GB2086386A

GB2086386A - Pyrimidine derivatives

Info

Publication number: GB2086386A
Application number: GB8131704A
Authority: GB
Original assignee: May and Baker Ltd
Current assignee: May and Baker Ltd
Priority date: 1980-10-27
Filing date: 1981-10-21
Publication date: 1982-05-12
Also published as: GB2086386B

Abstract

Compounds of the general formula:- <IMAGE> wherein R<1> represents a methyl or ethyl group, R<2> represents a bromine or chlorine atom, and R<3> represents a hydrogen, chlorine, bromine or iodine atom, a straight- or branched-chain alkyl or alkenyl group containing up to 4 carbon atoms, or a cyano or trifluoromethyl group, have been found to possess antimalarial properties. The compounds can be prepared by reacting a 2,4-diamino-5-hydroxy-6-alkylpyrimidine, or a basic salt thereof, with a biphenyloxypropyl compound having an acid residue of a reactive ester (e.g. a halogen atom or a p- tolylsulphonyl or methylsulphonyl group) attached to the terminal carbon atom of the n-propyl group.

Description

SPECIFICATION Pyrimidine derivatives The invention relates to new pyrimidine derivatives, to a process for their preparation, to compositions containing them, and to their use as pharmaceuticals.

British Patent Specification No. 1 546937 discloses inter alia that 2,4-diaminopyrimidine derivatives of the general formula:

(wherein R represents a hydrogen atom or a methyl or ethyl group, X represents an alkylene group of 1 to 10 carbon atoms, Y represents an oxygen or sulphur atom or a bond, and Ar represents an optionally substituted aryl group, except that Ar-Y-X does not represent a benzyl group when R represents a hydrogen atom) and pharmaceutically acceptable acid addition salts thereof have antimicrobial activity.

The aforementioned British Patent Specification No. 1 546937 includes the statement "Suitable groups Ar include phenyl, naphthyl, anthranyl, phenanthryl and phenyl substituted by from 1 to 5 atoms or groups selected from fluorine, chlorine, bromine, lower alkoxyl, lower acyloxyl, lower alkyl, lower alkenyl, C56 cycloalkyl, Cs. 6 cycloalkenyl or lower alkylthio.When used herein the term 'lower' means that the group contains up to 6 carbon atoms", and the following values of Ar appear in the Examples:- cyclohexyl-chloro-phenyl, dichlorophenyl, naphthyl, phenanthryl, pentachlorophenyl, tetrachlorophenyl, trichlorophenyl, propenyl-bromo-phenyl, bromophenyl, propenyl-methoxy-phenyl, trimethoxyphenyl, dimethoxyphenyl, methoxyphenyl, ethylthiophenyl, phenyl, and chlorophenyl.

British Patent Specification No. 1 546937 does not mention or disclose biphenyl or substituted biphenyl as a possible value for symbol Ar in any part, including the Examples and Claims.

It has now unexpectedly been found that, related in structure to the millions of compounds within the scope described in detaii in British Patent Specification No. 1 546937, there are a small group of substituted biphenyl compounds which are of particularly outstanding utility as antimalarials.

Accordingly, the present invention provides pyrimidine derivatives of the general formula:

(wherein R1 represents a methyl or ethyl group, R2 represents a bromine or chlorine atom, and R3 represents a hydrogen, chiorine, bromine or iodine atom, a straight- or branched-chain alkyl or alkenyl group containing up to 4 carbon atoms, or a cyano or trifluoromethyl group) and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula Il are much more active as antimalarials than the compounds particularly described in British Patent Specification No. 1 546937 (hereinafter referred to for convenience as "the compounds of B.P. 1 546937"), and this is especially important against strains of malarial infections which are resistant to known antimalarial agents. The compounds of formula II are also less toxic than the compounds of B.P. 1 546937. This surprising advantage in antimalarial therapeutic index is particularly remarkable because the compounds of formula II are of no activity, or of only low activity, as antibacterials.Indeed, this constitutes another advantage for the compounds of formula II because antimalarial compounds are commonly administered over a long period for their prophylactic effect. Many medical practitioners prefer not to administer antibacterial compounds over extended periods because of the risk of developing resistant strains of bacteria. The compounds of formula II may be administered continuousiy with no danger of developing resistant strains of bacteria.

A particularly preferred compound of formula II is 2,4-diamino-5-[3-44-(4-chlorophenyl)phenoxyi- propoxyj-6-methylpyrimidine of formula:

and pharmaceutically acceptable acid addition salts thereof. Another preferred compound of formula II is 2,4-dia mino-5-[3-f2-bromo-4-(4-bromophenyl)phenoxy )propoxy]-6-methylpyrimidine of formula.

and pharmaceutically acceptable acid addition salts thereof.

By the term "pharmaceutically acceptable acid addition salts" as used in this specification is meant acid addition salts the anions of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of formula II are not vitiated by side-effects ascribable to those anions.

As well as being useful in themselves as active compounds, acid addition salts of the compounds of formula II are useful for the purposes of purification of the parent compounds of formula II, for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those skilled in the art. The parent compounds of formula II can be regenerated from their acid addition salts by known methods, for example by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

Suitable acid addition salts for use in pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fu ma rates, maleates, methylene-bis-P-hydroxynaphthoates. gentisates and di-ptoluoyltartrates.

According to a feature of the present invention, the compounds of formula II may be converted to their acid addition salts by known methods, for example, by reaction with the appropriate acid in solution in a suitable solvent, e.g. ethanol, followed if necessary by evaporation of part or all of the solvent, and collection of the solid salt.

It is to be understood that, where in this specification reference is made to the compounds of formula II, it is intended to refer also, where the context so permits, to acid addition salts of the compounds of formula II.

By the term "known methods" as used in this specification is meant methods heretofore used or described in the literature.

According to a feature of the present invention, the compounds of formula II are prepared by the process which comprises the reaction of a 2,4-diamino-5-hydroxy-6-alkylpyrimidine of the general formula:

(wherein R1 is as hereinbefore defined) or a basic salt thereof, for example an alkali metal (e.g. sodium or potassium) salt, with a biphenyloxypropyl compound of the general formula:

wherein R4 represents the acid residue of a reactive ester, for example a halogen (e.g. bromine or chlorine) atom or a p-tolylsulphonyl or methylsulphonyl group, and R2 and R3 are as hereinbefore defined.The reaction is preferably carried out in a polar solvent medium, for example in a mixture of tetrahydrofuran and methanol, and optionally at an elevated temperature, for example the reflux temperature of the reaction mixture.

The compounds of formula V may be prepared by the methods described by R. Hull, Journal of the Chemical Society, (1956), 2033.

Compounds of formula VI may be prepared by the application or adaptation of known methods.

According to a feature of the present invention, the compounds of formula il may be used to treat malaria.

The compounds of formula II are especially useful in the treatment of malaria, as they are able effectively to treat malarial infections which are resistant to known antimalarial agents. The compounds of formula il can be used alone or in association with other therapeutic agents and, in some circumstances, mixtures of the compounds of formula II with other antimalarial compounds have antimalarial activities which are much higher than would be expected from mere arithmetic addition of the activities of the individual components of the mixture, and this is especially important against malarial infections which are resistant to other antimalarial compounds.Good examples of other therapeutic agents which may be used in association with the compounds of formula 11 include sulphonamides, e.g. sulphadiazine [i.e. 2-sulphanilamidopyrimidine], sulphadoxine [i.e. 5,6-dimethoxy- 4-sulphanilamidopyrimidine], sulphadimethoxine [i.e. 2,6-dimethoxy-4-sulphanila midopyrimidine] and sulphalene [i.e. 2-methoxy-3-sulphanilamidopyrazine], and sulphones, for example dapsone [i.e. bis(4aminophenyl) sulphone].

The usefulness of the compounds of formula II is enhanced by the fact that they have a toxicity in mammals which is moderately low.

The properties of the compound of formula III are illustrated by the following laboratory tests.

Similar tests were carried out on 35 of the 39 specifically described compounds of B.P. 1546937 and one compound, 2,4-dia mino-6-methyl-5-[3-(4-chlorn-2-cyclohexylphenoxy)prnpoxy]pyrimidine (hereinafter referred to as "reference compound RCA") was found to be at least 4 times as active against malaria as any of the other 34 compounds. The test results for reference compound RCA are given for comparison with those for the compound of formula Ill, and it is clear that the compound of formula Ill is very much more active than reference compound RCA against sensitive and resistant strains of malaria and, furthermore, that the compound of formula Ill is much less toxic in dogs than reference compound RCA.

The other compounds of formula II, for example the compound of formula IV, have similar advantages over reference compound RCA and the other compounds of B.P. 1546937.

Antimalarial activity (a) The test compounds were tested in mice, against Plasmodium yoellinigeriensis (strain N67), which is sensitive to pyrimethamine, and against a strain of Plasmodium yoelii nigeriensis [strain PR (derived from strain N67)] which is resistant to pyrimethamine, and also against pyrimethamine sensitive Plasmodium berghei (strain N30).

Pyrimethamine [i.e. 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine] is an antimalarial compound which is an article of commerce.

In the experiments, the mice were each infected intraperitoneally with about 1 06 trophozoites. The test compound was administered orally daily for 4 days, beginning on the day of infection, and peripheral blood smears of the mice were observed 2 or 3 times per week for a total of 21 days. The numbers of mice cured were counted and the dose required to cure 50% of mice tested (CD50) was calculated.

The results obtained are shown below in Table I.

TABLE I

Test Daily dose Number of Number of CD50 Compound Strain I mg /kg mice tested mice cured mg /kg /day 2.0 31 31 N67 0.5 32 28 0.3 0.125 32 2 The compound 20.0 15 15 of formula III 2.0 24 24 N30 0.5 24 14 0.45 0.125 24 0 25 31 31 N67 5 32 17 5 1 32 2 Reference 100 32 32 compound PR 10 RCA 100 24 24 N30 10 24 5 15 1 24 0 (b) Mice were each infected intraperitoneally with about 106 trophozoites of strain N67 of Plasmodium yoelii nigeriensis. The compound of formula III was administered orally in one sing!e dose given 48 hours after infection, and the mice were observed for a total of 21 days. The numbers of mice cured were counted and the dose required to cure 50% of mice tested (CD50) was calculated.

The results obtained are shown below in Table II, in comparison with a test using pyrimethamine against the same organism.

TABLE II

Dose Number of Number of CD50 Compound mg /kg mice tested mice cured mg /kg The 20.0 8 8 compound of 2.0 8 1 3.5 formula Ill 0.2 8 0 50.0 8 0 pyrimeth- (maximum greater amine tolerated dose) than 5.0 8 0 50 In comparison an oral dose of 200 mg/kg of reference compound RCA was adrNinistered to each of 8 mice 24 hours after infection, and only 2 mice were cured, giving a CD50 of greater than 200 mg/kg.

It is to be noted that administration of an antimalarial drug 24 hours after infection should generally be more efficacious than administration 48 hours after infection.

Toxicity Acute oral toxicity in mice Mice were treated with a single dose of the compound of formula Ill by the oral route, and were observed until all survivors had appeared to be healthy for 3 consecutive days. The LD50 dose (dose required to kill 50% of the mice tested) was then calculated. The results obtained are shown below in Table Ill.

TABLE Ill

Dose Number of Number of LD50 mg/kg mice tested mice killed mglkg 1000 5 3 approximately 500 5 0 1000 In a similar test on reference compound RCA an oral dose of 1000 mg/kg killed 2 out of 5 mice, giving an LD50 figure of approximately 1000 mg/kg.

Toxicity in dogs The compound of formula Ill was found to be clinically well-tolerated by dogs when administered orally in gelatin capsules for a period of one month at dosages of 1, 3 and 9 mg/kg/day. The compound of formula III was also clinically well-tolerated by 5 of the 6 dogs which received the highest dosage of 1 5 mg/kg/day.

In contrast, reference compound RCA was found to be clinically badly tolerated even at doses of 3 mg/kg/day, with deaths occurring at higher doses.

The following Examples illustrate the preparation of the compounds of the present invention.

EXAMPLE 1 2,4-Diamino-5-hydroxy-6-methylpyrimidine dihydrogen sulphate (137.5 g) was added to a stirred solution of sodium methoxide [prepared by dissolving sodium (39.8 g) in anhydrous methanol (2350 ml)]. The stirred mixture was heated at reflux for 30 minutes and then for a further 1 50 minutes during the gradual addition of a solution of 3-[4-(4-chlorophenyl)phenoxy]propyl bromide (188 g) in anhydrous tetrahydrofuran (940 ml) and then the mixture was stirred and heated at reflux for a further 1 8 hours.

Part of the solvent (approximately 2400 ml) was removed by distillation at atmospheric pressure and the remaining mixture was diluted with water (3000 ml). The resulting suspension was cooled to 400 C, and the solid was filtered off, washed well with water and dried at 850C. The solid was then dissolved in hot dimethylformamide (1000 ml) and the resulting solution was filtered through diatomaceous earth and treated, successively, with concentrated hydrochloric acid (50 ml) and acetone (2000 ml). The resulting suspension was cooled to 1 00C and filtered, and the solid was washed well with acetone to give 2,4-diamino-5-[3-{4-(4-chlorophenyl)phenoxy}propoxy]-6-methylpyrimidine monohydrochloride (178 g), m.p. 263-2650C (with slight decomposition).

Elemental analysis:- C, 57.1;H, 5.2; Cl,16.6; N, 13.2%; C20H22CI2N402 requires C, 57.0; H, 5.3; CI, 16.8; N, 13.3%.

3-[4-(4-Chlorophenyl)phenoxy]propyl bromide of formula VI, used as a starting material, was prepared as follows:- A methanolic solution of sodium methoxide prepared by dissolving sodium (35.7 g) in anhydrous methanol (300 ml) was treated with 4-(4-chlorophenyl)phenol (311 g) and the resulting solution was added to a stirred solution of 1,3-dibromopropane (850 ml) in anhydrous methanol (500 ml) at reflux during a period of 6 hours. The mixture was stirred at reflux for a further period of 1 8 hours and was then evaporated to dryness in vacuo. The crystalline residue was triturated with petroleum ether (b.p.

40--600C), filtered off and dried, and was then triturated with aqueous potassium hydroxide solution (1500 ml; 5% w/v), filtered off, washed well with water and dried. The solid was subjected to fractional crystallisation from a mixture of isopropanol and acetone. The first crop was discarded. The second crop (161 g) was dissolved in acetone, filtered, and evaporated. The third crop (53 g) was recrystallised from ethanol. The fourth crop was recrystallised from isopropanol and then twice from ethanol. The purified second, third and fourth crops were combined and dissolved in acetone, and the solution was filtered through diatomaceous earth. It was concentrated in vacuo to a volume of 300 ml and was then diluted with a mixture of methanol (200 ml) and water (500 ml).The resulting solid was filtered off and washed with water to give 3-[4-(4-chlorophenyl)phenoxyjpropyl bromide (194 g), m.p. 103-1 050C.

EXAMPLE 2 By proceeding in a manner similar to that described in Example 1 but replacing the 3-[4-(4chlorophenyl)phenoxy]propyl bromide used as a starting material by the appropriate quantities of the corresponding biphenyloxypropyl bromides of formula VI, there were prepared the following compounds, which were crystallised from the solvents indicated.

2,4-dia mino-S-[3-{2-brnmo-4-(4-brnmophenyl)phenoxyjprnpoxy]6methyIpyrimidine monohydrochloride, m.p. 255-2570C (from a mixture of dimethylformamide and acetone), and 5-[3-j2-al lyl-4-(4-chlorophenyl)phenoxyipropoxy]-2,4-dia mino-6-methylpyrimidine monohydrochloride, m.p. 241-2430C (from methanol).

By again proceeding in a similar manner to that described in Example 1 but omitting the treatment with hydrochloric acid and using the appropriate biphenyloxypropyl bromides of formula VI, the following compounds were obtained as free bases and crystallised from the solvents indicated.

2,4-diamino-5-[3-{4-(4-bromophenyl)phenoxy}propoxy]-6-methylpyrimidine, m.p. 1 98-2000C (from a mixture of tetrahydrofuran and ethyl acetate); 2,4-diamino-5-[3-{2-chloro-4-(4-chlorophenyl)phenoxy }prnpoxyj-6-methylpyrimidine, m.p.

191-1 930C (from a mixture of dimethylformamide and tetrahydrofuran); 2,4-diamino-5-[3-2-bromo-4-(4-chlorophenyl)phenoxy propoxy]-6-methylpyrimidine, m.p.

1 78-1 800C (from a mixture of dimethylformamide and methanol); 2,4-diamino-5-[3-{4-(4-chlorophenyl)-2-methylphenoxy propoxyJ-6-methylpyrimidine, m.p.

207-2090C (from a mixture of dimethylformamide and acetone); 2,4-diamino-5[3{4-(4-chlorophenyl)-2-ethylphenoxy}propoxy]-6-methylpyrimidine, m.p. 144-1 40C (from a mixture of dimethylformamide and ethanol); 2,4-dia mino-5-[3-{4-(4-bromophenyl)-2-ethylphenóxy )propoxyj-6-methylpyrimidine, m.p.

146-1 480C (from a mixture of dimethylformamide and ethanol); 2,4-dia mino-5-[3-{4-(4-chlorophenyl)-2-iodophenoxy}-propoxy propoxy]-6-methylpyrimidine. m.p.

172.5-1 73.50C (from a mixture of dimethylformamide and acetone); 2,4-diamino-5-[3-{2-tert-butyl-4-(4-chlorophenyl)phenoxy tpropoxy]-6-methylpyrimidine hydrate, m.p.

165-1 660C (from methanol): Elemental analysis:- C, 64.5; H, 6.8; CI, 7.8; N, 12.9; H20, 1.9%; C24H29CIN402: 0.5H20 requires C, 64.3; H, 6.75; CI, 7.9; N, 12.5; H20, 2.0%; 2,4-dia mino-5-[3-{4-(4-chlorophenyl)-2-iso-propylphenoxy Ipropoxyf-6-methylpyrimidine ethanolate, m.p. 140-1440C (from a mixture of dimethylformamide and ethanol): Elemental analysis:- C, 64.0; H, 6.9; CI, 7.7; N, 12.5;-OC2H5, 5.8%; C23H27ClN402:0.5C2HsOH requires C, 64.1; H, 6.7; CI, 7.9; N, 12.5; -OC2H , 5.8%; 2,4-diamino-5-[3-{2-butyi-4-(4-chiorophenyl)phenoxy }propoxy]-6-methylpyrimidine ethanolate, m.p.

129-1310C (from ethanol): Elemental analysis:- C, 64.9; H, 7.1; Cl, 7.4; N, 11.8%; C24H29CIN402:0.8C2HsOH requires C, 64.9; H, 7.1; CI, 7.4; N, 11.7%; 2,4-diamino-5[3-{4(4-chlornphenyl)-2-trifluoromethylphenoxy{propoxyl-6-methylpyrimidine ethanolate, m.p. 145-1 480C (from a mixture of dimethylformamide and ethanol): Elemental analysis:- C, 55.1; H, 5.2; CI, 6.6; F, 11.5; N, 1 1.6%; C21H20CIF3N402:C2HsOH requires C, 55.4; H, 5.25; Cl, 7.1;F, 11.4; N, 11.2%; 2,4-diamino-5-!3-f4-(4-chlorophenyl)-2-propylphenoxy }propoxy]-6-methylpyrimidine, m.p.

106-1 08 0 C [from a mixture of petroleum ether (b.p. 60--800C) and toluene], and 2,4-diamino-5-[3-(4-(4-chlorophenyl)-2-cyanophenoxy )propoxy]-6-methylpyrimidine hydrate, m.p.

231-2320C (from a mixture of dimethylformamide and acetone): Elemental analysis:- C, 60.2; H, 4.8; CI, 8.3; N, 16.4; H20, 1.4%; C21H20CIN5O2:O.4H2O requires C, 60.5: H, 5.0; CI, 8.5; N, 16.8; H2O, 1.7%.

By proceeding in a similar manner to that described in Example 1 but replacing the 2,4-diamino-5hydroxy-6-methylpyrimidine dihydrogen sulphate, used as a starting material, by the appropriate quantity of 2,4-diamino-6-ethyl-5-hydroxypyrimidine dihydrogen sulphate, there was prepared 2,4-dia mino-5-[3-I4-(4-chlorophenyl)phenoxy ipropoxy]-6-methylpyrimidine monohydrochloride, m.p.

261-2630C.

The present invention includes within its scope pharmaceutical compositions which comprise at least one compound of formula II in association with a pharmaceutically acceptable carrier or coating, and optionally together with one or more other antimalarial compounds or other therapeutic agents. In clinical practice the compositions of the present invention will normally be administered orally, rectally or parenterally.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions the active compound or compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. -Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing the active compound or compounds with or without the addition of diluents or excipients.

Solid compositions for rectal administration include suppositories formulated in manner known perse and containing the active compound or compounds.

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or suspending media are propylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in a sterile injectable medium immediately before use.

The percentages of active ingredients in the compositions of the invention may be varied, it being necessary that they should constitute a proportion such that a suitable dosage for the desired antimalarial effect shall be obtained. Obviously several unit dosage forms may be administered at about the same time. Generally the compositions, should contain 0.1% to 80% by weight of active ingredient, especially when in tablet form.

The dose employed depends upon the desired antimalarial effect, the route of administration and the duration of the treatment. In the adult, the doses are generally between 0.01 and 100 mg (preferably between 0.01 and 1.0 mg) of compound of formula II per kg body weight per day, and optionally together with between 1.0 and 50 mg (preferably between 1.0 and 10 mg) of another antimalarial compound or another therapeutic agent per kg body weight per day by oral administration.

The compounds of formula II may be administered each day or, according to the wishes of the medical or veterinary practitioner, less often, e.g. weekly.

The present invention provides a method of treating or preventing malaria in man and other warmblooded animals which comprises administering to the human or animal an amount of a compound or compounds of formula II sufficient to combat a malarial infection.

The present invention further provides a method of treating or preventing malaria in man and other warm-blooded animals which comprises administering to the human or animal an amount of a compound'or compounds of formula II and another antimalarial compound or another therapeutic agent sufficient, in combination, to combat a malarial infection.

The following Composition Example illustrates pharmaceutical compositions according to the present invention.

COMPOSITION EXAMPLE Capsules for oral administration were made up in the usual manner by filling No. 2 size gelatin capsules each with 155 mg of the following composition L 2,4-dia mino-5-[3-I4-(4-chlorophenyl)phenoxyj- propoxy]-6-methylpyrimidine monohydrochloride 50 mg potato starch 100 mg magnesium stearate 2.5 mg Aerosil (a registered Trade Mark) 2.5 mg

Claims

1. Pyrimidine derivatives of the general formula:

wherein R' represents a methyl or ethyl group, R2 represents a bromine or chlorine atom, and R3 represents a hydrogen, chlorine, bromine or iodine atom, a straight- or branched-chain alkyl or alkenyl group containing up to 4 carbon atoms, or a cyano or trifluoromethyl group, and pharmaceutically acceptable acid addition salts thereof.

2. 2,4-Diamino-5-f3-j4-(4-chlorophenyl)phenoxy}propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

3. 2,4-Dia mino-5-[3-{2-bromo-4-(4-bromophenyl)phenoxy} propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

4.5-r3-l2-Ailyl-4-(4-chiorophenyl)phenoxyfpropoxyS-2t4-diamino-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

5. 2A-Diamino-5-[3A4-(4-brnmophenl)phenoxy}prnpoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

6. 2,4-Diamino5-[3-j2-chloro-4(4-chIorophenyl)phenoxy{propoxyj-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

7. 2A-Diamino-5-[3A2-bromo-4-(4-chlornphenyl)phenoxy}prnpoxyj-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

8. 2 ,4-Dia mino-5-[3-{4-(4-ch Iorophenyl)-2-methylphenoxyjpropoxy]-6-methylpyrim idine and pharmaceutically acceptable acid addition salts thereof.

9.2,4-Diamino-5-[3-{4-(4-chlorophenyl)-2-ethylphenoxy}propoxyl-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

1 0. 2,4-Diamino-5-[3-{4-(4-bromophenyl)-2-ethylphenoxy{propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

11. 2,4-Dia mino-5-[3A4-(4hlornphenyI)-2-iodophenoxy}prnpoxy]-6-methylpynmidine and pharmaceutically acceptable acid addition salts thereof.

12. mino-5-[3-{2-tert-butyl-4-(4-chlorophenyl)phenoxy}propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

13. 2,4-Dia mino-5-[3-(4-(4-chlorophenyl)-2-iso-propylphenoxy}propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

14. 2,4-Dia mino-5-[3-f2-butyl-4-(4-chlorophenyl)phenoxy}propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

1 5. 2 A-Diamino-5-[3-(4-(4-chlornphenyl)-2-trifluornmethylphenoxyiprnpoxy]-6- methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

16. 2,4-Dia mino-5-[3-{4-(4-chlorophenyl)-2-propylphenoxyjpropoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

17. 2,4-Dia mino-5-[3-f4-(4-chlorophenyl)-2-cyanophenoxy}propoxy]-6-methylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

1 8. 2,4-Diamino-5-[3-j4-(4-chlorophenyl)phenoxyjpropoxy]-6-ethylpyrimidine and pharmaceutically acceptable acid addition salts thereof.

1 9. A process for the preparation of a pyrimidine derivative as claimed in claim 1 which comprises the reaction of a 2,4-diamino-5-hydroxy-6-alkylpyrimidine of the general formula.

(wherein R' is as defined in claim 1), or a basic salt thereof, with a biphenyloxypropyl compound of the general formula:

wherein R4 represents the acid residue of a reactive ester, and R2 and R3 are as defined in claim 1.

20. Process according to claim 19 in which an alkali metal salt of the pyrimidine starting material of general formula V is employed as reactant.

21. A process according to claim 19 or 20 in which R4 in the starting material of general formula VI represents a halogen atom or a p-tolylsulphonyl or methylsulphonyl group.

22. A process according to claim 19, 20 or 21 followed by the step of converting by known methods a pyrimidine derivative of the general formula depicted in claim 1 thus obtained into an acid addition salt.

23. A process for the preparation of a pyrimidine derivative of the general formula depicted in claim 1, or acid addition salt thereof, substantially as hereinbefore described with especial reference to Example 1 or2.

24. Pyrimidine derivatives of the general formula depicted in claim 1 and acid addition salts thereof when prepared by the process - as appropriate - claimed in claim 1 9, 20, 21,22 or 23.

25. Pharmaceutical compositions which comprise, as active ingredient, at least one pyrimidine derivative as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or coating.

26. Pharmaceutical compositions according to claim 25 substantially as hereinbefore described with especial reference to the foregoing Composition Example.

27. A pyrimidine derivative as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of malaria in man and other warmblooded animals.