GB2093451A - Nitroimidazole derivatives - Google Patents

Nitroimidazole derivatives Download PDF

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GB2093451A
GB2093451A GB8205139A GB8205139A GB2093451A GB 2093451 A GB2093451 A GB 2093451A GB 8205139 A GB8205139 A GB 8205139A GB 8205139 A GB8205139 A GB 8205139A GB 2093451 A GB2093451 A GB 2093451A
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nitroimidazole
methyl
platinum
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

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Abstract

Platinum(II)-containing complexes of nitroimidazoles of the formula:- [X]2Pt<II)<Z<1>)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 Z<1> 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 cancery and in combatting anaerobic bacterial infections.

Description

SPECIFICATION Nitroimidazole derivatives This invention relates to new platinum(ll)-containing complexes of nitroimidazole compounds, to processes for their preparation and to pharmaceutical compositions containing them.
The present invention provides platinum(ll)-containing complexes of nitroimidazoles of the general formula: [X]2Pt"(Z')2 wherein X represents a 2for, 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 the heterocyclic, i.e. imidazole, ring, and Z1 represents a pharmaceuticallyacceptable 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)nitroimidazol 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 Za, is meant a ligand which, when 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 pharmacological properties of the compound of formula I are not vitiated by side-effects ascribable to those species.
Preferably Z1 represents a bromine, iodine or, more particularly, chlorine atom or (Z1)2 represents a bidentate ligand of the general formuia:--
wherein R' 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 CR'R2 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 may be different but are preferably the same.
Within the definition of CR'R2 in formula 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)nitroimidazole 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)nitroimidazole 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 1position of the imidazole ring. Suitable substituents on the 1-, 2- and 4- or 5-positions of the imidazole ring of 2-, 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 N-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 straightor 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 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 amines; when X represents a nitroimidazole carrying a substituent which comprises a carboxy group, pharmaceutically-acceptable salts thereof may be formed. It is to be understood that such esters and salts constitute a feature of the invention.
Particularly suitable substitued 2-, 4- or 5-(mono)nitroimidazole molecules represented by the symbol X are molecules selected from the group consisting of metronidazole [1 -(2-hydroxyethyl)-2methyl-5-nitroimidazole, hereinafter also identified by the abbreviation 'MNZ'], dimetridazole [1,2 dimethyl-5-nitroimidazole], ipronidazole (1 -methyl-2-isopropyl-5-nitroimidazole), tinidazole [1-(2 ethylsulphonylethyl)-2-methyl-5-nitroimidazole], 2-methyl-4 (or 5)-nitroimidazole, 1-carboxymethyl-2- methyl-5-nitroimidazole, nimorazole [1 -(2-N-morpholinylethyl-5-nitroimidazole] ornidazole [1-(3 chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole], ronidazole [ 1 -methyl-2-carba moyl methyl-5- nitroimidazole], secnidazole [1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole], 1-methyl-5nitroimidazole, 2-[2-(4-carboxy-phenoxy)ethylthio]-1 -methyl-5-nitroimidazole, bamnidazole [1 -(2- carbamoyloxyethyl)-2-methyl-S-nitroimidazolej, flu nidazole [1 -(2-hydroxyethyl)-2-(p-fluorophenyl)-5- nitroimidazole], 2-hydroxymethyl-l -methyl-5-nitro-imidazole, 1-ethoxycarbonylmethyl-2-methyl-5- nitroimidazole, 2-isopropyl-4 (or 5)-nitroimidazole, 2-hydroxymethyl-4 (or 5)-nitroimidazole, 1-(2hydroxyethyl)-2-methyl-4-nitroimidazole, 1 ,2-dimethyl-4-nitroimidazole, 1 -(2-hydroxyethyl)-2-hydroxy- methyl-5-nitroimidazole, misonidazole [1 -(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazolej, benznidazole [N-benzyl-1-(2-nitroimidazolyl)-acetamide], azomycine (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, 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 of such phosphate, phosphite and sulphate esters, for example metronidazole hemisuccinate, metronidazole phosphate and metronidazole sulphate and their salts containing pharmaceutically-acceptable cations, for example 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 amines, and when X represents 1 -carboxymethyl-2-methyl-5-nitroimidazole or 2-[2-(4-carboxyphenoxy)ethylthio] 1-methyl-5-nitroimidazole, pharmaceutically-acceptable salts thereof.
By the term 'pharmaceutically-acceptable salts', as used in this specification, 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(ll)-containing complexes of general formula I are not vitiated by side-effects ascribable to those cations. Preferably the salts are watersoluble. 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 pharmaceuticaliy-acceptable salts and esters, where the context so permits.
The platinum(ll)-containing complexes of formula I, which are all square planar, may be in the trans or the cis-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 cisconfiguration.
A particularly preferred class of compounds of formula I comprises those wherein X represents metronidazole, more especially cis-dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole- N3]platinum(11) of the formula:
hereinafter referred to for convenience as cis-Pt(MNZ)2CI2 or as "Compound A".
Other important individual compounds of formula I include: diido-bis[1 -(2-hydroxyethyl)-2-methyl-S-nitroimidazole-N3]platinum(lI); B dichloro-bis( 1 ,2-dimethyl-5-nitroimidazole-N3]platinu m(l I);C dichloro-bis(1-methyl-2-isopropyl-5-nitroimidazole-N3]platinum(11); D dichloro-bis[1 -(2-ethylsulphonylethyl)-2-methyl-S-nitroimidazole-N3jplatinum(ll); E dichloro-bis( 1 -carboxymethyl-2-methyl-S-nitroimidazole-N3]platinum(ll); F dichloro-bis[ 1 -(2-hydrnxyethyl)-2-hydrnxymethyl-S-nkrnimidazole-AO]platinum(ll); G trans-dichloro-bis[1 -(2-hyd roxy-3-methoxy-n-propyl)-2-nitroi midazole-N3]platinu m(l 1); H cis-(cyclobutane- 1 1 -dicarboxylate-0,0')-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole N3]platinum(11); cis-bjs[1 -(2-hydrnxyethyI)-2-methyl-S-nitrnimidazole-N-(malonato-O,O')platinum(l I);J cis-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitromidaole-N ]-(methylmalonato-O,O')platinum(I l); K cis-(dimethylmalonato-O,O')-bis[1 (2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(11); L cis(ethylmalonato-O,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(II); M cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitrolmidazole-N ](isopropylmalonato-O,O1)platinum(II); N cis-(benzylmalonato-O,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitrolmidazole-N ]platinum(II); O dichloro-bis[1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N ]platinum(II); P dichloro-bis[1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitrolmidazole-N ]platinum(II); Q dichloro-bis[1-(2-hydroxyethyl)-2-(p-fluorophenyl)-5-nitroimidazole-N ]platinum(II);R dichloro-bis( 1 -methyl-2-carbamoyloxymethyl-5-nitroimidazole-N3]platinum(11); S dichloro-bis[1-(2-carbamoyloxyethyl)-2-methyl-5-nitrolmidazole-N ]platinum(II) ; T dichloro-bis[1-(2-N-morpholinylethyl)-5-nitroimidazole-N ]platinum(II) ; U dichloro-bis[2-hydroxymethyl-1-methyl-5-nitroimidazole-N3]platinum(11); V dichloro-bis[1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole-N ]platinum(II) ; W dichloro-bis(1-methyl-5-nitroimidazole-N3]platinum(11); X dichloro-bis[2-methyl-1-(2-phosphatoethyl)-5-nitrolmidazole-N ]platinum(II) ; Y dichloro-bis[2-[2-(4-carboxyphenoxylethylthio]-1-methyl-5-nitroimidazole-N ]platinum(II) ; Z dichloro-bis( 1 ,2-dimethyl-4-nitroimidazole-N3)platinum(l I); AA dichloro-bis[1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole-N ]platlnum(II) ;BB cis-bis[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ](phenylmalonato-O,O')platinum(II) ; and CC dibromo-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(II) ; 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. lymphomas, 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(ll)-containing complexes of general formula I increase the sensitivity of hypoxic tumour cells to X-rays and may be administered in conjunction with the X-ray therapy of solid cancers to increase the effectiveness of the radiation therapy.
For example Compound A (the compound of formula 111) in tests produced an enhancement ratio of 2.4 when given as a pretreatment to hypoxic X-irradiated cells in 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 symbol " < " means "less than or equal to").
TABLE 1
Compound A G P S U X Z DD Bacteroides fragllis 1.6 1.6 1.6 0.2 6.2 12.5 0.4 1.2 Peptostreptococcus 0.8 0.6 3.1 0.4 12.5 25 0.8 1.8 anaerobius Pusobecterium #0.1 8.2 0.2 0.016 6.2 6.2 0.2 0.08 necrophorum Ciostridium welchil 1.6 0.1 3.1 0.4 6.2 25 0.8 0.8 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 mg/kg animal body weight when administered intraperitoneally and greater than 2000 mg/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 Z1 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: Q2Pt"(z1 )4 IV wherein Q represents an alkali metal, for example sodium or potassium, atom and Z' is as hereinbefore defined, the ligands represented by Z' being different or, preferably, the same. Reaction may be effected in water or an aqueous organic solvent, e.g. aqueous ethanol, at a temperature from 15 to 1 000C.
For example, cis-Pt(MNZ)2Cl2 of formula Ill, according to a feature of the present invention, is prepared by reaction of metronidazole with an alkali metal chloroplatinite and more especially potassium chloroplatinite (K2PtCI4). Reaction may be effected in water at 1 SO1 000C, preferably at 400--600C.
According to a feature of the present invention, certain compounds of formula I may be prepared from other compounds of formula I.
For example, a compound, within general formula I, of the general formula: [X]2PtllY2 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 liquid to replace Y.
Thus, according to a feature of the present invention, cis-Pt(MNZ)2CI2 is prepared by treating cis Pt(MNZ)2l2 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 formula II and X is as hereinbefore defined may be prepared by the reaction of 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 treatment with an acid of the general formula: (HOOC)2CR'R2 VI (wherein R' and R2 are as hereinbefore defined) followed by neutralisation of the solution by the addition of a suitable 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 precipitated 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 nitroirnidazole compound contains a free hydroxy group, monoesters thereof with dicarboxylic aliphatic acids, phosphate esters, phosphite esters and sulphate esters, may be prepared by the application or adaptation of methods known per se for the preparation of substituted nitroimidazole compounds. Some are articles of commerce.
Pharmaceutically-acceptable salts of the aforesaid monoesters, phosphate esters, phosphite esters and sulphate esters, and pharmaceutically-acceptable salts of the platinum(ll)-containing complexes of general formula I wherein X represents a nitroimidazole carrying a substituent which includes a carboxy group, for example 1 -carboxymethyl-2-methyl-S-nitroimidazole, may be prepared by the application or adaptation of methods known per se, either 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 form an appropriate platinum(ll)-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 In them 'NMR' and 'UV' represent 'nuclear magnetic resonance spectrum' and 'ultra-violet absorption spectrum', respectively. Often only the most important features of these spectra are given.
Polarography was carried out using a dropping mercury electrode. Potentials were measured with reference to a silver/silver chloride electrode, using a polarograph in the differential pulse mode.
Samples were prepared as approximately 100 ,uM in phosphate buffer (pH 7.0). Peak potentials (Ep) were recorded.
EXAMPLE 1 Compound Metronidazole (6.85 g; 40 mmoi) was suspended in water (300 ml) and stirred with gentle heating (500 C). K2PtCI4 (8.3 g; 20 mmol) was added and stirring with gentle heating was continued for one hour. The solution changed in colour from cloudy reddish-orange to clear yellow. cis-Pt(MNZ)2CI2 then precipitated.After cooling, the supernatant liquid was decanted off and reduced in volume in a rotary evaporator to precipitate further cis-Pt(MNZ)zCi2. The cis-Pt(MNZ)2Ci2 precipitates were combined, washed first with a mixture of ethanol and diethyl ether, and then washed with diethyl ether, and dried in air to give cis-Pt(MNZ)2CI2 (12.16 g; yield 91.3%) in the form of yellow crystals having the following characteristics: (a) Elementary analysis: calculated: C,23.68; H,2.96; N, 13.81; Cl,11.67% found: C,23.09; H,3.24; N, 13.59; Cl,11.37%.
(b) NMR in acetone-De: singlet at 3.01 p.p.m., two triplets centred at 3.95 and 4.65 p.p.m., and a multiplet centred at 8.45 p.p.m.
(c) U.V.: absorption A max. 304 nm, extinction coefficient (E) 1.2x104M-1cm-1.
(d) Polarography: Ep= -0.27V.
(e) Melting point 178-181 0C, followed by resolidification and melting (with decomposition) at 257 2S90C.
A sample of Pt(MNZ)2CI2, 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; N, 13,81; Cl, 11.67 found: C,23.46; H,3.12; N, 13.87; Cl, 11.47.
The molecular structure, including the cis-configuration, of the product Pt(MNZ)2CI2 prepared as described above was confirmed by X-ray crystallography: the crystal system was monoclinic with Space Group P21/a; cell constants: a=l 5.906A, b=10.169A, c=1 2.729A, P=l 09.740, Z=4. The structure was refined to R=0.074.
EXAMPLE 2 Compound B Potassium iodide (4 g) was added to a solution of K2PtCI4 (415 mg; 1 mmol) in water (20 ml). The colour of the solution changed from orange-red to deep red. Metronidazole (342 mg; 2 mmol) 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 was washed with a mixture of ethanol and diethyl ether, and then with diethyl ether, to give diiodo-biws[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(II) (570 mg; yield 72%), having the following characteristics: (a) Elementary analysis: calculated: C, 18.10; H,2.28; N,10.62; 1,32.09% found: C,17.83; H,2.36; N,10.71; 1,32.17% (b) NMR 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 Diiodo-bis[1 -(2-hydroxyethyl)-2-methyl-S-nitroimidazole-N3jplatinum(ll) (316 mg; 0.4 mmol; obtained as described in Example 2) was suspended in water (25 ml) and silver nitrate (136 mg; 0.8 mmol) was added. The solution was then stirred for several hours, during which time the colour changed to pale yellow. Precipitated silver iodide was removed by centrifugation and excess potassium chloride was added to the separated supernatant liquid. cis-Pt(MNZ)2CI2 precipitated and was collected.
washed with a mixture of ethanol and diethyl ether and then with diethyl ether to give cis-Pt(MNZ)2CI2, identical to the product obtained in Example 1.
EXAMPLE 4 Compound C, D and E Dimetridazole (0.282 g; 2 mmol) was suspended in water (20 ml) and stirred with gentle heating (500 C). K2PtCl4 (0.415 g; 1 mmol) was added and stirring with gentle heating was continued for one hour. After cooling, the 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 further quantity of solid.
The precipitates were combined, washed with a mixture of ethanol and diethyl ether, and then with diethyl ether, and then dried in air, to give dichloro-bis(1 ,2-dimethyl-5-nitroimidazole-N3]platinum (0.456 g), 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; Cl, 13.20%.
(b) NMR in dimethylsulphoxide-D6: singlets at 2.80 and 3.80 p.p.m. and a multiplet centred at 8.52 p.p.m.
(c) U.V.: absorption A max. 304 nm.
(d) Polarography: Ep -0.34V.
(e) Melting point: 174-1 760C.
By proceeding in a similar manner, but replacing the dimetridazole, used as a starting material, by ipronidazole and tinidazole respectively, there were prepared: (1) dichioro-bis(1 -methyl-2-isopropyl-5-nitroimidazole-N3)platinum(1í) having the following characteristics: (a) Elementary analysis: calculated: C, 27.80; H,3.64; N, 13.90; Cl, 11.75%, found:C,27.13; H, 3.59; N, 13.48; Cl, 11.87%.
(b) NMR 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 A max. 308 nm.
(d) Melting point: 2200C (with decomposition).
(2) dichloro-bis[1 -(2-ethylsulphonyIethyl)-2-methyl-S-nkrnimidazole-N]platinum(I 1) having the following characteristics: (a) Elementary analysis: calculated: C, 25.26; H, 3.42; N, 11.05; Cl, 9.34; S, 8.42%; found: C, 25.58; H, 3.62; N, 11.04; Cl, 9.39; S, 8.54%.
(b) NMR 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 A max. 302 nm.
(d) Polarography: Ep -O.37V.
(e) Melting point 145-1470C.
EXAMPLE 5 Compound F 1-Carboxymethyl-2-methyl-5-nitroimidazole (0.370 g; 2 mmol) was suspended in water (20 ml) and stirred. K2PtCI4 (0.41 5 g; 1 mmol) 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 volume 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(1-carboxymethyl-2-methy-5-nitroimidazole-N ]platinum(II) dihydrate (0.48 g), having the following characteristics.
(a) Elementary analysis: calculated: C, 21.42; H, 2.68; N, 12.49; Cl, 10.56%; found: C,21.11; H,2.48; N, 12.26; Cl 10.75%.
(b) NMR 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 A max. 305 nm.
(d) Polarography: Ep -0.35V.
(e) Melting point 223-225 C.
EXAMPLE 6 Compound G 1 -(2-Hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (0.374 g) was suspended in water with stirring and gentle heating. K2PtCI4 (0.415 g) was added and stirring with gentle heating was continued for 2 to 3 hours until the reaction mixture became clear. The solution thus obtained was then cooled to approximately 0 C 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, to give dichloro-bis[1 -(2- hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole-N ]platinum(II) (0.46 g) having the following characteristics: (a) Elementary analysis: calculated: C,22.50; H,2.81; N, 13.12; Cl. 11,09%; found: C, 22.35; H, 2.97; N, 13.01; Cl, 11.90%.
(b) NMR 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 A max. 291 nm.
(d) Polarography: Ep -0.22V.
(e) Melting point 1 87-1 890C.
EXAMPLE 7 Compound H Misonidazole (0.20 g; 1.0 mmol) and K2PtCI4 (0.207 g; 0.5 mmol) were dissolved in a mixture of ethanol and water (1:1 volume; 15 ml) and the solution was stirred for three hours at ambient temperature. The 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 to give trans-dichlorobis[1 -(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazole-N ]platinu m(l 1) having the following physical characteristics: (a) Elementary analysis: calculated: C,25.13; H,3.29; N, 12.57; Cl, 10.62%; found: C,24.81; H,3.36; N, 12.57; Cl, 10.66%.
(b) Melting point 213-21 5 C.
(c) X-ray crystallography: the crystal system was monoclinic with Space Group P21/a; celi constants: a=8.1 34 A, b=1 3.014 A, C=1 1,323 A, ss=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.
EXAMPLE 8 Compounds 1, J, K, L, M, N and 0 A stirred suspension of cis-dichloro-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole N ]platinum(II) (100 mg) in water (10 ml) at 600C was treated with silver nitrate (54.4 mg) and the stirring at 600C was then continued for 4 hours. The resulting mixture was allowed to cool and was then filtered, and the filtrate was treated with cyclobutane-1 ,1 -dicarboxylic acid (23.7 mg). The pH of the resulting solution was adjusted to 7 by treatment with the appropriate quantity of aqueous sodium carbonate solution.The resulting solution was treated with acetone (50 ml) and filtered, and the filtrate was freeze dried, to give cis-(cyclobutane-1 ,1 -dicarboxylato-0,0')-bis[1 -(2-hydroxyethyl)-2-methyl-5 nitroimidazole-N3]platinum(ll) (107 mg) in the form of a pale yellow solid, m.p. 219-2330C (with decomposition), ([M+Na]+ (field desorption mass spectrometry) 702 a.m.u. (125Pt)], NMR in D20: multiplet centred at 8.25 p.p.m.
By proceeding in a similar manner, but replacing the cyclobutane-1 , 1 -dicarboxylic acid, used as a starting material, by the appropriate quantities of malonic acid, methylmalonic acid, dimethylmalonic acid, ethylmalonic acid, isopropylmalonic acid and benzylmalonic acid, respectively, there were prepared cis-bis[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]-(ma lonato-O,O')platinu m(l 1) in the form of a yellow solid, m.p. 980C (with decomposition); NMR in D20: multiplet centred at 8.3 p.p.m.; cis-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]-(methylmelonato-O,O'~platinum) 1) in the form of a yellow solid, m.p. 1350C (with decomposition);NMR in D20: multiplet centred at 8.25 p.p.m.; cis-(dimethylmsionato-O,O')-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(II) in the form of a yellow solid, m.p. 80-900C (with softening and decomposition); cis-(ethylmalonato-O,O')-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platin u m(l 1), m.p.
223-2250C; cis-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]-(isopropylmelonato-platinum(II) in the form of a yellow solid, m.p. 1 200C (with decomposition); NMR in D20: multiplet centred at 8.25 p.p.m.; and cis-(benzyl ma lonato-O,O')-bis[1 -(2-hydrnxyethyl)-2-methyl-S-nitroimidazole-NjpIatinum(l I) in the form of a yellow solid, m.p. 930C (with decomposition); NMR in D20: multiplet centred at 8.25 p.p.m.
EXAMPLE 9 Compounds P, Q, R, S, T, U, V, W,X, G, and Y By proceeding in a manner similar to that described hereinbefore in Example 1, but replacing the metronidazole, used as a starting material, by the appropriate quantity of the corresponding 5nitroimidazole, there were prepared: (1) dichloro-bis[1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N ]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 ; Cl, 10.9%.
(b) NMR 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.
(c) Melting point: 120-1 300C [followed by resolidification at 1 600C and melting (with decomposition) at 270-2800C].
(2) dichloro-bis[1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 23.84; H, 2.86; N, 11.9%; found: C, 23.9; H, 2.85; N, 12.0%.
(b) NMR in acetone-D6: singlet at 3.00 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: 148-1490C.
(3) dichloro-bis[1-(2-hydroxyethyl)-2-(o-fluorophenyl)-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 34.38; H, 2.62; N, 10.93%; found: C, 34.5; H, 2.68; N, 10.9%.
(b) Melting point: 203-205 C.
(4) dichloro-bis(1-methyl-2-carbamoyloxymethyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C,21.63; H,2.42; N, 16.82; Cl, 10.64%; found: C,21.5; H, 2.52; N, 17.2; Cl, 10.4%.
(b) Melting point: 2070C.
(5) dichloro-bis[1-(2-carbamoyloxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 24.22; H, 2.90; N, 16.14; Cl, 10.21%; found: C, 23.9; H, 2.92; N, 16.2; Cl, 10.2%.
(b) Melting point: partial melting at 1 300C with resolidification at 1 800C and remelting at 190-200 C.
(6) dichloro-bisx[1-(2-N-morpholinylethyl)-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 30.09; H, 3.93; N, 15.6; Cl, 9.87%; found: C, 29.6; H, 3.87; N, 1 5.5; Cl, 9.9%.
(b) Melting point: 111 C (with some resolidification at 1 700C followed by decomposition at 247-3000C).
(7) dichloro-bis[2-hydroxymethyl-1-methyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 20.70; H, 2.43; N, 14.48; Cl,12.22%; found: C, 20.6; H, 2.5; N, 14.6; Cl, 12.0%.
(b) NMR in acetone-D6: singlets at 4.2 and 5.45 p.p.m. and a multiplet centred at 8.3 p.p.m.
(c) Melting point: 11 ObC (with resolidification at 1 30-1 4S0C followed by darkening at 250-300 C).
(8) dichloro-bis(1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 27.75; H, 3.20; N, 12.14; Cl,10.24%; found: C, 27.8; H, 3.40; N, 12.4; Cl,9.7%.
(b) Melting point: 120-1 300C [followed by resolidification at 185-222 C. and remelting (with decomposition) at 258-260 C].
(9) dichloro-bis(1-methyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 18.47; H, 1.91; N, 16.16; Cl, 13.63%; found: C, 18.1; H, 1.71; N, 15.8; Cl, 13.7%.
(b) Melting point: darkens at 275 C followed by melting (with decomposition) at 320-3300C.
(10) dichloro-bis[1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C, 22.50; H, 2.81; N, 13.12%; found: C,22.14; H,2.81; N,13.0%.
(b) NMR 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: 230-231 0C (with decomposition).
(11) dichloro-bis[2-methyl-1 -(2-phosphatoethyl)-5-nitroimidazole-N3]platinume I I).
(a) NMR in D2O: singlet at 2.90 p.p.m., 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--2050C (with decomposition), darkening at 1 75-1 800C.
EXAMPLE 10 Compound 2-[2-(4-Carboxyphenoxy)ethylthio]-1-methyl-5-nitroimidazole (373 mg) was suspended in water (10 ml) and stirred with gentle heating (500C). K2PtCI4 (207 mg) was added and stirring with gentle heat was continued for one hour. The solution changed in colour from cloudy 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 to give dichloro bis [2-[2-(4-carboxyphenoxy)ethylthio]-1 -methyl-5 nitroimidazole-Njjplatinum(ll) tetrahydrate (480 mg), having the following characteristics.
(a) Elementary analysis: calculated: C, 31.7; H, 3.48; N, 8.54; H20, 7.3%; found: C, 32.1; H, 2.99; N, 8.6; H20, 7.9%.
(b) Melting point: 184-1 860C (with decomposition).
EXAMPLE 11 Compounds AA and BB 1 ,2-Dimethyl-4-nitroimidazole (141 mg) was suspended in water (10 ml) and stirred with gentle heating (80 C). K2PtCI4 (207 mgg) 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. The precipitate was filtered off from the cooled mixture and washed with diethyl ether. The yellow crystalline product was dried in air to give dichloro-bis(1,2-dimethyl-4-nitroimidazole- N3)platinum(ll) (271 mg), having the following characteristics: (a) Elementary analysis: calculated: C,21.91; H,2.57; N, 15.33; Cl, 12.93%; found: C, 21.7; H, 2.49; N, 15.5; Cl, 12.9%.
(b) Melting point: above 3600C (darkens at 2600C).
By proceeding in a similar manner, but replacing the 1 ,2-dimethyl-4-nitroimidazole, used as a starting material, by the appropriate quantity of 1 -(2-hydroxyethyl)-2-methyl-4-nitroimidazole, there was prepared dichloro-bis [1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole-N ]platinum(II).
(a) Elementary analysis: calculated: C,23.69; H,2.98; N, 13.82; CI, 11.66%; found: C, 23.4; H, 2.93; N, 13.7; Cl,11.8%.
(b) NMR in acetone-D6: multiplet centred at 8.2 p.p.m.
EXAMPLE 12 Compound CC By proceeding in a manner similar to that described hereinbefore in Example 8, but replacing the cyclobutane-1,1 -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 N3](phenylmalonato-O,O')-platinum(ll), in the form of a yellow solid, m.p. 101 OC (with decomposition).
EXAMPLE 13 Compound By proceeding in a manner similar to that described hereinbefore in Example 2, but replacing the potassium iodide, used as a starting material, by the appropriate quantity of potassium bromide, there was prepared dibromo-bis[1 -(2-hyd roxyethyl)-2-m ethyl-5-nitroimidazole-NJ] platinum(ll), in the form of a yellow solid, m.p. 268-2690C (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 least one compound of general formula I or salt thereof in association with a pharmaceuticallyacceptable carrier or coating. In clinical practice the compounds of the present invention may be administered orally, rectally, vaginally or parenterally.
Solid compositions for oral administration 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. The compositions may also comprise, as is normal practice, additional substances 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 elixers containing inert diluents 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 according 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 excipients.
Solid compositions for rectal or vaginal administration include suppositories and pessaries formulated in manner known per se.
Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emuisions. Examples of organic solvents or suspending 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 be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporation 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 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 that a suitable dosage shall be obtained. Obviously several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of 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, a compound of general formula I, or more especially the compound of general formula Ill, will generally be administered before irradiation of the cancer (normally up to five hours before administration of the radiation) 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 1 5 and 20 repetitions over a period of 3 to 4 weeks and a compound of general formula I, or more especially the compound of formula Ill, may be administered in conjunction with each repetition of the irradiation at the aforementioned doses. When administered to combat anaerobic bacteria the dose is generally 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 (28)

1. Platinum(ll)-containing complexes of nitroimidazoles of the general formula: [X] 2Pt (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 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 S-(mono)- nitroimidazole molecule represented by the symbol X.
2. Complexes according to claim 1 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.
3. Complexes according to 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.
4. Complexes according to claim 1 wherein the 4- or 5-(mono)nitroimidazole is substituted in the 1- and 2-positions of the imidazole ring.
5. Complexes according to any one of the preceding claims 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, 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 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.
6. Complexes according to any one of the preceding claims in which the symbol X represents 1 -(2 hydroxyethyl)-2-methyl-5-nitroimidazole, 1 ,2-dimethyl-5-nitroimidazole, 1 -methyl-2-isopropyl-5- nitroimidazole, 1 -(2-ethylsu lphonylethyl)-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 hyd roxy-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]-l -methyl-5-nitroimidazole, 1 -(2-carbamoyloxyethyl)-2-methyl-5- nitroimidazole, 1 -(2-hydroxyethyl)-2-(p4luorophenyl)-5-nitroimidazole, 2-hydroxymethyl- 1-methyl-S- nitroimidazole, 1 -ethoxycarbonylmethyl-2-methyl-S-nitroimidazole, 2-isopropyl-4(or 5)-nitroimidazole, 2-hydroxymethyl-4(or 5)-nitroimidazole, 1 -(2-hydroxyethyl)-2-methyl-4-nitroimidazole, 1,2-dimethyl-4nitroimidazole, 1 -(2-hyd roxyethyl)-2-hyd roxymethyl-5-nitroimidazole, 1 -(2-hydroxy-3-methoxy-npropyl)-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, monoesters thereof with dicarboxylic aliphatic acids, and pharmaceutically-acceptable salts thereof, and, when a substituent group in the 1 - or 2position 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)ethylthio]1 -methyl-5-nitroimidazole, pharmaceutically-acceptable salts thereof.
7. Complexes according to any one of claims 1 and 3 to 6 wherein X represents 1-(2hyd roxyethyl)-2-methyl-5-nitroimidazole.
8. Complexes according to any one of the preceding claims wherein Z' represents a bromine, iodine or chlorine atom or (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, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group or CR1R2 represents a cycloalkyl or cycloalkenyl group.
9. Complexes according to claim 8 wherein alkyl groups and moieties and alkenyl groups contain up to 6 carbon atoms, aryl groups and moieties are phenyl, and any cycloalkyl and cycloalkenyl groups contain from 3 to 8 carbon atoms.
1 0. Complexes according to any one of the preceding claims wherein X represents chlorine.
11. A complex according to claim 1 named in any one of the foregoing Examples.
1 2. cis-Dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(11).
13. Dichloro-bis[1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole-N3]platinum(11).
1 4. Dichloro-bis[1 -(2-hydroxy-n-propyl)-2-methyl-S-nitroimidazole-N3jplatinum(I 1).
1 5. Dichloro-bis( 1 -methyl-2-carbamoyloxymethyl-5-nitroimidazole-N3]platinum(11).
1 6. Dichloro-bis[1 -(2-N-morpholinylethyl)-S-nitrnimidazole-AO]plarinum(Il).
1 7. Dichloro-bis(l -methyl-5-nitroimidazofe-N3]platinum(ll)
1 8. Dichlorn-bis{2-[2-(4-carboxyphenoxy)-ethylthioj-1 -methyl-S-nitrnimidazole-AO)platinum(II).
1 9. Dibromo-bis[1 -(2-hydroxyethyl)-2-methyl-S-nitroimidazole-N3]platinum(I I).
20. A process for the preparation of a complex according to claim 1 which comprises reacting a nitroimidazole compound corresponding to the symbol X, as defined in claim 1 , with a platinite salt of the general formula: Q2Pt"(Zl)4 wherein Q represents an alkali metal and Z1 is as hereinbefore defined, the ligands Z1 being the same or different.
21. A process for the preparation of a complex of general formula I which comprises treating a complex of the general formula: [X]2Pt"Y2 V (wherein X is as defined in claim 1 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.
22. A process for the preparation of a complex of general formula I wherein (Z1)2 represents a bidentate ligand of general formula II and X, R1 and R2 are as hereinbefore defined, which comprises the reaction of a compound of general formula V depicted in claim 21, in the cis-configuration, wherein X is as defined in claim 1 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)2CR1 R2 (wherein R1 and R2 are as defined in claim 1), followed by neutralisation with a suitable base.
23. 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 20, 21 or 22 or the conversion by methods known per se of a complex of general formula I into such a pharmaceutically acceptable salt.
24. Process according to claim 21, 22, 23 or 24 substantially as hereinbefore described in any one of the foregoing Examples.
25. A complex according to claim 1, or a pharmaceutically-acceptable salt thereof, when prepared by a process claimed in any one of claims 20 to 24.
26. A pharmaceutical composition which comprises a compound of general formula I or a pharmaceutically-acceptable salt thereof in association with a pharmaceutically-acceptable carrier or coating.
27. A pharmaceutical composition according to claim 26 substantially as hereinbefore described.
28. A complex according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapy, in conjunction with X-ray therapy of cancer or in combatting anaerobic bacteria.
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GB2122194A (en) * 1982-06-18 1984-01-11 May & Baker Ltd New metal complexes of nitro- substituted pyrazoles, imidazoles and isothiazoles
EP0287317A2 (en) * 1987-04-13 1988-10-19 The British Columbia Cancer Foundation Platinum complexes with one radiosensitizing ligand
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