JPH02294A - Platinum coordination compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [AB is diamine bidentate ligand; Ar is (substituted) phenyl; R is lower alkyl]. EXAMPLE:$/Bis (beta-methylphenylpyruvato) (trans-l-1, 2-diaminocyclohexane) platinum(II). USE:An antitumor agent. PREPARATION:A platinum dihydroxy complex expressed by formula II is reacted with a 3-aryl-2-oxocarboxylic acid derivative expressed by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel platinum coordination compounds having antitumor activity. More specifically, the present invention provides novel antitumor 3-
The present invention relates to a platinum coordination compound having an aryl-2-oxocarboxylic acid derivative as a ligand.

[Conventional technology]

Since the discovery of excellent antitumor activity in cisplatin (cis-dichlorodiammine platinum) (Nature.

See also Lord 1.385 (1969)], its anti-I! Extensive development research has been carried out as a tumor autopsy, and it is now already in clinical use in several countries.

However, cisplatin has strong side effects such as nephrotoxicity, nausea, vomiting, and hearing loss, and has low water and fat solubility, making it difficult to administer. There is a limit. In order to overcome these drawbacks, many researchers are actively conducting research on the synthesis of second-generation platinum complexes that have stronger antitumor properties and fewer side effects than cisplatin. Under these circumstances, cis-diammine (1,1-cyclobutanediylupoxylate) platinum (
Platinum complexes such as (■), cis-dichloro-trans-dihydroxybisisoprobylamine) platinum (■), and cis-diammine glycolado platinum (II) are known to have clinical usefulness in clinical trials [Cancer and Chemistry]. Therapy, earthworks
(4), 1043 (1987)], and recently as carrier ligands, 1,2-diaminocyclohexane, 2-(aminomethyl)cyclohexylamine, 1
Alicyclic diamines such as -(aminomethyl)cyclooctylamine have attracted attention, and many technologies have been disclosed regarding platinum complexes in combination with leaving groups such as pyruvate, glycolad, cyclobutane dicarboxylad, and substituted phthalad.

(For example, JP-A-61-171493, JP-A-61-
No. 229893, JP-A-61-87692, JP-A-6
No. 1-15892, JP-A-62-59289, Publications).

[Problem that the invention seeks to solve]

However, no one has yet been found that is sufficiently satisfactory in its antitumor activity.The purpose of the present invention is to provide a novel platinum complex with excellent antitumor activity and fewer side effects! It's about offering one meal.

As a result of intensive studies to solve the above problems, the present inventors succeeded in synthesizing a new platinum coordination compound having 3-aryl-2-oxocarboxylic acid as a ligand as a leaving group, and this compound It was confirmed that P-388 mouse leukemia cells have a strong growth-inhibiting effect, leading to the completion of the present invention.

[Means for solving problems]

The present invention relates to a novel platinum coordination compound represented by the general formula (wherein AB represents a diamine bidentate ligand, Ar represents an unsubstituted or substituted phenyl group, and R represents a lower alkyl group). 7 The clear gold coordination compound of the present invention represented by the general formula (1) is
A diamine bidentate ligand represented by Ar3 is used as a carrier ligand, and 3-aryl-2 is used as a leaving group.
- It is a platinum (n) iff substance characterized by having an oxocarboxilado group.

As the diamine bidentate ligand, ethylendiamine, 1.
2-diaminopropane, 1,3-diaminopropane, 1
．． 3-diaminobutane, 2,3-diaminobutane, N,
Aliphatic chain diamine compounds such as N'-dimethylethylenediamine, 1,2-diaminocyclohexane, 1,2
-Diaminocyclopenkune, 1,2-diaminocyclohebutane, 1゜2-diaminocyclooctane, 2-(aminomethyl)cyclopentylamine, 2-(aminomethyl)cyclohexylamine, 2-(aminomethyl)cyclooctylamine , 2-(aminomethyl)pyrrolidine, N
Examples include alicyclic diamine derivatives such as -ethyl-2-(aminomethyl)pyrrolidine, 2-(aminomethyl)piperidine, N(2-aminoethyl)pyrrolidine, and N-(2-aminoethyl)piperidine. .

Also, for example, those having two asymmetric carbon atoms at the 1st and 2nd positions, such as 1,2-diaminocyclohexane, have 3
Although there are isomers of the species, ie, trans-11 trans-d, and cis isomer (meso isomer), the present invention includes all those in which these isomers alone or a mixture thereof are used as a ligand.

On the other hand, 3-end-rou 2- as a leaving group
Examples of oxocarboxylic acids include 3-phenyl-2-oxobutanoic acid, 3-(4'-methylphenyl)-2-oxobutanoic acid, 3-(4'-ethylphenyl)-2-oxobutanoic acid, 3-(4' -isoprobylphenyl)-2-
Oxobutanoic acid, 3-(4'-isobutylphenyl)-
2-oxobutanoic acid, 3-(2',4'-dimethylphenyl)-2-oxobutanoic acid, 3-(3',4'-dimethylphenyl)-2-oxobutanoic acid, 3-(4'cyclohexylphenyl) -2-oxobutanoic acid, 3-(4
'-Methoxyphenyl)-2-oxbutan fi, 3-
(3',4'-dimethoxyphenyl)-2-oxobutanoic acid, 3-(4'-chlorophenyl)-2-oxobutanoic acid, 3-(4'-fluorophenyl)-2-oxobutanoic acid, 3(4'- bromophenyl)-2-oxobutanoic acid, 3-(3',4'-dichlorophenyl)-2-
Oxobutanoic acid, 3-(3',4'-difluorophenyl)-2-oxobutanoic acid, 3-(3',5'-difluorophenyl)-2-oxobutanoic acid, 3-(4'-
Nitrophenyl)-2-oxobutanoic acid, 3-(4'-
dimethylaminophenyl) = 2-oxitubutanoic acid, 3-
(4'-acenalaminophenyl)-2-oxobutanoic acid, 3-(3'-methylphenyl)-2-oxobutanoic acid, 3-(3'-methoxyphenyl)-2-oxobutanoic acid, 3- (4'-n propylphenyl)2-oxobutanoic acid, 3-(3',4'-methylenedioxyphenyl)-2-oxobutanoic acid, 3-(4'-phenoxyphenyl)-2-oxobutane #3-phenyl-2
-Oxopenconic acid, 3-(4'-methylphenyl)-
2-oxopentanoic acid, 3-(4'-ethylphenyl)
-2-Oxopentanoic acid, 3-(4'-isobutylphenyl)-2-oxopencuic acid, 3-(4'-chlorophenyl)-2-oxopencune M, 3-(4'-fluorophenyl)-2-oxopentane Examples include acids such as 3-(4'-bromophenyl)-2-oxopentanoic acid.

The platinum coordination compound represented by the general formula (1) according to the present invention comprises a platinum dihydroxy complex represented by the general formula (wherein AB represents the same meaning as above) and a 3-aryl- It can be produced by reacting with a 2-oxocarboxylic acid derivative.

Furthermore, the platinum coordination compound represented by the general formula (1) according to the present invention includes a platinum dinitrado complex represented by the formula (in the formula, AB represents the same meaning as above) and a platinum dinitrado complex represented by the general formula (3). 3- shown
It can be produced by reacting an aryl-2-oxocarboxylic acid derivative in the presence of a base. In this reaction, a 3-aryl-2-oxocarboxylic acid derivative and a base are reacted in advance, and -a formula (wherein 71.r and R represent the same meanings as above) is used.
(In the formula, Ar and R represent the same meanings as above, and M represents an alkali metal.) By reacting this with the dinitradoplatinum complex (4), the general The compound of the present invention represented by formula (1) can be produced.

In any of these reactions, the reaction can be carried out in a suitable solvent, but it is preferable to use water as the solvent. The reaction can also be carried out in a mixed solvent. Further, this reaction can be carried out at a temperature ranging from a low temperature to a high temperature that does not decompose the complex, but the reaction time can be shortened by carrying out the reaction under appropriate heating conditions of about 30 to 60°C.

Raw material platinum complex (2) or (4) and carboxylic acid derivative (3)
) is reacted with its metal salt (3') to form complexes (2) and (4) with carboxylic acid derivatives (3) and (3).
'), for complexes (2) and (4),
The carboxylic acid derivatives (3) and (3') are preferably used in an amount of 2 to 3 times the mole.

Further, in the reaction between the dinitradoplatinum complex (4) and the 3-aryl-2-oxocarboxylic acid derivative (3), it is necessary to carry out the reaction in the presence of a base. Usable bases include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and sodium methoxide, sodium ethoxide,
Alkali metal alkoxides such as potassium methoxide can be used. The amount of the base to be used is preferably 1 to 2 times the mole of the 3-aryl-2-oxocarboxylic acid derivative (3).

The platinum complexes represented by general formulas (2) and (4), which are raw material complexes, can be prepared, for example, according to the methods described in JP-A-53-31648, JP-A-56-500849, and the like.

Typical platinum compounds of the present invention are shown in Table 1: New Platinum Coordination Compounds.

Table-1 Novel Platinum Coordination Compounds (Continued) Table-1 Novel Platinum Coordination Compounds (Continued) The platinum coordination compound of the present invention can be used, for example, for P-388 murine leukemia I! ! When examining the growth inhibitory activity against tumor cells, for example, the compound of the present invention, bis(β-methylphenylpyruvato)(trans-1-1°2-diaminocyclohexane)platinum, was tested in mice at a concentration of 0.19 μg/m1. P-388L can inhibit tumor cell growth by 50%.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Test Examples. The melting point, elemental analysis values, and spectrum measurements of the new platinum coordination compound obtained in this way were
Shown in Table and Table 3.

Example 1 An aqueous solution of nitric acid (340 qr, 1.0 mmol) was added to dichloro(trans-J-1,2-diaminocyclohexane) ζ (TI) (380 qr, 2.0 mmol), and the mixture was heated at 60°C in the dark. The mixture was stirred for 3 hours.

The silver chloride precipitate was filtered off, and a 1% potassium chloride aqueous solution was added to the filtrate, and the precipitated silver chloride was filtered off. The filtrate aqueous solution containing dinitrado(trans-ffi-1,2-diaminocyclohexane)platinum(n) was poured into a tank under reduced pressure, ethanol was added, and the precipitated white solid of dinitradoplatinum(II) complex was isolated by filtration. . This complex (215■
, 0.50rnmo
Dihydroxy (trans-6-1,
2-diaminocyclohexane) platinum (■ aqueous solution (approximately 1
50ml) was obtained. Add 3-phenyl-2-oxobutanoic acid (225 μm) to this aqueous solution.

1.26 mmol) was added and stirred at room temperature for 3 hours. After the reaction, bis(β-methylphenylbilbat) was precipitated.
(trans-1-1,2-diaminocyclohexane)platinum (■) [Compound No. 1] was filtered off, washed with water, and then dried under reduced pressure. The yield was 61% based on the dinitradoplatinum (■) complex.

Example 2 NH□ OH C.I.

Dinitrad (trans-1
-1,2-dianocyclohexane)platinum(II) (
215 g, 0.50 mmo 1-) of dihydroxy(trans-1-1,2-diaminocyclohexane)platinum (
II), and 3-(p-fluorophenyl-2-oxobutanoic acid (246nr, 1
．． After the completion of the reaction, bis(β-methyl(p-fluorophenylpyruvato))(trans-j!-1,2-diaminocyclohexane)platinum (■) [compound Number 2] was filtered out,
After washing with water, it was dried under reduced pressure. The yield is dinitradoplatinum (n
) was 69% based on the complex.

Example 3 OH2 Ox HS Phenyl-2-oxobutanoic acid (93,0■, 0.52
mmol) aqueous solution (20 ml) and IN sodium hydroxide aqueous solution (0.6 ml) were added and stirred at room temperature for 6 hours. After the completion of the reaction, (β-methylphenylpyruvato) (trans-1-1,2 -diaminocyclohexane) platinum (■) [Compound No. 1] was filtered off, washed with water, and then dried under reduced pressure. The yield was 48% based on dinitradoplatinum(II).

00CH.

Dinitrado(trans-7-1,2-diaminocyclohexane)platinum (■
) (100m, 0.23mmo 1) to water (30n
1) and dried in this aqueous solution. The yield is 6 based on dinitradoplatinum(II).
It was 9%.

Example 5 II ll 00CH* Dinitrado(trans-1-1,2-diaminocyclohexane)platinum(I
I) 3-phenyl-2-oxobutanoic acid sodium salt (100s+r, 0.23mmo 1) in an aqueous solution
88.0+qr, 0.48 mmo 1) was added and stirred at room temperature for 6 hours. After the completion of the reaction, the precipitated bis(β-methylphenylpyruvato)(trans-!-1,2-diaminocyclohexane)platinum(II) [Compound No. 1] was filtered off, washed with water, and then dried under reduced pressure (00C)Is. Dinitrado(trans-1-1,2-diaminocyclohexane)platinum (u
) (100■, 0.23mmol) in an aqueous solution of 3
-(p-cyclohexylphenyl)2-oxobutanoic acid sodium salt (134■.

0.47 mmol) and stirred at room temperature for 6 hours.

After the reaction was completed, the precipitated bis(β-methyl(p-cyclohexylphenylpyruvato))(trans-11,2-diaminocyclohexane)platinum (11) [Compound No. 3] was filtered off, washed with water, and then dried under reduced pressure. did. The yield was 70% based on dinitradoplatinum (n).

Example 6 Sodium acid salt (520m, 2.03mmo 1) was added and stirred at room temperature for 6 hours. Bis(β-methyl(p-isobutylphenylbilbat)) precipitated after the completion of the reaction (
Trans-/-1,2-diaminocyclohexane) platinum (■) [Compound No. 4] was separated by filtration, washed with water, and then dried under reduced pressure. The yield was 79% based on 18 dinitradoplatinum(II) bodies.

Example 7 ooct+.

To an aqueous solution of dinitrado(trans-f-1,2-diaminocyclohexane) platinum complex (433 mg, 1.0 mmol) prepared by the same method as in Example 1, p-isobutylphenyl-2-oxobuta1h NOl C10°0CIIs 1 Group 00CI (s dichloro(trans-d!-1,2-diaminocyclohexane) platinum (■”) (380■, 1.Ommol
) was added with an aqueous solution of silver nitrate (340 μm, 2.0 mmol 1), and the mixture was stirred at 60° C. for 3 hours in the dark. The silver chloride precipitate was removed by filtration, and a 1% aqueous potassium chloride solution was added to the filtrate, and the precipitated silver chloride was removed by filtration.

The filtrate aqueous solution containing dinitrado(trans-dl-1,2-diaminocyclohediFsan)platinum(II) was dried under reduced pressure at 1/Q km, and ethanol was added to precipitate a white solid of the R form of dinitradoplatinum(n). was isolated by filtration. This complex (1031W, 0.24mmo 1) was newly added to 3
Dissolved in 9 ml of water. To this aqueous solution was added 3-phenyl-2-oxobutanoic acid sodium salt (150 g, 0.0 g).
An aqueous solution (50 ml) of 81 mmo No. 5] was filtered out, washed with water, and then dried under reduced pressure. The yield was 79% based on dinitradoplatinum(II).

Example 8 3-(p-isobutylphenyl)- was added to an aqueous solution of dinitrado(trans-dI-1,2-diaminocyclohexane)platinum complex (50, OLIw, 0.115 mmol) prepared by the same method as Example 7. An aqueous solution (50 ml) of sodium 2-oxobutanoate (66,0+v, 0.24 mmol) was added and stirred at room temperature for 3 hours. Bis(β-isobutylphenylpyruvato) precipitated after the completion of the reaction. -diaminocyclohexane) platinum (U) [Compound No. 6] was separated by filtration, washed with water, and then dried under reduced pressure. The yield was 76% based on dinitradoplatinum(II).

Example 9 Dichloroethylenediamine platinum (II) (2000
w, 6.13 mmol), nitric acid m (2080 w.

An aqueous solution of 12.2 mmol 1) was added, and the mixture was stirred at 60° C. for 3 hours in the dark. The silver chloride precipitate was filtered off, and the filtrate was further added with 1
% potassium chloride aqueous solution was added, and the precipitated silver chloride was filtered off. The filtrate aqueous solution containing dichloroethylenediamineplatinum (TI) was concentrated under reduced pressure, ethanol was added, and the precipitated solid dinitradoplatinum (n) complex was isolated by filtration.

This complex (100 g, 0.264 mmo +) was freshly dissolved in 3 Q m 1 of water. To this aqueous solution was added 3-phenyl 2-oxobutanoic acid sodium salt (106 μm).

Bis(β-methylphenylpyruvato)ethylenediamine platinum (■) was precipitated after one reaction, in which an aqueous solution (50ml) of 0.527mmol) was added and stirred at room temperature for 6 hours.
[Compound No. 7] was separated by filtration, washed with water, and then dried under reduced pressure. The yield was 71% based on dinitradoplatinum(II).

fruit Execution example It was 73% based on the standard.

Example QCHs Dinitradoethylenediamine platinum complex (200■, 0.527mmo+) prepared by the same method as Example 9
3-(p-fluorophenyl)-2-oxobutanoic acid sodium salt (230 tries, 1.05 mmo
1) was added and stirred at room temperature for 6 hours. After the completion of the reaction, bis(β-methyl(p-fluorophenylpyruvat)) was precipitated.
Ethylenediamine platinum (■) [Compound No. 8] was filtered off, washed with water, and then dried under reduced pressure. Yield is dinitradoplatinum<n)0CHs Dinitradoethylenediamine platinum complex prepared by the same method as in Example 9 (221■, 0.583 mmol)
To an aqueous solution (30 ml) of 3-(p-isobutylphenyl)-2-oxobutanoic acid sodium salt (500 sir
, 1.95 mmo +) and stirred at room temperature for 6 hours. After the completion of the reaction, the precipitated bis(β-methyl(p-isobutylphenylbilbat))ethylenediamine platinum complex [Compound No. 9] was separated by filtration and diluted with water. After washing, it was dried under reduced pressure. The yield was 73% based on dinitradoplatinum(n).

Example 12 II II 1 0CHs 3-( Sodium p-methylphenyl)-2-oxobutanoate (198μ, 0.46mmol) was added and stirred at room temperature for 6 hours. After the completion of the reaction, bis(β-methyl(p-methylphenylbilbat)) (trans -J
-1,2-diaminocyclohexane) platinum (■) [Compound No. 10] was filtered off, washed with water, and then dried under reduced pressure. After the completion of the reaction, bis(β-methyl(p-methylphenylpyruvato))(trans-J-1,2-diaminocyclohexane)platinum (■ ) [Compound number was given.

■0CH3 Dinitrado(trans-1-1,2-diaminocyclohexane)platinum(I
f) 3 in an aqueous solution of (200 m, 0.46 mmol)
-(p-Methoxyphenyl)-2oxobutanoic acid sodium salt (212■, 0.460CHs Dinitrad (trans-1-1,2-diaminocyclohexy-2-oxobutanoic acid sodium salt) prepared by the same method as Example 1 (225■.

0.46 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours.

After the completion of the reaction, the precipitated bis(β-methyl(p-hal(t)
,.

probylphenylpyruvat)) (trans-#-1,2
-diaminocyclohexane)platinum(II) Example 15 Dinitrado(trans-J-1,2-diaminocyclohexane)platinum(II) prepared by a method similar to Example 1
) (200 g, 0.46 mmo +) in an aqueous solution of 3
-(p-phenoxyphenyl)-2oxobutanoic acid sodium salt (270 μ, 1.0 mmol) was added and stirred at room temperature for 6 hours. )) (trans-1
-1,2-diaminocyclohexane) platinum (■) [Compound No. 15] was separated by filtration, washed with water, and then dried under reduced pressure.

The yield was 78% based on dinitradoplatinum(II).

Example 0 Hexane) Platinum (■) [Compound No. 12] was separated by filtration,
After washing with water, it was dried under reduced pressure. The yield is dinitradoplatinum (n
) was 53%.

001’ll.

■ Dinitrado(trans-!-diaminocyclohexane)platinum(Il) (2
00m, 0.46mmol) in an aqueous solution of 3-(m-methylphenyl)-2-oxobutanoic acid sodium salt (1
98+W, 0.46 mmol was added and stirred at room temperature for 6 hours. Bis(β-methyl(m-methylphenylpyruvato)) (trans-1-1,2-diaminosic pharmacological efficacy test example) Growth inhibitory effect on cultured mouse lymphocytic leukemia cells (P-388)] Cultured mouse lymphocytic leukemia cells (P-388) were
5X1 in RPAI-1640 medium supplemented with % live fetal serum.
It was adjusted to 0' cells/ml and incubated at 37° C. for 48 hours in the presence of the compound of the present invention. The number of floating cells was measured using a Coulter counter, and a dose-response curve was created based on the growth inhibition rate relative to the sample without the addition of the compound, and ICI was performed. I asked for The results are shown in Table 4.

Although 0.5% or less DMSO coexisted as a solvent for the compound, the growth inhibition rate in the presence of 0.5% DMSO was 10% or less.

Table-4 Mouse leukemia cultured cells containing platinum coordination compound (P-388)
Growth inhibitory effect

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, AB represents a diamine bidentate ligand. Ar represents an unsubstituted or substituted phenyl group, and R represents a lower alkyl group.) A platinum coordination compound represented by