CA2035314C - Triazole antifungal agents - Google Patents

Abstract

The invention provides antifungal compounds of the formula:- and pharmaceutically acceptable salts thereof, wherein R is phenyl substituted by 1 to 3 substituents each independently selected from halo, -CF3 and -OCF3;
R1 is C1-C4 alkyl;
R2 is H or C1-C4 alkyl;
X is CH or N; and Y is F or Cl.

Description

PLC 517 (SPC 7704) 'IItIAZOLE AD1TIFUNGAL AGENTS
'Ifiis invention relates to triazole derivatives which have antif:ungal activity.
More particularly this invention relates to 2-aryl-3-(3-halopyridi.n-4-yl or 5-halopyrimidin-4-yl)-1-(lI-I-1,2,4-triazol-1-yl)alkan-2-of derivatives which are useful in the tre<atrnent of fungal infections in animals, including human beings.
Some of the c~ounds of the present invention are disclosed in a general sense in our E~zropean patent Application No.
89307920.2 (EP-A-0357241) but none of them are specifically described or exenq~lified therein.
It has ncxa been discovered that the founds of the present invention have a surprisingly high level of antifungal activity, in particular against Asperctillus sip. fungi, which is mainly attributable to their une~~ectedly good pharmacoki.netic properties which result in longer half-lives (t%= values).
'ifie inveaotion provides antifungal agents of the formula:-RI- R~
0!!
_ _ ... ( ! ) Y ~v/

PAC 517 (SPC 7704) and pharmaceutically acceptable salts thereof, wherein ft is phenyl substituted by 1 to 3 substituents each independently selected from halo, --CI'3 amd -OCF3' Rl is Cl-C4 alkyl;
R2 is H or C1-C4 alkyl;
X is C'fi or N; and Y is I' or Cl.
In the above definition of compounds of the formula (I) halo is F, C1, Sr or I and C3 and C4 alkyl groups may be straight- or branched-chain. Preferred alkyl g~~ups are methyl and ethyl.
E~ca~les of R include 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chl.orophenyl, 2-bramophenyl, 2-iodophenyl, 2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chl.orophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl and 2-trifluoro~thoxyphenyl.
R is preferably phenyl substituted by 1 to 3 halo substituents, more preferably by 1 or 2 halo substituents.
Yet more preferably R is phenyl substituted by 1 or. 2 substituents each independently selected from fluoro and chloro.

PLC S17 (SPC 7704) Preferred individual embodiments of R include 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-c7~lorophenyl and 2, 4-dlchlorophr~nyl.
Most preferably R i.s 2-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or ?.,4-dichlorophenyl.
Preferably Rl i.s methyl.
Preferably R? is H or methyl.
Most preferably RZ is H.
Preferably R1 is methyl and R2 is H or methyl.
Most preferably R1 is methyl and R2 is H.
Preferably X is N.
Preferably Y is F.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from acids which form non-toxic salts such as the hydrochloride, hydrobramide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. For a review on suitable pharmaceutical salts see Berge et al, J. Pharm. ~ci., 66, 1-19 (1.977).
Wtlere R1 is identical. to R2, the corc~ounds of the formula (I) contain one rhiral centre and therefore exist as a pair of enantiomer~~ (a .racem<~te) .
Where R1 and R2 are different, the co~ounds of the formula (I) contain at least two chiral centres (*) arx3 therefore exist as at least two diastereoisa<neric pairs of enanticrmers, i.e.

PLC 517 (SPC 7704) Rl K2 i~ ~ 2 ~ j ___ :v N
It The invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof.
separation of diastereoisamers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a d_iastereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared frc8n a corresponding optically pure intermediate or by resolution, either by H.P.L.C. of t.~ie racemate using a suitable rhiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid, e.g. 1R-(-)- or 1S-(-1-)-10-camphorsulphonic acid.
The preferred can~ounds of the formula (.C) when R2 is II have the ?.R,3S- configuration, i.e.
Rl fl N ~\ N ~~~ 121 ~ ~ jy ~~ ~ .
I
It y.~N

Particularly preferred individual embodiments of the compounds of the present invention are 2R,3S-2-(2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 2R,3S-2-(2-chlorophenyl)-3-(3-fluoropyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 2R,3S-2-(2-fluorophenyl)-3-(3-fluoropyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-~yl)-1-(1H-1,2,4-triazol-1-yl(butan-2-ol, and 2R,3S-2-(2,4-dichlorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, and pharmaceutically acceptable salts thereof.
In another aspect, the invention provides a process for the preparation of the compoundsof formula (I), which process comprises:
(a) reacting a 1'-deprotonated form of a compound of the formula:

~~~? x F~ (1 ~) ~ ~ (II) rr Y
wherein Rl, R2, X and Y are as defined above, with a compound of the formula:

f,.A ~
~.i' ~ ~ ~l' 5a N
~_N (III) R
wherein R is as defined above;
(b) reacting a compound of the formula:
Rl R2 O
X
or N
R Y
(IV) (VI) wherein R, Rl, R2, X and Y are as defined above and Z is a leaving group, either with a base salt of 1H-1,2,4-triazole or with 1H-1,2,4-triazole in the presence of an additional base;
(c) for the preparation of a compound of the formula:
(IA>
N
wherein R, Rl, R2 and Y are as defined above, reducing a compound of the formula 5b 69387-149 (XI) N N
Z' wherein R, R1, R2 and Y are as defined above and Z2 and Z3 are each independently selected from H and a group that may be selectively removed by reduction, with the proviso that Z2 and Z3 cannot both be H;
any of the said processes being optionally followed by conversion of the compound of the formula (I) to a pharmaceutically acceptable salt thereof.
The compounds of the formula (I) provided by the invention may be prepared by the following methods:
1) All the compounds of the formula (I) may be prepared as shown in Scheme 1:
Scheme 1 R1 7.) Base, solvent X A compound of the formula (I) R
N
Y ~ N 0 N
(II) ~r1 R
(III) PLC S17 (SPC 7704) .~,,~~r,;J~B~y, d' wherein R, Rl, R2, X and Y are as defined for a compound of the formula (I).
In a typical procedure a compound of the formula (II) is deprotonated by the addition of approximately one equivalent of a suitable base, e.g. lithium diisopropylamide, or sodium or potassitun bis(trimethylsilyl)amide, and the resulting salt (preferably the lithium, sodium or potassium salt) is reacted in situ with a ketone of the formula (III). The reaction is typically carried out at from -80° to -50°C, preferably at from -70° to -6o°C, in a suitable organic solvent, e.g.
tetrahydrofuran, toluene or diethyl ether, and under an inert atmosphere, e.g. nitrogen or argon.
The starting materials of the formula (II) are either knaNm compounds (e.g. see D. h. Comins et al, Hetemcycles, 22, 339 (1984)) or may be prepared by conventional procedures in accordance with literature precedents. The starting materials of the fot~mzla (III) are either known founds (e. g. see EP-A-44605, EP-A-69442 or G&-A-1464224) or may be prepared by similar methods to those described therefor.
2) All the compounds of the forrrni7.a (I) may also be prepared as shown in Schc~.me 2:-PLC 517 (SPC 7704) Scheme 2 i; ~ R l '/. Rl 1 (~i ~Y ~ o r_ R Y~N IZ ~\ , Y
(lV) (Vl) A base salt of a compound of the formula:-N' Nli solvent ~N/
H
or ~ base, solvent A compou:id of the formula (I) wherein R, R1, R2, X and Y are as defined for a found of the formula (I) and Z is a suitable leaving group, e.g. chloro, bromo or C1-C4 alkanesulphonyloxy (such as methanesulphonyloxy).
E~camples of suitable base salts of 1H-1,2,4-triazole are alkali metal, preferably sodium and potassium, and tetraalkylammonium, preferably tetra-n-butylammonium (see US-A-4259505), salts.
~Ifie reac.-tion is preferably carried out using an epoxide of the formula (N) as the starting material. If a compound of the formula (VI) is used in this process, it is probable that the reaction mechanism dictates, at least in part, that the corresponding epoxide of the formula (IV) is fornx~i in situ under the reaction conditions. The process is therefore, in PlC 517 (SPC 7704) ~ i:~
tY C~ :.1~ ~ T
B
this respect, similar to that utilising an epoxide of the formula (1V) as the starting material.
then a base salt of 1H-1,2,4-triazole is used, the reaction is typica7.ly carried out at from room terr~eratLiz-a to 100°C, preferably at abo(,it 60°C when using the sodium salt of 1I7-7.,?.,4-triazole, aril preferably at about room temperature when using the corresponding tetra-n-butylammoniwn salt, in a suitable organic solvent, e.g. N,N-dimethylformamide or tetrahydrof-~, Alternatively, the reaction. may be carried out using 1H-1,2,4-triazole in the presence of an additional suitable base, e.g. Na2003 or KZ~3, preferably at fin 50° to 100°C in a suitable solvent, e.g. N,N-dimethylforn~amide, methanol or aqueous acetone.
~e intermediate of the formula (IV) and (VI) may be prepared by conventional techniques as s~~.lsed by the following methods shoran in Sche~ 3 and 4:-Scheme 3 Rl -l.) Base, solvent X
Rz ' --~' G Rl I
Y z ) Otl ~X
R
R ~ y~
(II) (V) (VI) ItI (1 'X 1 It y \ N
(IV) PLC 517 (SPC 7704) ~,~a ~, e~ rJ V

wherein R, Rl, R2, X and Y are as defined for a cayourxi of the formula (I) and Z is a leaving group, preferably C1 or Br.
In a typical pn~cedure, a ~ow~d of the fornmla (II) is deprotonated by the addition of approximately one equivalent of a suitable base, e.g. lithium diisopropylamide, or sodium or potassium bis(trimethylsilyl)amide, and the resulting organometallic intermediate is reacted in situ with a compound of the formula (V). The reaction is typically carried out at from -80° to -50°C, preferably at about -70°C, in a suitable organic solvent, e.g. tetrahydrofuran, toluene or diethyl ether, and under an inert atmosphere, e.g. nitrogen or argon. The cxm~ound of the fornnua (VI) formed need not be isolated and is generally cyclised in situ after a period of stirring at a higher temperature,- e.g.
room ten~erature, to provide an oxizane of the formula (IV).
A compour)d of the formula (VI) when Z is chloro or bromo may also be prepared by reacting an epoxide of the formula (IV) with the appropriate hydrogen halide under anhydrous conditions.

PLC 577 (SPC 7704) Schett~ 4 Uli C X
'1 N
Y
0 ,X
(:CO~(C1-C~~ alky.l) (VI:I) R Y~N
K I2~- (VIII) X X
KZ/~~~ ~ a /
~N 1 Y ~ l;ase , (where RZ = C1-C4 (C1-C4 a:Lkyl)G1 alkyl) R Y ~ N Base, (C1-C4alkyl)Z1 R Y ~ N
(X).
(where R2 = C1_C4 alkyl) (IX) Epoxidation Epoxidation It.l.
Rl 2. ~ O

X
K Y \:/N
R
Y
(1V) (lVA) (Sahere Rz = C.i-C;~~ alkyl ) PLC 517 (SPC 7704) t,rherein R, Rl, R2, X and Y are as defined for a compound of true formula (I) and ZI is a suitable leaving group, e.g. Cl, Br, I or methanesulphonyloxy.
In a typical procedure a compound of the formula (VIII), (IX) or (X) is prepared directly from an ester of the formula (VII) by reaction with an organometallic W termediate derived by deprotonation of a compound of the formula:-Cti3 or R2 N
Y
Y
(II) as appropriate, wherein Rl, R2, X and Y are as defined for a armpOUnd of the fortaula (I), with approximately one equivalent of a suitable base, e.g. lithium diisopropylamide or sodium bis(trimethylsilyl)amide. The reaction is typically carried out at from -80° to -50°C, preferably at about -70°C, in a suitable organic solvent, e.g. tetrahydzlofuran or diethyl ether, and under an inert atmosphere, e.g. nitrogen or argon.
Alternatively, a found of the formula (IX) or (X) may be prepared by reacting, respectively, a cott~ound of the fornnlla (VIII) or (IX) with approximately one equivalent of a suitable base, e.g. sodium hydride, followed by alkylation of the resul.l<.lnt carban:ion in ~-i_tu with a ~n.aitable alkylatirx3 agent. 'l't1e reacticsn is; typically carried out at from 0°C to roam temperature i.n a suitable organic solvent, e.g. N,N-dimethylformamide.

P L C 5 1 7 < S p C 7 7 0 4 ) ~ ~,~ ~ i~ ~ ~ l Preferably, alkylation of a cc~ound of the formula (VIII) or (IX) is performed under phase transfer conditions, e.g. using NaOH/[CH3(CH2)3)qN~ eHS04/I-I?O/C1-ICl3/(Cl-C~ alkyl)Z1 (wherein Z1 is preferably iodo), at from 0°C to roam temperature, and typically at room temperature.
E~oxidation of a ketone of the formula (IX) or (X) i.s performed using conventional methods, e.g. u_sing dimethyloxosulphoni.um methylide (e.g. see J.A.C.S. [1965), 87, 1353) or chloromethyllithiwn (e. g. see Tet. Lett. [1986), 795).
3) The co~ounds of the formula (I) wherein R, R1, R2 and Y are as defined for a compour)d of the formula (I) and X is N may be prepared as shown in Scheme 5:-Scheme 5 Rl R2 OH
N~N i N L3 Repuotion ~ oompound of - j the formula (I) R N
wiaerei.n X is N
GZ
(XI) wherein R, Rl, R2 and Y are as defined for a compound of t.hc formula (I) and Z2 and Z3 are each independently selected from II
and a group that may be selectively removed by reduction, with the proviso that Z" and Z3 cannot both be H. Preferably Z2 is the PlC 517 (SPC 7704) group that may be selectively removed by reduction and Z3 is H.
Preferably the group that may be selectively remavc~d by reduction ... is halo (defined as F, C1, Br or I) and most preferably is chloro_ When ,aid group is halo, preferably chl.oro, the preferred method of reduction is by hydrogenolysis. In a typical proce~3ure a compound of the formula (XI) is subjected to hydrogenol.ysis using a suitable catalyst, e.g. palladium-on- charcoal, and a suitable solvent, e.g. ethanol, optionally in the presence of an additional suitable base, e.g. sodium acetate. The reaction may be carried out at from room te~erature to the reflux temperature of the solvent and at a pressure of from 1 to 5 atmospheres (100 kPa to 500 kPa), but generally proceeds satisfactorily at about roam tx~rg~xature and at about aerie pressure.
The intermediates of the formula (XI) wherein one of Z2 and Z3 is H and the other is a group that may be selectively removed by reduction may be conveniently prepared as shoum in Scheme 6:-Scheme 6 l3 1) 13a:>e, solvent _ --__.__r1 Cou~pc>unci of t Im~ f e» nnn I ;~ ( \ I ) () '/. L N~ N
-.
1;
(X11) (111) arc s » csPC mop wherein R, Rl, R2 and Y are as defined for a confound of the forlrrula (I) and one of Z2 and Z3 is H and the other is a group that may be selectively removed by reduction. the reaction may be carried out by a similar procc~ure to that describexl in Method (1) .
The intliates of the formula (XI) wherein one of Z2 and Z3 is H and other is a group that may be selectively remove by reduction may also be prepared by an analogous procedure to that described in Method (2).
The starting materials of the formula (XII) may be prepared by conventional procedures such as are illustrated in the following Preparations section.
The intermediates of the fornn~la (XI) wherein Z2 and Z3 are each a group that may be selectively removed by reduction may be prepared by an analogous procedure to that described in Method (2) by using an appropriate epoxide starting material which may be prepared as shown in Scheme 7 using oornrentional procedures:-PLC 517 (SPC 7704) ~..~ ~.i ~. .aL
Scheme 7 C:OZ (C1-C4alkyl) N~Z3 COZ(C~-(:alkyl) I 1) Base, so7.vent y \ 2) RCO.Z p /N ~y3 y - J I
y \ N
R !1 1) Hydrolysis/aecarboxylation 2) Alkylation Ri R2 3 ~ N
0 /N~Z Epoxidation \ N
R Y

wherein R, R1, R2 and Y are as defined for a compound of the formula (I), Z2 and Z3 are each a group that may be selectively removed by reduction and Z~ is chloro or C1-C~ alkoxy.
X1,11 of the above reactions are conventional arld appropriate reagents and reaction conditions for ttreir performance and procedures for i~>olating the desired products will tx~ well known to those skilled in the art, in accordance with literature prece~c3ents and by reference to the Facalr>ples hereto.

PlC 517 <SPC 7704) _ A pharmaceutically acceptable acid addition salt is readily prepared by mixing together solutions containing the free base and the desired acid. 'Ifie salt generally precipitates from solution and is collected by filtration, or is recovered by evaporation of the solvent.
The compounds of the formula (I) and their salts are anti-fungal agents, useful in the curative or prophylactic treatment of fungal infections in animals, including humans. For example, they are useful in treating topical fungal infections in man caused by, among other organisms, species of Candida, Trichotahyton, Microsporwn or E~idermophyton, or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal car)didiasis). They can also be used in the treatment of systemic fungal infections caused by, for example, species of ~ida (e. g. Candida albicans), Cryptococcus neoforn~ans, As-oe iln~lus flavus, Acne ir~lus fumiqatus, Coecidioides, Paracoccidioides, Histoplasma or Blastomyces.
Trae compounds of the present invention have been found to have unexpecteclly good activity against the clinically important ~r~illus spp. fungi. This is mainly attributable to their unexpectedly good phannacokinetic properties which result in longer half-lives (t; values).
The in vitro evaluation of the antifungal activity o.f the compounds can be performed by determining the minimum inhibitory concentration (m.i.c.), which is the concentration of 'the test compounds, in a suitable medium, at which growth of the particular micro-organism fails to occur. In practice, a series of agar plates, each having the test compound incorporated at a particular PLC 517 (SPC 7704) K.1 ~ s~ ~ Jx concentration, is inoculated with a standa~ culture of, for example, Candida albicans, and each plate is then incubated for 4F3 hours at 37°C. The plates are then examined for the presence or absence of growth of the fungus and the appropriate m.i.c. value is noted. Othex micro-orr~anisms used in such tests can. include ~ls~erctillus fiunigatus, Tricho~hyton ~. , I~Sicrosponxm spp. , ,~idermo h on flocc:osum, Ccxxidioides inmriti s and ~Ibrulopsis dlabrata.
The in vivo evaluation of the co~ounds can be carried out at a series of dose levels by intraperitoneal or intravenous injection, or by oral achninistration, to mice which are inoculated with, e.g., a strain of Carx7ida albicans or Asper il~lus fumiaatus.
Activity is based on the survival of a treated group of mice after the death of an untreated gtroup of mice. The dose level at which the compound provides 50% protection against the lethal effect of the infection (PD50) is noted. For Aspergillus sue. infection models, the number of mice cured of the infection after a set dose allows further assessment of activity.
For human use, the antifungal cc~rrpounds of the formula (I) and their salts can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier. selected with regard to the intended route of administration and standar~:3 pharmaceutical practice. For example, they can be adm.ini.stered orally in the form of t<~blets containing such cocir»entr a:~ ~;t.trrch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They call PLC 517 (SPC 770L) be injected parenterally, for e~le, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used i.n the form of a sterile aqueous solution which may contain other substanc:e_s, for example, enough salts or glucose to rr~ce the solution isotonic with blood.
The solubility of a con~-~ourxi of the formula (I) :in an aqueous medium rnay be improved by rcxr~lexation with a hydroxyalkyl derivative of a cyclodextrin in the preparation of an appropriate pharmaceutical carrposition. Preferably the cyclodextrin used is alpha-, beta-, or gamma-cyclodextrin and most preferably is beta-cyclodextrin. Preferably the hydroxyalkyl derivative is a hydroxypropyl derivative.
For oral and parenteral administration to human patients, the daily dosage level of the antifungal compounds of the formula (I) and their salts will be from 0.01 to 20 mg/kg (in single or divid~i doses) when administered by either the oral or parenteral route. Thus tablets or capsules of the armpounds will contain from 5 ng to 0.5 g of active oompour)d for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for.
an individual patient and it will vary with the age, weight and response of the particular patient. 'fhe above dosages- are exemplary of the average case; there can, of course, be irxli.vidual instance's where higher or lcxrer dor-x~ge ranges urc~ rrx~rit(~(l; <uxl such are within the scope of this invention.
Alternatively, the antifungal compounds of formula (I) c~ln tx administered in the form of a suppository or pc~ssary, or they may be applied topically .in the form of a lotion, solution, cream, ointment or chrsting p(x,~7er. For example, they can be incorporated PLC 517 (SPC 7704) into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between I and 100, into an ointment consisting of a white wax or white soft paraffin base together wiih such stabilizers and preservatives as may be required.
Thus the invention further provides a ptarn~aceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention yet further provides a c~ound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament, in particular as an antifungal agent.
The invention also provides the use of a c~pound of the formula (I), or of a pharmaceutically acceptable salt or co~osition thereof, for the manufacture of an antifungal agent.
The invention yet further provides a method of treating an animal (including a human being) to cure or prevent a fungal infection, which irises treating said animal with an effective amount of a compound of the formula (I), or with, as appropriate, a pharmaceutically acceptable salt or composition thereof.
The invention also provides rx)vel intermediates of the formulae (IV), (VI) and (XI), 4-ethyl-5-fluoropyridimine and 4-chloro-6-ethyl-5-fluoropyr.imidine.
'lfie follcxai.rx~ I:5!amlple:~ illustrate the prep~zrz~t:ion of the compourxls of the formula (I). It is believed that ermntiomeric pair B, when referred to i.n any following 31e or Hreparation, and the products of EScamples 1, 3, 4 and 5 (in each of which only one of the two possible enantiomeric pairs was obtained) are a racemic mixture of the 2R,3S- and 2S,3R- enantiomers.

P~c s » csvc ~~op ZO
E~CAMPI~ 1 3-(3-Chl_oro~yridin-~1=yl)~?-(_2,4-difluorophenyl)-1-(1H-7.,2,4-triazol-7.-yl ) butan-2=of cla cI
ca., 1.) 1.17A, 'I'fIF
M
_ -~ 1 N~ ~ 0 F
F
F
To a solution of diisopropylamine (1.01 g, 10 r~unol) in dry THF (60m1) at -60°C and under a nitrogen atmosphere eras added dropwise a 1.6 M solution of n-butyllithium in hexane (6.25m1, 10 mmol). The mixture was allowed to warm to -20°C then retooled to -70°C and to the resulting solution of lithium diisopropylamide (LDA) (10 mnol) at -70°C was added dropwise 3-chloro-4-ethylpyridine (see D. L. Comins et al, Heterocycles, ??, 339 ( 1984 ) ) ( 1. 41 g, 10 nm~ol ) . 'fhe resulting mixture was ;stirred at this temperature for 15 minutes after which time a solution of 1-(2,4-clif:7uoroph~nyl.)-?.-(7Ii-7,2.,4-t:ri<»ol-1.-yl)~~t-hnnone (7..7.'i g, mmol ) i n 'I7-II~' ( 1.5m1 ) wZ:a added . 'I'hi > mixture way; a:l l owed to warns to room temperwture over a 30 minute perri.od and tl~e reaction w-as quenchc~l by the addition of water (30m1) and extractexl with FLC 517 (SPC 7704) 7 ~ ....
~~~eJ:~~~-Zl ethyl acet<~te (3 x 60m1). 'fhe combined oceanic extracts were dried over magnesiLml sulphate, filtered, concentrated under reduced pressure and the title co~ound isolated by "flash"
chromatography on silica eluting with ethyl acetate. 'Ifile product was recrysta:Llised from ethyl acetate (yield = 0.46 g), m.p.
182-184°C. Found: 0,55.?6; I-1,4.15; N,15.23; C17tI15C1F2N40 requires: 0,55.98; FI,4.14; N,15.36%.

2-(2,4-Difluorophen-yl)3--(3-fluoropyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-of cH3 F CH., ~.
r I
~I / 1) LDA, THF
1 ~~ N
H 2) ~ i ,\

F
F
The reaction was carried out by a similar method to that described for Exarr~lE 1 using 4-ethyl-3-fluoropyridine (see Preparation 1) instead of 3-chloro-4-ethylpyr:id.ine as the :=.tmrti.rlg material.. Column chromat:ogra:lphy of the cnlde raaction L>r(:x_3nca. on silica using ethyl acetate as the eluant first gave, after combination and evaporation of the appropriate fractions, the title co~ound, enantiomeric pair A, m.p. 178-181°C, which was characterised by H-NMf2 spectroscopy.

FLC 517 (Sf'C 7704) -I~IR (CDC13): d = 1.6 (d, 3H), 3.95 (q, 11-1), 4.7 and 5.15 (AB q, 2H) , 5.1 (s, l1-I (OH) ) , 6.5 (m, 1H) , 6.7 (m, 1H) , 6.95 (m, 113) , 7.45 (t, 113) , 7.8 (s, 13-I) , 7.95 (s, ltd) , 8.15 (s, lt3) , 8.2.5 (d, 1H) ppm.
Fl~rther elution with 95:5 ethyl acetate/methanol provided, after combination and evaporation of the appropriate fractions, the impure title compound, enantiameric pair B. 'Ibis was further purified by colwnn chromatography on silica using 93:7:1 dirhloromethane/methanol/0.880 aqueous anunonia as the eluant. The appropriate fractions were combined and evaporated to provide, after trituration with diethyl ether, the title cc~ound, enantiomeric pair B, m.p. 188-9°C. Faur+d: C,57.63; H,4.32;
N,15.71; C17H15F3N4oØ25 H20 requires: C,57.87; H,4_43;
N,15.88%.
~antiomeric pair B eras resolved by H.P.L.C. using a chiral support (Q-~AC~L ~ OG) and eluting with 1:1 isopropanol/heme.
The appropriate fractions were combined and evaporated to provide the resolved individual enantiomers, each contaminated with the chiral support.
Each inure enantiomer was further purified by column chromatography on silica using dichloromethane/methanol (95:5) as the el.uant. 'Ibe appropriate fractions were combinec:I atx3 evaporated to give, after triturat.i.on with hex~ne/<liethyl ether, purified individual enantiomer.
One enantiomer of m.p. 57-59°C and [a]fir' -59° (c =-ltnc3/ml in methanol ) and another. of. m. p . 56-57 ° C and [ a ] D5 -+- 5'7 ° ( c = lrng/ml in methanol) were obtained.

PLC 517 (SPC 770~~) ~CAMPLES 3 to 6 The follcxaing tabulated founds of the general formula:-Ofl N~N
w R Y ~ N
were prepared by a similar method to that described for ale 1 using the appropriate 4-ethyl-3-halopyridine and 1-(halophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone as the starting materials.

K~~~,;_,,,.,4, 2J~ ~,~3.~~.3~~ .:
o~ O
r., z z ~ v a W r r-t vo ~ ~ti ~r ~ ~-I ~r a~ m x -~ z x N ~ In tf1 tf1 O~ S-! ~D O ~1 10 CO O d' 01 O V' ll~ d' l~ V' U ~ x V
U co U co m ~ co N
l~ U U f~ U U
U t~ u1 to M
.-i N M
- Z

'.' a t~. V
n rs s ~ s3 ~~~~~~s~.
I
I
I
I

I
I
I
I
~r; . i CO N 1 In d' t ~

1 ~
I
o\o '~.., ~ o\o I o Z o\
o . fa r° i ..
O~ d' ~.-I I M
O~ tf7 I ~ ~V
d' r-i ' ri I ~ ~-i a I ~r 1-a x .~ z x z i x .~, .. ° ~ i .. y o x ~, i ~ 1a .-.; ~,:
O d' I O ~r ~D d~ I ~
<f' x tn x I tt1 x U ;c I
~?, r~-I ~ U r~-f a: i G~, U U (~ U U I t~ U U
I
I
-~ i -~
_ 1 1 ~ ~ 1 I
M N
_z -z _z r~
o, z° ~ '°

PLC 517 (SPC 7%04) (1) Column chromatography was carried out on silica with a gradient elution using 2:1 ethyl acetate/dichloramethane followed by ethyl acetate as the eluant. The resulting solid obtained was triturated with diethyl ether to provide the desired product.
(2) See E3carnple 1 for reference to starting material.
(3) See Preparation 1 for starting material.
(4) Column chromatography was carried out on silica with a gradient elution using 2:1 ethyl acetate/dichl.oromethane followed by ethyl acetate as the eluant. The appropriate fractions were cr~mbined and evaporated and the material obtained was further purified by column chromatography on silica using 93:7:1 dichloramethane/methanol/0.880 aqueous ammonia as the eluant. The appropriate fractions were combined and evaporated and the residue triturated with diethyl ether to provide the desired product.
(5) The enantiameric pair obtained was resolved by H.P.L.C. using a similar method to that described in E7~mple 2. This provided the individual enantiomers, one of m.p. 83-84°C and [a]D5-80° (c = lmg/ml in methanol) and the other of m.p.
78-79°C and (a]D5 +82° (c = lmg/ml in methanol).
(6) Column chromatography was carried out on silica using 80:20:1.5 hexane/isopropanol/ 0.880 aqueous a7mnonia as the eluant. The appropriate fractions were combined and evaporated and the material obtained was further purified by column chromatography on silica using 97:3 ethyl acetate/
ethanol as the eluant. 'lfie appropriate fract.iorl~~ were combined and evaporatc~l to provide the separated enantiomeric pairs. Each enantiomeric pair. was triturated with diethyl ether to provide the desired product.
(7) The enantiameric pair obtained was resolved by H.P.L.C. using a similar method to that described in lle 2.

.:3:~~ci-,r.A :i ~.~ ~~~~y=
PLC 517 (SPC 7704) E~{AMPLE 7 _?_~~ 4-Di f luorophenyl ) -3- L5-f Luoropyr. imidi-n-4-yl ) -1- ( 1H-1, 2 , 4-tri-azol-1-yl~ butan-2-of Elz > for cn., Pa/c, 1 -~- N~~~ 1 N CH3COZNa' \-- N
CZI1~02-1 r.
A solution of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1--yl)butan-2-ol, enantiomeric pair B (see Preparation 2(iii)) (0.307 g, 0.8 Irmrol) in ethanol (20m1) was hydrogenated at atri~pheric pressure and at room te~erature in the presence of 10% pallad_iwnron-charcoal (30 mg) and sodiwn acetate (0.082 g, 1 rrmrol). After 5 hours a further 10 mg of loo palladiwn-on-charcoal was added arrd hydrogenation was continued for an additior~al 1 hour period. ~Ihe catalyst was removed by filtration and the filtrate was concentrated in vaeuo.
"Flash" chromatography of the residue on silica using 97:3 ethyl ac<_>tate/methanol as tW a c~-lm<)nt provided, after coml~inr~t::ion and evaporation of appropriate fractions and trituration with diethyl ether, the title compowx3, enantiomeric pair 13, (0.249 g, F39~), m.p. 127°C. Found: C,55.08; (1,4.00; N,19.96; 0161-1141~3N5~
requires: C,55.01; H,4.01; N,20.05%.

PLC S17 (SPC 7704) ~~ ~ ~~ux.~,,~
~.i ~J ~ ~3 _~. ~.

A sample of the title wzd, enantiomeric pair B, (O.lOSg, 0.3 rmnol) and 1R-(-)-10-camphorsulphonic acid (0.07g, 0.3 mmol) were dissolved in methanol (4m1) then cooled to 0'C for 2 hours.
fhe resulting crystalline solid was collected by filtration to give 2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(13i-1,2,4-triazol-1-yl)butan-2-of 1R-(-)-10-camphorsulphonate 0.5 methanol (0.06g), m.p. 176°C, [aJDS-49.5° (c = 2 mg/ml in methanol). Found: C,53.09; H,5.36; N,11.43; C26H30F3N505S'0.5 CH30Fi re~lires: C,53.27; H,5.36; N,11.730. The absolute configuration of the cou~pound was confirmed by single crystal X-ray analysis.
The filtrate from the crystallisation was evaporated in vacuo and partitioned between dichloromethane (lOml) and saturated aqueous sodium bicarbonate solution (5m1). The organic layer was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue and 15-(+)-10-ca»>phorsulphonic acid (0.468, 0.2 ltunol) were dissolved in methanol (3m1) then cooled to 0°C for 2 hours. The crystalline solid was collected by filtration to give 2S,3R-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-of 1S-(+)-10-cair~horsulphonate 0.5 methanol (0.052g), m.p. 176°C, [a)D5+ 54.5° (c = 2mg/ml in methanol). Found: C,53.27; H,5.31;
N,11.64; C26ti30F3N505S. 0.5 CH30H requires: C,53.27; H,5.36;
N, 1.7..73 0.

PLC 517 (SPC 7704) ~s31'F~;~Wg A
r.o 3 tJ =i e~
A sample of the 1R-(-)-10--camphorsulphonate salt (1.22g, 2.1 mmol) prepared according to the above method was partitioned between dichloramethane (20m1) and saturated acJueous sodium bicarbonate (3m1). The organic layer. was washed with water (5m1) then dried aver magr~sium sulphate, filtered and evaporate i.n vacuo to give 2R,3S-2-(2,4-difluorophenyl.)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-of (0.64g), m.p. 127°C, [a)D5 -62' (c = l.mg/ml in methanol).
A sample of the 1S-(+)-10-carnphorsulphonate salt (1.17g, 2.0 mtnol) prepared aoco~ing to the above method was treated by a similar method to that described above for the 1R-(-)-10-camphorsulphonate salt to give 2S,3R-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-of (0.63g), m.p. 127°C, (a)D5 +59.5° (c = 2mg/ml in methanol).

~2,4-Difluorophern7l)-3-(5-fluoropyrimidin-4 yl)-1-(1H-1 2 4-triazol-1 yl)butan-2-ol, enantiameric pair B
cii.S
r.n.j ~ ) f (c;n.;) .j~, ~ ~ ~nv;~ ,'riir can _ ~ . ~~ i: , i ~. . " i, ~s , i ~
v ~ _ _ , i ~I ~ ~-I/ .. Il., PlC 517 CSPC 7704) ;~~i ~...~,~
yr )J ~~i °~ cs~ ~. ' To Tflf (200m1) was added sodiLUn bis(trimethylsilyl)amide (79m1 of a 1.OM solution in THF) and the solution cooled to -65°C
under nitrogen. A solution of 4-ethyl-5-fluoropyrimidine (lOg) (see Preparation 8) in TfIF' (100m1) was added over 30 minute_.s.
After stirring for 3 hours at -65°C the thin slurry was treated with a solution of 1-(2,4-difluorophenyl)-2-(1fI-1,2,4-triazol.-1.-yl)ethanone (17.7g) in 'fFff (1U0m1.), dropwise over 30 minutes.
'lfie solution was stirred for a further 1 hour at -65°C and then treated with acetic acid (20m1). After wanni.ng to -20°C the solution was washed with water (200m1) and the oceanic layer separated and combined with an ethyl acetate (200m1) back extract of the aqueous phase. The combined organic layers were concentrated under reduced pressure to provide a solid that was triturated with diethyl ether (23om1) and filtered. The filtrate was concentrated under reduced pressure and chramatographed on silica with 1:1 diethyl ether/ethyl acetate as the eluent. The fractions containing the title found were combined, concentrated under reduced pressure and the residue chromatographed on silica with 1:1 ethyl acetate/hexane as the eluent. The appropriate fractiorLS were combined and evaporated under reduced pressure to provide the purified title compound (0.82g), m.p. 125-127°C. Found: C,54.89; H,4.06; N,19.66;
C16II14F3N50 requires: C,55.01.; II,4.01; N,?Ø05.

PLC 517 (SPC 7704) (AMPLE 9 2-(2,4-Difluorophen~lL3-(5-fluoropvrimidin-4-yl)-7.-(1H-1 2 4-triazol-1-yl)butan-2-ol, enantiomeric pair A
~2ie title co~x~und was prepared by a similar metlood to that used in Exa~le 7 using 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(lI3--1,2,4-triazol-1-yl)butan-2-ol, enantiameric pair A (sec Preparation 2(iii)) as the starting material. Znis gave the product, m.p. 137°C. Found: C,54.B9;
H,4.06; N,19.82; C1~F314F3N5C requires: C,55.01; H,4.01; N,20.050.
F~At~'LE 10 3-(5-C~loropyrimidin-4-yl)-2-(2 4-difluorophen~l'v-1-(1H-1 2 4-tri-azol-1-yl)butan-2-ol, enantian~xic~air B
CH3 HZ, 10~ Pd/C, CH., OH ~~~
N~N ~ CH3C02Na, N N
N CI ~ N

PlC 517 (SPC 7704) A solution of 3-(4,5-dichloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (see Preparation 6(iii)) (0.58 g, 1.46 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of loo palladium-on-charcoal (45 mg) and sodi~nn acetate. (122 mg, 1.5 nm~ol) for 7 hours. 'fhe catalyst was then removed by filtration and the filtrate was concentrated under reduced pressure. "Flash" chrcs~natography of tl~e residue on silica using ethyl acetate as the eluant provided, after combination and evaporation of the appropriate fractions, the title compound (0.35 g, 720), m.p. 128°C. Found: C,51.68;
H,3.89; N,18.58; C16H14C1F2N50Ø3 H20 requires: C,51.76; H,3.94;
N,18.87%.

3-y5-C~l.oropyrimidin-4 yl)~z-(2 4-difluon~phenyl, -1-(1H-1 2 4-triazol-1-yl)butan-2ro1, enantiomeric pair A
The title compound was obtained by a similar method to that used in F~cample 10 using 3-(4,5-dichloropyrimidln-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair A (see Preparation 6(iii)) as the starting material. 'this gave the product as a gum that was characterised by 1tI-NMR
spectroscopy.
-~-NMR (CDC13) a -= 1.50 (d, 3H) , 4.4 (q, 111) , 4.67 and 4 .82 (Ar3 q, 2H) , 6.35 (s, 1H (OII) ) , 6.45 (m, 7Ii) , 6.62 (m, lE~) , 7.07 (m, lIl) , 7.6 (s, 1H), 8.05 (s, 1H), 8.5 (s, 1H), 8.8 (s, lI-I) ppm.

PLC 517 (SPC 7704>

~MPIES 12 to 16 Zhe following tabulated ~ow~ds of the general forniula:-N~ /N
~N R g were prepared by a similar method to that described for F~arnple 10 using the appropriate 2-aryl-3-(4-chloro-5-fluoropyrimidin-6-yl)-1-(~I-i-1,2,4-triazol-1-yl)butan-2ro1 as the starting materi~..l.

3y N r-~
O O r-1 N N O O
CO
zoo z n~zovzwz r-i ~- ~i ~ ~ N
M
CO ~ CO ~ O
~D e--I l0 n-1 M ~ O N ~ O tD q7 N ~ N N S-1 rl v' .~ V' ~ Z tr .li <r fa M ~.-i x: -~i x ~~ x z x ~~ z x ~ z r~ ~- r; m ~ti Ll~ ~ S-1 M 'M S-I M M ~ 10 'd' ~ d' ~ O V' ,~ O d' N :n M
z x ~ znx ~ ~ x ~ ~ x ° ~ x N U N ~ U N ~- U .-i ~- U .-t ~- U ~ ~--..-1 G=. ~-I
?m-1 c~ r~-I O~ ~~-1 N .~-1 N ~.~..~ N
r1 U U ~ ~ .-i ,~-i ~
UU G~,UU f~.UU t~UU
U
~r t~ j '-t ''~-I
f.~. ~-'~i p ~ o U
-~-i ~y ~ ~ CO ~ GA
~r y c~ .-, ~'-' CJ .-i U
cJ
\ / \ \ ~ \ / \
v ~z PLC S17 (SPC 7704) (1) Column chromatography was Carried out on silica using 96:4 ethyl aCetate/methanol as the eluant.
(2) Column Chromatography was Carried out on silica using isobutylmethylketone as the eluant.
(3) See Preparation 3 for starting material.
(4) See Preparation 4 for starting material.
(5) See Preparation 5 for starting material.
(6) The enantiameric pair obtained was resolved by H.P.L.C. using a similar method to that described in EXarcg~le 2.

PLC 517 (SPC 7704) FJCAMPL~E 17 An ac;ueous saline solution of 2R,3S-2-(2 4-clifluorophenylL
3-(5-fluoropyrimidin-4-yl)-1-(17~-1,2,4-triazol-1-yl)butan-2-of and hydro~pyl-!3-cyclodeotrin Hydroxypropyl-Q-cyclodertr.in (Molar Sutxtitution = 0.41, lg) was placed in a 10m1 volumetric flask and dissolved in distilled water (ca. 7m1). Sodium chloride (90mg) was added and dissolved in the solution and the volume made up to lOml with distilled water. The resulting solution was added to 2R,3S-2-(2,4-difluorophenyl)-3-(5-fluorropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-of (100mq) (see Example 7) in a vial and the mixture was sonicated for 15 minutes and then further mixed by mechanical rotation of the vial for 2 days. A further quantity of hydroxypxnpyl-Q- cyclodextrin (200mg) was then added and the mixture mixed by mechanical rotation of the vial for 1 hour to provide the title solution.

PLC 517 (SPC 7704) _ ~~.~~n~~~r Zfie following Preparations illustrate the preparation of certain novel starting materials used .in the EScamples.
Pre ration 1 4-Ethyl-3-fluoropyrid.ine Ctt3\
I~ 1) L,DA, 7'11F l N
2) C2H5I N
To a stirred solution of I~ (200 ~1) in dryi~' (400 ml) (prepared by a similar method to that used in Fle 1) at -70°C
aril under a nitrogen a~phere was added dropwise 3-fluoro-pyridine (20 g, 200 mmol). After 30 minutes at this te~erature ethyl iodide (60 g, 370 mmol) was added dropwise to the reaction and the mixture was allowed to warm slowly to between -10° and -5°C whereupon an exotherm accvrred and the txture rose to 15° to 20°C. The mixture was stirred for a further 30 minutes after which time the reaction was quenched by the addition of water (50 ml) and the organic pHase separated. The aqucom pt)a~;e was extracted with ether (3 x 50 ml) and the combined on~an:ic layers were dried over m;oln~s.ium ~~ulphate and cor~cu~trut=c~c~ ~oxler reduced pressure. 1fie resulting liquid was distil=Led at atmospheric pressure to yield the title compound (13 g), b.p.
154-158°C, which was ct~racterised by 11I-NMR spectroscopy.

PLC 517 (SPC 7704) ~~3~1~~~~

lei-NMR (CDC13): b = 1.25 (t, 3H, J = 10 Hz), 2.s5 (q, 2H, J = 10 Hz), 7.1 (t, lli, J = 8Hz), 8.3 (d, lli, J = 8Hz), 8.33 (s, 1H) ppm_ Pre~rati.on 2 3- 4-Chloro-5-fluoro~r._imidin-6-yl)-2-L 4-difluorophon~ 1-!11-I-1 2 4-tr.iazol-1-yl)bUtap-?.-o1 CI13 I' Cfi3 .N
OCfIICH3 ( 1. ) CH30Na, CH30}i IdH
0 0 - ~ F
(2) /NH
HC
~ NH2.CH3COZH
(i) (ii) POC13 N
F ~ N

1) LDA, THF
(ii.i.) z) ~
N
,:
Cfi., N~ N

;, ,:
F

PLC 517 (SPC 770~~> ~ a s (i) 6-Ethyl-5-fluoropyrimidin-4(3H)-one To a solution of sodium methoxide (8.64 g, 160 ~nol) in methanol (50 ml) at 0°C was added a solution of ethyl a-fluoropropionylacetate (see E. D. gerr3mann et al, J.
Chem. Soc., 1959, 3278 and D. J. Burton et al, Tet. Lc_tt., 30, 6113 (1989)) (12.96 g, 80- rranol) and formamidine acetate (8.32 g, 80 mmol) in methanol (50 ml) and the resulting mixture was stirred at 0°C for. 1 hour, overnight at room temperature and finally for 30 minutes order reflex. Zne mixture was cooled and the excevs sodiwn methoxide was neutralised by the addition of glacial acetic acid (10 g).
The reaction was concentrated under reduced pressure and the residue was dissolved in hot ethyl acetate, the insoluble sodium acetate was removed by filtration and the filtrate was concentrated under reduced pressure. "Flash"
chromatography of the residue using ethyl acetate as the eluant provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the title compound (5.5 g, 480), m.p. 105-106°C. Found:
C,50.38; H,4.85; N,19.63; C6H.~FN20 requires: C,50.70;
H,4.93; N,19.720.
The title compound may also be prepared as described .i.n I're~x~ration 7.
(ii) 4-Chloro-G~thyl-5-fluoro~pyrimi.dine A mixture of the product of part (i) (6.4 g, 45 mmol) aril phosphoryl chloride (30 ml) was heated under reflex for 3 hours. 'fhe excess phosphoryl chloride was removed by PLC 517 (SPC 770G) 6y~ s9.~~
~~t~=J.~~~'.~
distillation under reduced pressure and the residue was poured into ice--water. The resulting mixture was extracted with methylene chloride (3 x 50 ml) and the combined organic extracts were washed with water and dried aver magnesiwn sulphate. Zfie solvent was removed under reduced pressure and the resulting oil was distilled under rc~uced pressure to provide the title c~ound (4.81 g, 660), b.p. 74°C at 22 rrQn Hg, which was characterised by 1H-NMR spectroscopy.
-I~IR (CDC13): d = 1.3 (t, 3H, J = lOHz), 2.9 (q, 2H, J =
lOHz), 8.68 (s, 1H) ppm.
(iii) 3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2 4-difluorophen~l)-1-(1H-1,2,4-triazol-1-yI)butan-2rol To a solution of IIaA (20 mmol) in THF1 (50 ml) (prepared by a similar method to that used in ale 1) under a nitrogen atmosphere and at -70°C was added dropwise a solution of the product of part (ii) (3.2 g, 20 mmol) in THF1 (30 ml) over 15 minutes. The resulting mixture was stirred at this te.~rperature for 3 hours. To the resulting solution was added a solution of 1-(2,4-difl.uorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (4.46 g, 20 mmol) in Z'f-IF
(50 ml) and the mixture was maintained at -70°C for 7. hour and then at -50"C for a fmrther 1 hour. The rc~~~caion w~~~:
quenched by the addition of a solution of glacial acetic acid (1.2 g) in water (10 ml) and the mixture was allowed to wazm to roam temperature. 'Ihe organic phase was separated, the aqueous phase extracted with ethyl acetate PLC S17 (SPC 7704) / ~t~ h . i (20 ml) and the combined organic layers were dried over magnesiwn sulphate and concentrated under reduced pressure.
Column chromatography of the residue on silica using 3:2 ethyl acetate/diethyl ether as the eluant first gave, after c:ambination and evaporation of appropriate fractions and trituration with diethyl ether, the title co~?our~d, enantiomeric pair B (0.94 g, 12%), m.p. 92°C. Found:
C,49.93; H,3.57; N,18.17; C16H13C1F3N50 requires:
C,50.06; H,3.39; N,18.25%.
Further elution gave, after ccxnbination and evaporation of appropriate fractions, the title corr4pour)d, enantiameric pair A contaminated with ketone starting material. 'I'his was purified by several reczystallisations from diethyl ether to provide the product, m.p. 132°C. Found: C,49.93;
H,3.58; N,18.23: C16H13C1F3N50 requires: C,50.06; H,3.39;
N,18.25%.
(1) TfIF may be replaced by toluene.

aLC 517 (SPC 7704) Preparations 3 to 5 'Ifi)e following tabulated ~owx~s of the general fornntla:-(;f1 j Oll N~N
~N~

were prepared by a similar method to that described in Preparation 2(iii) using 4-chloro-6-ethyl-5-fluoropyrimidine and the appropriate 1-aryl-2-(~I-I-1,2,4-triazol-1-yl)ethanone as the starting materials.

~~it~,~r~~4~

_ __ 1 I I
I I

1 t I I
I I

I I
I I

I I
I .. 1 O I N ,-1 I rH ~j I ~
i r-I
zo~~zo~zo~~i o ' N , z o~ z ov I O ~ r-i ~ I r-i M ~ CO
O ~ O~ ~ ~ ~ f . ~ ~ O ~ lJ
~ 1 -I
I M ~.-1 . M .,.1 :x '~ x z ; x '~ x 1 .. I .
s-I ~;
o~'i ;~o In~'~i~:~'o ~'o o~ o N Z 1 c~ z M o O M j p O M In c~
w N x 1 m N x In ~ x 1 n U .-~I ~. j U ~'i .. U ,-N ~. 1 U ~ ~~ U .-M ._ ~ N d' N M r-i I r-1 . ,--, rtf tD tn tD W ~ !n ~ tOn !~ U U ~ C~ U U fy U U ~ k. V U f=. U U

I
_ I I
V ~ ~ i o ~r i I i '1 I
N
a~ ~ ~ i ~ r' ri I I

I I

''1 ~ ~ ~ f~ 1 R' LO
I j I I

r-I .-i I'' V V
-I
>~

+~
M
~n %~'~~~~~~ r~
PLC S17 (SPC 7704) r;a'i _I_'reparation 6 3-j4~5-Dichlor~imi.din-6-yl)-2-(2 4-difluoro_phenyl)-1(1H-1 j ?L4-triarol-1-yl~ butyn__?._ of Cti3 OCII j I II

1.) CHjON;i , CIi30Fl (1) ~Nfl Chl3 Z) IiC~
N112. CH3COOH CH3 ' 1 N
NH aq. HZO2, T
~1 p c.HCl NH

(ii) 0 (ii) POC13 N
N

1) I,DA, 'CIIF
2) N~N 0 F
_N
r,.. C I1., ( i i i ) 1:
N/ N
N
F

PLC S17 (SPC 7704) ~~i°~~~ ~ ,!.
(i) 6-Ethylp~rimidin-4f3H)-ore To a solution of sodium methoxide (4.19 kg, 77.6 mol) and forn~amidine acetate (3.0 kg, 28.8 mol) in methanol (45 L) at 5-1o°C was added slowly a solution of methyl propionylacetate (2.5 kg, 19.2 mol) in methanol (10 L) maintaining the t~~erature below 20°C throughout the addition. fhe resulting mixture was stirred at roam ter~erature overnight after which time the pH was adjusted to 7 by the addition of concentrated taydrochloric acid. The reacfi ion mixture was concentrated under reduced pressure to ca. l0 L in volume, diluted with water (10 L) and was extracted with 2-butanone (2 x 30 L). The combined organic extracts were concentrated under reduced pressure to ca. 2 L in volume and diluted with ethyl acetate (4 L). The desired product crystallised from the solution (2.4 kg, 700) and was recrystallised from isopropanol to yield a product of m.p.
132-134°C. Found: C,58.45; H,6.37; N,22.41; C6H8N20 requires:
C,58.05; H,6.50; N,22.57%.
(ii) 4,5-Dichloro-6-ethylpyrimidine To a solution of 6-ethylpyrimidin-4(3H)-one (the product of part (i)) (18.6 g, 150 mmol) in concentrated hydrochloric acid (120 ml) at 30-40°C was added dro~ri.se a 30 wt.
sol.i.)tion of hydrogen peroxide i.n water (18 ml) over a period of 30 minutes (slight exotherm result~a) and the resulting mixture was stirred overnight at 40'C. 'fhe mixture was concentrated under reduced pressure and the residue was suspended~dissolved in toluene and the toluene removed under reduc~l pressure.

P L C S 1 7 ( S P C 7 7 0 4 ) ~'~ ,rx~' =~"~ 57 a 'fhe residue was dissolved in phosphon~s oxychloride (150 ml) and heated under reflux for 3 hours after which time the excess phosphorus oxychloride was removed under reduced pressure. 1'he residue was poured into ice/water, extracted with methylene chloride (3 x 50 ml) and the combined o~an:ic extxact s were washed with water. (30 ml) and driec:3 aver magnesium sulphate. The solvent was removF.xt under reduced pressure and the resulting oil was distilled under reduced pressure to yield the title con~our~d (5.4 g, 200), b.p. 104°C at 22 mm Hg, which was characterised by 1H-NMR
~pY-1H-I~1R (CDC13): 6 = 1.3 (t, 3H, J = lOHz), 3.04 (q, 2H, J =
lOHz) , 8.75 (s, II~i) ppm.
(iii) 3-(4,5-Dichloropyrim_idin-6-yl)-2-(2 4-difluorophenyll-1-11H-1,2,4-txiazol-1~1)butan-2-of To a solution of III. (13.6 mmol) in THF (50 ml) (prepared by a similar method to that used in ale 1) at -70°C was added dropwise 4,5-dirhloro-6-ethylpyrimidine (the product of part (ii)) (2.37 g, 13.3 mmol) and the resulting solution was starred at this temperature for 10 minutes. A
solution of 1-(2,4-difluorophenyl)-2-(1tI-1.,2,4-triazol-1-yl)ethanone (2.97 g, 13.3 rmx)1) .i.n '19I1'' (50 ml) was added to the reaction mixture at such a rate so a.~ t.o maintain the reaction tx~erature below -50"C. After stirrirxJ at -70°C fUr 1 hour and at -50'C for a further 1 hour. t:he reaction was quenchod by the addition of loo aqueous acetic acid (11. ml).

PAC St7 (SPC 7704) 'I7~e organic phase was separated, the aqueous phase extracted with ethyl acetate (2 x 20 ml) and the combined organic layers were dried aver magnesirnn sulphate. After removal of the solvent under r~luced pressure, the residue was triturated with diethyl ether (25 ml) and the unreacted ketone starting material (1.'7 g) was remove by filtration.
'ifie filtrate Gras concentrated under rFxiuced pressure and "flash" chrarnatography of the residue on silica using 65:35 ethyl acetate/diethyl ether as the eluant first provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the title can~ound, enantiomeric pair B as a solid (670 mg, 13%), m.p. 124°C.
Found: C,47.78; H,3.33; N,17.13; C1~13C12F2N50 requires:
C,48.00; H,3.25; N,17.500.
Fwrther elution gave, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the title compound, enantiomeric pair A as a solid (527 mg, 10%), m.p. 137°C. Found: C,48.02; H,3.30; N,17.39;
C16H13C12F2N50 requires: C,48.00; H,3.25; N,17.500.

PLC 517 (SPC 7704) ~i Preparation 7 6-)~1~5-fluor~im.i.d.in-4 3H -one ~~~~~s () C 1.
~NH - t'OCl j,C~115N(CH~1 t' I ~-. N
i N ~0 (i) N 1 H
i) CH3CHZMgBr, (ii) DME,THF
ii) AcOH

F ~ N (iii) F /~N
i CH3CH2 I N ~C1 \ aq.K.Mn04 CH3CH2 N~C1 H
(iv) aq.NaOH

U
~NII (~) I~'~ NII
(;~ (;II. ~ J
II J,(;II,3(;OINa, ~ l_ Pc!/C, CZl-1501-i PLC 517 (SPC 7704) E~ r., ~ A .i k.~ '~~

(i) 2,4-Dichloro--5-fluoropyrimidine 'Ib phosphorus oxychloride (141.4g) at 25°C was addal powdered 5-fluorouracil (20g). fhe revolting slurry was heated to 90'C and N,N-dimethylaniline (37.3g) was added over 1 hour. . The reaction was then heat~l at ref lox for 5 hour s and log of the phosphorus oxychloride was removed by distillation. 'fhe mixture was then cooled to 25°C and quenched into 3N F-iC.l (200ni1) at 0°C, portionwise over 1 hour. 'Ifie title compound was then extracted from the mixture using dichloromethane (z x 7om1). The rombir)ed dichloramethane layers were washed with water (50m1) and concentrated under vacutnn to give an oil (24g), which was characterised by 1H-i~~IR and mass spectmetry.
-I~~IR (CDCl3) : d = 8.5 (s, 1H) ppm.
Mass Spec.: m/e = 166.
(ii) 2,4-Dichloro-7. 6-dihydro-6-ethyl-5-fluoropyrimidine To magnesiim~ turnings (4.27g) in tetrahydn~furan (56m1) was added a solution of bromoethane (19g) in Tfil' (19m1) over_ 5 hours. To this slurry at 0'C was added a ~-~olution of the product of part (i) (24g) in 1.,2-climethoxyethane (70niL~
over 1 hour. Z'he reaction was quenched at 1.0"C us.itx7 glacial acetic acid (10g) to give <z solution of the tit:l.e compound which was usc~3 directly in the next step.

rLC 517 (SPC 7704) ~~~ r~ ~', .~ x.~, t3 e.~ ~ ~ ~ ''.S
(iii) 2,4-Dichloro-6-ethyl-5-fluoropyrimidine To the solution obtainc~l as the product of part (ii) was added a solution of potassitun permanganate (23g) in water (260m1) over 2 hours, keeping the tenq~erature of the reaction below 20°C. 5N hydrochloric acid (30m1) was then added followed by a solution of scdiwn metabisulphite (14g) in water (42m1). After decolourisation of the mixture the product was extracted into ethyl acetate (250m1). The organic layer. was then concentrated to give an oil. The oil was partitioned between dichloromethane (50m1) and 2N
sodiwn hydroxide (105m1) and the organic layer was washed with 5o brine (100m1). The organic layer was concentrated to give a solution of the title fund which was used directly in the next step.
(iv) 2-Cfil.oro-6-ethyl-5-fluoropyrimidin-4 (3H)-one To the solution obtained as the product of part (iii) was added water (6m1). The mixture was stirred at 80°C and 4N sodium hydroxide (45m1) was added slowly wer 2 hours.
At the end of this period the reaction was cooled and washed with dirhloromethane (15m1). 'Ifie aqueous layer was then added to dirhloromethane (60m1) and the pH adjusted tc~
1 with concentrated hydrochloric acid. 'Ifie organic layer P(C 517 (SPC 7704) ~a ~ ~ eJ~ ~.
t, E~ ~ .x :~

was separated and the pH adjusted to 3 using concentrated aqueous arrm~onia solution. The precipitate of ammonimn chloride was removed by filtration and the filtrate was then concentrated to a volume of 15m1 and diluted with ethyl acetate (150m1). ibis solution was concentrated to a volume of 30niL and the crystals of the title compound that formed were collected by filtration and dried (8g), thin characterised by lii-Nt~t and mass spectrometry.
lI-1-I~R (dmso-d6): d = 7.3 (exchangeable), 2.4 (m, 2H), 1.1 (t, 3H) ppm.
Mass Spec.: m/e = 176.
(v) 6-Ethyl-5-fluoropyrimidin-4(3H -one To the product of part (iv) (6g) in ethanol (60m1) was added sodium acetate (5.5g) and 5% palladium-on-carbon (0.6g). The mixture was hydrogenated at 3 atmospheres pressure for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated to a volume of lOml then mixed with water (2ml) and dichlorornethane (80m1). Toluene (32m1) was added and the solution w-as concentrate to a volume of 5-6m1 and then mixed with further toluene (8m1) . 'lfie crystals of the title cotnpourxi that separated were isolated by filtration arx3 characterised by tl-IZMR and mass spectrometry (Yield =
3.9g).

i'LC S17 (SPC 7704) ~~ ~~ ~ U' 3.L ..~
(DSO-~d6): d = 8.0 (s, 1H), 2.5 (m, 2H), 1.15 (t, 3H) ppm.
Mass spec.: m/e = 142.
Preparation 8 4-Ethyl.-5-fluoropyrimidine N~C1 H2,Pd/C, Z CH3C02Na,~ F \ N
F

A mixture of 2,4-dichloro-6-ethyl-5-fluoropyrimidine (lOg) (see Preparation 7(iii)), sodium acetate (8.83g), 50 palladiwn-on-Charcoal (500 "wet", 2g) and methanol (30m1) was hydrogenated at 50°C and 3 atmospheres pressure for 5 hours. ~'he resulting slurry wa s filtered carefu.l.ly through a u~l.lul.ose-kk~_,exl filter-a.id, the pad was washed with further metal :anol (5m1) and the re salting orange filtrate was distilled at 64 'C a~xl atmospheric pressure to provide a Colourless distillate. ibis was pa.rti.tioned between crater (300m1) and ether (40m1) and the two PLC 517 (SPC 7704) phases separated. The organic phase eras washed with water (4 x 50m1), dried aver MgS04 and the solvent was removed at room temperature under reduce-d pressure to provide the title compound as a pale yellow liquid (2.2g).
Pr~~ration 9 2-Cnlor(r4-ethyl-5-fluoropyrimidine (:(>1C112C11~
J
C.1 CH3CH(C02CIiZCfl3)L, CI'':j ~()ZCIIICH3 /\N tdali,TliF
\ ~ / IN
N Cl (i) w ~
N ~1 (ii) aq.HCI,CH3C02H
H jCtI3 t' /\~
~I ~
~N ' I:I
(i) 2-Methyl-2-~~2-chloro-5-fluoropyri.midin-4-ylj-1,3-propanedioc acid, diethyl ester.
Sodium hydride (600 oil dispersion, 2.F3g) and diethyl methylmalonate (6g) were react:exa ot: -:lo"C in 'I~-II~ ('1.()Oml.) .
After 30 minute) a solution of 2,4--d.ic:hl.oro-5-fluoropyrimidine (5g) (s(~ Preparation '7) in 'I7iF (25m1) was added over 30 m.i.nutes at -10'C. 'fhe r(action was partitioned between dirhloramethane (20(1m1) and water (200m1), acidified with PLC 517 (SPC 7704) acetic acid and the layers separated. 'I9ze organic layer was concentrated under reduced pressure to an oil and chromatographed on silica gel using dichloromethane as the eluent. This gave, after the combination and evaporation of appropriate fractions, the title carnpound (9g) which was characterised using ~-I-NMI2 and mass spectrometry.
~~-NMR (CDC13) : d = 8.5 (d, 1Hi) , 4.6 (m, 4H) , 1.9 (s, 3f-I) , 1.3 (t, 3H) ppm.
Mass spec.: ~/e = 304.
(ii) 2-C~iloro-4-ethyl-5-fluoropyrimidine The product of part (i) (3.2g) was dissolved in acetic acid (25m1) and diluted with 5N HC1 (l0ml). After heating the mixture at 100°C for 16 hours the mixture was cooled and partitioned between water (3Qml.) and dichlox~omethane (45m1). The dichloromethane layer was separated, dried and concentrated under reduced pressure to give an oil. W'he title ca~ound was isolated by chromatography on silica gel using dichlorometl one as the eluent. Ifie product was characterised by 1H-NMR and mass sper_trometry (yield =-350mg).
1HI-NMR (CI7C13) : d = 8.4 (s, 1H) , ?..9 (m, 111) , 7 . 3 (t, 311) ppm.
Mass spec.: m/e = 160.

PLC 517 (SPC 7704) 6y ax,~ u1 ~j Z" ''~ '~ ,J1 °~' C' .:_ ;e ~~sessment of in vivo activity aaainst Asperqillus fumigatus in mice Using the general test procedure outlined on page 17 of the description, a group of mice eras inoculated with a strain of -rgillus finniaatus. F.~~ch mou~:e was then treated with the test compound at a standard dcx>e of 20 mg/kg b.i.d. for ~ days. ~l'he mice were then assessed on the tenth day.
Activity is based on the suxvival of a treated group of mice after the death of an untreatc-.d group of mice, and also on the number of mice cured of the infection.
The results obtained in a comparative study using two compounds described in the specific ales of the present application and two compounds described in the specific F~mples of European Patent Application No. 89307920.2 (EP-A-0357241) are shown in the followir~ table:-SE, ,.
v ,D G.
G

f: 1u W _. ~-(n U vJI
_~ :7 L U tf1 t!1 cJ u. ~.i f~. 'o CJ c up O N m V uJ N
m CJ r C1 ~r~
i~ ~ w c1. O
;~ ~. w 4J w O
., fa .n a.
a ~
a o tr sa ur on s.. m a o (a a a u-, ,n a m -~ w .,-1 v v E m m a.J
~ m m 9 ~ a sa E w a o x sa w v w o ..
C I M
'_-.
G V V
U ~-- ~"
G ._. I
G
L
i ..
..
___ _. _____ __ _ _ __ _ I
.U ~
.
~
::.
C;

O G U i :J
m 7 .,.I ::
I
.
.
' O ~ ~ ~
t :
O
S::

41 t1 ('J N ~ ~ O Ir (j (-.n U E wJ U t,., .~' .

C. O N O ~ 1 a C' v U .-1 .~ CW ~ U ~ t~ ('J I

_.
:_ ) CJ
cL
.

4~.
v a..l E ~ >., U.
rl I
.

i (:-a c0 (U rl i::
v; N
:.
.--.I
O

n7 al eJ x G (o .~-( -W
a.
w, I
' v W al C1. (~
n.
o~
~

I
:
=
C.
~_ m>
I

I

r. ~~ . ~, rM ~ e'J ~ ~ .i =.~~

v .o a.

a a ~ o G ?~

_ co ~.

fn v N N
' ~ :5 D sp ,n n a V y c Q! !n rl ~ -o ~ w r ul E-amL o ' :J tn Ul U

W

G-L
O

x ~.
w ..1 ~ w o ..
v w ---. ----.-__._..._______...___....._._..._........_..G

O

r1 v .a P.
' a ~

~ o a s~ 0 a.

O c0 v~ , ~ V

T
~

-r y ~ tD N
1 'O
N H

N a M 'o N N

tn N
T~

s~ a G
w CL O O .D

x s~ j, v w d w G
o v .r, w o u~

c w L
z a s~

v a z w a ~ ~ G

.~
a x ''' w o c c O U

a' -r. v v V ~' Cz. v J-n V

w 3 T

r-f a a~

T
F
r_a C to O

U tn 'b N N

U U
--___.___.-__.T_ __.._~.._..__..___.._......._''J
..._....

.. (:l v 'b L. N y .
U 0.

; U 'a -U .ri t.. ;J

O G CJ ~~ ~' O '1J 'J
I

L a 'rl v 4:
O ~ ~ 1, E O C 'O

al CS. n v ~ G 1. p N r~ au ~ ~~ ~.a a 6 f: M v w a . G
~ 'b G O 4 1-n to C U
~ ~

41 U , Ql Cl ~ ~U .
j . , = oe .r~
~

a.
r-a ~. v a w ~ U a, E: t: f~
a. m .r~ " ~r o .r~

w rn 6 m s~ ~-, p ~
G
~

v v x G ~u ~ w w a. ~-, .
_ a ~. o r~ ~J W v a. x v ~o a.rn U .-~ ..1 W _ C. 6 00 ~ tn -_-__ n

Claims (43)

1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein R is phenyl substituted by 1 to 3 substituents each independently selected from halo, -CF3 and -OCF3; R1 is C1-C4 alkyl; R2 is H or C1-C4 alkyl; X is CH or N; and Y is F or Cl.

2. A compound as claimed in claim 1 wherein R is phenyl substituted by 1 or 2 halo substituents.

3. A compound as claimed in claim 2 wherein R is phenyl substituted by 1 or 2 substituents each independently selected from fluoro and chloro.

4. A compound as claimed in claim 3 wherein R is 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl.

5. A compound as claimed in claim 4 wherein R is 2-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl.

6. A compound as claimed in any one of claims 1 to 5 wherein R1 is methyl.

7. A compound as claimed in any one of claims 1 to 6 wherein R2 is H or methyl.

8. A compound as claimed in claim 7 wherein R2 is H.

9. A compound as claimed in any one of claims 1 to 8 wherein X is N.

10. A compound as claimed in any one of claims 1 to 9 wherein Y is F.

11. A compound as claimed in any one of claims 1 to 7 wherein R1 is methyl, R2 is H or methyl and X is N.

12. A compound as claimed in claim 11 wherein Y is F.

13. A compound as claimed in any one of claims 1 to 6 wherein R2 is H and which has the 2R,3S- configuration, that is .

14. The compound 2R,3S-2-(2,4-difluorophenyl)-3-(3-fluoro-pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or a pharmaceutically acceptable salt thereof.

15. The compound 2R,3S-2-(2-chlorophenyl)-3-(3-fluoro-pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or a pharmaceutically acceptable salt thereof.

16. The compound 2R,3S-2-(2-fluorophenyl)-3-(3-fluoro-pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or a pharmaceutically acceptable salt thereof.

17. The compound 2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoro-pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or a pharmaceutically acceptable salt thereof.

18. The compound 2R,3S-2-(2,4-dichlorophenyl)-3-(5-fluoro-pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18 together with a pharmaceutically acceptable diluent or carrier.

20. A pharmaceutical composition as claimed in claim 19 in which the compound or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18, is complexed with a hydroxyalkyl derivative of a cyclodextrin.

21. A pharmaceutical composition as claimed in claim 20 wherein said hydroxyalkyl derivative is a hydroxypropyl derivative and said cyclodextrin is alpha- or beta-cyclodextrin.

22. The use of a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18 as a medicament.

23. The use of a compound or of a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18 as an antifungal agent.

24. A process for preparing an antifungal agent, which process comprises admixing a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18 with a pharmaceutically acceptable diluent or carrier.

25. A commercial package containing, as active pharmaceutical ingredient, a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18, together with instructions for the use thereof as an antifungal agent.

26. A process for the preparation of a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein R is phenyl substituted by 1 to 3 substituents each independently selected from halo, -CF3 and -OCF3; R1 is C1-C4 alkyl; R2 is H or C1-C4 alkyl; X is CH or N; and Y is F or Cl; which process comprises:
(a) reacting a 1'-deprotonated form of a compound of the formula:
wherein R1, R2, X and Y are as defined above, with a compound of the formula:
wherein R is as defined above;
(b) reacting a compound of the formula:
wherein R, R1, R2, X and Y are as defined above and Z is a leaving group, either with a base salt of 1H-1,2,4-triazole or with 1H-1,2,4-triazole in the presence of an additional base;
(c) for the preparation of a compound of the formula:

wherein R, R1, R2 and Y are as defined above, reducing a compound of the formula:
wherein R, R1, R2 and Y are as defined above and Z2 and Z3 are each independently selected from H and a group that may be selectively removed by reduction, with the proviso that Z2 and Z3 cannot both be H;
any of the said processes being optionally followed by conversion of the compound of the formula (I) to a pharmaceutically acceptable salt thereof.

27. A process as claimed in claim 26(a) in which said deprotonated form is a lithium, sodium or potassium salt of the compound of the formula (II).

28. A process as claimed in claim 26(b) in which Z is chloro, bromo or C1-C4 alkanesulphonyloxy.

29. A process as claimed in claim 26(b) in which a compound of the formula (IV) is used.

30. A process as claimed in any one of claims 26(b), 28 and 29 in which said base salt of 1H-1,2,4-triazole is either a sodium, potassium or a tetra-n-butylammonium salt.

31. A process as claimed in claim 30 in which said additional base is sodium or potassium carbonate.

32. A process as claimed in claim 26(c) in which Z2 is a group that may be selectively removed by reduction and Z3 is H.

33. A process as claimed in claim 26(c) in which said group that may be selectively removed by reduction is halo.

34. A process as claimed in claim 33 in which said halo group is chloro.

35. A process as claimed in any one of claims 26(c), 32, 33 and 34 in which said reduction is carried out by hydrogenolysis using a palladium-on-charcoal catalyst.

36. A process as claimed in claim 35 in which sodium acetate is also present.

37. A process as claimed in any one of claims 26 to 36 wherein R is phenyl substituted by 1 or 2 halo substituents.

38. A process as claimed in claim 37 wherein R is phenyl substituted by 1 or 2 substituents each independently selected from fluoro and chloro.

39. A process as claimed in claim 38 wherein R is 2-fluoro-phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl; R1 is methyl: and R2 is H.

40. A process as claimed in claim 39 wherein R is 2-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl or 2,4-dichlorophenyl, R1 is methyl R2 is H; and Y is F.

41. A process as claimed in any one of claims 26 to 40 which includes the step of separating from other optical isomer, a compound of the formula (I) wherein R2 is H and which has the 2R,3S-configuration, that is .

42. A compound of the formula:
wherein R, R1, R2, X and Y are as defined in claim 1.

43. 4-Ethyl-5-fluoropyrimidine or 4-chloro-6-ethyl-5-fluoropyrimidine.