CS235311B2 - A process for producing complex 2,2-disubstituted platinum (1,3-alkanediamine) - Google Patents

Abstract

The method for producing a complex 2,2-disubstituted 1,3-alkanediamine of platinum of the general formula I in which the general symbols have the meaning explained in the description, according to the invention is based on the fact that an aqueous solution of potassium chloroplatinate of the formula KoPtCl. is reacted with a saturated aqueous solution of potassium iodide, then an amine is added and the compound is isolated from the reaction mixture and the group X in it is optionally converted into another anion.

Description

The invention relates to a process for the preparation of novel diaminoplatinum complexes which are suitable for the treatment of cancer, such as malignant tumors and malignant tumors. The invention also relates to pharmaceuticals formed using said complex compounds.

Dianinopleth complexes are known from an article published by A. P. Zipp and S. 0.

Zlpp in J. Chem. Kd., 54/12//1977/, p. 739, where I describe the use of cis-dichloro-diaamine felt for the treatment of cancer. In the article ee states that platinum compounds have a broad spectrum as anticancer agents, but their serious disadvantage is that they are toxic to the kidneys. As a method to prevent the toxic effect on the kidneys, a combination of cis-dichloro-diaamine felt and another substance or the use of large amounts of fluids or other procedures that cause adequate renal flow have been proposed. In addition, the publication mentions a number of other aainoplatinum complexes, including the compound of the general formula V

According to the Medical Bulletin, vol. 7, no. 1, pp. 114 to 134, a large number of diaminoplete complexes, among them cis-dichloro-diaminoplete, are used for the treatment of cancer. The greatest disadvantage of these substances is their toxicity to the kidneys.

In Chem. and Eng. Newa, June 6, 1977, pages 29 and 30, ci-dichloro-diaine felt and its use for the treatment of cancer are also described. Its greatest disadvantage is its toxicity to the kidneys.

An article in Cancer Chemotherapy Reports, Vol. 1, Vol. 59, No. 3, pp. 629-64, May-June 1965, indicates that cis-dichloro-diamine platinate is toxic to the kidneys. Because this compound is toxic to the kidneys and has a low therapeutic index, other platinate complexes are being sought that are suitable for the treatment of cancer. For this purpose, combinations of cis-dichlorodiamine platinate and other chemotherapeutic agents have been tested, and new platinum complexes have been similarly tried, but they have been found to be too toxic. For example, cis-dichloro-biscyclopentylamine platinate has been found to be slightly toxic to the kidneys, but shows toxicity to allesin. In addition, it is suggested that the so-called platinum blue, a mixture of varying amounts of 5 or more inseparable compounds, may be used in the treatment of cancer.

A large number of diainoplatinum complexes are known from Dutch published patent applications Nos. 7304882 and 7703752, among them the compound of the aforementioned formula V.

In all compounds containing a nucleus, the nitrogen atoms are directly bonded to the nucleus. The compounds of the first three applications mentioned were compared with cis-dichloro-delamine and were found to have better effects. None of these applications mentions any toxicity to the kidneys.

New diainoplatinum complexes have now been discovered that are particularly suitable for cancer treatment and have little or no renal toxicity.

The diaaminoplatinum complexes according to the invention have the general formula I

C --NH ₂ X in which

R, and _R2 independently represent a hydrogen atom or an alkyl group with 1 to 20 carbon atoms | a cycloalkyl group with 3 to 7 carbon atoms in the ring, an aryl or aralkyl group β 1 to 20 carbon atoms in the alkyl residue, or R, and Rg together form a cycloalkyl group having 3 to 7 carbon atoms in the ring,

Rj and R^ independently represent a hydrogen atom or an alkyl group with 1 to 20 carbon atoms, an aryl group with 1 to 20 carbon atoms, an aryl or aralkyl group with 1 to 20 carbon atoms in the alkyl residue and

X represents an anionic group selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, phthalate, acetate, oxalate, malonate, substituted malonate, carboxylate, substituted carboxylate and isocitrate.

Compounds of general formula 11 are preferred.

c-nh ₂ x *3 where

Rp, R^ and X have the meanings given above.

The platinum-containing cis-dichloro-1,1-di(aminomethyl)cycloalkane of the general formula 111 is conveniently used.

NH.

-NH .Cl

Cl (III) where n is 2 to 7, preferably 3 to 5.

Particularly expediently used is cis-dichloro-1,1-di(aminomethyl)cyclohexane platinum of the formula IV ch ₂ — nh _{2 z} ci \_X / ^Ρχ · 'CH ₂ —NHf Cl (IV)

In general formulas I and II, the anionic group X has the above-mentioned meaning, preferably it means chloride, bromide or iodide, a sulfate residue or an optionally substituted carboxylate residue, such as an oxalate or malonate group, which is optionally substituted.

The subject of the invention is a process for the production of the above-mentioned compounds, which is carried out by a known procedure. The process for the production of compounds of general formula 1 according to the invention is based on the fact that an aqueous solution of potassium chloroplatinate of the formula KgPtCl^ is reacted with a saturated aqueous solution of potassium iodide, then an amine of the general formula is added

235311. 4 where R, to R| have the above-mentioned meaning, and the compound of general formula 1 is isolated from the reaction mixture, in which R,, Rg, R-j and R^ have the above-mentioned meaning and X represents an iodine atom, and in the obtained compound ee, the group X is optionally converted into another anion by reaction with an aqueous solution of a compound of general formula XX, in which X has the desired above-mentioned meaning.

Extensive research conducted by the National Cancer Institute, Bethesda (USA) and the European Organization for Research and Treatment of Cancer, Brussels (Belgium) has shown that the compounds of the invention have a high therapeutic effect against cancer.

In contrast to the felt complexes which are known and used to combat cancer, such as cis-dichlorodiamine tetrachloride (EDD), it has also been found that the compounds which can be produced according to the invention have little or no toxic effect on the kidneys.

As shown in the therapeutic efficacy values given in Table A below, the novel compounds have interesting activity against a large number of different types of malignant tumors, such as P 388 lymphocytic leukemia, L 1210 lymphoid leukemia, ependymoblastoma and B 16 melanoma. The therapeutic efficacy of the novel compounds is higher than that of cis-dichlorodiamine tetrahydrofuran, which is used as an experimental clinical chemotherapeutic agent.

A very serious disadvantage for the practical use of cyan-dichloro-diammine felt, as well as all other felt complexes and anticancer effects that have been known so far, is, as already mentioned above, the high toxicity of these compounds. The most dangerous is the toxicity to the kidneys, which actually limits the doses that can be applied in practice.

Despite considerable research in this area, it has not yet been possible to develop compounds that are comparable in terms of anticancer activity to cla-dlchloro-diamine, but which have significantly lower renal toxicity.

Surprisingly, it has been found that the compounds obtainable by the process according to the invention have no side effects on the kidneys. This can be determined by histological examination of rats which have received toxic doses of the compound of the above-mentioned formula IV, the compound of the formula VII or

^CH2 _{- NH2OXPt}

_CH2 - _NH2 ' ^/XO

(Vil.) and related compounds of this type, while similar tests with oiz-dlechloro-dlamin felt showed serious kidney damage.

None of the new complexes have a deleterious effect on renal function. As is generally accepted, the most important method for determining renal toxicity is the determination of the percentage of blood urea nitrogen (BUN), i.e. the determination of the non-protein nitrogen (NPN).

As can be seen from Table B, the compounds according to the invention have no effect on the urea nitrogen content in the blood. Both at the dose corresponding to the amount and at the dose corresponding to the amount M50, the urea nitrogen content in the blood is identical and the control value* cia-Dichloro-diamine felt, on the contrary, at the dose LD ₁₀ after the indicated time causes an increase in the urea nitrogen content by a factor of four, this increase being no less than a factor of ' 11 at the dose LD^q.

Table A

a) anticancer effect on the mouse

Compound Mouse type ^b Malignant tumor ⁰ ' Dose per injection _T / _C d) * formula IV 06. P.S. 6.25 201 3.12 181 1.56 153 formula IV 06 LE 12.5 334 6.25 180 3.12 145 formula IV 03 EM 6.00 126 formula IV 02 Bl 6.00 208 3.00 ¹ 208 1.50 190 PCD 02 Bl 2.0 197 formula VII 06 P.S. 25.0 226 ’2.5 177 6.25 162 formula VII 06 LE 80.0 138 formula VII 03 EM 12.5 163 6.25 130 Formula VIII® ¹ 06 LE 12.5 289 formula IX® LE >2.5 323 -__β) formulas XI ' 06 LE 12.5 274 formula X® 06 LE 12.5 148

a) more detailed information on the test method and its interpretation is given in Instruction 14, Screening data summary interpretation and outline of current screening, Drug Evaluation Branch, National Cancer Institute, Bathasda, Maryland 20014, USA, 1977.

b) 02 = designation mySi Bg Dg (BDF),

- mouse designation C 57 Bl/6, = designated mySi ODgFj tCDF,).

c) PS = P 386 lymphocytic leukemia,

LE = L· 1210 lymphoid leukemia,

EM = ependymoblastoma,

B, = B,g melanocarin.

d) Duration of use of treated mouse (T) relative to untreated mouse (C).

The therapeutic effect is significant if the T/C ratio is greater than or equal to 125.

e) The formulas of the compounds are given in the example section.

Table B

Percentage of urea nitrogen in blood after treatment with felt complexes (in rats).

Compound Dose (m/kg) Number of days after Injection Percentage of urea nitrogen in blood formula IV 8 (LD, ₀ ) 0 10 2 10 4 15 formula IV 15 ( _LD50 ) 0 10 2 15 4 17 control - 0 10 attempt 2 9 4 11

PDD 3 <U>, ₀ ) 0 2 10 13 4 52 7.6 ( _LD50 ) 0 10 2 78 4 148

The preparation of the compounds listed above, i.e. the compounds of Tables A and B, is illustrated in the following examples.

The following examples illustrate the invention without limiting it in any way.

Example 1 d1 ois-Diiodo-1,1-di(amonomethyl)cyclohexane platinum of formula VI

To a solution of 16 g of potassium chloroplatinate of the formula ⁱⁿ 60 ml of water is added a solution of 26.4 g of potassium iodide of the formula KI in 20 ml of water and the mixture is heated for 5 minutes on a water bath.

Then 6.4 g of 1,1-di(aminomethyl)cyclohexene are added and after stirring for 5 minutes the precipitate is filtered off with suction and washed three times with hot water, twice with cold ethyl alcohol and twice with ether. The yield is 22.1 g.

Analogously to Example 1, the following compounds are prepared.

Example 2 cis-Dichloro-1,1-di(amonomethyl)cyclohexane platinum of formula XV above Analysis:

Calcd: 23.53% C, 4.45 * H, 6.87% N, 47.80 « Pt, found: 23.32 « C, 4.46% H, 6.86% N, 47.63% Pt.

Example 3 cis-Cyclopentemethylenemaloneto-1,1-di(aminomethyl)cyclohexane platinum of formula VII above.

Analysis (in % by weight):

Calculated: 37.86% C, 5.56% H, 5.52% N, 38.46% Pt,

Found: 37.50% C, 5.50% H, 5.60% N, 38.19% Pt.

Example 4 cis-Dichloro-(2-methyl-2-ethyl)-1,3-propanediamine platinum of formula VIII

NH, .Cl

CH, CH ₂ X ch ₃ -ch ₂ ch ₂ ² x / Pt (VIII) • NH

Cl

Yield: 55%

Analysis (in % by weight):

Calcd: 18.86 « C, 4.22% H, 7.33 N, 51.04% Pt, 18.55% Cl, Found: 18.73% C, 4.14% H, 7.26 N, 51.33% Pt, 18.69% Cl.

Example 5 cis-Dichloro-2,2-diethyl-1,3-propanediamine platinum of formula IX

CH ₃ -CH, /CH ₂ -nh ₂ Cl (IX) / ^c z'' ¹ ch ₃ -ch ₂ ^x ch ₂ -nh ₂ Cl

Yield: 70%.

Analysis (in % by weight):

Calculated: 21.22% C, 4.58% H, 7.07% N, 49.24% Pt, 17.89% Cl, found: 21.04% C, 4.50 « H, 7.02% N, 49.43% Pt, 17.83% Cl.

Example 6 cis-Dichloro-1,1-di(aminomethyl)cyclopentane platinum of formula X ch ₂ -nh ₂ ^c, '- <η ₂ - nh^ ^X ci

Yield: 70%.

Analysis (in % by weight):

Calculated: 21.33% C, 4.09% H, 7.11% N, 49.49% Pt, 17.98% Cl, found: 21.36% C, 4.10% H, 7.14% N, 49.27% Pt, 17.91% Cl.

(X),

235311 8

Example 7 Platinum cyan-1,1-D1(aminomethyl)cyclohexane sulfate of formula XI

CH,-»»,

C\ of ⁸⁰ · — CH ₂ — NH/

Analysis (in % by weight)i

Calcd: 22.17% C, 4.19 » H, 6.46 # N, found: 22.02% C, 4.68 » H, 6.31% N.

Example 6 cls-Dichloro-1,1-di(aminomethyl)cyclobutane platinum of formula XII (Π)

CH,-NH, .Cl ² \pt ^Z .Z ch ₂ —nh ₂

Ai (XII)

Analysis (in % by weight)i

Calcd: 18.96 « C, 3.71% H, 7.37 « N, 51.31 » Pt, 18.65 # Cl, found: 18.95 » C, 3.67% H, 7.37 » N, 51.02% Pt, 18.47% Cl.

Example 9 cis-Dlchloro-2,2-dibenzyl-1,3-propanediamine platinum of formula XIII (¾¾-Cť _{2 x} CH ₂ Z ^C \ c ₆ h ₅ — ch ₂ ch ₂

Analysis (v3> mass):

Calcd: 39.24 « C, 4.26 « H, 5.38 « N, found: 39.81% C, 4.38% H, 5.73% N.

Example 10

-NH,

Cl from ^pt

-nh ₂ ^x ci (XIII) dl3-Dichloro-2,2-dliopropyl-1,3-propanediamine of the formula XIV

CH' CH ₂

CH$

Analysis (in % by weight):

Calculated: 25.48% C, 5.23 « H, 6.60% N, found: 26.31% C, 5.39% U, 6.90 « N.

Example 11

CH ₃ >h CH,-NH ₂ 1

CH< \ / \ /

J 'p' o+ ^ch 3 _s A

-nh ₂

Cl

Pt /\

Cl (XIV) cis-4-Carboxylphthalato-1,1-di(aminomethyl)cyclohexane platinum of formula XV

About About

II II

CH ₂ and

CH,

-NH, _/0 . _nh /A_c^

Cx^O-Q-H (XV),

Severografia, n. p., MOST

Price 2.40 CZK

Analysis (in % by weight)

Calcd: 36.24 » C, 4.29 # H, 4.97 # N, found: 36.42% C, 4.13% H, 4.77% N.

Example 12 cis-1,1-Di(aminomethyl)cyclohexane-bis-platinum chloride acetate of formula XVI ._, CH, and

CH,

-NH,

-NH

Analysis (in % by weight):

Calcd: 27.49 » C, 4.23% H, 5.34% M, found: 27.43% O, 4.21% H, 5.55 « N.

O

II

-c-ch ₂ ci c-ch,ci

II ² o

(XVI)

Example 13 cis-2,2-Diethyl-1,3-propanediamine platinum sulfate of formula XVII

Analysis (in % by weight):

CH,—CH, CH,-NH

V ch ₃ -ch ₂ \:h ₂ -NH ^>PtSO ₄ (XVII)

Calcd: 19.95 » C, 4.27 » H, 6.65 » N, found: 20.06% C, 4.46% H, 6.68 » N.

Example 14 Platinum cia-1,1-Di(aminomethyl)cyclohexanemalonate of formula XVIII O aCH ₂ -NH, _/0 -C Η (XVIII) / ^pt \_X

CH ₂ -NH ₂ oC H

Analysis (ν', JS mass): q

Calcd: 30.07% C, 4.59 * H, 6.38 « H, 44.40% Pt, 14.57 « 0, found: 29.98% C, 4.54% H, 6.32% H, 44.32 « Pt, 14.57% O.

Example 5: cis-1,1-Si(aminomethyl)cyclohexanehydroxymalonate of platinum (II) formula O

XIX ch ₂ ch ₂ •nh _{2 x} o-nh ₂

X

CHOH

Analysis (in % by weight): O

Calculated: 29.01% C, 4.43% H, 6.15% N, 42.84 » Pt, 17.58% O, found: 28.77% C, 4.38% H, 6.18% M, 42.96% Pt, 17.54% O.

(XIX) (XX)

Example 16 platinum(II)-2,2-Diethyl-1,3-diaminopropane-2-ethylmalonate formula XX O

Analysis (in % by weight):

CH ₃ -CH ₂ /CH ₂ -NH ₂ o/C ''pt ch ₃ -ch ₂ \;h ₂ -nh^ \>CH,—CH,

Calc'd + 2 H ₂ O: 29.33 # C, 5.74 » H, 5.70 « X, found + 2 HgO: 29.23 % C, 5.64 « H, 5.71 % X.

Example 17 cis-2,2-Disthyl-1,3-diaminopropane-2-hydroxymalonate of platinum formula XXI O ch ₃ -ch _{2 z} CH ₂ -NH ₂ C

X / ^pt ch ₃ -ch ₂ \:h ₂ +nh ₂ X

Analysis (of the following):

Calc'd + 1/2 H ₂ 0s 26.55 » C, 4.68 % H, 6.19 » N, found + 1/2 HgO: 26.67 * C, 4.56 % H, 6.23 * N, (XXI)

Example cis-1,,-Di(aminoethyl)cyclohexan-2-ethylalonate platinum of formula XXII O _ ch ₂ CH,

-NH _2χ /0.Pt

-nh ₂ X)(XXII) ch ₂ -ch ₃

Analysis: (in % by weight)

Calc'd + 1.5 HgO: 31.57 » C, 5.50 « H, 5.67 « N, 17.79 ».0, 39.4% Pt, found + 1.5 H ₂ 0: 31.36% 0, 5.47% H, 5.69 « N, 18.02 » O, 39.5 « Pt.

Example

Sodium s&l els-2,2-diethyl-1,3-diaminopropane-2-hydromyalonate of valid formula XXIII o

CH ₃ -CH ₂ .CH.-NH, . O

X >

ch ₃ -ch ₂ Xh ₂ -nh ₂ Xq-c

X ' 'ONa (XXIII)

0.5 g of the hydroxyalconate derivative prepared according to Example 17 (formula XXI) is suspended in 25 ml of water.

1.105 ml of 0.1X sodium hydroxide is added and the mixture is stirred for 30 minutes at room temperature. The clear solution is evaporated and the remaining solids are filtered off.

Yield: 0.4 g (72% \

Analysis (in * mass)

Calc'd + 2 H ₂ O: 23.91 » C, 4.61 « H, 5.58 « X, not found + 2 H ₂ O: 23.75 « H, 4.44 XH, 5.52 « X.

Example 20 cis-1,1-Di(aminomethyl)cyclohexane-1,1-cyclobutanecarboxylate of the formula XXIV

O

II

CH2 _{- NH2} /O-c

CH,-NH ₂ C ^{2 2} II o

Analysis (in % by weight):

Calc.+ H ₂ 0: 33.80% C, 5.27% H, 5.63 * N, not found + HgO: 33.98% C, 5.02% H, 5.77% N.

Example 21 cis-2,2-Diethyl-1,3-diaminopropane-1,1-cyclobutanecarboxylate of the formula XXV O

CH ₃ -CH ₂ CH ₂ -ΝΗ _2χ OC .

/VX/ (XXV) ch ₃ -ch ₂ xh ₂ -nh ₂ sc ⁱⁿ

Analysis (in % by weight): O

Calculated + 2.5 HgO: 30.46% C, 5.70 » H, 5.47 * N, 38.07% Pt, found + 2.5 HgO: 30.40% C, 5.44% N, 5.37 # N, 38.16% Pt.

Example 22 cis-1,1-Di(aminomethyl)cyclohexane platinum isocitrate

------ o 'ch ₂ -nh ₂

Analysis (in % by weight):

Calculated: 31.88% C, 4.59% H, 5.31% N, found: 30.8% C, 4.9% H, 5.0% N.

Claims (1)

Method for producing complex 2,2-disubstituted 1,2-alkanediamine of platinum general formula I r ₄ R, ,C-NH ₂ X \ C Pt /V / \ wr ₂ ^x c—nh ₂ X Ø ₃ in which R, and R ₂ independently represent a hydrogen atom or an alkyl group with 1 to 20 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms in the ring, an aryl or aralkyl group with 1 to 20 carbon atoms in the alkyl residue, or R, and R ₂ together form a cycloalkyl group having 3 to 7 carbon atoms in the ring, Rj and R^ independently of each other represent a hydrogen atom or an alkyl group with 1 to 20 carbon atoms, an aryl or aralkyl group with 1 to 20 carbon atoms in the alkyl residue and X represents an anion group selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, phthalate, acetate, oxalate, malonate, substituted malonate, carboxylate, substituted carboxylate and isocitrate, characterized in that an aqueous solution of potassium chloroplatinate of the formula KgPtCl^ is reacted with a saturated solution of potassium iodide, then an amine of the general formula is added where R, to R^ have the above-mentioned meaning, and a compound of the general formula I is isolated from the reaction mixture, in which Rj, Rg, R-j and R^ have the above-mentioned meanings and X denotes an iodine atom, and in the obtained compound, the group X is optionally converted into another anion by reaction with an aqueous solution of a compound of the general formula XX, in which X has the desired above-mentioned meaning.