BE892245A - PLATINUM NITROIMIDAZOLIC COMPLEXES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

       

  Platinum nitroimidazole complexes, process for their preparation and pharmaceutical compositions containing them.

  
The present invention relates to new complexes,

  
 <EMI ID = 1.1>

  
dice for their preparation and pharmaceutical compositions containing them.

  
The present invention resides in complexes containing

  
 <EMI ID = 2.1>

  

 <EMI ID = 3.1>


  
in which X represents a molecule of (mono) nitro-2, or preferably

  
 <EMI ID = 4.1>

  
rence, carries at least one substituent, and which can be coordinated to platinum by position 3 of the heterocyclic ring, that is to say

  
 <EMI ID = 5.1>

  
known to specialists for not being able to coordinate with platinum more strongly than the nitrogen atom at position 3 of the imidazole ring of a molecule of (mono) nltro-2, -4 or -5 imidazole represented by the symbol X, complexes which have interesting properties which can be used in the treatment of cancer and to combat anaerobic bacterial infections.

  
By the term "pharmaceutically acceptable ligand", as

  
 <EMI ID = 6.1>

  
means a ligand which, when separated from the compound of formula (I), forms only substances which are relatively harmless to the animal organism when the compound is used in therapeutic doses, so that the beneficial pharmacological properties of

  
 <EMI ID = 7.1>

  
more particularly chlorine, or else (Z <1>) 2 represents a bidentate ligand of general formula:

  

 <EMI ID = 8.1>


  
in which R and R, which may be identical or different, each represents a hydrogen atom or an alkyl or aryl group,

  
 <EMI ID = 9.1>

  
represents a cycloalkyl or cycloalkenyl group. The dotted lines indicate the attachment to the platinum atom in the general formula (I).

  
When (Z <1>) 2 represents two single-tooth ligands, they can be different but are preferably the same.

  
 <EMI ID = 10.1>

  
alkyl groups and radicals and alkenyl groups preferably contain up to 6 carbon atoms, the aryl groups and radicals are preferably phenyl, and the cycloalkyl and cycloalkenyl groups preferably contain from 3 to 8 carbon atoms.

  
The molecules of (mono) nitro-2 imidazoles represented by the symbol X preferably have a substituent in at least one of the positions

  
 <EMI ID = 11.1>

  
imidazoles represented by the symbol X preferably have a substituent on at least one of positions 1 or 2 of the imidazolic ring or on position 4 or 5 of the imidazolic ring which is not occupied by the

  
 <EMI ID = 12.1>

  
by the symbol X are preferably substituted on position 2 of the imidazolic ring and can be unsubstituted or, if preferred, substituted on position 1 of the imidazolic ring. Suitable substituents in positions 1, 2 and 4 or 5 of the imidazo ring

  
 <EMI ID = 13.1>

  
the symbol X are atoms or groups which are known to specialists to be unable to coordinate with stronger platinum-

  
 <EMI ID = 14.1> <EMI ID = 15.1>

  
the symbol X. Consequently, substituents containing atoms or groups, for example the mercapto group, which are well known to coordinate very strongly with platinum, should be avoided.

  
The substituents which are preferred are the alkyl groups which are unsubstituted or substituted by one or more atoms or groups chosen from hydroxy, alkoxy, alkylsulphonyl, carboxy,

  
 <EMI ID = 16.1>

  
and halogen atoms, preferably chlorine; phenyl groups substituted by halogen atoms, preferably fluorine; and alkylthio groups substituted by a phenoxy group, which is substituted by carboxy; alkyl and alkoxy groups and residues

  
 <EMI ID = 17.1>

  
of carbon.

  
When a substituent group in a substituted nitroimidazole molecule represented by the symbol X contains a free hydroxy group, the substituent can form monoesters with aliphatic dicarboxylic acids in which the aliphatic residue, i.e. alkyl, contains 1 containing 6 carbon atoms, and with the pharmaceutically acceptable salts thereof and, when a substituent group in the abovementioned molecules of nitroimidazole contains

  
a free hydroxy group, the substituent can form phosphoric, phosphorous or sulfuric esters and their salts containing

  
 <EMI ID = 18.1>

  
alkalis such as potassium or sodium, alkaline earth metals such as calcium or magnesium, ammonium salts and amine salts with pharmaceutically acceptable amines; when X represents a nitroimidazole carrying a substituent which contains a carboxy group, its pharmaceutically acceptable salts can be formed. It should be understood that such esters and salts constitute a characteristic of the invention.

  
The molecules of (mono) nitro-2, -4 or -5 substituted imidazole represented by the symbol X which are particularly suitable are molecules chosen from the group consisting of metronidazole [(2-hydroxyethyl) -1 2-methyl-nitro- 5 imidazole, also designated in

  
 <EMI ID = 19.1>

  
nitro-5 imidazole), ipronidazole (1-methyl-2-isopropyl-5 nitro-imidazole), tinidazole [(2-ethylsulfonyl ethyl) -i methyl-2 nitro-5

  
 <EMI ID = 20.1>

  
in the abovementioned molecules of substituted nitroimidazole contains a free hydroxy group, their monoesters with aliphatic dicarboxylic acids in which the aliphatic residue, that is to say alkyl, preferably contains from 1 to 6 carbon atoms, and with the salts pharmaceutically acceptable thereof, and, when

  
 <EMI ID = 21.1>

  
substituted contains a free hydroxy group, their phosphoric, phosphorous and sulfuric esters and the pharmaceutically acceptable eels of these phosphoric, phosphorous and sulfuric esters, for example metronidazole hemisuccinate, metronidazole phosphate and sulfate and their salts containing pharmaceutically cations acceptable, for example alkali metal salts, such as potassium or sodium, alkaline earth metal salts, such as calcium or magnesium, ammonium salts and amine salts with pharmaceutically acceptable amines , and, when X represents carboxymethyl-1 methyl-2 nitro-5 imidazole or [(4-carboxyphenoxy) -2 ethylthio] -2 methyl-1 nitro-5 imidazole, their pharmaceutically acceptable salts.

  
 <EMI ID = 22.1>

  
used in this text, we mean salts whose cations are relatively harmless to the animal organism when used in therapeutic doses, so that the beneficial pharmacological properties of complexes containing platinum (II) of formula

  
 <EMI ID = 23.1>

  
attributable to these cations. Preferably these salts are soluble in water. Suitable salts include alkali metal salts, such as sodium and potassium, alkaline earth metals, such as calcium and magnesium, ammonium salts and pharmaceutically acceptable amine salts. the amines which are suitable for forming such salts are well known and include, for example, amines deriving in theory from the replacement of one or more of the hydrogen atoms of ammonia by groups, which can be identical or different when more than one hydrogen atom is replaced, chosen, for example, from alkyl groups containing from 1 to 6 carbon atoms and hydroxyalkyl groups containing 2 or 3 carbon atoms.

  
In the present text, when reference is made to the compounds of

  
 <EMI ID = 24.1>

  
are all of square planar structure, can be in cis or trans configuration, but it should be noted that the geometry requires that the compounds

  
 <EMI ID = 25.1>

  
especially a ligand of formula (II), are in the cis configuration.

  
A class of compounds of formula (I) which is particularly preferred comprises the compounds in which X represents the

  
 <EMI ID = 26.1>

  

 <EMI ID = 27.1>


  
 <EMI ID = 28.1>

  
"Compound A".

  
Among the other important individual compounds of formula
(I), we can cite:

  
 <EMI ID = 29.1>

  
 <EMI ID = 30.1>

  
platinum (II).

  
The compounds A to DD have been assigned to the compounds for easy reference in the remainder of this text, for example in Table I.

  
X-ray irradiation is a widely used method for the treatment of many cancers, by the destruction of neoplastic cells. However, a problem that we are often

  
 <EMI ID = 31.1>

  
lymphomas, carcinomas and sarcomas, through therapy

  
X-rays, is that a substantial proportion of solid tumor cells are hypoxic and relatively insensitive to X-ray irradiation.

  
It has now been found that complexes containing platinum (II) of general formula CI) increase the sensitivity to

  
 <EMI ID = 32.1>

  
administered in conjunction with solid cancer x-ray therapy to increase the effectiveness of radiation therapy.

  
For example, compound A (the compound of formula III), in the tests, generates a strengthening ratio of 2.4 when it is given as pretreatment to hypoxic cells irradiated with X-rays in vitro, at a concentration of 50 micromoles, nontoxic.

  
In addition, the compounds are active against anaerobic bacteria and, therefore, are useful in the treatment or prevention of conditions such as pelvic inflammation, toothache and gingivitis and brain abscesses, and are of interest. to minimize disorders following operations such as vaginal or intestinal surgery.

  
The minimum inhibiting concentrations of the compounds of formula (I), expressed in micrograms per milliliter, against various

  
 <EMI ID = 33.1>

  
 <EMI ID = 34.1>

  

 <EMI ID = 35.1>


  

 <EMI ID = 36.1>
 

  
The value of the compounds of formula CI) is reinforced by their remarkably low toxicity with regard to mammals. For example,

  
 <EMI ID = 37.1>

  
body weight of the animal when administered intraperitoneally and greater than 2000 mg per kg of body weight when administered orally.

  
 <EMI ID = 38.1>

  
application or adaptation of known methods.

  
According to a characteristic of the present invention, the

  
 <EMI ID = 39.1>

  
corresponding to the symbol X, as defined above, with a platinum salt of general formula:

  

 <EMI ID = 40.1>


  
in which Q represents an alkali metal atom, for example sodium or potassium, and Z <1> is as defined above, the

  
 <EMI ID = 41.1>

  
identical. The reaction can be carried out in water or in an aqueous organic solvent, for example aqueous ethanol, at a temperature of 15 to 100 [deg.] C.

  
 <EMI ID = 42.1>

  
According to a characteristic of the present invention, certain compounds of formula (I) can be prepared from other compounds

  
 <EMI ID = 43.1>

  
For example, a compound, encompassed by the general formula (I), of general formula:

  

 <EMI ID = 44.1>
 

  
(in which X is as defined above and Y is an atom

  
 <EMI ID = 45.1>

  
what is followed by treatment with a source from another ligand to replace Y.

  
Thus, according to a characteristic of the present invention,

  
 <EMI ID = 46.1>

  
silver nitrate in an aqueous medium, which is followed by treatment with a source of chloride ions, for example an alkali metal chloride, such as potassium chloride.

  
According to another characteristic of the present invention,

  
 <EMI ID = 47.1>

  
be prepared by reacting a compound of general formula (V) in the cis configuration (in which X is as defined above and Y is a bromine, iodine or, preferably, chlorine atom) with nitrate of silver in an aqueous medium, then treatment with an acid of general formula:

  

 <EMI ID = 48.1>


  
 <EMI ID = 49.1>

  
neutralization of the solution by addition of a suitable base, such as an alkali metal carbonate such as sodium carbonate. The solution is treated with an organic solvent miscible with water, such as acetone, filtered to remove the precipitated mineral by-products and the filtrate is evaporated in vacuo to obtain the compound of

  
 <EMI ID = 50.1>

  
symbol X, including when a substituent group in the substituted nitroimidazollque compound in question contains a hydroxy group

  
 <EMI ID = 51.1>

  
their phosphoric, phosphorous and sulfuric esters can be prepared by application or adaptation of methods known per se

  
 <EMI ID = 52.1>

  
are marketed products.

  
The pharmaceutically acceptable salts of the aforementioned monoesters, phosphoric, phosphorous and tallow esters, and the pharmaceutically acceptable salts of the complexes containing platinum (II) of general formula (I) in which X represents a nitroimidazole bearing a substituent which contains a carboxy group, for example 1-carboxymethyl-2-methyl 5-nitro Imidazole, can be prepared by application or adaptation of methods known in

  
 <EMI ID = 53.1>

  
required corresponding to the symbol X, as defined above, in the form of a pharmaceutically acceptable salt in the preparation reactions described above, either from an appropriate complex containing platinum (II), of general formula (I) , obtained by the preparation reactions described above.

  
By the expression "methods known per se" as used in the present text, is meant methods previously used or described in the literature.

  
The following examples illustrate the preparation of

  
 <EMI ID = 54.1>

  
In their text, "NMR" and "UV" mean respectively "nuclear magnetic resonance spectrum" and "ultraviolet absorption spectrum". Often only the most important characteristics of these spectra are given.

  
Polarography is carried out using a mercury drop electrode. The potentials are measured by reference to a silver / silver chloride electrode, using a differential polarograph. Approximately 100 µM samples are prepared in phosphate buffer (pH 7.0). We record the potentials of

  
peaks (Ep).

  
EXAMPLE 1

  
Compound A

  
 <EMI ID = 55.1>

  
so. After cooling, the supernatant liquid is separated by decantation and its volume is reduced in a rotary evaporator to

  
 <EMI ID = 56.1>

  
91.3%) in the form of Yellow crystals having the following characteristics:
a) Elementary analysis:
 <EMI ID = 57.1>
 b) NMR in acetone-D &#65533; : singlet at 3.01 ppm, two centered triplets <EMI ID = 58.1> d) Polarography: Ep = -0.27 V. e) Melting point 178-181 [deg.] C, fusion followed by resolidification and from a merger (with decomposition) at 257-259 * C.

  
 <EMI ID = 59.1>

  
described above, leaving a saturated solution in a mixture of water and acetone to evaporate at room temperature, which gives yellow crystals, the elementary analysis of which is as follows:

  

 <EMI ID = 60.1>


  
The molecular structure, encompassing the cis configuration,

  
 <EMI ID = 61.1>

EXEMPT 2

  
Compound B

  
4 g of potassium iodide are added to a solution of

  
 <EMI ID = 62.1>

  
of metronidazole and the solution is stirred. This takes on a slightly lighter color and an orange-yellow product precipitates. After cooling and centrifugation, the supernatant is separated by decantation and the residue is washed with a mixture of ethanol and diethyl ether, then with diethyl ether, which gives 570 mg of

  
 <EMI ID = 63.1> a) Elementary analysis:
 <EMI ID = 64.1>
 <EMI ID = 65.1>

  
EXAMPLE 3

  
Compound A

  
 <EMI ID = 66.1>

  
several hours, during which the color changes to pale yellow. The precipitated silver iodide is removed by centrifugation and an excess of potassium chlorine * is added to the separated supernatant.

  
 <EMI ID = 67.1>

  
in example 1.

  
EXAMPLE 4

  
Compounds C, D and E

  
 <EMI ID = 68.1>

  
gently for an hour. After cooling, the supernatant liquid is separated by decantation from the precipitate which has formed. The volume of the supernatant liquid is reduced in a rotary evaporator to precipitate a new quantity of solid. The precipitates are combined, washed with a mixture of ethanol and diethyl ether, then with diethyl ether, and dried in air, which

  
 <EMI ID = 69.1>

  
platinum (II) having the following characteristics:

  
 <EMI ID = 70.1>
 <EMI ID = 71.1>
 <EMI ID = 72.1> e) Melting point: 174-176 [deg.] C.

  
By proceeding in a similar manner, but replacing the dimetridazole used as starting material with ipronidazole and tinidazole, respectively, we prepare:

  
1) Dichloro-bis (2-methyl-isopropyl-5-nitro-5 imidazole-N <3>) _ platinum (II) having the following characteristics:
a) Elementary analysis:
 <EMI ID = 73.1>
 <EMI ID = 74.1> a) Elementary analysis:
 <EMI ID = 75.1>
 <EMI ID = 76.1> c) UV: absorption Xmax: 302 nm. d) Polarography: Ep = -0.37 V. <EMI ID = 77.1>

  
EXAMPLE 5

  
Compound F

  
 <EMI ID = 78.1>

  
for a few hours. After cooling, the supernatant liquid is decanted to separate it from the precipitate which has formed and its volume is reduced in a rotary evaporator to precipitate the solid further. The combined precipitates are washed successively with a mixture of ethanol

  
 <EMI ID = 79.1>

  
following features:
a) Elementary analysis:
 <EMI ID = 80.1>
 <EMI ID = 81.1>

  
EXAMPLE 6

  
Compound G

  
 <EMI ID = 82.1>

  
heating gently for 2 to 3 hours until the reaction mixture becomes clear. Then the solution is cooled as well

  
 <EMI ID = 83.1>

  
formed, washed with a mixture of ethanol and diethyl ether, then with diethyl ether, and dried in a desiccator, which gives 0.46 g of dichloro-bis [(2-hydroxyethyl) ) -l hydroxymé-

  
 <EMI ID = 84.1>

  
following: a) Elementary analysis:
 <EMI ID = 85.1>
 <EMI ID = 86.1>

  
EXAMPLE 7

  
Compound H

  
0.20 g (1.0 mmol) of misonidazole and 0.207 g are dissolved.
(0.5 mmol) of K2PtC14 in 15 ml of a mixture of ethanol and water

  
 <EMI ID = 87.1>

  
ambient temperature. The solution becomes light yellow and left to stand in the dark for three weeks. The crystals are collected in the form of fine yellow needles which have formed, which

  
 <EMI ID = 88.1> a) Elementary analysis:
 <EMI ID = 89.1>
 b) Melting point: 21'-215 From c) X-ray crystallography: the crystal system is mono- <EMI ID = 90.1>

  
at R = 0.0536. X-ray crystallographic analysis confirms the trans arrangement of the ligands around the platinum atom.

  
EXAMPLE 8

  
Compounds I, J, K, L, M, N and 0

  
 <EMI ID = 91.1>

  
tion resulting, by treatment with the appropriate amount of an aqueous solution of sodium carbonate. The resulting solution is treated with 50 ml of acetone, filtered and the filtrate is dried with

  
 <EMI ID = 92.1>

  
By proceeding in a similar manner, but replacing the cyclobutanedicarboxylic acid-1,1 used as starting material by the appropriate amounts of malonic acid, methylmalonic acid, dimethylmalonic acid, ethylmalonic acid, Isopropylmalonic acid and benzylmalonic acid, respectively, we prepare:

  
 <EMI ID = 93.1>

  
 <EMI ID = 94.1>

  
EXAMPLE 9

  
Compounds P, Q, R, S T, U, V, W, X, G and Y

  
By proceeding in a similar manner to that described above in Example 1, but by replacing the metronidazole used as starting material by the appropriate quantity of the corresponding 5-nitro-imidazole, the following is prepared:

  
 <EMI ID = 95.1> a) Elementary analysis:
 <EMI ID = 96.1>
 b) NMR in acetone-D6: singlet at 2.95 ppm, doublet at 1.25 ppm, <EMI ID = 97.1> a) Elemental analysis:
 <EMI ID = 98.1>
 <EMI ID = 99.1>

  
 <EMI ID = 100.1> a) Elementary analysis:
 <EMI ID = 101.1>
 b) Melting point: 203-205 [deg.] C.

  
 <EMI ID = 102.1> a) Elementary analysis:
 <EMI ID = 103.1>
 b) Melting point: 207 [deg.] C.

  
5) Dichloro-bis [(2-carbamoyloxy ethyl) -1 2-methyl-5-nitro imida-

  
 <EMI ID = 104.1> a) Elementary analysis:
 <EMI ID = 105.1>
 b) Melting point: partial melting at 130 [deg.] C with resolidification <EMI ID = 106.1>

  
platinum (II):
a) Elementary analysis:
 <EMI ID = 107.1>
 b) Melting point: lll'C (with a certain resolidification <EMI ID = 108.1>

  
platinum (II): a) Elementary analysis:
 <EMI ID = 109.1>
 <EMI ID = 110.1> a) Elementary analysis:
 <EMI ID = 111.1>
 <EMI ID = 112.1> a) Elementary analysis:
 <EMI ID = 113.1>
 <EMI ID = 114.1> a) Elementary analysis:
 <EMI ID = 115.1>
 b) NMR in acetone-D6: triplets at 3.95, 4.80 and 5.45 ppm and a centered multiplet at 8.40 ppm. <EMI ID = 116.1>

  
 <EMI ID = 117.1>

  
EXAMPLE 10

  
Compound Z

  
 <EMI ID = 118.1>

  
shake by heating gently for one hour. The color of the solution changes from a cloudy reddish orange to a light yellow. 1.0 ml of glacial acetic acid is then added and a yellow precipitate is immediately formed. This precipitate is separated by filtration from the cooled mixture, then washed with diethyl ether. We dry

  
 <EMI ID = 119.1>

  
following:
a) Elementary analysis:
 <EMI ID = 120.1>
 <EMI ID = 121.1>

  
EXAMPLE it

  
Compounds AA and BB

  
 <EMI ID = 122.1>

  
for 6 hours. The color of the solution changes from a cloudy reddish orange to a light yellow, then there is a precipitation. The precipitate is separated by filtration from the cooled mixture and washed with diethyl ether. The yellow crystalline product is air dried,

  
 <EMI ID = 123.1> platinum (II) having the following characteristics:
a) Elementary analysis:
 <EMI ID = 124.1>
 <EMI ID = 125.1>

  
By following a similar procedure, but replacing the 1,2-dimethyl-4-nitroimidazole used as starting material with

  
 <EMI ID = 126.1> a) Elementary analysis:
 <EMI ID = 127.1>
 b) NMR in acetone-D6: multiplet centered at 8.2 ppm.

EXAMPLE 12

  
CC compound

  
By proceeding in a similar way to that described above

  
 <EMI ID = 128.1>

  
yellow solid, P.F. 101 [deg.] C (with decomposition).

EXAMPLE 13

  
 <EMI ID = 129.1>

  
By proceeding in a similar manner to that described above in Example 2, but by replacing the potassium iodide used as starting material with the appropriate amount of bromide.

  
 <EMI ID = 130.1>

  
Elementary analysis:

  

 <EMI ID = 131.1>


  
The present invention encompasses in its field pharmaceutical compositions which comprise at least one compound of general formula (I) or one of its salts, in combination with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the present invention will be administered orally, rectally, vaginally or parenterally.

  
Solid compositions for oral administration include tablets, pills, powders and granules. In these solid compositions, one or more of the active compounds are mixed with at least one inert diluent such as starch, sucrose or lactose. These compositions can also comprise, as is common practice, additional substances other than inert diluents, for example lubricants, such as magnesium stearate.

  
Liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing the inert diluents usually used in pharmacy, such as water and paraffin oil. In addition to the inert diluents, these compositions can also include adjuvants, such as wetting agents, suspending agents, sweetening and flavoring agents, perfumes and preservatives.

  
The compositions according to the invention for oral administration also include capsules of absorbable substance, 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 prepared eggs

  
 <EMI ID = 132.1>

  
The preparations according to the invention for parenteral administration include aqueous, hydro-organic or organic sterile solutions, suspensions or emulsions. As organic solvents or suspension media, there may be mentioned propylene glycol,

  
polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions can also include adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants. These compositions can be sterilized, for example by filtration through a filter retaining bacteria,

  
by incorporation of sterilizing agents, by irradiation or by heating. They can also be manufactured in the form of sterile solid compositions, which can be dissolved extemporaneously in sterile water or another sterile injectable medium.

  
 <EMI ID = 133.1>

  
according to the invention is variable, but it is necessary that it represents a proportion such that a suitable dosage is obtained. It is of course possible to administer several forms of unit dosage approximately in

  
 <EMI ID = 134.1>

  
the desired therapeutic effect, the mode of administration, the duration of treatment and the patient's condition. When given in conjunction with X-ray cancer treatment to increase the effectiveness of radiation therapy, a compound of general formula
(I), or more especially the compound of general formula (III), will generally be administered before the irradiation of the cancer (normally up to 5 hours before the administration of the radiations) in doses

  
from 0.1 to 500, preferably from 1 to 200, mg per kg of body weight.

  
It is normal, in the practice of X-ray cancer therapy, to repeat the irradiation a certain number of times during the treatment, for example between 15 and 20 repetitions over a period of 3 to 4 weeks and one can administer a compound of general formula

  
 <EMI ID = 135.1>

  
with each repetition of the irradiation at the doses indicated above. When administered to combat anaerobic bacteria, the dose is generally between 0.1 and 500, more especially between 1 and
200, mg per kg of body weight, and this dose may also be repeated at Intervals as prescribed by the doctor or surgeon.

CLAIMS

  
1. Nitroimidazole complexes containing platinum (II), having the general formula:

  

 <EMI ID = 136.1>


  
in which X represents a molecule of (mono) nitro-2, -4 or -5

  
 <EMI ID = 137.1>


    

Claims (1)

 <EMI ID = 138.1> 4. Complexes according to claim 3, in which the sym-  <EMI ID = 139.1> imidazole.  <EMI ID = 140.1>  <EMI ID = 141.1>  <EMI ID = 142.1>  <EMI ID = 143.1> each represents a hydrogen atom or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group, or else CR <1> R <2>  <EMI ID = 144.1> the alkyl groups and radicals and alkenyl groups containing up to 6 carbon atoms, the aryl groups and radicals being phenyl, and any cycloalkyl or cycloalkenyl group containing from 3 to 8 carbon atoms.  <EMI ID = 145.1> 7. A process for the preparation of a complex according to claim 1, characterized in that a nitroimldazolic compound corresponding to the symbol X, as defined in claim 1, is reacted with a platinum salt of general formula:  <EMI ID = 146.1> in which Q represents an alkali metal and Z is as defined  <EMI ID = 147.1> 8. Process for the preparation of a complex of general formula (I), characterized in that a complex of general formula is treated:  <EMI ID = 148.1> (in which X is as defined in claim 1 and Y is a halogen atom) with silver nitrate in an aqueous medium, then treatment with a source of another ligand to replace Y. 9. Method of preparation of a complex of general formula  <EMI ID = 149.1> general (II) and X, R 1 and R2 are as defined above,  <EMI ID = 150.1> X is as defined in claim i and Y is a chlorine, bromine or iodine atom, with silver nitrate in an aqueous medium, then treatment with an acid of general formula:  <EMI ID = 151.1> (in which fil and R <2> are as defined in claim 5), then neutralization using an appropriate base. 10. Process for the preparation of pharmaceutically acceptable salts of monoesters with aliphatic dicarboxylic acids, and phosphoric, phosphorous and sulfuric esters of complexes according to claim 1 and in which the nitroimidazole represented by the symbol X has a substituent which contains a free hydroxy group , and pharmaceutically acceptable salts of the complexes in which the nitroimidazole represented by the symbol X has a substituent which contains a carboxy group, characterized in that a nitroimidazole is used in the form of a pharmaceutically acceptable salt in a process as claimed in claims 7, 8 or 9, or by the transformation, by methods known per se, of a complex of general formula (I) into such a pharmaceutically acceptable salt. 11. Pharmaceutical compositions which contain, as  <EMI ID = 152.1> pharmaceutically acceptable salts, in combination with a pharmaceutical carrier or coating.