CS235310B2 - Method of complex 2,2-disubstituted 1,3-platinous alkanediamine production - Google Patents

Description

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

Diaminoplatium complexes are known from the article by A. P. Zlpp and S. G. Zlpp in J. Chem. Ed., 54/12 (1977), p. 739, and disclose the use of felting cis-dichloro-diemine for treating cancer. The article states that platinum compounds have a broad spectrum of anti-cancer agents, but their serious drawbacks are that they are toxic to the kidneys. As a method to prevent toxic effects on the kidney, a combination of cis-dlchloro-diamine and another substance or the use of large amounts of fluids or other processes that cause the appropriate kidney flow has been suggested. In addition, a number of other amino platinum (II) complexes are disclosed, including, but not limited to, a compound of formula (V)

(IN)

Wedley Medical Bulletin, Vol. 7, No. 1, pp. 114-134 discloses a large number of diamino-platinum (II) complexes, including cis-dlchloro-diamine-platinum (II) for the treatment of cancer. Here too, the greatest disadvantage of these substances is their renal toxicity.

In Chem. And Eng. The News of June 6, 1977 also describes, on pages 29 and 30, cis-dichloro-diamine platinum and its use in the treatment of cancer. Its major disadvantage is its renal toxicity.

From the article in Cencer Chemotherepy Reporte, Part 1, Vol. 59, No. 3, pp. 629-641 of May and June 1965 that cis-dlchlorodiamine platinum is also toxic to the kidney. Since this compound is toxic to the kidneys and has a low therapeutic index, other platinum (II) complexes that are useful in the treatment of cancer are sought. For this purpose, they tested combinations of knitted cis-dichloro-diamine and other chemotherapeutic agents and similar and tested new platinum complexes, but were found to be too toxic. For example, it has been found that platinum cis-dichloro-biecyclopentalamine is poorly toxic to the kidneys but exhibits spleen toxicity. Furthermore, it is mentioned that 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 diaminoplatinum (IV) complexes are known from Dutch Patent Applications 7304880, 7304881, 7304882 and 7703332, among them the compound of the above formula V. In all compounds containing a nucleus, nitrogen atoms are directly bound to this nucleus. The compounds of the first three mentioned applications were compared with cis-dichloro-diamine platinum and were found to have better effects. None of these applications disclose anything about kidney toxicity.

New diaminoplatinum (II) complexes have now been discovered which are particularly useful for the treatment of cancer and have little or no kidney toxicity.

The diaminoplatinum (II) complexes of the invention have the general formula (I)

(I) in which

H ₁ and R _{2 are} each independently hydrogen or C 1 -C 20 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 20 eryl or eralkyl in the alkyl radical, or S ₁ and Hg 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 eralkyl 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 II are preferred

R4 c c <:

c «3

-NH, X (Pt) \ -NH, X (II) wherein

R1, R1 and X are as defined above.

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

CH,

CH,. NH, Cl

Λ /

Pt / \

- nh ₂ Cl (III) wherein n represents 2 to 7, preferably 3 to 5.

Particularly preferable to use the cis-dichloro-1, 1-di (aminomethyl) cyclohexane platinum IV _nh ₂ CH ₂ CH ₂ pi ^ -NH ₂ Cl (IV)

In formulas (I) and (II), anionic group X preferably has the meaning given above, preferably a chloride, bromide or iodide, a sulfate residue or an optionally substituted carboxylate residue, such as an oxolate or malonate group, which is optionally substituted.

The present invention provides a process for the production of the above compounds by a process known per se.

235310 4

The process for the preparation of the compounds of the general formula X according to the invention is based on the addition of a solution of potassium chloroplatinate of the formula KgtCl2 to the hydrochloride of the compound of the formula

1,

H χ Λ c * / \? 3 R ₂ CH NH ₂ NH ₂ wherein to R ^ are as defined above, the mixture was boiled, then a solution of sodium hydroxide in water until a pH 6, and in the resulting compound optionally, the group X is converted to another anion by treatment with an aqueous solution of a compound of formula X in which X is as defined above.

Extensive research conducted by the National Cancer Institute, Bethesda (USA) and the European Research and Care Organization! Cancer, Brussels (Belgium) has shown that the compounds of the invention have a high therapeutic effect against cancer. In contrast to the felt-like complexes known to date and used to combat cancer, such as cis-diohloro-diamine platinum (PDD), it has also been greened that the compounds produced by the method of the invention have little or no kidney toxic effect.

As shown by 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 lymphocytic leukemia, L 1210 lymphoid leukemia, ependymoblastoma and B 16 melanocarcin. The therapeutic effect of the novel compounds is greater than that of the cis-dihloro-diamine felt, which is used as an experimental clinical chemotherapeutic.

A very serious disadvantage for the practical use of the cis-dichloro-doamine felt, as well as all other platinum anti-cancer complexes which have been known so far, is, as mentioned above, the high toxicity of these compounds. The most dangerous is renal toxicity, which actually limits the doses that can be applied in practice.

Despite considerable research in this field, it has not been possible to develop compounds which are comparable to scis-dichloro-diamine, but which have significantly lower renal toxicity, in terms of anti-cancer activity.

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 histologically examined rats that received toxic doses of the compound of the above formula IV, the compound of the formula VII

O ^εΗ 2_ΝΗ _{2χρ /} Ο_έ ch ₂ _nh / ^{í í} M M

O and related compounds of this type, while similar tests with ois-dichloro-diamine felt showed severe kidney damage.

Neither of the new complexes has a profound effect on kidney activity. As is generally recognized, an important method for determining kidney toxicity is by determining the percentage of blood urea nitrogen (BUN), ie the determination of non-protein nitrogen (NPN).

As shown in Table B, the compounds of the invention have no effect on the blood urea nitrogen content. As for the dose corresponding to the amount of LD ₁₀ and the dose corresponding to the amount of BD ₁₀ , the blood urea nitrogen content is identical to the control value. Conversely, the cis-dichloro-diamine at the LD 50 dose at the indicated time increases the urea nitrogen content to fourfold, which is not less than a factor of 11 at the LD 50 dose.

Table A β

anti-cancer effect on mice

Compound Mouse type C) Malignant tumor Dose for injection (mg / kg) t / c ⁾ (%) of formula IV 06 / PS 6.25 201 3.12 181 1, 56 153 of formula IV 06 / LE 12.5 243 6.25 180 3.12 145 of formula IV 03 / ΕΠ '· ’ 6.00 126 of formula IV 02 / Bl 6.00 208 3.00 208 1, 50 190 PDD 02 / Bl 2,0 197 of formula VII pers PS 25.0 226 2.5 177 6.25 162 of formula VII 0ο LE 80.0 138 of formula VII 03 / EM 12.5 163 o, 25 130 θ) of formula VIII 06 / LE 2.5 289 of formula IX ^H H 06 / LE 12, v 323 of formula XI ^e ^ 06 / LE 2,5 274 E) of formula X ' 06 / LE 12.5 148

(a) more detailed information on the test method and its interpretation is given in Instruction 14, Drug Evolution Brench, Bethesda, Karylend 20014, USA, 1977.

b), 02 = mouse designation Bg D ^ (BDF), = mouse designation C 57 BL / 6, = mouse designation CDgF ^ (CDFp.

c) PS = P 388 lymphocytic leukemia,

LE = 1,1210 lymphoid leukemia,

EM = ependymoblastoma,

B = melenocarcinoma.

d) Time of use of the treated mouse (T) in relation to the mouse (C). The therapeutic effect is significant when the T / C ratio is greater than or equal to 12 µm.

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 (mg / kg)

Number of days after injection

Percentage of blood urea nitrogen

of formula IV 0 (LD, ₀ ) 0 2 4 10 10 15 Dec of formula IV 15 (LD ₅₀ ) 0 10 2 15 Dec 4 17. control experiment - 0 10 2 9 4 1 1 PDD 2 (LD ₁₀ ) 0 10 2 13 4 52 7.6 (H> ₅₀ ) 0 10 2 78 4 148

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

The following examples illustrate the invention without limiting it.

Example 1

Platinum cis-dichloro-1,1-di (eminomethyl) cyclobutane (XII '- ^{x x} ₂ ) - ( ₂ ) (XII)

Dissolve 2,8 g of 1,1-di (aminomethyl) cyclobutane, 2 g of hydrochloric acid and 6,2 g of potassium chloroplatinate of the formula K ^ PtCl4 in 50 ml of water, heat to 95 to 100 ° C and add dropwise to this solution. 1.2 g of sodium hydroxide in 25 ml of water at a rate to maintain an approximate pH of 6.

The resulting precipitate was filtered off with suction, washed with water and dried. The product is taken up in 250 to 300 ml of liquid aminoacid and filtered. After evaporation of the amine, the product was washed with 2N hydrochloric acid and then with water and dried. The yield is 3.7 g, which is about 65% of theory.

Analysis (% of weight):

calculated: 18.96% C, 3.71% H, 7.37% N, 51.31% Pt, 18.65% Cl;

Found: C 18.95%, H 3.67%, N 7.37%, Pt 51.02, Cl 18.47%.

The following compounds were prepared in analogy to Example 1.

Example 2

Knitted cis-dichloro-2,2-dibenzyl-1,3-propyndiamine of the formula XIII

(XIII)

Yield: 45%.

Analysis:

calculated: 39.24% C, 4.26% H, 5.38% N;

Found: C, 39.81; H, 4.38; N, 5.73.

Example 3 Platinum cis-dichloro-2,2-diidopropyl-1,3-propanediamine of formula XIV

CH

C

CH ·

CH CH ₂ -NH ₂ Cl

Pt

The procedure is as in Example 1.

Analysis (% by weight):

calculated:

found:

H, 5.23; H, 6.60; % C, 26.31;% H, 5.39;

Example 4 Cis-diiodo-1,1-di (aminomethyl) cyclohexane felt of formula VI (VI)

To a solution of 16 g of potassium chloroplatinate of formula KgPtCl2 in 160 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.

Then 6.4 g of 1,1-di (aminoraethyl) cyclohexane 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 ethanol and twice with ether. Yield 22.1 g. The following compounds were prepared analogously:

EXAMPLE 5 Knit-Dichloro-1,1-di (aminomethyl) cyclohexane of formula (IV) above

Analysis:

calculated: 23.53 * C, 4.45% H, 6.87% N, 47.80% Pt;

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

Exemplary cis-cyclopentamethylenemalonate-1,1-di (aminomethyl) cyclohexane of formula VII above

Analysis:

calculated: 37.86% C, 5.56% H, 5.52% N, 38.46 56 Pt} found: 37.50 »C, 5.50% H, 5.60 55 N, 38.19% Pt.

EXAMPLE 7 Plain cis-dichloro- (2-methyl-2-ethyl) -1,3-propanediamine VIII

CH 3 / CH ₂ -NH _;

Cl

Pt (VIII)

CH 3 -CH 2 CH ₂ —nh ₂

Cl

Analysis:

calculated: 18.86% C, 4.22% H, 7.33 56 N, 51.04 56 Pt, 18.55% Cl

18.73 56 C, 4.14 56 H, 7.26 56 N, 51, 33 56 Pt, 18.69 56 Cl found:

EXAMPLE 8 Platinum (II) cia-dichloro-2,2-diethyl-1,3-propanediamine IX

CH,

CH,

-ch ₂ ch ₂ ^ C ^ / \

-ch ₂ ch ₂ nh ₂ Cl \ /

Pt

-NH,

Cl

Analysis:

calculated: 21.22% C, 4.58% H, 7.07% N, 49.24% Pt, 17.89% Cl;

Found:% C, 21.04;% H, 4.50;% N, 7.02;% Pt: 49.43;

Example 9 cis-dichloro-1,1-di (aminomethyl) cyclopentane platinum of formula X ₂ CH ₂ -NH ^. Cl ch ₂ —nh ₂ Cl (ix) (X)

Analysis;

calculated:

found:

C, 21.33; H, 4.09; N, 7.11; Pt, 49.49; Cl, 17.98; H, 4.10; N, 7.14; Pt, 49.27; Cl, 17.91.

EXAMPLE 10 Platinum (1,1-di (atninomethyl) cyclohexane sulfate _{) of the} formula XI ch ₂ -nh ₂

PtSO ₄ ch ₂ —nh ₂ (xi)

Analysis:

calculated:

found:

% C, 22.17;% H, 4.19;% N / 6.46; % C, 22.02;% H, 4.62;

Ex.

II

C-O-H

235310 10

Analysis:

calculated: 36.24% C, 4.29% Η, 4.97% Ni found: 36.42% C, 4.13% H, 4.77% N.

EXAMPLE 12 Platinum (I) -l1-di (aminomethyl) cyclohexane-bis-chloroacetate (XVI)

O

II aCH, - NH 3 OC-CH ₂ CH ₂ —nh ₂ ^{x X} O - c-ch ₂ ci (XVI)

Analysis:

calculated: 27.49% C, found: 27.43% C,

H, 4.23; N, 5.34. H, 4.21; N, 5.55.

Example 13 Platinum (II) cis-2,2-diethyl-1,3-propanediamine sulfate (XVII)

CH ₃ -CH ₂ ^ / CH ₂ ^-NH-C \> Tso ₄ CH ₃ -CH ₂ CH ₂ -NH ₂ (XVII)

Analysis:

calculated: 19.95% C, found: 20.06% C,

H, 4.27; H, 6.65; N, 4.46; N, 6.68.

EXAMPLE 14 Platinum (1,1-di (aminomethyl) cyclohexanemalonate) isomer XVIII

2 \ 7

O

Analysis:

calculated:

found:

30.07% C, 29.98% C,

H 4.59, H 4.54,

N 6.38, N 6.32,

44.40% Pt, 44.32% Pt,

14.57% 14.57% o;

O.

(XVIII)

1

Example 15 Cia-1,1-di (aminoraethyl) cyclohexanedroxymalonate of formula XIX

O

....... _ i

Analysis:

calculated: 29.01% C, found: 28.77% C,

EXAMPLE 16 X-ray cis-2,2-diethyl-1,3-diaminopropane-2-ethylmalonate of formula XX

G <X oh ₂ —nh / \ —c on o

4.43%%, 6.15% N, 42.84% Pt, 17.58 ϋ 4.38% H, 6.18% N, 42.96% Pt, 17.54 S (XIX)

0;

0.

ch ₃ -ch ₂ ch ₂ -nh _{2x from} oC Pt / \ / \ ch ₃ -ch ₂ ch ₂ -nh ₂ oX

-Cch ₂ -ch ₃ (XX)

Analysis:

calculated + 2 HgO: C 29.33% 5 5.74% H 5.70;

found; + 2 H ₂ O:% C, 29.23;% H, 5.64;% N, 5.71.

Example 17 Cis-2,2-diethyl-1,3-disrainopropane-2-hydroxymalonate of formula XXI ch ₃ -ch ₂ ch ₂ -nh ₂ °

CH ₃ -CH ₂ CH ₂ -NH ₂ ° C OH

Analysis:

Calculated + 1/2 H, > 0: C 26.55, H 4.68, N 6.19; found + 1/2 H ₂ O: C 26.67, H 4.56, N 6.23, (XXI)

Example 18 Platinum (II) cis-1,1-di (aminomethyl) cyclohexane-2-ethylmalonate

O <

ch ₂ ch ₂ -NH,

NH · pX

X

O-C CHo — CH ·,

II ^{of J} o

(XXII)

Analysis: calculated +1,5 HgO: 31.57% C, 5.50% H, 5.67% K, 17,79% 0, 39.4% Pt; found; +1,5 HgO: 31.36% C, H, 5.47; N, 5.69. 18.02% O 39.5% Pt. Example 1 ad 19 Sodium salt cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonate of formula XXIII

CH, -CH ₂ CH ₂ -NH _2xO Pt ^of o

II

-C

CH ₃ -CH 2 O 4 OC

II o

ONa (XXIII)

0.3 g of the hydroxymalonate derivative of the formula XXI prepared according to Example 17 is suspended in 23 ml of water. Add 1,105 ml of 0.1 K sodium hydroxide solution and stir the mixture for 30 minutes at room temperature. The clear solution was evaporated and the residual solid dried. Yield: 0.4 g (72%).

Analysis:

calculated + 2 HgO: C 23.91, H 4.61%, N 5.58%;

Found + 2 HgO: C 23.75, H 4.44, N 5.52.

EXAMPLE 20 Platinum cis-1,1-di (aminomethyl) cyclohexane-1,1-cyclobutanecarboxylate of formula XXIV ch ₂ -nh ₂ -nh ₂ -nh

II c

C

II o

Analysis:

H, 5.27; N, 5.63. Found: + HgO: C, 33.90, H, 5.02, N, 5.77.

(XXIV) 235310

Example 21 Platinum (II) cis-2,2-diethyl-1,3-diaminopropyne-1,1-cyclobutanecarboxylate

ch ₃ -ch, ch _{2 —} NH _{2 s} ^ 0- 'pt ch ₃ -ch ₂ ch ₂ nh ₂ o - O II II O (XXV) Analysis: calculated +2.5 Η ,, Ο: H, 5.70; N, 5.47. 33,07% Pt! found +2.5 H ^ O: C, 30.40; H, 5.44; N, 5.37. 38,16% Pt.

Example cis-1,1-di (8minomethyl) cyclohexanisocitrate felt of formula XXVI

-WH, O-

Pt — nh ₂ ^ II c — ch ₂ (XXVI) c — CH II I

About HC-OH

AND

COOH

Analysis:

calculated:

found:

31.88% C, 30.8% C,

4.59% «, 4.9% H,

N, 5.31. 5,0% K.

Claims (1)

SUBJECT OF THE INVENTION The present invention relates to a process for the preparation of a complex 2,2-disubstituted 1,3-alkanediamine of felt of formula I R4 \ Z 'c ^H / w R? 3ι ^r 3 -NH, X \ z Pt Z \ -NHj X (I) in which K i and x g are each independently hydrogen or C 1 -C 20 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 20 aryl or aralkyl in the alkyl radical, or R ₁ and R 6; together form a cycloalkyl group having 3 to 7 carbon atoms in the ring, R ^ and R ^ are each independently hydrogen or C 1 -C 20 alkyl, C 1 -C 20 aryl or aralkyl in the alkyl radical, and 23531 O. . X a modified enion group selected from the group consisting of chloride, bromide, iodide sulfate, nitrate, phthalate, acetate, oxalate, malonate, substituted malonate, carboxylate, substituted carboxylate with isocitrate, characterized in that the potassium chloroplatinate solution of formula K ^ PtClCl is added to the hydrochloride of a compound of the formula R4 — ^nh 2 '/ R4 / ^X A ³ r ₂ č-NH ₂ H where B, as defined above, is boiled, followed by the addition of a solution of sodium hydroxide in water until the pH of solution 6 is reached, and optionally the group X is converted to another anion by adding an aqueous solution of a compound of formula KX X is as defined above.