JPS6137796A - Organoplatinum complex and antitumor agent containing it - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> and R<2> are H, or lower aliphatic amine; D and E are ammonia, or D and E are bonded to form nitrogen-containing compound shown by the formula II (R<3> and R<4> are H, or lower alkyl), or group shown by the formula III (R<7> and R<8> are bonded to alkylene)]. EXAMPLE:1-(1,3-Dioxolan-2-yl)-7-oxabicyclo[2,2,1]heptane-2,3-dicarboxy lato-( cis-1, 2-diaminocyclohexane)platinum(II) complex. USE:An antitumor agent. PREPARATION:For example, a compound [e.g., dichloro-(cis-1,2-diaminocyclohexane)platnium(ii), etc.] shown by the formula IV (Q is halogen) is dissolved in water, reacted with silver nitrate, a precipitated solid material is filtered, the filtrate is reacted with a 1-(1,3-dioxolan-2-yl)-7-oxabicyclo[2,2,1]heptan-2,3-dicarboxylate.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel organic platinum complex and an antitumor agent containing the complex.

[Conventional technology]

Many organic platinum complexes have already been proposed as therapeutic agents for tumors (see, for example, JP-A-54-160749 and JP-A-55-15280).

[Problem that the invention seeks to solve]

However, no antitumor activity has been found that is sufficiently satisfactory.

An object of the present invention is to provide a novel organoplatinum complex with excellent antitumor activity and an antitumor agent containing the same as an active ingredient.

[Means for solving problems]

To summarize the present invention, the first invention of the present invention relates to an organic platinum complex, which has the following general formula 1: [wherein R1 and R3 represent hydrogen or a lower alkyl group, and D and E are , ammonia or lower aliphatic amine? or - taken together, the following general formula ① or l: (wherein Hs-R" u represents hydrogen or a lower alkyl group, R7 and 1 (aH further taken together to form an alkylene group) Shows the nitrogen-containing compound composition shown in
It is characterized by being expressed as.

Further, the second invention of the present invention relates to an antitumor agent, and is characterized in that it contains an organic platinum complex represented by the above general formula 1 as an active ingredient.

The organic platinum complex of the present invention represented by the general formula I is a platinum complex represented by the following general formula (1): (wherein D and E have the same meanings as in formula 1, and Q#: t represents a halogen). It can be manufactured using a complex as a raw material. The platinum complex of the above formula ■ is a platinum complex,
It can be derived from nitrogen-containing compounds represented by D and E.

Among the groups and E in formulas I and (2), specific examples of lower aliphatic amines include propylamine, isopropylamine, ethylamine, dimethylamine, ethylmethylamine, diethylamine, methylglobilamine, methylisopropylamine, Examples include ethylmethylamine, ethylisopropylamine, dipropylamine, and pylamine, of which isopropylamine is particularly preferred. Examples of the compound of formula (1) are (is or trans, the same applies hereinafter)-1,2-diaminocyclohexane, 3-methyl-1,2-diaminocyclohexane, 4-meth-fk-1,2-diaminocyclohexane f''/ ,
5.4-dimethyl-1,2-diaminocyclohexane,
3,5-dimethyl-1,2-diaminocyclohexane,
Examples include 6,6-dimethyl-1,2-diaminocyclohexane, among which cis-1,2-diaminocyclohexane is particularly preferred. Furthermore, compounds of formula I include specific VC units such as ethylenediamine, N-
Methylethylenediamine, N,H-dimethylethylenediamine, N,N'-dimethylethylenediamine, N,
N, N'-trimethylethylenediamine, N, N,
H: N'-tetramethylethylenediamine, 1-aminoethylpyrrolidine, 2-methyl-1-aminoethylpyrrolidine, 3-methyl-1-aminoethylpyrrolidine, 1-(N-methylaminoneethylpyrrolidine, 1-
(N-ethylaminoJ ethylpyrrolidine 1,2-methyl-1-(N-methylaminoethylpyrrolidine, etc.), among which 1-aminoethylpyrrolidine is particularly preferred.

To prepare the entire complex of the present invention represented by the general formula I from the compound represented by the general formula 1v, K is prepared by dissolving 1 part by weight of the compound represented by the general formula (1) in 100 to 200 parts by weight of water, and after cooling. , silver nitrate 1 1.0 to 50 mol per mol of the compound represented by the general formula (2), preferably i 1.1-2.2
Added in molar ratio, usually 10-100°C, preferably 2
The reaction is usually carried out for several hours to several hundred hours in the dark WrVc at a temperature of 0 to 60°C. After separating the precipitated solid tF from the reaction mixture and concentrating it under reduced pressure as necessary, 1-(1,
5-dioxolan-2-yl)-7-oxabicyclo(
2,2,1) Hebuta, 15 to 15 to 1 mole of a 2,5-dicarboxylic acid based on 1 mole of the compound
0.7 moles and reacted at a temperature of 10 to 60° C. for several hours to several hundred hours. The reaction mixture thus obtained is dried under reduced pressure, the dried product is treated with methanol, and methanol is removed from the methanol-soluble portion to obtain the compound represented by the general formula (2) of the present invention. .

Examples of the compounds of the present invention obtained in this manner include butterflies, specifically the following compounds. However, here, (1,5-dioxolan-2-yl 2) means (4-methyl-1,5-dioquinran-2-yl)
, (4,5-dimethyl-1#3-dioxolan-2-yl), (4-ethyl-1,5-dioxolan-2-yl), (5-ethyl-1,5-dioxolan-2-yl)
, (4,5-diethyl-1,5-dioxolan-2-yl), and (4-ethyl-5-methyl-1,5-dioxolan-2-yl) are also included.

1-(1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,5-dicarboxylado-diammineplatinum(I), 1-(1,5-dioxolane -2-yl)-7-oxabicyclo(2,2,1
) hebutane-2,5-dicarboxylado-ammine-dimethylamine platinum (1), 1-(1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,13hebutane-2, 3-dicarpoxylateamine-ethylmethylamine platinum (1), 1-(1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxy Lado-bis(dimethylamine)platinum(1), 1-(1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-45-dicarboxylad-bis(diethylamine) Platinum (1), 1-(1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,5-dicarboxylado-bis(methylpropylamine) platinum ( 1), 1-(1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylad-bis(methylisopropylamine)platinum (■n, 1-(1,3-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,5-dicarboxylado-bis(ethylglobylamine-platinum(I), 1- (1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylado-bis(ethylisopropylamine)platinum (1)
, 1-('1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,5-dicarboxylad-bis(dipropylamine)platinum (1), 1- (1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylado-bis(diisopropylamine)platinum (1), 1-'(1, 5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,5-dicarboxilado-(cus-1,2-diaminocyclohexane)
Platinum (n), 1-(1,!l-dioxolan-2-yl)-7-oxapicic is (2,2,1)hebutane-2,3-dicarboxilado-(trans-1,2-diaminocyclohexane) platinum(II), 1-(1j-dioxolan-2-yl)-7-oxabicyclo(2,2,1)butane-2,3-dicarboxylad-(ethylenediamine-platinum(1), 1- (1,5-dioxolan-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylado-(KN,N,'N'Nthiramethylethylenediamine)platinum ( ], 1-(1,3-dioxolane-2-ilun-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylad-(1-aminoethylpyrrolidine)platinum (■n, 1-(1j-dioxolan-2-yln-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylate [2-me,thyl-j-(N-methylamino)ethylpyrrolidine) Platinum (1), etc. can all be mentioned.

The novel organoplatinum complex represented by the general formula I according to the present invention is believed to bind to DllA in tumor cells and completely inhibit DNA biosynthesis, and has relatively small side effects as an antitumor agent, and is effective against various tumors. For example, it has excellent medicinal efficacy against various tumors such as leukemia, lung cancer, and melanoma.

Therefore, the novel complex of the present invention can be used as an antitumor agent alone or in the form of a composition in which the complex is combined with a pharmaceutically acceptable carrier.

The dosage of the antitumor agent of the present invention varies depending on the patient's condition and the type of tumor, but the dose of the complex of the present invention as an active ingredient per day is 5 to 500 mt/kg, especially (5 to 100 mt/kg).
Wlkg Vc may be administered.

Examples of dosage forms include injections, herbal medicines, and locally administered preparations. Examples of injections include aqueous or oil-based suspensions, solutions, powdered drugs that dissolve before use, and freeze-dried preparations. It can be prepared using a conventional method. The administration site is preferably subcutaneous or intravenous. Since the platinum (I) complex of the present invention is extremely easily immersed in water, it does not cause any problems in the preparation of injections.

Herbal medicines can be prepared using commonly used base ingredients. As the base, for example, polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc. are employed.

Examples of topical preparations include ointments and creams, which can be prepared using commonly used base materials. Examples of bases include liquid paraffin, senal alcohol, white petrolatum, squalane, lanolin, etc.
Examples include cholesterol and glycerin fatty esters.

The antitumor agent of the present invention can also be used as an oral agent. Examples of oral preparations include tablets, capsules, granules, fine granules, powders, syrups, etc. Granules, 51a granules, and powders can also be used as sachets. Examples of excipients used in these include lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate, gum arabic, etc. .

〔Example〕

Next, the present invention will be fully explained in detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 1-(1,5-dioxolan-2-yl)-
7-Oxabicyclo[2,7,1]hebutane-2,! I
-Dicarboxylado(cis-1,2-diaminocyclohexane)platinum(II) (Synthesis) Dichloro-(cis-1,2-diaminocyclohexane)
Platinum (former L40f) was heated and dissolved in water 67-. Silver nitrate α562-t- was added thereto and allowed to react in the dark at room temperature for one day, and the precipitated solid was filtered out. 1-(1j-dioxolan-2-yl)-7-oxabicyclo(2,2
゜1] Hebutane-2,3-dicarboxylic acid disodium C
L57tf was added and the mixture was allowed to react at room temperature for 3 days.

Floating objects? After heating with F, the P-formed metal was dried to dryness under reduced pressure at 30 to 40°C. The dried product was extracted with methanol using a Soxhlet extractor. The obtained yellow liquid was dried under reduced pressure to obtain a pale yellow solid with a yield of 1561 (50%).

(Properties) Elemental analysis value 054.87% (calculated value 5 & 11%) H4
Example 2 1-(1,5-dioxolan-2-yl)-7-
Oxabicyclo(2,2,1)butane-2,5-dicarboxylado-(trans-11,2-diaminocyclohexane platinum) was synthesized according to Example 1.

Yield 64% Elemental analysis value 0 5178 t (calculated value 36.11 thin H4, 45% (calculated value 4.66 thin N 4.62% (same 4,95 th) 2-il)-7
-Oxabicyclo(2,2,1)butane-2,3-dicarboxylad-diammineplatinum(II) (Synthesis of cis-dichloro-diammineplatinum(1).

α302 was dissolved in total water at 100 dK100'C, silver nitrate a54F was added at room temperature, and the mixture was allowed to react in the dark for 1 day. Reaction mixture I was filtered through Celite and concentrated under reduced pressure below soc to about 1/5 volume of P#. To the residual liquid was added 0.37t'1-disodium 1-(1,3-dioxolan-2-yl)-7-oxabicyclo(2,2,1)butane-2,5-dicarboxylate, and at room temperature The reaction was allowed to proceed for 1 day. The reaction mixture is dried under reduced pressure at 50° C. or lower, and the methanol-soluble portion is collected from the dried product. Then, methanol was distilled off under reduced pressure to obtain a white crystalline solid in a yield of 0.58 t (yield 75%).

(Properties) mp, 300°C or higher (turns black at 210A-220°C) Elemental analysis value 0 24.76% (calculated value 25.
99%) H 51% (same 557- N 5.62% (same 5.51ts) Example 4 1-
(1,t-dioquinran-2-yl)-7-oxabicyclo(2,2,1)hebutane-2,3-dicarboxylad-(1-aminoethylpyrrolidineplatinum(I)) Example 1 Synthesized according to the following procedure.

Yield 56 inches 292-298°C (decomposition) (202-21
(Turns black at 0℃) Elemental analysis value 0 3472% (calculated value 5611
%) H4, 26% (4.65%) N 4.95% (4.95%) Example 5 Anti-tumor activity effect on mouse experimental tumor P688 1) Animals used: BDF, mouse, female 6 weeks (average weight 17-IIIF) 1 group 6 2) Carcinoma Hpssa used (lymphocytic leukemia cells 10 cells/mouse, intraperitoneal administration 5) Sample administration method: BDF'! P388 to mouse
'ii- 24 hours after inoculation, intraperitoneal administration once a day for 5 consecutive days 4) Evaluation method: Effects were shown as prolongation of the average survival period (Eq.L8%) compared to the control group.

The results are all shown in Table 1 below.

Table 1 As shown in Table 1, the compounds of the present invention have significant antitumor activity against murine leukemia P388.

〔Effect of the invention〕

As explained above, the novel organoplatinum complex of the present invention is
It has excellent efficacy as an antitumor agent.

Patent applicant Mitsui Petrochemical Industries Ltd. Suntory Ltd.

Claims (1)

[Claims] 1. The following general formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] [In the formula, R^1 and R^2 represent hydrogen or a lower alkyl group, D and E represent ammonia or a lower aliphatic amine, or together represent the following general formula II or I
II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II], ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] (In the formula, R^3 to R^8 are hydrogen or lower An organic platinum complex represented by the following formula: a nitrogen-containing compound (representing an alkyl group, and R^7 and R^8 may further be taken together to form an alkylene group). 2. The following general formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R^1 and R^2 represent hydrogen or a lower alkyl group, and D and E represent ammonia. or represents a lower aliphatic amine, or together represents the following general formula II or I
II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II], ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] (In the formula, R^3 to R^8 are hydrogen or (represents a nitrogen-containing compound represented by a lower alkyl group, and R^7 and R^8 may be further taken together to form an alkylene group) Contains an organic platinum complex represented by the following as an active ingredient. An antitumor agent characterized by: