JPS5931792A - Novel metal complex of heterocyclic ring - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel metal-containing complexes of heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them.

The present invention provides properties useful for use in treating cancer and in combating infections caused by anaerobic bacteria and, when Ml represents a gold atom, in treating disorders of the joints. -25 General formula % Formula % [In the formula, Ml is gold (A), Nono radium (■),
Rhodium (2), platinum mt and platinum Φ) full atom representation,
Xl is a 6-14- or 5-(mono)nitropyrazole molecule, which may be unsubstituted but preferably has at least one substituent, and is connected to the metal M1 at the 2-position of the pyrazole ring. ), or a 4- or 5-(mono)nitroisothiazole molecule (which may be unsubstituted but preferably carries at least one substituent and is coordinated to the metal M1) or when Ml represents gold (6), palladium (■), rhodium ([10) or a platinum atom, xl can also be 2- or preferably 4-
or a 5-(mono)-ditroimidazole molecule, which may be unsubstituted, but preferably has at least one substituent, and coordinates with the metal M1 at the 6-position of the imidazole ring. ) can also be represented, and more than one group x1
is present in the compound of general formula I, in particular when Ml represents a palladium ([[), platinum or platinum(II) atom], the abovementioned nitropyrazole, nitroisothiazole or nitroimidazole The molecules may optionally be linked together (e.g., in pairs), where zl and z2 each represent a pharmaceutically acceptable ligand and % (Z5)- is a pharmaceutically acceptable anion. , m represents 2, or Ml is gold [phase]
) atom, m represents 1; when Ml represents a rhodium atom, m represents 6 or 4; n represents 2; or when Ml represents a gold-valent atom, m represents 1; n represents 6, and when M) represents a rhodium (2) atom, if m represents 3 27-, then n Id 5, if m represents 4, n represents 2, and p is 0. or when Ml represents a platinum atom, p represents 2 and q represents 0, or Ml represents a rhodium (lII) atom, m represents 4, and n represents When q represents 2, q represents 1] is provided.

As used herein with respect to the symbols z1 and z2, "
The term ``pharmaceutically acceptable ligand'' refers to compounds of formula I which, when free, form only those chemical species that are relatively harmless to the animal body when used in therapeutic amounts;
Ligands are meant such that the beneficial properties of the compounds of formula (1) are not compromised by side effects caused by those species.

Preferably zl represents a halogen such as bromine, iodine, more particularly a chlorine atom, and z228- represents a halogen such as a bromine, iodine or chlorine atom or a hydroxy group, or when n represents at least 2, in particular Ml is palladium (If), platinum W)
or platinum ω) atoms, the pair of z11 positions (which can be expressed as (Z')2) has the general formula (wherein R1 and R2 are the same or different and each represent a hydrogen atom or alkyl, represents an aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group, or 0RIR2 represents a cycloalkyl or cycloalkenyl group and r is 0 or 1
) can represent a bidentate ligand. The dotted line indicates the bond with the metal atom M1.

Regarding the definition of 0RIR2 in Formula 29 Formula 1, alkyl and alkenyl groups preferably contain up to 6 carbon atoms, aryl groups are preferably phenyl and cycloalkyl and cycloalkenyl groups preferably contain from 3 to 8 carbon atoms. contains carbon atoms.

The ligands represented by zl and/or z2 may be different, but are preferably the same.

Similarly, the term "pharmaceutically acceptable anion", as used herein with reference to the symbol (z5)'', means that when released from a compound of formula I, it can be used therapeutically in an animal body. only forms chemical species that are relatively harmless to
Therefore, it refers to anions such that the beneficial properties of the compounds of 2 are not impaired by the side effects caused by those chemical species.

=30- Preferably z6 represents a halogen such as bromine, iodine, more particularly a chlorine atom, so that Cz5>- represents the corresponding halide ion.

two or several X to which compounds of formula I are bonded together
When containing one group, each bond may be a single bond or a polyvalent group such as an alkylene group such as a methylene group. In the present specification, references to the group X1 in 1 to 1 are also understood to refer to the combined group x1, either together or separately, unless the context contradicts. do. That is, for example, two groups x
1 are combined together and reference is made to Xl, unless the context contradicts b [X') or to half of the 12 groups. .

1-13-1 of the pyrazole ring of the 3-14- or 5-(mono)nitropyrazole molecule represented by the symbol X1
in the 4- or 5-position, or in the 4- or 5-(
at the 3-14-7 or 5-positions of the inthiazole ring of a mono)nitroisothiazole molecule, or at the 1-12- or 4- or 5-positions of the imidazole ring of a 2-14- or 5-(mono)nitroimidazole molecule; Suitable substituents at the positions include the nitrogen atom at the 2-position of the pyrazole ring represented by The metal M1 is stronger than the nitrogen atom at the 6-position of
Atoms or groups known to those skilled in the art that cannot be coordinated with

Preferred substituents are unsubstituted or substituted with one or several atoms or groups selected from hydroxy, alkoxy, alkylsulfonyl, carboxyalkoxycarbonyl, carbamoyloxy, benzylcarbamoyl and N-morpholinyl groups and halogen, preferably chlorine atoms. substituted alkyl groups, phenyl groups substituted by one or more halogen (preferably fluorine) atoms, and alkylthio groups substituted by phenoxy groups, the phenoxy group being substituted by carboxy; In that case, the alkyl and alkoxy groups may be linear or branched, preferably 1-
Contains 4 carbon atoms.

If the substituent in the substituted heterocyclic molecule represented by the symbol containing 1 to 6 carbon atoms] and pharmaceutically acceptable salts thereof, and wherein the substituent in the substituted heterocyclic molecule described above is When containing groups, the substituents include esters of phosphoric acid, phosphorous acid or sulfuric acid, and their salts containing pharmaceutically acceptable cations such as alkali metals such as potassium or sodium salts, alkaline earth metals such as calcium or may form magnesium salts, ammonium salts and amine salts with pharmaceutically acceptable amines, and when Xl represents a heterocycle having a substituent containing a carboxy group, the pharmaceutically acceptable salts can be formed. It is understood that such esters and salts constitute a feature of the invention.

As used herein, the term "pharmaceutically acceptable salt" refers to the general formula salts in which the beneficial properties of the metal-containing complexes are not impaired by side effects caused by their cations. Preferably the salt is water soluble. Suitable salts include alkali metals such as sodium and potassium;
Included are alkaline earth metals such as calcium and magnesium, and ammonium salts and pharmaceutically acceptable amine salts. Suitable amines for forming such salts are well known and include, for example, one or more hydrogen atoms carried by ammonia, such as alkyl groups containing from 1 to 6 carbon atoms and two or more hydrogen atoms. Substituted with a group selected from hydroxyalkyl groups containing 3 carbon atoms (but where more than one hydrogen atom is substituted, the groups may be the same or different) Includes amines theoretically derived by

In this specification, when a compound of formula (1) is described, it is intended that, if the context allows, the pharmaceutically acceptable salts and esters thereof are also included in the description.

The 2-(mono)nitroimidazole molecule represented by the symbol x1 preferably has a substituent at least one of the 1-14- or 5-positions of the imidazole ring.

The 4- or 5-(mono)nitroimidazole molecule represented by the symbol x1 preferably has a 1-
or has a substituent at least one of the 2-positions or at least one of the 4- or 5-positions of the imidazole ring not occupied by a nitro group. The 4- or 5-(mono)nitroimidazole molecule represented by the symbol x1 is preferably
and is substituted in the imidazole ring position.
unsubstituted or preferably substituted at the first position
Substituted at position.

Particularly suitable substituted 2-1 represented by the symbol x1
The 4- or 5-(mono)nitroimidazole molecule is metronidazole [1-(2-hydroxyethyl)-2-
Methyl-5-nitroimidazole, hereinafter abbreviated as "MNZJ", cimetridazole [1,2-dimethyl-5-nitroimidazole], ibronitasol (1-methyl-2-isopropyl- 5-nitroimidazole), tinitasol [1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole], 2-methyl-4-(also 1d5)-nitroimidazole, 1-carboxymethyl-2 -Methyl-5-nitroimidazole, Nimorazole [1-(2-N-morpholinylethyl)-5-nitroimitasol], Ornidazole [1-(5-chloro-2-hydroxy-n-propyl)] -2-methyl-5-=)leumitasol], lonitasol [1-methyl-2-carbamoyloxymethyl-5-nitroimidazole], secnitasol [1-(2-hydroxy-n-propyl)-2
-methyl-5-nitroimidazole], 1-methyl-5
-nitroimidazole, 2-(2-(4-carboxyphenoxy)ethylthio]-1-methyl-5-nitroimixol, bamnitasole [1-(2-carbamoyloxymethyl)-2-methyl-5-nitro imidazole]
, flunitasol (1-(2-hydroxyethyl)-2
-(p-fluorophenyl)-5-nitroimidazole], 2-hydroxymethyl-1-methyl-5-nitroimidazole, 1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole, 2-isopropyl- 4(or 5)-nitroimidazole, 2-hydroxymethyl-4(i or 5)
- ditroimidazole, 1-(2-hydroxyethyl)
-2-methyl-4-nitroimidazole, 1,2-dimethyl-4-ditroimidazole, 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, misonidazole [1-(2-human axy-6-nodoxy-n-propyl)-2-ditroimidazole],
Molecules selected from the group consisting of penznidazole [N-benzyl-1-(2-nitroimidazolyl)acetamide], azomycin (2-nitroimidazole) and 4(5)-nitroimidazole, and substituted nitroimidazole as described above. When the substituent in the 1- or 2-position of the molecule contains a free hydroxy group, dicarboxylic aliphatic acids [where the aliphatic (e.g. alkyl) moiety preferably contains 1 to 6 carbon atoms] are used. containing] and pharmaceutically acceptable salts thereof, and one of the above-mentioned substituted nitroimidazole molecules.
When the - or 2-position substituent contains a free hydroxy group, esters of phosphoric acid, phosphorous acid or sulfuric acid and pharmaceutically acceptable salts of such esters of phosphoric acid, phosphorous acid and sulfuric acid, e.g. Metronidazole hemisuccinate, metronidazole phosphate and metronidazole sulfate and their salts containing pharmaceutically acceptable cations such as alkali metals such as potassium or aluminum alkaline earth metals such as calcium or magnesium salts, ammonium salts and amine salts with pharmaceutically acceptable amines, and xl
represents 1-carboxymethyl-2-methyl-5-nitroimidazole or 2-(2-(4-carboxyphenoxy)ethylthio)-1-methyl-5-nitroimidazole, the pharmaceutically acceptable It's salt.

The complexes of formula (1) when Ml represents an atom of palladium or platinum, all of which are square planar, can be present in the trans or cis configuration.

A particularly preferred group of compounds of formula I includes those where xl represents metronidazole.

Another particularly preferred group of compounds of formula I includes those where xl represents 1-methyl-4-nitropyrazole.

Another particularly preferred group of compounds of formula I includes those where xl represents methylnitroisothiazole.

41- Another particularly preferred group of compounds of formula I includes the general formula %, where X2 is a substituted or unsubstituted (mono)nitroimidazole molecule as defined above. Examples include metronidazole and z4 represents a halogen atom.

Another particularly preferred group of compounds of formula I includes compounds of the general formula % where X2 and z4 are as defined above.

Another particularly preferred group of compounds of formula (1) includes the general formula (%), where X2, z5 and z4 are as defined above.
2- as defined above, and m, n and q are as defined above, i.e. m=5, n=3 and q
=o or m=4, n=2 and q=i).

Another particularly preferred group of compounds of formula (1) includes compounds of the general formula %, where N2, N2 and N4 are as defined above.

Another particularly preferred group of compounds of formula (1) includes the general formula %formula% (However, z4 in the formula is as defined above.

and N6 represents a substituted or unsubstituted (mono)nitropyrazole molecule as defined above.

Another particularly preferred group of compounds of formula I include the general formula % wherein 24 is as defined above and N4 is substituted or substituted as defined above. (representing an unsubstituted (mono)nitroisothiazole molecule).

Important individual compounds of formula I include:

A, trichloro-(1-(2-hydroxyethyl)-2)
-Methyl-5-nitroimidazole-NB) Gold (e)
, B trichloro-(1,2-dimethyl-5-ditroimidazole-N3) gold [phase], 0 tribromo-[1-(2-hydroxyethyl)-2
-Methyl-5-ditroimidazole-N3]gold(2), D dichloro-bis[1-(2-hydroxyethyl)-
2-Methyl-5-nitroimidazole-N3] palladium (II), E dichloro-bis(1,2-dimethyl-5-nitroimidazole-N3) palladium (■), F dichloro-bis(1-(2- hydroxy-n-propyl)-2-
Methyl-5-ditroimidazole-Hl) Noceradium ω), G) Chloro-bis[1-(2-hydroxy-6-nodoxy-n-propyl)-2-ditroimidazole-N3] Palladium(II), H Trichloro-tris(1-(2-hydroxyethyl)-2-methyl-5-
Nitroimidazole-IJ4]Rhodium Tsukuda), E dichloro-tetrakis(1-(2-hydroxyethyl)-2-methyl-5-nitro45-Midazole-NM)Rhodium(t)chloride, J Tetrachloro-bis(1 -(2-hydroxyethyl)-2
-Methyl-5-nitroimidazole-N6] para:) rum, K tetrachloro-bis(1,2-:)methyl-5-nitroimidazole-N5) Platinum, L tetrachloro-bis(1) -(2-hydroxy-n-propyl)-
2-Methyl-5-nitroimidazole-N5] platinum (
), M Q chloro-dihydroxy-his[1-(2
-hydroxyethyl)-2-methyl-5-nitroimidazole-N5'J platinum 11'), N)chloro-dihydroxy-bis(1,2--)methyl-5-ditroimidazole-N5) platinum ( 46-P dichloro-[his-(4-nitrohyrazole-1-
il) methane-N2. N2')] platinum ω), Q dichloro-bis[5-methyl-4-ditroisothiazole] platinum(II), Oyohi R dichloro-bis[6-methyl-
5-Ditroisothiazole]platinum(II), The letters A-R are hereinafter designated for the compound for ease of designation.

Compounds of formula (1) are preferably used in the treatment of cancer in combination with x-ray therapy.

Irradiation with X-rays is a widely used treatment method for many types of cancer by destroying neoplastic cells. However, a problem often encountered when treating solid cancers, such as lymphomas, carcinomas, and sarcomas, with x-ray therapy is that a substantial proportion of cells in solid tumors are in a state of hypoxia and are sensitive to x-ray irradiation. It is relatively insensitive.

Metal-containing complexes of general formula I increase the sensitivity of hypoxic tumor cells to X-rays and can therefore be administered in combination with X-ray therapy of solid cancers to increase the effectiveness of radiation therapy.

For example, in tests, Compound J caused a 1.4 increase in sensitivity when administered as a pretreatment to X-rayed hypoxic cells in vitro at a concentration of 10 micromolar.

Furthermore, compounds of formula (I), especially compounds of formula I when Xl represents a substituted or unsubstituted (mono)nitroimidazole as defined above, are active against anaerobic bacteria; They are therefore useful in treating or preventing such conditions, e.g. inflammatory diseases of the lower back, dental diseases and gingivitis, and brain abscesses, and they are useful in e.g. vaginal surgery and small intestine surgery. Useful in minimizing post-surgical morbidity.

Compounds of formula I in which Ml represents a gold(2) atom are also useful in treating diseases of the joints.

The compound of formula (1) can be prepared by applying or adapting known methods.

According to the features of the present invention, the formula ■ (wherein, Ml, xl, z
1, z2, z3, m, n% p and q are as defined above). 0 or a platinum (b) atom), the nitroimidazole compound corresponding to the symbol X1 as defined above is represented by the general formula Ml, Zl, 49-z2.n and p are as defined above,
When Ml represents a rhodium valence atom, day represents O; when Ml represents a gold (lI[) atom, day represents 1; and when Ml represents palladium (II), platinum (
1'i') or a platinum ([) atom, day represents 2 and t represents 0, or Ml represents a rhodium(2) atom and n represents 2; t represents 0). The reaction is carried out in water or an aqueous organic solvent such as aqueous ethanol or aqueous acetone at a temperature of 5 DEG to 100 DEG C.

When Ml represents a rhodium(6) atom, the reaction is preferably carried out in the presence of traces of mild reducing agents such as sodium hypophosphite or even in the presence of ethanol.

Salts of formula (1) can be prepared by applying or adapting known methods. In some cases, salts of the formula (II) can be prepared in situ, which is advantageous especially when operating on a large scale.

For example, the manufacturing method for these is as follows.

(1) Compounds of the general formula % formula % (wherein Q, 1 and zl are as defined above) have the general formula X and ■(Ql)(z
') MAu” (Zl)5
M (wherein, c41 and zl
are as defined above) together in situ.

(11) Compounds of the general formula % formula % (wherein Ql and zl are as defined above) have the general formula X (as defined above) and W paIr(zl)2 XI
It can be prepared in situ by reacting together compounds V, where zl is as defined above.

QiD A compound of the general formula % (wherein Q is as defined above) is prepared by dissolving the metal platinum in an aqueous medium, removing the excess aqueous medium by evaporation, and then forming a compound of the general formula It can be prepared in solution by careful treatment, preferably in aqueous solution, using a compound of the formula % where Q, 1 are as defined above.

Ov) general formula % formula % (wherein Ql is as defined above)
can be prepared by treating a solution of a compound of formula XV (prepared as described above) with an appropriate amount of hydrazine.

For example, in accordance with another feature of the invention, Compound A is prepared by reacting metronidazole with an alkali metal salt of chloroauric acid, such as NaAuOR4. The reaction is preferably carried out in water or aqueous acetone at 5-100°C, preferably at 10-60°C.

According to another feature of the invention, the compound metronidazole is an alkali metal salt of chloropalladate, more particularly potassium chloropalladate (K2PaOfi4).
) is produced by reacting with The reaction is preferably carried out in water at 15-100°C, preferably 20-60°C.

According to another feature of the invention, compound H is prepared by reacting me53-tronidazole with a rhodium halide, more particularly rhodium trichloride (Rh01g). The reaction is preferably carried out in water at 15-100°C, preferably 70-90°C.

According to another feature of the invention, Compound J is prepared by preparing metronidazole in aqueous ethanol as an alkali metal salt of dichloroplatinic acid, and more particularly potassium dichloroplatinate (K2P).
tOj26) t or sodium dichloroplatinate (Na
2PtOλ6). The reaction is preferably carried out in water at 15-100°C, preferably at 60-100°C.
It is carried out at 80°C.

Another feature of the invention is that compound O is N-methyl-
4-nitropyrazole is combined with the alkali metal salt of monochloroplatinic acid, more specifically potassium monochloroplatinate (x2pt
c44). The reaction is preferably carried out in water at 15-100°C, preferably at 40-60°C.
Performed at °C.

54- According to another feature of the invention, compound Q is 5-methyl-
4-Nitroisothiazole is converted into an alkali metal salt of monochloroplatinic acid, more specifically potassium monochloroplatinate (K2
It is produced by reacting with ptap, 4).

The reaction is preferably carried out in water and at 15° to 100°C, preferably 40 to 60°C.

According to another feature of the invention, certain compounds of formula (1) can be prepared from other compounds of formula (2).

For example, the general formula CM'(Xl)m(Yl)n(Z2) included in the general formula ■
') i X's (where Ml, Xl, Z2
．． The compound of 25, m, n% p and q are as defined above and Yl is a halogen atom) may contain another source of ligand for replacing Yl, e.g.
It can be treated with location ligands. In some cases it may be desirable to treat with silver nitrate in an aqueous medium before treatment with another source of ligand.

According to another feature of the present invention, the formula ■ [wherein %
(Zl)2 represents a bidentate ligand of the formula and in the case of rhodium compounds when n represents 3, the third ligand z1 is as defined above)] of the general formula [where Ml, xl ,Yl,z2,
m%n1p and q are as defined above,
two ligands Y1 (or two of the three ligands Y1 in the case of gold compounds and rhodium compounds when n represents 6) are present in the cis configuration] in an aqueous medium. in which R1, R2 and r are as defined above, followed by addition of a suitable base such as an alkali metal carbonate such as sodium carbonate. It is produced by neutralizing the solution. treating the solution with a water-miscible organic solvent such as acetone;
Removal of precipitated inorganic by-products and evaporation of the p-liquid under vacuum affords the required compound of formula I. Prior to treating the compound with adult acid, it can be treated with silver nitrate in an aqueous medium.

According to another feature of the present invention, the formula ■ (wherein, M
l represents a platinum ω atom, z-1 represents a halogen atom, z2 represents a halogen atom or a hydroxy group, and Xl, z5, m, n, p and q are as defined above). The compounds are prepared from platinum (Il)-containing complexes of the general formula %, where Xl and zl are as defined above, preferably by oxidation in an aqueous medium, where z2 carries a hydroxy group. When z2 represents a halogen atom, the oxidation is carried out using a suitable halogen such as chlorine gas or bromine or a bromine source such as an aqueous Misawa potassium solution. Generally the reaction occurs between 0 and 100°C.

A compound of formula XX (wherein X4 and zl are as defined above) is a heterocyclic compound corresponding to the symbol X1 as defined above with the general formula %formula% (wherein, Ql and zl are as defined above and the ligands represented by zl are different or preferably the same). The reaction is carried out in water or an aqueous organic solvent such as aqueous ethanol.
It is carried out at a temperature of 5-100°C.

Formula XX, where zl is as defined above and xl represents a substituted or unsubstituted (mono)nitroisotisol molecule.
The compounds are described in UK Patent Application No. '209345IA and corresponding patent applications in other countries, such as US Patent No. 350,885.

Another feature of the invention provides for formula I, where Ml
represents a palladium OI) atom; Xl, Zl, z2.
Z5, m%n, p and q are as defined above) is designated by the symbol x1 as defined above.
A nitropyrazole, nitroisothiazole or nitroimidazole compound corresponding to the general formula % in an aqueous medium such as water or an aqueous organic solvent such as aqueous ethanol or aqueous acetone at a temperature of 5° to 100° C., preferably 20° to 60° C. [ wherein Ql and Zl are as defined above].

When the substituent in the above-mentioned substituted heterocyclic compound contains a free hydroxy group, the symbol includes monoesters, phosphoric esters, phosphorous esters, and sulfuric esters with dicarboxylic aliphatic acids. The substituted heterocyclic compound corresponding to x1 can be produced by applying or adapting methods known per se for the production of the above-mentioned substituted heterocyclic compounds. Several are commercial products.

Pharmaceutically acceptable salts of the above monoesters, phosphoric acid esters, phosphorous acid esters and sulfuric acid esters, and metals of general formula (1) (wherein, Xl represents a heterocyclic compound having a substituent containing a carboxyl group) The pharmaceutically acceptable salts of the containing complexes can be prepared by applying or adapting methods known per se with the symbol x1 as defined above.
from a suitable substituted heterocyclic compound corresponding to in the form of a pharmaceutically acceptable salt in the above-mentioned production reaction, or from a suitable metal-containing complex of general formula (2) obtained by the above-mentioned production reaction. can be manufactured.

The expressions "known methods" or "methods known per se" as used herein mean methods used to date or described in the literature.

In order to better understand the present invention, the production of the compound of general formula (1) and the production of intermediates will be explained below using Examples.

Example 1 Compounds A and B Metronidazole (215 mg) was dissolved in acetone (15-)
and the resulting solution is added at room temperature to a solution of IJium dihydrate (500 η) in water (15 rnl). The acetone is evaporated at room temperature, the precipitate formed is evaporated and washed with diethyl ether to give trichloro-(1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N3]gold@) (560 !
, m, p, 168-176°C) is obtained in the form of yellow crystals.

Calculated value: 15.19 1.91 8.8,5 22.
4 Actual measurement value: 15.0 1.82 8.8 22.2
Trichloro 2-lo(1,2-dimethyl-5-ditroimidazole-N
5) Gold ([) (m, p, 158-171°C) is obtained.

Elemental analysis once willow - 1 rainbow 1 east C1 Calculated value: 13.51 1.59 9.46 23.
95 actual measurement value: 15.6 1.41 9.3 23
．． 7NMR (in acetone-D6): S, 00.4,50
and a singlet at 8.65 p, p, m.

Example 2 Compound C To a stirred solution of potassium tetrabromideaurate (100 q) in water (10 n/) is added metronidazole (60 µ) and the resulting mixture is stirred at room temperature for 1 hour. When the crystals formed are separated and washed with diethyl ether (dichloromethane), tribromo-(1-(2-hydroxyethyl)-
2-Methyl-5-ditroimitasole N') Gold (2
) [70 rng, m, p. 149-150℃ (decomposition)]
is obtained in the form of red crystals.

Elemental analysis 0ji) H@) Nji) Calculated value: 11.86 1,49 6.91 Actual measurement: 1
1.8 1.29 6.8 NMR (in acetone-D6): singlet at 2.95 and 8.65 ppm, 4
, 05 and 4. A triple line centered on the Bp bullet.

Example 6 Compounds E and F Metronidazole (342~) in ethanol (30m)
A solution of potassium palladiumate (3
Add to the solution of 26, 4■). The ethanol is slowly evaporated over 16 hours, the precipitate formed is separated and washed with diethyl ether. , m, p
. 244°C (sea bream)] is obtained in the form of yellow crystals.

Elemental analysis Cji) "Oan'r") N5) OQ, (%) Calculated value: 27.74 !1.49 1<5.17 1
3.65 Actual value: 27.5 5.51 16.1
13.8 NMR (in acetone-D6): 3.19 and 8.1! Singlet at ippm, triplet centered at 6.95 and 4.65 ppm.

Working in a similar manner but replacing the metronidazole used as starting material by appropriate amounts of dimetridazole and secnidazole, the following compounds are prepared, respectively.

cyclolobis(1,2-umethyl-5-=)loimitas-'/l/-II3)';y:)lam GI)
(m-p, 293-294°C (decomposed).

Elemental analysis 65- Cji) H part) N (%) of1
part) Calculated value: 26.13 307 18.29 15.
43 Actual value; 26.4 3.22 17.9 14
．． 9 and Hisychlorobis [1-(2-Hi10xyn
-Propyl 2-2-methyl-5-nitroimidazole-
N3] palladium ω) Cm-p. 270℃ or higher (decomposition)
].

Elemental analysis once (%L-11'') - 〇 Store) Calculated value! 0.70 4.05 15.55 12.95
Actual value: 1.10 4.07 15.1 12.2
'1 Example 4 Compound G Palladium chloride (89η) was added to a stirred solution of sodium chloride (120η) in water (20n/) and 1
Continue stirring for an hour. Next, misonidazole (20 [1
rIq) and acetone (2-) and continue stirring for 15 minutes at room temperature. The resulting mixture is heated on a steam bath for 1 hour and then cooled in a water bath. The formed crystals were separated and washed with diethyl ether to give dichloro-bis-1-(2-hydroxy-3-methoxy-n-propyl)-2-nitroiotasol-N6]palladium(II) (22 oq, m,
p, 193-195°C) is obtained in the form of yellow crystals.

Elemental analysis 0 (support)) H 俤) N (%) aft,
(b) Calculated value: 29.01 3.83 14.50
12.21 Actual value: 28.6 3.70 14.2
12.3 NMR (in aceto 7-D6): 3. s
Singlet at ppm, multiplet at 4.0-4.7 ppm and doublet at 7.35 and 7.55 ppm.

Example 5 Compound H Metronidazole (513 ■) in ethanol (1 m/)
A solution of water (5Tnt) moderated rhodium @) pentahydrate (
281#v) and the resulting solution is heated on a steam bath for 6 hours and then allowed to cool to room temperature.

The precipitate formed is separated by furnace and washed with diethyl ether to give trichlorotris[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N5]rhodium@) (650rNi, m, p. 230°C or higher). (decomposition)] is obtained in the form of light brown crystals.

Elemental analysis (Rh(MNz)goIl, g: for 2H20) -μm-) -H@)-1) "μ1 Calculated value: 28.49 4.12 16.62 14.02 Actual value: 28.33. 84 L6.4 14.2 Example 6 The compound emetronidazole (780+W) is dissolved in water (10 tnt) by heating on a steam bath. The solution is treated with rhodium(III) chloride pentahydrate (281~) and heating is continued for 1 hour until the solution turns orange. This solution is then treated with sodium phosphite (2 .mu.), the solution becomes bright yellow and a precipitate forms. The precipitate was separated and washed with diethyl ether to give dichloro-tetrakis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N5)C
ldium@) chloride (720q, m, p, 198-2
01° C.) is obtained in the form of yellow crystals.

Elemental analysis ([Rh(MNZ)40x2)”0J2-:2
For H20) 0 (a) Hshi) N leech) 0
λ leech) Calculated value 11.00 4.34 18.07 11
44 actual value: 50.6 3.75 17.7 11
7 Example 7 Compounds J, and L Meltonidazole (34
24) in water (50 m/). Potassium dichloroplatinate (486 wv) is added to the solution and heating is continued for 16 hours, during which time a 69-precipitate forms. The precipitate is separated and washed with diethyl ether to give tetrachlorobis[1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole-N
5) Platinum M [62o~, m, p, 208~210℃ (
decomposition)] is obtained in the form of yellow crystals.

Elemental analysis C blunt) H@) sum) aX zhong) - Calculated value: 21.22 2.67 12.37 20.88
Actual value: 21.2 2.69 12.3 19.3
NMR (in acet:/-D6): 2.80 and 3.2
Singlet at 0 ppm, 4.00.4.50 and 8
．． Multiplet at 40 ppm.

Working in a similar manner but replacing the metronidazole used as starting material by appropriate amounts of dimetridazole and secnidazole, respectively, the following compounds are prepared.

=70-tetrachloro-bis(1,2-)methyl-5-ditroimidazole-N5) platinum (m, p, 252-255
℃).

Elemental analysis C (%) H (%) Nji) Calculated value: 19.4 2.28 13.57 Actual measurement @
: 19.5 2.28 15.11 (MR (in acetone-D6); singlet at 2.6-4.1 ppm and multiplet centered at 8.2 ppm. and tetrachloro-bis[1-(2 -hydroxy-n-propyl)
-2-methyl-5-nitroimidazole-NM] platinum ω
Cm, p, becomes dark at 260°C and melts at 310°C (accompanied by decomposition)].

Elemental analysis (pt (secnidazole) 2aλ4:2H20
) C (%) Hji) N@) Calculated value: 22.6 3.55 11.51 Actual value:
22.7 '5.52 11.2 NMR (acetone-
in D6): doublet centered at 13 ppm, 3
．． Singlet at 2 ppm, 4.5 and 8.4 ppm
multiplet with center at .

Example 8 Compound M cis-dichloro-bis(1-(2-human90xyethyl)-2-methyl-5-ditroimidazole-N5]platinum(II) (700 μ) was suspended in water (27), Heat aqueous hydrogen peroxide solution (8-1100vo#) on a steam bath
and continue heating for 6 hours. This mixture was allowed to stand at room temperature for 2 days, the precipitate formed was filtered out and washed with diethyl ether to give dichlorodihydroxy-bis[1-(2-hydroxyethyl-2-methyl-5-nitroimidazole-N3)platinum ( wealth) [350■, m,
p, 209-213°C (decomposition)] is obtained in the form of pale yellow crystals.

Elemental analysis (pt(MNz)201z(oH)2:2a2
o) 0 dull) ” Liao L - Mi Stirupichi Calculated value: 21.37 3.59 12.4<S Actual value: 21.6 3.05 12.5 NMR (acetate: /
-D+s): singlet at 6.05'ppm, 6
, 90. Multiplets centered at 4.70 and 8.4 ppm.

Example 9 Compounds M and N cis-dichloro-bis[1-(2-hydroxyethyl)
-2-methyl-5-nitroimidazole-N5) platinum (
] II (5001 Da) in an aqueous hydrogen peroxide solution (30 ml
．． 20 van) and then heat the stirred mixture on a steam bath for 5 hours.

The pH of the clear bright yellow solution resulting from K is adjusted to 7 by treatment with aqueous hydroxide solution (2N). The solution is then treated dropwise with an aqueous solution of the enzyme catalase (1 g, w/w) until all unreacted hydrogen peroxide is gone. The solution was subjected to ultrap-filtration to remove the enzyme, and the filtrate was lyophilized to 13-dichlorodihydroxy-bis(1-(2
-hydroxyethyl)-2-methyl-5-nitroimidazo/I/ -N5:l platinum W) (550 .mu.) is obtained in hydrated form, which decomposes at about 170.degree.

Elemental analysis (Pt(MNZ)2(12(OH)2:3.5
) C (%) Hji) N (4) for H20
0ρ1%) H2O (sub)) Calculated value: 21.08
5.14 12.06 10.12 9.2 Actual value: 2
0.41 3.84 11.91 10.0 (S 8
．． 9 Proceed in a similar manner but using the appropriate amount of cis-
When replaced with cyclobis(1,2-)methyl-5-nitroimidazole-NM)platinum (IF), dichloro-dihydroxy-bis(1,2-Umethyl-5-nitroimidazole-N5)platinum (IF) is obtained. Manufactured.

Example 10 Compounds 0 and P A suspension of 1-methyl-4-nitropirasif-4- -l (S811Iv) in water (30 mg) was stirred with mild heating at 50° C. ) and stirring continued for 1 hour with gentle heating. The solution changes color from cloudy red-orange to clear yellow;
A precipitate is then formed.

The mixture is cooled, the solids removed, and washed with diethyl ether to give dichloro-bis[1-methyl-4
-nitropifuzole-N5) Platinum(II) (670m
g) is obtained in the form of yellow crystals.

Elemental analysis - A transparent - Nihacho - Calculated value: 18.47 1.91 16.16 1
3.63 Actual value: 18.2 1.81 16.0
13.7 Working in a similar manner, but replacing the 1-methyl-4-nitroberazole used as starting material with an appropriate amount of bis(4-nitropyrazol-1-yl)methane, dichloro[bis(4 -nitropyrazole-1-
il) methane-N2. N) Platinum(II) Cm, p,
31 o C (decomposition)] is produced.

Elemental analysis 0 (%), H port) N (%) - 0 ft (!
%) Calculated value: 16.6B 1.20 16.6
7 14.0/) Actual value: 16.8 1.12 1
6.7 13.5 Example 11 Compound Q 5-Methyl-4-nitroisothiazole (375-
) is stirred with mild heating (50° C.), treated with potassium chloroplatinate (540 mg) and stirring is continued for 1 hour with mild heating. The solution turns from cloudy red-orange to clear yellow and a precipitate forms. The precipitate is filtered from the cooled mixture and washed with diethyl ether to give dichloro-bis[5-methyl-4
-nitrothiazole] platinum (n) [700■, II
1. p, 560℃ or higher (becomes dark at 260℃ or higher)
] is obtained in the form of yellow crystals.

Elemental analysis ``Chukuro''``Mount'' Yasushi) a4ji) S dull) Calculated value:
17:331.4510.1112.7911.57
Actual value: 17. [] 1.33 9.8 13.1
11.4 Example 12 Compound R Water (50rnt) Nakazutsu-Potassium chloroplatinate (621
) was stirred with mild heating (60 °C), treated with a solution of 3-methyl-5-nitroisothiazole (4521F) in acetone (15-), and continued stirring for 1 hour with mild heating. do. The resulting mixture is heated on a steam bath for 8 hours and then cooled. The precipitate formed is separated and washed with diethyl ether to form dichloro-his[6-methyl-5-nitrothiazole].
-Platinum (■) (530■) is obtained in the form of yellow crystals.

77- Elemental analysis 0 (%) H (%) Nφ) 0℃ (%) S (
b) Calculated value: 17.331.4510.11 12.
7911.57 Actual value: 17.4 1.5610.0
12. <S 11.5 Example 16 Compound metronigesy/l/(100#) in water (20 mg)
) (7) Pour the solution into potassium chloropalladate (K2pa
P'ojL6) (100 .mu.) and the mixture is left at room temperature for 24 hours. The yellow precipitate that forms is separated and washed with diethyl ether to give dichloro-bis[1-(2-hydroxyethyl)-2-methyl-5-
ditroimidazole-N3]palladium(II)[12
0ki, m, p, 244°C (decomposition)] is obtained.

Elemental analysis a&6) H value) N(4) Calculated value: 27.74 5.49 1 (5,1778- Actual value: 27.2 3.41 15.9 Reference example 1 Metronidazole (6, a5y) was dissolved in water ( 5[10m1.
) and stir with gentle heating (50° C.). Potassium monochloroplatinate (8,3F) is added and stirring is continued with gentle heating for 1 hour. The solution changes from cloudy red-orange to clear yellow and forms a precipitate. After cooling, the supernatant liquid is separated by decanting and its volume is reduced in a rotary evaporator to form further precipitate. The precipitates were combined, washed first with a mixture of ethanol and diethyl ether, then with diethyl ether, and air-dried to give cis-cyclobis[1-
(2-Hydroxyethyl)-2-methyl-5-nitroimitasole-NJn gold (■) (12,16F) was obtained in the form of yellow crystals, which melted at 178-181 °C and then solidified again. , and melts with decomposition at 257-259°C.

Reference Example 2 Dimetridazole (0,282F) is suspended in 20ml of water and stirred with gentle heating (50°C). Potassium chloroplatinate ((3,415t) is added,
Stirring is then continued for 1 hour with gentle heating. After cooling, the supernatant liquid is separated from the precipitate generated by decantation. Further solids precipitate when the volume of the supernatant is reduced using a rotary evaporator. The precipitates were combined, washed with a mixture of ethanol and diethyl ether, then diethyl ether, and then air-dried to give dichloro-bis(1,
2-:) Methyl-5-nitroimitazole-N6) Platinum ITI) (0,456f, m, p, 174-176°C)
is obtained.

Elemental analysis Cji) ” (Nji) Oki fL Calculated value: 21.89 2.55 15.32 12.9
5 Actual measurement value: 21.46 2.74 14.74 13
．． 20 Included within the scope of this invention are pharmaceutical compositions containing at least one compound of general formula (1) or a salt thereof together with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the invention may be administered orally or
It can be administered rectally, vaginally or parenterally.

Solid compositions for oral administration include compressed tablets, tablets, powders and granules. In such solid compositions one or more active substances are mixed with at least eleven inert diluents such as starch, sucrose or lactose. As is common practice, additives other than inert diluents, such as lubricants such as magnesium stearate, are also included in the composition.

81- Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art industry, such as water and liquid paraffin. Contains agents. Such compositions can contain, in addition to inert diluents, adjuvants such as wetting and suspending agents and sweetening, flavoring, perfuming, and preservative agents. Compositions for oral administration according to the invention also include capsules of absorbable material, such as gelatin, containing one or more active substances with or without diluents or excipients. .

Solid compositions for rectal or vaginal administration include:
Includes skewers and UQ trousers formulated in a manner known per se.

Formulations for parenteral administration according to the invention include sterile aqueous, aqueous-organic and organic 82- 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 also contain adjuvants such as stabilizers, preservatives, wetting agents,
Emulsifiers and dispersants may also be included. They can be sterilized, for example, by filtration using a bacterial filter, by incorporating a sterilizing agent into the composition, or by irradiation or heating. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or certain sterile injectable media immediately before use.

The percentage of active ingredient in the compositions of the invention may vary, but the proportions should be such that a suitable dosage will be obtained. Clearly, several dosage unit forms can be administered at about the same time. The dosage to be used will be determined by the physician and will depend on the desired therapeutic effect, route of administration and duration of treatment and health status of the patient. When administered in combination with cancer X-ray therapy to enhance the effectiveness of radiotherapy, 0 per body weight is usually administered before irradiating the cancer (generally within 5 hours before administering radiation).
．． The compound of general formula I is administered in doses of 1 to 500, preferably 1 to 200. Generally, in X-ray therapy for cancer, irradiation is repeated many times during the treatment process. For example 3
In practice, 15 to 20 repetitions over a period of ~4 weeks are carried out, and the compound of general formula I can be administered at the dosages indicated for each repetition of irradiation. When administered for the eradication of anaerobic bacteria or for the treatment of joint disorders, the dosage is generally 0.5 kg/Kp of body weight.
1 to 500 q, more particularly 1 to 200 η, and this dosage can also be administered repeatedly at regular intervals according to the physician's instructions.

Patent applicant: May & Baker Limited8
5- Continuation of page 1 Priority claim June 18, 1982 ■ United Kingdom (GB
) ■ 8217723 ■ June 18, 1982 ■ United Kingdom (GB) ■ 8217724 9 June 18, 1982 ■ United Kingdom (GB) ■ 8217725 @ June 18, 1982 [phase] United Kingdom (GB) ■ 82
17726 @ June 18, 1982 ■ United Kingdom (GB) ■ 8217727 0 Inventor Peter John Sadler 48 Hallowryld Park Crescent, Middlesex, United Kingdom

Claims (1)

[Claims] 1) General formula % formula %) [where Ml is gold (2), /ξradium ([[)
, rhodium(2), platinum□□□ or platinum (If) atom, xl represents a 3-14- or 5-(mono)nitropyrazole molecule, which is unsubstituted or has at least one substituent and can coordinate with the metal M1 at the 2-position of the pyrazole ring), or a 4- or 5-(mono)nitroisothiazole molecule, which is unsubstituted or carries at least one substituent. and coordinate with the metal M1), or Ml is gold (2), palladium (■
), rhodium (HD or platinum ω atom), XI also represents a 2-14- or 5-(mono)nitroimidazole molecule (which may be unsubstituted or carry at least one substituent) , and can coordinate with the metal M1 at the 6-position of the imidazole ring), and when more than one group X1 is contained in the compound of the general formula The thiazole or nidroimiguzole molecules may optionally be linked together, where zl and z2 each represent a pharmaceutically acceptable ligand, and (z5)- is a pharmaceutically acceptable anion. and m represents 2 or %, or when Ml represents a gold (2) atom, m represents 1, and when Ml represents a rhodium (2) atom, m
id 5 or 4, n represents 2, or) n Iri when 41 represents a gold (2) atom
3, Ml represents a rhodium (a) atom, if m represents 3, n represents 6, if m represents 4, n represents 2, p represents 0, and Ml represents When representing a platinum cup atom, p represents 2, q represents O, and Ml represents a rhodium (2) atom, m
represents 4, and when n represents 2, represents 1]. 2) Xl has at least one substituent 6-14-
or represents a 5-(mono)nitropyrazole molecule, 4-ma&fd5-(mono)nitrothiazole with at least one substituent, or Ml is gold, noradium, rhodium, or ) or a platinum atom, xl represents a 2-14- or 5-(mono)nitroimidazole molecule having at least one substituent. 3) The (mono)nitroimidazole molecule is 4- or 5-
The complex according to claim 1 or 2, which is a (mono)nitroimidazole. 4) If zl represents a halogen atom and z2 represents a halogen atom or a hydroxy group, or n represents at least 2, the pair of z1 ligands also has the general formula (where R1 and R2 are the same or different and each represents a hydrogen atom or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group, or 0RIRQ represents a cycloalkyl or cycloalkenyl group, and r is 0 or 1
4. A complex according to claim 1.2 or 3, which can also represent a bidentate ligand. 5) Regarding the definition of 0RIR2 in formula ■, alkyl and alkenyl groups contain up to 6 carbon atoms;
5. A complex according to claim 4, wherein the aryl group is phenyl and the cycloalkyl and cycloalkenyl groups have 3 to 8 carbon atoms. 6) The complex according to claim 4 or 5, wherein zl represents a chlorine atom. 7) Ml is palladium), platinum (foundation) or platinum 01
) atom, n represents at least 2, and the pair of z1 ligands is represented by the general formula (1) according to claim 4.
6. A complex according to claims 1 to 5, which represents a bidentate ligand having the following. 8) Ligands z1 and/or z2 are the same, -δ
- A complex according to claims 1 to 7. 9) Claims 1 to 3 in which z3 represents a halogen atom
Complex according to item 8. 10) Claims 1 to 1 in which Z6 represents a chlorine atom
Complex according to item 9. 11) 6-14- or 5- represented by the symbol x1
1 of the pyrazole ring of (mono)nitropyrazole (molecule)
a substituent at the -16-14- or 5-position, or 4
- or 5-substituent at the 3-14- or 5-position of the inthiazole ring of a (mono)nitroisothiazole molecule or the 1-12- or 2-14- or 5-of the imidazole ring of a (mono)nitroimidazole molecule. The substituent at the 4- or 5-position is unsubstituted or one selected from hydroxy alkoxyalkylsulfonyl, carboxy, alkoxycarbonyl, carbamoyloxy, pendylcarpamoyl and N-morpholinyl groups, and halogen. or an alkyl group substituted by several atoms or groups, a phenyl group substituted by one or several halogen atoms, and an alkylthio group substituted by carboxy and substituted by a phenoxy group, and with the symbol When the substituent in the substituted heterocyclic molecule represented by When the substituent in the ring molecule contains a free hydroxy group, it is an ester of phosphoric acid, phosphorous acid, and sulfuric acid, and a pharmaceutically acceptable cation-containing salt thereof, and xl is a carboxy group. 11. The complex according to claims 1 to 10, which is a pharmaceutically acceptable salt thereof when it represents a heterocycle having a substituent containing. 12) A complex according to claim 11, wherein the halogen substituent on the alkyl group is chlorine and the halogen substituent on phenyl is fluorine. 13) 1-14-1 or 5- whose heterocycle is an imidazole ring
a 2-(mono)nitroimidazole molecule having a substituent in at least one of the nitro-positions, or in at least one of the 1- or 2-positions of the imidazole ring, or 4 of the imidazole ring that is not occupied by a nitro group. 4- or 5 with a substituent in the - or 5-position
-(Mono)nitroimidazole molecule, the complex according to claims 1 to 12. 14) 4- or 5-(mono) in which the heterocycle has a substituent in the 2-position of the imidazole ring and is unsubstituted or substituted in the 1-position of the imidazole ring
Claims 1 to 2 are nitroimidazole molecules.
Complex according to item 13. 15) the imidazole ring is substituted at the 1-position,
A complex according to claim 14. 16) Symbol x1 is 1-(2-hydroxyethyl)-2-
Methyl-5-ditroimidazole, 1,2-dimethyl-
5-nitroimidazole, 1-methyl-2-isopropyl-5-nidoe' imidazole, 1-(2-ethylsulfonylethyl)-2-mef-5-nitroimitasole, 2-methyl-4-(t or 5)-nitroimidazole, 1-carboxymethyl-2-methyl-5-nitroimidazole, 1-(2-N-morpholinylethyl)-5
-Ditroimi/-〇-zole, 1-(3-chloro-2-hydroxy-n-propyl)-2-methyl-5-ditriimidazole, 1-methyl-2-carmemoyloxymethyl-5-di Troimi, dazole, 1-(2-hydroxy-n-propyl)-
2-methyl-5-ditroimidazole, 1-methyl-5
-Ditroimidazole% 2-C2-(4-carboxyphenoxy)ethylthio]-1-methyl-5-nidotetraimidazole, 1-(2-carbamoyloxyethyl)-
2-Methyl-5-ditroimidazole, 1-(2-hydroxyethyl)-2-(p-fluorophenyl)-5-
Nitroimidazole, 2-hydroxymethyl-1-methyl-5-nitroimidazole, 1-ethoxycarbonylmethyl-2-methyl-5-nitroimidazole 2-isopropyl-4(tl-t5)-nitro-10-imidazole, 2 -Hydroxymethyl-4 (or 5)
-nitroimidazole, 1-(2-hydroxyethyl)
-2-methyl-4-ditroimidazole, 1.2-:
) Methyl-4-nitroimidazole, 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, 1-(2-hydroxy-3-methoxy-n-
propyl)-2-nitroimidazole, N-benzyl-
1-(2-nitroimidazolyl)acetamide, 2-nitroimidazole or 4(5)-nitroimidazole, and the substituent at the 1- or 2-position of the substituted nitroimidazole molecule is a free hydroxy group. represents a monoester thereof with a dicarboxylic aliphatic acid, and a pharmaceutically acceptable salt thereof, and a substitution at the 1- or 2-position of the above-mentioned substituted nitroimidazole molecule. When the group contains a free hydroxy group, phosphoric, phosphorous or sulfuric esters thereof and pharmaceutically acceptable salts of such phosphoric, phosphorous and sulfuric esters, and pharmaceutically acceptable salts thereof; represents a salt containing a cation, and xl is 1-carboxymethyl-2-methyl-5-nitroimidazole or 2-(2-(4-carboxyphenoxy)ethylthio)-1-methyl-5-=)loimidazole The complex according to any one of claims 1 to 15, wherein the complex represents a pharmaceutically acceptable salt thereof. 17) The complex according to claims 1 to 16, wherein Xl represents 1-(2-hydroxyethyl)-2-methyl-5-ditroimidazole. 18) The complex according to claims 1 to 16, wherein xl represents 1-methyl-4-nitropyrazole. 19) The complex according to claims 1 to 16, wherein Xl is methylnitroisothiazole. 20) General formula % formula %[[ where X2 represents a substituted or unsubstituted (mono)nitroimidazole molecule as defined in claim 1, and z4 (representing a halogen atom)
Complexes according to Items 6 and 8 to 17. 21) General formula % formula %) (However, in the formula, X2 and z4 are defined in claim 20.
18. A complex according to claims 1 to 17, having the following properties: 13-22) General formula (wherein, X2 and z4 are defined in claim 20)
z5 is as defined in claim 1, and m, n and q
is as defined in claim 1, i.e. rn = 3, n = 3 and q = o mind is m = 4
, n=2 and (L=1). 25) General formula % formula % (However, in the formula, xl and z4 digits Claim No. 20
and z2, as defined in claim 1). 24) General formula % Formula % where z4 is as defined in claim 20 and X5 is substituted or substituted as defined in claim 1 1.2 and 4 to 12, representing a (mono)nitropyrazole molecule which is not 25) General formula % Formula % where Z4 is as defined in claim 20 and x4 is substituted or substituted as defined in claim 1 1.2 and 4 to 12, representing a (mono)nitroisothiazole molecule which is not 26) Trichloro-1-(2-hydroxyethyl)-2
-Methyl-5-nitroiotasol-N3]gold(a), trichloro-(1,2-:)methyl-5-nitroimidazole-N3)gold(a), )rif C1% -[1-(2- hydroxyethyl)-
2-Methyl-5-nitroiotasol-N3] gold (2)
, dichloro-bis[1-(2-hydroxyethyl)-2-
Methyl-5-ditroimidazole-N5 ] palladium (II), cyclorhobis (1,2-u methyl-5-nitroimidazole-N5 ) palladium (II), II cyclobis [1-(2-hydroxy- n-propyl)-2-
Methyl-5-nitroimidazole-N5 ] palladium (IF), dichloro-bis[1-(2-hydroxy-3
-Me)xy-n-propyl)-2-nidroimiguzole-N5) palladium ω), trichloro-tris(1-
(2-hydroxyethyl)-2-methyl-5-nitroimitazole-N5) rhodium, cyclotetrakis (1-(2-hydroxyethyl)
-2-Methyl-5-nitroimidazole-N5] rhodicum(a) chloride, teto')chloro-bis[1-(2-
Hydroxyethyl)-2-methyl-5-nitroimidazole-N5) Platinum Co., Ltd., Tetrachloro-bis(1,2-9methyl-5-nitroimidazole-H&) Platinum, Tetrachloro-bis1-
(2-hydroxy-n-propyl)-2-methyl-5-
Nido 17- loimidasilu N5] Platinum (Incorporated), dichloro-dihydroxy-bis[1-(2-hydroxyethyl)-2-
Mef-5-nitroimidazole-N3] platinum, dichloro-dihydroxy-bis(1,2-'; methyl-5-nitroimidazole-N5)l platinum dichloro-bis[1-methyl-4-nitropyrazole-N2 ]Platinum (I[), dichloro-[His(4-nitropyrazol-1-yl)
Methane-N? , N2', E] platinum (H), cyclolobis[5-methyl-4-nitroisothiazole] platinum (I
[), and cyclolobis[3-methyl-5-nitrothiazole]platinum C). 18-27) Nitropyrazole, nitroisothiazole or [Ml is gold 0, palladium (■), rhodium (E)
or when it represents a platinum ω atom (claim 1)
The nitroimidazole compound corresponding to the symbol
l, Zl, Z2, n o and p are as defined in claim 1, and Ml is rhodium (I
t) When representing an atom, S represents 0 and Ml represents gold (
2) When representing an atom, 6 represents 1, and Ml
represents a palladium 01), platinum and t represents 1). 28) A process according to claim 27, wherein when Ml represents a rhodium ωO atom, the reaction is carried out in the presence of a mild reducing agent. 29) General formula % formula %) (wherein Ml, xl, z2, z3, m1n, p and q are as defined in claim 1, and Yl is a halogen atom) A process for the preparation of complexes of the general formula (2), which comprises treating the complex with silver nitrate, optionally in an aqueous medium, and then with another source of ligand to replace Yl. 150) In the general formula as described in claim 29, Ml, xl, Z2, m. n, p and q are as defined in claim 1, and Yl is as defined in claim 29, and two ligands y1 (or gold compound and in the case of rhodium compounds in which n represents 3, two of the three ligands Y1) are present in the cis configuration] optionally treated with silver nitrate in an aqueous medium. and then treated in an aqueous medium with an acid of the general formula %, where R1, R2 and r are as defined in claim 4,
Then, the solution is made neutral by adding a suitable base.
2 represents a bidentate ligand of formula ■, and Ml, XI
, z2, z5. m%n, p and q are as defined in claim 1, and in the case of gold-21= compounds and rhodium compounds when n represents 3, the third ligand z1 is as defined in claim 1). 61) General formula % formula %) (wherein, Xl and zl are defined in claim 1
The platinum ω)-containing complex (as defined in Section 2)
When z2 represents a hydroxy group, oxidation is performed using hydrogen peroxide, and when z2 represents a halogen atom, oxidation is performed using an appropriate halogen. zl represents a halogen atom, z2 represents a halogen atom or a hydroxy group, and Xl, Zl, m, n1p and q are as defined in claim 1)
A method for producing a complex having 22-32, the symbol x as defined in claim 1
A nitropyrazole, nitrothiazole or nitroimidazole compound corresponding to 1 has the general formula %, where Q1 is as defined in claim 27, and zl is as defined in claim 1. of the general formula I, where Ml is palladium (Ir)
represents an atom, and xl, zl, z2, z5, m%n
, p and q are as defined in claim 1). 6! I) by using the heterocyclic compound in a pharmaceutically acceptable form in the process according to claims 27 to 62 or by converting the complex of general formula I into such a pharmaceutically acceptable form by methods known per se. a monoester with a dicarboxylic aliphatic acid, which consists of converting the complex into a salt acceptable to the dicarboxylic aliphatic acid, and the complex according to claim 1 (provided that the heterocyclic molecule represented by the symbol x1 of the complex is free). Pharmaceutically acceptable salts and complexes of phosphoric acid, phosphorous acid and sulfuric acid esters (having a substituent containing a hydroxy group) (provided that the heterocyclic compound represented by the symbol x1 of the complex has a substituent containing a carboxy group) A method for producing a pharmaceutically acceptable salt of. 64) The method of claims 27-'56 substantially as described in Examples 1-15 above. ! +5) The complex according to claim 1 or a pharmaceutically acceptable salt thereof, produced by the method according to claims 27 to 34. 36) A pharmaceutical composition comprising a complex of general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or coating. 67) A pharmaceutical composition according to claim 66 substantially as described above. 68) Claim 1 for use in treating cancer, optionally in combination with X-ray therapy, or in combating anaerobic bacteria, or in treating arthritis
A complex or a pharmaceutically acceptable salt thereof as described in Section 3.