CA1189074A

CA1189074A - Nitroimidazole derivatives

Info

Publication number: CA1189074A
Application number: CA000396880A
Authority: CA
Inventors: Christopher J. Coulson; Peter J. Sadler
Original assignee: May and Baker Ltd
Current assignee: May and Baker Ltd
Priority date: 1981-02-24
Filing date: 1982-02-23
Publication date: 1985-06-18
Also published as: FI820569L; DK76382A; AU8065082A; DE3206610A1; SE8201100L; IT1195782B; IE52557B1; CH654315A5; NL8200712A; FR2500449B1; IT8219842A0; LU83968A1; FR2500449A1; IE820359L; GR74776B

Abstract

A B S T R A C T

Platinum(II)-containing complexes of nitroimidazoles of the formula:-{X]2PtII(z1) 2 I
wherein X represents a 2-, 4- or 5-(mono)nitroimidazole molecule which is unsubstituted or carries at least one substituent, and which can coordinate to platinum through the 3-position of the heterocyclic ring, and z1 represents a pharmaceutically-acceptable ligand known 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 are of use in the therapy of cancer and in combatting anaerobic bacterial infections.

Description

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 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~

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 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.

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~

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.

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 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.

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~

(c) U.V.: absorption~ max. 305nm.
(d) Polarography: Ep = -0.35V.
(e) Melting point 223-225C.

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 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.

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 (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.

.~

(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 (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).

_ 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 -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~

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).

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~

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.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the preparation of platinum(II)-containing complexes of nitroimidazoles of the general formula:

[X] ptII(z1)2 I

wherein X represents a 2-, 4- or 5-(mono)nitroimidazole molecule which is unsubstituted or carries at least one substituent, and which can coordinate to platinum through the 3-position of the heterocyclic ring, and Zl represents a pharmaceutically-acceptable ligand known 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, which comprises: reacting a nitroimidazole compound correspond-ing to the symbol X, as defined above, with a platinite salt of the general formula:

Q2ptII(z1)4 wherein Q represents an alkali metal and Z1 is as hereinbefore defined, the ligands Z1 being the same or different, or treating a complex of the general formula:

{X}2PtIIY2 V

(wherein X is as defined above and Y is a halogen atom) with silver nitrate in an aqueous medium, followed by treatment with a source of an alternative ligand to replace Y.

2. Process for the preparation of platinum(II)-containing complexes of nitroimidazoles of the general formula:

[X]2PtII(Zl)2 I

wherein X represents a 2-, 4- or 5-(mono)nitroimidazole molecule which is unsubstituted or carries at least one substituent, and which can coordinate to platinum through the 3-position of the heterocyclic ring, and Zl represents a pharmaceutically-acceptable ligand known 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, which comprises: reacting a nitroimidazole compound correspond-ing to the symbol X, as defined above, with a platinite salt of the general formula:

Q2PtII(Zl)4 wherein Q represents an alkali metal and Zl is as hereinbefore defined, the ligands Zl being the same or different.

3. Process for the preparation of platinum(II)-containing complexes of nitroimidazoles of the general formula:

[X]2PtII(Z)2 wherein X represents a 2-, 4- or 5-(mono)nitroimidazole molecule which is unsubstituted or carries at least one substituent, and which can coordinate to platinum through the 3-position of the heterocyclic ring, and Zl represents a pharmaceutically-acceptable ligand known not to be capable of coordinating to platinum more strongly than the 3-position nitrogen atom of the imadazole ring of a 2-, 4- or 5-(mono)-nitroimidazole molecule represented by the symbol X, which comprises: treating a complex of the general formula:

[X]2PtIIY2 V

(wherein X is as defined above and Y is a halogen atom) with silver nitrate in an aqueous medium, followed by treatment with a source of an alternative ligand to replace Y.

4. Process for the preparation of a complex of general formula I as claimed in claim 3, wherein (Z1)2 represents a bidentate ligand of general formula II

II

wherein Rl and R2, which may be the same or different, each represents a hydrogen atom or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group or CRlR2 represents a cycloal-kyl or cycloalkenyl group, and X is as defined in claim 3, which comprises the reaction of a compound of general formula V depicted in claim 3, in the cis-configuration, wherein X
is as defined above and Y is a chlorine, bromine or iodine atom with silver nitrate in an aqueous medium, followed by treatment with an acid of the general formula:

(HOOC)2CRlR2 (wherein R1 and R2 are as defined above), followed by neutra-lisation with a suitable base.

5. Process for the preparation of pharmaceutically-acceptable salts of the monoesters with dicarboxylic aliphatic acids, and phosphate, phosphite and sulphate esters of complexes according to claim 1, in which the nitroimidazole represented by the symbol X has a substituent which contains a free hydroxy group and pharmaceutically acceptable salts of complexes in which the nitroimidazole represented by the symbol X has a substituent which contains a carboxy group, which comprises utilising a nitroimidazole in the form of a pharmaceutically acceptable salt in a process as claimed in claim 1 or the conversion by methods known per se of a complex of general formula I into such a pharmaceutically acceptable salt.

6. Process as claimed in claim 1, wherein the symbol X represents a 2-(mono)nitroimidazole having a substituent in at least one of the 1-, 4- or 5-positions of the imidazole ring.

7. Process as claimed in claim 1, wherein X
represents a 4- or 5-(mono)nitroimidazole having 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 a nitro group.

8. Process as claimed in claim 1, wherein the 4-or 5-(mono)nitroimidazole is substituted in the 1- and 2-positions of the imidazole ring.

9. Process as claimed in claim 1, wherein the substituents on the nitroimidazoles represented by the symbol X are alkyl groups unsubstituted or substituted by one or more atoms or groups selected from hydroxy, alkoxy, alkylsulphonyl, carboxy, alkoxycarbonyl, carbamoyloxy, benzylcarbamoyl and N-morpholinyl groups and halogen atoms; phenyl groups substituted by halogen atoms; and alkylthio groups substituted by a phenoxy group which phenoxy group is substituted by carboxy and, when a substituent group in the nitroimidazole contains a free hydroxy group, monoesters thereof with dicarboxylic aliphatic acids, and pharmaceutically-acceptable salts thereof, and when a substituent in the nitroimidazole contains a free hydroxy group, phosphate, phosphite and sulphate esters thereof and their salts containing pharmaceutically-acceptable cations and, when X represents a nitroimidazole carrying a substituent which comprises a carboxy group, pharmaceutically acceptable salts thereof.

10. Process as claimed in claim 9, wherein the symbol X
represents 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, 1,2-dimethyl-5-nitroimidazole, 1-methyl-2-isopropyl-5-nitroimidazole, 1-(2-ethylsulphonylethyl)-2-methyl-5-nitroimidazole, 2-methyl-4 (or 5)-nitroimidazole, 1-carboxymethyl-2-methyl-5-nitroimidazole, 1 (2-N-morpholinylethyl)-5-nitroimidazole, 1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole, 1-methyl-2-carbamoyloxymethyl-5-nitroimidazole, 1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole, 1-methyl-5-nitroimidazole, 2-[2-(4-carboxyphenoxy)ethylthio]-1-methyl-5-nitroimidazole, 1-(2-carbamoyloxyethyl)-2-methyl-5-nitroimidazole, 1-(2-hydroxyethyl)-2-(p-fluorophenyl)-5-nitroimidazole, 2-hydroxymethyl-1-methyl-5-nitroimidazole, l-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole, 2-isopropyl-4(or 5)-nitroimidazole, 2-hydroxymethyl-4(or 5)-nitroimidazole, l-(2-hydroxyethyl)-2-methyl-4-nitroimidazole, 1,2-dimethyl-4-nitroimidazole, 1-(2-hydroxyethyl)-2-hydroxy-methyl-5-nitroimidazole, 1-(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazole, N-benzyl-1-(2-nitroimidazolyl)acetamide, 2-nitroimidazole and 4(5)-nitroimidazole, and, when a substituent group in the 1- or 2-position of the aforesaid substituted nitroimidazole molecules contains a free hydroxy group, mono-esters thereof with dicarboxylic aliphatic acids, and pharma-ceutically-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 pharma-ceutically-acceptable salts of such phosphate, phosphite and sulphate esters, and their salts containing pharmaceutically-acceptable cations, and when X represents l-carboxymethyl-2-methyl-5-nitroimidazole or 2-[2-(4-carboxyphenoxy)ethylthio]-l-methyl-5-nitroimidazole, pharmaceutically-acceptable salts thereof.

11. Process as claimed in claim 4, wherein alkyl groups and moieties and alkenyl groups contain up to 6 carbon atoms, aryl groups andmoieties are phenyl, and any cycloalkyl and cycloalkenyl groups contain from 3 to 8 carbon atoms.

12. Process as claimed in claim 1, wherein Z1 represents chlorine.

13. Process as claimed in claim 10, wherein X
represents 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole.

14. Process as claimed in claim 2, which comprises reacting metronidazole with potassium iodide added to a solution of K2PtCl4 to prepare diiodo-bis [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II).

15. Process as claimed in claim 2, which comprises reacting dimetridazole with K2PtCl4 to prepare dichloro-bis (1,2-dimethyl-5-nitroimidazole-N3) platinum (II).

16. Process as claimed in claim 2, which comprises reacting ipronidazole with K2PtCl4 to prepare dichloro-bis (1-methyl-2-isopropyl-5-nitroimidazole-N3) platinum (II).

17. Process as claimed in claim 2, which comprises reacting tinidazole with K2PtCl4 to prepare dichloro-bis[1-(2-ethylsulphonylethyl)-2-methyl-5-nitroimidazole-N3]
platinum (II).

18. Process as claimed in claim 2, which comprises reacting 1-carboxymethyl-2-methyl-5-nitroimidazole with K2PtCl4 to prepare dichloro-bis(1-carboxymethyl-2-methyl-5-nitroimidazole-N3) platinum II.

19. Process as claimed in claim 2, which comprises reacting 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole with K2PtCl4 to prepare dichloro-bis [1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole-N3] platinum (II).

20. Process as claimed in claim 2, which comprises reacting misonidazole with K2PtCl4 to prepare trans-dichloro-bis [1-(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazole-N3]
platinum (II).

21. Process as claimed in claim 3, which comprises treating cis-dichloro-bis [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with cyclobutane-1, 1-dicarboxylic acid to prepare cis-(cyclobutane-1,1-dicarbo-xylato-O ,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II).

22. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with malonic acid to prepare cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]-(malonato-O,O') platinum (II).

23. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with methylmalonic acid to prepare cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]-(methylmalonato-O,O')platinum (II).

24. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with dimethylmalonic acid to prepare cis-(dimethylmalonato-O,O')-bis[1-(2-hydroxy-ethyl)-2-methyl-5-nitroimidazole-N3] platinum (II).

25. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with ethylmalonic acid to prepare cis-(ethylmalona-to-O,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II).

26. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with isopropylmalonic acid to prepare cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole-N3]-(isopropylmalonato-0,0') platinum (II).

27. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II) with silver nitrate in an aqueous medium, followed by treatment with benzylmalonic acid to prepare cis-(benzylmalona-to-O,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II).

28. Process as claimed in claim 2, which comprises reacting ornidazole with K2PtCl4 to prepare dichloro-bis[1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N3]
platinum (II).

29. Process as claimed in claim 2, which comprises reacting flunidazole with K2PtCl4 to prepare dichloro-bis [1-(2-hydroxyethyl)-2-(p-fluorophenyl)-5-nitroimidazole-N3]
platinum(II).

30. Process as claimed in claim 2, which comprises reacting bamnidazole with K2PtCl4 to prepare dichloro-bis [1-(2-carbamoyloxyethyl)-2-methyl-5-nitroimidazole-N3]platinum (II).

31. Process as claimed in claim 2, which comprises reacting 2-hydroxymethyl-1-methyl-5-nitroimidazole with K2PtCl4 to prepare dichloro-bis[2-hydroxymethyl-1-methyl-5-nitro-imidazole-N3]platinum(II).

32. Process as claimed in claim 2, which comprises reacting 1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole with K2PtCl4 to prepare dichloro-bis-(1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole-N3)platinum(II).

33. Process as claimed in claim 2, which comprises reacting 2-methyl-1-(2-phosphatoethyl)-5-nitroimidazole with K2PtCl4 to prepare dichloro-bis[2-methyl-1-(2-phosphatoethyl)-5-nitroimidazole-N3]platinum[II).

34. Process as claimed in claim 2, which comprises reacting 1,2-Dimethyl-4-nitroimidazole with K2PtCl4 to prepare dichloro-bis (1,2-dimethyl-4-nitroimidazole-N3)platinum(II).

35. Process as claimed in claim 2, which comprises reacting 1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole with K2PtC14 to prepare dichloro-bis[1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole-N3]platinum(II).

36. Process as claimed in claim 3, which comprises treating cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II) with silver nitrate in an aqueous medium, followed by treatment with phenylmalonic acid to prepare cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3](phenylmalonato-O,O')-platinum(II).

37. Process as claimed in claim 2, which comprises reacting secnidazole with K2PtCl4 to prepare dichloro-bis[1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N3]platinum(II).

38. Process as claimed in claim 2, which comprises reacting ronidazole with K2PtCl4 to prepare dichloro-bis (1-methyl-2-carbamoyloxymethyl-5-nitroimidazole-N3)platinum (II).

39. Process as claimed in claim 2, which comprises reacting nimorazole with K2PtCl4 to prepare dichloro-bis[1-(2-N-morpholinylethyl)-5-nitroimidazole-N3]platinum(II).

40. Process as claimed in claim 2, which comprises reacting 1-methyl-5-nitroimidazole with K2PtCl4 to prepare dichloro-bis(1-methyl-5-nitroimidazole-N3)-platinum(II).

41. Process as claimed in claim 2, which comprises reacting 2-[2-(4-carboxyphenoxy)ethylthio]-1-methyl-5-ni-troimidazole with K2PtCl4 to prepare dichloro-bis{2-[2-(4-carboxyphenoxy)ethylthio]-1-methyl-5-nitroimidazole-N3}
platinum (II).

42. Process as claimed in claim 2, which comprises reacting potassium bromide added to a solution of K2PtCl4 with metronidazole to prepare dibromo-bis[1-(2-hydroxye-thyl)-2-methyl-5-nitroimidazole-N3]platinum(II).

43. Process as claimed in claim 2, which comprises reacting metronidazole with K2PtCl4 to prepare cis-dichlroro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum (II).

44. Process as claimed in claim 3, which comprises treating cis-Pt(MNZ)2I2 with silver nitrate in an aqueous medium, followed by treatment with potassium chloride to prepare cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II).

45. Platinum (II)-containing complexes of nitro-imidazoles of the general formula:

[X]2PtII(Z1)2 I

wherein X represents a 2-, 4- or 5-(mono)nitroimidazole molecule which is unsubstituted or carries at least one substituent, and qhich can coordinate to platinum through the 3-position of the heterocyclic ring, and Z represents a pharmaceutically-acceptable ligand known 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, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.

46. Complexes according to claim 45, wherein X
represents a 2-(mono)nitroimidazole having a substituent in at least one of the 1-, 4- or 5-positions of the imidazole ring, whenever obtained by a process as claimed in claim 6 or its obvious chemical equivalents.

47 . Complexes according to claim 45, wherein X
represents a 4- or 5-(mono)nitroimidazole having 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 a nitro group, whenever obtained by a process as claimed in claim 7 or its obvious chemical equivalents.

48 . Complexes according to claim 45, wherein the 4- or 5-(mono)nitroimidazole is substituted in the 1- and 2-positions of the imidazole ring, whenever obtained by a process as claimed in claim 8 or its obvious chemical equivalents.

49. Complexes according to claim 45, wherein the substituents on the nitroimidazoles represented by the symbol X are alkyl groups unsubstituted or substituted by one or more atoms or groups selected from hydroxy, alkoxy, alkyl-sulphonyl, carboxy, alkoxycarbonyl, carbamoyloxy, benzyl-carbamoyl and N-morpholinyl groups and halogen atoms; phenyl groups substituted by halogen atoms; and alkylthio groups substituted by a phenoxy group which phenoxy group is substituted by carboxy and, when a substituent group in the nitroimidazole contains a free hydroxy group, monoesters thereof with dicarboxylic aliphatic acids, and pharmaceutically-acceptable salts thereof, and when a substituent in the nitroimidazole contains a free hydroxy group, phosphate, phosphite and sulphate esters thereof and their salts contain-ing pharmaceutically-acceptable cations and, when X represents a nitroimidazole carrying a substituent which comprises a carboxy group, pharmaceutically acceptable salts thereof, whenever obtained by a process as claimed in claim 9 or its obvious chemical equivalents.

50. Complexes according to claim 45, in which the symbol X represents 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, 1,2-dimethyl-5-nitroimidazole, 1-methyl-2-isopropyl-5-nitro-imidazole, 1-(2-ethylsulphonylethyl)-2-methyl-5-nitroimidazole, 2-methyl-4(or 5)-nitroimidazole, 1-carboxymethyl-2-methyl-5-nitroimidazole, 1-(2-N-morpholinylethyl)-5-nitroimidazole, 1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole, 1-methyl-2-carbamoyloxymethyl-5-nitroimidazole, 1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole, 1-methyl-5-nitroimidazole, 2-[2-(4-carboxyphenoxy)ethylthio]-1-methyl-5-nitroimidazole, 1-(2-carbamoyloxyethyl)-2-methyl-5-nitroimidazole, 1-(2-hydroxy-ethyl)-2-(p-fluorophenyl)-5-nitroimidazole, 2-hydroxymethyl-1-methyl-5-nitroimidazole, 1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole, 2-isopropyl-4(or 5)-nitroimidazole, 2-hydroxy-methyl-4(or 5)-nitroimidazole, 1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole, 1,2-dimethyl-4-nitroimidazole, 1-(2-hydroxy-ethyl)-2-hydroxymethyl-5-nitroimidazole, 1-(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazole, N-benzyl-1-(2-nitro-imidazolyl)acetamide, 2-nitroimidazole and 4(5)-nitroimidazole, and, when a substituent group in the 1- or 2-position of the aforesaid substituted nitroimidazole molecules contains a free hydroxy group, monoesters thereof with dicarboxylic aliphatic acids, 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 of such phosphate, phosphite and sulphate esters, and their salts containing pharmaceutically-acceptable cations, and when X represents 1-carboxymethyl-2-methyl-5-nitroimidazole or 2-[2-(4-carboxyphenoxy)ethylthiol-1-methyl-5-nitroimidazole, pharma-ceutically-acceptable salts thereof whenever obtained by a process as claimed in claim 10 or its obvious chemical equivalents.

51. Complexes according to claim 45, wherein X represents 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, whenever obtained by a process as claimed in claim 13 or its obvious chemical equivalents.

52. Complexes according to claim 45, wherein (Z1)2 represents a bidentate ligand of the general formula:

II

wherein R1 and R2, which may be the same or different, each represents a hydrogen atom or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group or CR1R2 represents a cycloalkyl or cycloalkenyl group, whenever obtained by a process as claimed in claim 4 or its obvious chemical equivalents.

53. Complexes according to claim 45, wherein (Z1)2 represents a bidentate ligand of the general formula:

wherein R1 and R2, which may be the same or different, each represents a hydrogen atom or an alkyl, phenyl, phenylalkyl, alkenyl, cycloalkyl or cycloalkenyl group or CR1R2 represents a cycloalkyl or cycloalkenyl group, alkyl groups and moieties and alkenyl groups containing up to 6 carbon atoms, and any cycloalkyl and cycloalkenyl groups containing from 3 to 8 carbon atoms, whenever obtained by a process as claimed in claim 11 or its obvious chemical equivalents.

54. Complexes according to claim 45, wherein Z1 represents chlorine whenever obtained by a process as claimed in claim 12 or its obvious chemical equivalents.

55. Diido-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] platinum (II), whenever obtained by a process as claimed in claim 14 or its obvious chemical equivalents.

56. Dichloro-bis(1,2-dimethyl-5-nitroimidazole-N3)platinum(II), whenever obtained by a process as claimed in claim 15 or its obvious chemical equivalents.

57. Dichloro-bis(1-methyl-2-isopropyl-5-nitro-imidazole-N3)platinum(II), whenever obtained by a process as claimed in claim 16 or its obvious chemical equivalents.

58. Dichloro-bis[1-(2-ethylsulphonylethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 17 or its obvious chemical equivalents.

59. Dichloro-bis-(1-carboxymethyl-2-methyl-5-nitroimidazole-N3)platinum(II), whenever obtained by a process as claimed in claim 18 or its obvious chemical equivalents.

60. Dichloro-bis[-(2-hydroxyethyl)-2-hydroxy-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 19 or its obvious chemical equivalents.

61. Trans-dichloro-bis[1-(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 20 or its obvious chemical equivalents.

62. Cis-(cyclobutane-1,1-dicarboxylato-O,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum (II), whenever obtained by a process as claimed in claim 21 or its obvious chemical equivalents.

63. Cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole-N3]-(malonato-O,O')platinum(II), whenever obtained by a process as claimed in claim 22 or its obvious chemical equivalents.

64. Cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole-N3]-(methylmalonato-O,O')platinum(II), whenever obtained by a process as claimed in claim 23 or its obvious chemical equivalents.

65. Cis-(dimethylmalonato-O,O')-bis-[1-(2-hydroxy-ethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 24 or its obvious chemical equivalents.

66. Cis-(ethylmalonato-O,O')-bis[1-(2-hydroxy-ethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 25 or its obvious chemical equivalents.

67. Cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole-N3]-(isopropylmalonato-O,O')platinum(II), whenever obtained by a process as claimed in claim 26 or its obvious chemical equivalents.

68. Cis-(benzyl-malonato-O,O')-bis[1-(2-hydroxy-ethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 27 or its obvious chemical equivalents.

69. Dichloro-bis[1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitro-imidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 28 or its obvious chemical equivalents.

70. Dichloro-bis[1-(2-hydroxyethyl)-2-(p-fluoro-phenyl)-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 29 or its obvious chemical equivalents.

71. Dichloro-bis[1-(2-carbamoyloxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 30 or its obvious chemical equivalents.

72. Dichloro-bis[2-hydroxymethyl-1-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 31 or its obvious chemical equivalents.

73. Dichloro-bis(1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole-N3)platinum(II), whenever obtained by a process as claimed in claim 32 or its obvious chemical equivalents.

74. Dichloro-bis[2-methyl-1-(2-phosphatoethyl)-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 33 or its obvious chemical equivalents.

75, Dichloro-bis(1,2-dimethyl-4-nitroimidazole-N3)platinum(II), whenever obtained by a process as claimed in claim 34 or its obvious chemical equivalents.

76. Dichloro-bis[1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 35 or its obvious chemical equivalents.

77. Cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole-N3]-(phenylmalonato-O,O')-platinum(II), whenever obtained by a process as claimed in claim 36 or its obvious chemical equivalents.

78. Dichloro-bis[1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 37 or its obvious chemical equivalents.

79, Dichloro-bis(1-methyl-2-carbamoyloxymethyl-5-nitroimidazole-N3)platinum(II), whenever obtained by a process as claimed in claim 38 or its obvious chemical equivalents.

80. Dichloro-bis[1-(2-N-morpholinylethyl)-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 39 or its obvious chemical equivalents.

81. Dichloro-bis(1-methyl-5-nitroimidazole-N3)-platinum(II), whenever obtained by a process as claimed in claim 40 or its obvious chemical equivalents.

82. Dichloro-bis{2-[2-(4-carboxyphenoxy)ethyl-thio]-1-methyl-5-nitroimidazole-N3}platinum(II), whenever obtained by a process as claimed in claim 41 or its obvious chemical equivalents.

83. Dibromo-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 42 or its obvious chemical equivalents.

84. Cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 43 or its obvious chemical equivalents.

85. Cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(II), whenever obtained by a process as claimed in claim 44 or its obvious chemical equivalents.