CN1203080C - Antitumour platinum (II) compound using camphor acid radical as ligand - Google Patents

Abstract

The invention discloses a class of platinum (II) coordination compound with effective anticancer activity, which is characterized in that it is a novel platinum (II) coordination compound formed by the reaction of camphorate radical as complex anion and platinum amine complex cation, and discloses its preparation method In vitro inhibitory effects of typical compounds on human leukemia cells, ovarian cancer cells, liver cancer cells and lung cancer cells. The composition of this type of compound is represented by the right formula: wherein the camphoric acid group in formula (1), formula (2) and formula (3) can be its DL racemate, D type optical isomer [(1R, 3S) -(+)-camphorate] or L-type optical isomer [(1S,3R)-(-)-camphorate]. The R groups in the formula (1) are identical, and are respectively a hydrogen atom, a C _1-5 alkyl group or a C _1-8 oxaalkyl group; the cyclohexanediamine in the formula (2) is 1,2-trans ring Hexamethylenediamine, the absolute configuration of the two chiral carbon atoms (marked with ^* ) is R configuration or S configuration; 4,5-bis(aminomethyl)-2-alkane in formula (3) The R ₁ and R ₂ represented by the base-1,3-dioxolane are the same or different, and are respectively a hydrogen atom or a C _1-5 alkyl group, or can be linked with a carbon atom to form a cycloalkyl group, two chiral The absolute configuration of carbon atoms (marked with ^* ) is R configuration or S configuration. The platinum complexes of the present invention include all stereoisomers represented by the above chemical formulas and mixtures thereof.

Description

Antitumor Platinum(II) Complexes with Camphorate as Ligands

technical field

The present invention relates to novel platinum(II) complexes having potent antitumor activity, processes for their preparation and in vitro antitumor properties of typical compounds of said platinum(II) complexes.

Background technique

In the research of cisplatin anticancer drugs, the characteristics of the anion as the leaving group have a great influence on the activity of the drug. If an unstable leaving group is used, the toxicity of the compound will increase; if an inert leaving group is used, the compound is generally inactive. Since the successful development of carboplatin containing cyclosuccinate, dicarboxylic acids have been playing an important role in the research and development of anti-tumor platinum (II) complex drugs. Such as oxalic acid, malonic acid and norcantharidic acid have been practically used. Therefore, it is an important way to design and synthesize cisplatin compounds with low toxicity and good water solubility containing dicarboxylic acid groups to improve anti-tumor preparations.

Contents of the invention

The purpose of the present invention is to provide novel cisplatin (II) complexes containing dibasic carboxylate radicals. These complexes have low toxicity, good water solubility and effective antitumor activity, and are used for treating human tumors. The invention discloses a novel platinum (II) coordination compound, which is characterized in that the novel platinum (II) coordination compound is formed by using camphorate radical as complex anion and platinum amine complex cation to react. The composition of this type of compound is represented by following (1), (2), (3) formulas:

Wherein the camphorate in formula (1), formula (2) and formula (3) can be its racemate, D-type optical isomer [(1R, 3S)-(+)-camphorate] or L-type Optical isomers [(1S,3R)-(-)-camphorate]. The R groups in the formula (1) are identical, and are respectively a hydrogen atom, a C _1-5 alkyl group or a C _1-8 oxaalkyl group; the cyclohexanediamine in the formula (2) is 1,2-trans ring Hexamethylenediamine, the absolute configuration of the two chiral carbon atoms (marked with *) is R configuration or S configuration; 4,5-bis(aminomethyl)-2-alkane in formula (3) The R ₁ and R ₂ represented by the base-1,3-dioxolane are the same or different, and are respectively a hydrogen atom or a C _1-5 alkyl group, or can be linked with a carbon atom to form a cycloalkyl group, two chiral The absolute configuration of carbon atoms (marked with *) is R configuration or S configuration. The platinum complexes of the present invention include all stereoisomers represented by the above chemical formulas and mixtures thereof.

Another object of the present invention is to provide methods for preparing platinum(II) complexes represented by formula (1), formula (2) and formula (3). In the synthesis of these divalent platinum complexes, they first obtain the platinum compound containing the diamine coordination of the dihalide ion by potassium tetrachloroplatinate and the relevant diamine (ammonia) ligand, by formula (4a) and (4b) represent. Then, under the condition of avoiding light and passing nitrogen, by method A: using silver ions to remove the halide ions of dihalide diamine (ammonia) platinum (II), the resulting intermediate reacts with the camphorate of monovalent alkali metal cations or ammonium ions Obtain cis-(camphorate)·diamine (ammonia) platinum (II) compound; or obtain cis-(camphorate) by method B: using silver camphorate and dihalogenated diamine (ammonia) platinum (II) ) · Diamine (ammonia) platinum (II) compound.

Hal in formulas (4a) and 4(b) represents Cl ^- , Br ^- and I ^- ions, wherein the R groups in formula (4a) are the same, respectively hydrogen atom or C _1-5 alkyl or C _1-8 Oxaalkyl, the arc attached to the amine nitrogen atom in formula (4b) means that two amine groups are connected by an alkyl group.

Another object of the present invention is to disclose the in vitro inhibitory effects of typical compounds in the above-mentioned platinum (II) complexes on human leukemia cells, ovarian cancer cells, liver cancer cells and lung cancer cells.

Representative compounds of the invention include:

Cis-(DL-camphorate)·diamminoplatinum(II) (slightly: GS-1a);

Cis-(D-camphorate) · diammine platinum (II) (slightly: GS-1b);

Cis-(DL-camphorate)·diisopropylamine platinum(II) (shortly: GS-2a);

Cis-(D-camphorate) · diisopropylamine platinum (II) (slightly: GS-2b);

Cis-(DL-camphorate)·(1,2-trans-cyclohexanediamine) platinum(II) (slightly: GS-3a);

Cis-(D-camphorate)·(1,2-trans-cyclohexanediamine) platinum(II) (slightly: GS-3b);

Cis-(DL-camphorate)·[(1R,2R)-1,2-trans-cyclohexanediamine]platinum(II) (shortly: GS-4a);

Cis-(D-camphorate)·[(1R,2R)-1,2-trans-cyclohexanediamine]platinum(II) (shortly: GS-4b);

Cis-(DL-camphorate)·[(1S,2S)-1,2-trans-cyclohexanediamine]platinum(II) (shortly: GS-5a);

Cis-(D-camphorate)·[(1S,2S)-1,2-trans-cyclohexanediamine]platinum(II) (shortly: GS-5b);

Cis-(DL-camphorate)[4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (shortly: GS-6a);

Cis-(D-camphorate)[4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (shortly: GS-6b);

Cis-(DL-camphorate)·[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (slightly: GS-7a);

Cis-(D-camphorate)·[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (slightly: GS-7b);

Cis-(DL-camphorate)·[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (slightly: GS-8a).

Cis-(D-camphorate)·[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (slightly: GS-8b);

cis-(DL-camphorate) · bis(2-methoxyethylamine) platinum(II) (shortly: GS-9a);

cis-(D-camphorate)·bis(2-methoxyethylamine)platinum(II) (abbreviation: GS-9b).

The invention is further illustrated by the following examples, which, however, do not limit the invention.

The structures of the compounds prepared according to the present invention have been confirmed by different analytical methods such as elemental analysis, infrared spectroscopy, proton nuclear magnetic resonance spectroscopy and cationic electrospray mass spectroscopy. The following are examples of some representative compounds prepared by the method of the present invention.

Detailed ways

Embodiment 1: Synthesis of cis-(DL-camphorate) diammine platinum (II)

cis-diiododiammine platinum (II) (0.97 g, 2 mmol) and silver nitrate (0.68 g, 4 mmol) were mixed and added to water (50 ml), and reacted at 60° C. for 24 hours in the dark and nitrogen. Diatomaceous earth assisted filtration, the aqueous solution of DL-camphoric acid (0.40 g, 4 mmol) and sodium hydroxide (0.16 g, 4 mmol) was added to the filtrate, and the reaction was carried out under nitrogen at 60 ° C for 16 hours in the dark, and the solution was concentrated , a large amount of white solid was precipitated. Filter, wash repeatedly with water, ethanol and ether, and dry under vacuum at 60°C to obtain 0.41 g (48%) of the product.

IR(KBr): 3424vs(br), 3266vs(br), 2967m, 2881w, 1594vs, 1544vs, 1460m, 1384vs, 1355vs

¹ H-NMR (D ₂ O/TMS): δ0.47-0.67 (m, 3H), 0.91-1.08 (m, 6H), 1.24-1.31 (s, 1H), 1.60 (s, 1H), 1.74- 1.75(s, 1H), 2.08(m, 1H), 2.55-2.56(s, 1H)

ESI-MS: [M+methanol+H] ⁺ =460 (30%), [M+H] ⁺ =428 (6%)

Example 2: Synthesis of cis-(DL-camphorate) two (isopropylamine) platinum (II)

cis-diiodo·bis(isopropylamine)platinum(II) (1.13 g, 2 mmol), silver nitrate (0.68 g, 4 mmol) were mixed and added to water (50 ml), and reacted in the dark at 60°C under nitrogen gas After 24 hours, diatomaceous earth was assisted to filter, and the aqueous solution of DL-camphoric acid (0.40 g, 4 mmol) and sodium hydroxide (0.16 g, 4 mmol) was added to the filtrate, and it was reacted in the dark at 60° C. for 16 hours, The solution was concentrated and a large amount of white solid precipitated out. It was filtered, washed repeatedly with water, ethanol and ether, and dried under vacuum at 60°C to obtain 0.39 g (38%) of the product.

IR(KBr): 3430s(br), 3217s(sh,br), 2971vs, 2880w, 1595vs(br), 1462m, 1383vs, 1351vs, 1164w, 1118w

¹ H-NMR (DMSO-d ⁶ /TMS): δ0.70-0.85 (m, 3H), 0.97-1.26 (m, 18H), 1.44-2.36 (br, 4H), 2.64-2.70 (br, 1H, CH), 2.96-3.18 (m, 2H), 5.85-5.99 (br, NH ₂ )

ESI-MS: [M+methanol+H] ⁺ =544 (100%), [M+H] ⁺ =512 (44%)

Example 3: Synthesis of cis-(D-camphorate)·[(1R,2R)-1,2-trans-cyclohexanediamine] platinum(II)

Cis-dichloro[(1R, 2R)-1,2-trans-cyclohexanediamine] platinum (II) (0.76 g, 2 mmol), silver nitrate (0.68 g, 4 mmol) were mixed and added to water ( 50 milliliters), under 60 ℃, shielded from light and reacted with nitrogen for 24 hours, diatomaceous earth assisted filtration, added the aqueous solution of D-camphoric acid (0.40 gram, 4 mmol) and sodium hydroxide (0.16 gram, 4 mmol) in the filtrate , React at 60°C for 16 hours in the dark and pass through nitrogen, the solution is concentrated, and a large amount of white solid is precipitated. Filter, wash repeatedly with water, ethanol and ether, and dry under vacuum at 60°C to obtain 0.65 g (64%) of the product.

IR(KBr): 3424vs(br), 3226s(sh,br), 2939s, 2872w, 1598vs(br), 1457m, 1381vs, 1350s, 1169w, 1126w, 1063w

¹ H-NMR (DMSO-d ⁶ /TMS): δ0.84-0.91 (m, 3H), 1.09-1.20 (m, 6H), 1.28 (m, 4H), 1.48 (m, 2H), 137-1.62 (m, 3H), 2.08-2.22 (m, 3H), 2.41-2.57 (m, 3H), 5.87-6.44 (br, NH ₂ )

ESI-MS: [M+methanol+H] ⁺ =540 (100%), [M+H] ⁺ =508 (40%)

Embodiment 4: synthesizing cis-(D-camphorate) [(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum ( II)

cis-diiodo[(4R,5R)4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (1.25 g, 2 mmol) , silver nitrate (0.68 grams, 4 mmol) was mixed and added to water (50 milliliters), and under 60 ℃, the reaction was 24 hours in the dark and led to nitrogen, and diatomaceous earth was assisted to filter, and D-camphoric acid (0.40 grams, 4 mmol) was added in the filtrate. ) and an aqueous solution of sodium hydroxide (0.16 g, 4 mmol), reacted in the dark at 60° C. under nitrogen for 16 hours, the solution was concentrated, and a large amount of white solid was precipitated. Filter, wash repeatedly with water, ethanol and ether, and dry under vacuum at 60°C to obtain 0.55 g (49%) of the product.

IR(KBr): 3424s(br), 3220s(sh,br), 2966m, 2881w, 1620-1559s(br), 1460m, 1383vs, 1357s, 1125m, 1093s

¹ H-NMR (DMSO-d ⁶ /TMS): δ0.77-1.14 (m, 15H), 1.58-2.03 (m, 3H), 2.45-2.87 (m, 7H), 3.22-3.30 (m, 2H) , 4.82 (s, 1H), 6.40-7.50 (br, NH ₂ )

ESI-MS: [M+methanol+H] ⁺ = 600 (34%)

Embodiment 5: synthesizing cis-(D-camphorate) [(4S, 5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum ( II)

cis-diiodo[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (1.25 g, 2 mmol ), silver nitrate (0.68 g, 4 mmol) were mixed and added to water (50 milliliters), and reacted in the dark under nitrogen for 24 hours at 60 ° C, diatomaceous earth assisted filtration, and D-camphoric acid (0.40 g, 4 milliliters) was added to the filtrate mol) and sodium hydroxide (0.16 g, 4 mmol) in aqueous solution were reacted at 60° C. for 16 hours in the dark under nitrogen, and the solution was concentrated to precipitate a large amount of white solid. It was filtered, washed repeatedly with water, ethanol and ether, and dried under vacuum at 60°C to obtain 0.42 g (37%) of the product.

IR(KBr): 3427s(br), 3218s(sh,br), 2966m, 2881w, 1621-1560s(br), 1461m, 1381vs, 1358s, 1124m, 1094s

¹ H-NMR (DMSO-d ⁶ /TMS): δ0.72-1.14 (m, 15H), 1.58-1.95 (m, 3H), 2.45-2.87 (m, 7H), 3.15-3.20 (m, 2H) , 4.80 (s, 1H), 6.50-7.20 (br, NH ₂ )

ESI-MS: [M+methanol+H] ⁺ = 600 (100%)

Example 6: Synthesis of cis-(DL-camphorate) two (2-methoxyethylamine) platinum (II)

cis-diiodo·bis(2-methoxyethylamine) platinum(II) (1.20 g, 2 mmol), silver nitrate (0.68 g, 4 mmol) were mixed and added to water (50 ml), 60°C React under nitrogen for 24 hours in the dark, assist filtration with diatomaceous earth, add DL-camphoric acid (0.40 g, 4 mmol) and aqueous solution of sodium hydroxide (0.16 g, 4 mmol) to the filtrate, and keep away from light at 60°C Nitrogen was passed to react for 16 hours, the solution was concentrated, and a large amount of white solid was precipitated. Filter, wash repeatedly with water, ethanol and ether, and dry under vacuum at 60°C to obtain 0.54 g (50%) of the product.

IR(KBr): 3447m(br), 3217m, 3122m, 2963m, 2882m, 2829w, 1610vs, 1457m, 1378vs, 1346vs, 1119s, 1052m

¹ H-NMR (DMSO-d ⁶ /TMS): δ0.545-0.712 (m, 3H), 0.93-1.15 (m, 6H), 1.22-2.35 (m, 4H), 2.49 (m, 1H), 2.623 (m, 2H), 3.06(s, 3H), 3.42(s, 2H), 5.57-5.91(br, NH ₂ )

ESI-MS: [M+methanol+H] ⁺ =576 (40%)

Note: Because the isotopes with higher abundance of Pt elements include ¹⁹⁴ Pt, ¹⁹⁵ Pt and ¹⁹⁶ Pt, the quasi-molecular ion peaks of the ESI-MS mass spectrum of the above compounds have three isotope peaks with higher abundance.

In vitro inhibitory effects of some typical compounds on human leukemia cells, ovarian cancer cells, liver cancer cells and lung cancer cells

Efficacy evaluation of monomeric compounds:

Experimental method: trypan blue dyeing method, SRB colorimetric method

Cell lines: HL-60 human leukemia cells, 3AO human ovarian cancer cells, BEL-7402 human liver cancer cells, A549 human lung cancer cells.

Experimental design: The drug concentration was divided into five groups: 100, 10, 1, 0.1, 0.01 (μg/ml). The inhibition rate was calculated according to the curative effect evaluation. Observe the inhibition of tumor cell growth by drugs at different concentrations, cisplatin and carboplatin as reference.

The in vitro inhibitory rate data of the relevant compounds on four kinds of tumor cells are shown in Table 1, Table 2, Table 3 and Table 4.

Table 1. Inhibitory rate of compounds on human leukemia cells (HL-60) in vitro Number of HL-60 viable cells at each concentration (μg/ml) (×10 ⁴ /ml) Percentage of cell growth inhibition (%) at each concentration (μg/ml) sample name Time Ctrl Zero 466 100 10 1 0.1 0.01 100 10 1 0.1 0.01 GI ₅₀ GS-1aGS-1bGS-2aGS-2bGS-4aGS-4bGS-7aGS-7bcisplatin carboplatin 0 8 37 48 500 2 34 41 500 29 41 48 500 26 32 36 560 1 22 49 500 5 25 40 490 0 22 47 500 0 1 24 370 0 6 28 470 10 32 40 49 100 95 23 0 0100 100 30 12 0100 43 13 0 0100 50 35 25 0100 100 60 0 0100 100 53 15 0100 100 60 0 0100 100 100 55 5 23100 305 1040 90 10 0 10 2.570.423.752.610.970.340.970.030.101.06

Table 2. Inhibition rate of compounds on human ovarian cells (3AO) in vitro The number of viable cells of 3AO cells at each concentration (μg/ml) (×10 ⁴ /ml) Percentage of cell growth inhibition (%) at each concentration (μg/ml) sample name Time Ctrl Zero 0.770.25 100 10 1 0.1 0.01 100 10 1 0.1 0.01 GI ₅₀ GS-1aGS-1bGS-2aGS-2bGS-4aGS-4bGS-7aGS-7bcisplatin carboplatin 0.42 0.53 0.66 0.66 0.650.36 0.59 0.64 0.69 0.660.46 0.55 0.63 0.55 0.550.45 0.49 0.47 0.51 0.500.49 0.43 0.43 0.56 0.550.29 0.4 0.45 0.55 0.530.41 0.36 0.53 0.55 0.570.27 0.41 0.49 0.52 0.540.29 0.28 0.45 0.52 0.53 0.3 0.52 0.55 0.55 0.61 67 46 21 21 2379 35 25 15 2160 42 27 42 4262 54 58 50 5254 65 65 40 4292 71 62 42 4669 79 46 42 3896 69 54 48 4492 94 62 0 48 4 15.320.827.70.10.250.251.280.220.1410.8

Table 3. In vitro inhibitory effect rate of compounds on human liver cancer cells (BEL-7402) Number of live cells of BEL-7402 cells at each concentration (μg/ml) (×10 ⁴ /ml) Percentage of cell growth inhibition (%) at each concentration (μg/ml) sample name Time Ctrl Zero 1.440.43 100 10 1 0.1 0.01 100 10 1 0.1 0.01 GI ₅₀ GS-1aGS-1bGS-2aGS-2bGS-4aGS-4bGS-7aGS-7bcisplatin carboplatin 0.28 1.07 1.22 1.22 1.160.36 0.76 1.29 1.33 1.220.85 1.24 1.2 1.21 1.240.99 1.03 1.15 1.16 1.180.4 0.85 0.97 1.12 1.210.43 0.9 1.01 1.14 1.20.53 0.53 1.21 1.19 1.070.37 0.5 1.17 1.21 1.140.31 0.30 0.96 1.00 1.130.31 1.23 1.26 1.21 1.23 100 37 22 28100 67 15 11258 20 24 23 2045 41 28 26100 58 32 23100 53 29 2490 23 24 37100 93 22 30100 44 31100 21 18 23 21 11.35.1364.7>1001.865.022.261.890.2313.4

Table 4. In vitro inhibition rate of compounds on human lung cancer cells (A549) The number of living cells of A549 cells at each concentration (μg/ml) (×10 ⁴ /ml) Percentage of cell growth inhibition (%) at each concentration (μg/ml) sample name Time Ctrl Zero 1.950.34 100 10 1 0.1 0.01 100 10 1 0.1 0.01 GI ₅₀ GS-1aGS-1bGS-2aGS-2bGS-4aGS-4bGS-7aGS-7bcisplatin carboplatin 0.43 1.28 1.84 1.92 1.740.47 1.06 1.76 1.86 1.841.25 1.68 1.79 1.82 1.571.11 1.52 1.71 1.67 1.560.57 1.83 1.54 1.68 1.690.73 0.96 1.77 1.76 1.560.56 1.12 1.64 1.7 1.550.81 0.91 1.68 1.82 1.770.40 0.32 1.04 1.62 1.580.39 1.46 1.56 1.49 1.57 94 42 7 2 1392 55 12 6 743 17 10 8 2452 27 15 17 2486 7 25 17 1676 61 11 12 2486 52 19 16 2571 65 17 8 1196 100 57 21 22447 29 30 78.58.1>1008438.76.668.875.230.6715.7

For the graph of the GI ₅₀ value of the compound on the corresponding tumor cells, please refer to the attached drawing of the description. Among them: Figure 1 is the GI ₅₀ value of the compound on HL-60 cells, Figure 2 is the GI ₅₀ value of the compound on 3AO cells, Figure 3 is the GI ₅₀ value of the compound on BEL-7402 cells, and Figure 4 is the GI ₅₀ value of the compound on A549 cells.

Claims (3)

1. A class of platinum (II) coordination compounds with effective anticancer activity, its stereoisomers or mixtures thereof, is characterized in that such compounds are represented by the following formula: Wherein the camphorate in formula (1), formula (2) and formula (3) can be its DL racemate, D type optical isomer [(1R, 3S)-(+)-camphorate] or L Type optical isomer [(1S, 3R)-(-)-camphoric acid radical]; R groups in formula (1) are the same, respectively hydrogen atom, C _1-5 alkyl or C _1-8 oxa-alkane base; cyclohexanediamine in formula (2) is 1,2-trans cyclohexanediamine, and the absolute configurations of the two chiral carbon atoms marked with ^* are all R configuration or S configuration; formula The 4,5-bis(aminomethyl)-2-alkyl-1,3-dioxolane in (3) R ₁ and R ₂ are the same or different, and they are hydrogen atoms or C _1-5 An alkyl group may be linked with a carbon atom to form a cycloalkyl group, and the absolute configurations of the two chiral carbon atoms marked with ^* are both R configurations or S configurations. 2, according to the preparation method of the described platinum (II) complex of claim 1, it is characterized in that the platinum compound that the dihalide ion diamine coordination of formula (4) represents is under the condition of avoiding light and flowing nitrogen, by using silver ion Remove the halide ion of dihalide diamine (ammonia) platinum (II), and the obtained intermediate reacts with the camphorate of monovalent alkali metal cation or ammonium ion to obtain cis-(camphorate) diamine (ammonia) platinum (II) compounds; Hal in formula (4a) and (4b) represents Cl- ^, Br ^- or I ^- ion, wherein the R group of formula (4a) is defined by formula (1) in claim 1, and formula (4b) is connected in The arc on the amine nitrogen atom represents that two amine groups are connected by an alkyl group as defined by formula (2) or formula (3) in claim 1. 3. The use of the platinum(II) complex according to claim 1 in the preparation of antitumor drugs that have effective inhibitory effects on human leukemia cells, ovarian cancer cells, liver cancer cells and lung cancer cells.

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