Note: Descriptions are shown in the official language in which they were submitted.
DE SCRIP~IO~
"NITROIMIDAZOLE DERIVATIVES "
This invention relates to new platinum~
containing complexes of nitroimidazole compounds, to
processes for their preparation and to pharmaceutical
compositions containing them.
The present invention provides platinum(II)~
containing complexes of nitroimidazoles of the general
~ormula:-
~X~ ptII(zl)
wherein X represents a 2- or, preferably. 4- or 5-~mono)-
nitroimidazole molecule which may be unsubstituted or,
preferably, carries at least one substituent, and which
~ can coordinate to platinum through the 3-position of ~he
heterocyclic, i.e. imidazole. ring, and zl represents
a pharmaceutically-acceptable ligand known to those
skilled in the art not to be capable of coordinating
to platinum more strongly than the 3-position nitrogen
atom of the imidazole ring of a 2-, 4- or 5-(mono)nitro-
imidazole molecule represented by the symbol X.which possess
valuable properties of use in the therapy of cancer and in
combatting anaerobic bacterial infections.
By the term "pharmaceutically-acceptable
ligand", as used in this specification to refer to
symbol zl, is meant a ligand which, w~hen displaced
from the compound of formula I, forms only species
which are relatively innocuous to the animal organism
when used in therapeutic doses so that the beneficial
phanmacological properties of the compound of formula I
are not vitiated by side-effects ascribable to those
species.
Preferably zl represents a bromine, iodine or.
more particularly, chlorine atom or (Z1)2 represents
a bidentate ligand of the general formula:-
___--O--C
\c~lR2 II
~ )--c
lo
wherein Rl and R2, which may be the same or different,
each represents a hydrogen atcm or an alkyl, aryl,
aralkyl, alkenyl, cycloalkyl or cycloalkenyl group
or CRlR2 represents a cycloalkyl or cycloalkenyl group.
The dotted lines indicate bonding to the platinum atom
in general formula I.
When (Z1)2 represents two monodentate ligands
they nay be different but are preferably the same.
:~8~7~
Within the definition of CRlR2 in ~ormula II,
alkyl groups and moieties and alkenyl groups preferably
contain up to 6 carbon atoms, aryl groups and moieties
are preferably phenyl, and cycloalkyl and cycloalkenyl
groups preferably contain from 3 to 8 carbon atoms.
2-(Mono)nitroimidaæole molecules represented
by the symbol X have, preferably, a substituent in at
least one of the 1-, 4- or 5-positions of the imidazole
ring. 4- or 5-(Mono)nitroimidazole molecules represented
by the symbol X have, preferably, a substituent on at
least one of the 1- or 2-positions of the imidazole ring
or the 4- or 5-position of the imidazole ring which is not
occupied by the nitro group. 4- or 5-(Mono)nitro-
imidazole molecules represented by the symbol X are
preferably substituted in the 2-position of the imidazole
ring and may be unsubstituted or, as is preferred.
substituted in the l-position of the imidazole ring.
Suitable substituents on the 1-, 2- and 4- or 5-positions
of the imidazole ring of 2-i 4- or 5-(mono)nitroimidazole
molecule represented by the symbol X are those atoms
or groups which are known to those skilled in the art
not to be capable of coordinating to platinum more
strongly than the 3-position nitrogen atom of the
imidazole ring of a 2-, 4- or 5-(mono)nitroimidazole
molecule represented by the symbol X. Accordingly,
substituents containing atoms or groups, for example the
4 --
mercapto group, which are well known to coordinate very
strongly with platinum, should be avoided.
Preferred substituents are alkyl groups
unsubstituted or substituted by one or more atoms or
groups selected from hydroxy, alkoxy, alkylsulphonyl,
carboxy, alkoxycarbonyl, carbamoyloxy, benzylcarbamoyl
and ~-morpholinyl groups and halogen, preferably chlorine
atoms phenyl groups substituted by halogen, preferably
fluorine, atoms; and alkylthio groups substituted by a
phenoxy group which phenoxy group is substituted by
carboxy: alkyl and alkoxy groups and moieties may be
straight- or branched-chain and contain from 1 to 4
carbon atoms.
When a substituent group in a substituted
nitroimidazole molecule represented by the symbol X
contains a free hydroxy group, the substituent may form
monoesters with dicarboxylic aliphatic acids, wherein
the aliphatic, e.g. alkyl, moiety preferably contains
from 1 to 6 carbon atoms, and pharmaceutically-acceptable
salts thereof, and, when a substituent group in the
aforesaid substituted nitroimidazole molecules contains
a free hydroxy group, the substituent may form phosphate,
phosphite or sulphate esters and their salts containing
pharmaceutically-acceptable cations, for example
7~L
alkali metal, e.g. potassium or sodium, salts,
alkaline earth metal, e.g. calcium or magnesium. salts,
ammonium salts and amine salts with pharmaceutically
acceptable c~mines; when X represents a nitroimidazole
carrying a substituent which comprises cl carboxy group,
pharmaceutically-acceptable salts thereof may be formed.
It is to be understood that such esters and salts
constitute a ~eature of the invention.
Particularly suitable substituted 2-, 4-
or 5-(mono)nitroimidazole molecules represented by the
symbol X are-molecules selected from the group consisting
of metronidazole [1-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole, hereinafter also identified by the
abbreviation IMNZI~, dimetridazole [1,2-dimethyl-
5-nitroimidazole~, ipronidazole (1-methyl-2-isopropyl-
5-nitroimidazole), tinidazole Ll-(2-ethylsulphonylethyl)-
2-methyl-5-nitroimidazole~, 2-methyl-4(or 5)-nitroimidazole,
l-carboxymethyl-2-methyl-5-nitroimidazole, nimorazole
[1-(2-N-morpholinylethyl)-5-nitroimidazole~, ornidazole
El- ( 3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole~,
ronidazole [1-methyl-2-carbamoyloxymethyl-5-nitroimidazole],
secnidazole [1-(2-hydroxy-n-propyl)-2-methyl-5-nitro-
imidazole~, l-methyl-5-nitroimidazole, 2-[2-~4-carboxy-
phenoxy)ethylthio~-1-methyl-5-nitroimidazole, bclmnidazole
[1-(2-carbamoyloxyethyl)-2-methyl-5-nitroimidazole~,
flunidazole [1-(2-hydroxyethyl)-2-(~-fluorophenyl)-5-
-- 6 --nitrQimidazole~, 2-hydroxymethyl-1-methyl-5-nitro-
imidazole, l-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole.
2-isopropyl-~(or 5~-nitroimidazole. 2-h~droxymethyl-
4(or 5)-nitroimidazole, 1-(2-hydroxyethyl)-2-methyl-4-
nitroimidazole, 1,2-dimethyl-4-nitroimidazole,
1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole,
misonidazole [1-~2-hydroxy-3-methoxy-n-]propyl)-2-nitro-
imida~ole~, benznidazole [N-benzyl-1-(2-nitroimidazolyl)-
acetamide~, azomycine (2-nitroimidazole) and 4(5~-nitro-
imidazole, and, when a substituent group in the 1- or
2-position o~ the aforesaid substituted nitroimidazole
molecules contains a free hydroxy group, monoesters
thereof with dicarboxylic aliphatic acids, wherein the
aliphatic, e.g. alkyl, moiety preferably contains from 1 to
6 carbon atoms. and pharmaceutically-acceptable salts
thereof, and, when a substituent group in the 1- or
2-position of the aforesaid substituted nitroimidazole
molecules contains a free hydroxy group, phosphate, phosphite
or sulphate esters thereof and pharmaceutically-acceptable
salts o~ such phosphate, phosphite and sulphate esters,
for example metronidazole hemisuccinate, metronidazole
phosphate and metronidazole sulphate and their salts
containing pharmaceutically-acceptable cations, for example
al~ali metal, e.g. potassium or sodium, salts, alkaline
earth metal, e.g. calcium or magnesium, salts, ammonium salts
and amine salts with pharmaceutically acceptable amines, and
when X represents ~-carboxymethyl~2-methyl-5-nitroimidazole or
2-~2-(4-car~oxyphenoxy~ethylthio]-1-methyl-5-nitroimidazole,
pharmaceutically-acceptable salts thereof.
~L~8~
By the te~m 'pharmaceutically-acceptable salts',
as used in this specificationl is meant salts the cations
of which are relatively innocuous to the animal organism
when used in therapeutic doses so that the beneficial
pharmacological properties of the platinum(II)-containing
complexes of gener~ formula I are not v:itiated by side-
effects ascribable to those cations. Preferably the salts
are water-soluble. Suitable salts include the alkali
metal, e.g. sodium and potassium, alkaline earth
metal, e.g. calcium and magnesium, and ammonium salts
and pharmaceutically-acceptable amine salts. Amines
suitable for forming such salts are well known and
include, for example, amines derived in theory by the
replacement of one or more of the hydrogen atoms of ammonia
by groups, which may be the same or different when more
than one hydrogen atom is replaced, selected from, for
example, alkyl groups containing from 1 to 6 carbon atoms
and hydroxyalkyl groups containing 2 or 3 carbon atoms.
In this specification when reference is made to
compounds of formula I reference is also intended to their
pharmaceutically-acceptable salts and esters, where the
context so permits.
The platinum(II~-containing complexes of formula I,
which are all square planar, may be in the trans or the
c -configuration, but it is to be noted that geometry
dictates that the compounds of formula I wherein (Z1)2
represents a bidentate ligand, especially a ligand of
formula II, are in the cis-configuration.
~LB9074
A particularly preferred class of compounds of
formula I comprises those wherein X represents
metronidazole, more especially cis-dichloro-bis[l-(2-
hydroxyethyl~-2-methyl-5-nitroimidazole-:N3~platinum(II)
5 of the formula:-
Cl \ / Cl
Pt III
~M~Z ~ ~P~Z )
hereinafter referred to for convenience as
cis-Pt(M~Z)2C12 or as "Compound A".
Other important individual compounds of formula I
include:-
diiodo-bis[l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-
N3~platinum(II), B
dichloro-bis~1,2-dimethyl-5-nitroimidazole-~3)platinum(II); C
dichloro-bis(l-methyl-2-isopropyl-5-nitroimidazole-~3)-
15 platinum(II); D
dichloro-bis[l-(2-ethylsulphonylethyl)-2-methyl-5-
nitroimidazole-E3}platinum(II); E
dichloro-bis(l-carboxymethyl-2-methyl-5-nitroimidazole-
N3~platinum(II) F
20 dichloro-bis[1-(2-hydroxyethyl)-2-hydroxymethyl-5-
nitroimidazole-~33platinum(II); G
390~
trans-dichloro-bis[l-(2-hydroxy-3-metho.xy-n-propyl)-2-
nitroimidazole-N ~platinum(II),
cis-(cyclobutane-l,l-dicarboxylatO-0,0')-bis[1-(2-
hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), I
5 cis-bis[l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]-
(malonato-0,0~)platinum(II~; J
cis-bis~1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole ~3~-
(methylmalonato-0,0')platinum(II), K
cis-(dimethylmalonato-0,0')-bis[l-(2-hydroxyethyl)-2-
10 methyl-5-nitroimidazole-~3~platinum(II), L
CiS- ( ethylmalonato-0,0')-bis[l-(2-hydroxyethyl)-2-methyl-
5-nitroimidazole-~3]platinum(II), M
cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]-
(isopropylmalonato-0,0')platinum(II):
cis-(benzylmalonato-0,0'~bis~1-(2-hydroxyethyl)-2-
methyl-5-nitroimidazole-N3~platinum(II): o
dichloro-bis[1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-
~3~platinum(II), P
dichloro-bis[1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-
20 nitroimidazole-N33platinum(II), Q
dichloro-bis[l-(2-hydroxyethyl)-2-(~-fluorophenyl)-5-
nitroimidazole-~ ~platinum(II), R
dichloro-bis(l-methyl-2-carbamoyloxymethyl-5-nitroimidazole-
N3]platinum(II); S
25 dichloro-bis[1-(2-carbamoyloxye-thyl~-2-methyl-5-
nitroimidazole-~3]platinum(II); T
-
~3~7~
-- 10 --
dichloro-bis[l-(2-~-morpholinylethyl)-5-nitroimidazole-
N3~platinum(II), U
dichloro-bis[2-hydroxymethyl-1-methyl-5~-nitroimidazole-
N3~platinum(II), V
5 dichloro-bis~l-ethoxycarbonylmethyl-2-methyl-5-
nitroimidazole- 3)platinum(II), W
dichloro-bis(l-methyl-5-nitroimidazole-N3~platinum(II); X
dichloro-bis[2-methyl-1-(2-phosphatoethyl3-5-nitroimidazole-
N3~platinum(II), Y
dichloro-bis{2-[2-(4-carboxyphenoxy)ethylthio~-1-methyl-
5-nitroimidazole-~3~platinum(II); Z
dichloro-bis(1,2-dimethyl-4-nitroimidazole-N3)platinum(II), AA
dichloro-bis~l-(2-hydroxyethyl)-2-methyl-4-nitroimidazole-
~3~platinum(II), BB
cis-bis~1-(2-hydroxyethyl~-2-methyl-5-nitroimidazole-M3~-
(phenylmalonato-0,0 )platinum(II), and CC
dibromo-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3~-
platinum(II). DD
The letters A to DD are assigned to the
compounds for easy reference later in the specification,for example in the Table.
Irradiation with X-rays is a widely used method
for the treatment of many cancers, by the destruction of
the neoplastic cells. However, a problem which is
frequently encountered in the treatment of solid cancers,
e.g. lymp~omas, carcinomas and sarcomas, by X-ray therapy,
is that a substantial proportion of the cells in solid
tumours are hypoxic and are relatively insensitive to
irradiation with X-rays.
It has now been found that the platinum~
containing complexes of general formula I increase the
sensitivity of hypoxic tumour cells to ~C-rays and may be
administered in conjunction with the ~-ray therapy of
solid cancers to increase the effectiveness of the
radiation therapy.
For example Compound A (the compound of
formula III) in tests produced an enhancement ratio of
2.4 when given as a pretreatment to hypoxic X-irradiated
cells _ vitro, at a non-toxic 50 micromolar concentration.
Furthermore, the compounds are active against
anaerobic bacteria and, accordingly, they are
of utility in the treatment or prevention of conditions
such as pelvic inflammatory disease, dental disease and
gingivitis, and brain abscess, and they are of value in
minimising disease following operations such as
vaginal surgery and intestinal surgery.
The minimum inhibitory concentrations of compounds
of formula I, expressed in micrograms per millilitre,against
various anaerobic bacteria in vitro, are shown below in
Table I ~where the s~mbol " ~ " means "less than or
equal to").
-- î2 --
R N ~ .
~D ~D ~D
r~l ~ ,1 ~
}a . . o
O O O O
~1 ~ O
_
~D C~ ~ ~1
. . .
O ~ O
_ _0 ~0 _
U
O .~ ~ .
.,, ~q ~ ~,, ~ o ~a
~ O ,1 o ,Q O ~ .,1 ,1
O S~ ~1 lQ O 0 4 s~ r~
~:4 a~ ,~ o h R o ~ ~
1~ ~ t~ ~ ~11 O ~ ~ ~J
o ~ a ~ 0 ~q o o ~1
V ~ S~ ~ ~ ~ ~ ~I g)
m ~ ~ 0 ~ ~ c~
_
The value of the compounds of formula I is enhanced
by their remarkably low mammalian toxicity. For example,
the LD50 of Compound A in mice is 300 m~/kg animal body
weig~t when administered intraperitoneally and greater
than 2000mg/kg animal body weight when administered
orally.
Compounds of formula I may be prepared by the
application or adaptation of known methods.
According to a feature of the present invention
compounds of formula I, wherein X and zl are as
hereinbefore defined, are prepared by reaction of a
nitroimidazole compound corresponding to the symbol X, as
hereinbefore defined, with a platinite salt of the general
formula:-
Q ptII(zl) IV
wherein Q represents an alkali metal, for example sodiumor potassium, atom and zl is as hereinbefore defined,
the ligands represented by zl being different or,
preferably, the same. Reaction may be effected in water
or an aqueous organic solvent, e.g. aqueous ethanol, àt
a temperature from 15 to 100Co
~74
For example, cis-Pt(M~Z)2C12 of formula III,
according to a feature of the present invention, is prepared
by reaction of metronidazole with an alkali metal
chloroplatinite and more especially potassium chloro-
platinite (K2PtC14). Reaction may be effected in waterat 15-100C, preferably at 40-60C.
According to a feature of the present
invention, certain compounds of formula I may be
prepared from other compoundsof formula I.
For example, a compound, within general formula I,
of the general formula:-
~X~ 2Pt Y2 V
(wherein X is as hereinbefore defined and Y is a halogen
atom) can be treated with silver nitrate in an aqueous
medium, followed by treatment with a source of an
alternative ligand to replace Y.
Thus, according to a feature of the present
invention, cis-Pt(MNZ)2C12 is prepared by treating
cis-Pt(MNZ)2I2 with silver nitrate in an aqueous medium,
followed by treatment with a source of chloride ions,
for example an alkali metal chloride, e.g. potassium
chloride.
According to a further feature of the present
invention, compounds of formula I wherein (Z1)2
represents a bidentate ligand of ~ormula II and X is as
hereinbefore defined may be prepared by the reaction o~ a
compound of the general formula V in the cis-configuration
(wherein X is as hereinbefore defined and Y is a bromine,
iodine or. preferably, chlorine atom) with silver
nitrate in an aqueous medium, followed by ~reabment with
an acid of the general formula:-
~HOOC)2CRlR2 VI
(wherein Rl and R2 are as hereinbefore defined) followed
by neutralisation of the solution by the addition of asuitable base such as an alkali metal carbonate, e.g.
sodium carbonate. The solution is treated with a water-
miscible organic solvent, such as acetone, and filtered
to remove ~recipitated inorganic byproducts and the
filtrate is evaporated in vacuo to give the required
compound of formula I.
Substituted nitroimidazole compounds
corresponding to the symbol X, including, when a
substituent group in the aforesaid substituted nitro-
imidazole compound contains a free hydroxy group,monoester~ thereof with dicarboxylic aliphatic acids,
phosphate esters, phosphite esters and
- 16 -
sulphate esters. may be prepared by the application or
adaptation of methods known E~ se for the preparation
of substituted nitroimidazole compounds. Some are
articles of commerce.
S Pharmaceutically-acceptable salts of the
aforesaid monoesters, phosphate esters, phosphite esters
and sulphate esters, and pharmaceutically-acceptable
salts of the platinum(XI)-containing complexes of general
formula I wherein X represents a nitroimidazole carrying
a substituent which includes a carboxy group, for
example l-carboxymethyl-2-methyl-5-nitroimidazole,
may be prepared by the application or adaptation of methods
known per se, ei~ther by utilising an appropriate
substituted nitroimidazole compound corresponding to the
symbol X, as hereinbefore defined, in the form of a
pharmaceutically-acceptable salt in the preparative
reactions hereinbefore described or from an appropriate
platinum(II)-containing complex of general formula I
obtained by the preparative reactions hereinbefore
described.
By the expression "methods known per se" as used
in the present specification is meant methods heretofore
used or described in the literature.
- 17 -
The following Examples illustrate the
preparation of compounds of general formula I.
In them 'NMR' and ' Wl represent 'nuclear
magnetic resonance spectrum' and 'ultra-violet
S absorption spectrum', respectively. Often only the
most important features of these spectra are given.
Polarography was carried out using a droppiny
mercury electrode. Potentials were measured with
reference to a silver/silver chloride electrode, using
10 a polarograph in the diffexential pulse mode. samples
were prepared as approximately 100~ in phosphate
buffer (pH 7.0). Peak potentials (Ep) were recorded.
_XAMPLE _
Compound A
Metronidazole (6.85g' 40mmol) was suspended
in water (300ml) and stirred with gentle heating (50C).
K2PtC14 (8.3g, 20mmol) was added and stirring with
gentle heating was continued for one hour. The
solution changed in colour from cloudy reddish-orange
20 to clear yellow. cls-Pt(MNZ)2C12 then precipitated.
After cooling, the supernatant liquid was decanted off
and reduced in volume in a rotary evaporator to
precipitate further cis-Pt(M~Z)2C12. m e cis-Pt(MNZ)2C12
precipitates were combined, washed first with a mixture
25 of ethanol and diethyl ether, and then washed with
diethyl ether, and dried in air to give cis-Pt(M~Z)2C12
(12.16g, yield 91.3%) in the form of yellow crystals
having the followiny characteristics:-
5D7~
- 18 _
(a) Elementary analysis:
calculated: C,23.68; H,2.96; ~,13.81; Cl,11.67%;
found: C,23.09; H,3.24, N,13.59: C1,11.37%.
(b) NMR in acetone-D6: singlet at 3.01p.p.m., two triplets
centred at 3.95 and 4.65 p.p.m., and a multiplet
centred at 8.45 p.p.m.
(c) U.V.: absorption~ max. 304nm, extinction coefficient
() 1.2x104M lcm 1~
(d) Polarography: Ep = -0.27V.
10 (e) Melting point 178-181C, followed by resolidification
and melting (with decomposition) at 257-259C.
A sample of Pt(M~Z)2C12, obtained as described
above, was recrystallized by allowing a saturated
solution in a mixture of water and acetone to evaporate
at ambient temperature, to give yellow crystals having
the following elementary analysis:-
calculated: C,23.68; H,2.96; ~,13,81; Cl,11.67;
found: C,23.46, H,3.12, ~,13.87; C1,11.47.
The molecular structure, including the cis-
configurati~nl of -the product Pt(M~Z)2C12 prepared as
described above was confirmed by X-ray crystallography:
the crystal system was monoclinic with Space Group P21/a,
cell constants~ a = 15.906A, b = 10~169A, c = 12.729A,
~ = 109.74, z = 4. The structure was refined to R = 0.074
7~
-- 19 --
EXAMPLE 2
Compound B
Potassium iodide (4g) was added to a solution
of K2PtC14 (415mg; lmmol) in water (20 ml). Ihe colour
of the solution changed from orange-red to deep red.
5 Metronidazole (342 mg; 2mmol) was then added and the
solution was stirred. The solution became slightly
lighter in colour and an orange-yellow product
precipitated. After cooling and centrifuging, the
supernatant liquid was decanted off and the residue
10 was washed with a mixture of ethanol and diethyl ether,
and then with diethyl ether, to give diiodo-bis[l-(2-
hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II)
(570mg; yield 72%), having the following characteristics:-
(a) Elementary analysis:
calculated: C,18.10; H,2.28; N,10O62; I,32O09%;
found: C,17.83, H,2.36, N,10.71; I,32.17%~
(b) ~MR in acetone-D6: singlet at 3.01 p.p.m., two
triplets centred at 3.95 and 4.65 p.p.m., and a
multiplet centred at 8.5 p.p~m.
EXAMPLE 3
Compound A
Diiodo-bis[l-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole-N3]platinum(II) (316mg, 0.4mmol, obtained
as described in Example 2) was suspended in water (25 ml~
25 and silver nitrate (136mg; 0.8mmol) was added. The
- 20 -
solution was then stirred for several hours, during
which time the colour changed to pale yellow.
Precipitated silver iodide was removecl by centrifugation
and excess potassium chloride was added to the separated
supernatant liquid. cls-Pt~M~Z)2C12 precipitated and
was collected, washed with a mixture of ethanol and
diethyl ether and then with diethyl ether to give cis-
Pt(MNZ)2C12, identical to the product obtained in Example 1.
_XAMPLE 4
10 Compound Cl D and E
Dimetridazole (0.282g, 2mmol) was suspended
in water (20 ml) and stirred with gentle heating (50C).
K2PtC14 (0.415g, lmmol) was added and stirring with gentle
heating was continued for one hour. After cooling, the
15 supernatant liquid was decanted off from the precipitate
which had formed. The supernatant liquid was reduced
in volume in a rotary evaporator to precipitate a fur-ther
quantity of solid. The precipitates were combined,
washed with a mixture of ethanol and diethyl ether, and
20 then with diethyl ether, and then dried in air, to give
dichloro-bis(1,2-dimethyl-5-nitroimidazole-N3)platinum (II)
(0.456g), having the following characteristics:-
(a) Elementary analysis:
calculated: C,21.89; H,2.55; N,15.32, Cl,12.95%,
found: C,21.46, H,2.74, N,14.74; C1,13.2~%.
~9~
(b) MMR in dimethylsulphoxide-~6 singlets at 2.80 and
3.80 p.p.m~ and a multiplet centred at 8.52 p.p.m.
(c) U.V.: absorption~ max~ 304nm.
(d) Polarography: Ep = -0.34V.
5 te) Melting point: 174-176C.
By proceeding in a similar manner, but replacing
the dimetridazole, used as a starting material, by
ipronidazole and tinidazole respectively, there were
prepared:-
10 (1) dichloro-bis(l-methyl-2-isopropyl-5-nitroimidazole-
~3)platinum(II) having the following characteristics:-
(a) Elementary analysis:calculated: C,27.80; H,3.64; ~,13.90; C1,11.75%;
found: C,27.13; H,3.59; N,13.48; Cl,11.87%.
(b) ~MR in acetone-D6: doublet at 1.55 p.p.m.,
singlet at 4.13 p~p.m., septet at 4.97 p.p.m.,
and a multiplet centred at 8.45 p~p.m.
(c) U.V.: absorption~ max. 308nm.
(d) Melting point: 220C (with decomposition).
20 (2) dichloro-bis[1-(2-ethylsulphonylethyl)-2-methyl-5-
nitroimidazole-~3]platinum(II) having the following
characteristics:-
~a) Elementary analysis:calculated: C,25.26; H,3.42; ~,11.05;Cl,9.34,S,8.42%;
foundo C,25~58; H,3.62; N,11.04;Cl,9~39,Sl8.54%.
7~
(b) ~MR in acetone-D6: triplets at 1.36, 3.68 and
4.88 p.p.m., singlet at 3.00 p.p.m., quartet at
3.20 p.p.m., and multiplet centred at 8.12 p.p.m.
~c) U.V.: absorption~ max. 302nm.
5 (d) Polarography: Ep = -0.37V.
(e) Melting point 145-147C.
EXAMPLE 5
Compound F
l-Carboxymethyl-2-methyl-5-nitroimidazole
10 (0.370g, 2mmol) was suspended in water ~20ml) and
stirred. K2PtC14 (0.415g, lmmol) was added and stirring,
without heating, was continued for one hour. After
cooling, the supernatant liquid was decanted from the
precipitate which had formed and it was reduced in
15volume in a rotary evaporator to precipitate a further
quantity of solid. The combined precipitates were
washed with a mixture of ethanol and diethyl ether and
then with diethyl ether, and then were dried in air, to
give dichloro-bis(l-carboxymethyl-2-methyl-5-nitro-
20 imidazole-~3)platinum(II) dihydrate (0.48g), having the
following characteristics:-
(a) Elementary analysis:
calculated: C,21.42; H,2.68; M,12.49, Cl,10.56%,
found: C,21.11; H,2.48; ~,12.26, Cl,10.75%~
25 (b) ~MR in D20: singlets at 2.70 and 4.74 p.p.m~ and a
multiplet centred at 8.18 p.p.m~
074
- 23 -
(c) U.V.: absorption~ max. 305nm.
(d) Polarography: Ep = -0.35V.
(e) Melting point 223-225C.
EXAMPLE 6
5 Compound G
1-(2-Hydroxyethyl)-2-hydroxymethyl-5-nitro-
imidazole (0.374g) was suspended in water with stirring
and gentle heating. K2PtC14 (0.415g) was added and
stirring with gentle heating was continued for 2 to 3
10 hours until the reaction mixture became clear. I~he
solution thus obtained was then cooled to approximately
QC and the precipitate which formed was collected,
washed with a mixture of ethanol and diethyl ether and
then with diethyl ether, and then dried in a desiccator,
15 to give dichloro-bis[1-(2-hydroxyethyl)-2-hydroxymethyl-
5-nitroimidazole-~3]platinum(II) (0.46g) having the
following characteristicsO-
(a) Elementary analysis:
calculated: C,22.50; H,2.81; ~,13.12; Cl,11.09%;
found: C,22.35, H,2097; ~,13.01; Cl,11.90%.
(b) ~MR in acetone-D6: singlet at 4.74 p.p.m., triplets
at 3.88 and 4.62 p.p.m., and a multiplet centred
at 8.20 p.p.m.
(c) U.V.: absorption~ max. 291nm~
25 (d) Polarography: Ep = -0.22V.
~e) Melting point 187 189C.
L89(~74
- 24 -
EXAMPLE 7
C~
Misonidazole (0.20g; l.Ommol) and K2PtC14
(0~207g; 0.5mmol) were dissolved in a mixture of ethanol
5 and water (1:1 volume; 15 ml) and the solution was
stirred for three hours at ambient temperature. ~he
solution became clear yellow in colour and was then
left to stand in the dark for three weeks. The fine
yellow needle-shaped crystals which formed were collected
10 to give trans-dichloro-bis[1-(2-hydroxy-3-methoxy-n-
propyl)-2-nitroimidazole-~3]platinum(II) having the
following physical characteristics:-
(a) Elementary analysis:
calculated: C,25.13; H,3.29: N,12.57; Cl,10.62%;
found: Cr24.81, H,3.36; ~,12.57, Cl,10.66%.
(b) Melting point 213-215C.
(c~ X-ray crystallography: the crystal system was
monoclinic with Space Group P21/a; cell constants:
a = 8.134A, b = 13.014A, c = 11,323A, ~ = 91.47,
Z = 2. The structure was refined to R = 0.0536.
The X-ray crystallographic analysis confirmed the
trans-disposition of the ligands around the platinum
atom.
EXAMoeLE 8
Compounds I L J, K,_L, M, ~ and O
A stirred suspension of c -dichloro-bis[1-(2-
hydroxyethyl)-2-methyl-5-nitroimidazole-~3]platinum(II)
)74
_ 25 -
(lOOmg) in water (10 ml) at 60C was treated with silver
nitrate (54.4mg) and the stirring at 60C was then
continued for 4 hours. The resulting mixture was allowed
to cool and was then filtered, and the filtrate was
5 treated with cyclobutane~ dicarboxylic acid (23.7mg).
The pH of the resulting solution was adjusted to 7 by
treatment with the appropriate quantity of aqueous sodium
carbona-te solution. The resulting solution was treated
with acetone (50ml) and filtered, and the filtrate was
10 freeze dried, to give cis-(cyclobutane-l,l-dicarboxylato-
0,0')-bisC1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-
~3]platinum(II) (107mg) in the form of a pale yellow solid,
m.p.219-233C (with decomposition), ~M + ~a]~ (field
desorption mass spectrometry) 702 a.m.u~(l95Pt)} I ~MR
15 in D20: multiplet centred at 8.25 p.p.m.
By proceeding in a similar manner, but replacing
the cyclobutane-l,l-dicarboxylic acid, used as a starting
material, by the appropriate quantities of malonic acid,
methylmalonic acid, dimethylmalonic acid, ethylmalonic
20 acid, isopropylmalonic acid and benzylmalonic acid,
respectively, there were prepared:-
cis-bis[l-(2-hydroxyethyl)-2-methyl-5-nitro-
imidazole-~3]-(malonato-O,OI)platinum (II~ in the form
of a yellow solid, m.p~ 98C (with decomposition~, ~MR
25 in D20: multiplet centred at 8.3 p.p9m.,
- 26 _
cis-bisC1-(2-hydroxyethyl)-2-methyl-5-ni~ro-
imidazole-N3]-(methylmalonato-O,O')platinUm~II) in the
rorm of a yellow solid, m.p. 135C (with decomposition):
NMR in D~O: multiplet centred at 8.25 p.p.m.'
cis-(dimethylmalonato-O,O'~-bisC1-(2-hydroxy-
ethyl)-2-methyl-5-nitroimidazole-~3]platinum(II) in the
orm of a yellow solid, m.p~ 80-90C (with softening
and decomposition);
CiS- (ethylmalonato-O,O')-bis[l-(2-hydroxy-
10 ethyl)-2-methyl-5-nitroimidazole-N ]platinum(II),m.p. 223-225C;
Ci s-bis[l-(2-hydroxyethyl)-2-methyl-5-nitro-
imidazole-~3]-(isopropylmalonato-O,O')platinum( :rI ) in
the form of a yellow solid, m.p. 120C (with decomposition),u
~MR in D2O: multiplet centred at 8~25 p.p.m.; and
ClS- ( benzylmalonato-O,O')-bis[l-(2-hydroxyethyl)-
2-methyl-5-nitroimidazole-~3]platinum(II) in the form of
a yellow solid, m.pu 93C (with de~omposition~; NMR in
D2O. multiplet centred at 8.25 p.p.m.
EXAMPLE 9
20Compounds P, Q, R, S, T, U, V, W, X, G and Y
By proceeding in a manner similar to that
described hereinbefore in Exa~le 1, but replacing the
metronidazole, used as a starting material, by the
appropriate quantity o~ the corresponding 5-nitroimidazole,
25there were prepared:-
~B9074
- 27 -
(1) dichloro-bis~1-(2-hydroxy-n-propyl~-2-methyl-5-
nitroimidazole-N3]platinum(II):-
(a) Elementary analysis:
calculated: C,26.42, H,3~48; N,13.21; Cl,11.14%;
found: C,26~1, H,3.6, N,12.9; C1,10.9%.
(b) ~MR in acetone-D6: singlet at 2,95 p.p.m.,
doublet at 1.25 p~p.m., multiplet at 4.0-4.75
p.p.m. and a multiplet centred at 8.32 p.p.m.
tc) Melting point: 120-130C [followed by
resolidification at 160C and melting (with
decomposition) at 270-280C].
(2) dichloro-bisCl-(3-chloro-2-hydroxy-n-propyl)-2-
methyl-5-nitroimidazole-N3]platinum(II).
(a) Elementary analysis:
calculated: C,23.84; H,2.86; ~,11.92%,
found: C,23.9; H,2.85; N,12.0%.
(b) ~MR in acetone-D6: singlet at 3O00 p.p.m.,
doublet at 3.75 p.p~m., multiplet at 4.2 to
5.0 p.p.m~ and a multiplet centred at 8.3 p.p.m.
(c) Melting point: 148-149C.
(3~ dichloro-bis~1-(2-hydroxyethyl)-2-(~-fluorophenyl)-
5-nitroimidazole-~3]platinum(II).
(a) Elementary analysis:
calculated: C,34.38; H,2.62; N,10.93%,
found: C,34.5; H,2.68, ~,10.9%.
(b) Melting point: 203-205C.
.~
- 28 -
(4) dichloro-bis(l-methyl-2-carbamoyloxymethyl-5-
nitroimidazole-N3)platinum(II).
(a) Elementary analysis:
calculated: C,21.63; H,2042; ~,16.82; Cl,10.64%;
found: C,21.5 H,2.52; N,17.2 Cl,10.4%.
(b) Melting point: 207C~
~5) dichloro-bis~l-(2-carbamoyloxye~hyl)-2-methyl-5-
nitrolmidazole-~3]platinum(II).
(a~ Elementary analysis:
calculated: C,24.22; H,2.90; ~,16.14; Cl,10021%;
found: C,23.9, H,2.92; N,16.2; Cl,10.2%.
(b) Melting point: partial melting at 130C with
resolidification at 180C and remelting at
190-200C.
15 (6) dichloro-bis~l-(2-~-morpholinylethyl)-5-nitro-
imidazole-~3]platinum(II).
(a) Elementary analysis:
calculated: C,30.09; H,3O93; N,15O6; Cl,9.87%;
found: C,29.6; H,3.87; N,15.5: C1~9~9%o
(b) Melting point: 111C (with some resolidification
at 170C followed by decomposition at 247-300C).
(7) dichloro-bis~2-hydroxymethyl-1-methyl-5-nitro-
imidazole-N3~platinum(II).
~a) Elementary analysis:
calculated: C,20.70; H,2.43; ~,14.48; Cl,12.22%;
found: C,20.6; H,2.5; M,14.6; Cl~12.0%~
(b) ~MR in acetone-D6: singlets at 4.2 and 5O45 p.p.mO
and a multiplet centred at 8.3 p.p.m.
~8907~a
- 29 -
(c) Melting point: 110C ~with resolidification at
130-145C followed by darkening at 250-300C).
(8) dichloro-bis(l-ethoxycarbonylmethyl-2-methyl-5-
nitroimidazole-~3)platinum(II).
(a) Elementary analysis:
calculated: C,27.75; H,3.20; ~,12.14; Cl,10.24%:
found: C,27.8; H,3.~0 ~,12.4; Cl,9.7%.
(b) Melting point: 120-130C [followed by
resolidification at 185-222C and remelting
(with decomposition) at 258-260C].
(9) dichloro-bis(l-methyl-5-nitroimidazole-~3)-
platinum(II).
(a) Elementary analysis:
calculated: C,18.47; H,l.91; ~,16.16; Cl,13.63%:
found: C,18.1; H,1.71; N,1508; Cl,13.7%.
(b) Melting point: darkens at 275C followed by
melting (with decomposition) at 320-330C.
(10) dichloro-bis~1-(2-hydroxyethyl)-2-hydroxymethyl-5-
nitroimidazole-N3]platinum(II).
(a) Elementary analysis:
calculated: C,22~50; H,2.81; N,13.12%;
found: C,22.14; H,2.81; ~,13.0%.
(b) ~MR in acetone-D6: triplets at 3.95, 4.80 and
5.45 p.p.m. and a multiplet centred at 8.40 p.p.m.
(c) Melting point: 230-231C (with decomposition).
74
_ 30 _
(11) dichloro-bis[2-methyl-1-(2-phosphatoethyl)-5-
nitroimidazole-~3]platinum(II).
(a) NMR in D20: singlet at 2.90 p.pOm., two
triplets centred at 4.3 and 4.8 p.p.m. and
a multiplet centred at 8.4 p.p.m.
(b} Melting point: 202-205C (with decomposition~,
darkening at 175-180C.
EXAMPL~ 10
Compound Z
2-[2-(4-Carboxyphenoxy)ethylthio]-l-me-thyl-5-
nitroimidazole (373 mg) was suspended in water (10 ml)
and stirred with gentle heating (50C). K2PtClL~ (207 mg)
was added and stirring with gentle heat was continued
for one hour. The solution changed in colour from cloudy
15 reddish-orange to clear yellow. Glacial acetic acid
(1.0 ml) was then added and a yellow precipitate was
immediately formed. The precipitate was filtered off
from the cooled mixture and then washed with diethyl
ether. The yellow crystalline product was dried in air
20 to give dichloro-bis{2-[2-(4-carboxyphenoxy)ethylthio]-
l-methyl-5-nitroimidazole-~ ~platinum(II) tetrahydrate
(480 mg), having the following characteristics:-
(a) Elementary analysis:calculated: C,31.7; H,3.48; N,8054; H20,7.3%,
~ound: C,32.1; E,2~99; ~,8.6; H20,7.9%.
(b) Melting point: 184-186~C ~with decomposition).
~L~8~4
- 31 -
EXAMPLE 11
-
Compounds AA and BB
1,2-Dimethyl-~-nitroimidazole (141 mg) was
suspended in water (10 ml) and stirrecl with gentle
5 heating (80C). K2PtC14 (207 mg) was added and stirring
with gentle heating was continued for six hours. The
solution changed in colour from cloudy reddish-orange
to clear yellow, and then precipitation occurred. I~e
precipitate was filtered off from -the cooled mixture
10 and washed with diethyl ether. The yellow crystalline
product was dried in air to give dichloro-bistl,2-
dimethyl-4-nitroimidazole-~3)platinum(II) (271 mg),
having the following characteristics:-
~a) Elementary analysis:
calculated: C,21091: H,2.57; N,15.33, Cl,12.93%;
found: C,21.7 H,2.49: ~,15.5; Cl,12.9%.
(b) Melting point: above 360C ~darkens at 260C).
By proceeding in a similar manner, butreplacing the 1,2-dimethyl-4-nitroimidazole, used as a
20 starting material, by the appropriate quantity of 1-(2-
hydroxyethyl)-2-methyl-4-nitroimidazole, there was prepared
dichloro-bis[l-(2-hydroxyethyl)-2-methyl~4-nitroimidazole-
~3]platinum(1I~
~a) Elementary analysis:
calculated: C,23.69; H,2.98; ~,13.82; Cl,11.66%,
found: C,23.4; H,2.93; ~,13.7, Cl,11.8%.
(b) ~MR in acetone-D6: multiplet centred at 8.2 p.p.m~
74
EXAMPLE 12
Compound CC
By proceeding in a manner similar to that
described hereinbefore in Example 8, but replacing the
5 cyclobutane~ dicarboxylic acid, used as a starting
material, by the appropriate quantity of phenylmalonic
acid there was prepared cis-bis[1-(2-hydroxyethyl)-2-
methyl-5-nitroimidazole-~3]-(phenylmalonato-0,0'~-
platinum(II), in the form of a yellow solid, m.p. lOl~C
10 (with decomposition).
EXAMPLE 13
Compound DD
By proceeding in a manner similar to that
described hereinbefore in Example 2, but replacing the
15 potassium iodide, used as a starting material, by the
appropriate quantity of potassium bromide, there was
prepared dibromo-bis~l-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole-~3]platinum(II), in the form of a yellow
solid, m.p. 268-269C (with decomposition).
~a) Elementary analysis:
calculated: C,20.67; H,2.60, N,12.05; Br,22.92%,
found: C,20.1, H,2.69; N,11.9; Br,23.5%.
The present invention includes within its
scope pharmaceutical compositions which comprise at
25 least one compound of general formula I or salt thereof
in association with a pharmaceutically-acceptable carrier
~L~8~
or coating~ In clinical practice the compounds of ~he
present invention may be administered orally, rectally,
vaginally or parenterally~
Solid compositions for oral administration
5 include compressed tablets, pills, powders and granules.
In such solid compositions, one or more of the active
substances is admixed with at least one inert diluent
such as starch, sucrose or lactose. m e compositio~s
may also comprise, as is normal practice, additional
lOsubstances other than inert diluents, e.g. lubricating
agents, such as magnesium stearate.
Liquid compositions for oral administration
include pharmaceutically acceptable emulsions, solutions,
suspensions, syrups and elixirs containing inert
15diluents commonly used in the art such as water and
liquid paraffin. Besides inert diluents such
compositions may comprise adjuvants, such as wetting
and suspending agents, and sweetening, flavouring,
perfuming and preserving agents. The compositions
20according to the invention for oral administration
also include capsules of absorbable material such as
gelatin, containing one or more of the active substances
with or without the addition of diluents or excipientsa
Solid composi*ions for rectal or vaginal
25administration include suppositories and pessaries
formulated in manner known E~ seO
~Li39~
34 --
Preparations according to the invention for
parenteral administration include sterile a~ueous,
aqueous-organic, and organic solutions, suspensions
and emulsions. Examples of organic solvents or suspending
5 media are propylene glycol, polyethylene glycol,
vegetable oils such as olive oil and injectable organic
esters such as ethyl oleate~ These compositions may
also contain adjuvants such as stabilising, preserving,
wetting, emulsifying and dispersing agents. They may
10 be sterilized by, for example, filtration through a
bacteria-retaining filter, by incorp~ration in the
compositions of sterilizing agents, by irradiation or
by heating. They may also be manufactured in the form
of sterile solid compositions, which can be dissolved
15 in sterile water or some sterile injectable medium
immediately before use.
The percentage of active ingredient in the
compositions of the invention may be varied, it being
necessary that it should constitute a proportion such
20 that a suitable dosage shall be obtained. Obviously
several unit dosage forms may be administered at about
the same timeO The dose employed will be determined by
the physician, and depends upon the desired therapeutic
effect, the route of administration and the duration of
25 the treatment, and the condition of the patient. When
administered in conjunction with X ray therapy of cancer
to increase the effectiveness of the radiation therapy,
~8~07~
_ 35 -
a compound of general formula I, or more especially the
compound of general formula III, will generally be
administered before irradiation of the cancer (normally
up to ive hours before administration of the radiation)
5 at doses of from 0.1 to 500, preferably from 1 to 200,
mg~kg body weight. It is normally the practice in the
X-ray therapy of cancers to repeat the irradiation on a
number of occasions during a course of treatment, for
example between 15 and 20 repetitions over a period of
10 3 to 4 weeks and a compound of general formula I, or
more especially the compound of formula III, may be
administered in conjunction with each repetition of
the irradiation at the aforementioned doses. When
administered to combat anaerobic bacteria the dose is
15generally between 0.1 and 500, more especially between
1 and 200, mg/kg body weight, and this dose may also
be repeated at intervals as the physician or surgeon
directs.
