CS235311B2 - Method of complex 2,2-disubstituted 1,3-platinous alkanediamine production - Google Patents

Abstract

A method for producing a complex 2,2-disubstituted 1,3-alkanediamine of Formula I in which the general symbols have the meaning explained in the description according to the invention is based the chloroplatinate aqueous solution potassium formula of KoPtCl. he reacts and saturated with an aqueous iodide solution potassium, adding amine and reacting the compound ee Isolates the compound and therein optionally, X is converted to another anion.

Description

The invention relates to a process for the production of novel diaminoplatinum complexes which are suitable for the treatment of cancer, such as cancer swelling and cancer. The invention also relates to medicaments produced using said complex compounds.

Dianin-complex complexes are known from an article published by A. P. Zipp and S. 0.

Zlpp in J. Chem. Kd., 54 (12) (1977), p. 739, which discloses the use of felted cis-dichloro-diaain for the treatment of cancer. In the article ee states that the platinum compounds have a broad spectrum as anticancer agents, but their serious disadvantage is that they are toxic to the kidneys. As a method of avoiding toxic effects on the kidneys, a combination of felt cie-dichloro-diaain and another substance, or the use of large amounts of fluids or other processes that cause the renal flow in question has been suggested. In addition, a number of other α-alatoplatinous complexes are mentioned in the publication, including the compound of formula V

Wedleý Médieal Bulletin, Vol. 7, No. 1, pp. 114-134 discloses a large number of diaainoplethy complexes e, among them cis-dichloro-diaminosporonate for the treatment of cancer. They also report the greatest disadvantage of these substances to their renal toxicity.

Chem. and Eng. Newa, and on June 6, 977, no 29 and 30 are also disclosed for Cie-Dichloro-Diaain Felt and its use in the treatment of cancer. Its greatest disadvantage is its renal toxicity.

From the article in Cancer Chemotherapy Seports, Part 1, Vol. 59, No. 3, atr. 629-64, it appears from May and June 1965 that the kidney is toxic to the kidney. Since this compound is toxic to the kidneys and has a low therapeutic index, they are looking for other felt complexes that are useful in the treatment of cancer. For this purpose, cis-dichlorodiamine combinations were tested. platinum and other chemotherapeutics, and similarly, new platinum complexes have been tried, but have been found to be toxic. For example, it has been found that Cationic Dichloro-Bycyclopentylamine Felt is of low toxicity to the kidneys, but exhibits toxicity to alesine. In addition, so-called platinum blue, a mixture of different amounts of 5 or more inseparable compounds, can be used to treat cancer.

A large number of diaainoplatinum (II) complexes are known from Dutch published patent applications Nos. 7304882 and 7703752, among them the compound a above mentioned of formula (V).

In all compounds containing a nucleus, the nitrogen atoms are directly attached to the nucleus. The compounds of the first three applications were compared with cis-dl-chloro-dlemin felts and were found to have better effects. None of these applications disclose anything about kidney toxicity.

New diaainoplatinous complexes have now been discovered which are particularly suitable for the treatment of cancer and have little or no kidney toxicity.

The diaainoplatin complexes of the invention have the general formula I

C - NH ₂ X wherein

R 1 and R _{2 are each} independently hydrogen or C 1 -C 20 alkyl C 3 -C 7 cycloalkyl, aryl or aralkyl β 1 to 20 carbon atoms in the alkyl radical, or R 8 and R 8 together form a cycloalkyl group having 3 to 7 carbon atoms in the ring,

R 1 and R 2 are each independently hydrogen or C 1 -C 20 alkyl, C 1 -C 20 aryl, C 1 -C 20 aryl or aralkyl in the alkyl radical, and

X is 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 formula 11 are preferred

c-nh ₂ x * 3 where

R p R 6 and X are as defined above.

Suitably, cis-dichloro-1,1-di (aminomethyl) cycloalkane (III) is used

NH.

-NH .Cl

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

Particularly expedient is the use of cis-dichloro-1,1-di (aminomethylcyclohexane platinum of the formula IV ch ₂ - nh _{2 from} C 1 / ^X / CH ₂ -NHf Cl (IV)

In formulas I and II, anionic group X is as defined above, preferably chloride, bromide or iodide, sulfate or optionally substituted carboxylate, such as oxalate or malonate, which is optionally substituted.

The present invention provides a process for the production of the above compounds by a process known per se. The process for the preparation of the compounds of the formula I according to the invention is based on reacting an aqueous solution of potassium chloroplatinate of the formula KgPtCl2 and a saturated aqueous solution of potassium iodide, then adding an amine of the formula

235311. 4 wherein R 1 to R 1 The compound of formula (I) in which R @ 1, R @ 3, R @ 1 and R @ 2 are as defined above and X is iodine is isolated from the reaction mixture and optionally converted to another anion by reaction with an aqueous solution of a compound of formula XX wherein X is as defined above.

Extensive research conducted by the National Cancer Institute, Bethesda (USA) and the European Organization for Research and Cancer 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 known and used to date to combat cancer, such as cis-diehloro-diamiau platinum (EDD), it has been found that the compounds produced by the present invention have little or no toxic effect on the kidneys .

As shown in the therapeutic effect values shown in Table A below, the novel compounds have an interesting effect against a large number of different types of cancer, such as P 388 lymphoeytic leukemia, L1210 lymphoma leukemia, ependymoblastoma and B16 melanocareinoma. The therapeutic effect of the novel compounds is greater than that of the cis-dihloro-diamine, which is used as an experimental clinical chemotherapeutic agent.

A very serious disadvantage for the practical use of cannabis di-dichloro-diammonium, as well as the other cannabis complexes and the anti-cancer activity known hitherto, is the high toxicity of these compounds. The most dangerous is renal toxicity, which actually limits the doses that can be administered in the pr.

Despite considerable research in this field, ee has not yet developed compounds which are comparable in terms of anti-cancer activity to cla-dlchloro-diamine, but which have a significantly lower kidney toxicity.

Surprisingly, it has been found that the compounds obtainable by the process of the invention have no kidney side effects. This can be determined by histologic examination of rats that received toxic doses of the compound of the above formula IV, the compound of the formula VII

CH ₂ -NH ₂ O ^X Pt

CH ₂ -NH ₂ ' ^{/ X} O

(Vil.) And related compounds of this type, while serious kidney damage was found in similar tests and with oiz-chlorodilamine.

Neither of the new complexes has a deleterious effect on renal function. As is generally accepted, the recording method for determining kidney toxicity consists in determining the percentage of blood urea nitrogen (BUN), i.e. the determination of the protein protein (NPN).

As can be seen from Table B, the compounds of the invention have no effect on the urea nitrogen content in the blood. As at a dose corresponding to the amount and dose corresponding plurality M50 content močovinováho nitrogen in the blood was identical to the control value * cis-dichloro-diamine fuzzy contrast, at a dose LD _1Q after that time causes the increase of content močovinováho nitrogen four times, said svýšení not Manel than factor 11 at the LD 50 dose.

Table A

(a) anticancer effect on the dishwasher

Compound Mouse type ^b Cancer ⁰ ' Dose for injection _T / _C (d) * of formula IV 06 / PS 6.25 201 3.12 181 1.56 153 of formula IV 06 / LE 12.5 334 6.25 180 3.12 145 of formula IV 03 / EM 6.00 126 of formula IV 02 / Bl 6.00 208 3,00 ¹ 208 1.50 190 PCD 02 / Bl 2,0 197 of formula VII 06 / PS 25.0 226 2.5 177 6.25 162 of formula VII 06 / LE 80.0 138 of formula VII 03 / EM 12.5 163 6.25 130 of formula VIII® ¹ 06 / LE 12.5 289 of formula IX® LE > 2,5 323 -__ β) of formula XI ' 06 / LE 12.5 274 of 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 and Outline of Current Screeen, Drug Evaluatlon Branch, National Cencer Institute, Bathasda, Maryland 20014, USA, 1977.

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

- mouse designation C 57 B1 / 6, = mouse designation ODgF 1 tCDF 1).

c) PS = P 386 lymphocytic leukemia,

LE = L · 1210 lymphatic leukemia,

EM = ependymoblastoma,

B = B, g with melanocarein.

d) Time of use of treated mice (T) relative to untreated mice (C).

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

e) Formula compounds are given in the Examples 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 the blood of formula IV 0 (LD, ₀ ) 0 10 2 10 4 15 Dec of formula IV 15 (LD ₅₀ ) 0 10 2 15 Dec 4 17 control - 0 10 try 2 9 4 11

PDD 0 <U>, ₀ ) 0 2 10 13 4 52 7.6 (LD ₅₀ ) 0 10 2 78 4 148

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

The following examples illustrate the invention without limiting it.

EXAMPLE 1 Platinum VI-diiodo-1,1-di (amonomethyl) cyclohexane VI

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

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

In analogy to Example 1, the following amino acids were prepared.

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

C, 23.53; H, 4.45; N, 6.87; N, 47.80. Found: C, 23.32; H, 4.46; N, 6.86; Pt.

EXAMPLE 3 Platinum-Cyclopentemethylenemalonethio-1,1-di (aminomethyl) cyclohexane of formula (VII) above.

Analysis (% by weight):

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

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

Example 4 Platinum cis-Dichloro- (2-methyl-2-ethyl) -1,3-propanediamine VIII

NH, Cl

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

Cl

Yield: 55%

Analysis (% by weight):

C, 18.86; H, 4.22; H, 7.33; Pt, 51.04; Cl, 18.55. Found: C, 18.73; H, 4.14; 51.33% Pt, 18.69% Cl.

Example 5 Platinum cis-Dichloro-2,2-diethyl-1,3-propanediamine 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 (% by weight):

Calculated: C 21.22, H 4.58, N 7.07, Pt 49.24, Cl 17.89, Found: C 21.04, H 4.50, 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 2 ^X ci

Yield: 70%.

Analysis (% by weight):

H, 4.11; N, 7.11; N, 49.49; Cl, 17.98. Found: C, 21.36; H, 4.10; 7.14%. N, 49.27% Pt, 17.91% Cl.

(X),

235311 8

Example 7 Platinum (II) cia-1,1-D1 (aminomethyl) cyclohexane sulfate

CH, - »»,

C \ of ⁸⁰ · - CH ₂ - NH /

Analysis (% by weight) i

N, 6.46. Found: C, 22.02; H, 4.68; N, 6.31.

EXAMPLE 6 Platinum Dichloro-1,1-di (aminomethyl) cyclobutane of formula XII (Π)

CH, -NH ² · Cl \ pt ^Z .Z CH ₂ -NH ₂

Ai (XII)

Analysis (% by weight) i

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-dichloro-2,2-dibenzyl-1,3-propanediamine platinum of formula XIII (CT-¾¾ _{2 x} CH ₂ Z ^C \ C ₆ H ₅ - CH ₂ CH ₂

Analysis (v3> mass):

Calculated: C, 39.24; H, 4.26; N, 5.38. Found: C, 39.81; H, 4.38; N, 5.73.

Example 10

-NH,

Cl of ^pt

-nh ₂ ^x ci (XIII) dl3-Diehloro-2,2-dliaopropyl-1,3-propanediamine platinum XIV

CH ₂ CH ₂

CH $

Analysis (% by weight):

H, 5.23; N, 6.60. Found: C, 26.31; U, 5.39; N, 6.90.

Example 11

CH ₃ > h CH, -NH ₂ 1

CH <\ / \ /

J 'p' o + ^ch 3 _with A

-nh ₂

Cl

Pt / \

Platinum (IV) cis-4-carboxyphthalate-1,1-di (aminomethyl) cyclohexane (XV)

O O

II II

CH ₂ a

CH,

-NH _{/ 0th n} / a / c

C x ^ O-Q-H (XV)

Severography, n. P., MOST

Price 2,40 Kčs

Analysis (% by weight)

H, 4.97; N, 4.97. Found: C, 36.42; H, 4.13; N, 4.77.

EXAMPLE 12 Platinum-1,1-Di (aminomethyl) cyclohexane-bis-chloroacetate of formula XVI, CH, and

CH,

-NH,

-NH

Analysis (% by weight):

H, 4.23; M, 5.34. Found: 27.43; H, 4.21;

O

II

-c-ch ₂ or c-ch, ci

II ² o

(XVI)

Example 13 Platinum (II) cis-2,2-diethyl-1,3-propanediamine sulphate of formula XVII

Analysis (% by weight):

CH, CH, CH, -NH

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

N, Found: C, 20.06; H, 4.46; N, 6.68.

Example 14 Platinum (II) cia-1,1-di (aminomethyl) cyclohexanemalonate of formula (XVIII) O and CH ₂ -NH, _(O- C (XVIII)) ^pt .

CH ₂ -NH ₂ C H

Analysis (ν ', JS mass): q

C, 30.07; H, 4.59; H, 6.38; H, 44.40; Pt, 14.57; found: C, 29.98; H, 4.54; 6.32%. H, 44.32% Pt, 14.57% O.

Example 5 Platinum (I) cis-1,1-Si (aminomethyl) cyclohexanhydroxymalonate of formula (O)

XIX ch ₂ ch ₂ • nh _{2 x} o-nh ₂

X

C OH

Analysis (% by weight): 0

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

(XIX)

Example 16 cie-2,2-Diethyl-1,3-dieminopropane-2-ethylmalonate

Analysis (% by weight):

CH ₂ CH ₃ / CH ₂ -NH ₂ O / C 'PT CH ₃ -CH ₂ \ h ₂ -NH ^ \> CH, -CH,

Calculated + 2 H ₂ O: 29.33 C, 5.74 H, 5.70 X, found + 2 H 6 O: 29.23% C 5.64 H, 5.71% X.

Example 17 2,2-cis-1,3-Disthyl dieminopropan-2-hydroxymalonét platinum XXI O CH ₃ -CH ₂ CH ₂ -NH _{from 2} C

X / ^pt ch ₃ -ch ₂ : h ₂ + nh ₂ X

Analysis (luno tonnage):

Calculated + 1/2 H ₂ O ₅ 26.55 C, 4.68% H, 6.19 N, found + 1/2 H 6 O: 26.67 C, 4.56% H, 6.23 * N , (XXI)

Example cis-1, - Platinum (1-aminoethyl) cyclohexanes-2-ethylaalonate of formula XXII O-ch ₂ CH,

-ΝΗ _2χ /0.Pt

-nh ₂ X) (XXII) ch ₂ -ch ₃

Analysis: (% by weight)

Calculated + 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 % H, 5.47; N, 5.69; N, 18.02; O, 39.5;

Example

Platinum (II) -sodium 2,2-diethyl-1,3-diaminopropane-2-hydromyaalonate of formula XXIII o

CH ₃ -CH ₂ .CH.-NH ₃ . O

X>

ch ₃ -ch ₂ Xh ₂ -nh ₂ Xq-c

X 'ONa (XXIII)

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

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

Yield: 0.4 g (72%).

Analysis (in * weight)

Calculated + 2 H ₂ O: 23.91 ° C, 4.61 ° H, 5.58 ° X, found + 2 H ₂ O: 23.75 ° H, 4.44 XH, 5.52 ° X.

EXAMPLE 20 Cottonseed cis-1,1-Di (aminomethyl) cyclohexane-1,1-cyclobutanecarboxylate of formula XXIV

O

II

CH ₂ -NH _2/0-C

CH, -NH ₂ C ^{2 2} II o

Analysis (% by weight):

Calcd. + H ₂ 0: 33.80% C, 5.27% H, 5.63 * N + HgO started up: 33.98% C, 5.02% H, 5.77% N.

Example 21 Cotton-2,2-Diethyl-1,3-diaminopropane-1,1-cyclobutanecarboxylate of Formula XXV O

CH ₃ -CH ₂ CH ₂ -ΝΗ _2χ OC.

/ VX / (XXV) CH ₃ -CH ₂ -NH ₂ H ₂ ^oc

Analysis (% by weight): 0

+ 2.5 HgO: C, 30.46; H, 5.70; H, 5.47; N, 38.07; found + 2.5 Hg: C, 30.40; N, 5.44. 5.37. N, 38.16% Pt.

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

------ o 'ch ₂ -nh ₂

Analysis (% by weight):

H, 4.59; N, 5.31. Found: C, 30.8; H, 4.9; N, 5.0.

Claims (1)

A process for the preparation of a complex 2,2-disubstituted 1,2-alkanediamine of platinum (I ₎ R, C-NH ₂ X \ C Pt / V / \ wr ₂ ^x c - nh ₂ X Ř ₃ in which R 1 and R _{2 are} each independently hydrogen or C 1 -C 20 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 20 aryl or aralkyl, or R 2, and R ₂ together form a cycloalkyl group having 3 to 7 carbon atoms in the ring, R 1 and R 2 are each independently hydrogen or C 1 -C 20 alkyl, C 1 -C 20 aryl or aralkyl in the alkyl radical, and X is 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, characterized in that the aqueous solution of potassium chloroplatinate of formula KgPtCl? reacting with a saturated solution of potassium iodide, then adding an amine of the formula wherein R 1 to R 2 are as defined above, and isolating a compound of formula I wherein R 1, R 3, R 3 and R 3 are as defined above; X represents an iodine atom, and in the obtained compound ee the group X optionally converts into another anion by reaction with an aqueous solution of the compound of formula XX, in which X is as defined above.