JPS61293990A - Novel organoplatinum compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is formula II; R is H or lower alkyl). EXAMPLE:cis-[Glycolato(2-)-O<1>, O<2>](2-aminomethylpyridine)platinum(II). USE:An antitumor agent having low toxicity. PREPARATION:A complex expressed by formula III is reacted with a compound expressed by formula IV, preferably in an aqueous solution at 30-70 deg.C within 10 day s or a complex expressed by formula V is treated with a base, preferably in aqueous solution at 30-70 deg.C. For, example, the complex expressed by formula III is a novel substance and can be produced by treating a complex expressed by formula VI with a base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an organic platinum complex useful as a pharmaceutical compound and a method for producing the same.

[Prior art]

Cisp♂paper [Chemical name: cis-dichlorodiammine platinum (
H) ) was discovered to have antitumor effects [
Nature + - (Nature) e Vol. 222, 38
5 (1969)], organic platinum complexes using various amines as ligands have been synthesized, and their antitumor effects have been investigated. However, these platinum complexes are known to be toxic to the W viscera and auditory organs [e.g.
and chemotherapy (0ancer and che
*Volume 3, page 133 (198
1)). Therefore, the development of organic platinum complexes with strong antitumor effects and low toxicity is desired.

[Structure and effects of the invention]

The organic platinum complex of the present invention is represented by the following general formula (however,
A represents a group represented by the formula: -o-cocH-o-, and R represents a hydrogen atom or a lower alkyl group. ) The organic platinum complex (I) of the present invention exhibits excellent antitumor activity and is a compound useful as a medicine. For example, leukemia L-
When examining the survival effect on mice transplanted with 1210 cells, the compound of the present invention, cis-[glycolide (2
-)-0", 0" (2-aminomethylpyridine) platinum (I) was administered intraperitoneally at 50 W/ky/day.
The survival period of the mice can be extended by more than 700%. In addition, the organoplatinum complex (1) of the present invention has low toxicity. For this reason.

The organic platinum complex of the present invention is effective against prostate cancer and light tumors.

It can be used to treat ovarian cancer, malignant lymphoma, leukemia, breast cancer and other malignant tumors.

As the organic platinum complex of the present invention, in general formula (1),
Compounds in which R is a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group can be mentioned. Among these, preferred compounds include the general formula (
Compounds in which R is a hydrogen atom or a methyl group can be mentioned.

Further, the complex (1) of the present invention is a planar complex.

It can take any of the following structures (1-a) and (I-b).

(T-a) (1-b) (However, R has the same meaning as above.) Furthermore, for complex (1-a) and complex (I-b).

When the group R is a lower alkyl group, there may be an optically active form based on the asymmetric carbon atom of the group represented by the formula: -o-coaH-o-. Therefore, the organoplatinum complex (I) of the present invention is the above complex (1-a), the complex (
1-b), mixtures thereof, complex (I-a) or complex (
According to the present invention, the complex (I) includes both the optically active form of 1'-b) and any mixture of such optically active forms. (However, R has the same meaning as above) or by treating a complex represented by the general formula (However, R has the same meaning as above) with a base. can do.

The reaction between the complex (...) and the compound ([) is in an aqueous solution.

It can be implemented as appropriate. The reaction is carried out at 0 to 100°C
It is particularly preferable to carry out the reaction at a temperature of 30 to 70°C. The reaction will be completed within 10 days if carried out at room temperature, but the nine reactions can be completed in a short period of time by heating.

On the other hand, the base treatment of the complex (ff) can be appropriately carried out in an aqueous solution. For example, the base is 1.

Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide: Alkali metal carbonates such as sodium carbonate and potassium carbonate can be used. The reaction is 0N10
Preferably it is carried out at 0°C, especially at 30-70°C.

The raw material complex (fl) of the present invention is novel and can be produced, for example, by treating a complex represented by the formula with a base. The base treatment is 0. For example, an aqueous solution of complex (V) is OH
type anion exchange resin [for example, Amberlite (A, m
berite) I RA 400 (manufactured by Rohm and Haas), Diaon SA-
2OA (manufactured by Mitsubishi Chemical Industries, Ltd.), Dovex (Dovr)
ex) X (manufactured by Dow Chemical Company)]. Furthermore, since complex (II) is unstable in a solid state, 9 it is usually preferable to use it in the next reaction step as a solution.

On the other hand, the raw material complex (IT) is 9, for example, JP-A-59-139
It can be produced according to the method described in No. 360.

When the organic platinum complex (i) of the present invention is used for medical purposes,
Any dosage form suitable for oral or parenteral administration may be used, but parenteral administration is particularly preferred. Moreover, the organic platinum complex (1) can also be used in combination with an excipient. Suitable excipients include, for example, gelatin, lactose,
Mention may be made of glucose, salt, starch, magnesium stearate, talc, vegetable oils and other pharmaceutical excipients. The formulation may be a solid formulation such as a tablet, pill, or capsule, or a liquid formulation such as a solution, suspension, or emulsion. Furthermore, when compound (1) is administered parenterally, it can be used as an injection or a half-open form,
Injections are particularly preferred. For injections, compound (I) can be used in the form of an isotonic solution. As the tonicity agent in this case, for example, mannitol, sodium chloride, glucose, sorbitol, glycerol, xyl alcohol, fructose, maltose, mannose, etc. can all be suitably used. The preparation should also be sterilized and (
or) may contain auxiliary agents such as preservatives and stabilizers. The dose of Compound (I) depends on the administration method and the age of the patient.
The preferred daily dosage, which varies depending on body weight, condition and disease being treated, is usually about 20-1000 capes/rI1. Especially about 50-50019/rIl.

1 In this specification, the term "lower alkyl group" refers to a group having 1 carbon number.
~4 alkyl group In the present specification, the following symbols at the end of the name of the ligand: -0, O, and -01 have the formula: -ococH-o
- and -OH This indicates that the ligand represented by H-OH is coordinated to the platinum (I) ion by the atom marked with .

Experimental Examples The therapeutic effects of the organic platinum complex of the present invention were tested using the following methods and compounds using mice transplanted with various cancer cells.

〔experimental method〕

Group of 5 female mice (ICR strain 1 body weight 19-2.11
), Ehrlich ascites cancer cells (IXIO cells) were intraperitoneally transplanted. A physiological saline solution of the specimen was administered intraperitoneally to the mice once a day for 5 consecutive days starting 24 hours after transplantation, and 7 days after the first administration.

The amount of ascites was measured.

Group of 4 to 6 male mice (BDF, line 1 body weight 19~
23)) Leukemia L-1210 cells (1 x 10s cells) are intraperitoneally transplanted. Starting 24 hours after transplantation, a physiological saline solution of the specimen was administered intraperitoneally to mice once a day for 5 consecutive days, and the effects were determined by comparing the average survival days of the specimen-administered group and the non-administered group.

[Examination body]

Compound Mu Compound Juro 1 Cis-[Glycolade (2-)-2 Cisplatin (Control Compound) [Results] The experimental results are shown in Tables 1 and 2 below.

Table 1 Effect of suppressing the growth of Ehrlich ascites carcinoma [Experimental method (A)] Notes (maximum dose that inhibits proliferation by 100%) (cl: M, E, D, = minimum effective dose (minimum dose that inhibits growth of Ehrlich ascites carcinoma by 100%) (d): therapeutic index = M, T, D, / M, E, D
.

Table 2: Survival prolongation effect on mice transplanted with leukemia L-1210 cells [Experimental method (B)] Note: (b): Number of surviving mice for 60 days = Number of mice surviving for 60 days/Number of mice used (C): Treatment coefficient = OoD, / I, L, S, **HOCH*C
O,H Complex (V)-1 → Complex (If) (1-a-1) (I-b-1) Cis-dinitrato(2-aminomethylpyridine)platinum (■) [Complex (V)) 4.27P Heat and dissolve in 150 d of water. After cooling, the solution was added to an OH type anion exchange resin Diaion 8A-
Process with 2OA. Eluate [cis-dihydroxo(2-
Aminomethylpyridine) platinum (■) [containing complex (■)] was mixed with 0576 g of glycolic acid in a stopper while stirring, and the reaction solution was allowed to stand at room temperature overnight. The reaction solution was further concentrated to 30.

Warm to 60°C for 6 hours. The reaction solution was cooled, the precipitated crystals were collected by filtration, and recrystallized from water to form cis-[glycolad(2-)-ox, o3) (2-aminomethylpyridine) platinum (■)[complex (I- a-1) and complex (1
A mixture of equal amounts of -b-1)) 1.9SP is obtained as pale yellow crystals. Yield: 5L 7% Decomposition point: 263°C N, 7.39: Pt, 51.94 IR spectrum: Figure 1 (I-a-2) (I-b-2) Cis-dinitrato(2-aminomethylpyridine) platinum ( II)
C complex ff): 12.147 and lactic acid 0.45 mm were treated in the same manner as in Example 1 to obtain cis-[lactato(2-)-0', O deprived] (2-aminomethylpyridine).
1.201 of platinum (If) monohydrate (mixture of equal amounts of complex (1-a-2) and complex (1-b-2)) is obtained as pale yellow crystals. Yield: 58.5 Decomposition point: 2 steps at 5°C Elemental analysis value (CeHnN*Os Pt-HtO) Calculated value ('K): C, 26,41; H03,42: N,
6.85: Pt, 47.68 actual value (a): C
,26,34:H,3,50:N,6.89;
Pt, 47.59 IR spectrum: Figure 2 Example 3 Complex (I-a-1) Ten complex (I-b-1) Cis-di[Glycolade (1-)-0”) (2-aminomethylpyridine) Platinum ( n) 2.27.P is dissolved in water 151j by heating. To this solution, 5g of IN sodium hydroxide aqueous solution is added and heated to 60° C. for 6 hours.

By cold welding, filtering the precipitated crystals, and recrystallizing from water,
cis-[glycolad(2-)-〇'', 02](2-aminomethylpyridine)platinum(It) (complex (I-a-1
) and complex (1-b-1) (1.15%) are obtained as pale yellow crystals. Yield: 61.0% The physical properties of this product matched those of the standard prepared in Example 1.

Production Example Complex (v) Complex (ff) cis-dinitrato(2-aminomethylpyridine)platinum (■) [Complex (V)) 114iP is dissolved by heating in 75d+c of water. After cooling, the solution was added to an OH type anion exchange resin Diaion 8A-
Cis-dihydroxo(2-aminomethylpyridine)platinum (■) [Complex (II)] 1.73
It is obtained as a pale brown powder which is unstable in y-.

N, 8.13: Pt, 56.08

[Brief Description of the Drawings] Figure j1!1 and Figure $2 show the IR spectra of the following compounds. Figure 1: Cis-[Glycolad(2-)-0'', O fable] (
2-aminomethylpyridine) platinum (1N)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, A is a group represented by the formula: ▲ Numerical formula, chemical formula, table, etc. ▼, R is a hydrogen atom or a lower alkyl group An organic platinum complex represented by 2. Complexes represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and compounds represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R represents a hydrogen atom or a lower alkyl group.) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by the reaction of ) A method for producing an organic platinum complex. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R represents a hydrogen atom or a lower alkyl group.) A general formula characterized by treating the complex with a base ▲ Numerical formulas, chemical formulas, tables, etc. etc. ▼ (However, A represents a group represented by the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and R has the same meaning as above.) A method for producing an organic platinum complex represented by the following. 4. An organic platinum complex represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼. 5. A method for producing an organic platinum complex represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ characterized by treating the complex represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼.