CA1196004A

CA1196004A - Platinum-diamine complexes, a method for the preparation thereof, a method for the preparation of a medicine using such a platinum-diamine complex for the treatment of cancer as well as a medicine thus formed

Info

Publication number: CA1196004A
Application number: CA000413154A
Authority: CA
Inventors: Jan Berg; Eric J. Bulten; Francois Verbeek
Original assignee: Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Current assignee: Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Priority date: 1982-10-08
Filing date: 1982-10-08
Publication date: 1985-10-29

Abstract

ABSTRACT

The invention relates to novel platinum-diamine complexes suitable for the treatment of cancer and having little or no kidney toxicity. A method for the preparation of these complexes is described.

Description

3g:

The invention relates to novel platinum-diamine complexes, and to a pharmaceutical compos~tion using such a platinum-diamine complex for the treatment of cancer, for example, malignant swellings and malignant tumors in mammals.

S Plakinum-diamine complexes are known from the article by A. P. Zipp and S. G. zipp/ J.Chem.Ed., 54 (12) (1977), page 739~ which describes the application of ci^~-platinum diamine dichloride ~PDD) for the treatment of cancerO It is known that platinum compounds have a broad spectrum of activity as antitumor agents, but also that they have serious drawbacks, in particular that they are toxic to the kidneys. Cis-platinum diamine dichloride is often used in combination with another substance or administered with large quantities of liquid or other techniques are used to bxin~ about an adequate flow~through of the kidneys, as a method for counteracting kidney toxicity. A number of other platinum amine complexes are known including compounds having the formula:

,NH2 / Cl Pt (5) ~ \ / \~
NH2 Cl Wadley Medical Bulletin, Vol. 7, No. 1, pp. 114-134, discloses a large number of platlnum diamine complexes, including cis-platinum diamine dichloride, for the treat-ment of cancer. Here, too, the kidney toxicity is stated as the most important drawback of thes~ compounds.

Chem. and Eng. News, 6th June 1977, pp. 29-30, also des-cribes cis-platinum diamine dichloride and lts application for the treatment of cancer. Kidney toxicity is al50 mentioned as the most important drawback of these compounds.

In an article in Cancer Chemotherapy Reports Part 1, Vol. 59, No. 3, May/June 1975, ppç 629-641. The kidney toxicity of cis-platinum diamine dichloride is also reported. Because of the toxicity of PDD to the kidney and its low therapeutic index, other platinum complexes for the treatment of cancer have been sought. For this purpose combinations of cis-platinum diamine dichloride with other chemotherapeutic agents were tested. Novel platinum complexes were also tried, but they were also found to be too toxic. It was found, for instance, that although cis-dichlorobiscyclopentyl amine platinum(II) is only slightly toxic to the kidneys, it is toxic to the ;~ spleen. So-called "platinum blues", a mixture of differ-ent amounts of five or more inseparable components have also been disclosed for the treatment of cancer.

U.S. Patents 3,892,790; 3,904,663; 4,119,653; and 4,182,724 as well as Japanese Patent 49013316 and German Patent

2,318,020 disclose a large number of platinum diamine com-plexes, including the compound having formula (5) above.
In all of these compounds with a nucleus, nitrogen atoms are linked directly ~p theLnucleus. The compounds of the first three 9 ~ were compared with cis-platinum diamine dichloride and were found to have better effects. None of the patent applications states anything about toxicity.

Toxicity is a very serious drawback of PDD, we well as all ~ Ç~l ,,,~

0~

other anti-cancerous platinum complexes that have been used so far. The high toxicity of these compounds, especially the kidney toxicity which :i5 the moat dangerous one, actually limits the dose of th~ drug that can be given to a subject.

In spite of the considerable research in this field prior to this inventiont no one has ~ucceeded in developing compounds with anti-cancerous activit:y comparable to that of PDD, but with significantly lower toxicity, especially kidney toxicity.

Novel platinum diamine complexes have now been found that are suitable for the treatment of cancer in mammals and that display little or no kidney toxicity.

The platinum diamine complexes according to the invention are characterized by the formula:

Rl C~NH2 X
\ / H \ /
C Pt (1) / \l / \

wherein Rl and R2 independently of each other may be selected from the group consisting of hydrogen, an alkyl group having 1-20 carbon atoms, a cycloalkyl group having from 3 7 carbon atoms in the ring, an aralkyl group and an aryl group, whereas Rl and R2 together may form a cycloalkyl group having 3-7 carbon atom~ in the ring and having the formula:

~4~

R~
C _ NH~ X

~ \7 / \
,C- _ NH~ X

wherein n is 2 to 7 and wherein R3 and R4 independently of each okher are selected from the group consisting of hydrogen, an alkyl group having 1-20 carbon atoms, an aryl group or an aralkyl group having 1 20 carbon atoms in the alkyl group and X is an anionic group, providing that when X is either chloxine or malonato, Rl~ ~2~ R3 and R4 are not each H;
when X is chlorine and Rl and R~ are each H, R3 and R4 are not each methyl; when X is chlorine and Rl and R2 are each methyl, R3 and R4 are not each H, and when X is chlorinP
Rl is hydrogen and R2 is methyl and R3 and R4 are not each : hydrogen.

Compounds having the following formula:

/ t --NH2 x / H

~H / \ ( 2 ) I

in which R3, R4 and X has the same meaning as in formula 1 are preferred, for example, cis-dichloro~ di(aminomethyl) cycloalkyl. platinum(II), having the formula:

f ~2 ~ H2 Cl (C ~ 2 ~ Cl wherei.n n is 2~7, preferabl~ 3-5 and cis-dichloro-l, l-di (aminomethyl) cyclohexyl platinum~II) having the following formula:

CH --- NH Cl \ Pt / (4) ~ \CH ~NH / Cl In formulas 1-2 the anionic group X preferably is a chlorine, bromine or iodine, sulphate, phthalate, acetate, carboxylate, an oxalate, malonate or substituted malonate group and iso-citrate. 'rhe acetate can be, for example, chloroacatate.
The substituents on a malonate group could be, for example, hydroxy or ethyl.

The present invention provides a process for the production of a 2,2-substituted 1,3-alkane diamine platinum (II) complex having the formula l4 R C NH X

C Pt (1 / \l / \
R2 C _ _ NH~ X

in which each Rl and R2 is independently a hydrogen atom, an alkyl group having 1-20 carbon atoms, a cycloalkyl group having 3-8 carbon atoms i.n the ring, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group, or Rl and R2 together with the C-atom to whlch they are joined form a cycloalkyl group having 3 8 carbon atoms in s the ring, R3 and R4 independently of each other represerlt a h~drogen atom, an alkyl group having 1-20 caxhon atoms, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group, and each X represents or both Xs taken together represent an anionic yroup selected from the group consisting of sulphate, ma:Lonate; alkyl, cycloalkyl, hydroxy or metal oxide subskituted malonate, carboxylate, acetate; chloro, bromo or lodo substi-tuted acetate, phthalate, carboxy substituted phthalate, and isocitrate which comprises:

(a) reacting a compound of the formula (.1) in which Rl, R2, R3 and R4 have the meanings indicated above and X is iodine, bromine or chlorine with a silver salt in an aqueous mediumr removing the silver halide formed and reacting the product with an aqueous solution of KX, NaX~ or HX, : 20 wherein X has the meaning indicated above;

~b) reacting a compound of the formula (1) in which Rl, R2, R3 and R4 have the meanings indicated above and X is iodine with a silver salt AgX wherein X has the meaning indicated above in aqueous medium or (c) reacting an aqueous solution of K2 PtC14 with a saturated aqueous solution of potassium iodide and sub-sequently adding an amine of the formula H
Rl C NH2 \ / 4 / \ 13 wherein R1~ R21 R3 and R4 have the meanings indicated a~ove, and recovering a compound of khe formula (1) in which Rl, R2, R3 and R4 have the meanings indicated above and X .is iodine and i~ desired convextiny X into another anion according to reaction (a) or (b) o.r (d) adding a solution of Ee2 PtCl~ to the hydrochloride of an amine o~ the formula Rl C --~NH2 \ / R4 C

/ \ i3 wher~in Rl, ~2~ R3 and R4 have the meanings indicated above, boili~g the mixture, and adding a solution of sodium hydroxide in water until the pH of the solution remains at 6 recovering a compound of the formula (1) in which Rl, R2, R3 and R4 have the meanings indicated above and X is chlorine, and if desired converting X into another anion according to reaction (a) or (b).

The invention further relates to a pharmaceutical composition in which these nov~l compounds are used as the active ingredi~nt~ In preparing the pharmaceutical compositions, the novel compounds are mixed with known liquid or solid carriers to form inject~ble liquids or oral preparations.

An extensive research program carried out by the National Cancer Institute, Bethesda, Maryland, and the European Organization for Research on the Treatment of Cancer, Brussels, Belgium, has shown that when compared to PDD, compounds ~ccording to this invention, particularly compounds

3~

having the ~ollowing ~ormulas display a high fherapeutic activity against a great number of dif:Eerent mammalian types of tumor, such as P 388 lymphocytic leukemia (PS), L~1210 lymphoid leukemia (LE), ep~3ndymoblastoma (EM), B 16 melanocarcinoma (Bl) and a line of L-1210 leukemia resistant to cis-PDD (LE/cis-PDD):

< CH2- ~ .NH2 Cl CH2 _ NH2 Cl CH3 ~ CH~ MH Cl (8) CH3-CE12 CH2- --NH~ \ Cl CH ~CH CH2-- --NH / Cl C~ -CH / \ CH --- -- NH / Cl CH~ N~2 Cl r\/ \ /
(10) CH- - NH Cl ~ CH-2~ --NH2 tS04 (11) CH2 - \ p~ 12) o~

C6H5_CH2~CH2 --- NH2. ~Cl 6 5 2 ~'H2---NH2 Cl 11:~3 CJ~
c f~3 \ /(~2 NH2\ f 1 C~CH / \ NE12Cl ( 14 ) . CH3 C X Z 2 ~ / C)O

O
O
C~2 IIH2 0--C~C-O-H (15 CH2 - ~NH o~

~CH2 ---NH2 0_C-cH2cl (16 ,, NH2 0_C-CH2Cl CH3--cH CH
2 ~
jC~ jPtSO4 ~17) CH3--CE~ CH2~ NH;~

0~ ~t X (18) CH - ~ NE~ O~ ~ H

C~, / \ Y t 19 C~2 ----- NH ' o . OH

O
The results of the~e experime~ts are set f orth in Table A.
It is important to note that compounds, such as those having formulas 17, 18 or 19 appeared to be even more effective against the cis-PDD resistant line of L~-1210 than they are against the parent line of L-1210. In several cases complete cures were observed with the novel compounds, an effect which was not observed with cis-PDD.

More detailed information concerning the testing procedure and their in~erpretation are contained in Instruction 14, Scrsening Data Summary, Interpretation and Outline of Current Screen, Dxug Evaluation Branch, National Cancer Institute, B~thesda, Maryland, 20014 ~19771.

Table A. Anti-cancerous actlvity in mlce Compound Mouse CodeTumorDose/ T/C*
injection (~) (mg/kg) ~ormula 4 CD2Fl PS 6.25 201 3.12 181 1.56 153 Formula 4 CD2Fl L~ 12.50 234 3.12 145 Formula 4 C57BL/6 EM 6.00 126 Formula 4 B6D2(BDF)Bl 6.00 208 3~00 20~
1.50 190 PDD B6D2(BDF~Bl 2-~0 197 Formula 7 CD2Fl PS 25.00 2?6 12.50 177 6.25 162 Formula 7 CD2Fl LE 80.00 138 Formula 7 57Bh/6 EM 12.50 163 6.25 130 Formula 8 CD2Fl LE 12.50 289 Formula 9 CD2~1 LE 12.50 323 ~ormula 11 CD2~1 LE 12.50 274 Formula 10 CD2Fl LE 12.50 148 Formula 12** BDFl LE 15.00 208 Formula 13 BDFl LE 50.00 135 * Period of survival i.s the ratio of survival times of the treated mice (T) to untreated mice (C); the therapeutic activity is significant at T/C ~ 125. The figures include dying mice only. A cure is defined as a mouse free of tumors 45 days after injection, as deter~ined by visual inspection at autopsy.
** For Formula 12--cis PDD the mice were injec~ed with 106 L-1210 ascites cells. One I.P. injection of the test compound was given to each of six mice.

3C)~
Table A. (cont.) Anti-cancerous acti~ity in mice Compound Mouse Code Tumor Dose/ T/C*
injection (%) (mg/kg) Formula 14 BDFl LE 50.00 178 Formula 15 BDFl LE 40.00 200 Formula 16 BDFl LE 6.00 207 Formula 17 BDFl LE 12.00 200 Formula 17 BDFl LE/cis PDD 6.00 ~S00 (3/6) Formula 18 BDFl LE 64.00 200 (1/6) Formula 18 BDFl LE/Cis PDD 16.00 230 Formula 19 BDFl LE, 36.00 246 Formula 19 BDFl LE/cis PDD 24.00 ~500 (3/6) Cis PDD BDFl LE 8.00 183 Cis RDD BDFl LE/ciS PDD 4-8 106-121 Table L. Percentage of urea nitrogen in the blood after administering platinum complexes (in the rat).
Compound Dose Number of Percentage of (mg/kg) days after urea-nitrogen iniection in blood ..
Formula 4 8(LDlo) 2 10

4 15 Formula 4 15(LD50) 0 10 -- _ _ _ _ _ _ _ Controls - 2 10 ____________~________________________________________________ 30Cis PDD 3(LDlo) 2 103 7.6(LD50) 2 180 4 14~

Blood urea nitrogen (BUN~ levels were also evaluated for the mice treated with compounds having formulas 12-19 on 4, 7 and 11 days after drug administration. In comparison with rats treated with cis-PDD, none of khe compounds havlng formulas 12 19 caused a signi~icant elevation o~ the BUN
values.

The data in Table B demo~strate that compounds according to this invention do not have any effect on the urea-nitrogen content in the blood ~BUN). Both at doses correspondi~g with the LD10-amount and at those corresponding with the ~D50-amount the urea-nitrogen contents in the blood are identical to the control values. BUN values ~ 30 mg% are generally considered indicative of drug-induced nephrotoxicity. In contrast, PDD at a L~10-dose, 4 days after injection, caused about a quadruple increase in the urea nitxogen content. It was found by means of a histological examination of rats after treatment with toxic doses of compounds of this invention, that these compounds display little or no kidney toxicity.

The preparation of the compounds listed in Tables A and B
are shown in the following examples.

The compounds were prepared according to the method by S. C.
Dhara; Indian J. Chem. 8, 193 ~1970~.

Example 1 Cis-diiodo~ di(aminomethyl~ cyclohexane platinum(II) ~6) having the formula:

CH2-~ NH
2 \ / (6) C~2 NH2 3~0~

To a solution of 16 g K2PtC14 in 160 ml of water a solution of 26.4 g KI in 20 ml of water ~ere added and the mixture was heatecl for 5 min. in a water bath.

~Iereupon 6~4 g l~l-di~aminomethyli cyclohexane were added and S after the mixture had been ~3tirred for 5 minutes, the precipi-tate was sucked and washed l:hree times with hot water, twice with cold ethyl alcohol and twice with ether.

Yiald 22.1 g.

Cis-dichloro~l,l-di(aminomethyl) cyclohexane platinum(II) ~4) 11.8 g of the diiodo derivative, prepared according to Example 1, were added to a solution of 6.6 g AgNO3 in 48 ml water.

After the mixture had been stirred for 10 minutes at 95-lU0C, the AgI was filtered off and washed with water. To the clear filtrate 3.28 g KCl were added and the mix-ture was stirred for 12 min. at 9S-100C. After the mixture had been cooled~
the precipitate was sucked and washed with water.

Yield: 6.0 g.

Analysis tpercentage by weightl-Calcul.: C:23.53; H:4.45; N:6.87; Pt:47.80;
Found: 23~32; 4.46; 6.86; 47.63.

Example 3 Cis-l, l-di(aminomethyl~_c~clohexane pla-tinum(II) sulphate (11) having the formula:

CH ~ NH
> tSO4 ~11) CH-- -NH

2 g diiodo derivative, prepared as in Example 1, were 8US-pended in lS0 ml water. Aft:er stirring during 20 hours with 1,0 g Ag2SO4 the AgI was filtered off and washed with H2O.
The clear ~iltrate was evaporated.

Yield : 1.1 g~ 80% by weight.
Analysis (% by weight~:
Calcul.o C:22.17; H:4.19; N:6,46;
Found : 22.02; 4.62; 6~31.

Example 4 Cis-4-carboxY~hthalato~ di(aminometh~ cyclohexane platinum __ _ _ _ (II) having ormula 15.

1.2 g of the dichloro derivative prepared according to Example 2 (formula 4), were added to a ~olution of lg AgNO3 in 25 ml of water.

After the mixture has been stirred for 1 h. at 40C the AgCl was filtered off and washed with water.

To the clear filtrate 0.63 g of 1,2,4-tricarboxybene~ene were added and the mixture was stirred for 2 h. at xoom temperature. The precipitate was sucked and washed with water.

Yield 0.8 g (45% by weight) Analysis (~ by weight~
Calcul.: C:36.24; H:4.23; N:4.97 Found : 36.42; 4.13; 4.77.

O~

~.

Cis~ aminomethyl~-cyclohexane-~is(c'h'Loroacetato) platinum(rIJ having formula 16.

1.6 g of the dichloro derivat.ive prepared according to ~xample 2 (~ormula 4), were added to a solution o 1.28 g AgNO3 in 25 ml of water.

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

To the clear filtrate a solution of 0.73 g of monochloroacetic acid and 0.45 g KOH in 25 ml of water were added and the mixture was stirred for 2 h. at room temperature. The precipitat~ was sucked and washed with water.

Yield: 1.3 g (65% by weight)~
Analysis (~ by weight):
lS Calcul.: C:27.49; H:4.23; H:5.34;
Found : 27.43; 4.21; 5.55.

The following compounds were prepared as in Example 3.

Example 6 Cis-2,2-die~yl-1,3-propanediamine platinum(II~ sulphate having formula 17~

Yield: 90% by weight.
Analysis (~ by weight):
Calcul.: (`:19.95; H:4.27; N:6.65;
~ound: 20.06; 4.46; 6.68.

Example 7 Cis~ di~aminomethyl)-cyclohexanemalonato platinum(II~

6~
1~

having formula 18.

1.6 g of the dichloro derivative prepared according to Example 2 (formula 4~, were added to a solution of 1.28 g AgNO3 in 25 ml of water.

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

To the clear filtrate a sc~lution of 0.4 g of malonic acid and 0.455 g KOH in 10 ml of waker was added~

Ater ~tirring for 2 h. at room temperature the precipitate was filtered off and dried.

Yield: 1.0 g (59~ by weight).
Analysis (~ by weight):
Calcul.: C:30.07; H:4.59; H:~.38; Pt:44.40; 0:14.57;
Found: 29.98; 4.54; 6.32; 44032; 14.57.

Cis~ dl(aminomethyl) cyclohexanehxdroxymalonate platinum (_ having the formula:
o \P / X (19) o 1.6 g of the dichloro derivative prepared according to Example II (formula 4) were added to a solution of 1.28 g AgNO3 in 25 ml of water.

!

~fter stirring the mixture for 1 h. at 40C *he AgCl was filtered off and washed ~ith.water.

To the clear filtrate a solution of 0.456 g of hydroxymalonic acid and 0.455 g KOH in 10 ;ml of water was added.

After stirring for 2 ho at room temperature the precipitate was filtered off and dri~d.

Yleld 77~ by weightO
Allalysis (% by weight):
Calcul.: C:29.01; H:~.43; N:6.15; Pt:42.84; 0:17.58;
Foundo 28.77; 4.38; 6~18; 42.96; 17.54.

Compounds having the following formulas not listed in Table A were prepared according to Example 7:

o CH3 CH2 \ / CH2-NH2 \ / ---C X (20) CH3-CH2/ CH2-N~:~ O ~ CE~2-CH

\ / \ / - C H
CH -CH / \ CH2-N~I / \ o - c ~ OH (21) 2 ~H2 ~ / - ~ X H (22) CH -Cll2 CH2-NH2 / - ~ X (23) CEI3-C ~ CH2-NE~ / O - C Na ~H ~ NH2 O - C
~ 2 ~ ~24) Exam~le 9 Cls 2 2-diethyl-1,3-diaminopropane 2-ethylmalonato ~latinum ~ having formula 20.

Yield: 65% by weight.
Analysis (~ by weigh~):
Calcul. + 2H20: Co29~33; H 5074; N 5~70;
Found : 29.23; 5~64; 5~71 Example 10 Cis-2,2-~ yl-1,3-diaminopropane 2-hydrox~malonato platinum (II) having formula 21.

Yield: 87~ by ~eight.
Analysis (~ by weight):
Calcul. ~ 1/2 H20: C 26~55; H 4~68; No6 Found : 26~67; 4~56; 6~23 Example ll Cis l,l-di(:aminom~thyl)c~clohexane 2-ethyl-malonato l`atinum ~II) having formulal 22.

Yield: 64% by weight~
Analysis ~% by weight):
Calcul. ~ 1,5 El20: C:31.57; H:5.50; N:5.67; 0:17.79; Pt:39.43;
Found : 31.36; 5.47; 5.69; 18~02; 39.58.

Cis-2,2 diethyl-1,3-diamin~propane 2-h~droxymalonato_~latinum ~ sodium salt having formula 23.

O.5 g of the hydroxymalonato derivative prepared according to Example 17 (formula 21) were suspended in 25 ml of water.

10105 ml of 0.1 N NaOH were added and the mixture was stirred for 30 min. at room temperature.

The clear solution was evaporated and the remaining solid dried.

Yield: 0.4 g (72% b~ weight).
Analysis (% by weight):
CaLlculO +2 H20: C:23.91; H:4.61; N:5.58;
Found :23.75; 4.44; 5.52.

Example 13 Cis~ a et~)cyclohexane l!l-cyclobutanedicarboxy-having formula 24.

2 g of the dichloro compound, prepared according to Example 2 (formula 4) were added to a solution of 1.6 g AgN03 in 25 ml of walter~

o~

After stirring the mixture for 1 h. at 40C the AyÇ1 was filtered off and washed with water.

To the clear filtrate a solution of 0.677 g of 1, l-cyclo-butanP~icarboxylic acid and 0.547 g of KOH in 10 ml of water.

After 2 h. at room temperature and 1 h. at 0C the white precipitate wa.s filtered ofE and dried.

Yield. 1.4 g (62% by weight)~
Analysis t% by weight):
Calcul. + H20: C:33.80; H~5~27; N:5.63;
Found 33.98; 5.02; 5.77.

Compounds having the following formulas were prepared as in Example 13:

O
CH3-CH2 \ / C 2 2 \ 0_ - C
/ C \ / Pt ~ (25) O

2 N~2 \ / C - CH2 (26) - COOH

Example 14 Cis-2,2-diethyl-1,3-diaminopropane l,l-cyclobutanedicarboxy-lato platinum(II) having formula 25.

o~

Yield: 64~ by welght.
Analysis (~ by weight):
Calcul. -~2.5 ~I20: C:30~46; H:5.70; N:5.47; Pt:38.07;
Found : 30.40; 5.44; 5.37; 38.16.

Example 15 C s~ di~amlnometh~l)cy~loheXane platinum(II) isocitrate having formula 26.

4 g of the dichloro compound, prepared according to Example 2 (formula 4) were added to a solution of 3.2 g AgN03 in 30 ml of water.

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

To the clear filtrate a solution of 2.85 g of DL-isocitric acid di-sodium salt in 15 ml of water were added and the mixture was stirred for 2 h. at room temperature. The precipitate was sucked off and washed with water.

Yield: 3.5 g (68~ by weight).
Analysis (~ by weight):
Calcul: C:31.88; H:4.59; H:5.31;
Found : 30.8; 4.9; 5Ø

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1 A process for the production of a 2,2-substituted 1,3-alkane diamine platinum (II) complex having the formula (1) in which each R1 and R2 is independently a hydrogen atom, an alkyl group having 1-20 carbon atoms, a cycloalkyl group having 3-B carbon atoms in the ring, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group, or R1 and R2 together with the C-atom to which they axe joined form a cycloalkyl group having 3-8 carbon atoms in the ring, R3 and R4 independently of each other represent a hydrogen atom, an alkyl group having 1-20 carbon atoms, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group, and each X represents or both Xs taken together represent an anionic group selected from the group consisting of sulphate, malonate; alkyl, cycloalkyl, hydroxy or metal oxide substituted malonate, carboxylate, acetate;
chloro, bromo or iodo substituted acetate, phthalate, carboxy substituted phthalate, and isocitrate which comprises:

(a) reacting a compound of the formula (1) in which R1, R2, R3 and R4 have the meanings indicated above and X is iodine, bromine or chlorine with a silver salt in an aqueous medium, removing the silver halide formed and reacting the product with an aqueous solution of KX, NaX, or HX wherein X has the meaning indicated above;

(b) reacting a compound of the formula (1) in which R1, R2, R3 and R4 have the meanings indicated above and X is iodine with a silver salt AgX wherein X has the meaning indicated above in aqueous medium or (c) reacting an aqueous solution of K2 PtC14 with a saturated aqueous solution of potassium iodide and subsequently adding an amine of the formula wherein R1, R2, R3 and R4 have the meanings indicated above, and recovering a compound of the formula (1) in which R1, R2, R3 and R4 have the meanings indicated above and X is iodine and if desired converting X into another anion according to reaction (a) or (b) or (d) adding a solution of K2 PtC14 to the hydrochloride of an amine of the formula wherein R1, R2, R3 and R4 have the meanings indicated above, boiling the mixture, and adding a solution of sodium hydroxide in water until. the pH of the solution remains at 6 recovering a compound of the formula (1) in which R1, R2, R3 and R4 have the meanings indicated above and X is chlorine, and if desired converting X into another anion according to reaction (a) or (b).

2. A process as claimed in claim 1 for the production of cis-4-carboxyphthalato-1,1-di(aminomethyl)-cyclohexane platinum(II) having the formula:

(15)

3. A process as claimed in claim 1 for the production of cis-1,1- di(aminomethyl)-cyclohexane-bis(chloroacetato) platinum(II) having the formula:

(16)

4. A process as claimed in claim 1 for the production of cis-2,2-diethyl-1,3-propanediamine platinum(II) sulphate having the formula:
(17)

5. A process as claimed in claim 1 for the production of cis-1,1-di(aminomethyl)cyclohexanemalonato platinum(II) having the formula:
(18)

6. A process as claimed in claim 1 for the production of cis-1,1-di(aminomethyl)cyclohexanehydroxymalonato platinum(II) having the formula:

(19)

7. A process as claimed in claim 1 for the production of cis-2,2-diethyl-1,3-diaminopropan2 2-ethylmalonato platinum(II) having the formula:
(20)

8. A process as claimed in claim 1 for the production of cis-2,2-diethyl-1,3-diaminopropane 2-hydroxymalonato platinum(II) having the formula:

(21)

9. A process as claimed in claim l for the production of cis-1,1-di(aminomethyl)cyclohexane 2-ethylmalonato platinum(II) having the formula:

(22)

10. A process as claimed in claim 1 for the production of cis-2,2-diethyl-1,3-diaminopropane 2-hydroxymalonato platinum(II) sodium salt, having the formula:

(23)

11. A process as claimed in claim 1 for the production of cis-1,1-di(aminomethyl)cyclohexane 1,1-cyclobutanedi-carboxylato platinum(II) having the formula:

(24)

12. A process as claimed in claim 1 for the production of cis-2,2-diathyl-1,3-diaminopropane l,l-cyclobutanedicarboxy-lato platlnum(II) having the formula:

(25)

13. A process as claimed in claim 1 for the production of cis-1,1-di(aminomethyl)-cyclohexane platinum(II) isocitrate having the formula:

(26)

14. A process as claimed in claim 1, 2 or 3 including the further step of purifying the product to a state of purity rendering it administerable to humans.

15. A process as claimed in claim 4, 5 or 6 including the further step of purifying the product to a state of purity rendering it administerable to humans.

16. A process as claimed in claim 7, 8 or 9 including the further step of purifying the product to a state of purity rendering it administerable to humans.

17. A process as claimed in claim 10, 11 or 12 including the further step of purifying the product to a state of purity rendering it administerable to humans.

18. A process as claimed in claim 13 including the further step of purifying the product to a state of purity rendering it administarable to humans.

19. A 2,2-substituted 1,3-alkane diamine platinum(II) complex of the formula:

(1) in which R1 and R2 is independently a hydrogen atom, an alkyl group having 1-20 carbon atoms, a cycloalkyl group having 3-8 carbon atoms in the ring, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group, or R1 and R2 together with the C-atom to which they are joined form a cycloalkyl group having 3-8 carbon atoms in the ring, R3 and R4 independently of each other represent a hydrogen atom, an alkyl group having 1-20 carbon atoms, an aryl group or an aralkyl group having 1-20 carbon atoms in the alkyl group, and each X represents or both Xs taken together represent an anionic group selected from the group consisting of sulphate, malonate; alkyl, cyclo-alkyl, hydroxy or metal oxide substituted malonate, carboxylate, acetate; chloro, bromo or iodo substituted acetate, phthalate, carboxy substituted phthalate, and isocitrate whenever prepared by a process according to claim 1 or by its obvious chemical equivalent.

20. Cis-4-carboxyphthalato-1,1-di(aminomethyl)-cyclo-hexane platinum(II) whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

21.Cis-1,1-di(aminomethyl)-cyclohexane-bis(chloroacetttato) platinum(II) whenever prepared by the process of claim 3 or by its obvious chemical equivalent.

22. Cis-2,2-diethyl-1,3-propanediamine platinum(II) sulphate whenever prepared by the process of claim 4 or by its obvious chemical equivalent.

23. Cis-1,1-di(aminomethyl)cyclohexanemalonato platinum(II) whenever prepared by the process of claim 5 or by its obvious chemical equivalent.

24. Cis-1,1-di(aminomethyl)cyclohexanehydroxymalonato platinum(II) whenever prepared by the process of claim 6 or by its obvious chemical equivalent.

25. Cis-2,2-diethyl-1,3-diaminopropane 2-ethylmalonato platinum(II) whenever prepared by the process of claim 7 or by its obvious chemical equivalent.

26. Cis-2,2-diethyl-1,3-diaminopropane 2-hydroxymalonato platinum(II) whenever prepared by the process of claim 8 or by its obvious chemical equivalent.

27. Cis-1,1-di(aminomethyl)cyclohexane 2-ethylmalonato platinum(II) whenever prepared by the process of claim 9 or by its obvious chemical equivalent.

28. Cis-2,2-diethyl-1,3-diaminopropane 2-hydroxymalonato platinum(II) sodium salt whenever prepared by the process of claim 10 or by its obvious chemical equivalent.

29. Cis-1,1-di(aminomethyl)cyclohexane 1,1-cyclobutanedi-carboxylato platinum(II) whenever prepared by the process of claim 11 or by its obvious chemical equivalent.

30. Cis-2,2-diethyl-1,3-diaminopropane 1,1-cyclobutanedi-carboxylato platinum(II) whenever prepared by the process of claim 12 or by its obvious chemical equivalent.

31. Cis-1,1-di(aminomethyl)-cyclohexane platinum(II) iso-citrate whenever prepared by the process of claim 13 or by its obvious chemical equivalent.