CA1200495A - Pyrimidine-2-sulphides and their s-oxides for use in medicine and methods of use therefor, pharmaceutical compositions containing them, processes for their preparation and suchcompounds when novel per se - Google Patents

Abstract

ABSTRACT

A pharmaceutical composition comprising as active ingredient a com-pound of the formula:- [wherein X represents a fluorine, chlorine or bromine atom; n is 1 or 2; R1 and R2, which may be the same or different, each represents a hydrogen atom or a C1-4 alkyl group, a carboxyl group or a group of the formula -COORa (in which Ra represents a C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl group, a C3-8 cycloalkyl or C3-8 cycloalkenyl group, an araliphatic group with up to 4 carbon atoms in the aliphatic moiety, which moiety may be saturated or un-saturated, and up to 10 carbon atoms in the aryl moiety or a C6-10 aryl group, the aryl moiety or group being optionally substituted by a C1-4 alkyl group);
and R3 represents an unsubstituted C1-8 alkyl or C3-8 cycloalkyl group or an unsubstituted aralkyl group with up to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety or an unsubstituted C6-10 aryl group, the aryl moiety or group optionally carrying a C1-4 alkyl group]
or, where an acidic group is present, a physiologically compatible salt thereof, in association with a pharmaceutical carrier or excipient. The compositions are of interest in combating abnormal cell proliferation.

Description

The present invention relates to the S-oxides of pyrimidine-2-sulphides and more particularly to pharmaceutical compositions compris;ng the S-oxides of pyrimidine-2-sulphides as active ingredients.
The compositions are of interest in combating abnormal cell proliferation.

Abnormal cell proliferation is the basic cause of a number of diseases such as cancers, leukaemias, cutaneous cellular proliferation, e.g.
contact dermatitis or psoriasis, or auto-immune diseases where proliferation of lymphocytes leads to an undesirable immune response against some of the normal tissues of the body.
The present invention is based on the discovery that compounds of the formula:

N~X

R S()n ~ N R2 [wherein X represents a halogen atom; n is 0, l or 2; Rl and R2, which may be the same or different, each represents a hydrogen atom or a Cl_4 alkyl group, a carbamoyl group, a mono- or di Cl 4 alkyl-carbamoyl group, a carboxyl group or a group ofthe formula -COORa (in which Ra represents a Cl 8 alkyl, C2_8 alkenyl or C2_8 alkynyl group, a C3 8 cycloalkyl or C3 8 cycloalkenyl group, an araliphatic group with up to 4 carbon atoms in the aliphatic !

moiety, which moiety may be saturated or unsaturated, and up to 10 carbon atoms in the aryl moiety or a C6 10 aryl group, the aryl moiety or group being optionally substituted by a Cl ~ alkyl group);
and R3 represents a Cl 8 alkyl, C2 8 alkenyl or C2 8 alkynyl group, a C3 8 cycloalkyl group, a C3_8 cycloalkenyl group, the group Het (Het being a 3-9 membered heterocyclic ring having one or more heteroatoms selected from oxygen, nitrogen or sulphur and optionally carrying a fused ring group or carrying one or more Cl 4 alkYl or C6-10 aryl group~)t a Cl_~ alkyl, C2_8 alkenyl or C2 8 alkynyl group substituted by the group Het (as herein defined), an araliphati~ group with up to 4 carbon atoms in the aliphatic moiety which moiety may be sa~urated or unsaturated and up to 10 carbon atoms in the aryl moiety or a C6_10 aryl group, the aryl moi~ty or group being optionally substituted by a Cl 4 alkyl group, said moieties or groups being optionally substituted by one or more substituents selected independently from R [wherein Re represents a halogen atom or an oxo, nitrol hydroxy, -ORb, -SRb, RbSO, RbSO2- (wherein Rb is as defined for Ra (as hereinbefore defined) or Het (as hereinbefore defined) and is optionally substituted by one or more substituents selected from halogen, oxo, amino, hydroxy, Het as herein defined, -ORa, RaCOO-, -SRa, RaSO- and RaSO2-) Rb COO- twherein Rb is as defined for Ra and is optionally substituted by one or more substituents selected from halogen, oxo, amino, hydroxy, Het as herein defined, -ORa, RaCOO-, -SRa, RaSO- and RaSO2- or Rb is as defined for Het), Cl 8 alkanoylamino or di(Cl 8 alkyl) phosphonate group or an amino group of the formula:-RC
-N in which Rc and Rd, which may be the same ' - 3 ~

or different, each represents a hydrogen atom or a Cl ~ alkyl, C7 10 aralkYl or C6-10 aryl group the aryl group the aryl moiety or group optionally being substitutec7 by a Cl_4 alkyl group or a 5 to 10 membered heterocyclic ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur; with the proviso that R3 is other than a l-alkyl-5-nitro-imidazolyl-2-alkyl group when n is 0] and, where an acidic or basic group is present, the salts thereoE possess the ability to inhibit cell proliferation.
Abnormal cell p-roliferation can be combated by administration of a drug which irreversibly interferes with cell-division. Such drugs are generally only able to attack the cells during a particular phase of the cell cycle, for example the S~phase during which DNA is synthesised~ Although th-e drug cannot distinguish between abnormal and normal cells which are in the phase susceptible to attack, use can be made of the fact that a significant proportion of normal cells, which are of importance in this context (e.g. bone marrow) generally have a shorter cell cycle length than many abnormal cells, such as tumour cells, and hence recover their numbers more rapidly. This effect is further aided by virtue of the fact that, generally a smaller proportion of normal cells would be in cell cycle at the time o$ drug administration compared with the situation in the abnormal cells, thus providing a larger reservoir from which cells can be recruited for replenishment of normal cells damaged by the drug. The abnormal cell populations are therefore more readily decreased by carefully timed sequential administration of the drug.
Another way in which such a drug can be used to combat abnormal cell proliferation is to administer a preliminary drug which acts to arrest reversibly the cycle of cell division in a particular phase, for example the metaphase, so that when the drug has been eliminated from the system, all the cells resume division synchronously. However, the cell division cycle of the abnormal cells will generally be different from that of the normal cells, and a time can be selected at which the abnormal cells are susceptible to attack by the irreversibly acting drug while the normal cells are in a resistant phase.
The compounds of the present invention inhibit DNA synthesis and are thus particularly useful in combating abnormal cell proliferation.
Certain of the compounds of formula I have been described generally in Belgian Patent Specification No. 847,234 as intermediates, without any physiological activity being ascribed to them and without any specific compounds being named. Moreover 5-chloro- and 5-bromo-

2-methanesulfonyl pyrimidine and the 4-carboxy derivatives thereof and 5-fluoro-2-methanesulfonyl pyrimidine are specifically disclosed in Budesinsky Z and Vavrina J. Collect. Czech Chem. Commun. 37 ~1972) 1721, but, again, no physiological activity is ascribed to these compounds.
The present invention relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically compatible salt thereof which compound of formula I is generally disclosed in the aforementioned Belgian Patent Specification, but for which no physiological activity has been disclosed.
The present application is divided out of Canadian Patent Applicatlon Serial No. 368,409 which claims processes for preparing the novel compounds of Eormula 1 and the physiologically compatible salts thereo:E and such compounds when prepared by the claimed processes.
Thus according to the present inven-tion there is provided a pharmaceutical composition comprising as active ingredient a compound o-f the formula:-~\ X
N 1~ I
~ )n N R

[wherein X represents a :Eluorine, chlorine or bromine atom; n is 1 or 2; and Rl and R2, which may be the same or different, each represents a hyd.rogen atom or a Cl 4 alkyl group, a carboxyl group or a group of the formula -COORa ~in which Ra represents a Cl 8 alkyl, C2 8 alkenyl or C2 8 alkynyl group, a C3 8 cycloalkyl or C3 8 cycloalkenyl group, an araliphatic group with up to 4 carbon atoms in the aliphatic moiety, which moiety may be saturated or unsaturated, and up to 10 carbon atoms in the aryl moiety or a C6_10 aryl groupr the aryl moiety or group being optionally substituted by a Cl 4 alkyl group); and R3 represents an unsubstituted Cl_8 alkyl group or an unsubstituted aralkyl group with up to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety or an unsubstituted C6_10 aryl group, the aryl moiety or group optionally carrying ., ~

6 ~

a Cl 4 alkyl group], or where an acidic group is present, a physiologically compatible salt thereof, in association with a pharmaceutical carrier or excipient.
It will be understood that the term "pharmaceutical composition" as used herein, which includes compositions for administration to humans as well as veterinary compositions, is not intended to include mere solutions of the compounds of formula I ln non-sterile water or a common organic solvent.
The compositions may be formulated for pharmaceutical administration in any suitable manner. Thus~ compositions will normally be in a form suitable for oral, rectal, topical or parenteral administration, such as tablets, coated tablets~ capsules, granules, solutions, suppositories, and topical creams, ointments and lotions or sterile solutions in pyrogen-free water for injection or infusion.
The pharmaceutical compositions of the present invention are thus conveniently presented in sterile form.
The compositions will generally be administered at a daily dose level in the range 0.25 to 7~0 g of the compound of the invention; the compositions will conveniently be formulated in dosage units, each dosage unit typically containing from 50 mg to 1.0 g of the compound of the invention, though units containing as much as 5 g may occasionally be suitable.
Conventional carrier and excipient ingredients may be used, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, animal and vegetable fats, paraffin derivatives, glycols, propellants, and various wetting, dispersing, emulsifying, flavouring and preserving agents.

- 7 ~

The terms used in the above definitions of the compounds of formula I are more particularly discussed below.
Cl_~ alkyl~ C2_8 alkenyl and C2_8 alkynyl groups preferably contain up to 4 carbon atoms.
The term "aryl" as used herein relates to aromatic ring systems with up to 10 carbon atoms e.g. phenyl or naphthyl. The term "aryl", it will be understood, also includes within its scope aromatic ring systems substituted by a Cl_4 alkyl group e.g. a ~-tolyl group~
R and R , which may be the same or different, may for example each represent a hydrogen atom or a Cl 4 alkyl group. Preferably only one of Rl and R is other than hydrogen or Cl ~ alkyl, at least one desirably being hydrogenO It is especially preferred that both of Rl and R2 are hydrogen. Where Rl and/or R is esterified carboxyl, this is preferably C1_4 alkoxycarbonyl.
The term "araliphaticl' as used herein relates to aralkyl groups with up to 4 carbon atoms in the alipha~ic portion, optionally substituted in the aryl ring as indicated above.
Examples of such araliphatic groups thus include benzyl and phenethyl groups.

- 8 ~

The radical X in the compounds of formula I
may be fluorine, chlorine or bromine.
Compounds of formula I wherein n is 2 are preferred, the sulphones being somewhat more active than the sulphoxides.
Certain of the compounds of formula I may exist in salt form. Where acidic groupings are present in the compounds of formula I salts may be formed with alkali metal or alkaline earth metals e.g. sodium, potassium~ magnesium or calcium or ammonium (including substituted ammonium) salts. However, in general, non-ionic compounds of the invention are preferred~
It will be appreciated that the salts of the compounds of formula I for use in pharmaceutical compositions are the physiologically compatible salts. Other salts may however be useful in the preparation of the compounds of formula I and the physiologically compatible salts thereof.
Preferred compounds of the present invention, include compounds of formula I in which R3 represents a Cl 4 alkyl group, an aralkyl group (in which the alkyl moiety contains 1-4 carbon atoms and the aryl moiety is a phenyl group optionally carrying a Cl 4 alkyl group) or a phenyl group optionally carrying a Cl 4 alkyl group. In such compounds n is preferably 2 and Rl and R2 are preferably hydrogen.
Compounds of the present invention of particular interest in view of their physiological activity also include the following compounds:
2-Methylsulfonyl-5-chloropyrimidine, 2-Benzy]sulfonyl-5-chloropyrimidine, 2-Benzylsulfonyl 5-bromopyrimidine, and 2-Ben~ylsulflnyl-S-chloropyrimidine.

It will be appreciated that certain of the compounds of formula I will exit ln geometrically or optically active isomeric forms. The present invention extends to cover all of these isomeric forms.
The compounds of formula I as hereinbefore defined may be prepared by a variety of different methods known per se as detailed hereinafterO Thus a compound of formula I as hereinbefore defined in which n is 2 may for example be prepared by oxidising a compound of the formulao R

R S()m ~ N ~ II

wherein R1, R2, R3 and X are as hereinbefore defined and m is 0 or 1.
The compound of formula I wherein n is 1 is preferably prepared by oxidising a corresponding compound of the formula II (wherein m is O and ~1, R2, R3 and X are as hereinbefore defined) to form a compound of formula I wherein n is 1.
The oxidation of the compound of formula II
may be effected by any convenient method including the use of 1) a manganese oxidising agent, for example a permanganate preferably potassium permanganate, conveniently in the presence of an acid e.g. acetic acid; 2) the use of chlorine or a hypochlorite e.g.
sodium hypochlorite in an aqueous solution of the sulfide or sulfoxide or 3) the use of a pero~ide or peracid oxidising system such as hydrogen peroxicle conveniently in the present of an acid e.g. acetic acid advantageously at ambient temperature, or more preferably, _-chloroperbenzoic acid conveniently at a low temperat~re e.g. at a temperature from -30C
to -5C, or the use of a molybdenum peroxide conveniently in the presence of water and/or hexamethyl-phosphoramide.
In general each oxidation method may be employed to prepare either the sulfone or the sulfoxidet the reaction conditions e.g. reaction time, temperature or excess of reagent being altered depending upon the desired product. Thus if it is desired to prepare the sulfone, longer reaction times, higher temperatures and/or excess oE the oxidising agent may for example be used.
It is preferred, however, to effect oxidation to the sulfoxide by for example the use of 1) m-chloro-perbenzoic acid conveniently at a low temperature, e.g. at a temperature of from -30C to -5C, to avoid further oxidation to the sulfone; 2) hydrogen peroxide~
conveniently in the presence of an acid, e.g. acetic acid, advantageously at a low temperature, e.g. ambient temperature, an excess of the oxidising reagent being avoided in order to reduce sulfone formation; and

3) hydrogen peroxide and selenium dioxide, advantageously under neutral conditions, conveniently in the presence of a solvent, e.g. an alkanol such as methanol.
These processes are preferred for sulfoxide production because the oxidation reaction may be terminated more readily at the sulfoxide stage. The course of the oxidation may, for example, be monitored using chromatographic techniques.

Where it is desired to prepare the sulfone the oxidation may, for examplel be effected 1~ by the use of m chloroperbenzoic acid, conveniently in the presence of a solvent e~g. dichloromethane, 5 the oxidation being, for example, effected at a higher temperature than for sulfoxide formation; 2) by the use of hydrogen peroxide conveniently in the presence of an acid, e.g. acetlc acid, the oxidation being, for example, effected in the presence of an excess of the oxidising agent and/or at a higher temperature than for sulEoxide formation, 3) the use of chlorine, for example in aqueous so]ution, this method being preferred for sulfone formation especially when the sulfide (compound of formula II) is less readily oxidizable; 4) the use of a manganese oxidising agent, for example, potassium permanganate, conveniently in the presence of an acidt e.y. acetic acid, this method also being preferred for formation o~ the sulfone, by virtue of the higher yields which may 2n be obtained in comparison with milder oxidising agents;
and 5) the use of molybdenum peroxide, conveniently in the presence of water and/or hexamethylphosphoramide, this method also being preferred for sulfone formation.
A compound of formula II in which m is 0, used as starting material, is conveniently first prepared by condensing a compound of the formula:-NH
R35 ~ ~ NH2 III

-- 12 ~ 4~

(wherein R3 is as hereinbeEore defined) or an acid addition salt thereof with a compound of the formula ~ X ~ IV

o ~C ~R2 (wherein Rl, R~ and X are as hereinbefore defined) or a functional derivative thereof such as an enol, enol ether, enol thioether, enamine or im;ne derivative whereby a compound of formula II in which m is 0 is obtained.
The condensation is conveniently effected under acid canditions~ preferably in a solvent such as an alcohol e.g. ethanol. Where Rl and R each represent hydrogen the reaction is advantageously effected at ambient temperature. A functional derivative of a compound of formula IV may for example be derived by reaction of both carbonyl groups of the compound of formula IV with a dialkylamine such as dimethylamine; one of the imine groups so produced may rearrange in such a compound to the enamine form.
The compound of formula II in which m is 0 may also be prepared, for example, by reaction of a compound of the formula Rl ~ x v y ~ N ~ R

(wherein R , R and X are as hereinbefore defined and Y represents a leaving atom or group) with a thiol of the formula R3SH or a thiolate of the formula ~ 3SJ ~ Mn ~ VI

(wherein R3 is as hereinbefore defined, M represents the stabilising cation and n represents the charge on the cation) whereby a compound of formula II
in ~hich m is 0 is obtained.
The reaction of the compound of formula ~T
with the compound of formula VI is conveniently effected by the use of a compound of formula V
in which Y represents a halogen atom e.g. a chlorine or bromine atom. The reaction is a nucleophilic subs~itution reaction, the nucleophile being in the form R3S and thus where the compound of formula VI
is used in the form of a thiol, the reaction is preferably efected in the presence of a base suf-ficiently strong to remove the thiol proton to give the aforementioned nucleophile. Preferred bases include alkoxides~ for example alkali metal and alkaline earth metal alkoxides such as sodium or potassium alkoxides e.g. ethoxides. The reaction is conveniently effected at an elevated temperature preferably at the reflux temperature of the reaction mixture.
The compound of formula II may also be prepared, for example, by reacting a compound of the formula ~',';.

Rl N ~ X
~ ll VII
S ~N ,v~ R

(wherein Rl, R2 and X are as hereinbefore defined) ~ith a reagent serving to alkylate the sulphur atom to add a group R3 thereto, for example an alcohol R30H or an alkylating derivative thereof.
Such an alkylating derivative may be of the formula: R Y VIII
(wherein R3 and Y are as hereinbefore defined~.
The reaction is preferably effec~ed in the presence of a base of by phase-transfer catalysis, for example by the use of a triethylbenzylammonium compound, e.g. the chloride, hereinafter referred to as TEBA.
Moreover, the reaction is preferably effected using a compound of formula VIII in which Y represents a halogen atom e.g. a chlorine or bromine atomO
The reaction is conveniently efected at ambient temperature.
An alternative alkylating derivative is an acetal of the alcohol R30H, for example an acetal with a dialkylformamide such as dimethylformamide.
The reaction of the alcohol R30H with the thione of formula VII requires the presence of a condensation catalyst, for example a di-t-alkyl acetal of a dialkylformamide. The alkyl groups present in the dialkylformamide may have 1-5 carbon atoms, methyl being preferred. The t-alkyl groups are preferably neo-pentyl groups. The reaction is generally effected at elevated temperature.

.~ i - 15 ~

~ he compounds of formula I in which n = 2 may also be formed directly from compounds of the formula V ~wherein R1, R2, X and Y have the above meanings) by reaction with a sulphinic acid of the formula R3S02H or a salt thereoE. Where the acid is used the reaction should be efEected in the presence of a base~ The salt of the sulfinic acid may for example, be an alkali metal or alkaline earth metal or a tertiary organic base salt. The reaction may be effected in a polar solvent such as an alkanol e.g. methanolO A quaternary ammonium salt such as triethylbenzylammonium chloride may usefully be present as a phase transfer catalyst for the salt, usefully in the presence of lithium chloride.
Processes for preparing the compounds of formula I of the present invention will now be more particularly described in the following Examples, which are by way of illustration only. The production of the starting compounds is illustrated in the Preparations~

- ,~

Preparation 1 2-Phenylthio-5-chloropyri.midine A solution of thiophenol (60 mmol) in 0.43 M
sodium ethoxide (150 ml) and a solution of 2,5-dichloro-pyrimidine ~ ) in absolute ethanol (90 ml) weremixed and heated under reflux for 2 h. The cold mixture was then filtered, the filtrate evaporated, the residual material dissolved in chloroform (150 ml), the chloroform sol.ution washed with 2 M NaOH (2 x 15 ml) and water (15 ml) and the dried (MgSO4) solution evaporated leaving an oily material which crystallized in the cold; yield 70~, m.p. 47C (ligroin). 1H
NMR (CDC13~: ~ 7.4(Ph), 8.33 (H-4, H-6).
Preparation 2 lS 2-Benzylthio-5-chloropyrimidine Method A:
A solution oE S-chloropyrimidine-2-thione (4.6 mmol) and 2 M NaOH (7 ml) was mixed with a solution o~
benzyl bromide (6.9 mmol) and triethylbenzylammonium chloride (TEBA; 4.6 mmol~ in dichloromethane (20 ml).
The two-phase system was vigorously stirred at room temperature for 16 h, the layers separated, the aqueous solution extracted with dichloromethane, the dichloro-methane solutions combined and washed with water, and the dried (MgSO4) solution evaporated; yield 46~o The crude product was sufficiently pure for the successive oxidation. 1H NMR (CDC13): S 4.45 (CH2), 7.28 (Ph), 8.41 (H-4 r H - 6) .
Met od B:
A solution of 1,3-bis-N,N-dimethylamino-2-chloro-trimethinium perchlorate (38.3 mmol) and benzylisothio-uronium chloride (40.7 mmol) was prepared in methanol (100 ml) and tert-BuOK (40.7 mmol) added portionwise.
The reaction mixture was stirred at room temperature for 30 min after the addition was completed, when additional t_ -BuOK (38.3 mmol) was added and the mixture heated under reflux for 2.5 h. The precipitate - ~7 ~

was removed, the solvent distl]]ed from the filtrate, water (20 ml) added to the residue, the aqueous solution extracted with ether, the ether solution dried (MgSO4), and HCl gas passed through the solution at 0C.
The precipitated salt is dissociated when dried in vacuo and the HCl is lost; yield 43%. m.p. 57C
(dil. MeOH). lH NMR (CDC13): ~ 4.33 (CH2), 7.26 (Ph), 8.40 (H-4, H-6).
Preparation 3 2-Phen lthio-5-bromo~Yrimidine Y ..
The title compound was prepared from 2-chloro-5-bromo-pyrimidine and thiophenol as described in Example l; y;eld: 90% of a non-crystalline product which was pure enough Eor the successive oxidation.
MS _/e: 267 (M, 100~ NMR (CDC13): ~ 7.4 (Ph), 8.50 (H~4, H-6~.
Preparation 4 2-Benzylthio-5-chlor ~
5-Chloropyrimidine-2-thione (8 mmol) and N ,N-dimethylformamide dibenzyl acetal (8 mmol~ were heated together in acetonitrile (40 ml) at 70~C for 90 min.
The solvent was then distilled off, the residue dissolved in ether (50 ml), the ether solution extracted with 2 M NaOH (2 x 5 ml), washed with water (5 ml) and dried (MgSO4) and gaseous HCl passed into the solution.
The title compound was precipitated as the HCl-salt;
yield 80%. (Physical data: as detailed in Example 2).
Preparation S
2-Methylthio-4-methoxycarbonyl-5-chlorOI~rimidine A solution of 2-methylthio-4-carboxy-5 chloro-pyrimidine (31 mmol) in thionyl chloride (50 ml) was heated under reflux for 60 min~ Excess thion~l chloride was distilled off, the residual materlal dissolved 21~
;n methanol (70 ml), the solut;on heated under reflux for 30 min, excess methanol distilled off, the residue dissolved in chloroform, the ch]oroform solution washed with sodium bicarbonate and water, and the dried (MgSO4) solution evaporated and the residue distilled; yield 78%, b.p. 108-110C/0.15 mmHg.
lH NMR (CDC13~: ~ 2.56 (SMe), 4.00 (OMe), 8.63 (H-6).
Preparation 6 2-Benzylthio-5 bromopyrimidine Benzyl thiol (22 mmol) was added to 0.146 M
ethanolic NaOEt (15Q ml) at room temperature followed by 2-chloro-5-bromopyrimidine (20 mmol). The mixture was stirred at room temperature for 70 min, heated under reflux for 40 min, the solvent evaporated off at reduced pressure, the residue extracted with chloroform (100 ml), the chloroform solution washed with 2 M
NaOH, and the dried (MgSO4) solution evaporated;
yield 81~, m.p. 68-69C (dil. MeOH). H NMR (CDC13):
~ 4.36 (CH2), 7.26 (Ph), 8.50 (H-4, H-6).

19 ~ 5 Pre~aration 7 2-Benzylthio~4,6-dimethyl-5-brom~ midine 2-Chloro-4,6-dimethyl-5-bromopyr;midine (10 mmol) was added to a solution of benzylthiol (11 mmol~
and 0.138 M NaOEt in ethanol (80 ml). The mixture was stirred at room temperature for 70 min and then heated under reflux for 40 min. The solvent was then dis~illed off, the residue extracted with chloroform (50 ml), the chloroform solution washed with 2 M
NaOH and the dried (MgSO4) solution evaporated to leave the sulfide which was purified by distillation;
yield 94%, b.p. 232-234~C/15 mmHg. lH NMR (C13CF):
2,50 (Me-4, Me-6), 4.26 (CH2), 7.20 (Ph).
Preparation 8 2-Phenylthio-5-fluoro~yrl_ dine A solution of 2-chloro-5-fluoropyrimidine (10 mmol) in ethanol (15 ml) was added dropwise over 5 min to a solution prepared Erom thiophenol (10 mmol) and 0.43 M NaOEt in ethanol (25 ml~. Subsequently the mixture was heated to boiling and refluxed for 2 hours, filtered hot, the filtrate evaporated, the residue extracted with chloroform (50 ml), the chloroform solution shaken with 2 M NaOH (2 x 10 ml), then shaken with water (10 ml) and the solution evaporated; yield 69%. lH NMR (CDC13): ~ 7.4 (Pyr), 8.23 (H-4, H-6) o Example l 2-Methy~sulfinyl-5-chloropyrimi-line A solutlon of 2-methylthio-5-chloropyrimidine (13 mmol) in chloroform (85 ml) was cooled to -20C
and _-chloroperbenzoic acid (17 mmol) added with stirring. The mixture was stirred for 40 min at -20C and for 4 h at 0C and left at this temperature overnight. The chloroform solution was then washed with 1 M potassium carbonate (3 x 10 ml) and the dried (MgSO4) solution evaporated. The residual oily material crystallized on standing; yield 80%
m.p. 48C (n-heptane). 1H NMR (CDC13): ~ 2.93 (Me), 8.83 (2H-4,6).
Example 2 2-Benæylsulfinyl-5-chloropYrimidine 85~ m-Chloroperbenzoic acid (1.5 mmol) was added to a solution of 2-benzylthio-5-chloropyrimidine (1.5 mmol) in dichloromethane (25 ml) at -10C and the solution left at 0C for 18 ho The dichloromethane solution was then washed with saturated aqueous solutions of Na2SO3 and NaHCO3, and the dried (MgSO4) solution was evaporated to leave the title compound; yield 88~, m.p. 92C (iPrOH). 1H NMR (CDC13) ~ 4.30 and

4.33 (CH2), 7.23 (Ph), 8.73 (H-4, ~ 6)-Example 32-Methylsulfinyl-5-bromopyrimidine The title compound ws prepared by oxidation of 2-methylthio-5-bromopyrimidine by _-chloroperbenzoic acid in chloroform as described in Example l; yield 90~, m.p. 90C (n-heptane). ~H NMR (CDC13): ~ 2091 (Me), 8.90 (H-4, H-6).

Example 4 2-Benzylsulflnyl-5-br _ ~yrimidine 85~ m-Chloroperbenzoic acid (1.5 mmol~ was added to a solution of 2-benæylthio-5-bromopyr;midine (1.5 mmol) in dichlorome~hane (25 ml) at -10~C and the solution left a 0C for 18 h. The dichloromethane solution was then washed with saturated aqueous solutions of Na2SO3 and NaHCO3, and the dried (MgSO4) solution evaporated to leave the title compound; yield 91~, m.p. 101C (iPrOH). lH NMR (CDC13); ~ 4.26 and 4.31 (CH2~, 7.16 (Ph~, 8.80 (H-4, H-6~.
Example 5 2-Phenylsulfiny~ -chloropyrimidine 30% hydrogen peroxide solution (0.8 g~ was added to a sol,ution of 2-phenylthio-5-chloropyrimidine (5 mmol~ in acetic acid (4 ml) and left at room temperature for 60 h. The solut;on was then diluted (25 ml) and the precipitate purified by thick-layer (2 mm) chromatography on silica qel 60F (Merck~. The plates were developed with EtOAc; yield 50% m.p. 115C (ligroin).
H NMR (CDC13): ~ 7.4 and 7.8 (Ph), 8.71 (H-4, H-6).
Example 6 2-Benzylsulfonyl-5-bromopyrimidine A solution of 2-benzylthio-5-bromopyrimidine (10.6 mmol) and 85% _-chloroperbenzoic acid (31.8 mmol) in dichloromethane (200 ml) was left at room temperature for 3 days. The solution was then washed with saturated Na2SO3 (3 x 15 ml~, washed with saturated NaHCO3 (3 x 10 ml~ and the dried (MgSO4) dichloromethane solution evaporated to yield the title compound, yield 93%, m.p. 142-143C (iPrOH~. lH NMR ~CDC13):
4-73 (CH2), 7.~6 (Ph~, 8.90 (H-4, H-6)~

:`
~

Example 7 2-Benzylsulfonyl-4,6-dimethyl-5~bromopyrimidine A solution of 2-benzylthio--4,6 dimethyl-5-bromo-pyrimidine (5 mmol~ and 85% m-chloroperbenzoic acid (15.9 mmol) in dichloromethane (100 ml) was left at room temperature for 3 days. The solution was then shaken with saturated Na2S03 aq. (3 x ]5 ml~, saturated NaCH03 aqO (3 x 10 ml) and the dried MgS04 solution evaporated to leave the sulfone; yield 94~, m.p. 138-139C (iPrOH). 1H NMR (TFA~: ~ 2.83 (Me), 4.93 (CH2) r 7.33 (Ph~-Example 8 2-Phenylsulfonyl 5-chloropyrimidine 30% hydrogen peroxide solution (2 g~ was added to a solution of 2-phenylthio-5-chloropyrimidine (18 mmol) in acetic acid (14 ml~O After 2 days at room temperature another 2 g of 30~ hydrogen peroxide solution was added and the resultant solution heated at 50C Eor 4 h. The sulfone was precipitated on 20 dilution of the cold solution ~100 ml); yleld 80~, m.p. 103C (ETOH). H NMR (CDC131: ~ 7.6 and 8.1 (Ph, m) 8083 (H-4, H-6).
Example 9 Phenylsulfonyl-5-bromop~rimidine 2-Phenylthio-5-bromopyrimidine (prepared as described in Preparation 3) was oxidised by hydrogen peroxide as described for the chloro analogue in Example 8; yield 75%, m.p. 103C (iPrOH). lH NMR
(CDC13): ~ 7.6 and 8.1 (Ph, m) 8.90 (H-4, H 6~.

~x~ e 10 _.
2-Methylsul o~ 4 metho 5-ch]oropyrimidine A solutlon of 2-methylthio-4-methoxycarbonyl-

5-chloro-pyrimidine (10 mmol) and 30~ hydrogen peroxide (2.5 g) in acetic acid (8 ml~ was left at room temperature for 3 d. The mixture was then poured onto ice, the mixture neutralised with sodium bicarbonate and extracted with chloroform, and the chloroform solution evaporated.
The oily residue slowly crystallised on standing;
yield 74%, m.p. 96C (EtOH). ~ NMR (CDC13): ~ 3.38 (S02Me), 4.06 (OMe), 7.91 ~H-6).
Example 11 2-Benzylsulfonyl-5-chloropyrimidine A solution of 2-benæylthio-5-chloropyrimidine (3.7 mmol~ and potassium permanganate (5.2 mmol) in 1 N acetic acid (12 ml) was kept at room temperature until TLC (silica gel with EtOAC) showed the oxidation to be complete (ca. 3C min). The mixture was then diluted and neutralized with sodium bicarbonate.
The precipitate was collected by filtration, sucked dry and washed with chloroform. The chloroform washing were used to extract the aqueous filtrate, the chloroform solution washed with a little water, dried (MgS04) and evaporated. Yield 30%, m.p. 122-124C (iPrOH).
H NMR (CDC13); ~ 4.75 (CH2)l 7.28 (Ph), 8.83 (2 H-4 6).
Example 12 2-(4-Tolysulfonyl)-5-bromopyrimidine A mixture of 2-chloro-5-bromopyrimidine ~3.6 mmol), ~-toluenesulfinic acid Na-salt (6 mmol), TEBA
(6 mmol) and LiBr (1.0 g) in EtOH (30 ml) was heated under reflux for 20 h when TLC monitoring (silica gel/benzene) showed the reaction to be complete.
The solvent was removed as reduced pressure, water (25 ml) added to the residue, the aqueous solution f - 24 ~

left at 0C and the precipitate collected an~7 extracted with chloroform. Evaporation of the chloroform solution left the title compound; yield 22~, mOp. 142-144C
(iPrOM). lH NMR (CDC13): ~ 2.43 (Me), 7.30 and 7.96 (Ph), 8.90 (H-4, ~-6).
Ç~13 2-(4-Tol~l)sulf -A mixture of 2-chloro-4,6-dimethyl-5-bromopyrimidine (5 mmol) ~-toluenesulfinic acid Na-salt (8.3 mmol) and catalytic amounts of iodine and Cu-powder in ethanol (60 ml) was heated under reflux for 3 days.
The solvent was then distilled off, the residue extracted with chloroform (100 mml), the chloroform solution washed with aq. saturated NaHCO3 and the dried (MgSO4) solution evaporated to leave the sulfone; yield 23%, m.p. 157-158C (iPrOH). lH NMR (DMSO-d6) S 2.43 (Me-Ph), 2.63 (4-Me, 6-Me), 7.43 and 7~86 (Ph).
Example 14 2-Phenylsulfonyl-5-fluoro~yrimidine 2-Phenylthio-5-fluoropyrimidine t4 mmol~ was dissolved in acetic acid (5 ml), 30~ ~22 (0-5 ml) added and the resultant solution stirred at room temperature for 3 days. The product was precipitated by addition of ice cold water (35 ml); yield 71%, 25 m.p. 105C (iPrOH). 1H NMR (CDC13): ~ 7.5-8.1 (Ph), 8.65 (H-4, H-6).

- 25 ~

Pharmaceutical composition ~amples Example A
Injection solution 5 l. Active ingredient 500 mg 2. Polysorbate 80 l.25 mg 3. Sodium chloride 20 mg . Water for injection to2.5 ml The s~erile active ingredient, comminuted as a very fine powder, is dispersed aseptically in an aqueous vehicle containing the wetting agent (Polysorbate 80) and sufficient sodium chloride to produce an approximately isotonic solution, thus providing a suspension which may be used for deep intramuscular injection. Buffer salts may be incorporated (with a consequent reduction in the quantity of sodium chloride) to provide a suspension at the appropriate pH to ensure optimum stability of the compound before injection. The product may be presented as a dry filled vial of active ingredient with a sterile ampoule of the remaining ingredients to permit extemporaneous preparation of the suspension immediately before injection.
Exam~le B
25 Injection _olution l. Active ingredient lO~ mg 2. Aluminium monostearate 5 mg 3. Fractionated coconut oil to l ml Sterile active ingredient in the form of a very fine powder is dispersed aseptically in a sterile olly vehicle containing a suspending agent whose structure is built up during the heat sterilisation of the vehicle. Such a product may be presented as a pre-prepared suspension for intramuscular injection.
The dose administered may be adjusted by alteration of the dose volume. The product may be presented in multidose vials, sealed with oil resistant rubber plugs to permit w;thdrawal of the required dose volume.

Tablets ]. Active ;ngredient 250 mg 2. Lactose 100 mg 5 3. Maize starch 20 mg 4. Polyvinyl pyrrolidone 5 mg 5. Magnesium stearate 5 mg Ingredients 1, 2 and 3 may be blended, mixed to a crumbly consistency with an alcoholic solution of 4, dried at atmospheric presure~ the resulting granules passed through a 20 mesh wire sieve, and the resulting product bl.ended with 5 and compressed into tablets using suitable punches and dies in a tablet compression machine. The tablets may have a thin film coat of, for example hydroxypropyl methyl cellulose applied to them to mask any unpleasant taste.

Claims (24)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition comprising as active ingredient a compound of the formula:- [wherein X represents a fluorine, chlorine or bromine atom; n is 1 or 2; R1 and R2, which may be the same or different, each represents a hydrogen atom or a C1-4 alkyl group, a carboxyl group or a group of the formula -COOR (in which Ra represents a C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl group, a C3-8 cycloalkyl or C3-8 cycloalkenyl group, an araliphatic group with up to 4 carbon atoms in the aliphatic moiety, which moiety may be saturated or unsaturated, and up to in carbon atoms in the aryl moiety or a C6-10 aryl group, the aryl moiety or group being optionally substituted by a C1-4 alkyl group); and R3 represents an unsubstituted C1-8 alkyl group or an unsubstituted aralkyl group with up to 4 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety or an unsubstituted C6-10 aryl group, the aryl moiety or group optionally carrying a C1-4 alkyl group] or, where an acidic group is present, a physiologically compatible salt thereof, in association with a pharmaceutical carrier or excipient.

2. A composition as claimed in claim 1 wherein a compound of formula I is used in which R1 and R2, which may be the same or different, each represents a hydrogen atom or a C1-4 alkyl group.

3. A composition as claimed in claim 2 wherein a compound of formula I is used in which R1 and R2 each represents a hydrogen atom.

4. A composition as claimed in any one of the preceding claims wherein a compound of formula I is used in which R3 represents a C1-4 alkyl group, or an aralkyl group in which the aryl moiety or group is a phenyl group optionally carrying a C1-4 alkyl group.

5. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a methyl group.

6. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a benzyl group.

7. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a tolyl group.

8. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a p-tolyl group.

9. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a C1-4 alkyl group, or an aralkyl or aryl group in which the aryl moiety or group is a phenyl group optionally substituted by a C1-4 alkyl group and n is 2.

10. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a methyl group and n is 2.

11. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a benzyl group and n is 2.

12. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a tolyl group and n is 2.

13. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a p-tolyl group and n is 2.

14. A pharmaceutical composition as claimed in claim 1 which comprises 2-methylsulfonyl-5-chloropyrimidine as active ingredient.

15. A pharmaceutical composition as claimed in claim 1 which comprises 2-benzylsulfonyl-5-chloropyrimidine as active ingredient.

16. A pharmaceutical composition as claimed in claim 1 which comprises 2-benzylsulfonyl-5-bromopyrimidine as active ingredient.

17. A pharmaceutical composition as claimed in claim 1 which comprises 2-benzylsulfinyl-5-chloropyrimidine as active ingredient.

18. A composition as claimed in any one of claims 1 to 3 in sterile form.

19. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a C1-4 alkyl group, or an aralkyl or aryl group in which the aryl moiety or group is a phenyl group optionally substituted by a C1-4 alkyl group, said composition being in sterile form.

20. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a methyl, benzyl or p-tolyl group, said composition being in sterile form.

21. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a C1-4 alkyl group, or an aralkyl or aryl group in which the aryl moiety or group is a phenyl group optionally substituted by a C1-4 alkyl group and wherein n is 2, said composition being in sterile form.

22. A composition as claimed in any one of claims 1 to 3 wherein a compound of formula I is used in which R3 represents a methyl, benzyl or p-tolyl group and n is 2, said composition being in sterile form.

23. A composition as claimed in claim 14 or claim 17 in sterile form.

24. A composition as claimed in claim 15 or claim 16 in sterile form.