Note: Descriptions are shown in the official language in which they were submitted.
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
13 -
1 2
(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~
- ,~
- 16
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
- 20 -
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).
- 21 -
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)~
:`
~
- 22
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~.
- 23 -
~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.
- 26 -
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.
