GB2122194A - New metal complexes of nitro- substituted pyrazoles, imidazoles and isothiazoles - Google Patents

Abstract

Metal-containing complexes of heterocycles of the general formula:- ÄM<1)<X<1>)m(Z<1>)n(Z<2>)pÜ<q+)<Z<3>)q <- > I wherein M<1> represents a gold(III), palladium(II), rhodium(III), platinum(IV) or platinum(II) atom, X<1> represents a 3-, 4- or 5- (mono)nitropyrazole molecule (which may be unsubstituted or carries at least one substituent, and which can coordinate to the metal M<1> through the 2-position of the pyrazole ring) or a 4- or 5-(mono)-nitroisothiazole molecule (which may be unsubstituted or carries at least one substituent, and which can coordinate to the metal M<1>) or, when M<1> represents a gold(III), palladium(II), rhodium(III) or platinum(IV) atom, X<1> may also represent a 2-, 4- or 5- (mono)nitroimidazole molecule which may be unsubstituted or carries at least one substituent, and which can coordinate to the metal M<1> through the 3-position of the imidazole ring, the said nitropyrazole, nitroisothiazole or nitroimidazole molecules being optionally linked together when more than one moiety X<1> is contained in the compound of general formula I, Z<1> and Z<2> each represents a pharmaceutically acceptable ligand, (Z<3>)-represents a pharmaceutically acceptable anion, m represents 2 or, when M<1> represents a gold(III) atom, m represents 1 or, when M<1> represents a rhodium(III) atom, m represents 3 or 4, n represents 2 or, when M<1> represents a gold(III) atom, n represents 3 or, when M<1> represents a rhodium(III) atom, n represents 3 when m represents 3 or n represents 2 when m represents 4, p represents zero or, when M<1> represents a platinum(IV) atom, p represents 2, q represents zero or, when M<1> represents a rhodium(III) atom and m represents 4 and n represents 2, q represents 1 possess utility in the therapy of cancer, optionally in conjunction with X-ray therapy, or in combatting anaerobic bacteria, or in the treatment of arthritis.

Description

SPECIFICATION New metal complexes of heterocycles This invention relates to new metal-containing complexes of heterocyclic compounds, to processes for their preparation and to pharmaceutical compositions containing them.

The present invention provides metal-containing complexes of heterocycles of the general formula: [M1(X1)m(Z1)n(Z2)p]q+ (Z3)q [wherein M' represents a gold(lil), palladium(ll), rhodium(lll), platinum(lV) or platinum(ll) atom, X1 represents a 3-, 4- or 5-(mono)nitropyrazole molecule (which may be unsubstituted or, preferably, carries at least one substituent, and which can coordinate to the metal M' through the 2-position of the pyrazole ring) or a 4- or 5-(mono)nitroisothiazole molecule (which may be unsubstituted or, preferably, carries at least one substituent, and which can coordinate to the metal M1) or, when M' represents a gold(lil), palladium(ll), rhodium(lil) or platinum(lV) atom, X' may also represent 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 the metal M1 through the 3-position of the imidazole ring, the said nitropyrazole, nitroisothiazole or nitroimidazole molecules being optionally linked together (for example in pairs) when more than one moiety X1 is contained in the compound of general formula I, especially when M1 represents a palladium(ll), platinum(lV) or platinum(ll) atom, Z' and Z2 each represents a pharmaceutically acceptable ligand, (Z3)- represents a pharmaceutically acceptable anion, m represents 2 or, when M1 represents a gold(lll) atom, m represents 1 or, when M' represents a rhodium(lll) atom, m represents 3 or 4, n represents 2 or, when M1 represents a gold(lll) atom, n represents 3 or, when M' represents a rhodium(lll) atom, n represents 3 when m represents 3 or n represents 2 when m represents 4, p represents zero or, when M1 represents a platinum(lV) atom, p represents 2, q represents zero or, when M' represents a rhodium(lll) atom and m represents 4 and n represents 2, q represents 1] which possess valuable properties of use in the therapy of cancer and in combatting anaerobic bacterial infections and, when M' represents a gold(lll) atom, in the treatment of arthritic disorders.

By the term "pharmaceutically acceptable ligand", as used in this specification to refer to symbols Z' and Z2, 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 properties of the compound of formula I are not vitiated by side-effects ascribable to those species.

Preferably Z' represents a halogen, e.g. bromine, iodine or, more particularly, chlorine, atom and Z2 represents a halogen, e.g. bromine, iodine or chlorine, atom or a hydroxy group, or when n represents at least 2 then, especially when M1 represents a palladium(ll), platinum(lV) or platinum(ll) atom, a pair of the ligands Z1, which may be referred to as (Z1)2, may represent a bidentate ligand of the general formula:

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 CR1R2 represents a cycloalkyl or cycloalkenyl group, and r represents 0 or 1. The dotted lines indicate bonding to the metal atom M1.

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.

The ligands represented by Z' and/or Z2 may be different but are preferably the same.

Similarly, by the term "pharmaceutically acceptable anion", as used in the specification to refer to symbol (Z3)-, iS meant an anion which, when displayed 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 properties of the compound of formula I are not vitiated by side-effects ascribable to those species.

Preferably Z3 represents a hajogen, e.g. bromine, iodine or, more particularly, chlorine, atom so that (Z3)- represents the corresponding halide ion.

When the compound of formula I contains two or more moieties Xl linked together, each linkage may be a single bond or a polyvalent radical such as an alkylene, e.g. methylene, group. In this specification when reference is made to a moiety X' reference is also intended to linked moieties X' taken together or separately, where the context so permits. Thus, as an illustration, when two moieties X' are linked together then when reference is made to X1 reference is also intended to the [X']2 moiety or to half the [X']2 moiety, where the context so permits.

Suitable substituents on the 1-, 3-, 4- or 5-positions of the pyrazole rings of 3-, 4- or 5-(mono)nitropyrazole molecules or on the 3-, 4- or 5-positions of the isothiazole rings of 4- or 5-(mono)nitroisothiazole molecules or on the 1-, 2- or 4- or 5-positions of the imidazole rings of 2-, 4- or 5-(mono)nitroimidazole molecules 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 the metal M' more strongly than the 2position nitrogen atom of the pyrazole ring or the coordinating heteroatom of the isothiazole ring or the 3-position nitrogen atom of the imidazole ring of a (mono)nitroheterocycle molecule represented by X'.

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 one or more 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 preferably contain from 1 to 4 carbon atoms.

When a substituent group in a substituted heterocycle molecule represented by the symbol X1 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 heterocycle 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; and when X' represents a heterocycle carrying a substituent which contains 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.

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 properties of the metal-containing complexes of general formula I are not vitiated 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.

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 X1 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.

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 'MNZ'], dimetridazole [1,2dimethyl-5-nitroimidazole], ipronidazole (1 -methyl-2-isopropyl-5-nitroimidazole), tinidazole [1-(2 ethylsulphonylethyl)-2-methyl-5-nitroimidazole], 2-methyl-4-(or 5)-nitroimidazole, 1 -carboxymethyl2-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-carbamoyloxymethyl- 5-nitroimidazole], secnidazole [ 1 -(2-hydroxy-n-propyl)-2-methyl-5-nitroi midazole], 1 -methyl-5-nitro- imidazole, 2-[2-(4-carboxyphenoxy)ethylthio]-1 -methyl-5-nitroimidazole, bamnidazole [1-(2 carbamoyloxyethyl)-2-methyl-5-nitroimidazole], flu nidazole [1 -(2-hydroxyethyl)-2-(p-fl uorophenyl)-5nitroimidazole], 2-hydroxymethyl- 1 -methyl-5-nitroimidazole, 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- hydroxymethyl-5-n itroim idazole, m isonidazole [ 1 -(2-hydroxy-3-methoxy-n-propyl)-2-nitroi midazole], 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 substitued nitro imidazole molecules contains. a free hydroxy group, monoesters thereof with dicarboxylic aliphatic acids, wherein the aliphatic, e.g. alkyl, moWety 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-nitroim idazole or 2- [2-(4-carboxyphenoxy)ethylthio]- 1 -methyl-5-nitroimidazole, pharmaceutically acceptable salts thereof.

The complexes of formula I wherein M' represents a palladium(ll) or a platinum(ll) atom, which are all square-pianar, may be in the trans or the cis-configuration.

A particularly preferred class of compounds of formula I comprises those wherein X' represents metronidazole.

Another particularly preferred class of compounds of formula I comprises those wherein X' represents 1-methyl-4-nitropyrazole.

Another particularly preferred class of compounds of formula I comprises those wherein X' represents a methylnitroisothiazole.

Another particularly preferred class of compounds of formula I comprises those of the general formula Au"'(X2)(Z4)3 111 wherein X2 represents a substituted or unsubstituted (mono)nitroimidazole molecule as hereinbefore defined, e.g. metronidazole, and Z4 represents a halogen atom.

Another particular preferred class of compounds of formula I comprises those of the general formula: Pd"(X2)2(Z4)2 IV wherein X2 and Z4 are as hereinbefore defined.

Another particularly preferred class of compounds of formula I comprises those of the general formula: [Rhlll(X2)m(Z4)n]S+ (Z3)q V wherein X2, Z3 and Z4 are as hereinbefore defined and m, n and q are as hereinbefore defined, that is to say either m=3, n=3 and q=0, or else m=4, n=2 and q=1.

Another particularly preferred class of compounds of formula I comprises those of the general formula: PtlV(X2)2(Z4)2(Z2)2 VI wherein X2, Z2 and Z4 are as hereinbefore defined.

Another particularly preferred class of compounds of formula I comprises those of the general formula: Pt"X3)2(Z4)2 VII wherein Z4 iS as hereinbefore defined and X3 represents a substituted or unsubstituted (mono)nitropyrazole molecule as hereinbefore defined.

Another particularly preferred class of compounds of formula I comprises those of the general formula: Pt"(X4)2(Z4)2 VIII wherein Z4 iS as hereinbefore defined and X4 represents a substituted or unsubstituted (mono)nitroisothiazole molecule as hereinbefore defined.

Important individual compounds of formula I include: trichloro-[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]gold(I II); A trich loro-( 1 ,2-dimethyl-5-nitroimidazole-N3)-gold(Il 11 ); B tribromo-[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]gold(lIl); C dichloro-bis[1 -(2-hydroethyl)-2-methyl-5-nitroimidazole-N3]palladium(I I); D dichloro-bis( 1 ,2-dimethyl-5-nitroimidazole-N3)-palladium(ll); E dichloro-bis[1 -(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-AP]-palladium(l I);F dichloro-bis[ 1 -(2-hydrnxy-3-methoxy-n-prnpyl)-2-nitrnimidazole-N]- palladium(ll); G trichloro-tris[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]rhodium(III); H dichloro-tetrakis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3] rhodium(l 11) chloride;I tetrachloro-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole- N3]platinum(lV); J tetrachloro-bis(1,2-dimethyl-5-nitroimidazole-N3)platinum(1V); K tetrachloro-bis[ I -(2-hydroxy-n-propyl)-2-methyl-5-nitroi midazole-N3]- platinum(lV); L dichloro-dihydroxy-bis[ 1 -(2-hydrnxyethyI)-2-methyI-5-nitrnimidazoIe-N]-pIatinum (lV); M dichloro-dihydroxy-bis(1,2-dimethyl-5-nitroimidazole-N ]platinum(IV);N dichloro-bis[l -methyl-4-nitropyrazole-N2]platinum(ll) ; 0 dichloro-[bis(4-nitropyrazol- 1 -yl)methane-N2,N2']platinum(ll); P dichloro-bis[5-methyl-4-nitroisothiazole]platinum(Il); and Q dichloro-bis[3-methyl-5-nitroisothiazole]platinum(II). R The letters A to R are assigned to the compounds for easy reference later in the specification.

The compounds of formula I are of use in the treatment of cancer, preferably in conjunction with X-ray therapy.

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 been found that the metal-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.

Furthermore, compounds of formula I, especially the compounds of formula I wherein X' represents a substituted or unsubstituted (mono)nitroimidazole as hereinbefore defined, 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.

Compounds of formula I wherein M' represents a gold(lil) atom are also of use in the treatment of arthritic disorders.

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 M', X', Z1, Z2, z3, m, n, p and q are as hereinbefore defined, are prepared by reaction of a nitropyrazole, nitroisothiazole or [when M' represents a gold(lil), palladium(ll), rhodium(lil) or platinum(lV) atom] a nitroimidazole compound corresponding to the symbol X1, as hereinbefore defined, with a salt of the general formula:: (Q1)sM1(Z1)n+s(Z1)t(Z2)p IX wherein Q1 represents an alkali metal, for example sodium or potassium, atom, M1, Z1, Z2, n and p are as hereinbefore defined, and s represents zero when M' represents a rhodium(lil) atom, s represents 1 when M' represents a gold(lll) atom and s represents 2 when M' represents a palladium(ll), platinum(lV) or platinum(ll) atom, and t represents zero, or t represents 1 when M' represents a rhodium(lil) atom and n represents 2. Reaction may be effected in water or an aqueous organic solvent, e.g. aqueous ethanol or aqueous acetone, at a temperature from 50 to 1 000C.

When M1 represents a rhodium(lil) atom, the reaction is preferably carried out in the presence of a trace of a mild reducing agent, for example sodium hypophosphite or even ethanol.

Salts of formula IX may be prepared by the application or adaptation of known methods. In some circumstances it is possible to prepare the salt of formula IX in situ and this can constitute an advantage, especially when operating on a large scale.

For example (i) compounds of the general formula: (Q1)Au"'(Z1)4 X wherein Q' and Z1 are as hereinbefore defined) may be prepared in situ by the reaction together of compounds of the general formulae XI and XII:- (01)(Z1) Xl Au"'(Z')3 XII wherein Q' and Za are as hereinbefore defined.

(ii) Compounds of the general formula (01)2Pd"(Z1)4 XIII wherein Q' and Z' are as hereinbefore defined may be prepared in situ by the reaction together of compounds of general formula XI (as hereinbefore defined) and XIV:- Pdll(Z')2 XIV wherein Za is as hereinbefore defined.

(iii) Compounds of the general formula: (Q')2Pt'VCI6 XV (wherein O' is as hereinbefore defined) may be prepared in solution by dissolving platinum metal in aqua regia, allowing the excess of aqua regia to evaporate off, and then treating carefully with a compound of the general formula: (O')OH XVI (wherein Q' is as hereinbefore defined), preferably in solution in water.

(iv) Compounds of the general formula (Q1 )2Pt"C14 XVII (wherein Q1 is as hereinbefore defined) may be prepared by treatment of a solution of a compound of formula XV (prepared as hereinbefore described) with the appropriate quantity of hydrazine.

For example, according to a further feature of the present invention, compound A is prepared by reaction of metronidazole with an alkali metal chloroaurate, e.g. sodium tetrachloroaurate (NaAuCI4).

Reaction is preferably effected in water or aqueous acetone at 5o1 000C, preferably at 100--300C.

According to a further feature of the present invention, compound D is prepared by reaction of metronidazole with an alkali metal chloropalladite, more especially potassium chloropalladite (K2PdCI4). Reaction is preferably effected in water at 1 5O1 000C, preferably at 200--600C.

According to another feature of the present invention, compound H is prepared by reaction of metronidazole with a rhodium halide, more especially rhodium trichloride (RhCI3). Reaction is preferably effected in water at 150--1000C, preferably at 700--90"C.

According to another feature of the present invention, compound J is prepared by reaction of metronidazole with an alkali metal chloroplatinate, more especially potassium chloroplatinate (K2PtC16) or sodium chloroplatinate (Na2PtCI6), in aqueous ethanol. Reaction is preferably effected in water at 150--1000C, preferably at 600---800C.

According to another feature of the present invention, compound 0 is prepared by reaction of Nmethyl-4-nitropyrazole with an alkali metal chloroplatinite, more especially potassium chloroplatinite (K2PtCI4). Reaction is preferably effected in water at 150--1000C, preferably at 400--600C.

According to a further feature of the present invention, compound Q is prepared by reaction of 5methyl-4-nitroisothiazole with an alkali metal chloroplatinite, more especially potassium chloropiatinite (K2PtCI4). Reaction is preferably effected in water at 15 -100 C, 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 [M'(X')m(Y')n(Z2)p]q+ (Z3)- XVIII (wherein Ma, Xt, Z, Z3, m, n, p and q are as hereinbefore defined and Y' is a halogen atom) can be treated with a source of an alternative ligand, for example another halogen ligand, to replace Y1.

Treatment with silver nitrate in an aqueous medium before the treatment with the source of the alternative ligand is desirable in some instances.

According to a further feature of the present invention, compounds of formula I wherein (Z1)2 represents a bidentate iigund of formula II and M1, X1, Z2, Z3, m, n, p and q as hereinbefore defined (and, in the case of gold compounds, and rhodium compounds wherein n represents 3, the third ligand Z' is as hereinbefore defined) are prepared by the treatment of a compound of the general formula XVIII wherein M', X', Y1, Z2, m, n, p and q are as hereinbefore defined, the two ligands Y' (or, in the case of gold and rhodium compounds wherein n represents 3, two of the three ligands Y') being in the cisconfiguration, with an acid of the general formula:: (HOOC)2(CR1 R2)r XIX (wherein R1, R2 and rare as hereinbefore defined) in an aqueous medium 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 by-products and the filtrate is evaporated in vacuo to give the required compound of formula I. Before the compound is treated with the acid of formula XIX it may be treated with silver nitrate in an aqueous medium.

According to a further feature of the present invention compounds of formula I wherein M' represents a platinum(lV) atom, Z' represents a halogen atom, Z2 represents a halogen atom or a hydroxy group and X', Z3, m, n, p and q are as hereinbefore defined, are prepared from platinum(ll)- containing complexes of the general formula: Pt"(X1)2(Z1)2 XX (wherein X1 and Z' are as hereinbefore defined) by oxidation, preferably in an aqueous medium, by means of hydrogen peroxide when Z2 represents a hydroxy group or by means of the appropriate halogen when Z2 represents a halogen atom, e.g. chlorine gas or bromine or a source thereof, e.g.

aqueous potassium triiodide solution. Generally the reaction takes place between 0 and 1 000C.

Compounds of formula XX, wherein X' and Z' are as hereinbefore defined may be prepared by reaction of a heterocyclic compound corresponding to the symbol X', as hereinbefore defined, with a platinite salt of the general formula: (Q')2Pt"(Z')4 XXI wherein Q' and Z1 are 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, art a temperature from 150 to 1000C.

Compounds of formula XX, wherein Z1 is as hereinbefore defined and X' represents a substituted or unsubstituted (mono)nitroimidazole molecule, are described in the specification of British Patent Application No. 2093451A and corresponding applications in other countries, for example United States Serial No. 350885.

According to a further feature of the present invention compounds of formula I wherein M' represents a palladium(ll) atom, X1, Z1, Z2, Z3, m, n, p and q being as hereinbefore defined, are prepared by reaction of a nitropyrazole, nitroisothiazole or nitroimidazole compound corresponding to the symbol X', as hereinbefore defined, with a salt of the general formula (Q1)2PdlV(Z1)6 XXII wherein Q' and Z' are as hereinbefore defined, in an aqueous medium, e.g. in water or an aqueous organic solvent, e.g. aqueous ethanol or aqueous acetone, at a temperature from 50 to 1 000C, preferably from 200C to 600C.

Substituted heterocyclic compounds corresponding to the symbol X', including, when a substituent group in the aforesaid substituted heterocyclic 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 the said substituted heterocyclic 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 metal-containing complexes of general formula I wherein X' represents a heterocyclic compound carrying a substituent which includes a carboxy group, may be prepared by the application or adaptation of methods known per se, either by utilising an appropriate substituted heterocyclic 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 metal-containing complex of general formula I obtained by the preparative reactions hereinbefore described.

By the expression "known methods" or "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 and the Reference Examples illustrate the preparation of intermediates.

Example 1 Compounds A and B Metronidazole (21 5mg) was dissolved in acetone (1 5ml) and the resulting solution was added to a solution of sodium tetrachloroaurate dihydrate (500mg) in water (1 5ml) at room temperature. The acetone was allowed to evaporate at room temperature and the resulting precipitate was filtered off, and washed with diethyl ether, to give trichloro-L1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole- N3]gold(lll) (560mg), in the form of yellow crystals, m.p. 168-1 730C [Elemental analysis.

calculated: C, 15.19; H, 1.91: N, 8.86; Cl, 22.41%; found: C, 15.0; H, 1.82; N, 8.8; CI, 22.2%].

By proceeding in a similar manner, but replacing the metronidazole, used as a starting material, by the appropriate quantity of dimetridazole, there was prepared:- trichloro-( 1 ,2-dimethyl-5-nitro imidazole-N3)gold(lll), m.p. 158-171 0C [Elemental analysis:-- calculated: C, 13.51; H, 1.59; N, 9.46; Ci, 23.93%; found: C, 13.6; H, 1.41: N, 9.3; CI, 23.7%; NMR (in acetone-D6): singlets at 3.00, 4.30 and 8.65 p.p.m.].

Example 2 Compound C Metronidazole (30mg) was added to a stirred solution of potassium tetrabromoaurate (100mg) in water ( 1 Oml) at room temperature and the resulting mixture was stirred at room temperature for one hour. The resulting crystals were filtered off, and washed with diethyl ether (2ml), to give tribromo-[1 - (2-hydrnxyethyl)-2-methyI-5-nitrnimidazoIe-N]goId(IlI) (70mg) in the form of red crystals, m.p. 149 1 500C (with decomposition) [Elemental analysis: calculated: C, 11.86; H, 1.49; N, 6.91%; found: C, 11.8; H, 1.29; N, 6.8%; NMR (in acetone-D6): singlets at 2.95 and 8.65 ppm, triplets centred at 4.05 and 4.8ppm].

Example 3 Compounds D, E and F A solution of metronidazole (342mg) in ethanol (30ml) was added to a solution of potassium chloropalladite (326.4mg) in water (20ml). The ethanol was evaporated slowly during 16 hours, and the resulting precipitate was filtered off and washed with diethyl ether, to give dichloro-bis[1 -(2- hydroxyethyl)-2-methyl-5-nitroimidazole-N3]palladium(11) (51 Omg), in the form of yellow crystals, m.p.

2440C (with decomposition). [Elemental analysis:- calculated': C, 27.74; H, 3.49; N, 16.17; CI, 13.65%; found: C, 27.5; H, 3.51; N, 16.1; Cl, 13.8%; NMR (in acetone-D6): singlets at 3.19 and 8.1 3ppm, triplets centred at 3.95 and 4.65ppm].

By proceeding in a similar manner, but replacing the metronidazole used as starting material by the appropriate quantities of dimetridazole and secnidazole respectively, there were prepared L dichloro-bis( 1 ,2-dimethyl-5-nitroimidazol/-N3)palladium(Il), m.p. 293-2940C (with decomposition).

[Elemental analysis: calculated: C, 26.13; H, 3.07;N, 18.29; Cl, 15.43%; found: C, 26.4; H, 3.22; N, 17.9; CI, 14.9%]; and dichloro-bis[1-(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole- N3]palladium(ll), m.p. above 2700C (with decomposition) [Elemental analysis:-- calculated: C, 30.70; H, 4.05; N, 15.35; Cl ,1 2.95; found: C, 31.10; H, 4.07; N, 15.1; CI, 12.2].

Example 4 Compound G Palladium dichloride (89mg) was added to a stirred solution of sodium chloride (120mug) in water (20ml) at room temperature and the stirring was continued for one hour. Misonidazole (200mg) and acetone (2ml) were then added and the stirring was continued for 1 5 minutes at room temperature.

The resulting mixture was heated on the steam bath for one hour, and then was cooled in an ice bath.

The resulting crystals were filtered off and washed with diethyl ether to give dichloro-bis-[1 -(2- hydroxy-3-methoxy-n-propyl)-2-nitroimidazole-N3]palladium(II) (220mg), in the form of yellow crystals, m.p. 193-1 950C. [Elemental analysis: calculated: C, 29.01; H, 3.83; N, 14.50; CI, 12.23%; found: C, 28.6; H, 3.70; N, 14.2; Cl, 12.3%; NMR (in acetone-D6):-singlet at 3.3ppm, multiplet at 4.0--4.7ppm and doublets at 7.35 and 7.55ppm].

Example 5 Compound H A solution of metronidazole (51 3mg) in ethanol (1 ml) was added to a solution of rhodium(lll) chloride trihydrate (281 mg) in water (5ml) and the resulting solution was heated on the steam bath for 6 hours and then was allowed to cool to room temperature. The resulting precipitate was filtered off, and washed with diethyl ether, to give trichloro-tris[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole N3]rhodium(lll) (650mg), m.p. above 2300C (with decomposition), in the form of pale brown crystals [Elemental analysis: Rh(MNZ)3C13:2H20: requires C, 28.49; H, 4.12; N, 16.62; Cl, 14.02%; found: C, 28.3; H, 3.84; N, 16.4; CI, 14.2%].

Example 6 Compound I Metronidazole (780mg) was dissolved in water ( 1 Oml) by heating on the steam bath. The solution was treated with rhodium(lll) chloride trihydrate (281 mg) and the heating was continued for one hour until the solution became orange. The solution was then treated with sodium hypophosphite (2mg), whereupon the solution became bright yellow and a precipitate was formed. The precipitate was filtered off and washed with diethyl ether to give dichloro-tetrakis[1 -(2-hydroxyethyl)-2-methyl-5 nitroimidazole-Nj]rhodium(lll) chloride (720mg) in the form of yellow crystals, m.p. 198-201 C [Elemental analysis: calculated for [Rh(MNZ)4C12]+CI-:2H20:- C, 31.00; H, 4.34; N,18.07; CI, 11.44%; found: C, 30.6; H, 3.75; N, 17.7; Cl, 11.7%].

Example 7 Compounds J, K and L Metronidazole (342mg) was dissolved in water (50ml) by heating on the steam bath. Potassium chloroplatinate (486mg) was added to the solution and heating was continued for 16 hours, during which time a precipitate occurred. The precipitate was filtered off and washed with diethyl ether to give tetrachloro-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(1V) (620mg) in the form of yellow crystals, m.p. 208-2100C (with decomposition). [Elemental analysis: calculated: C, 21.22; H, 2.67; N, 12.37; CI, 20.88%; found: C, 21.2; H, 2.69; N, 12.3; Cl, 19.3%; NMR (in acetone-D6): two singlets at 2.80 and 3.20ppm, multiplets at 4.00, 4.50 and 8.40ppm].

By proceeding in a similar manner, but replacing the metronidazole, used as a starting material, by the appropriate quantities of dimetridazole and secnidazole, respectively, there were prepared.

tetrachloro-bis(1,2-dimethyl-5-nitroimidazole-N3)platinum(1V), m.p. 252-253 C. [Elemental analysis:-calculated: C, 19.4; H, 2.28; N, 13.57%; found: C, 19.3; H, 2.28; N, 13.19/0; NMR (in acetone-D6): singlets at 2.6 and 4.1 ppm and a multipletcentred at 8.2ppm]; andtetrachloro-bis[1-(2- hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N3]platinum(1V), melting point: darkens at 2600C and melts at 31 00C (with decomposition). [Elemental analysis: calculated for Pt(secnidazole)2C14:2H2O:- C, 22.6; H, 3.53; N, 1 1.31 %; found:C, 22.7; H, 3.52; N, 1 1.2%; NMR (in acetone-D6): doublet centred at 1 .3ppm, a singlet at 3.2ppm, multiplets centred at 4.5 and 8.4ppm].

Example 8 Compound M cis-Dichloro-bis[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-AP]platinum(II) (700mg) was suspended in water (20ml), heated on the steam bath and treated with aqueous hydrogen peroxide solution (8ml; 100vol), and the heating was continued for 6 hours.The mixture was left for 2 days at room temperature and the resulting precipitate was filtered off and washed with diethyl ether, to give dichlorodihydroxy-bis[1-(2-hydroxyethyl-2-methyl-5-nitroimidazole-N ]platinum(IV) (350mg) in the form of pale yellow crystals, m.p. 209-21 30C (with decomposition) [Elemental analysis: calculated for Pt(MNZ)2C12(OH)2:2H20: C, 21.37; H, 3.59; N, 12.46%; found: C, 21.6; H, 3.05; N, 12.5%; NMR (in acetone-D6): singlet at 3.05ppm, multiplets centred at 3.90, 4.70 and 8.4ppm].

Example 9 Compounds M and N cis-Dichloro-bist 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(11) (500mg) was suspended in aqueous hydrogen peroxide solution (30ml; 20vol) and the stirred mixture was heated on the steam bath for 5 hours. The pH of the resulting clear bright yellow solution was adjusted to 7 by treatment with aqueous sodium hydroxide solution (2N). The solution was then treated dropwise with an aqueous solution of the enzyme catalase (1% w/w) until no unreacted hydrogen peroxide remained.

The solution was subjected to ultrafiltration to remove the enzyme and the filtrate was freeze dried, to give dichlorodihydroxy-bis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]platinum(IV) in a hydrated form (350mg), which decomposed at approximately 1700C. [Elemental analysis: C,21.08; H, 3.14; N, 12.06; CI, 10.12; H20, 9.2%; Pt(MNZ)2Cl2(OH)2:3. 5H20 requires: C, 20.41; H, 3.84; N, 11.91; CI, 10.06; H20, 8.9%].

By proceeding in a similar manner, but replacing the starting material by the appropriate quantity of cis-dichloro-bis(1,2-dimethyl-5-nitroimidazole-N )platinum(II), there was prepared dichlorodihydroxy-bis( 1 ,2-dimethyl- 1 -5-nitroimidazole-N3)platinum(lV).

Example 10 Compounds 0 and P A suspension of 1 -methyl-4-nitropyrazole (381 mg) in water (30ml) was stirred with gentle heating at 500C and treated with potassium chloroplatinite (621 mg), and the stirring with gentle heating was continued for one hour. The solution changed in colour from cloudy reddish orange to clear yellow, and a precipitate was-formed. The mixture was cooled and the solid was filtered off and washed with diethyl ether, to give dichloro-bis[1-methyl-4-nitropyrazole-N ]platinum(II) (670mg) in the form of yellow crystals [Elemental analysis: calculated: C, 18.47; H, 1.91;N, 16.16; Cl, 13.63%; found: C, 18.2; H, 1.81; N, 16.0; Cl, 13.7%].

By proceeding in a similar manner, but replacing the 1-methyl-4-nitropyrazole, used as a starting material, by the appropriate quantity of bis(4-nitropyrazol-1 -yl)methane, there was prepared dichloro[bis(4-nitropyrazol-l -yl)methane-N2,N2']platinum(ll), m.p. 31 00C (with decomposition) [Elemental analysis: calculated C, 16.68; H, 1.20; N, 16.67; Cl,14.06%; found: C, 16.8; H, 1.12; N, 16.7; Cl, 13.5%].

Example 11 Compound O A suspension of 5-methyl-4-nitroisothiazole (375mg) in water was stirred with gentle heating (500C) and treated with potassium chloroplatinite (540mg), and stirring with gentle heating was continued for one hour. The solution changed colour from cloudy reddish-orange to clear yellow, and a precipitate was formed, which was filtered off from the cooled mixture and washed with diethyl ether, to give dichloro-bis[5-methyl-4-nitroisothiazole]platinum(ll) (700mg), in the form of yellow crystals, m.p. above 3600C (darkening above 2600C) [Elemental analysis: calculated: C, 17.33; H, 1.45; N, 10.11; Cl, 12.79; S, 1 1.57%; found: C, 17.0; H, 1.33; N, 9.8; Cl, 13.1; S, 1 1.4%].

Example 12 Compound R A solution of potassium chioroplatinite (621 mg) in water (30ml) was stirred with gentle heating (600C) and treated with a solution of 3-methyl-5-nitroisothiazole (432mg) in acetone (1 5ml) and the stirring with gentle heating continued for one hour. The resulting mixture was heated on a steam bath for eight hours and then cooled. The resulting precipitate was filtered off and washed with diethyl ether to give dichloro-bis[3-methyl-5-nitroisothiazole]platinum(ll) (530mg) in the form of yellow crystals.

[Elemental analysis:-- calculated: C, 17.33; H, 1.45; N, 10.11; CI, 12.79; S, 11.57%; found: C, 17.4; H, 1.36; N, 10.0; CI, 12.6; S, 11.5%].

Example 13 Compound D A solution of metronidazole (1 OOmg) in water (20ml) was treated with potassium chloropalladate (K2Pd'VCi6) (100mug), and the mixture was left to stand at room temperature for 24 hours. The resulting yellow precipitate was filtered off and washed with diethyl ether to give dichloro-bis[1 -(2-hydroxy ethyl)-2-methyl-5-nitroimidazole-N3]palladium(l I) (1 2Omg), m.p. 2440C (with decomposition) [Elemental analysis: calculated C, 27.74; H, 3.49; N, 16.17%; found: C, 27.2; H, 3.41; N, 15.9%].

Reference Example 1 Metronidazole (6.85g) was suspended in water (300ml) and stirred with gentle heating (500C).

Potassium chloroplatinite (8.3g) was added and stirring with gentle heating was continued for one hour. The solution changed in colour from cloudy reddish-orange to clear yellow, and a precipitate was formed. After cooling, the supernatant liquid was decanted off and reduced in volume in a rotary evaporator to give a further precipitate. The 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-dichloro bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]-platinum(II) (12.1 69) in the form of yellow crystals, m.p. 178-181 0C, followed by resolidification and melting (with decomposition) at 2572590C.

Reference Example 2 Dimetridazole (0.2829) was suspended in water (20ml) and stirred with gentle heating (500C).

Potassium chloroplatinite (0.4159) 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(ll) (0.456g), m.p. 174-1 760C [Elemental analysis: calculated: C, 21.89; H, 2.55; N, 15.32; CI, 12.95%; found: C, 21.46: H, 2.74; N, 14.74; CI, 13.20%].

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 elixirs 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 end 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 emulsions. 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 sterilised by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising 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 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 may be administered in conjunction with each repetition of the irradiation at the aforementioned doses. When administered to combat anaerobic bacteria or arthritic disorders 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 directs.

Claims (38)

Claims

1. Metal-containing complexes of heterocycles of the general formula [M1(X1)m(Z1)n(Z2)p]q+ (Z3)q wherein M' represents a gold(lll) palladium(ll), rhodium(lil), platinum(lV) or platinum(ll) atom, X1 represents a 3-, 4- or 5-(mono)nitropyrazole molecule (which may be unsubstituted or carries at least one substituent, and which can be coordinate to the metal M1 through the 2-position of the pyrazole ring) or a 4- or 5-(mono)nitroisothiazole molecule (which may be unsubstituted or carries at least one substituent, and which can coordinate to the metal M1) or, when M' represents a gold(lil), palladium(ll), rhodium(lil) or platinum(lV) atom, X' may also represent a 2-, 4- or 5-(mono)nitroimidazole molecule which may be unsubstituted or carries at least one substituent, and which can coordinate to the metal M' through the 3-position of the imidazole ring, the said nitropyrazole, nitroisothiazole or nitroimidazole molecules being optionally linked together when more than one moiety X' is contained in the compound of general formula I, Z1 and Z2 each represents a pharmaceutically acceptable ligand, (Z3)represents a pharmaceutically acceptable anion, m represents 2 or, when M' represents a gold(lll) atom, m represents 1 or, when M1 represents a rhodium(lll) atom, m represents 3 or 4, n represents 2 or, when M' represents a gold(lll) atom, n represents 3 or, when M1 represents a rhodium(lll) atom, n represents 3 when m represents 3 or n represents 2 when m represents 4, p represents zero or, when m' represents a platinum(lV) atom, p represents 2, q represents zero or, when M' represents a rhodium(lll) atom and m represents 4 and n represents 2, q represents 1.

2. A complex according to claim 1 wherein X1 represents a 3-, 4- or 5-(mono)nitropyrazole molecule which carries at least one substituent, a 4- or 5-(mono)nitroisothiazole which carries at least one substituent or, when M' represents a gold(lil), palladium(ll), rhodium(lil) or platinum(lV) atom, a 2-, 4- or 5-(mono)nitroimidazole molecule which carries at least one substituent.

3. A complex according to claim 1 or 2 wherein the (mono)nitroimidazole.molecule is a 4-or 5 (mono)nitroimidazole.

4. A complex according to claim 1, 2 or 3, wherein Z' represents a halogen atom and Z2 represents a halogen atom or a hydroxy group, or when n represents at least two then a pair of the ligands Z' may also represent 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 and r represents 0 or 1.

5. A complex according to claim 4 wherein, in the definition of CR1R2 in formula II, alkyl groups and moieties and alkenyl groups contain up to 6 carbon atoms, aryl groups and moieties are phenyl, and cycloalkyl and cycloalkenyl groups contain from 3 to 8 carbon atoms.

6. A complex according to claim 4 or 5 wherein Z' represents a chlorine atom.

7. A complex according to any one of claims 1 to 5 wherein M' represents a palladium(ll), platinum(lV)or platinum(ll) atom, n represents at least 2, and a pair of the ligands Z' represents a bidentate ligand of general formula II depicted in claim 4.

8. A complex according to any one of the preceding claims wherein the ligands Z' and/or Z2 are the same.

9. A complex according to ahy one of the preceding claims wherein Z3 represents a halogen atom.

10. A complex according to any one of the preceding claims wherein Z3 represents a chlorine atom.

11. A complex according to any one of the preceding claims wherein the substituents on the 1-, 3-, 4- or 5-positions of the pyrazole rings of 3-, 4- or 5-(mono)nitropyrazole molecules or on the 3-, 4or 5-positions of the isothiazole rings of 4- or 5-(mono)-nitroisothiazole molecules or on the 1-, 2- or 4or 5-positions of the imidazole rings of 2-, 4-, or 5-(mono)nitroimidazole molecules represented by the symbol X1 are alkyl groups unsubstituted or substituted by one or more atoms or groups selected from hydroxy, alkoxyl, alkylsulphonyl, carboxy, alkoxycarbonyl, carbamoyloxy, benzylcarbamoyl and Nmorpholinyl groups and halogen; phenyl groups substituted by one or more halogen atoms; and alkylthio groups substituted by a phenoxy group which phenoxy group is substituted by carboxy and, when a substituent group in a substituted heterocycle molecule represented by the symbol X' contains a free hydroxy group, monoesters thereof with dicarboxylic aliphatic acids, and pharmaceutically acceptable salts thereof, and when a substituent group in the substituted heterocycle molecules contains a free hydroxy group, phosphate, phosphite and sulphate esters thereof and their salts containing pharmaceutically acceptable cations and, when X' represents a heterocycle carrying a substituent which contains a carboxy group, pharmaceutically acceptable salts thereof.

12. A complex according to claim 11 wherein halogen substituents on alkyl groups are chlorine and halogen substituents on phenyl are fluorine.

13. A complex according to any one of the preceding claims wherein the heterocycle is a 2 (mono)nitroimidazole molecule having a substituent on at least one the 1-, 4- or 5-positions of the imidazole ring, a 4- or 5-(mono)nitroimidazole molecule having a substituent on at least one of the 1or 2-positions of the imidazole ring or the 4- or 5-position of the imidazole ring which is not occupied by the nitro group.

14. A complex according to any one of the preceding claims wherein the heterocycle is a 4- or 5 (mono)nitroimidazole molecule having a substituent in the 2-position of the imidazole ring and which is unsubstituted or substituted in the 1-position of the imidazole ring.

1 5. A comple according to claim 14 in which the imidazole ring is substituted in the 1-position.

1 6. A complex 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-ethylsulphonylethyl)-2-methyl-5-nitroimidazole, 2-methyl-4-(or 5)-nitroimidazole, 1 -carboxymethyl-2-methyl-5-nitroimidazole, 1 -(2-N-morphol inylethyl )-5-nitroimidazole, 1 (3-chloro-2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole, 1 -m ethyl-2-ca rba moyloxymethyl-5-nitroimidazole, 1 -(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole, 1-methyl-5-nitroimidazole, 2-[2-(4carboxyphenoxy)ethylthio]- 1 -methyl-5-nitroimidazole, 1 -(2-carba moyloxyethyl)-2-methyl-5-nitroim idazole, 1 -(2-hydroxyethyl)-2-(p-fluorophenyl)-5-nitroimidazole, 2-hydroxymethyl- 1 -methyl-5-nitro im idazole, 1 -ethoxycarbonylmethyl-2-methyl-5-nitroim idazole, 2-isopropyl-4-(or 5)nitroimidazole, 2hydroxymethyl-4(or 5)-nitroimidazole, 1 -(2-hydroxyethyl)-2-methyl-4-nitroimidazole, 1 ,2-di methyl-4- n itroimidazole, 1 -(2-hydroxyethyl)-2-hydroxymethyl-5-nitroim idazole, 1 -(2-hydroxy-3-methoxy-npropyl)-2-nitroimidazole, N-benzyl- 1 -(2-nitroimidazolyl)acetamide, 2-nitroimidazole or 4(5)-nitro- imidazole 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 cat.ons, and when X1 represents 1 -carboxymethyl-2-methyl-5-nitroimidazole or 2-[2-(4-carboxy phenoxy)ethylthio]- 1 -methyl-5-nitroimidazole, pharmaceutically acceptable salts thereof.

1 7. A complex according to any one of the preceding claims wherein X' represents 1-(2hydroxyethyl)-2-methyl-5-nitroimidazole.

1 8. A complex according to any one of claims 1 to 1 6 wherein X' represents 1 -methyl-4-nitropyrazole.

19. A' complex according to any one of claims 1 to 16 wherein X' represents a methylnitroisothiazole.

20. A complex according to any one of claims 1 to 6 and 8 to 17 conforming to the general formula; Au"'(X2)(Z4)3 111 wherein X2 represents a substituted or unsubstituted (mono)nitroimidazole molecule as defined in claim 1 and Z4 represents a halogen atom.

21. A complex according to any one of claims 1 to 17 conforming to the general formula: Pd11(X2)2(Z4)2 IV wherein X2 and Z4 are as defined in claim 20.

22. A complex according to any one of claims 1 to 6 and 8 to 17 conforming to the general formula: [Rh"'(X2)m(Z4)n]q+ (Z3)- V wherein X2 and Z4 are as defined in dlaim 20, Z3 is as defined in claim 1 and m, n and q are as defined in claim 1, that is to say either m=3, n=3 and q=O, or else m=4, n=2 and q=1.

23. A complex according to any one of claims 1 to 17 conforming to the general formula: PtlV(X2)2(Z4)2(Z2)2 VI wherein X2 and Z4 are as defined in claim 20 and z2 is as defined in claim 1.

24. A complex according to any one of claims 1, 2 and 4 to 12 conforming to the general formula: Ptl'(X3)2(Z4)2 VII wherein Z4 is as defined in claim 20 and X3 represents a substituted or unsubstituted (mono)nitropyrazole molecule as defined in claim 1.

25. A complex according to any one of claims 1,2 and 4 to 12 conforming to the general formula: Pt"(X4)2(Z4)2 VIII wherein Z4 iS as defined in claim 20 and X4 represents a substituted or unsubstituted (mono)nitroisothiazole molecule as defined in claim 1.

26. A complex according to claim 1 selected from the group consisting of trichloro-[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]gold(III); trichloro-( 1 ,2-dimethyl-5-nitroimidazole-N3)gold(lll tribromo-[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3)gold(111); dichloro-bis[1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazoIe-N ]palladium(II); dichloro-bis(1 ,2-dimethyl-5-nitroimidazole-N3)palladium(11); dichloro-bis[ 1 -(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N3]palladium (l l); dichloro-bis[ 1 -(2-hydroxy-3-methoxy-n-propyl)-2-nitroimidazole-N ]palladium(II); trichloro-tris[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ] rhodium(l l l);; dichloro-tetrakis[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ] rhodiu m(ll 1) chloride; tetrachloro-bis[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(IV); tetrachloro-bis( 1 ,2-dimethyl-5-nitroimidazole-N3)platinum(1V); tetrachloro-bis[1 -(2-hydroxy-n-propyl)-2-methyl-5-nitroimidazole-N3] platinum(lV); dichloro-dihydroxy-bis[ 1 -(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N ]platinum(IV); dichloro-dihydroxy-bis( 1 ,2-dimethyl-5-nitroimidazole-N3)platinum(1V); dichloro-bis[ 1 -methyl-4-nitropyrazole-N]platinum(II); dichloro-[bis(4-nitropyrazol-1 -yl)methane-N2,N2t-platinum(ll);; dichloro-bis[5-methyl-4-nitroisothiazole]platinum(II); and dichioro-bis[3-methyl-5-nitroisothiazole]platinum(ll).

27. A process for the preparation of a complex according to claim 1 which comprises reacting a nitropyrazole, nitroisothiazole or [when M' represents a gold(lil), palladium(ll), rhodium(lil) or platinum(lV) atom] a nitroimidazole compound corresponding to the symbol X1, as defined in claim 1, with a salt of the general formula:: (Q)sM1(z1)n+s(z1)t(z2)p IX wherein Qi represents an alkali metal atom, M1, Z1, Z2, n and p are as defined in claim 1, and s represents zero when M' represents a rhodium(lil) atom, s represents 1 when M' represents a gold(lil) atom and s represents 2 when M' represents a palladium(ll), platinum(lV) or platinum(ll) atom and t represents zero or t represents 1 when M1 represents a rhodium(lil) atom and n represents 2.

28. A process according to claim 27 wherein, when Ml represents a rhodium(IlI) atom, the reaction is carried out in the presence of a mild reducing agent.

29. A process for the preparation of a complex of general formula I which comprises treating a complex of the general formula: [M1(X1)m(Y1)"(Z2)p]q+ (Z3)q XVIII (wherein M', X', Z2, Z3, m, n, p and q are as defined in claim 1 and Y1 is a halogen atom) with a source of an alternative ligand, to replace Yl optionally after treatment with silver nitrate in an aqueous medium.

30. A process for the preparation of a complex of general formula I wherein (Z1)2 represents a bidentate ligand of formula II and M', X', Z2, Z3, m, n, p and q are as defined in claim 1 and in the case of gold compounds, and rhodium compounds wherein n represents 3, the third ligand Z1 is as defined in claim 1 which process comprises the treatment, optionally after treatment with silver nitrate in an aqueous medium, of a compound of the general forula XVIII depicted in claim 29, wherein M', X', Z2, m, n, p and q are as defined in claim 1 and V1 is as defined in claim 29, the two ligands Y' (or, in the case of gold and rhodium compounds wherein n represents 3, two of the three ligands Y') being in the cis-configuration, with an acid of the general formula:: (HOOC)2(CR1R2), XIX (wherein R1, R2 and rare as defined in claim 4) in an aqueous medium followed by neutralisation of the solution by the addition of a suitable base.

31. A process for the preparation of a complex of general formula I wherein M' represents a platinum(lV) atom, Zl represents a halogen atom, Z2 represents a halogen atom or a hydroxy group and X1, Z3, m, n, p and q are as defined in claim 1, which comprises the oxidation of a platinum(ll)containing complex of the general formula: Pt"(X1)2(z1)2 XX (wherein X' and Z1 are as defined in claim 1) by means of hydrogen peroxide when Z2represents a hydroxy group or by means of the appropriate halogen when Z2 represents a halogen atom.

32. A process for the preparation of a complex of general formula I wherein M' represents a palladium(ll) atom, and Xa, Z1, Z2, Z3, m, n, p and q are as defined in claim 1, which comprises the reaction of a nitropyrazole, nitroisothiazole or nitroimidazole compound corresponding to the symbol X1, as defined in claim 1, with a salt of the general formula: (Q')2Pd'V(Z')B XXII wherein Q' is as defined in claim 27 and Z1 is as defined in claim 1.

33. A 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 heterocyclic molecule represents by the symbol X1 has a substituent which contains a free hydroxy group and pharmaceutically acceptable salts of complexes in which the heterocyclic compound represented by the symbol X' has a substituent which contains a carboxy group, which comprises utilising a heterocyclic compound in the form of a pharmaceutically acceptable salt in a process as claimed in any one of claims 27 to 32 or the conversion by methods known per se of a complex of general formula I into such a pharmaceutically acceptable salt.

34. A process according to any one of claims 27 to 33 substantially as hereinbefore described in any one of Examples 1 to 13.

35. A complex according to claim 1, or a pharmaceutically acceptable salt thereof, when prepared by a process claimed in any one of claims 27 to 34.

36. A pharmaceutical composition which comprises a complex of general formula I or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating.

37. A pharmaceutically composition according to claim 36 substantially as hereinbefore described.

38. A complex according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, optionally in conjunction with X-ray therapy, or in combating anaerobic bacteria, or in the treatment of arthritis.