Heterocyclic compounds

This invention relates to pyrimidine derivatives for treating material and bacterical infestions in humans and animals.

The present invention relates to pyrimidine derivatives, their preparation 
and compositions containing them. 
U.S. Pat. No. 3,723,429 discloses inter alia that compounds of the formula 
(I): 
##STR1## 
wherein A is a divalent aliphatic group and B is an optionally substituted 
hydrocarbon group have antimicrobial activity. Such compounds are not 
particularly well distributed in the body after oral administration to 
mammals and so it would be of advantage if a class of compounds of similar 
activity could be found that were better distributed but not more toxic 
after oral administration. Such a group of compounds has now been 
discovered. 
Accordingly the present invention provides the compounds of the formula 
(II): 
##STR2## 
and pharmaceutically acceptable salts thereof wherein R is a hydrogen atom 
or a methyl or ethyl group; X is an alkylene group of 1 to 10 carbon 
atoms; Y is 0, S or a bond; and Ar is an aryl group. 
The alkylene group X may be straight or branched chain but is most suitably 
straight chained. Particularly suitable groups X include those of the 
formula --(CH.sub.2).sub.n -- where n is an integer of from 1 to 6. 
Most suitably Y is an oxygen atom. 
Suitable groups Ar include phenyl, naphthyl, anthranyl, phenanthryl and 
phenyl substituted by from 1 to 5 groups selected from fluorine, chlorine, 
bromine, lower alkoxyl, lower acyloxyl, lower alkyl, lower alkenyl, 
C.sub.5-6 cycloalkyl, C.sub.5-6 cycloalkenyl or lower alkylthio. 
When used herein the term `lower` means that the group contains 1-6 carbon 
atoms. 
Particularly suitable compounds of the formula (II) include those of the 
formula (III): 
##STR3## 
and pharmaceutically acceptable salts thereof wherein R and Ar are as 
defined in relation to formula (II) and m is 1, 2, 3 or 4. 
Favoured values for the group Ar include the phenyl and naphthyl groups and 
phenyl substituted by one more more groups selected from chlorine, 
bromine, lower alkoxyl, lower alkyl, lower alkenyl, C.sub.5-6 cycloalkyl 
and C.sub.5-6 cycloalkenyl. 
One particularly suitable sub-group of compounds of the formulae (II) and 
(III) is that wherein R is a hydrogen atom. 
Another particularly suitable sub-group of compounds of the formulae (II) 
and (III) is that wherein R is a methyl group. 
Certain favoured compounds of the formulae (II) and (III) include those 
wherein Ar is a phenyl, mono-, di- or tri- substituted phenyl especially 
phenyl substituted by cyclohexyl or cyclopentyl and optionally substituted 
by a further 1 or 2 groups. 
Particularly favoured compounds of the formulae (II) and (III) include 
those wherein Ar is a group of the sub-formula (a): 
##STR4## 
wherein R.sub.1 is a hydrogen, fluorine, chlorine or bromine atom or a 
methyl or methoxyl group and R.sub.2 is a hydrogen, fluorine, chlorine or 
bromine atom or a methyl or methoxyl group. 
Most suitably R.sub.1 is a hydrogen, chlorine or bromine atom. 
Most suitably R.sub.2 is a hydrogen, chlorine or bromine atom. 
Certain preferred moieties of the sub-formula (a) are those of the 
sub-formula (b): 
##STR5## 
wherein R.sub.3 is a hydrogen, fluorine, chlorine or bromine atom or a 
methyl or methoxyl group. 
More suitably R.sub.3 is a hydrogen, chlorine or bromine atom. 
Preferably R.sub.3 is a hydrogen atom. 
The acid addition salts of the compounds of the formula (II) may be any 
formed with a pharmaceutically acceptable inorganic or organic acid such 
as hydrochloric, orthophosphoric, acetic, succinic, lactic, citric, 
fumaric, tartaric or the like acid. 
In a further aspect the present invention provides a process for the 
preparation of the compounds of the formula (II) and their salts which 
process comprises the reaction of a compound of the formula (IV): 
##STR6## 
or a basic salt thereof wherein R is a hydrogen atom or a methyl or ethyl 
group; and a compound of the formula (V): 
EQU Ar--Y--X--Z (V) 
wherein Ar, Y and X are as defined in relation to formula (II) and Z is a 
group readily displaceable by a nucleophile. 
An alternative process of this invention for the preparation of those 
compounds of the formula (II) wherein Y is 0 comprises the reaction of a 
compound of the formula (VI): 
##STR7## 
wherein R and X are as defined in relation to formula (II) and Z is as 
defined in relation to formula (V) with a compound of the formula (VII): 
EQU Ar--OH (VII) 
or a basic salt thereof wherein Ar is as defined in relation to formula 
(II). 
Suitable groups Z include Cl, Br, I, OSO.sub.2 CH.sub.3, OSO.sub.2 C.sub.6 
H.sub.4 CH.sub.3 and the like. 
Suitable basic salts of the compounds of the formulae (IV) or (VII) include 
alkali metal salts such as the sodium salt and other similar salts. 
The preceding reactions are normally carried out in relatively polar 
organic solvents such as dimethylformamide, dimethylsulphoxide, 
acetonitrile and the like. 
Normally the condensations are performed at a non-extreme temperature such 
as -20.degree. C. to 180.degree. C., more usually from 10.degree. C. to 
100.degree. C., for example from 25.degree. C. to 60.degree. C. 
The present invention also provides a pharmaceutical composition which 
comprises a compound of the formula (II) and a pharmaceutically acceptable 
carrier. 
Most suitably the composition will be adapted for oral or injectable 
administration. Preferred compositions will be adapted for oral 
administration. 
The compositions may be formulated by conventional methods, for example as 
described in U.S. Pat. No. 3,723,429. 
Particularly suitable compositions of this invention include tablets, 
capsules and other unit dosage forms which contain from 5 mg to 500 mg of 
active compound. Such compositions may be administered once or more times 
a day in order to provide a daily dose of 20-1000 mg and more usually 
50-500 mg for a 70 kg adult. 
The compositions of this invention may be used to treat malaria and/or 
bacterial infections. The compositions are of especial usefulness as they 
are able to effectively treat malarial infections which are resistant to 
many conventional anti-malarial agents. The good oral absorption 
properties of the compositions of this invention are an additional 
advantage that allows for their easy use. 
The compositions of this invention may also be used to treat bacterial 
infection as they possess antibacterial activity, for example against gram 
positive bacteria such as Staphylococcus aureus and against gram negative 
bacteria such as Escherichia coli and Proteus mirabilis. 
If desired the compositions of this invention may also contain an 
antibacterially active sulphonamide such as sulphamethoxazole. 
The hydroxy compounds of the formula (IV) may be prepared by the method of 
R. Hull, Journal of the Chemical Society, 1965, 2033.