FI76351B - FOERFARANDE FOER FRAMSTAELLNING AV 2,2-SUBSTITUERADE 1,3-ALKANDIAMINPLATINA (II) KOMPLEXER MED ANTITUMOERAKTIVITET. - Google Patents

Description

χ 76351

The invention relates to a process for the preparation of novel platinum diamine complexes. These compounds are therapeutically effective as anti-cancer agents, for example, for malignant swellings and malignancies.

10 Anti-tumor platinum diamine complexes are known from 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 is mentioned that platinum compounds have a broad spectrum of activity as antitumor agents, but also that they have serious drawbacks, especially because they are toxic to the kidneys. As a method of preventing renal toxicity, cis-platinum diamine dichloride has often been used in combination with another substance or has been administered in large volumes of fluid, or other methods have been used to achieve approximately adequate renal flow. Many other platinum: · amine complexes are known, including compounds of formula 25 NH C1

CQC

30 In Wadley Medical Bulletin, Vol. 7, No. 1, pp. 114-134, describes a large number of platinum diamine complexes, including cis-platinum diamine dichloride, for the treatment of cancer. Here again, the major drawback of these compounds is mentioned as renal toxicity.

2 76351

Also in Chem. and Eng. News, 6 th June 1977, pp. 29-30, describes cis-platinum diamine chloride and its use in the treatment of cancer. Here, too, the major drawback of these compounds is mentioned as mu-5 renal toxicity.

Also, Cancer Chemotherapy Reports Part 1, Vol 59, No. 3, May / June 1975, pp. 629-641 reports on the nephrotoxicity of cis-platinum (II) diamine dichloride. Due to the renal toxicity of PDD and its low therapeutic index, other platinum complexes have been sought to treat cancer. To this end, combinations of cis-platinum diamine (II) dichloride with other chemotherapeutic agents were studied, and new platinum complexes were also tested but found to be toxic. For example, it was found that although cis-dichloro-bicyclopentylamine platinum (II) is only mildly toxic to the kidneys, it is toxic to the spleen. To treat cancer, a so-called "Platinum blues" mixture has also been disclosed, a mixture of five or more inseparable ingredients in varying degrees.

In Dutch patent applications 73,04880; 73,04881; 73,04882 and 77,03,02 describe a large number of platinum diamine complexes, including a compound of formula 2 above. In all of these compounds having a ring core, the nitrogen atoms are attached directly to the ring. The compounds of the first three Dutch patent applications were compared with cis-platinum diamine dichloride and were found to have better effects. None of the patent applications mention anything about renal toxicity.

Dutch patent application 79 04740 discloses platinum diamine complexes of the formula 35 3 76351 f4 R ± \ '' f NH2 \ 're-' 'H V7 5 \ H / \

R 1 ------ NH 2 X

R 3 wherein and each independently is a hydrogen atom, or a substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group, or R and R together form a substituted or unsubstituted cycloalkyl group, R 1 and R 2 each independently is a hydrogen atom or an unsubstituted alkyl, aryl or Aral-15 alkyl group, and X is an anionic group.

New platinum diamine complexes of the formula have now been invented

Rx .CH2-NH2 ^ ^ ^ X

20, · · 0 0 'V ^ CH2-ΝΗ2 ^ "wherein R1 and R2 are each ethyl or together form a cyclohexyl group to which they are attached, and each X is a chloroacetate group or a nitrate group or they together form a group of formula 0 0 0 0

Il tl H tl —O — C — CH9 — c — O-, -O-C-CH-C-O-, 30 Z ’C2H5 0 0 0 0

II II 11 ·· -OC ^ -CO-, or -OCCO- ch2 <: h2 35 ^ H2 can be prepared in such a way that a compound of general formula 4 76351 R, CH "------ NH0 Cl / ' 2 2 c 'Pt' v \ / \ R2 CH2 --- NH4 Cl5 wherein and R2 are as defined above are reacted with an AgNO4 solution while stirring for 1 hour at about 40 ° C, the formed AgCl is removed by filtration and washed with water and the product remaining in the filtrate is reacted with a compound of formula

XH

wherein X is a monovalent group as defined above, or with a compound of formula

H-X-X-H

Wherein the groups X together form a divalent group as defined above, optionally in the presence of potassium hydroxide, and the product formed is collected by filtration and dried.

An extensive research program conducted by the National Cancer Institute, Bethesda, USA, and the European Organization for Research on the Treatment of Cancer, Brussels, Belgium, has shown that the compounds of this invention have good therapeutic activity against cancer, in contrast to platinum complexes. , Which have been known to date and have been used in practice to combat cancer such as cis-platinum diamine dichloride (PDD); studies have also shown that the compounds of the invention show little or no nephrotoxicity.

As can be seen from the therapeutic activity values listed in Table A, the new compounds have significant antitumor activity against a variety of tumor types, including P388 lymphocytic cancer (PS), L-1210 lymphoid blood cancer (LE), ependymoblastoma, and 35 B16 nuclear cancer. . The therapeutic effect of the corresponding new compounds is greater than that of cis-platinum diamine-76351 5 dichloride (PDD) used as an experimental clinical chemotherapeutic agent. The high toxicity of these compounds has already been mentioned as a very serious drawback of PDD used in practice, as well as of all other anticancer platinum (II) complexes hitherto known (with the exception of the complexes described in Dutch patent application 79 04740). , of which nephrotoxicity is the most dangerous and in fact limits the amount of dose that can be used in practice.

Surprisingly, the compounds of the invention do not have adverse renal side effects. This was demonstrated by histological examination in rats after treatment with 15 toxic doses of the compounds described below, whereas in a similar study using PDD, severe renal damage was observed.

The new complexes also do not have an adverse effect on renal function. A generally accepted, 20 major method for determining renal toxicity involves the assessment of the percentage of urea nitrogen in the blood (blood urea nitrogen, BUN), also indicated as non-protein nitrogen (non-protein nitrogen, NPN).

It further appears that the compounds of the invention have no distinct effect on blood urea nitrogen levels. For doses corresponding to both LD50 and LD50, blood urea nitrogen levels are identical to control values. In contrast, the compound PDD gives a dose of urea nitrogen which has quadrupled after the said times as the LD4 dose, increasing as the LD4 dose by at least a factor corresponding to a factor of 11.

The experiments used compounds of the formulas:

O

35 [mu] l / CH2 NH \ [[]]

ΧΛ CX0H 4 * CH0-NH „XD-L ϋΗ 2 2 '» 0 6 76351 o

UCH2-NH2 O-C2H4COOH

CH2-NH2 n 0 6.

- 0

II

_ yCH2-NH2 o-c-CH2CL

(_x

CH2-NH2 -C CH2 CL

II

0 L · o C2H5 CH2-NH2O-C C2H5 / Pl \ / x

C2Hc CHo-NH2 O-C

0

_R

0

C2-5 ^ CH2-NHa ^ / O-c H

C2H5 ^ V'CH2-NH2 ^ OH

II

0 “Ϊ c2h5 ch2-nh2 o-c y * '' x> C2H5 CHo-NHo -q '0 7 76351 -« ch2 — nh2 0-c c2h5

<X> <X

\ h2-NHo X-C H

0 11 ch2-nw2 0 \ ^> l- (N ° ä) 2

XCH2-HHZ

12.

- 0

II

XHo-NH2 .0-C

X X x>

XCH? NHo -C

II

0 11 p

C2H5 ^ CH2 NHg -C. B

X. „.X xC

C2H5 ch2 NH2 -C ^ ONq 0 11 0 CH2-NH2 -c <^ ch2-nh2 \ o- 8 7635 1 - °

CH 2 -NH 0 - C H

Οχ> v__cX, C \ CH-5-NH „u

ί ί Q

Table A

Anti-cancer effect in mice5

Compound mouse tumor0 dose / injection T / C

10 (see code mg / kg (%) roll above) __

Formula 4 06 HP 36.00 246 HP / cis-PDD 24.00> 500 (3/6)

Formula 5 BDF ^ LE 40.00 200 15 Formula 6 * BDF1 LE 6.00 207

Formula 7 * BDF1 LE 128 229 (1/6) LE / cis-PDD 64 144

Equation 8 BDF ^ LE 24 214 LE / cis-PDD 18 144 20 Equation 9 * BDF] L LE 128> 643 (4/6) LE / cis-PDD 96 150

Formula 10 * BDF1 LE 128> 643 (3/6) LE / cis-PDD 96 188

Formula 11 * BDF1 LE 8 229 25 Formula 12 BDF ^ LE 80 283; LE / cis-PDD 80 231

Formula 13 * BDF1 LE 30 217; LE / cis-PDD 15 188

Formula 14 * BDF1 LE 6 200 30 LE / cis-PDD 6 163

Formula 15 * _BDF, LE / cis-PDD_16_230 _ ± Compound a prepared according to the invention: for more detailed information on the test method and interpretation, see Instruction 14, Screening data summary interpretation and outline of current screen, Maryland, 20014, 1977 b: 02 = mouse code B ^ D ^ F, (BDF.); 0.3 = mouse code C 57 BL / 6; 06 = mouse-Rodi CD ^ (CDF.) C: PS = P 388 lymphocytic blood vessel; LE = L 1210 lymphoid blood cancer; EM = ependymoblastoma; B ^ = B ^ g dark cancer 9 7 6 3 51 d: Survival period is the ratio of survival times (T) of treated mice to survival times (C) of untreated mice; the therapeutic effect is significant when T / C _> 125. LE / cis-PDD indicates resistance to cis-PDD.

The invention is illustrated by the following examples. The method for preparing the compounds is analogous to that described in S.C. Dhara, Indian J. Chem. 8, 193 (1970).

Example 1 (Preparation of starting material) 10 Cis-dichloro-1,1-di (aminomethyl) cyclohexane-platinum (II) γ-γ 15 CH 2 -NH 2

To a solution of 16 g of PtCl 2 in 160 ml of water was added a solution of 26.4 K in 20 ml of water, and the mixture was heated in a water bath for 5 min.

6.4 g of 1,1-di (aminomethyl) -cyclohexane were then added and, after stirring for 5 minutes, the precipitate was filtered off with suction and washed three times with hot water, twice with cold ethyl alcohol and twice with ether. .

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

After stirring for 10 minutes at 95-100 ° C, the AgJ 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 min at 95-100 ° C. After cooling the mixture, the precipitate was filtered off with suction and washed with water. Yield: 6.0 g Analysis (% by weight): 35 Calculated: C 23.53; H 4.45; N 6.87; Pt 47.80;

Found: 23.32; 4.46; 6.86; 47.63.

76351 10

Example II

Cis-1,1-di (aminomethyl) -cyclohexane-bis (chloroacetate) platinum (II) (Formula 6) 1.6 g of the dichloro-5 derivative prepared according to Example I (Formula 3) were added to a solution of 1.28 g

AgNO 2 in 25 ml of water.

After stirring for 1 hour at 40 ° C,

The 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 filtered off with suction and washed with water.

Yield: 1.3 g (65% by weight) Analysis (% by weight):

Calculated: C 27.49; H 4.23; N 5.34;

Found: 27.43; 4.21; 5.55.

Example III

Cis-1,1-di (aminomethyl) cyclohexane malonate-20 platinum (II) (Formula 15) This compound is already mentioned in Dutch patent application 79 04740, but its preparation is important for the following examples.

1.6 g of the dichloro-25 derivative prepared according to Example I (formula 3) were added to a solution of 1.28 g of AgNO 2 in 25 ml of water.

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

To the clear filtrate was added a solution of 0.4 g of malonic acid and 0.455 g of KOH in 10 ml of water.

After stirring for 2 hours at room temperature, the precipitate was filtered off and dried.

Yield: 1.0 g (59% by weight)

Analysis (% by weight): 35 Calculated: C 30.07, H 4.59; N 6.38; Pt 44.40; 0 14.57;

Found: 29.98; 4.54; 6.32; 44.32; 14.57.

li 7 6 3 51

Example IV

Cis-2,2-diethyl-1,3-diaminopropane-2-ethylmalonate platinum (II) (Formula 7) was prepared according to the method of Example III.

5 Yield: 65% by weight

Analysis (% by weight):

Calculated + 2 H 2 <D: C 29.33; H 5.74; N 5.70;

Found: 29.23; 5.64; 5.71.

Example V

Cis-1,1-di (aminomethyl) cyclohexane-2-ethylmalonate platinum (II) (Formula 10) was prepared according to the method of Example III.

Yield: 64% by weight

Analysis (% by weight): Calculated + 1.5 H 2 = C 31.57, H 5.50; N 5.67; 0 17.79; Pt 39.43; Found: 31.36; 5.47; 5.59; 18.02; 39.58.

Example VI

Cis-1,1-di (aminomethyl) cyclohexane-1,1-cyclobutanedicarboxylate platinum (II) (formula 12) 2 g of the dichloro compound (formula 3) prepared according to Example I were added to a solution of 1.6 g of AgNO ^ In 25 ml of water.

After stirring for 1 hour at 40 ° C,

The 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 (% by weight):

Calculated + H 2 O; C 33.80; H 5.27; N 5.64;

Found: 33.98; 5.02; 5.77.

Example VII

Cis-2,2-diethyl-1,3-diaminopropane-1,1-cyclobutanedicarboxylate platinum (Formula 9) was prepared according to the procedure of Example VI.

12 7 635 1

Yield: 64% by weight

Analysis (% by weight):

Calculated + 2.5 H 2 O; C 30.46; H 5.70; N 5.47; Pt 38.07; Found: 30.40; 5.44; 5.37; 38.16.

5 Example VIII

Cis-1,1-bis (aminomethyl) cyclohexane-platinum (II) nitrate (Formula 11) 4 g of cis-dichloro-1,1-bis (aminomethyl) cyclohexane-platinum (II) (0.0097 mol) was suspended in 30 ml of tis-10 loaded water. To this was added 3.1 g of AgNO 2 (0.0182 moles) and then the mixture was heated at 40 ° C for 1 hour protected from light.

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

The clear filtrate was evaporated to dryness in vacuo.

Solid weight: 4.17 g (93.5 wt%)

Melting point: explodes at about 240 ° C; decomposes slowly at temperatures below 240 ° C Analysis (% by weight): Calculated: C 20.83; H 3.93; N 12.14;

Found: 20.9; 4.1; 11.9.

1 H-NMR spectrum in DMSO-d 6 (Varian T60) with respect to TMS: CH 2 (ring): 1.37 ppm CH 2 (NH 2): 2.30 ppm NH 2: 5.67 ppm satellites: 5.20 ppm: 6.18 ppm J195pt-1H: 58 Hz.

Example IX

Cis-1,1-bis (aminomethyl) cyclohexane-platinum (II) oxalate of formula 14.

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

To this was added 3.2 g of AgNO 2 (0.019 mol) and then the mixture was heated for 1 hour at 40 ° C protected from 13,735 l of light.

The silver chloride formed was filtered off and washed with distilled water (50 ml).

To the filtrate was added 2.02 g of potassium oxalate (0.01 to 5 moles), followed by stirring for 1 hour at room temperature.

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

10 Dry weight: 3.7 g (87% by weight)

Analysis (% by weight):

Calculated + 1.5 H2 =: C 26.55? H 4.68; N 6.19; Pt 43.13; 0 19.45;

Found: 26.6; 4.6; 6.2; 43.4; 19.2.

1 H-NMR spectrum in DMSO-d 6 (Varian T60) with respect to TM.S: CH 2 (ring): 1.32 ppm CH 2 (NH 2): 2.17 ppm NH 2: 5.45 ppm satellites: 4.83 ppm: 6.08 ppm δ J195pt_1H: 76 Hz.

Claims (8)

A process for the preparation of 2,2-substituted 1,3-alkanediamine platinum (II) complexes having antitumor activity and of the formula R, CH 2 - NH 2 X CH 2 -NH 2 0-O-C-CH 2 -C-O-, -O-C-CH-C-0-, -I C , characterized in that a compound of the general formula R 1 - NH 2 R 2 and R 2 are as defined above, reacted with an AgNO reacting with a compound of formula 76351 XH wherein X is a monovalent group as defined above, or with a compound of formula HXXH where groups X together form a above defined divalent group, optionally in the presence of potassium hydroxide and the product formed is recovered by filtration and dried. Process according to Claim 1, characterized in that a compound of the formula O - CH 2 --- NH 0-c-CH 2 Cl is prepared. 15. CH2-NH2 O-C- CH-Cl II * o 3. A process according to claim 1, characterized in that a compound of formula 20 ?, C2H5 / CH, 4. A process according to claim 1, characterized in that a compound of the formula c? H xCH? -NIX X> -c is prepared. 30 XC>,> 0 C2H5 CH2-NH2 "0-cX o Process according to claim 1, characterized in that a compound of the formula is prepared.