NO171276B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PLATINA (II) DIAMINE COMPLEXS - Google Patents

Description

The present invention relates to the production of new therapeutically effective platinum (II)-diamine complexes which are effective in the treatment of cancer, e.g. malignant swellings and malignant tumors.

Such platinum-diamine complexes are known from an article by A.P. Zipp and S.G. Zipp, J. Chem. Ed., 54 (12), (1977), page 739, which describes the use of cis-platinum diamine dichloride (PDD) for the treatment of cancer. It has been mentioned that the platinum compounds have a broad spectrum of activity as antitumour agents, but also that they have serious disadvantages, in particular that they are toxic to the kidneys. As a method to counteract the kidney toxicity, a cis-platinum diamine dichloride is often used in combination with other substances or administered with large amounts of liquid, or other methods are used to effect a sufficient flow through the kidneys. A number of other platinum-amine complexes are known, including compounds of formula 1:

Wadley Medical Bulletin, vol. 7, No. 1, pp. 114-134, discloses a large number of platinum-diamine complexes, including cis-platinum-diamine dichloride, for the treatment of cancer. Here, too, kidney toxicity is indicated as the most important disadvantage of these compounds.

Chem. and Eng. News, 6/6-1977, pp. 29-30, also discloses cis-platinum diamine chloride and its use in the treatment of cancer. Renal toxicity is also mentioned as the most serious disadvantage of these compounds.

In an article in Cancer Chemotherapy Reports Part 1, vol. 59, No. 3, May/June 1975, pp. 629-641, the renal toxicity of cis-platinum-II-diamine dichloride is also indicated. Due to the toxicity of PDD to the kidneys and its low therapeutic index, other platinum complexes for the treatment of cancer have been sought. To this end, combinations of cis-platinum-diamine-II dichloride with other chemotherapeutic agents were investigated. New platinum complexes were also tried, but they were found to be toxic. It was e.g. found that although cis-dichloro-biscyclopentyl-amine-platinum(II) is only slightly toxic to the kidneys, it is toxic to the spleen. So-called "platinum blues", a mixture of varying amounts of five or more inseparable components, has also been indicated for the treatment of cancer.

From US Patent Nos. 3,892,790 and 3,904,663,

BRD official publication no. 2 318 020 and BRD official publication no. 2 715 492 a large number of platinum-diamine complexes are known, here under the compound of formula 1 above. In all these compounds with a ring, nitrogen atoms are attached directly to the ring. The compounds in the first three publications were compared with cis-platinum diamine dichloride and found to

have a better effect. None of the publications state anything about kidney toxicity.

From NL patent application no. 79 04740 (corresponding to US patent document no. 4 410 544) there are known platinum-diamine complexes characterized by formula 2:

where R-^ and R 2 are independently a hydrogen atom or substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl, while R-j^ and R 2 together are a substituted or unsubstituted cycloalkyl group, R 3 and R 4 are independently a hydrogen atom or a substituted or unsubstituted alkyl, aryl or aralkyl group, and X is an anionic group.

It has now been shown that certain new platinum-diamine complexes are suitable for the treatment of cancer and exhibit little or no renal toxicity.

The invention thus provides an analogous process for the preparation of therapeutically active platinum (II) diamine complexes of the general formula: where R1 and R2 are both ethyl or, together with the carbon atom to which they are attached, form a cyclohexyl group, and each X is a chloroacetate group or a nitrate group or together form a group of the formula:

The new compounds are prepared according to the analogical method, in that a compound with the general formula:

where R 1 and R 2 have the meanings given above, is reacted with an AgNO^ solution, the AgCl formed is filtered off, and the remaining product in the filtrate is reacted with a compound of the formula: where X is a monovalent group as stated above, or with a connection with the formula:

where the two groups X together form a divalent group as indicated above, possibly in the presence of potassium hydroxide, and the product obtained is filtered off and dried.

A comprehensive research program conducted by the National Cancer Institute, Bethesda, U.S.A., and the European Organization for Research on the Treatment of Cancer, Brussels, Belgium,

have shown that the new compounds exhibit high therapeutic activity against cancer and furthermore that, in contrast to the previously known platinum complexes used to fight cancer, such as cis-platinum diamine dichloride (PDD), the new compounds exhibit little or no renal toxicity.

As can be seen from the therapeutically active values indicated in Table A, the new compounds exhibit significant antitumor activity against L-1210 lymphoid leukemia (LE). The therapeutic activity of the related new compounds is higher than that of cis-platinum diamine dichloride (PDD) which is used as an experimental clinical chemotherapeutic.

A very serious drawback of PDD platinum-II complexes with anti-cancer activity (with the exception of those described in the above-mentioned NL patent application no. 79 04740 (corresponding to US patent document no. 4,410,544)) is, as already mentioned the high toxicity of these compounds, the kidney toxicity being the most dangerous and actually limiting the dose that can be used in practice. Surprisingly, the new compounds show no harmful side effects on the kidneys. This was shown by means of a histological examination of rats after treatment with toxic doses of compounds described below, while in a similar study with PDD, severe kidney damage was found.

The new complexes also do not have any harmful influence on the function of the kidneys. A generally recognized, important method for determining kidney toxicity is the assessment of the percentage content of urea nitrogen in the blood (blood urea nitrogen, BUN), also referred to as "non-protein nitrogen" (NPN).

It has also been shown that the new compounds do not just have a simple influence on the urea-nitrogen content in the blood. Both for doses corresponding to the LD10 amount and for doses corresponding to the LD50 amount, the urea nitrogen content in the blood is identical to the control values. The compound PDD, on the other hand, gives an LD10 dose after the indicated periods of time already a fourfold increase in the urea nitrogen content, while this is increased by a factor of at least 11 at an LD50 dose.

The compounds known from NL patent application No. 79 04740, to which reference is made above, in the last paragraph on page 4, are represented in the table A below by the compound cis-1,1-di-(aminomethyl)-cyclohexane-malonate-platinum (II), which has the following formula:

a: For more detailed information about the test method

and the interpretation is referred to "Instruction 14", "Screening data summary interpretation and outline of current screen",

Maryland, 20014, 1977.

b: 02 = mouse code BgD2F1 (BDF^); 03 = mouse code C 57 BL/6;

06 = mouse code CD2F1 (CDF^.

c: LE = L 1210 lymphoid leukemia;

d: T/C is the ratio between the survival time of the treated mice (T) and the survival time of untreated mice

(C); the therapeutic activity is significant at

T/C <>> 125. LE/cis-PDD means resistance to cis-PDD.

The preparation of the above-mentioned compounds is illustrated in the following examples 1-7. The compounds were prepared according to the method of S.C. Dhara: Indian J. Chem. 8, 193 (1970).

First, however, the preparation of a starting material (known compound) will be described in an example A.

Example A. Preparation of a starting material, cis-dichloro-1,1-di-(aminomethyl)-cyclohexane-platinum(II)

(known from NL patent application no. 79 04740).

To a solution of 16 g of J^PtCl^ in 160 ml of water was added a solution of 26.4 g of Cl in 20 ml of water, and the mixture was heated for 5 minutes in a water bath.

Then 6.4 g of 1,1-di-(aminomethyl)-cyclohexane were added, and after the mixture had been stirred for 5 minutes, the precipitate was suctioned off and washed three times with hot water,

twice with cold ethyl alcohol and twice with ether.

11.8 g of the formed diiodo derivative was added to a solution of 6.6 g of AgNO 2 in 48 ml of water.

After the mixture had been stirred for 10 minutes at 95-100°C, Agl was filtered off and washed with water. To the clear filtrate was added 3.28 g of KCl, and the mixture was stirred for 12 minutes at 95-100°C. After the mixture had cooled, the precipitate was sucked off and washed with water. Yield: 6.0 g.

Analysis (wt%):

Example 1 Cis-1,1-di-(aminomethyl)-cyclohexane-bis-(chloroacetate)-platinum(II)

1.6 g of the dichloro derivative prepared according to Example A above (formula 3) was added to a solution of 1.28 g of AgNC>2 in 25 ml of water.

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

To the clear filtrate was added a solution of 0.73 g of monochloroacetic acid and 0.45 g of KOH in 25 ml of water, and the mixture was stirred for 2 hours at room temperature. The precipitate was suctioned off and washed with water.

Yield: 1.3 g (65% by weight).

Analysis (wt%):

Example 2 Cis-2,2-diethyl-1,3-diaminopropane-2-ethylmalonate-platinum(II) 2 g of dichloro-2,2-diethyl-7,3-propanediaminoplatinum(II), prepared as indicated in Example A above , was added to a solution of 1.66 g of AgN03 in 25 ml of water.

After stirring the mixture for 1 hour at 40°C (protected from light), the AgCl formed was filtered off and washed with water.

To the clear filtrate was added a solution of 0.64 g of 2-ethylmalonic acid and 0.544 g of KOH in 10 ml of water.

After stirring for 2 hours at room temperature, the reaction product was concentrated to approximately half the volume. The supernatant was filtered off and dried. 1.4 g of the desired compound was obtained.

Yield: 65% by weight.

Analysis (wt%):

Example 3 Cis-1,1-di-(aminomethyl)-cyclohexane-2-ethyl-malonate-platinum(II) 2 g of the dichloro derivative prepared as indicated in Example A above was added to a solution of 1.6 g of AgNO 3 in 25 ml of water.

After stirring the mixture for 1 hour at 40°C (protected from light), the AgCl formed was filtered off and washed with water.

To the clear filtrate was added a solution of 0.62 g of ethylmalonic acid and 0.55 g of KOH in 10 ml of water.

After stirring for 2 hours at room temperature, the precipitate was filtered off with suction of the liquid and dried. 1.4 g of the desired compound was obtained.

Yield: 64% by weight.

Analysis (wt%):

Example 4 Cis-1,1-di-(aminomethyl)-cyclohexane-1,1-cyclobutanedicarboxylate-platinum(II) 2 g of the dichloro compound prepared as indicated in Example A (formula 3) were added to a solution of 1, 6 g of AgNO.j in 25 ml of water.

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

To the clear filtrate was added a solution of 0.677 g of 1,1-cyclobutanedicarboxylic acid and 0.547 g of KOH in 10 ml of water.

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

To the clear filtrate was added a solution of 0.677 g of 1,1-cyclobutanedicarboxylic acid and 0.547 g of KOH in 10 ml of water.

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% by weight).

Analysis (wt%):

Example 5 Cis-2.2-diethyl-1,3-diaminopropane-1,1-cyclobutane-dicarboxylate-platinum(II) 2 g of dichloro-2,2-diethyl-7,3-propanediaminoplatinum(II), prepared as indicated in Example A above, was added to a solution of 1.66 g of AgNO 3 in 25 ml of water.

After stirring the mixture for 1 hour at 40°C (protected from light), the AgCl formed was filtered off and washed with water.

To the clear filtrate was added a solution of 0.699 g of 1,1-cyclobutanedicarboxylic acid and 0.544 g of KOH in 10 ml of water.

After stirring for 2 hours at room temperature, the reaction product was evaporated to approximately half the volume.

The supernatant was filtered off and dried. 1.5 g of the desired product was obtained.

Yield: 64% by weight.

Analysis (wt%):

Example 6

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

To this was added 3.1 g of AgNO 3 (0.0182 mol), and then the mixture was heated for 1 hour at 40°C under the exclusion of light.

The silver chloride formed was filtered off and washed with 10 ml of distilled water.

The clear filtrate was evaporated under reduced pressure. Weight of solids: 4.17 g (93.5% by weight).

Melting point: explodes at approx. 240°C, decomposes slowly at temperatures below 240°C.

<1>H-NMR spectrum in DMS0-d5 (VariarTT60) with respect to TMS: CH2 (ring) : 1.37 ppm

CH2 (NH2) : 2.30 ppm

NH 2 : 5.67 ppm

satellites: 5.20 ppm

: 6.18 ppm

<J>195pt_lH : 58 Hz

Example 7

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

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

To this was added 3.2 g of AgNO^ (0.019 mol), and then the mixture was heated for 1 hour at 40°C under exclusion of light.

The silver chloride formed was filtered off and washed with

50 ml of distilled water.

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

The solid formed was then sucked off, washed with distilled water and dried.

Weight, dry: 3.7 g (87% by weight)

Analysis (wt%):

<1>H-NMR spectrum in DMSO-dfa, (Varian^T60) with respect to TMS: CH2 (ring) : 1.32 ppm

CH 2 (NH 2 ) : 2.17 ppm

NH 2 : 5.45 ppm

satellites : 4.83 ppm

: 6.08 ppm

<J>195pt_lH : 76 Hz

Claims (1)

Analogous method for the preparation of therapeutically active platinum (II)-diamine complexes of the general formula: where R 1 and R 2 are both ethyl or together with the carbon atom to which they are attached form a cyclohexyl group, and each X is a chloroacetate group or a nitrate group or together form a group of the formula: characterized in that a compound with the general formula: where R1 and R2 have the meanings given above, is reacted with an AgN03 solution, the AgCl formed is filtered off, and the remaining product in the filtrate is reacted with a compound of the formula: where X is a monovalent group as indicated above, or with a compound of the formula: where the two groups X together form a divalent group as indicated above, optionally in the presence of potassium hydroxide, and the product obtained is filtered off and dried.