NL8302172A - METAL-CONTAINING COMPLEXES OF HETEROCYCLIC COMPOUNDS, METHODS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPLEXES. - Google Patents

Description

* W ..4 t N.0. 31,835 1

Metal-containing complexes of heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing these complexes.

The invention relates to new metal-containing complexes of heterocyclic compounds, to processes for their preparation and to pharmaceutical compositions containing these complexes.

The present invention provides metal-containing complexes of heterocyclic compounds of the general formula:

[M1 (X1) m (Z1) n (Z2) p] <1 + (Z3) "I

10 in which a gold (III), palladium (II), rhodium (III), platinum (IV) or platinum (II) atom represents X * - a 3-, 4- or 5- (mono) nitropyra -sole molecule (which can be unsubstituted or preferably contains at least one substituent, and which can coordinate via the position 2 of the pyrazole ring with the metal M *) or a 4- or 5- (mono) ni-15 troisothiazole molecule (which can be unsubstituted or preferably contains at least one substituent, and which can coordinate with the metal M ^) or, when M? - a gold (IXI), palladium (II), rhodium (III) - or represents platinum (IV) atom, X ^ may also represent a 2- or preferably 4- or 5- (mono) nitroimidazole molecule, which may be unsubstituted or preferably contains at least one substituent, via position 3 of the imidazole ring can coordinate with the metal M * *, wherein the above nitropyrazole, nitroisothiazole or nitroimidazole molecules may optionally be linked together (e.g., as pairs) when r than one unit X ^ - is present in the compound of the general formula I, especially when M * * represents a palladium (II), platinum (IV) or platinum (II) atom, and Z 2 each represent a pharmaceutically acceptable ligand, (Z3) ~ represents a pharmaceutically acceptable anion, means m 2 or, when a gold (III) atom represents m 1, or, when M? represents a ro-dium (III) atom, m means 3 or 4, n means 2, or, when M * * represents a gold (III) atom, n means 3, or, when a rhodium (III) atom represents, n means 3 when m means 3, or n means 2 when m 4 means, p means 0 or, when M * represents a platinum (IV) atom, p means 2, q represents 0 or, when M1 represents a rhodium (III) atom and m represents 4 and n means 2, q 1. The metal-containing complexes of the invention have valuable properties for use in the therapy of cancer and for combating anaerobic bacterial infections and, when H * represents a gold (III) atom, in the treatment of arthritic conditions.

By the term "pharmaceutically acceptable ligand" as used herein to designate the symbols "L1 and Z2" is meant a ligand which, when removed from the compound of formula I, forms only substances which are relatively are harmless to the organism of humans and animals when therapeutic doses are used, so that the beneficial properties of the compound of formula I are not negated by side effects attributable to such substances.

Preferably Z2 represents a halogen atom, for example a bromine, iodine, or in particular a chlorine atom, and 7 represents a halogen atom, for example a bromine, iodine or chlorine atom, or a hydroxy group, or when n represents at least 2, especially when M ^ represents a palladium (XI), platinum (IV), or platinum (II) atom, a pair of the ligands Z *, which may be designated as (Z *) 2.> a bidentate ligand with the general formula: 20 0

II

---- 0-C ^

(CRXR2) r II

---- 0-C ^

B

25 wherein R2 and R2, which may be the same or different, each represent a hydrogen atom or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl, or cycloalkenyl group, or CR1 -R2 represents a cycloalkyl or 30 represents cycloalkenyl group, and r represents 0 or 1. The dotted lines indicate the bond to the metal atom.

Within the definition of 31 31½2 in formula II, alkyl groups and units and alkenyl groups preferably contain up to 6 carbon atoms, aryl groups and units are preferably phenyl groups or 35 units and cycloalkyl and cycloalkenyl groups preferably contain 3- 8 carbon atoms.

The ligands represented by Z 1 and / or Z 2 may be different but are preferably the same.

The term "pharmaceutically acceptable anion", as used in this description to designate the symbol 8302172 • 4 »3 (Z3) ~, means an anion which, when removed from the compound of the formula I, only forms substances which are harmless to the organism of humans and animals when used in therapeutic doses, so that the beneficial properties of the compound of the formula I are not negated by side effects attributable to such substances.

Z3 preferably represents a halogen atom, for example a bromine, iodine or in particular a chlorine atom, so that (Z3) ~ represents the corresponding halide ion.

When the compound of formula I contains two or more linked units X ^, each bond may be a single bond or a polyvalent moiety, such as an alkylene group, for example, a methylene group. When reference is made in this description to a unit X ^, it also includes separate or interconnected units X *, when the context shows that this is possible. So, for example, if two units X ^ · are connected and when talking about X ^ -, then the [X ^ -] 2 unit or half of the [X ^] 2 unit is meant, if the context shows. that this is possible.

Suitable substituents in positions 1, 3, 4 or 5 of the pyrazole rings of 3-, 4- or 5- (mono) nitropyrazole molecules or in positions 3, 4 or 5 of the isothiazole rings of 4- or 5- ( mono) nitroisothia sole molecules or in positions 1, 2, 4 or 5 of the imidazole rings of 2-, 4- or 5- (mono) nitroimidazole molecules, represented by the symbol X ^, are those atoms or groups, known to the person skilled in the art to be unable to coordinate more strongly with the metal M1 than the nitrogen atom in position 2 of the pyrazole ring or the coordinating heteroatom of the isothiazole ring or the nitrogen atom in position 3 of the imidazole ring of a (mono nitrohetero cyclic molecule represented by X ^.

Preferred substituents are alkyl groups which may or may not be substituted by one or more atoms or groups such as hydroxyl, alkoxy, alkylsulfonyl, carboxyl, alkoxycarbonyl, carbamoyloxy, benzylcarbamoyl and N-morpholinyl groups and halogen atoms, Preferably chlorine atoms; phenyl groups substituted by one or more halogen atoms, preferably fluorine atoms; and alkylthio groups substituted by a phenoxy group, which phenoxy group is substituted by one or more carboxyl groups; alkyl and alkoxy groups and units can be straight or branched and preferably contain from 40 to 4 carbon atoms.

8302172 <* 4

When a substituent in a substituted heterocyclic molecule represented by the symbol X * contains a free hydroxyl group, the substituent may form monoesters with aliphatic dicarboxylic acids, wherein the aliphatic unit, for example the alkyl unit, is preferably 1 -6 carbon atoms, and pharmaceutically acceptable salts thereof, and when a substituent in the above substituted heterocyclic molecules contains a free hydroxyl group, the substituent may form phosphate, phosphite or sulfate esters and their salts, which contain pharmaceutically acceptable cations, e.g. alkali -10 metal salts, for example, potassium or sodium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium and amine salts with pharmaceutically acceptable amines; and when X 1 represents a heterocyclic ring containing a substituent containing a carbonoxyl group, pharmaceutically acceptable salts thereof can be formed. It will be understood that such esters and salts are part of the present invention.

By the term "pharmaceutically acceptable salts" used in this specification is meant salts, the cations of which are relatively harmless to the organism of humans and animals when used in therapeutic doses, so that the beneficial properties of the metal-containing complexes the general formula 1 cannot be negated by side effects attributable to such cations The salts are preferably water soluble Suitable salts include the alkali metal, for example sodium and potassium, alkaline earth metal, for example calcium and magnesium - and ammonium salts and pharmaceutically acceptable amine salts Amines suitable for forming such salts are known and include, for example, amines which are (theoretically) derived from ammonia by replacing one or more of the hydrogen atoms with groups equal or equal to 30. can be different when more than one hydrogen atom is replaced by a group such as, for example, alkyl groups with 1-6 carbon atoms and hydroxyalkyl groups with 2 or 3 carbon atoms.

When reference is made in this specification to compounds of the formula I, the pharmaceutically acceptable salts and esters thereof are also meant when this is apparent from the context.

Preferably 2- (mono) nitroimidazole molecules represented by the symbol X ^ contain a substituent in at least one of positions 1, 4 or 5 of the imidazole ring. 4- or 5- (mono) nitroimidazole molecules represented by the symbol X ^ preferably contain a substituent tuent in at least one of positions 1 or 2 of the imidazole ring or 8302172 • * 5 position 4 or 5 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 position 2 of the imidazole ring and may be unsubstituted or preferably substituted in position 1 of the imidazole ring.

Particularly suitable substituted 2-, 4- or 5- (mono Nitroimidazole molecules represented by the symbol X ^ are molecules such as metronidazole [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole, also below denoted by the abbreviation 'MNZ'], dime-10 tridazole [1,2-dimethyl-5-nitroimidazole], ipronidazole (1-methyl-2-isopropyl-5-nitroimidazole), tinidazole [1- (2-ethylsulfonylethyl) - 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-15-nitroimidazole], ronidazole [1-methyl-2-carbamoyloxymethyl-5-nitro-imidazole], secnidazole [ 1- (2-Hydroxy-n-propyl) -2-methyl-5-nitroimidazole], 1-methyl-5-nitroimidazole, 2- [2- (4-carboxyphenoxy) ethylthio] -1-methyl-5- nitroimidazole, bamnidazole [1- (2-carbamoyloxyethyl) -2-methyl-5-nitroimidazole], flunidazole [1- (2-hydroxyethyl) -2- (p-fluorophenyl) -5-20 nitroimidazole], 2- hydroxymethyl-1-methyl-5-nitroimidazole, 1-ethoxy-carbonyimethyl-2-methyl-5-nitroimidazole, 2-isopropyl-4 (or 5) -nitroimidazole, 2-hydroxymethyl-4 (or 5) -nitroimidazole, 1- (2-Hydroxyethyl) -2-methyl-4-nitroimidazole, 1,2-dimethyl-4-nitroimidazole, 1- (2-hydroxyethyl) -2-hydroxymethyl-5-nitroimidazole, misonidazole [1- (2 -hydroxy-3-25 methoxy-n-propyl) -2-nitroimidazole], benznidazole [N-benzyl-1- (2-nitroimidazolyl) acetamide], azomycin (2-nitroimidazole) and 4 (5) -nitroimidazole and when a substituent in position 1 or 2 of the above substituted nitroimidazole molecules contains a free hydroxyl group, monoesters thereof with aliphatic dicarboxylic acids, wherein the aliphatic unit, for example the alkyl unit, preferably contains 1-6 carbon atoms, and pharmaceutically acceptable salts thereof, and, when a substituent in position 1 or 2 of the above substituted nitroimidazole molecules contains a free hydroxyl group, its phosphate, phosphite or sulfate esters and pharmaceutically acceptable salts of such phosphate, phosphite and sulfate esters, for example, metonidazole hemisuccinate, metronidazole phosphate and metronidazole sulfate and salts thereof, which contain pharmaceutically acceptable cations, for example, alkali metal salts such as potassium or sodium salts, alkaline earth metal salts such as magnesium alkali metal salts such as ammonium salts and 40 amine salts with pharmaceutically acceptable amines, and when X ^ 8302172 is 6-1-carboxymethyl-2-methyl-5-nitroimidazole or 2- [2- (4-carboxyphenoxy) -ethylthio] -1-methyl-5-nitroimidazole represents pharmaceutically acceptable salts thereof.

The complexes of the formula I in which a palladium (II) or 5 represents a platinum (II) atom, all of which have a square, flat structure, may be in the trans or cis configuration.

A particularly preferred class of compounds of the formula I includes those compounds wherein X 1 represents metronidazole.

Another particularly preferred class of compounds of the formula I include those compounds wherein X * 1 represents methyl-4-nitropyrazole.

Another particularly preferred class of compounds. of the formula I includes those compounds wherein X * represents methyl nitroisothiazole.

Another particularly preferred class of compounds of the formula I include the compounds of the general formula:

Auni (X2) (Z4) 3 III

Wherein X2 represents an unsubstituted or substituted (mono) nitroimidazole molecule as defined above, for example, metronidazole, and Z4 represents a halogen atom.

Another particularly preferred class of compounds of the formula I include the compounds of the general formula: 25

PdII (X2) 2 (Z4) 2 IV

wherein X2 and Z4 have the above defined meanings.

Another particularly preferred class of compounds of the formula I include the compounds of the general formula:

[Rhm (X2) m (Z4) n] q + (Z3) 'V

wherein X2, Z3 and Z4 have the meanings defined above and m, n35 and q also have the meanings defined above, i.e. either m = 3, n = 3enq = 0 or m = s4, n = 2 and q = 1.

Another particularly preferred class of compounds of the formula I include the compounds of the general formula: 8302172 * 4 7

PtIV (X2) 2 (Z4) 2 (Z2) 2 VI

wherein X2, Z and Z4 have the above defined meaning.

Another particularly preferred class of compounds of the formula I include the compounds of the general formula:

Pti: i: (X3) 2 (Z4) 2 VII

10 wherein Z4 has the above defined meaning and X3 represents an unsubstituted or substituted (mono) nitropyrazole molecule, as defined above.

Another particularly preferred class of compounds of the formula I include the compounds of the general formula: 15

PtII (X4) 2 (Z4) 2 VIII

wherein Z4 has the above defined meaning and X4 represents an unsubstituted or substituted (mono) nitroisothiazole molecule, as defined above.

As individual important compounds of the formula I can be mentioned:

trichloro [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N3] gold (III); a

25 trichloro- (1,2-dimethyl-5-nitroimidazole-N3) -

gold (III); B

tribromo- [1- (2-hydroxyethyl) -2-methyl-5-nitro-

imidazole-N3) gold (III): C

dichloro-bis [1- (2-hydroxyethyl) -2-methyl-5-nitro-30 imidazole-N3] palladium (II); D

dichloro-bis (1,2-dimethyl-5-nitroimidazole-N3) -

palladium (II); E

dichloro-bis [1- (2-hydroxy-n-propyl) -2-methyl-5-nitroimidazole-N3] palladium (II); F

3 5 dichloro-bis [1- (2-hydroxy-3-methoxy-n-propyl) -2 -

nitroimidazole-N3] palladium (II); G

trichlorotris [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N3] rhodium (III); H

dichloro-tetrakis [1- (2-hydroxyethyl) -2-methyl-5-40 nitroimidazole-N3] rhodium (III) chloride; I

8302172 4 * 8 tetrachloro-bis [1- (2-hydroxyethyl) -2-methyl-5-

nitroimidazole-N3] platinum (IV); J

tetrachloro-bis (1,2 ~ dimethyl-5 ~ nitroimidazole-

N3) platinum (IV); K

5 tetrachloro-bis [1- (2-hydroxy-n-propyl) -2-methyl-

5-nitroimidazole-N3] platinum (IV); L

dichloro-dihydroxy-bis [1- (2-hydroxyethyl) -2-

methyl 5-nitroimidazole-N3] platinum (IV); M

dichloro-dihydroxy-bis (1,2-dimethyl-5-nitro-10 imidazole-N3) platinum (IV); N

dichloro-bis [1-methyl-4-nitroprazole-N2] platinum (II); 0 dichloro- [bis (4-nitropyrazol-1-yl) methane-

N2, N2 '] platinum (II); P

15 dichloro-bis [5-methyl-4-nitroisothiazole] -

platinum (II); Q

and dichloro-bis [3-methyl-5-nitroisothiazole] -

platinum (II). R

20 The letters A-R designate the compounds in the description below.

The compounds of the formula I can be used in the treatment of cancer, preferably in combination with X-ray therapy. X-ray irradiation is a widely used method for treating cancer of many kinds by destroying the neoplastic cells. However, a problem often encountered in the treatment of solid cancer, for example lymphomas, carcinomas and sarcomas, by X-ray therapy, is that a significant proportion of the cells in solid tumors are hypoxic and relatively insensitive to X-ray irradiation.

It has been found that the metal-containing complexes of the general formula I increase the sensitivity of hypoxic tumor cells to X-rays and can be administered in combination with solid cancer X-ray therapy to enhance the effectiveness of radiotherapy.

Furthermore, the compounds of the formula I, in particular the compounds of the formula I, in which X ^ represents a (mono) substituted (mono) nitroimidazole, which is as defined above, are effective against anaerobic bacteria and can therefore be used. in the treatment or prevention of diseases such as inflammatory diseases in 8302172 9 fences, teeth disease and gingivitis, and abscesses in the brain, and they are valuable in minimizing diseases after surgery, such as vaginal surgery and intestinal surgery .

The compounds of the formula I, wherein M 1 - represents a gold (III) atom, can also be used for the treatment of arthritic conditions.

The compounds of the formula I can be prepared by applying or adapting known methods.

According to an aspect of the present invention, compounds of the formula I, wherein M?, X ^, Z ^, Z2, Z ^, m, n, p and q have the above defined meaning, are prepared by conversion of a nitropyrazole, nitroisothiazole or [when M * represents a gold (III), palladium (II), rhodium (III) or platinum (IV) atom] a nitroindazole compound, corresponding to the symbol X · * ·, as defined above, with a salt of the general formula:

(Q1) sM1 (Z1) ttfs (Z1) t (Z2) p IX

Wherein Q ^ represents an alkali metal atom, for example a sodium or potassium atom, Μ1, Z1, Z2, n and p have the meanings defined above and s represents 0 when M · * · represents a rhodium (III) atom, s 1 means when M? Represents a gold (III) atom and s means 2 when M * - represents a palladium (II), platinum (IV) or platinum (II) - atom, and t means 0, or t 1 means when M? Represents a rhodium (III) atom and n means 2. The reaction can be carried out at a temperature of 5-100 ° C in water or an aqueous organic solvent, for example, aqueous ethanol or aqueous acetone.

When M2 represents a rhodium (III) atom, the conversion 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 can be prepared using or adapting known methods. Under some conditions it is possible to prepare the salt of formula IX in situ and this can be an advantage, especially when working on a large scale.

For example: 40 (i) Compounds of the general formula: 8302172 M * 10

(Q1) AuIII (Z1) 4X

wherein and Z ^ have the above defined meaning, can be prepared in situ by reacting the compounds of the general formulas XI and XII:

(Q1) (Z1) XI

10

AuIII (Z1) 3 XII

wherein Q1 and Z1 have the meanings defined above.

(ii) Compounds of the general formula: 15

(Q1) 2PdII (Z1) 4 XIII

wherein and Z1 have the above defined meaning, may be prepared in situ by reaction of the compounds of the general formula XI (as defined above) and XIV:

PdII (Z1) 2 XIV

where t) has the above defined meaning.

(Iii) Compounds of the general formula:

(Q1) 2FtIVCl6 XV

»(Which has the above defined meaning) can be prepared in solution by dissolving platinum metal in king water, evaporating off the excess king water and then carefully treating with a compound of the general formula:

(Q1) 0H XVI

Wherein Q * has the above defined meaning, preferably in aqueous solution.

(iv) Compounds of the general formula: 8302172 i »w 11

(QI) 2PtIIcl4 XVII

wherein Q * has the above defined meaning, can be prepared by treating a solution of a compound of formula XV (prepared as described above) with the appropriate amount of hydrazine *

According to a further aspect of the present invention, compound A is prepared by reacting metronidazole with an alkali metal chloroaurate, for example, sodium tetrachloroaurate (NaAuCl 3). The conversion is preferably in water or aqueous acetone at 5-100 ° C, at preferably carried out at 10-30 ° C.

According to a further aspect of the present invention, compound D is prepared by reacting metronidazole with an alkali metal chloropalladite, especially potassium chloropalladite.

The conversion is preferably carried out in water at 15-100 ° C, preferably at 20-60 ° C.

According to a further aspect of the present invention, compound H is prepared by reaction with metronidazole with a rhodium halide, especially rhodium trichloride (RICL3). The conversion is preferably carried out in water at 15-100 ° C, preferably at 70-90 ° C.

In a further aspect of the present invention, compound J is prepared by reacting with metronidazole with an alkali metal chloroplatinate, especially potassium chloroplatinate (PdClg) or sodium chloroplatinate (VdClg), in aqueous ethanol.

The conversion is preferably carried out in water at 15-100 ° C, preferably at 60-80 ° C.

According to a further aspect of the present invention, compound 0 is prepared by reacting N-methyl-4-nitropyrazole with an alkali metal chloroplatinite, especially potassium chloroplatinite (K 2 ftCl 2). The conversion is preferably carried out in water at 15-100 ° C, preferably at 40-60 ° C.

According to a further aspect of the present invention, compound Q is prepared by reacting 5-methyl-4-nitriisothiazole with an alkali metal chlorplatinite, especially potassium chlorplatinite (K.2 PtCl4). The conversion is preferably carried out in water at 15-100 ° C, preferably at 40-60 ° C.

In a further aspect of the present invention, certain compounds of the formula I can be prepared from other compounds of the formula I.

8302172 * 12

A compound of the general formula I, for example a compound of the general formula:

[M1 (X1) m (T1) nCZ2) p] if '(Z3) q XVIII

5 wherein M ^, X ^, Z2, Z3, m, n, p and q have the above defined meaning and Y ^ represents a halogen atom can be treated with a source of another ligand, for example another halogen ligand, where Y * · is replaced. Treatment with silver nitrate in an aqueous medium for treatment with the source of the other ligand is desirable in some cases.

According to a further aspect of the present invention, compounds of the formula I, wherein (7 ^) 2 represents a bidentate ligand of the formula II and Μ? ·, X *, Z2, Z3, m, η, p and q de bo - have 15 defined meanings (and, in the case of gold compounds, and rhodium compounds wherein n means 3, the third ligand τ) has the above defined meanings), prepared by treatment ♦ of a compound of the general formula XVIII, where M · * ·, X ^ ·, Y ^ ·, Z2, m, n, p, and q have the meanings defined above, where in the two ligands Y · * · (or, in the case of gold and rhodium compounds, where n means 3, two of these three ligands Y ^ -) are in the cis configuration, with an acid of the general formula:

(H00C) 2 (CR1R2) r XIX

Wherein R 1, R 2 and r are as defined above in an aqueous medium, followed by neutralization of the solution by addition of a suitable base such as an alkali metal carbonate, eg 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 under reduced pressure to give the required compound of the formula I. Before the compound is treated with the acid of the formula XIX, it can be treated with an aqueous medium of silver nitrate.

According to a further aspect of the present invention, compounds of the formula I, wherein a platinum (IV) atom, Z ^ represents a halogen atom, Z2 represents a halogen atom or a hydroxyl group and X, Z, m, n, p and q the above defined 40 have the meaning, prepared from platinum (II) -containing complexes with 8302172 »« ► 13 the general formula:

PtII (X1) 2 (Z1) 2 XX

5 wherein X 1 and t) - have the above defined meaning, by oxidation, preferably in an aqueous medium, by means of hydrogen peroxide when 2? represents a hydroxyl group or by means of a suitable halogen when Z2 represents a halogen atom, for example chlorine gas or bromine or a source thereof, for example potassium triiodide solution in water * Generally the conversion takes place between 0 and 100 ° C.

Compounds of the formula XX, wherein X ^ and Z ^ have the above-defined meaning, can be prepared by reacting a heterocyclic compound, corresponding to the symbol X * -, as defined above, with a platinum salt of the general formula:

(Q1) 2PtII (Z1) 4 XXI

Wherein Q * and have the meanings defined above, wherein the ligands represented by 7? - are different or preferably the same. The reaction can be carried out at a temperature of 15-100 ° G in water or an aqueous organic solvent, for example rater-containing ethanol.

Compounds of the formula XX, in which it has the above-defined meaning and X ^ represents an unsubstituted or substituted (mono) nitroimidazole molecule, are described in British patent application 2,093,451A and corresponding patent applications in other countries, for example US patent application 350,885 .

According to a further aspect of the present invention, compounds of the formula I, wherein a palladium (II) atom represents, X ^, t), Z2, 7, m, n, p and q have the above defined meaning , prepared by reacting a nitropyrazole, nitroiso-thiazole or nitroimidazole compound corresponding to the symbol 35 X} as defined above with a salt of the general formula:

(Q1) 2PdIV (Z1) 6 XXII

40 wherein Q1 and 7? - have the above-defined meaning, environment containing water 8302172 14, for example in water or an organic solvent containing water, for example water containing ethanol or water containing acetone, at a temperature of 5-100 ° C, at preferably 20-60 ° C.

Substituted heterocyclic compounds corresponding to the symbol X ^ and when a substituent in the above substituted heterocyclic compound contains a free hydroxyl group, monoesters thereof with aliphatic dicarboxylic acids, phosphate esters, phosphite esters and sulfate esters, may be prepared by using or adapting methods known per se for the preparation of the above-mentioned substituted heterocycles. A number are commercially available.

Pharmaceutically acceptable salts of the above monoesters, phosphate esters, phosphite esters and sulfate esters and pharmaceutically acceptable salts of the metal-containing complexes of the general # 15 formula I, wherein X ^ a heterocyclic compound having a substituent, which includes a carboxyl group, may be prepared by use or adaptation of methods known per se or by use of a suitable substituted heterocyclic compound corresponding to the symbol X * * as defined above, in the form of a pharmaceutically acceptable salt in the above-described conversions for the preparation or from a suitable metal-containing complex of the general formula I, obtained according to the above-described conversions for the preparation.

The following Examples I-XIII describe the preparation of compounds of the general formula I and in Examples XIV and XV the preparation of intermediates.

Example I Compounds A and B

Metronidazole (215 mg) was dissolved in acetone (15 ml) and the resulting solution was added at room temperature to a solution of sodium tetrachloroaurate dihydrate (500 mg) in water (15 ml). The acetone was evaporated at room temperature and the resulting precipitate was filtered off and washed with diethyl ether, adding trichloro [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N 2 -j gold (III) (560 mg), in the form gave yellow crystals, mp 168-173 ° C.

[Elemental analysis: calculated: C 15.19 H 1.91 N 8.86 Cl 22.41 wt%; found: C 15.0 H 1.82 N 8.8 Cl 22.2 wt%].

Similarly, in which the 40 metronidazole used as starting material was replaced with the appropriate amount of dimetrida-8302172 15 sole, was prepared: trichloro (1,2-dimethyl-5-nitroimidazole-1 ^) gold (III), melting point 158-171 ° C.

[Elemental analysis: calculated: C 13.51 H 1.59 N 9.46 Cl 23.93 wt. Z; found: C 13.6 H 1.41 N 9.3 Cl Z 3.7 wt; MR (in acetone-Dg): singlets at 3.00, 4.30 and 8.65 ppm]

Example II Compound C

Metronidazole (30 mg) was added to a solution of potassium tetrabromaurate (100 mg) in water (10 ml) at room temperature with stirring and the resulting mixture was stirred at room temperature for 1 hour. The crystals formed were filtered off, washed with diethyl ether (2 ml), adding tribromo [1- (2-hydroxyethyl) -2-raethyl-5-nitro-15 imidazole-N4) gold (III) (70 mg) in gave the form of red crystals, mp 149-150 ° C (with decomposition).

[Elemental analysis: calculated: C 11.86 H 1.49 S 6.91 wt;

found: C 11.8 H 1.29 N 6.8 wt

MR (in acetone-Dg): singlets at 2.95 and 8.65 ppm, triplets centered at 4.05 and 4.8 ppm].

Example III Compounds D, E and F

A solution of metronidazole (342 mg) in ethanol (30 ml) was added to a solution of potassium chloropalladite (326.4 mg) in water (20 ml). The ethanol was slowly evaporated over 16 hours and the precipitate formed was filtered and washed with diethyl ether, adding dichloro-bis [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N ^] palladium (II ); (510 mg) in the form of yellow crystals gave mp 244 ° C (with decomposition).

[Elemental analysis: calculated: C 27.74 H 3.49 N 16.17 Cl 13.65 wt. Z;

found: C 27.5 H 3.51 N 16.1 Cl 13.8 wt

MR (in acetone-Dg): singlets at 3.19 and 8.13 ppm, triplets centered at 3.95 and 4.65 ppm].

In a similar manner, however, the metronidazole used as starting material was replaced with the appropriate amounts of dime tridazole, respectively. secnidazole, were prepared: dichloro-bis (1,2-dimethyl-5-nitroimidazole-N 4) palladium (II), mp 40 293-294 ° C (with decomposition).

8302172 16 [Elemental analysis: calculated: C 26.13 H 3.07 N 18.29 Cl 15.43 wt%; found: C 26.4 H 3.22 N 17.9 Cl 14.9 wt%; and dichloro-bis [1- (2-hydroxy-n-propyl) -2-methyl-5-nitroimidazole-N 4] pal-5 ladium (II), melting point above 270 ° C (with decomposition).

[Elemental analysis: calculated: C 30.70 H 4.05 N 15.35 Cl 12.95 wt%; found: C 31.10 H 4.07 N 15.1 Cl 12.2 wt%].

Example IV 10 Compound G

Palladium dichloride (89 mg) was added to a solution of sodium chloride (120 mg) in water (20 ml) at room temperature with stirring and stirring was continued for 1 hour. Misonidazole (200 mg) and acetone (2 ml) were then added and stirring was continued at room temperature for 15 min. The resulting mixture was heated on a steam bath for 1 hour and then cooled in an ice bath. The crystals formed were filtered and washed with diethyl ether, adding dichloro-bis [1- (2-hydroxy-3-methoxy-n-propyl) -2-nitroimidazole-N] palladium (II); (220 mg) in the form of yellow crystals / 20 m.p. 193-195 ° C.

[Elemental analysis: calculated: C 29.01 H 3.83 N 14.50 Cl 12.23 wt%; found: C 28.6 H 3.70 N 14.2 Cl 12.3 wt% NMR (in acetone-Dg): singlets at 3.39 ppm, multiplet at 4.0-4.7 ppm and doublets at 7.35 and 7.55 ppm].

Example V Connection H

A solution of metronidazole (513 mg) in ethanol (1 ml) was added to a solution of rhodium (III) chloride trihydrate (281-30 mg) in water (5 ml) and the resulting solution was heated on a steam bath for 6 hours and then the solution was allowed to cool to room temperature. The precipitate formed was filtered off and washed with diethyl ether, adding trichlorotris [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N4] rhodium (IXI) (650 mg), melting point above 230 ° C ( with decomposition), in the form of light brown crystals.

[Elemental analysis: Bh (MHZ) 3 Cl3.2 ^ O: calculated: C 28.49 H 4.12 N 16.62 Cl 14.02 wt%; found: C 28.3 H 3.84 N 16.4 Cl 14.2 wt%].

Example VI 40 Compound I

8302172 17

Metronldazole (780 mg) was dissolved in water (10 ml) by heating on a steam bath. The solution was treated with rhodium (III) chloride-trihydrate (281 mg) and heating was continued for 1 hour until the solution turned orange. The solution was then treated with sodium hypophosphite (2 mg), after which the solution turned pale 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-N 2] rhodium (III) chloride (720 mg) as yellow crystals mp 198-201 ° C.

[Elemental analysis: [Rh (MNZ) 4 Cl 2] + Cl 2 H 2 O: calculated: C 31.00 H 4.34 N 18.07 Cl 11.44 wt%; found: C 30.6 H 3.75 N 17.7 Cl 11.7 wt%].

Example VII Compounds J, K and L.

Metronldazole (342 mg) was dissolved in water (50 ml) by heating on a steam bath. Potassium chloroplatinate (486 mg) was added to the solution and heating was continued for 16 hours, during which time a precipitate formed. The precipitate was filtered off and washed with diethyl ether to give tetrachlorobis [1- (2-20 hydroxyethyl) -2-methyl-5-nitroimidazole-N4] platinum (IV) (620 mg) as yellow crystals, mp 208-210 ° C (with decomposition).

[Elemental analysis: calculated: C 21.22 H 2.67 N 12.37 Cl 20.88 wt%; found: C 21.2 H 2.69 N 12.3 Cl 19.3 wt%]; NMR (in acetone-Dg): two singlets at 2.80 and 3.20 ppm. multiplets at 4.00, 450 and 8.40 ppm].

In a similar manner, however, the metronidazole used as starting material was replaced with the appropriate amounts of dimetridridole, respectively. secnidazole, were prepared: tetrachlorobis (1,2-dimethyl-5-nitroimidazole-N 4) platinum (IV), mp 252-253 ° C.

[Elemental analysis: calculated: C 19.4 H 2.28 N 13.57 wt%; found: C 19.3 H 2.28 N 13.1 wt%; NMR (in acetone-Dg): singlets at 2.6 and 4.1 ppm and a multiplet centered at 8.2 ppm]; and tetrachlorobis [1- (2-hydroxy-n-propyl) -2-methyl-5-nitroimidazole-N ^] platinum (IV), melting point: darkens at 260 ° C and melts at 310 ° C (with 40 decomposition).

--- - · * "8302172 18 [Elemental analysis: calculated for Pt (secnidazole) 2 CI4.2H2O: C 22.6 H 3.53 N 11.31 wt%; found: C 22.7 H 3.52 N 11.2 wt%.

NMR (in acetone-Dg): doublet centered at 1.3 ppm, singlet centered at 3.2 ppm, multiplet centered at 4.5 and 8.4 ppm].

Example VIII Compound M

Cis-dichloro-bis [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N ^] - platinum (II) (700 mg) was suspended in water (20 ml), heated on a steam bath and treated with aqueous hydrogen peroxide solution (8 ml, 100 vol), and heating was continued for 6 hours. The mixture was kept at room temperature for two days and the precipitate formed was filtered and washed with diethyl ether, adding dichloro-dihydroxy-bis [1- (2-hydroxyethyl) -2-methyl-5-nitro-imidazole-15 N ^] platinum (IV) (350 mg) in the form of pale yellow crystals, mp 209-213 ° C (with decomposition).

[Elemental analysis: Pt (MNZ) 2 Cl 2 (0H) 2 2% O: calculated: C 21.37 H 3.59 N 12.46 wt%; found: C 21.6 H 3.05 N 12.5% wt%; MR (in acetone-Dg): singlet at 3.05 ppm, multiplets centered at 3.90, 4.70 and 8.4 ppm].

Example IX Compounds M and N

Cis-dichloro-bis [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N ^] - 25 platinum (II) (500 mg) was suspended in aqueous hydrogen peroxide solution (30 ml, 20 vol .%) and the mixture was heated on a steam bath with stirring for 5 hours. The pH of the clear, pale yellow solution obtained was adjusted to 7 by adding aqueous sodium hydroxide solution (2N). The solution was then treated dropwise with an aqueous solution of the enzyme catalase (1 wt%) until no unconverted hydrogen peroxide remained. The solution was ultrafiltrated to remove the enzyme and the filtrate was lyophilized, adding dichloro-dihydroxy-bis [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N] platinum (IV). a hydrated form (350 mg) which decomposed at a temperature of about 170 ° C. [Elemental analysis: C 21.08 H 3.14 N 12.06 Cl 10.12% 0 9.2% by weight; Ρί (ΜΝΖ) 2012 (0Η) 2 · 3.5H 2 O calculated: C 20.41 H 3.84 N 11.91 Cl 10.06% 0 8.9 wt%].

40 Similarly, wherein the starting material, however, was replaced with the appropriate amount of cis-dichloro-bis [1- (1,2-dimethyl-5-nitro-imidazole-N]] platinum (II). ), dichloro-dihydroxy-bis- (1,2-dimethyl-5-nitroimidazole-N 2) platinum (IV) was prepared.

Example X 5 Compounds 0 and P

A suspension of 1-methyl-4-nitropyrazole (381 mg) in water (30 ml) was stirred under gentle heating at 50 ° C and treated with potassium chloroplatinite (621 mg) and stirring with gentle heating for 1 hour continued. The color of the solution changed from 10 cloudy reddish-orange to bright yellow and a precipitate formed. The mixture was cooled and the solid filtered and washed with diethyl ether to give dichlorobis [1-methyl-4-nitropyrazole-N-platinum (II) (670 mg) as yellow crystals.

[Elemental analysis: calculated: G 18.47 H 1.91 N 16.16 Cl 13.63 wt%; found: C 18.2 & 1.81 N 16.0 Cl 13.7 wt%].

In a similar manner, however, where the 1-methyl-4-nitropyrazole used as starting material was replaced by the appropriate amount of bis (4-nitropyrazol-1-yl) methane, 20 dichloro [bis (4-nitropyrazole-1-) was prepared. yl) methane-N 2, N 2 '] platinum (II), mp 310 ° C (with decomposition).

[Elemental analysis: calculated: C 16.68 H 1.20 N 16.67 Cl 14.06 wt%; found: C 16.8 H 1.12 N 16.7 Cl 13.5 wt%].

Example XI Connection Q

An aqueous suspension of 5-methyl-4-nitriisothiazole (375 mg) was stirred under gentle heating (50 ° C) and treated with potassium chloroplatinite (540 mg) and stirred with gentle heating for 1 hour continued. The color of the solution changed from cloudy reddish-orange to bright yellow and a precipitate was formed, which was filtered off from the cooled mixture and washed with diethyl ether, giving dichloro-bis [5-methyl-4-microisothiazole] platinum ( II) (700 mg), in the form of yellow crystals, gave a melting point higher than 360 ° C (darkens at a temperature higher than 260 ° C).

[Elemental analysis: calculated: C 17.33 H 1.45 N 10.11 Cl 12.79 S 11.57 wt%; found: C 17.0 H 1.33 N 9.8 Cl 13.1 S 11.4 wt%].

Example XII 40 Compound R

8302172 20

A solution of potassium chlorplatinite (621 mg) in water (30 ml) was heated with gentle heating (60 ° C) and treated with a solution of 3-methyl-5-nitroisothiazole (432 mg) in acetone (15 ml) and stirring the process was continued for an hour under gentle heating. The resulting mixture was heated on a steam bath for 8 hours and then cooled. The precipitate formed was filtered and washed with diethyl ether to give dichloro-bis [3-methyl-5-nitroisothiazole] platinum (II) (530 mg) as yellow crystals. [Elemental analysis: calculated: C 17.33 H 1.45 N 10.11 Cl 12.79 S 11.57 wt; found: C 17.4 H 1.36 N 10.0 Cl 12.6 S 11.5 wt. Z].

Example XIII Compound D

A solution of metronidazole (100 mg) in water (20 ml) was treated with potassium chloropalladate (PdClg) (100 mg), and the mixture was allowed to stand at room temperature for 24 hours. The yellow precipitate formed was filtered off and washed with diethyl ether to give dichloro-bis [1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole-N 2] palladium (II) (120 mg), melting point 244 ° C (with decomposition).

[Elemental analysis: calculated: C 27.74 H 3.49 N 16.17 wt. Z; found: C 27.2 H 3.41 N 15.9 wt. Z].

Example XIV

Metronidazole (6.85 g) was suspended in water (300 ml) and stirred under gentle heating (50 ° C). Potassium chlorplatinite (8.3 g) was added and stirring with gentle heating was continued for one hour. The color of the solution changed from cloudy reddish-orange to bright yellow and a precipitate formed. After cooling, the supernatant was decanted and concentrated in a rotary evaporator to give an additional amount of precipitate. The precipitates were combined, first washed with a mixture of ethanol and diethyl ether and then diethyl ether and air dried to give cis-dichloro-bis [1- (2-hydroxyethyl) -2-methyl-5-nitro-imidazole. N4] - platinum (II) (12.16 g) in the form of yellow crystals, m.p. 178-181 ° C, followed by resolidification and melting (with decomposition) at 257-259 ° C.

Example XV

Dimetridazole (0.282 g) was suspended in water (20 ml) and stirred under gentle heating (50 ° C). Potassium chlorplatinite (0.415 g) 40 was added and stirring under gentle heating was continued for 8 hours 21 hours. After cooling, the supernatant was decanted from the precipitate formed. The supernatant was concentrated in a rotatable evaporator, with additional solids precipitating. The precipitates were combined, washed with a mixture of ethanol and diethyl ether and then with diethyl ether, then air dried to give dichloro-bis (1,2-dimethyl-5-nitroimL-dazole-N4)-platinum ( II) (0.456 g), m.p. 174-176 ° C.

[Elemental analysis: calculated: C 21.89 H 2.55 N 15.32 Cl 12.95% w; 10 found: C 21.46 H 2.74 N 14.74 Cl 13.20 wt. Z].

The invention also relates to pharmaceutical compositions comprising at least a compound of the general formula I or a salt thereof in combination with a pharmaceutically acceptable carrier or coating. In medicine, the compounds of the invention can be administered orally, rectally, vaginally or parenterally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. For such solid compositions, one or more of the active ingredients is mixed with at least one inert diluent such as starch, sucrose or lactose. The compositions may also contain, as is usual, additional substances different from inert diluents, for example lubricants, such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing the usual inert diluents such as water and liquid paraffin. In addition to inert diluents, such compositions may contain additives such as wetting and suspending agents and sweeteners, flavors, fragrances, and preservatives. The compositions of 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 diluents and / or excipients.

Solid compositions for rectal or vaginal administration include suppositories and vaginal suppositories, which are formulated in a manner known per se.

Compositions of the invention for parenteral administration include sterile water and / or organic solvent containing solutions, suspensions and emulsions. Examples of organic solvents or suspending agents are propylene glycol or polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain additives such as stabilizing, preserving, wetting, emulsifying and dispersing agents. For example, they can be sterilized by filtration through a bacteria retaining filter, by incorporating sterilizers into the compositions, or by irradiation or by heating. They can also be produced in the form of sterile solid compositions, which can be dissolved in sterile water or other sterile injectable medium immediately before use.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary to contain such amount that an appropriate dosage is obtained. Of course, various unit dosage forms can be administered at about the same time. The dose used will be determined by the physician and depends on the desired therapeutic effect, the route of administration and the duration of the treatment and the condition of the patient. When administered in combination with X-ray therapy to combat cancer or to enhance the effectiveness of radiation therapy, a compound of general formula I will generally treat the cancer (usually up to 5 hours before the start of irradiation) in doses of 0.1-500, preferably 1-200 mg / kg body weight. In X-ray therapy to combat cancer, it is common to repeat the irradiation a number of times during a treatment period, for example, 15-20 repetitions in a 3-4 week period, and a compound of the general formula 1 can be used in combination with any repeat irradiation at the above doses. When administered to control anaerobic bacteria or arthritic conditions, the dose is generally between 0.1 and 500, especially between 1 and 200 mg / kg body weight, and this dose may be as prescribed medical doctor be repeated intermittently.

8302172

Claims (5)

5 * Metal-containing complexes of heterocyclic compounds, characterized in that they correspond to the general formula: [M1 (X1) mCZ1) n (Z2) p], 1 + (Z3) q (I) in which M ^ a gold (III) - , palladium (II), rhodium (III), platinum (IV) or platinum (II) atom, X ^ represents a 3-, 4- or 5-mononitropyrazole-10 molecule (which may be unsubstituted or preferably contains at least one substituent, and which can coordinate via the position 2 of the pyrazole ring with the metal M? -) or a 4- or 5-mononitroisothiazole molecule (which may be unsubstituted or preferably at least one substituent contains, which can coordinate with the metal 15 M?) or, when M * represents a gold (III), palladium (II), rhodium (III) or platinum (IV) atom, X ^ · also may represent a 2-, 4- or 5-mononitroimida sole molecule (which may be unsubstituted or preferably contains at least one substituent, and which may coordinate with the metal M * - via position 3 of the imidazole ring), the bo -20 venge said nitropyrazole, nitroisothiazole or nitroimidazole molecules may optionally be linked when more than one residue X * is present in the compound of the general formula (I), each representing a pharmaceutically acceptable ligand, (Γ3Γ a pharmaceutically acceptable anion represents m the integer 2 or m when M * represents a gold (III) atom m represents the integer 1 or when M1 represents a rhodium (III) atom m represents the integer 3 or 4 n means the integer 2 or, when a gold (III) atom represents n the integer 3 or, when a rhodium (III) atom represents, n the whole 30 represents 3 when m means the integer 3 or n means the integer 2 when m means the integer 4, p means the integer 0 or, when a platinum (IV) atom represents p means the integer 2, q means the integer 0 or, when M1 represents a rhodium (III) represents atom and m is the integer 4 bet and n 35 means the integer 2, q means the integer 1. Complex according to claim 1, characterized in that it corresponds to the general formula (I), whose substituents in positions 1, 3, 4 or 5 of the pyrazole rings of the 5-mononitropyrazole molecules or in positions 3, 4 or 5 of the isothiazole rings of the 4 or 40 5-mononitroisothiazole molecules, or in positions 1, 2, 4 or 5 of the 8302172 V *. -v / imidazole rings of the 2-, 4- or 5-mononitroimidazole molecules represented by the symbol X * represent alkyl radicals which may or may not be substituted by one or more atoms or groups such as hydroxyl, alkoxy, alkylsulfonyl , carboxyl, alkoxycarbonyl, carbamoyloxy, benzylcarbamoyl and N-morpholinyl groups and halogen atoms, phenyl groups, which are substituted by one or more halogen atoms and alkylthio groups, which are substituted by a phenoxy group, which is phenoxy group substituted by a carboxyl group, and when a substituent in a substituted heterocyclic molecule represented by the symbol X ^ represents a free carboxyl group, its monoesters with aliphatic dicarboxylic acids and their pharmaceutically acceptable salts, and when a substituent in the substituted heterocyclic molecules contains a free hydroxyl group, its phosphate, phosphite or sulfate esters, the salts of which thereof form pharmaceutically barable cations, and when X 1 represents a heterocyclic ring substituent containing a carboxyl group, its pharmaceutically acceptable salts. Complex according to claim 1 or 2, characterized in that it corresponds to the general formula: Aum (X2) (Z4) 3 (III) 7 wherein X represents an unsubstituted or substituted mononitroimidazole molecule, as defined in claim 1, and Z4 represents a halo-25 atom. Complex according to claim 1 or 2, characterized in that it corresponds to the general formula: PdI] :( X2) 2 (Z4) 2 (IV) wherein X2 and Z4 have the meanings defined in claim 3. Complex according to claim 1 or 2, characterized in that it corresponds to the general formula: [RhIII (X2) m (Z4) n] 1 + (Z3) q (V) wherein X2 and Z4 have the meaning defined in claim 3 Z3 has the meaning defined in claim 1 and m, n and q have the meaning defined in claim 1, ie either m = 3, n = 3 and 40 q = 0 or m = 4, n = 2 and q = 1. 8302172 Complex according to claim 1 or 2, characterized in that it corresponds to the general formula: PtIV (X2) 2 (Z4) 2 (Z2) 2 (VI) 5 in which X2 and Z4 have the meanings defined in claim 3 and OZ the in claim 1 has defined meaning. Complex according to claim 1 or 2, characterized in that it corresponds to the general formula: PtII (X3) 2 (Z4) 2 (VII) wherein Z4 has the meaning defined in claim 3 and X3 represents a substituted or unsubstituted mononitropyrazole molecule, as defined in claim 1. Complex according to claim 1 or 2, characterized in that it corresponds to the general formula: PtII (X4) 2 (Z4) 2 (VIII) 20 in which Z4 has the meaning defined in claim 3 and X4 represents a substituted or unsubstituted mononitroisothiazole molecule, as defined in claim 1. Process for the preparation of a complex according to Claims 25 to 8, characterized in that a nitropyrazole, nitroisothiazole compound, or when M ^ is a gold (III), palladium (II), rhodium ( III) or platinum (IV) atom, a nitroimidazole compound corresponding to the symbol X ^ as defined in claim I, reacts with a salt of the general formula: 30 (Q1) sH1 (Z1) ttfs (Z1) t (Z2) p (IX) in which an alkali metal atom, Z2, n and p have the meaning defined in claim 1 and s represents the number 0 when M * represents a rhodium (III) atom, s the integer 1 means when a gold (III) represents atom and s means the integer 2 when M? Represents a palladium (II), platinum (IV) or platinum (II) atom, and t represents the number 0, or t the integer 1 means when M * represents a rhodium (III) atom and n represents the integer 2 -40. 8302172 -9 * < Process for the preparation of a complex according to claim 1, characterized in that a complex having the general formula: [Μ1 (Χ1) Λ (Τ1) η (Ζ2) ρ] ϊί · (Z3) q (XVIII) 5 wherein Μ *, X *, Z2, Z3, m, n, p and q have the meaning defined in claim 1 and Y * represents a halogen atom, treated with a source of another ligand, replacing Y1, optionally after treatment with silver nitrate in aqueous medium. 11. Process for the preparation of a complex of the general formula (I), wherein (Z *) 2 is a bidentate ligand of the general formula: 0 II 15 ---- 0-C ^ (CR1R2) r (II) - --- 0-C ^ ft 0 20, and M? ·, X ^, Z2, Z3, m, η, p and q have the meaning defined in claim 1 and, in the case of gold compounds and in the case of rhodium compounds, in which n represents the integer 3, the third ligand Z * has the meaning defined in claim 1, characterized in that a compound of the general formula XVIII according to general formula XVIII is optionally added, after treatment with silver nitrate in an aqueous medium. claim 10, wherein M?, X ^, Z2, m, n, p and q have the meaning defined in claim 1 and Y · has the meaning defined in claim 10, wherein the two ligands Y1 (or, in in the case of gold and rhodium compounds, where n is the integer 3, two of these three ligands Y ^) are in the cis configuration, treated with an acid with the general formula: (HOOC ^ iCR ^ -R2) ,. (XIX) 35 wherein R * and R2, which are the same or different, each represent a hydrogen atom or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group or CR ^ R2 represents a cycloalkyl or cycloalkenyl group and r represents the number 0 or 1 in an aqueous medium, followed by neutralization of the solution by addition of a suitable base. 8302172 12. Process for the preparation of a complex of the general formula (X), in which M represents a platinum (IV) atom, represents a halogen atom, Z represents a halogen atom or a hydroxyl group and X, Z , m, n, p and q have the meanings defined in claim 1, characterized in that a platinum (II) complex of the general formula: PtII (X1) 2 (Z1) 2 (XX) 10 is used in which X ^ and Z * have the meaning as defined in claim 1, oxidize with hydrogen peroxide when 7? Represents a hydroxyl group or with the aid of a suitable halogen when Z ^ represents a halogen atom. 13. A process for the preparation of a complex of the general formula (I), wherein a palladium (II) represents atom and X ^} Z ^} Z ^, Z ^, m, n, p and q de in claim 1 have a defined meaning, characterized in that a nitropyrazole, nitroisothiazole or nitroimidazole compound corresponding to the symbol X ^ as defined in claim 1 is reacted with a salt of the general formula: 20 (Q1) 2PdIV ( Z1) 6 (XXII) wherein Q ^ has the meaning defined in claim 9, and Z * has the meaning defined in claim 1. A process for the preparation of pharmaceutically acceptable salts of monoesters of aliphatic dicarboxylic acids, phosphate esters, phosphite esters and sulfate esters of complexes according to claim 1, wherein the heterocyclic molecule represented by the symbol X ^ contains a substituent containing a free hydroxyl group, and the pharmaceutically acceptable salts of the complexes, wherein the heterocyclic compounds represented by the symbol X ^ contain a substituent containing a carboxyl group, characterized in that a heterocyclic compound is in the form of a pharmaceutically acceptable salt used in a process according to claims 9-13 and converting in a known manner a complex of the general formula (I) into a pharmaceutically acceptable salt. Pharmaceutical composition, characterized in that it comprises a complex of the general formula (I) or one of its pharmaceutically acceptable salts in combination with an additive or a pharmaceutically acceptable coating. 8302172 * ~ Λί7- ® · ν · ά I £. AUG 10, 1983 Improvement of errata in the specification associated with patent application No. 83,1272 proposed by the applicant, dated 9 August 1983 2 Page. 7 »line 4" Z "change to" Z "page 11, line 20" (RhCI ^) "change to" (RhC13) "page 11, line 34 and page 19 line 27" nitriisothiazole "change to" nitroisothiazole ” 5 p. 16, line 24 »3.39” change to “3.3” Page. 20, line 15 Change "(KjPdOlg)" to "(EgPa 7Clg)” 8302172