JPH0762022B2 - Platinum complex compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel platinum complex compound having antitumor activity. More specifically, the present invention provides a novel antitumor α-
The present invention relates to a platinum complex compound having a hydroxycinnamic acid derivative as a ligand.

[Prior art]

Since the excellent antitumor activity of cisplatin (cis-dichlorodiamine platinum) was found [Nature, 222 , 385 (19
69)], a wide range of research and development as an antitumor agent has been carried out, and it is already clinically used in some countries now. However, cisplatin has strong side effects such as nephrotoxicity, nausea, vomiting, and deafness, and is poorly soluble in water and fat, and difficult to administer. There is. In order to overcome these drawbacks, many researchers have been actively conducting synthetic research on second-generation platinum complexes, which are more antitumor than cisplatin and have fewer side effects. Among these, platinum complexes such as cisdiammine (1,1-cyclobutanedicarboxylato) platinum (II), cisdichloro-trans-dihydroxy-bis (isopropylamine) platinum (IV) and cisdiammineglycolatoplatinum (II). In clinical studies, its clinical usefulness has been confirmed. [Cancer and Chemotherapy, Vol.14 (4), 1043 (1987)] Also, recently, as carrier ligant, 1,2-diaminocyclohexane, 2- (aminomethyl) cyclohexylamine,
Alicyclic diamines such as 1- (aminomethyl) cyclooctylamine are of interest and patents have been disclosed for many platinum complexes in combination with leving groups such as pyruvato, glycolato, cyclobutanedicarboxylate, substituted phthalatos. (For example, JP-A-61-171493, JP-A-61-229893, JP-A-61-87692, and JP-A-61-15892.
(See JP-A-62-59289, JP) [Problems to be Solved by the Invention] However, no sufficiently satisfactory antitumor activity has been found. An object of the present invention is to provide a novel platinum complex compound having excellent antitumor activity and few side effects.

As a result of intensive studies to solve the above-mentioned problems, the present inventors succeeded in synthesizing a novel platinum complex having an arylpyruvic acid as a ligand as a leving group, and this complex was transformed into P-388 mouse leukemia cells. On the other hand, it was confirmed that it has a strong growth inhibitory action, and the present invention was completed.

[Means for solving problems]

The present invention is represented by the following general formula (1) (In the formula, Is ethylenediamine, 1,2-diaminocyclohexane,
Represents N- (2-aminoethyl) pyrrolidine or 2-aminomethylpyridine, Ar is unsubstituted or substituted with a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group or a halogen atom. Represents an optional phenyl group. ) Relating to a novel platinum complex compound.

The platinum complex compound of the present invention represented by the general formula (1) is Platinum (II) characterized by having a diamine bidentate ligand represented by as a carrier ligand and having an unsubstituted or substituted benzylidene glycolato group as a leaving group
It is a complex. As the diamine bidentate ligand, ethylenediamine, 1,2-diaminocyclohexane, N- (2-aminoethyl) pyrrolidine or 2-aminomethylpyridine is used.

Further, for example, those having two asymmetric carbon atoms at the 1-position and the 2-position such as 1,2-diaminocyclohexane are three isomers, that is, trans-1, trans-d and cis isomers ( Meso isomers) exist, but in the present invention, all of these isomers alone or mixtures of these isomers are included.

On the other hand, an unsubstituted or substituted benzylidene glycolato group as a reeving group can be introduced by a corresponding α-hydroxycinnamic acid derivative. This α-hydroxycinnamic acid derivative is one isomer of the keto-enol tautomer of unsubstituted or substituted phenylpyruvic acid, and can be easily separated from the keto-enol mixture. (Refer to the following reference example) As an unsubstituted or substituted phenylpyruvic acid derivative which can be used, in addition to phenylpyruvic acid, 4-methylphenylpyruvic acid, 4-
Ethylphenylpyruvic acid, 4-isopropylphenylpyruvic acid, 2,4-dimethylphenylpyruvic acid, 3,4-
Dimethylphenylpyruvic acid, 4-methoxyphenylpyruvic acid, 3,4-dimethoxyphenylpyruvic acid, 4-
Chlorophenylpyruvic acid, 4-fluorophenylpyruvic acid, 4-bromophenylpyruvic acid, 3,4-dichlorophenylpyruvic acid, 3,5-dichlorophenylpyruvic acid, 2,4-dichlorophenylpyruvic acid, 2,4, difluorophenyl Pyruvate, 3,5-difluorophenylpyruvate, 4-methoxycarbonylphenylpyruvate, 4-hydroxycarbonylphenylpyruvate, 3-hydroxycarbonylphenylpyruvate, 4
Examples thereof include substituted phenylpyruvic acids such as hydroxyphenylpyruvic acid.

The platinum complex compound represented by the general formula (1) according to the present invention has the general formula (2) (In the formula, Represents the same meaning as described above. ) And a platinum dihydroxy complex represented by the general formula (3) (Wherein Ar represents the same meaning as described above).
-It can be produced by reacting with a hydroxycinnamic acid derivative.

Further, the platinum complex compound represented by the general formula (1) according to the present invention has the general formula (4) (In the formula, Represents the same meaning as described above. ) And a platinum dinitrate complex represented by the general formula (3) (Wherein Ar represents the same meaning as described above).
It can also be produced by reacting a hydroxycinnamic acid derivative in the presence of a base.

Although any of these reactions can be carried out in a suitable solvent, it is preferable to use water as the solvent, and a mixed solvent of water and a solvent such as alcohol, acetone, acetonitrile, or tetrahydrofuran that is sufficiently homogeneously mixed with water. It is also possible to react inside. Further, this reaction can be carried out within a range of low temperature to a high temperature at which the complex is not decomposed, but the reaction time can be shortened by carrying out under an appropriate heating condition of about 30 to 60 ° C. In the reaction of the complexes (2) and (4) with the α-hydroxycinnamic acid derivative (3), the α-hydroxycinnamic acid derivative (3) was added to the complexes (2) and (4) in 1- It is preferable to use 2 times the molar amount.

Further, as the base that can be used in the reaction of the dinitrato complex (4) and the α-hydroxycinnamic acid derivative (3), sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, etc. Inorganic bases and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium methoxide can be used. The amount of the base used is preferably 1 to 2 times the molar amount of the α-hydroxycinnamic acid derivative (3).

Platinum complexes represented by the general formulas (2) and (4), which are raw material complexes, are disclosed in, for example, JP-A-53-31648 and JP-A-56-500.
It can be prepared according to the method described in No. 849 and the like.

When the platinum complex of the present invention is examined for growth inhibitory activity against P-388 mouse leukemia tumor cells, for example, p-fluorobenzylidene glycolato (trans-l-1,2-diaminocyclohexane) which is a compound of the present invention is used.
Platinum can inhibit tumor cell growth by 50% at a concentration of 0.03 μg / ml.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. The melting point and spectral data of the obtained platinum complex are shown in Tables 2, 3 and 4.

Example 1 Dichloro (trans-l-1,2-diaminocyclohexane) platinum (II) (380 mg, 1.0 mmol) was added to silver nitrate (340 m
g, 2.0 mmol) aqueous solution (30 ml) was added, and the mixture was shielded from light at 3
Stir for hours. The silver chloride precipitate was filtered off, and the filtrate was 1%
An aqueous solution of potassium chloride was added and the precipitated silver chloride was filtered off.
The filtrate aqueous solution containing dinitrato (trans-l-1,2-diaminocyclohexane) platinum (II) was concentrated under reduced pressure, ethanol was added, and the precipitated white solid of the dinitratoplatinum (II) complex was isolated by filtration. This complex (430m
g) was newly dissolved in 30 ml of water, and the column was packed with OH ^- type ion exchange resin (Amberlite IRA400Cl- type was converted to OH ^- type at 50-60 ° C using 3N aqueous sodium hydroxide solution). Through dihydroxy (trans-l-1,2-
Diaminocyclohexane) platinum (II) aqueous solution (approx. 300 m
l) got. Α-Hydroxycinnamic acid (164
Acetone solution (50 ml) of mg, 1.0 mmol) was added, and the temperature was 40-50 ° C.
And stirred for 3 hours. After completion of the reaction, benzylidene glycolato (trans-l-1,2-diaminocyclohexane) platinum (II) which had precipitated was separated by filtration, washed with water and ethanol in this order, and dried in vacuum. The yield was 68% based on dinitratoplatinum (II).

The 400 MHz ¹ H-NMR spectrum is shown in FIG. 1.

Example 2 The dihydroxyplatinum (II) complex prepared by the same operation as in Example 1 and p-fluoro-α-hydroxycinnamic acid were reacted by the same operation as in Example 1 to obtain p-fluorobenzylidene glycolate (trans-l-1). , 2-Diaminocyclohexane) platinum (II) was obtained with a yield of 70%. 400MHz ¹
The 1 H-NMR spectrum is shown in Fig. 2.

Example 3 The dihydroxyplatinum (II) complex prepared by the same operation as in Example 1 and p-methoxy-α-hydroxycinnamic acid were reacted by the same operation as in Example 1 to obtain p-methoxybenzylidene glycolate (trans-l-1). , 2-Diaminocyclohexane) platinum (II) was obtained with a yield of 97%. 400MHz ¹
The 1 H-NMR spectrum is shown in Fig. 3.

Example 4 Dinitrato (trans-l-1,2-diaminocyclohexane) platinum (II) obtained by the same operation as in Example 1
(430 mg) was dissolved in 30 ml water. To this, 1.5 equivalents of the lithium salt of p-methyl-α-hydroxycinnamic acid prepared above was added, and the mixture was stirred in water at room temperature for 1 day. After the completion of the reaction, the precipitated solid is filtered, thoroughly washed with water and ethanol, and then vacuum dried to collect the target product, p-memelbenzylidene glycolate (trans-l-1,2-diaminocyclohexane) platinum (II). Obtained at a rate of 76%.

Example 5 Dichloro [2- (aminomethyl) pyridine] platinum (II)
An aqueous solution (100 ml) of silver nitrate (2.62 g, 15.42 mmol) was added to (2.89 g, 7.724 mmol), and the mixture was stirred at 60 ° C. for 3 hours in the dark. The silver chloride precipitate was filtered off, and a 1% aqueous potassium chloride solution was added to the filtrate, and the precipitated silver chloride was filtered off. An aqueous filtrate solution containing dinitrato [2- (aminomethyl) pyridine] platinum (II) was concentrated under reduced pressure, ethanol was added, and a white solid of a precipitated dinitratoplatinum (II) complex (2.87 g) was isolated by filtration. This complex (427 mg) was newly dissolved in 30 ml of water, and α-hydroxycinnamic acid (164 mg) was added thereto.
Sodium hydroxide aqueous solution (20 ml) was added and stirred at room temperature for 1 hour. After completion of the reaction, the precipitated solid was filtered, thoroughly washed with water and ethanol, and dried in vacuum to obtain the desired product benzylidene glycolato [2- (aminomethyl) pyridine] platinum (II) with a yield of 54%. It was found from its 400 MHz ¹ H-NMR spectrum (FIG. 5) that this product was an approximately 1: 1 mixture of two geometric isomers as shown in the above reaction formula. Example 6 Dihydroxy (ethylenediamine) platinum ( Using the II) complex and p-chloro-α-hydroxycinnamic acid as starting materials, p-chlorobenzylidene glycolato (ethylenediamine) platinum (II) was obtained in a yield of 92% by the same procedure as in Example 1.

Example 7 Using dihydroxy (ethylenediamine) platinum (II) complex and p-fluoro-α-hydroxycinnamic acid as raw materials,
By the same operation as in Example 1, the yield of p-fluorobenzylidene glycolato (ethylenediamine) platinum (II) was 88%.
Got with.

Example 8 Using dihydroxy (ethylenediamine) platinum (II) complex and p-methoxy-α-hydroxyketocinnamic acid as raw materials,
By the same operation as in Example 1, p-methoxybenzylidene glycolato (ethylenediamine) platinum (II) was obtained in a yield of 95%.
Got with.

Example 9 Using the dihydroxy (ethylenediamine) platinum (II) complex and α-hydroxycinnamic acid as starting materials, benzylidene glycolato (ethylenediamine) platinum (II) was obtained in a yield of 93% by the same procedure as in Example 1.

Example 10 A dibenzylato [1- (2-aminoethyl) pyrrolidine] platinum (II) complex and α-hydroxycinnamic acid were used as raw materials and the same procedure as in Example 5 was repeated to obtain benzylidene glycolato [1- (2-aminoethyl). ) Pyrrolidine] Platinum (II)
Was obtained with a yield of 82%.

Example 11 Dinitrato (1,2-diaminocyclohexane) platinum (I
I) The complex and 2,4-dimethyl-α-hydroxycinnamic acid were used as raw materials, and 2,4-dimethylbenzylidene glycolato (1,2-diaminocyclohexane) platinum (II) was collected by the same operation as in Example 5. The rate was 87%.

Example 12 The dihydroxyplatinum (II) complex prepared by the same procedure as in Example 1 and p-hydroxygalbonyl-α-hydroxycinnamic acid were reacted by the same procedure as in Example 1 to give p-
Hydroxycarbonyl benzylitene glycolate (trans-l-1,2-diaminocyclohexane) platinum (II) was obtained with a yield of 77%.

Reference Example 1 Chloroform was added to phenylpyruvic acid (mixture of keto-enol tautomers), stirred sufficiently, and insoluble white crystals were isolated by filtration. This was almost pure phenylpyruvic acid enol form (α-hydroxycinnamic acid). By removing the solvent from the filtrate, the keto form can be isolated in a substantially pure form. However, when the enol form is mixed, the same operation is repeated to obtain the pure phenylpyruvic acid (keto form). ) Can be obtained.

Table 1 shows the platinum complex compounds synthesized by the method shown in the above examples.

Pharmacological efficacy test example 1 [Proliferation inhibitory effect on mouse and lymphocytic leukemia cultured cells (P388)] 5 × 10 ⁴ mouse and lymphocytic leukemia cultured cells (P388) were added to 10% fetal calf serum-containing RPAI-1640 culture solution. Cells / ml, and cultured 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 prepared from the growth inhibition rate for the compound-free example, and the IC ₅₀ was determined. The results are shown in Table-5.

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

[Brief description of drawings]

1 to 5 are 400 MHz NMR spectra of each compound of compound numbers 1 to 5 corresponding to Examples 1 to 5. FIG. 6 is a compound corresponding to Example 10 of compound No. 10 400M
It is a Hz NMR spectrum.

Claims (1)

[Claims] 1. A general formula (In the formula, Is ethylenediamine, 1,2-diaminocyclohexane,
Represents N- (2-aminoethyl) pyrrolidine or 2-aminomethylpyridine, Ar is unsubstituted or substituted with a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group or a halogen atom. Represents an optional phenyl group. ) Platinum complex compound represented by.