KR910002536B1 - Preparation method of plantinum-diamine complexes - Google Patents

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Description

Method for preparing platinum-diamine complex

The present invention provides a novel platinum-diamine complex and a method for preparing the same, a method for preparing a pharmaceutical composition for use of the platinum-diamine complex in the treatment of cancer (eg malignant edema and malignancy) and using the method. To formulated compositions prepared.

Platinum-diamine complexes are known from J. Chem, Ed. 54 (12), (1977), p739 by APZipp and SGZipp, which use cisplatinum diaminedichloride (PDD) for the treatment of cancer. How to do this is described. This platinum compound has a wide range of activities as an antitumor agent and also has various drawbacks. In particular, these platinum compounds are highly toxic to the kidneys. To reduce the toxicity of cis-platinum diamine chloride to other kidneys, to use it in combination with other substances, to administer with a large amount of liquid, or to reduce the toxicity in the kidneys by properly draining from the kidneys. It is used. Many other platinum amine complexes are known, for example the compounds represented by formula (2) attached below are known.

Wadley Medical Bulletin, Vol. 7, No. 1, pp. 114-134 discloses a number of platinum diamine complexes, including cis-platinum diamine dichloride for the treatment of cancer. It also mentions that the most important drawback of these compounds is their renal toxicity.

In addition, Chem and Eng. News (1977.6.6), pp. 29-30 specify cis-platinum diamine chloride and the use of this compound for the treatment of cancer. Here too, renal toxicity is mentioned as the most important drawback of these compounds.

Cancer Chemotherapy Reports Part 1, Vol. 59, No. 3, May / June 1975, pp. 629-641, report on the nephrotoxicity of cis-platinum-II-diamine dichloride. Because of the toxicity of PDD to the kidney and its low therapeutic index, other platinum complexes for cancer treatment have been studied. In other words, combinations of cis-platinum diamine-II-dichloride and other chemotherapeutic agents were tested and new platinum complexes were studied, but these compounds were also found to be toxic. lost. For example, cis-dichloro-bis cyclopentylamine platinum (II) is almost nontoxic to the kidneys but also toxic to the spleen. Mixtures of five or more inseparable components in other amounts, called "platinum blue," are also disclosed for cancer treatment.

German Patent Application Nos. 73,04880, 73,04881, 73,04882 and 77,03752 disclose a number of platinum diamine complexes, including the compounds of formula (1). In all the above compounds having one nucleus, the nitrogen atom is directly bonded to the nucleus.

When the compounds of the Federal Republic of Germany Application Nos. 73,04880, 73,04881 and 73,04882 are compared with cis-platinum diamine dichloride, these compounds have been found to have a much better effect. That is, none of the patent applications mentions kidney toxicity.

In the Federal Republic of Germany Patent Application No. 79,04740, platinum diamine complexes are specified, which are compounds having the formula (1) attached below, wherein R ₁ 'and R ₂ ' are each hydrogen atoms or Substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group, R ₁ 'and R ₂ ' may be bonded together to be a substituted or unsubstituted alkyl, cycloalkyl group, and R ₁ 'and R ₂ ' are each hydrogen An atom or a substituted or unsubstituted alkyl, aryl or aralkyl group, and X is an anionic group.

The present invention relates to a novel platinum diamine complex represented by the following structural formula (I).

Wherein R ₁ and R ₂ are both ethyl groups or together form a cyclohexyl group with the carbon atom to which they are bonded, R ₃ and R ₄ are both hydrogen atoms, and X ₁ and X ₂ are both Chloro acetate groups or both are nitrate groups, or both together are malonate group, ethylmalonate group, hydroxymalonate group, carboxy phthalate group, cyclobutane-1,1-dicarboxylate group, or oxalate group And sodium salts of these groups.

The present invention also relates to a process for the preparation of the compounds, a process for the preparation of a pharmaceutical composition using the compounds as an active substance, and a formulated pharmaceutical composition prepared by the process.

International Cancer Society, Bethesda, U.S.A. And during extensive research by the European Cancer Treatment Research Institute, Brussels, Belgium, the compounds according to the invention have high therapeutic activity against cancer, unlike the platinum complexes known to date, and have cis-platinum diamine diamines. It has been found that compounds such as chloride (PDD) can be used practically in the treatment of cancer and that the compounds according to the invention have little or no toxicity to the kidneys.

From the therapeutically active levels specified in Table A, the novel compounds according to the invention are directed against various tumors such as P388 lymphocytic leukemia (PS), L-1210 lymphatic leukemia (LE), blastoma of the phase and B16 pigment cancer (B1). It can be seen that it has significant anti-tumor activity. The therapeutic activity of the compounds of the invention is much greater than the therapeutic activity of cis-platinum diamine dichloride (PDD) used in experimental clinical chemotherapy.

In addition to the PDDs actually used, all other anticancer platinum-II-complexes so far known (except for the compounds specified in German Patent Application No. 79,04740) are highly toxic as elevated, especially for the kidneys. Due to their high toxicity, dosages are limited in practical use.

However, the compounds according to the invention have no side effects on the kidneys. This was confirmed by histological studies after administration of the compounds listed below in rats at toxic doses, and similar experiments with PDDs revealed severe toxicity to the kidneys.

The novel complexes of the present invention do not have any adverse effect on elongation. In general, the general methods for measuring renal toxicity include the determination of the content of urea nitrogen (blood urea nitrogen, BUN) in the blood, and also the method of expressing the content of non-protein nitrogen (non-protein nitrogen, NPN). Can be.

It has been found that the compounds according to the invention also have no effect on the content of urea-nitrogen in the blood. In the case of doses corresponding to LD ₁₀ and LD ₅₀ , the urea nitrogen content in the blood was the same as the control. In contrast, when the PDD compound was administered at the dose of LD ₁₀ , the urethra-nitrogen content increased by four times that of the control and the control, and increased more than 11 times at the dose of LD ₅₀ .

TABLE A

a: More detailed information on experimental procedures and descriptions is given in vide Instruction 14, Screening data summary interpretation and outline of current screen, Maryland, 20014, 1977.

b: 02 = mouse code B ₆ D ₂ F ₁ (BDF ₁ ): 03 = mouse code

C57BL / 6: 06 = Jucood CD ₂ F ₁ (CDF ₁ )

c: PS = P388 lymphocytic leukemia:

LE = L1210 lymphatic leukemia:

Subcellular tumors on EM =: B ₁ = B ₁₆ pigmented cancer

d: Survival is the ratio of survival time (T) of treated mice to survival time (C) of untreated mice: therapeutic activity is significant at T / C ≧ 125.

LE / cis-PDD means anti-cis-PDD.

The preparation method of the above-mentioned compounds is illustrated by the following examples.

The compounds are prepared according to the method of S. C. Dhara: Indian J. Chem, 8, 193 (1970).

Example I

Cis-dichloro-1,1-di (aminomethyl) cyclohexane platinum (II) having formula (3) in the appended formula

To a solution of 16 g K ₂ PtCl ₄ dissolved in 160 ml of water was added a solution of 26.4 g of iodine and potassium (KI) dissolved in 20 ml of water and the mixture was heated in a water bath for 5 minutes.

Here, 6.4 g of 1,1-di (amino methyl) cyclohexane was added and the mixture was stirred for 5 minutes, after which the precipitate was filtered off three times with hot water, twice with cold ethyl alcohol and twice with ether. Washed.

11.8 g of diiodine derivative formed was added to a solution of 6.6 g of silver nitrate (AgNO ₃ ) dissolved in 48 ml of water.

The mixture was stirred at 95-100 ° C. for 10 minutes, filtered off with silver iodide (AgI) and washed with water. 3.28 g of potassium chloride was added to the clear filtrate and the mixture was stirred at 95-100 ° C. for 12 minutes. After cooling the mixture, the precipitate was washed by suction filtration.

Yield: 6.0g

Assay (% by weight)

Calculated Value: C; 23.53, H; 4.45, N; 6.87, Pt; 47.80

Found: C; 23.32, H; 4.46, N; 6.86, Pt; 47.63

Example II

Preparation of cis-1,1-di (aminomethyl) -cyclohexane hydroxymalonate platinum (II) having formula (4) in the appended formula

1.6 g of dichloro derivative (formula (3)) prepared according to Example I was added to a solution of 1.28 g of silver nitrate dissolved in 25 ml of water.

After stirring the mixture at 40 ° C. for 1 hour, silver chloride (AgCl) was filtered off and washed with water.

To the clear filtrate was added 0.455 g of potassium hydroxide and 0.456 g of hydroxy malonic acid dissolved in 10 ml of water.

After stirring for 2 hours at room temperature the precipitate was filtered off and dried.

Yield: 77 wt%

Assay (% by weight)

Calculated Value: C; 29.01, H; 4.43, N; 6.15, Pt; 42.84, 0; 17.58

Found: C; 28.77, H; 4.38, N; 6.18, Pt; 42.96, 0; 17.54

Melting Point: 248 ℃ (Decomposition)

Example III

Cis-4-carboxylphthalato-1,1-diaminomethyl) -cyclohexane-platinum (II) having the formula (5)

1.2 g of dichloro derivative (formula 3) prepared according to Example I were added to a solution of 1 g of silver nitrate dissolved in 25 ml of water.

The mixture was stirred at 40 ° C. for 1 hour, then silver chloride was filtered off and washed with water.

0.63 g of 1,2,4-tricarboxybenzene was added to the clear filtrate, and the mixture was stirred for 2 hours at room temperature. The precipitate was suctioned off and washed with water.

Yield: 0.8 g (45% by weight)

Assay (% by weight)

Calculated Value: C; 36.24, H; 4.29, N; 4.97,

Found: C; 36.42, H; 4.13, N; 4.77

Example IV

Cis-1,1-di (aminomethyl) cyclohexane-bis ((chloro acetate) -platinum (II) having the formula (6)

1.6 g of dichloro derivative (formula 3) prepared according to Example I was added to a solution of 1.28 g of silver nitrate dissolved in 25 ml of water.

After the mixture was stirred at 40 ° C. for 1 hour, silver chloride was filtered off and washed with water.

To the clear filtrate was added 0.45 g of potassium hydroxide and 0.73 g of monochloroacetic acid solution dissolved in 25 ml of water, and the mixture was stirred at room temperature for 2 hours.

The precipitate was suction filtered off and washed with water.

Yield: 1.3 g (65% by weight)

Assay (% by weight)

Calculated Value: C; 27.49, H; 4.23, N; 5.34,

Found: C; 27.43, H; 4.21, N; 5.55

Example V

Cis-1,1-di (amino methyl) -cyclohexane-malonate-platinum (II) having the formula (15)

The compound is already specified in German Federal Patent Application No. 79,04740, but its preparation is important for the following examples.

1.6 g of dichloro derivative (formula 3) prepared according to Example I was added to 1.28 g of silver nitrate solution dissolved in 25 ml of water.

After the mixture was stirred at 40 ° C. for 1 hour, silver chloride was filtered off and washed with water.

To the clear filtrate was added 0.455 g potassium hydroxide and 0.4 g malonic acid solution dissolved in 10 ml of water.

After stirring for 2 hours at room temperature, the precipitate was filtered off and dried.

Yield: 1.0 g (59% by weight)

Assay (% by weight)

Calculated Value: C; 30.07, H; 4.59, N; 6.38, Pt; 44.40, 0; 14.57

Found: C; 29.98, H; 4.54, N; 6.32, Pt; 44.32, O; 14.57

Example VI

Cis-2,2-diethyl-1,3-diaminopropane-2-ethylmalonate-platinum (II) having the structure (7) was prepared according to the method of Example V.

Yield: 65% by weight

Assay (% by weight)

Calculated + 2H ₂ 0: C; 29.33, H; 5.74, N; 5.70

Found: C; 29.23, H; 5.64, N; 5.71

Example VII

Cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonate-platinum (II) having the formula (8) was prepared according to the method of Example V.

Yield: 87% by weight

Assay (% by weight)

Calc. + 1 / 2H ₂ 0: C; 26.55, H; 4.68, N; 6.19

Found: C; 26.67, H; 4.56, N; 6.23

Sodium salt of this compound having formula (13) was prepared according to Example IX.

Example VIII

Cis-1,1-di (aminomethyl) cyclohexane-2-ethyl-malonate platinum (II) having the formula (10) was prepared according to the method of Example V.

Yield: 64 wt%

Assay (% by weight)

Calculated + 1.5H ₂ O: C; 31.57, H; 5.50, N; 17.79, Pt; 39.43

Found: C; 31.36, H; 5.47, N; 5.69, O; 18.02, Pt: 39.58

Example IX

Cis-2,2, -diethyl-1,3-diaminopropane-2-hydroxymalonate-platinum (II) sodium salt with formula (13)

0.5 g of hydroxy malonate derivative prepared according to Example VII (Structure Formula (8)) was suspended in 25 ml of water.

1.105 ml of 0.1N sodium hydroxide was added and the mixture was stirred at room temperature for 30 minutes.

The clear solution was evaporated to dryness and the residual solid was dried.

Yield: 0.4 g (72 wt%)

Assay (% by weight)

Calculated + 2H ₂ 0: C; 23.91, H; 4.61, N; 5.58

Found: C; 23.75, H; 4.44, N; 5.52

Example X

Cis-1,1-di (aminomethyl) cyclohexane-1,1-cyclobutanedicarboxylate-platinum (II) having the formula (12)

2 g of dichloro compound (formula 3) prepared according to Example I were added to 1.6 g of silver acid dissolved in 25 ml of water.

After the mixture was stirred at 40 ° C. for 1 ° C., silver chloride was filtered off and washed with water.

To the clear filtrate was added 0.547 g of potassium hydroxide dissolved in 10 ml of water and 0.677 g of 1,1-cyclobutane dicarboxylic acid solution.

After 2 hours at room temperature and 1 hour at 0 ° C., the white precipitate was filtered off and dried.

Yield: 1.4 g (62 wt%)

Assay (% by weight)

Calculated + H ₂ O: C; 33.80, H; 5.27, N; 5.63

Found: C; 33.98, H; 5.02, N; 5.77

Example XI

Cis-2,2-diethyl-1,3-diaminopropane-1,1-cyclobutane dicarboxylate platinum (II) having formula (9) was prepared according to the method of Example X.

Yield: 64 wt%

Assay (% by weight)

Calc. + 2.5H ₂ 0: C; 30.46, H; 5.70, N; 5.47, Pt; 38.07

Found: C; 30.40, H; 5.44, N; 5.37, Pt; 38.16

Example XII

Cis-1,1-bis (aminomethyl) cyclohexane platinum (II) nitrate having structural formula (11)

4 g cis-dichloro-1,1-bis (aminomethyl) cyclohexane platinum (II) (0.0097 mol) were suspended in 30 ml of distilled water.

To this solution was added 3.1 g of silver nitrate (0.0182 moles) and the mixture was heated to 40 ° C. for 1 hour while preventing light from entering.

The formed silver chloride was filtered off and washed with 10 ml of distilled water. The clear filtrate was evaporated under reduced pressure.

Weight of solid material; 4.17 g (93.5 weight%)

Melting Point: Explodes at about 240 ℃. Decompose slowly at temperatures below 240 ° C.

Assay (% by weight)

Calculated Value: C; 20.83, H; 3.93, N; 12.14

Found: C; 20.9, H; 4.1, N; 11.9

¹ H-NMR spectrum in DMSO-d ₆ (dispersed T60) based on TMS:

CH ₂ (ring): 1.37ppm

CH ₂ (NH ₂ ): 2.30ppm

NH ₂ : 5.67 ppm

Accompaniment: 5.20 ppm

6.18 ppm

J195Pt- ¹ H: 58 Hz

Example XIII

Cis-1,1-bis (aminomethyl) cyclohexane platinum (II) oxalate having formula (14)

4.1 g of cis-dichloro-1,1-bis (aminomethyl) cyclohexane platinum (II) (0.01 mol) was suspended in 30 ml of distilled water.

3.2 g of silver nitrate (0.019 mol) was added to the solution, and the mixture was heated to 40 ° C. for 1 hour while preventing light from entering.

The silver chloride formed was filtered off and washed with distilled water (50 ml).

2.02 g of potassium oxalate (0.01 mol) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour.

The solid thus formed was suctioned off, washed with distilled water and dried.

Dry weight; 3.7 g (87% by weight)

Assay (% by weight)

Calculated + 1.5H ₂ O: C; 26.55, H; 4.68, Pt; 43.13, 0; 19.45

Found: C; 26.6, H; 4.6, N; 6.2, Pt: 43.4, O; 19.2

¹ H-NMR spectrum in DMSO-d ₆ (dispersed T60) based on TMS:

CH ₂ (ring): 1.32ppm

CH ₂ (NH ₂ ): 2.17 ppm

NH ₂ : 5.45ppm

Accompaniment: 4.83ppm

6.08ppm

J195Pt- ¹ H: 58 Hz

Claims (7)

a) reacting a compound of formula (A) with K ₂ PtCl ₄ and KI to obtain a diiodine derivative of formula (B); b) filtering off the AgI precipitate obtained by adding the derivative to an aqueous AgNO ₃ solution, and then adding KCl to the clear filtrate to produce a dichloro derivative of the general formula (C); c) Platinum of the general formula (I) below comprising filtering the AgCl precipitate obtained by adding the derivative to an aqueous solution of AgNO ₃ and then reacting the clear filtrate with the compounds of the general formulas (D) and (F) (II)-Preparation of diamine complexes.

Wherein both R ₁ and R ₂ are each an ethyl group, or together with the carbon atoms to which they are attached form a cyclohexyl group, R ₃ and R ₄ are both hydrogen atoms and X ₁ and X ₂ are both Chloroacetate groups or both are nitrate groups, or both together are malonate groups, ethyl malonate groups, hydroxymalonate groups, carboxyphthalate groups, cyclobutane-1,1-dicarboxylate groups or oxalate groups Or sodium salts of these groups. The method of claim 1, wherein the compound of general formula (I) is a compound having the following structural formula (4).

The method of claim 1, wherein the compound of general formula (I) is a compound having the following structural formula (5).

The method of claim 1, wherein the compound of general formula (I) is a compound having the following structural formula (6).

The method of claim 1, wherein the compound of general formula (I) is a compound having the following structural formula (7).

The method of claim 1, wherein the compound of general formula (I) is a compound having the following structural formula (13).

The method of claim 1, wherein the compound of general formula (I) is a compound having the following structural formula (14).