,3,4,6-tetra O-acetylglucopyranosyl or 2,3,5-tri-0-benzoyl ss-D-ribofuranosyl group.

The term "aryl" as used herein relates, for example, to aromatic ring systems with up to 10 carbon atoms e.g. phenyl or naphthyl optionally substituted as indicated above, such as a phenyl or p-chlorophenyl group.

The term "aryl", it will be understood, also includes within its scope aromatic ring systems substituted by an aliphatic grouping such as an alkyl group e.g. with 1 to 4 carbon atoms e.g. a ptolyl group, or another aromatic ring such as phenyl, as in the diphenyl group.

The term "araliphatic" as used herein relates, for example, to aralkyl groups with up to 4 carbon atoms in the aliphatic portion, optionally substituted in the aryl ring as indicated above. The aliphatic portion may be unsaturated and may carry one or more substituents e.g. an oxo group.

Examples of such araliphatic groups thus include benzyl, phenethyl, trityl, styryl and phenacyl groups.

It will be appreciated that when an oxo group is situated on a carbon atom carrying an amino, mono- or di-alkylamino, hydroxy or etherified hydroxy group, then a carbonyl function such as a carbamoyl mono- or di al kylcarbamoyl, ureido, carboxy or esterified carboxy group will be present. Such carbonyl functions may be substituents on R4 groupings or may be the group R4 itself as in carbamoylthio groupings.

Where R4 carries an esterified hydroxyl or mercapto group, the esterifying group may be derived from an aliphatic, araliphatic, heterocyclic or aromatic carboxylic acid, for example a C25 alkanoic acid such as acetic acid or a C71, aroic acid such as benzoic acid.

Where R4 contains an esterified carboxyl substituent, or is itself such a substituent (namely a C1 alkyl group carrying both an oxo group and an etherified hydroxyl group) the esterifying group may be an aliphatic, arali phatic, heterocyclic or aryl group as defined above as, for example, in the 2-thienylmethox ycarbonylmethylthio grouping.

Esterified phosphonic acid groups as substituents in R4 include, for example, di(C1 8 alkyl)phosphonate groups e.g. di(C1 4 alkyl)phosphonate groups such as the diethylphosphonate group.

R4 in the compounds of formula I as hereinbefore defined may also, for example, represent a group or radical which may carry one or more primary, secondary or tertiary amino groups or acylamino, e.g. alkanoylamino groups.

Substituents on secondary and tertiary amino groups may, for example, be C14 alkyl, C610 aralkyl or aryl or heterocyclic groups having 5 to 10 ring members e.g. as defined above, examples being methyl, ethyl, phenyl and tolyl groups.

Compounds of formula I containing solubilising groups are of particular interest. Such compounds include for example, polyhydroxy containing groups such as groups derived - from carbohydrates, amino acids, hydroxy acids and phosphorus containing organic groups e.g. phosphoric acid derivatives, as well as basic heterocyclic rings such as the 2,4-dihydro-1 H-1,4-diazepinyl group.

Certain of the compounds of formula I may exist in salt form. Where acidic groupings are present in the compounds of formula I salts may be formed with alkali metal or alkaline earth metals e.g. sodium, potassium, magnesium or calcium or ammonium (including substituted ammonium) salts. Compounds according to the invention carrying basic, e.g. hydroxy or amino groups also in general, possess enhanced water solubility the latter of course forming acid addition salts e.g. with mineral acids such as hydrochloric acid or sulphuric acid or organic acids such as acetic, tartaric or citric acid. However, in general, non-ionic compounds of the invention are preferred. It will be appreciated that the salts of the compounds of formula I for use in pharmaceutical compositions are the physiologicdally compatible salts.Other salts may however be useful in the preparation of the compounds of formula I and the physiologically compatible salts thereof.

It will be appreciated that certain of the compounds of formula I will exist in geometrically or optically active isomeric forms. The present invention extends to cover all of these isomeric forms.

Compounds of formula I wherein A represents the group -CO-NR3- (wherein R3 is as herein before defined, but is other than hydrogen) and, where an acidic or basic group is present, the salts thereof are 5-trifluoromethyl analogues of the 5-halo derivatives described in our abovementioned British Patent and in our European Patent Application No.

81300031.2 possessing metaphase arresting ability which by virtue of its reversibility is of interest in combating abnormal cell proliferation. The compounds may be employed as described in our European Patent Application No. 81300031.2 and constitute one feature of the present invention.

According to a further feature of the present invention there is a process for the preparation of compounds of the invention as defined above wherein A represents the group -CO-NR3- (in which R3 is as hereinbefore defined, but is other than a hydrogen atom), which process comprises reacting a compound of formula I [wherein A represents the group -CO-NR3- (in which R3 represents a hydrogen atom] or a salt thereof, with an agent or agents serving to introduce the group R3, and, if desired converting a compound of formula I obtained into a salt thereof.

This agent may be of the formula R3Y [wherein R3 is as hereinbefore defined, but is other than a hydrogen atom and Y represents a leaving atom or group e.g. a halogen atom, a hydroxy or mercapto group, a reactive ether or ester derivative or an amino or substituted amino group (as hereinbefore defined)].

A compound of formula R3Y is advantageously used in which Y represents an iodine, bromine or chlorine atom or a hydrocarbonsulphonyl derivative such as a mesylate, brosylate or tosylate.

The reaction between the compound of formula I (wherein A represents the group -CO-NH-) and the compound of formula R3Y is conveniently effected in the presence of a polar solvent such as an alkanol e.g. ethanol or dimethylformamide. The reaction may also conveniently be effected in the presence of a base, e.g. a tertiary organic base such as triethylamine conveniently in the presence of a halogenated hydrocarbon such as dichloromethane or an ether; or in the presence of an inorganic base e.g. an alkali metal hydroxide, such as potassium hydroxide, or an alkali metal carbonate, such as sodium carbonate; or in the presence of a phase transfer catalyst such as benzyltrimethyl-ammonium chloride.

Where a salt of the compound of formula I (wherein A represents the group -CO-NH-) is used, an added base will not normally be required. Such a salt may, for example, be an alkali metal, e.g. sodium or potassium salt.

The group of formula -R3 may also be introduced by a two stage reaction in which the compound of formula I wherein A represents the group -CO-NH- is reacted with an O-silylating agent such as bis(trialkylsilylamine) e.g. a bis(trimethylsilylamine) to form an O-silyl derivative, e.g. a trialkylsilyl ether such as a trimethylsilyl ether; followed by reaction with a compound of the formula R3Y, preferably at an elevated temperature and conveniently in the absence of base. The reaction may also be effected, in the presence of a Lewis acid.

Where the reaction is effected at an elevated temperature the temperature is advanta geously within the range 80 to 160"C e.g.

about 120"C. This two stage reaction involving O-silylation is especially advantageous since this process leads to selective N-alkylation thus substantially avoiding the formation of unwanted O-alkylated products which would otherwise significantly reduce the yield of the compound of formula I.

The reagent serving to introduce the group R3 may, as indicated above, also be an alcohol of the formula R30H or a derivative thereof. It will be appreciated that the effective alkylating agent may be formed by loss of the hydroxyl group. In this case the reaction is carried out in the presence of a condensing agent such as an acetal of a C15 dialkylformamide e.g. dimethylformamide. The alkyl groups of the acetal are preferably neopentyl groups, thus dimethylformamide dineopentylacetal is a preferred condensing agent.

Alternatively, the compound of formula R3Y may be in the form of an acetal of a C15 dialkylformamide carrying at least one acetal group derived from the alcohol R30H.

The agent serving to introduce the group R3- may also be an unsaturated aliphatic compound wherein the unsaturated aliphatic grouping reacts with the ring nitrogen. Such reagents include, for example olefins and acetylenes. In general, it is preferred that the unsaturated bond should be activated.

The compound of formula I (in which A represents the group:- -CO-NH-) which thus possesses the formula:

is also an important intermediate, for example in the preparation of the compounds of formula I in which A represents the group -CO-NR3- (wherein R3 is as hereinbefore defined, but is other than a hydrogen atom) and has not been specifically described in the literature. These compounds thus constitute a further feature of the present invention.

In addition to the above, the present invention is also based on the discovery that 5trifluoromethylpyrimidin-2-one of formula II as hereinbefore defined may be prepared in good yield by hydrolysis of a compound of the formula:

wherein R5 represents a halogen atom or a group S(O),,R4 in which n is 0, 1 or 2 and R4 is as hereinbefore defined) and this hydrolysis process constitutes a further feature of the present invention.

The hydrolysis process may for example be effected by the use of a compound of formula Ill in which R5 represents the group -SO2R4 wherein R4 is as hereinbefore defined. A compound of formula Ill is preferably used however in which n is 2 and R4 represents an alkyl e.g. lower alkyl group (for example with 1 to 6 carbon atoms) such as an ethyl or methyl group.

Analogues of the sulphur containing compounds of formula Ill having a halogen atom in the 5-position of the pyrimidine ring have been described in detail in our European Patent Application No. 81300098.1 (Publication No. 33195) and preferred definitions of the group R4 in formula Ill above are given in detail in relation to the group R3 in formula I in this above-mentioned European Patent Application.

The hydrolysis of the compounds of formula Ill wherein R5 represents the group -SO2R4 (wherein R4 is as hereinbefore defined) is preferably effected by the use of a base such as an alkali metal hydroxide e.g. sodium or potassium hydroxide. The hydrolysis is conveniently effected at a temperature within the range 0 to 30"C e.g. at ambient temperature.

The hydrolysis of compounds of formula III wherein R5 represents a halogen atom, e.g. a chlorine atom, is preferably effected in the presence of an acid e.g. a mineral acid such as hydrochloric acid, preferably concentrated hydrochloric acid. This acid hydrolysis may conveniently be effected at a temperature of from about ambient temperature to about 65"C e.g. 45 to 55"C preferably about 50"C.

We were able to obtain good results by effecting the hydrolysis by the use of concentrated hydrochloric acid at about 50"C for about 40 minutes.

The sulphones of formula Ill are conveniently prepared by a method analogous to that described in our European Patent Application No. 81300098.1 (Publication No. 33195).

Thus for example the sulphones of formula Ill may be prepared by oxidation of the corresponding sulphoxide or sulphide of the formula:

(wherein R4 is as hereinbefore defined and m is O or 1), which processes constitute a further feature of the present invention. The sulphoxide of formula IV is conveniently prepared by oxidation of the corresponding sulphide of formula IV. In general the oxidation may be employed to prepare either the sulphone or the sulphoxide, the reaction condi tions e.g. reaction time, temperature or excess of reagent being altered depending upon the desired product. Thus if it is desired to prepare the sulphone, longer reaction times, higher temperature and/or excess of the oxidising agent may, for example, be used.

The oxidation may be effected by any convenient method including the use of 1) a manganese oxidising agent, for example a permanganate preferably potassium permanganate, conveniently in the presence of an acid e.g. acetic acid; 2) the use of chlorine or a hypochlorite e.g. sodium hypochlorite in an aqueous solution of the sulphide or sulphoxide; or 3) the use of a peroxide or peracid oxidising system such as hydrogen peroxide conveniently in the presence of an acid e.g.

acetic acid advantageously at ambient temperature, or more preferably, imchlornperbenzoic acid conveniently in the presence of a solvent e.g. dichloromethane and advantageously at a temperature from - 30"C to + 30"C conveniently at ambient temperature, or the use of a molybdenum peroxide conveniently in the presence of water and/or hexamethylphosphoramide.

The compound of formula IV (wherein m is O) is conveniently prepared by reaction of a compound of formula:

(wherein Y represents a leaving atom or group) with a thiol of the formula R4SH or a thiolate of the formula [R4S]o Mne Vl (wherein R4 is as hereinbefore defined, M represents the stabilising cation and n represents the charge on the cation) whereby a compound of formula IV in which m is O is obtained; which process constitutes a further feature of the present invention.

The reaction of the compound of formula V with the compound of formula VI is conveniently effected by the use of a compound of formula V in which Y represents a halogen atom e.g. a chlorine or bromine atom. The reaction is a nucleophilic substitution reaction, the nucleophile being in the form R4S- and thus where the compound of formula VI is used in the form of a thiol, the reaction is preferably effected in the presence of a base sufficiently strong to remove the thiol proton to give the aforementioned nucleophile. Preferred bases include alkoxides, for example alkali metal and alkaline earth metal alkoxides such as esodium or potassium alkoxides e.g.

ethoxides. The reaction is conveniently effected at an elevated temperature preferably at the reflux temperature of the reaction mixture. The reaction may for example be effected in the presence of any appropriate solvent such as dimethylformamide or dimethoxyethane.

The compound of formula V has been described by A. Serban et al. (German OLS 2,820,032). Thus the compound of formula V may be prepared by fluorination of the corresponding 5-trichloromethylpyrimidine (e.g. 2chloro-5-trichloromethylpyrimidine) with a mixture of antimony trifluoride and antimony pentachloride. We have found, however that the yield of trifluoromethyl derivative may be increased by use of antimony pentafluoride as the fluorinating agent.

The 2-chloro-5-trichloromethylpyrimidine is prepared by photochlorination of 2-chloro-5methylpyrimidine according to German Offenlegungsschrift 2,820,032, but in order to avoid the use of chlorine gas at elevated temperatures over several hours we have used N-chlorosuccimimide or sulfuryl chloride as the chlorinating agent, sulfuryl chloride being preferred. The 2-chloro-5-methylpyrimidine used as starting material is preferably used in the form of its salt, for example with a mineral acid, e.g. the hydrochloride salt.

The compounds of the formula:

(wherein R4 is as herein before defined and n is 0, 1 or 2) and, where an acidic or basic group is present, the salts thereof are trifluoromethyl analogues of the 5-halo derivatives described in our European Patent Application No. 81300098.1 possessing the ability to inhibit cell proliferation particularly by the inhibition of DNA synthesis. These compounds may thus be of interest for use against proliferating cells in the S-phase and may be employed as described in our above European Patent Application No. 81300098.1. These compounds thus constitute a still further feature of the present invention.

Certain compounds of formula I may exist in salt form. Where acidic groupings are present in the compounds of formula I salts may be formed with alkali metal or alkaline earth metals e.g. sodium, potassium, magnesium or calcium or ammonium (including substituted ammonium) salts. Such salts may be formed in the conventional manner e.g. by reaction with sodium or potassium hydroxide. Compounds of formula I carrying amino groups may form acid addition salts e.g. with mineral acids such as hydrochloric acid or sulphuric acid or organic acids such as acetic, tartaric or citric acid. Salts of the compounds of formula I may be converted to compounds of formula I per se by conventional techniques e.g. ion exchange.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula I (wherein A represents the group -CO-NR3or

in which R3 and R4 are as hereinbefore defined) or, where an acidic or basic group is present, a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compounds of general formula I and their physiologically compatible salts may be incorporated into the conventional preparations in either solid or liquid form.

The compositions may, for example, be presented in a form suitable for rectal, parenteral or topical administration e.g. intramuscular or intravenous administration. Preferred forms include, for example suppositories, creams, ointments and lotions, and suspensions and solutions e.g. for injection or infusion.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for human adults contain from 50 mg to 1.0 g of active ingredient. The dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 0.25 to 7.0 g in a day in human adults.

According to a further feature of the present invention there is provided a method of combating abnormal cell proliferation in a host which comprises administering to said host an effective amount of a compound of formula I or, where an acidic or basic group is present, a physiologically compatible salt thereof.

Where the compound of the invention is to be used as a metaphase arrest agent, it will normally be necessary to determine the cell division cycles, e.g. by cytofluorography or related techniques, of both the normal and abnormal cells and to prepare time schedules which indicate how long after administration of the drug the majority of the abnormal cells will reach a phase which is susceptible to attack by a chosen cytotoxic drug while the majority of normal cells are in a non-susceptible phase. These periods will naturally differ widely. Suitable cytotoxic drugs include cytosine arabinoside and hydroxyurea which are cytotoxic against cells in the S-phase. Since the S-phase is generally longer than the other phases, it is easier to find appropriate time schedules when using cytotoxic drugs in this phase.

Where a compound of the invention is used directly as an antimetabolite, it may be used alone or in conjunction with other cytotoxic drugs, according to accepted practice taking into account cell cycle considerations.

In the following Examples, which are given by way of illustration only, where gas chromatography (GC) was carried out a 3% SP2100 column was used in all cases accept for Preparation 1 (b) where a 3% SP-2250 column was used. The MS data detailed below are reported as MS[70eV; m/z(% rel. int.)].

Preparation 1 2-Chloro-5-trifluoromethyl pyrimidine a) 2-Chioro-5-trichlorometh ylpyrimidine Method A: 2-Chloro-5-methylpyrimidine [See D.J. Brown and P. Waring Aust. J. Chem.

26, 443 (1973)] (1.00 9, 7.8 mmol) in dry tetrachloromethane (125 ml) was treated with dry hydrogen chloride to precipitate the hydrogen chloride salt. NChloro-succinimide (5.21 g, 39.0 mmol) was added and the mixture irradiated with a 250 W high-pressure mercury lamp at reflux temperature for 3 hours before another portion of N-chlorosuccinimide (1.00 g, 7.5 mmol) was added. The mixture was heated for 1 hour, cooled, filtered and evaporated. The crude product was purified on a silica column (chloroform); yield 0.73 g (40%), m.p. 60"C (light petroleum). 1H NMR (CDCl3): 6 9.05 (H-4, H-6). (Found: C 26.32, H 1.06. Calc. for C5H2CI4N2: C 25.90, H 0.87).

Method B: The hydrogen chloride salt of 2chloro-5-methylpyrimidine (7.8 mmol) was prepared as above. Sulfuryl chloride (10 ml.

1 24 mmol) was added and the mixture irradiated with a 250 W high-pressure mercury lamp at reflux temperature for 3 hours before the cooled solution was filtered and evapo rated. The residue was dissolved in ether, filtered and evaporated to give the title com pound; yield 1.1 7 g (65%) more than 90% pure (GLC).

b) 2-Ch Ioro-5-trifluorometh yipyrimidin Antimony pentafluoride (2.0 ml, 28 mmol) was carefully added to 2-chloro-5-trichlorome- thylpyrimidine (3.50 g, 1 5 mmol) at 50"C under N2 and the mixture heated to 150 C over a period of 35 minutes, and then stirred at 150C for 1 5 minutes. The mixture was poured into ice/water (50 ml) and tartaric acid added (30 g in 75 ml of water). The product was extracted into ether (3 x 50 ml), washed with an aqueous solution of tartaric acid (20 9 in 50 ml of water), water (2 x 50 ml) and a saturated solution of sodium bicarbonate (50 ml).The solution was dried (MgSO4) and the ether removed at atmospheric pressure before the residue was distilled under vacuum: yield 1.40 9 (51%), b.p.

76-180 C/45 mmHg [for literature b.p. see German Offenlegungsschrift 2,820,032: 145 C/760 mmHg]. 'H NMR (CDCI3): 8 8.90 (H-4, H-6). MS 184/182(30/100, M).

155(15), 154(10), 147(25), 86(28), 75(26), 69(36). (Found: C 32.78, H 1.11, Calc. for C5H2CIF3N2: C 32.90 H 1.11).

Example 1 2-Eth ylthio-5-trifluorometh ylpyrimidine Potassium tert-butoxide (1 ;00 9, 8.9 mmol) was added to a solution of ethanethiol (0.66 ml, 8.9 mmol) in 1,2-dimethoxyethane (40 ml) at 5 C. The mixture was stirred for 10 minutes before 2-ch loro-5-trifluoromethylpyri- midine [prepared as described in Preparation 1 or in German Offenlegungsschrift 2,820,032] (1.60 9, 8.9 mmol) in 1,2-dimethoxyethane (10 ml) was added dropwise over 3 minutes. The mixture was stirred at room temperature for 2 hours and at 85C for 30 minutes, before water (125 ml) was added and the product extracted into chloroform.

The solution was dried (MgS04), evaporated and the residue distilled under reduced pressure; yield 1.40 9 (76%), b.p.

110-112'C/40 mmHg. 1H NMR (CDCl3): 8 1.41 (Et, J 7 Hz), 3.21 (Et, J 7Hz), 8.65 (H4, H-6). IR (film): 1540 cam~' (pyrimidine).

MS: 208 (100, M), 193 (39), 189 (17), 180 (41), 175(84), 174(25), 148 (34), 136 (16), 121(19), 75 (33).

Example 2 2-Benzylthio-5-trifluoromethylpyrimidine 2-Chloro-5-trifluoromethylpyrimidine [prepared as described in Preparation 1 or in German Offenlegungsschrift 2,820,032 (0.91 g, 5 mmol) in DMF (5 ml) was added to a mixture of benzyl mercaptan (0.59 ml, 5 mmol) and potassium tert-butoxide (0.56 g, 5 mmol) in DMF (15 ml) at 5"C under N2. The mixture was stirred for 10 minutes at 5C and for 1 hour at room temperature before the solvent was distilled off and the residue triturated with water.The product was extracted into ether and washed with water (5 x). The dried solution (MgS04) was evaporated and the residue recrystallized from pentane; yield 1.10 9 (81%), m.p. 65 C. 'H NMR (CDCl3): S 4.40 (CH2), 7.1-7.4 (Ph), 8.64 (H-4, H-6). IR (KBr): 1540 cell (pyrimidine). MS: 270 (30,M), 237 (30), 121(8), 91(100), 65 (18). Found: C 53.49, H 3.53. Calc. for Cl2HgF3N2S C 53.32, H 3.36).

Example 3 2-(2- Then ylthio)-5-trifluorometh ylpyrim idin e Prepared as described in Example 2, but using thenylmercaptan. Yield 60%, m.p.

73C (pentane). 'H NMR (CDCI3): S 4.60 (CH2). 6.7-7.2 (thiophene), 8.60 (H-4, H-6).

IR (KBr): 1600 cm-l. MS: 276 (13, M), 243 (14), 97 (100), 53 (7), 45 (12). (Found: C 4 3.66, H 2.55. Calc. for C,oH7F3N2S2: C H 3.47, 4 2.56).

Example 4 2-Ethylsulfonyl-5-trifluoromethylpyrimidine 90% mChloroperbenzoic acid (2.30 9, 12.1 mmol) in dichloromethane (5 ml) was added to a solution of 2-ethylthio-5-trifluoromethylpyrimidine (1.15 g, 5.5 mmol) in dichloromethane (25 ml). The mixture was stirred for 24 hours at room temperature before washing with aqueous sodium bicarbonate. The organic layer was separated, dried (MgS04) and evaporated. The product was recrystallized from ether/light petroleum; yield 1.00 9 (76%), m.p. 98 C. 'H NMR (CDCl3): 8 1.44 (Et, J7 Hz), 3.61 (Et, J7 Hz), 9.15(H4, H-6). IR KBr: 1320 and 1150 cm-l (sulfone). MS: 241(1, M + 1), 212(1), 176(8), 175(7), 149(9), 148(100), 121(15), 111(3).

(Found: C 23.16, H 2.99. Calc. for C7H7F3N2S02: C 35.00, H 2.94).

Example 5 2-Benzylsulfonyl-5-trifluoromethylpyrimidine prepared as described in Example \4 but using 2-benzylthio-5-trifluoromethylpyrimidine (see Example 2) as starting material. Yield 88%, m.p. 148 C. 'H NMR (CDCI3): 64.78 (CH2), 7.30 (PH), 9.11 (H-4, H-6). IR (KBr):1150 cm-1 (sulfone). MS: 302 (1,M), 238 (26), 237 (13), 91(100), 65(12).

(Found: C 47.76, H 3.30. Cain. for C12H9F3N2O2S: C 47.68, H 3.01).

Example 6 2-(2-Thenylsulfin yl)-5-trifluoromethylpyrimidine 90% m-Chloroperbenzoic acid (0.23 9, 1.2 mmol) was added to a solution of 2-(2-thenylthio)-5-trifluoromethyl-pyrimidine (0.28 g, 1.0 mmol) in dichloromethane (10 ml) at - 10'C.

The mixture was allowed to reach room temperature and was stirred overnight, before dichloromethane (10 ml) was added and the solution washed with aqueous sodium bicarbonate. The dried (MgSO4) solution was evaporated and the product purified on a silica column (chloroform); yield 0.17 9 (58%), m.p. 102C (chloroform/light petro leum). 1H NMR (CDCl3): 8 4.45 and 4.57 (CH2SO, J gem 1 3 Hz), 6.8-7.3 (thiophene), 9.00 (H-4, H-6). IR (KBr): 1050 cm-' (sulfoxide) MS: 196 (1), 148 (1), 147 (1), 99 (3), 97 (100), 69 (3), 53 (8). (Found: C 41.02, H 2.43. Calc. for C,oH7F3N20S2: C 41.09, H 2.42).

Example 7 2-(2-Then ylsulfon yl)-5-trifluorometh ylp yrim i- dine 90% m-Chloroperbenzoic acid (0.43 9, 2.2 mmol) was added to a solution of 2-(2-thenylthio)-5-trifluoromethylpyrimidine (0.28 9, 1.0 mmol) in dichloromethane (15 ml). The mixture was stirred at room temperature for 2 days before dichloromethane (10 ml) was added and the solution washed with aqueous sodium bicarbonate. The dried (MgSO4) solution was evaporated and the product purified on a silica column (chloroform); yield 0.13 g (42%), m.p. 134 C. 'H NMR (CDCl3): 8 5.08 (CH2), 6.9-7.4 (thiophene), 9.2 (H-4, H-6). IR (KBr): 1160 cm-' (sulfone). Ms: 308 (0.2 M), 275 (1), 244 (4), 243 (2), 199 (1), 97 (100), 53 (10). (Found: C 39.15, H 2.14.

Calc. for C10H7F3N2O2S2: C 38.95, H 2.29).

Example 8 5-Trifluoromethylpyrimidin-2-one Method A: 2-Chloro-5-trifluoromethylpyri mi- dine (1.25 9, 6.8 mmol) in conc. hydrogen chloride (5 ml was stirred at 50C for 40 min before the mixture was cooled and the pH adjusted to ca. 2. The solvent removed and the residue dried, extracted with boiling ethyl acetate (3 X 50 ml) and evaporated to give the title compound; yield 0.92 g (83%). The product can be purified by sublimation (110-120"0/0.01 mmHg) or by recrystallization from ethyl acetate. M.p. 200"C (de comp.). 1H NMR (acetone-d6: S 8.50 (H-4, H6), iR (KBr): 1720, 1670 and 1650cm-1 (lactam).MS 164(100, M), 145 (16), 136 (80), 117(15), 116(11), 90 (19), 89 (23), 75 (20), 69 (18), 68 (11). (Found: C 36.68, H 2.10. Calc. for C5H3N2F3O: C 36.59, H 1.85).

Method B: 2-Ethylsulfonyl-5-trifluoromethylpyrimidine (0.27 g, 1.1 mmol) in 1M sodium hydroxide (5ml) was stirred at room temperature for 10 minutes. The mixture was acidified (pH 2) and filtered. The filtrate was evaporated, dried and extracted with boiling ethyl acetate. The solvent was distilled off to give 5-trifluoromethylpyrimdin-2-one. Yield 0.12 g (67%).

Example 9 I -Propargyl-5-trifluoromethylpyrimidin-2-one Potassium tert-butoxide (0.11 g, 1.0 mmol) was added to a solution of 5-trifluoromethylpyrimidin-2-one (0.16 g, 1.0 mmol) in DMF (5 ml) and the mixture stirred for 5 minutes before propargylbromide (0.1 3 9, 1.1 mmol) was added. The mixture was stirred at room temperature overnight before the solvent was distilled off at reduced pressure and the residue triturated with water. The product was extracted into chloroform, dried (MgSO4) and evaporated. The residue was washed with ether and dried; yield 0.13 9 (64%), m.p.

106"C (sublimed at 90-100 C/0.1 mmHg).

1H NMR (CDCI3): 8 2.72 (t, J 3 Hz), 4.75 (d, J 3 Hz), 8.39 (H-4, J 3 Hz), 8.67 (H-6, J 4 Hz). IR (KBr): 3225 cm (=-CH), 1680 (CO), MS: 202 (46, M), 183 (6), 174 (4), 173 (69), 148 (21), 147 (18), 127 (5), 52 (10), 39 (100). (Found: 47.37, H 2.61. Calc. for C8H5F3N20: C 47.53, H 2.50).

Example 10 1 -(2- Thenyl)-5-trifluoromethylpyrimidin-2-one prepared as described in Example 9 but using thenyl bromide as starting material instead of propargyl bromide. Yield (80%), m.p.

153"C (sublimed at 110-120"C/0.01 mmHg). 1H NMR (CDCl3): 8 5.22 (CH2), 6.8-7.3 (thiophene), 7.85 (H-4, J 3 Hz); 8.55 (H-6, J3 Hz). IR (KBr): 1675cm-1 (CO). MS: 260 (32, M), 231(2), 199 (2), 148 (59), 98 (5), 97 (100), 69 (5). (Found: C 46.00, H 3.09. Calc. for C10H7F3N20S: C 46.15, H 2.72).

Example Ii 1 j(4-Chlornphenoxy)meth ylJ-5-trifluorometh VI- pyrimidin-2-one Triethylamine (0.14 ml, 1 mmol) was added to a mixture of 5- trifluoromethylpyrimidin-2-one (0.16 9, 1 mmol) in dichloromethane (10 ml) and the solution stirred for 5 minutes before 1-chloromethyloxy-4-chloro- benzene [see Preparation 3 in European Patent Application 82300106.0 (publication No.

0056319)] (0.189, 1 mmol) in dichloromethane (2 ml) was added. The mixture was stirred at room temperature overnight and at 40C for 3 hours before the solvent was distilled off and the residue triturated with water. The product was extracted into chloroform, dried (MgSO4) and evaporated. The residue was washed with ether and dried; yield 0.29 9 (95%), m.p. 98 C.1H NMR (CDCl3): 8 5.82 (CH2), 6.8-7.4 (Ph), 8.15 (H04, J3 Hz), 8.77 (H-6, J3 Hz). IR (KBr): 1690 cm-' (CO). MS: 285(1), 178 (7), 177(100)150 (10), 75(5). (Found: C 46.78, H 2.88. Calc.

for C,2H8CIF3N202: C 47.30, H 2.65).

Example 12 1 -[(2-Thenoyl)methyl]-5-trifluoromethylpyrimi- din-2-one prepared from 2-(a-bromoacetyl)-thiophene as in Example 11 in 94% yield, m.p. 186C (CH2C12). 'H NMR (MeCN-d3): 8 5.28 (CH2), 6.8-7.8 (thiophene), 8.18 (H-4, J3 Hz) 8.76 (H-6, J3 Hz). IR (KBr): 1675 cm-l (CO). MS: 288 (2,M), 177 (3), 126 (2), 111 (1Cfl), 83 (6), 39 (17). (Found: C 46.13, H 2.64. Calc.

for C11H7F3N2O2S: C 45.83, H 2.45).

Example 13 1 -Phenacyl-5-trifluoromethylpyrimidin-2-one prepared from phenacyl bromide in a similar manner .o that described in Example 11 in 70 ,0 yield, m.p. 210 C. 'H NMR (acetone d6): S 5.55 (CH2), 7.3-8.1 (Ph), 8.55 (H-4, J 3 Hz), 8.75 (H-6, J3 Hz). IR (KBr): 1690 cm-l (CO). MS: 282 (2,M) 263 (2), 177(2), 106 (7), 105 (100), 77(35). (Found: C 55.76, H 3.29. Calc. for C13HgF3N202 C 55.32, H 3.22).

Example 14 I -Benzyl-5-trifluoromethylpyrimidin-2-one prepared in a similar manner to that described in Example 11, but using benzyl bromide instead of 1 -chloromethoxy-4-chloroben- zene. Yield: 39%. m.p. 150"C. 1H-NMR (CDCl3): 8 5.07 (CH2), 7.31 (Ph), 7.80 (H-4 J 3 Hz), 8.53 (H-6, J 3 Hz): MS: 254 (57,M), 225(5), 198(1), 149(9), 91(100), 65(13).

Example 15 1-N-Methyl-N-phenylcarbamoyl methyl-5-trifluoromethylpyrimidin-2-one was prepared from a-chloro-N-methylaceton- itrile [see L. Heinisch, J. prakt. Chem. 317, 435 (1975)] and 5-trifluoromethylpyrimidin-2one in a similar manner to that described in Example 9. Yield: 96%. m.p. 195"C. 1H-NMR (CD3CN): S 3.25 (Me), 4.43 (CH2), 7.26 (Ph), 8.26 (H-4, J 3 Hz), 8.70 (H-6, J 3 Hz). MS: 311 (1.M), 205(21), 177(49), 148(12), 147(28), 1 34(18), 107(100), 106(25).

Claims (2)

1. 5-Trifluoromethylpyrimidines of the formula:

[wherein A represents the group -CO-NR3or

(wherein R3 represents a hydrogen atom, a glycosyl group or a C14 saturated or unsaturated, straight or branched chain, aliphatic hydrocarbyl group optionally substituted by one or more substituents selected from halogen atoms, oxo groups and optionally substituted hydroxyl, mercapto, carboxyl, carboxamido, amino, carbocyclic aryl and heterocyclic groups, such heterocyclic groups being Cattached 3-9 members, saturated, unsaturated or aromatic heterocyclic rings containing one or more hetero atoms selected from 0, N and S and optionally carrying a fused ring and/or optionally substituted by one or more substituents selected from halogen atoms and hydroxy, C14 alkoxy, amino, acylamino, nitro, oxo, C14 alkyl groups and monocyclic carbocyclic and heterocyclic aryl groups having 5-8 ring members; such a heterocyclic ring being saturated and having only a single heteroatom when there are 3 or 4 ring members; n is 0, 1 or 2 and R4 represents a C, 32 saturated or unsaturated, straight or branched, cyclic or acyclic aliphatic group or an araliphatic or heterocyclic substituted aliphatic group, a heterocyclic group or an aryl group which groups may if desired carry one or more substituents selected from halogen atoms and oxo, nitro, hydroxy, etherified hydroxy, esterified hydroxy, primary, secondary or tertiary amino, acylamino, etherified mercapto or -SO or -SO2 derivatives thereof and esterified phosphonic acid groups)] and where an acidic or basic group is present, the salts thereof,

2. 5-Trifluoromethylpyrimidines as claimed in claim 1 as herein specifically disclosed.