SU1570649A3 - Method of obtaining complex compounds of platinum - Google Patents

Abstract

The invention relates to complex compounds of platinum, in particular the preparation of compounds of the total f-ly @ where A is a C ₁ -C ₃ alkylene

R - H or absent

X and Y are halogen or (X + Y) - -O-C (O) - @ -C (O) -O-

N, M = 0 or under the condition that N = 1, then X and Y are halogen, which exhibit antitumor activity, which can be used in medicine. The goal is to create new, more active compounds of the specified class. The synthesis is carried out by the reaction of the diamine f-ly NH ₂ - (CH ₂ ) _M -A-CH ₂ -NH with platinum (2+) potassium chloride (taken better in equimolar amount, in aqueous medium at room temperature for 3 hours or 1 day) to obtain a compound with N = 0 and X and Y is a halogen, which is either isolated or, if necessary, treated with H ₂ O ₂ (taken in excess, in aqueous medium at room temperature or when heated to 80 ° C. 0.5 - 1 h) to obtain a compound with N = 1 and X and Y-halogen, or treated with silver nitrate (preferably taken in a molar ratio of 1: 2, at room temperature in an aqueous medium for 3 days), The dinitrate is treated with cyclobutane-1,1-dicarboxylic acid (taken in equimolar amount, at room temperature for 4 days) to give a compound with N = 0 and (X + Y) - -O - C (O) - CC (O) - O -, which, in comparison with the known compound f-ly @, has the best activity against colon 26 carcinomas (at a dose of 40 mg / kg, the degree of suppression of the development of ochiol increases from 14 to 79% and kg - from 45 to 98%). 4 hp f-ly, 7 tab.

Description

CH2- (SVDt

X

The invention relates to a process for the preparation of new platinum compounds of the general formula

g

Pf

G (CBP

BUT

R

Y

A-CH, s

C-SGy-alkylene; hydrogen or absent halogen, or together form a radical of formula

, 0

ohhhhhhhhhhhhhhhhh

0

a, t-0 or 1, provided 5 when p-19 X and Y are halogen, which can be used in medicine,

The purpose of the invention is the synthesis of new compounds that exhibit a higher antitumor activity in comparison with the known analogues.

Example 1. To a solution of platinum (II) potassium chloride (4S15 rs 0901 mol) in 100 ml of water is added a solution of 2-aminomestyrrolidine (1 g, 0.01 mol) in 10 ml of water. The resulting mixture is stirred for 1 day at room temperature. The resulting solid is collected by filtration, washed with water and dried at 60 ° C under reduced pressure for 3 hours to obtain 3 g of dichloro (2-aminomethylpyrrolidine) platinum (I). Output 82%, t „pl. 255-276 ° C (with decomposition).

Calculated,%: C 16.39; H 3.3; N 7.65.

C6HaClfcNPt

Found,%: C 16.4 H 3.26; N 7.5. {

IR Spectrum (KW), VMaKC CM s 3420 3230, 3170 (HH).

Silver nitrate (2.78 g, 0.0164 mol) was added to a suspension of the described product (3 g, 0.0082 mol) in 300 ml of water. The resulting mixture was stirred in the dark for 3 days at room temperature. The white precipitated silver chloride was removed by filtration using a mily-porous filter (0.22 µm). Filtrate"

five

0

S

0

five

five

O

five

containing unreacted silver nitrate, is treated with an aqueous solution of sodium chloride. The silver chloride formed is removed by filtration, and the filtrate is evaporated at a temperature below 40 ° C under reduced pressure to 60 ml. The disodium salt of cyclobutane-3,1-dicarboxylic acid (1.54 g, 0.0082 mol) is added to the resulting solution with stirring and the mixture is kept at room temperature for 4 days.

The resulting white crystalline substance is isolated by filtration, washed with water and dried with 60 ° C and reduced pressure for 3 hours to obtain dry cyclotbutane-3,1-dicarboxylate (2-aminomethyl-pyrrolidine) platinum (I) in the amount of 1, 86 g. Yield 52%, so pl. 235-255 ° С (with decomposition).

Calculated,%: C 30.2; H 4.15; K 6.4.

C "H 404Pt

Found,%: C 30.0; H 4.11; N 6.61,

IR spectrum (KBG), iax, cmH: 3080 (ha), 1640, I860 ().

The resulting dry product is recaptured from water to obtain in the form of a purified product 1.61 g of cyclobutane-1,1-dicarboxylate (2-aminomethylpyrrolidine) platinum (i) (compound 1). Total yield 45%, so pl. 215-220 ° C (with decomposition).

Calculated,%: C 30.2; H 4.15; And 6.4.

Found,%: C 30.02; H 4.13; N 6.43,

IR (KBr), 0Mafcc, 3100, 3190 (UN), 1590, 1635 ().

Example 2. To a solution of (S) - proline (25 g, 0.22 mol) and sodium hydroxide (8.7 g, 0.22 mol) in 150 ml of water, a solution of benzyl chloroformate (43.5 g, 0, 26 mol) and sodium hydroxide (11.6 g, 0.29 mol) in 35 ml of water with stirring and cooling with ice for 30 minutes, after which stirring is continued at the same temperature for 15 minutes. Excess benzyl chloroformate was removed from the reaction medium by extraction with 150 ml of chloroform. The aqueous layer was acidified with a 5N hydrochloric acid solution, and the resulting oily product was extracted with chloroform. After drying

five

Neither chloroform solution over magnesium sulfate or chloroform is removed by evaporation to give 52.2 g (g) -1-carbobenzoxypyrrolidine-2-carboxylic acid as an oil. Yield 96%.

To a solution of (h) -1-carbobenzoxypyrrolidine-2-carboxylic acid (52.2 g, 0.21 mol) and triethylamine (21.2 g, 0.21 mol) in 525 ml of chloroform is added at stirring and cooling with ice, isobutyl chloroformate (28.7 g, 0.21 mol), after which stirring is continued for 15 minutes. Dry ammonia is bubbled into the mixture for 1 hour, then the temperature is raised to room temperature and left overnight. A white precipitated precipitate was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue is dissolved in 200 ml of chloroform and washed with dilute aqueous hydrochloric acid and water, dried over magnesium sulfate. Chloroform was distilled off to obtain 45.8 (8) -carbobenzoxypyrrolidin-2-carbamide. Yield 88%.

(S) -l-Carbobene hydroxypyrrolidine-2-carboxamide (45.8 g, 0.18 mol is dissolved in 400 ml of absolute methanol and reduced catalytically in the usual way by adding 10 g of 10% palladium on carbon in a stream of hydrogen. After completion the catalyst is removed and the solvent is distilled off under reduced pressure. The residue is recrystallized from n-hexane and benzene, washed with n-hexane to give 18.8 g of (h) pyrrolidine-2-carboxamide as a white crystalline substance. Yield 89% mp 85-90 ° C.

To a solution of (h) -pyrrolidin-2-carboxamide (18.8 g, 0.16 mol) in 1 liter of dry tetrahydrofuran, while lithium aluminum hydride (33.9 g, 0.89 mol), is slowly added with stirring and ice-cooling. after which the mixture is boiled for 48 hours. After cooling, the reaction mixture is treated in the usual manner with water and tetrahydrofuran to obtain an oil.

The oil is distilled under reduced pressure to obtain 6.07 g of (S) -2-aminomethylpyrrolidine in a colorless liquid. Yield 37%, kp. 80-85 ° C (20 mm HQ). Ј + 10.02 °

(H2O)

0

five

20

five

five

0649

Based on (B) -2-aminomethylpyrrolidine according to the method of Example 1, (h) cyclobutane -, 1-dicarboxylate (2-aminomethylpyrrolidine) platinum (p) (compound 2) was obtained, mp. 240-255С (with decomposition).

Calculated,%: C 30.2; H 4.15; N 6.40.

C, (

Found,%: C 30.14; H 4.12; N.6,33.,

IR spectrum (KBg), A, ax, cm: 3100, 3190 (NH), 1590, 1635 (). Ozr + 39.17 ° (Neo).

Example 3. Based on (k) -proline by the procedure of Example 2, (E) -2-aminomethylpyrrolidine was obtained, b.p. 79-85 ° С (20 mm HQ), - 8.67 ° (Нг0).

But the procedure of example 1 based on (H) -2-aminomethylpyrrolidine obtained (k) -cyclobutane-, 1-dicarboxylate (2-aminomethylpyrrolidine) platinum (II) (compound 3), so pl. 248-257 (with decomposition).

C 30.2; H 4.15;

thirty

N

N

Calculated,%: 6.4.

. ° 4Pt

Found,%: C 30.08; H 4.09; 6.37.

IR spectrum (KBr), - 0MO (KC,

-g

cm :

3100,

90 (NH), 1590, 1635 (). -40.1 ° (NaO).

R emery 4-18. According to the method described in example 1, obtained ramM2 ° II

The 5 personal compounds (compounds 4-18) shown in Table 1.

Example 19. To a solution of platinum (I) potassium chloride (4.15 g, 0.01 mol) in 60 ml of water is added

0 solution of 2-aminomethyl azethidine (0.86 g, 0.01 mol) and the resulting mixture is stirred for 3 hours at room temperature. The resulting solid is collected by filtration, washed with water and dried for 3 hours at 60 ° C under reduced pressure to obtain 2.64 g of dichloro (2-aminomethyl azetidine) platinum (I) as a white solid.

50

properties. Yield 75%, t. (With decomposition).

square 215-235 С

18 ml of 31% aqueous hydrogen peroxide are added to a suspension of the described product (1.76 g, 0.005 mol) in 3 ml of water at room temperature and stirring. The reaction mixture is kept for 30 minutes at room temperature and 1 hour at 80 ° WITH. After cooling, the resulting substance is collected by filtration, washed with water, dried for 3 hours at 60 ° C and under reduced pressure of 1.16 g of cis-d and chloro-trans-β-dihydroxy (2-aminomethyl-azethidine) platinum (PG) (compound 19) as a light brown matter. Yield 60%, so pl. 200-220 ° C (with decomposition)

Calculated,%: C 12.44; H 3.13; N 1.7.5,

C CljNjOiPt

Found,%: C 12.61; H 3.16; N 7.13.

The 2-aminomethyl azethidine used in Example 19 as the starting compound was obtained by reducing azetidine-2-carboxamide in tetrahydrofuran with lithium aluminum hydride.

Examples 20-27. According to the method of Example 19, the compounds shown in Table 2 were obtained. 2 (compounds 20-27).

Test 1 „

In vivo testing of antitumor activity against cancer colon 26.

Small colon pieces of colon 26 (1-2 mm) are implanted subcutaneously in the lateral region of the abdomen in male CDFij / Crj mice (6 weeks old). Four days after implantation, mice with almost the same tumor size were divided into groups of 5-6 animals each, and the test compound was administered intraperitoneally to each mouse. 10 days after the start of compound administration, each mouse was sacrificed, the tumor was weighed to calculate the inhibition ratio growth (OIR) according to the following equation:

OIR (%)

C - T

100, (1)

where C and T are the average tumor mass, respectively, of the control and treated group

The results are shown in Table. 3-7. For comparison, the known compound cisplatin (TCHDP) and the known compound according to US Pat. No. 4,410,544 are used.

Test 2.

In vivo testing of antitumor activity against cancer colon 26.

five

0

five

0

five

0

five

0

five

Small colon pieces of colon 26 (1-2 mm) are implanted subcutaneously in the lateral region of the abdomen of male strain mice (7 weeks old). After 4 days after implantation, mice with almost the same tumor size are divided into groups of 5-6 animals in each group, and each compound is injected intraperitoneally at 4, 6 and 8 days after implantation at a dosage of 40 mg / kg. day. Fourteen days after implantation, each mouse was sacrificed and the tumor of each mouse was weighed to calculate the IIR according to equation (1).

The results are shown in Table. four.

Test 3.

Comparison of in vitro ability to bind plasma proteins of test compounds.

The solution of the test compound is added to the plasma obtained from rats of the SD strain in a volume ratio of 1:19, which corresponds to 5 µg / ml Pt. The resulting mixture is incubated in the dark at 37 ° C. At a predetermined time, samples are taken from the mixture, which are filtered through molecular sieve membranes by centrifugation. The content of Pt in the filtrate (unrelated to Pt) is determined by atomic absorption spectrophotometry.

The results are shown in Table. five,

Test 4 „

Determination of side effects.

Male mice of the strain (6 weeks old) were injected intraperitoneally with the test compound and 1.3 days later and 5 days after the administration, 3 mice were sacrificed to determine body weight and the level of urea nitrogen in the blood (abbreviated KMA).

The results obtained (body weight and KMA) are shown in Table. 6

From the results obtained in the test x 1 to 2 (Tables 3 and 4), it can be seen that the proposed compounds exhibit stronger antitumor activity and they are effective in a wider dosage range compared with the same indicators for CCPP.

In addition, despite the fact that platinum complex compounds bind to plasma proteins with the formation of inactive forms, the proposed compounds show a significantly lower tendency to plasma protein binding as compared to CCP. The proposed compounds have a reduced toxicity and high water solubility. and can be used in antitumor therapy.

The test results for antitumor activity against colon 2 carcinomas are given in table. 7,

From tab. 7 shows that the known compound has a much lower antitumor activity compared with any proposed compound.

In addition, in connection with antitumor activity at a dosage approximately equal to MFA (maximum tolerated dosage), each of the proposed compounds exhibits antitumor activity approaching 100%, while for a known compound this indicator is less than 60%.

Claims (5)

Invention Formula Method for preparing platinum complex compounds of general formula I (QH) n -X Y SNG-MNGH SNLP g1CH (ACP A I R CH And - With, -C3-alkylene; R is hydrogen or absent; X and Y - halogen, or together form a radical of the formula Where .0 -o-c-c : ABOUT n, t-0, or 1 on conditional conditions, about tl production , X and Y - halogen y u and with the fact that the diamine of formula II CH2-NH2 five where A, R, m have the indicated meanings, react with platinum (potassium chloride to obtain a compound of general formula (la), where, X and Y are halogen, and isolating it or, if necessary, treating it with hydrogen peroxide, to obtain the desired product (1b), where, X and Y are halide, or the compound (la) is treated with silver nitrate followed by treatment of the resulting dinitrate with cyclobutane-1,1-dicarboxylic acid to obtain the desired product of the general formula (1c), where, X and Y are together , 0 0 five 0 -o-s -o-cd / h Method according to claim one 2. The method according to claim 1, wherein the diamine derivative is reacted with an equimolar amount of platinum (I) potassium chloride in an aqueous medium at room temperature for 3 hours or one day. 3, the method according to claim. Characterized in that the compound of formula (la) is reacted with an excess of hydrogen peroxide in g water at 20-80 ° C for 0.5-1 h, 4. The method according to claim 1, characterized in that the compound 5 of formula (la) is reacted with silver nitrate in a molar ratio of 1: 2 at room temperature, in an aqueous medium for three days. 5. The method according to claim 1, wherein the dinitrate is reacted with an equimolar amount of dicarboxylic acid in an aqueous medium at room temperature for four days. Priority in relation to m: 09/12/84 with A - C-alkylene, X. and Y is halogen About II oo-oo about - ° -cV n - 1, 0; m - 0, 1; R-H or R is absent, 01.22.85 with A is C1-alkylene, X and Y is halogen, n is 1, m is O, R is hydrogen. 04/25/85 when A is Cr-alkylene, X and Y are halogen, n is 1, m is O, R is hydrogen, or X and Y together form a radical of the formula ohhhh -oh about n m -, O, R - hydrogen. 01 „08.85 with A — C — j-alkylene, X and Y together form a radical of the formula about -o-s -wasp/ about R is hydrogen. Table 1 Continuation of table 1 13HCH, 00 14HCHNSN, OO 15HCH, O O 16HH ten 17HH oh oh 18HH oh oh Melting point with decomposition. IR spectrum (KW) vtg . CM Ul C8H, 4Nz04Pt277-281 olclo snake Pt C8H (4Nz04Pt AN-CH CH3 II ° ( Pt N-CH3  CH3C, H16Ni ° 4Pt 265-270 259-268 205-215 264-269 275-285 24,173,557.05 24,113,537,01 26,273,926,81 26.213,856,63 26,273,926,81 26,223,896,75 24.173,557.05 24.113,477.13 26.273,926.81 26.183,836,57 26,273,926,81 26,303,866,55 3120 (NH), 1638, 1662, 169l () 3120 (HH). 1660, 1690 () 3140 (NH), 1645. 1670, 1690) 3135, 3210 (NH), 1655, 1698 () 3080, 3155 (NH), 1650, 1670. 1695 () 3250, 3220, 3140 (NH), 1700, 1680, 1660, 61 5 () Ut J about CT 4 VO Melting point with decomposition. Rl rl  (OH) nx table 2 pt ,: 191570649 Table 3 0 9 AO 60 80 120 160 40 60 80 120 160 40 60 80 120 160 40 60 80 120 160 40 79 87 98 97 Doom 73. 88 94 98 Doom 70 85 90 95 Doom 80 88 98 98 99 60 one 2 3 10 20 20 Continued table. 3 Table 4 98 99 95 99 82 one 20 26 CSDG1 Measurement object Compound dosage, mg / kg mouth Control (-) Compound 2 (60) Compound 3 (60) VDPD (12) Control (-) Compound 2 (60) Compound 3 (60) CCTsP (12) P 0.05. R Yu, 01. Table 5 9 7 10 62 14 eleven 3 86 38 15 14 93 Table 6 Days after administration 23.6 ± 1.023.7 ±, 4 -23.1 ± 1.419.9 ± 1, 23.4 ± 1.520.1 ± 1, 24.6 + 1,122.55 ± 1.1 17.10 ± 4.35 20.0 ± 2.617.7 ± 3.1 18.3 ± 3.113.8 + 1.8 23,3t4 ,,, 9 l v ABOUT Table 7 mpd