WO2011137739A1

WO2011137739A1 - Platinum (ii) complexes having n-alkyl substituted trans-1,2-diaminocyclohexanes as ligands and preparation method thereof

Info

Publication number: WO2011137739A1
Application number: PCT/CN2011/073630
Authority: WO
Inventors: 苟少华; 孙艳艳
Original assignee: 东南大学
Priority date: 2010-05-05
Filing date: 2011-05-04
Publication date: 2011-11-10
Also published as: CN102234295B; CN102234295A

Abstract

Platinum (II) complexes having N-alkyl substituted trans-1,2-diaminocyclohexanes as ligands and the preparation method thereof are provided. The structures of the platinum (II) complexes having N-alkyl substituted trans-1,2-diaminocyclohexanes as ligands are as shown by formula (1a) and formula (1b), in which Y is an anion of organic carboxylic acid, Z is a dianion of organic dicarboxylic acid, and R is C_3-8alkyl. The said preparation method is as follows: using trans-1,2-diaminocyclohexane protected by mon-Boc as a starting material to obtain the compound represented by formula (3), then reacting it with potassium platinate tetrahalide to obtain the said compound of formula (2), reacting the compound of formula (2) to obtain the said compound of formula (1a) or formula (1b). The platinum (II) complexes shown by formula (1a) and formula (1b) in the present invention have obvious inhibition on human liver cancer cells HepG-2, human breast cancer cells MCF-7, human lung cancer cells A549, and human colon cancer cells HCT-116.

Description

TECHNICAL FIELD The present invention relates to a fluorene-alkyl substituted trans 1,2-cyclohexanediamine as a ruthenium Platinum (Π) complex of ligand and preparation method thereof. BACKGROUND OF THE INVENTION In the past decade or so, based on an in-depth understanding of the mechanism of resistance to platinum complexes, research on platinum drugs has been no longer limited to the classical structure-activity relationship of cisplatin, and people have begun to explore new ways to develop new platinum drugs. To date, a number of non-classical platinum drugs have been designed that differ from the original structure-activity relationship, one of which is a sterically hindered platinum complex. Representative compounds of this type are ZD0473, which is currently in clinical trials, namely cis-dichloro*amino*(2-methylpyridine)platinum (11). Trans 1,2-cyclohexanediamine, especially its chiral isomer [ lR,2R-(-)-l,2-cyclohexanediamine, as a carrier ligand, is often used to prepare anti-tumor platinum Complexes, typical compounds such as the marketed drugs Oxaplatin and Miroplat in. The researchers hope to modify the basic structure of trans 1,2-cyclohexanediamine to prepare a new structure of platinum complexes as ligands, and further screen for high efficiency, low toxicity, water solubility or good fat solubility. A highly selective drug candidate. SUMMARY OF THE INVENTION A primary object of the present invention is to provide a platinum complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand.

It is also an object of the present invention to provide a process for the preparation of a platinum complex in which the above N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand.

a platinum (ruthenium) complex in which N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, the structure is as shown in formula (la) and formula (lb)

Formula (la) formula (lb)

Y in the formula (la) is an organic carboxylic acid anion, Z in the formula (lb) is an organic dicarboxylic acid dianion; in the formula (la) and the formula (lb), 1 is a 3⁄4 - 3⁄4 alkyl group, an asterisk * represents a chiral carbon atom, and the compound of the formula (la) and the formula (lb) is a chiral isomer having a 1R, 2R-configuration and/or a 2 configuration. The above C ₃ -C ₈ alkyl group may be a chain alkyl group or a cyclic alkyl group.

Preferably, Y in formula (la) is -C ₁₆ alkoxyacetate or C ₂ -C ₁₈ alkylcarboxylate; Z in formula (lb) is an organic dicarboxylic acid dianion, including oxalic acid Root, malonate, 1,1-cyclosuccinate, 3-hydroxy-1,1-cyclosuccinate, 3-alkoxy-1,1-cyclosuccinate, 3-aza-1, 1-cyclosuccinate, N-substituted 3-aza-1, 1-cyclosuccinate or camphordionate; N-substituted 3-aza-1, 1-cyclobutanedioate, substituent Benzyl substituted with benzyl, C _r C ₄ alkyl a benzyl group substituted with a dC ₄ alkoxy group or a halogen group, wherein the substituent on the benzyl group may be at any position of the aromatic ring.

Preferably, the structure of a platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand is represented by the formula ( lb ), wherein R is a butyl group and a cyclopentane group. Base, Z is oxalate, malonate, 1,1-cyclosuccinate; more preferred structure is: R is sec-butyl, cyclopentyl, Z is oxalate, malonate, 1,1-ring Succinate.

As another preferred embodiment, the structure of the platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand is as shown in formula (la) or formula (lb), wherein R Is propyl, Y is C ₂ -C ₄ alkoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1, 1 In the cyclosuccinate, the substituent is a benzyl group, a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group; a more preferred structure is: R is an isopropyl group, and Y is a different Propyloxyacetate or tert-butoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1,1-cyclobutanedioate In the above, the substituent is a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group.

A platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, as a reverse of the N-alkyl substitution described in the above formula (la) and formula (lb) Formula 1, 2-cyclohexanediamine is an intermediate of a platinum (ruthenium) complex of a ligand, and the structure is as shown in the formula (2):

Wherein, Hal represents Cl—, Br— or Γ, asterisk* represents a chiral carbon atom, and the compound of formula (2) is a chiral isoform having a 1R, 2R-configuration and/or a 2 configuration. Structure.

The preparation method of the platinum (ruthenium) complex in which the Ν-alkyl substituted trans 1,2-cyclohexanediamine is a ligand comprises the following steps: trans 1,2-cyclohexanediamine protected by a single Boc For the starting material (DW Lee, H.-J. Ha, WK Lee, Synthetic Communications, 2007, 37, 737-742), the compound represented by the formula (3) is obtained by the following Scheme I, and then the formula (3) The compound shown is reacted with potassium tetrahalide (potassium) hydride to give the compound of formula (2);

^ ( 3 ) The mono Boc protected trans 1,2-cyclohexanediamine is represented by the formula (4)

Formula (4)

Wherein Boc represents t-butoxycarbonyl; Route I is as follows:

In the route I, R is a C ₃ -C ₈ alkyl group according to any one of claims 1 to 6, the fatty aldehyde is a C ₃ - C ₈ chain alkyl aldehyde, and the aliphatic ketone is - 3⁄4 of a chain or cyclic alkyl ketone, when R is a chain alkyl group, a chain alkyl aldehyde or a chain alkyl ketone is used; when a chain alkyl aldehyde is used, R1 is. _{2 7} alkyl, R ₂ is a hydrogen atom; when a chain alkyl ketone is used, R 1 and R 2 are respectively a linear alkyl group of dC ₆ , the sum of the carbon atoms of the two should be less than 7 or equal to 7; In the case of a cyclic alkyl group, a cyclic alkyl ketone is used, wherein X is a C ₂ - C ₇ alkylene group. The preparation of the compound of the above formula (3) has been disclosed in the prior application (CN200910027237.8). When the Boc-protected trans 1,2-cyclohexanediamine is reacted with an aldehyde or a ketone, it is first dehydrated to form a Schiff base, which is generally isolated and purified for use in the next reaction. However, it is not suitable for the case where the reactants are low-grade fatty aldehydes or aliphatic ketones, because these reactants have a low boiling point, and no suitable organic solvent can be used for dehydration without aldehyde or ketone evaporation with steam; The base is generally liquid and difficult to purify. Therefore, for the reaction of Boc-protected trans 1,2-cyclohexanediamine with a fatty aldehyde or a fatty ketone, the Schiff base obtained in the first step of Scheme I can usually be directly separated into the next reaction without isolation.

The N-alkyl substituted trans 1,2-cyclohexanediamine prepared according to the route I method is mainly obtained in the form of its hydrochloride salt, and the hydrochloride salt and a quantitative base such as sodium hydroxide or potassium hydroxide in water. The corresponding N-monosubstituted trans 1,2-cyclohexanediamine can be obtained.

A specific method for obtaining a compound of the formula (2) by reacting a compound represented by the formula (3) with potassium tetrahalide (potassium)ate may be: a tetrahaloplatinum (potassium citrate) (6.00 mmol) and N - alkyl substituted trans 1,2-cyclohexanediamine (6.00 mmol) mixed in 50 In a solution of water, stir at room temperature overnight, with a large amount of yellow precipitate formed, filtered, washed repeatedly with water, absolute ethanol and diethyl ether, and dried to give a yellow powder.

The compound of the formula (2) can be produced according to a known reaction to produce a compound of the formula (la) or the formula (lb), as in any one of the following methods, method 1: in the absence of light, in an aqueous solution, by silver ion removal The halide ion in formula (2) is then reacted with an alkali metal salt or ammonium salt of Y as defined by formula (la) to form a platinum (ruthenium) complex represented by formula (la), or as defined by formula (lb) Reaction of an alkali metal salt or an ammonium salt of Z to form a platinum (ruthenium) complex represented by formula (lb); Method 2: a silver salt of Y defined by formula (la) in an aqueous solution under protection from light Reaction with a platinum (II) complex represented by the formula (2) to form a platinum (ruthenium) complex represented by the formula (la), or a silver salt of Z defined by the formula (lb) and a formula (2) The platinum (ruthenium) complex reacts to form a platinum (ruthenium) complex of formula (lb).

Specific steps are as follows:

method 1 :

The dihalo [N-alkyl substituted trans 1,2-cyclohexanediamine] platinum (II) (2.90 mmol) represented by the formula (2) was suspended in 100 mL of water, and silver nitrate (5.80 mmol) was added thereto. After 24 to 36 hours in the dark at 60 ° C, the diatomaceous earth was assisted by filtration. A 30 mL aqueous solution of sodium carboxylate (5.80 mmol) or sodium dicarboxylate (2.90 mmol) was added to the filtrate, and then reacted at 80 ° C for 24 to 48 hours in the dark, and the solution was concentrated to precipitate a large amount of solid. Filtration, repeated washing with water, ethanol and diethyl ether, and drying in vacuo to give the desired product.

Method 2:

Dihalo[N-alkyl substituted trans 1,2-cyclohexanediamine]platinum (n) (2.90 mmol) represented by formula (2) and freshly prepared silver carboxylate (2.90 mmol) or carboxylic acid Silver (1.45 mmol) was suspended in 100 mL of water, and reacted at 70 ° C for 24 to 48 hours in the dark, and then filtered with celite, and the filtrate was concentrated to precipitate a large amount of solid, which was filtered and dried in vacuo to give the desired product.

The compounds prepared by the process of the present invention have determined the molecular structure of the compounds by infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry. The platinum (Π) complex represented by the formula (la) and the formula (lb) of the present invention has a significant inhibitory effect on human liver cancer cell HepG_2, human breast cancer cell MCF-7, human lung cancer cell A549 and human colon cancer cell HCT-116. The inhibitory effects of related compounds and controls on different cancer cells are shown in Table 1. Specific embodiment

The invention is further illustrated by the following examples, which are not intended to limit the invention. Unless otherwise indicated, the configuration of the two chiral carbon atoms of the N-alkyl substituted trans 1,2-cyclohexanediamine ligand in the examples is 1R and 2R, respectively; in the magnetic resonance data, DACH Represents the backbone of trans 1,2-cyclohexanediamine.

Example 1. Preparation of Compound la (C ₁₆ H ₃₂ N ₂ ₆ Pt)

Prepared according to Method 1, pale yellow powder, yield: 51 o IR (KBr, cm" ¹ ): 3113 (br), 2935, 2871, 1616, 1450, 1385, 1198, 1116, 988, 942, 713, 595; 1H-NMR (J ₆ -DMSO/TMS, ppm) : δ 0.90 (t, 3H, CH ₂ C3⁄4), δ 2.06-1.02 (m, 12H, CH ₂ of DACH and CU ₃ CH ₂ CH ₂ ), δ 2.14 (m, 2H, NHCH ₂ ), δ 2.50- 2.34(m, 2Η, NHCH), δ 3.23(s, 6Η, OCH ₃ ), δ 3.81(s, 4Η, COCH ₂ 0), δ 5.11 (m, 1Η , CH ₂ NH), 56.10-5.99 (dd, 2Η CHNH2); ESI-MS: m/z [M+Na] ⁺ = 566 (100%) o Example 2. Compound 2a (C ₂₂ H ₄₄ N ₂ 0 Preparation of ₆ Pt)

Prepared according to Method 1, pale yellow powder, 55%. IR (KBr, cm-3461 (br), 3124, 2971, 2935, 2870, 1624, 1456, 1385, 1310, 1192, 1108, 892, 837, 712; 1H-NMR (J ₆ -DMSO/TMS, ppm) : δ 0.90(t, 3H, CH ₂ C3⁄4), δ 1.11(S, 18H, 2C (CH ₃ ) ₃ ), δ 1.95-0.98 (m, 12H, CH ₂ of DACH and CH ₃ CH ₂ CH ₂ ), δ 2.15 (m, 2H, NHCH ₂ ), δ 2.62-2.42 (m, 2Η, NHCH), δ 3.85(s, 4Η, COCH ₂ 0), δ 5.95 (m, 1Η, CH ₂ , 56.69-6.17 ( Dd, 2H, CHNH ₂ ); ESI-MS m/z: [M+Na] ⁺ = 650 (100%) o Example 3. Preparation of Compound 3a (C ₂₃ H ₃₅ N ₃ 0 ₅ Pt)

Prepared according to Method 2, light yellow powder, yield: 65%. IR (KBr, cm" ¹ ): 3417(br), 3078, 2936, 2865, 1627, 1495, 1458, 1380, 1250, 1048, 1025, 758; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 0.90(t, 3H CH ₂ C3⁄4), δ 0.98-1.96 (m, 12H, CH ₂ of DACH and CU ₃ CH ₂ CH ₂ ), δ 2.27 (m, 2H, NHCH ₂ ), δ 2.44-2.62 (m, 2Η, NHCH), δ 3.43(m, 2Η, CH ₂ Ph), δ 3.59(s, 3Η, PhOC3⁄4), δ 3.85-4.08(m, 4Η H ₂ ) ₂ ), δ 5.74(m, 1Η, CH ₂ NH), δ 6.21-6.26 (dd, ₂ Η, CHNH ₂ ), δ 6.88-7.21 (m, 4 Η, Ar-H); ESI-MS: m/z [M+H] ⁺ = 629 (100%).

Example 4. Preparation of Compound 4a (C ₂₂ H ₃₂ ClN ₃ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 55%. IR (KBr, cm" ¹ ): 3403 (br), 3189, 2936, 2861, 1591, 1471, 1443, 1358, 1210, 1183, 1049, 910, 871, 753, 698, 591; 1H-NMR (J ₆ -DMSO/ TMS, ppm): S0.92 (t, 3H, CH ₂ C3⁄4), 51.97-0.95 (m, 12H, CH ₂ of DACH and CH ₃ CH ₂ CH ₂ ), δ 2.32 (m, 2H, NHCH ₂ ), δ 2.75-2.50(m, 2Η, NHCH), 53.63(s, 2Η, CH ₂ Ph), 53.94-3.78(m, 4Η, N(CH ₂ j ₂ ), S5.20(m, 1Η, CH ₂ NH), 56.29-5.93 (dd, 2Η, CHNH ₂ ), 57.44-7.26 (m, 4Η, Ar-Η); ESI-MS m/z: [M+H] ⁺ = 634 (100%) Example 5. Preparation of Compound 5a (C ₂₂ H ₃₂ ClN ₃ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 54%. IR (KBr, cm" ¹ ): 3403 (br), 3092, 2937, 2862, 1596, 1473, 1455, 1379, 1210, 1181, 1130, 1078, 866, 785, 733, 682, 525; 1H-NMR ( J ₆ -DMSO/TMS, ppm): δ 0.90 (t, 3H, CH ₂ C3⁄4), δ 2.06-1.02 (m, 12H, CH ₂ of DACH and CU ₃ CH ₂ CH ₂ ), δ 2.27 (m, 2H , NHCH ₂ ), δ 2.75-2.50 (m, 2Η, NHCH), δ 3.60(s, 2Η, CH ₂ Ph), δ 3.86-3.77(m, 4Η, N(CH ₂ j ₂ ), δ 5.19(m , 1Η, CH ₂ NH), 56.28-5.91(dd, 2Η, CHNH ₂ ), 57.52-7.26(m, 4Η, Ar-Η); ESI-MS m/z: [M+H] ⁺ = 634 (100 %) Example 6. Preparation of Compound 6a (C ₂₂ H ₃₂ ClN ₃ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, Yield: 59% IR (KBr, cm" ¹ ): 3403 (br), 3094, 2936, 2864, 1615 1491, 1451, 1382, 1282, 1210, 1177, 1091, 1015 , 910, 855, 811, 773, 728, 699, 591; Ή-NMR (J ₆ -DMSO/TMS, ppm): δ 0.90 (t, 3H, CH ₂ C 3⁄4), δ 2.08-1.03 (m, 12H, CH ₂ of DACH and CH3CH2CH2), δ 2.27 (m, 2 Η, NHCH ₂ ), δ 2.84-2.50(m, 2Η, NHCH), S3.45(S, 2Η, CH ₂ Ph), δ 4.20-3.71(m, 4Η, N(CH ₂ j ₂ ), δ 5.75(m , 1Η, C3⁄4, 56.64-6.32(dd, 2Η, CHNH ₂ ), 57.51-7.25(m, 4Η, Ar-Η); ESI-MS m/z: [M+H] ⁺ = 634 (100%) Example 7. Preparation of Compound lb (C ₁₉ H ₃₈ N ₂ ₆ Pt)

Prepared according to Method 1, pale yellow powder, yield: 56%. IR (KBr, cm" ¹ ): 3448 (br), 3134, 2972, 2936, 2867, 1648, 1384, 1177, 1126, 1021, 934, 828, 715, 607; 1H-NMR (J ₆ -DMSO/TMS , ppm): δ 1.41-1.06 (m. 18H, CH(CH ₃ ) ₂ and 2CH(C3⁄4) ₂ ), δ 2.25-1.06 (m, 9H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 2.94-2.49 (m, 2H, NHCH), S3.65 (m, 2Η, 20CH(CH ₃ ) ₂ ), 53.97(m, 4H, (C0 ₂ ) ₂ CH ₂ 0 ), δ 5.42 (m, 1Η, CH ₂ NH . 55.65 (br, ₂ Η, CH ₂ NH ₂ ); ESI-MS m/z: [M+Na] ⁺ = 608 (100%).

Example 8. Preparation of Compound 2b (C ₂₁ H ₄₂ N ₂ ₆ Pt)

Prepared according to Method 1, pale yellow powder, yield: 59%. IR (KBr, cm" ¹ ): 3438 (br), 3150, 2973, 2937, 2869, 1616, 1385, 1252, 1192, 1099, 916, 892, 828, 713, 613, 529; 1H-NMR (J ₆ -DMSO/TMS, ppm): δ 1.40-1.07 (m, 24H, CH(C3⁄4) ₂ and 2C (CH ₃ ) ₃ ), δ 2.24-0.93 (m, 9H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 2.93-2.49 (m, 2H, NHCH), 53.89-3.58 (m, 4Η, (C0 ₂ ) ₂ CH ₂ 0), δ 5.38 (m, 1Η, CH ₂ NH), 55.59 (br, 2Η) CH2NH2); ESI-MS m/z: [M+Na] ⁺ = 636 (100%) Example 9. Preparation of Compound 3b (C ₂₂ H ₃₃ N ₃ _{5 5} Pt)

Prepared according to Method 2, white powder, yield: 54%. IR (KBr, cm" ¹ ): 3417(br), 3122, 2937, 2863, 1622, 1494, 1457, 1376, 1250, 1176, 1024; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.04- 2.10(m, 15H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 1.83-2.50(m, 4H, NHCH and NHCH ₂ ), δ 3.45(m, 2Η, CH ₂ Ph), δ 3.78(s , 3Η, PhOO3⁄4), δ 3.43-3.92(m, 4Η, NfCH ₂ j ₂ ), δ 5.45(m, 1Η, CH ₂ NH), δ 5.87-6.20(m, 2Η, CHNH ₂ ), δ 6.86-7.45 (m, 4Η, Ar-Η); ESI-MS: m/z [M+H] ⁺ = 615 (100%) Example 10. Preparation of Compound 4b (C ₂₂ H ₃₃ N ₃ _{5 5} Pt)

Prepared according to Method 2, white powder, yield: 51%. IR (KBr, cm" ¹ ): 3416(br), 3122, 2938, 2864, 1602, 1491, 1455, 1390, 1266, 1178, 1045; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.03- 2.12 (m, 15H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 1.92-2.5 l(m, 4H, NHCH and NHCH ₂ ), δ 3.45 (m, 2Η, CH ₂ Ph), δ 3.79 ( s, 3Η, PhOC3⁄4), δ 3.45-4.14(m, 4Η, NfCH ₂ j ₂ ), ^δ 5.50(m, 1Η, CH ₂ NH), δ 5.89-6.18(m, 2Η, CHNH2), δ 6.76-7.41 (m, 4Η, Ar-Η); ESI-MS: m/z [M+Na] ⁺ = 637 (50%) Example 11. Preparation of Compound 5b (C ₂₂ H ₃₃ N ₃ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, Yield: 60%. IR (KBr, cm" ¹ ): 3417(br), 2939, 2863, 1616, 1455, 1389, 1176, 1079, 957; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.03-2.10 (m, 15H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 1.82-2.30(m, 4H, NHCH and NHCH ₂ ), δ 2.27(s, 3Η, PhC3⁄4), δ 3.43(m, 2Η, CH ₂ Ph ), δ 3.61-4.08(m, 4Η, NfCH ₂ j ₂ ), δ 5.30(m, 1Η, CH ₂ NH), δ 5.89-6.35(m, 2Η, CHNH ₂ ), δ 7.10-7.32(m, 4Η , Ar-Η); ESI-MS: m/z [M+H] ⁺ = 599 (100%) Example 12. Preparation of Compound 6b (C ₂₂ H ₃₃ N ₃ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 59%. IR (KBr, cm" ¹ ): 3417(br), 3121, 2938, 2864, 1609, 1449, 1390, 1180, 1071, 916; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.03-1.93 ( m, 15H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 1.93-2.52 (m, 4H, NHCH and NHCH ₂ ), δ 2.27(s, 3Η, PhC3⁄4), δ 3.42(m, 2Η, CH ₂ Ph), δ 3.42-4.14(m, 4Η, NfCH ₂ j ₂ ), δ 5.30(m, 1Η, CH ₂ NH), δ 5.89-6.19(m, 2Η, CHNH ₂ ), δ 7.00-7.34(m , 4Η, Ar-Η); ESI-MS: m/z [M+Na] ⁺ = 621 (100%) Example 13. Preparation of Compound lc (C ₁₂ H ₂₂ N ₂ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 58%. IR (KBr, cm- ¹ ): 3446(br), 3199, 3103, 2938, 2864. 1703, 1672, 1452, 1385, 1249, 1173, 1068, 1032; 1H NMR (J ₆ -DMSO TMS, ppm): δ 0.84-1.17 (m. 6H, CH ₃ CHCH ₂ CH ₃ ), δ 1.18-2.25 (m, 10H, CH ₂ of DACH and CHCH ₂ CH ₃ ), δ 2.70-3.45 (m, 3H. NHCH and NH ₂ CH), δ 5.31 (d, 1 Η, CHNH), δ 5.85-6.13 (m, ₂ Η, CHNH ₂ ); ESI-MS: m/z [M+Na] ⁴ = 476 (100%).

Example 14. Preparation of Compound 2c (C ₁₃ H ₂₄ N ₂ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 63%. IR (KBr, cm- ¹ ): 3434(br), 3167, 3103, 2938, 2865, 1647, 1451, 1385, 1255, 1212, 1070, 1017; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 0.85-1.08 (m, 6H CH ₃ CHCH ₂ CH ₃ ), δ 1.23-2.14 (m, 10H, CH ₂ of DACH and CHCH ₂ CH ₃ ), δ 2.29-3.48 (m, 3H NHCH and NH ₂ CH), δ 3.22(m, 2Η, CH ₂ (CO) ₂ ), δ 5.21-5.94 (m, 3Η, C¥L ₂ NH and CHNH ₂ ) ; ESI-MS: m/z [M+Na] ⁺ = 490 ( 100%) Example 15. Preparation of Compound 3c (C ₁₆ H ₂₈ N ₂ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 59%. IR (KBr, cm- ¹ ): 3444(br), 3173, 3108, 2940, 2864, 1646, 1455, 1364, 1117, 1069, 1030; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 0.83- 1.21 (m, 6H CH ₃ CHCH ₂ CH ₃ ), δ 1.23-2.68 (m, 16H, CH ₂ of DACH and CHCH ₂ CH ₃ and cyclobutyl), δ 2.63-2.68 (m, 2H, NHCH), δ 3.43 ( m, 1 Η, NH ₂ CH), δ 4.31-5.86 (m, 3 Η, C?L ₂ NH and CHNH ₂ ); ESI-MS: m/z [M+Na] ⁺ = 530 (100%). Example 16. Preparation of Compound ld (C ₁₃ H ₂₄ N ₂ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 65%. IR (KBr, cm" ¹ ): 3434(br), 3122, 2941, 2863, 1647, 1453, 1363, 1251, 1119, 1071, 1023, 906, 777; 1H NMR (J ₆ -DMSO/TMS, ppm) : δ 0.89-1.09(m, 6H, CH ₂ CH(CH ₃ ) ₂ ), δ 1.12-2.15(m, 9H, CH(CH ₃ ) ₂ and CH ₂ of DACH), δ 2.12-2.44(m, 4H , NHCH2 and NHCH and NH ₂ CH), δ 3.12-3.23 (m, 2Η, CH ₂ (CO) ₂ ), δ 5.31-6.12 (m, 3Η, CH ₂ NH and CHNH2); ESI-MS: m/z [M+Na] ⁺ = 490 (100%) Example 17. Preparation of Compound 2d (C ₁₈ H ₃₆ N ₂ _{6 6} Pt)

Prepared according to Method 1, pale yellow powder, yield: 52%. IR (KBr, cm" ¹ ): 3425 (br), 3159, 3097, 2942, 2867, 1644, 1452, 1385, 1169, 1092, 959, 932, 741, 592; 1H-NMR (D ₂ 0/TMS, Ppm): 51.10-0.87 (m, 12H, CH(CH ₃ ) ₂ and 2CH ₂ C3⁄4), 52.27-1.10 (m, 9H, CH ₂ of DACH and (CH ₃ ) ₂ CH), S2.49 (m, 2ΗNHCH ₂ ), 53.90-3.42 (m, 12Η, NHCH and NHCH ₂ and C0 ₂ CH ₂ OCH ₂ CH ₃ ) ; ESI-MS m/z: [M+H] = 570 (100%)

Note: The N-substituted trans 1,2-cyclohexanediamine ligand is a racemate. Example 18. Preparation of Compound 3d (C ₂₂ H44N ₂ ₆ Pt)

Prepared according to Method 1, pale yellow powder, yield 58%. IR (KBr, cm-i): 3425 (br), 3159, 3097, 2942, 2867, 1644, 1452, 1385, 1169, 1092, 959, 932, 741, 592; 1H-NMR (D ₂ 0/TMS, Ppm) : S0.88(t, 6H, 2CH ₂ 03⁄4, S1.28(dd, 6H, CU(CH ₃ ) ₂ ), 52.27-1.06 (m, 17H, CH ₂ of DACH and (CH ₃ ) ₂ CH And 2CH3CH2CH2), 52.49 (m, ₂ Η, NHCH ₂ ), 53.39 (m, 6 Η, 20CH ₂ and NHCH ₂ ); ESI-MS m/z: [M+H] ⁺ = 626 (100%)

Note: The N-substituted trans 1,2-cyclohexanediamine ligand is a racemate. Example 19. Preparation of Compound le (C ₂₄ H ₃₇ N ₃ 0 ₅ Pt)

Prepared according to Method 2, light yellow powder, yield: 69%. IR (KBr, cm- ¹ ): 3422(br), 3263, 3129, 2940, 2864, 1611, 1515, 1462, 1390, 1345, 1251, 1180, 1033, 823; 1H NMR (J ₆ -DMSO TMS, ppm ): δ 1.03-1.08 (m, 9H, C(CH ₃ ) ₃ ), δ 1.27-1.55 (m, 8H, CH ₂ of DACH), δ 1.95 (m, 4H, NHCH ₂ and NHCH and NH ₂ CH) , δ 3.41-3.45(m, 4Η, CH ₂ NCH ₂ ), δ 3.52(s, 3Η, PhOC3⁄4), δ 3.71-3.77(m, 2Η, NCH ₂ Ar), δ 6.83-7.17(m, 4Η, ArH ; ESI-MS: [M+H] ⁺ = 643 (100%).

Note: The configuration of the two chiral carbon atoms of the N-substituted trans 1,2-cyclohexanediamine ligand is M and 2, respectively. Example 20. Preparation of Compound 2e (C ₂₄ H ₃₇ N ₃ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, Yield: 60%. IR (KBr, cm" ¹ ): 3420(br), 3121, 2940, 2863, 1615, 1518, 1455, 1387, 1339, 1209, 1168, 1036, 815; 1H NMR (J ₆ -DMSO/TMS, ppm) : δ 1.02-1. ll(m, 9H, C(CH ₃ ) ₃ ), δ 1.21-1.56(m, 8H, CH ₂ of DACH), δ 1.98-2.27 (m, 4H, NHCH ₂ and NHCH and

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Prepared according to Method 2, white powder, yield: 61%. IR (KBr, cm" ¹ ): 3418(br), 3090, 2934, 2858, 1622, 1453, 1375, 1178, 1067, 1028; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.08-1.48 ( m, 14H, CH ₂ of DACH and cyclopentyl), δ 1.72-2.11 (m, 4H, CH ₂ of DACH and cyclopentyl), δ 2.11 (m, 3H, CH of DACH and cyclopentyl), δ 3.43-3.60 (m, 4H, CH ₂ NCH ₂ ), δ 3.74-3.91 (m, ₂ Η, NCH ₂ Ar), δ 7.22-7.45 (m, 5 Η, ArH); ESI-MS: m/z [M+H] ⁺ = 625 ( 100%).

Example 27. Preparation of Compound 3g (C ₂₅ H ₃₇ N ₃ 0 ₄ Pt)

Prepared according to Method 2, white powder, yield: 60%. IR (KBr, cm" ¹ ): 3403 (br), 3104, 2935, 2858, 1609, 1450. 1383, 1176, 1069; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.06-1.50 (m, 12H, CH ₂ of DACH and cyclopentyl), δ 1.72-1.91 (m, 6H, CH ₂ of DACH and cyclopentyl), δ 2.16 (m, 3H, CH of DACH and cyclopentyl), δ 2.29(s, 3H, PhC3⁄4) , δ 3.36-3.58 (m, 4H, CH ₂ NCH ₂ ), δ 3.76 (m, ₂ Η, NCH ₂ Ar), δ 7.10-7.31 (m, 4 Η, ArH); ESI-MS: m/z [M] +H ⁺ = 639 (100%) Example 28. Preparation of Compound 4g (C ₂₅ H ₃₇ N ₃ 0 ₄ Pt)

Prepared according to Method 2, white powder, yield: 51%. IR (KBr, cm" ¹ ): 3421 (br), 3051, 2933, 2858, 1609, 1449, 1363, 1177, 1068, 1036; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 1.09-1.50 ( m, 12H, CH ₂ of DACH And cyclopentyl), δ 1.72-2.16(m, 6H, CH ₂ of DACH and cyclopentyl), δ 2.25(m, 3H, CH of DACH and cyclopentyl), δ 2.32(s, 3H, PhC3⁄4), δ 3.42-3.55( m, 4H, CH ₂ NCH ₂ ), δ 3.75-3.79 (m, ₂ Η, NCH ₂ Ar), δ 7.07-7.25 (m, 4 Η, ArH); ESI-MS: m/z [M+H] ⁺ = 639 (100%). Example 29. Compound lh (C ₁₉ H ₃₄ N ₂ 0 ₄ Pt

Prepared according to Method 2, light yellow powder, yield: 50%. IR (KBr, cm-i): 3420(br), 2939, 1596(br), 1457, 1384, 1350, 1173, 1126, 801; 1H NMR (J ₆ -DMSO TMS, ppm): δ 0.74-0.86 ( m, 3H, CCH ₃ of camphorato), δ 0.97-1.37 (m, 20H, CH ₂ of DACH and CHCH ₂ CH ₂ C, CH ₃ of camphorato and CH(CH ₃ ) ₂ ), δ 1.51 (m, 4H, CH ₂ of DACH), δ 2.01 (m, 3H, NHCH and CH of camphorato), δ 3.45 (m, 1 Η, CH(CH ₃ ) ₂ ), δ 5.80-6.80 (m, 3H, CHNH and CHNH ₂ ); ESI-MS: m/z [M+H] ⁺ = 550 (80%), [M+Na] ⁺ = 572 (20%)

Note: Camphorate is converted from natural camphoric acid. Example 30. Preparation of Compound 2h (C _2Q H ₃₆ N ₂ 0 ₄ Pt)

Prepared according to Method 2, light yellow powder, yield: 50%. IR (KBr, cm-i): 3429(br), 2957, 1603(br), 1457, 1382, 1348, 1169, 1125, 909, 801; 1H NMR (J ₆ -DMSO/TMS, ppm): δ 0.75 (m, 3H, CCH ₃ of camphorato), δ 0.89-1.39 (m, 21H, CH ₂ of DACH and CHCH ₂ CH ₂ C, CH ₃ of camphorato and NHCH ₂ CH ₂ CH ₂ C3⁄4 of n-Bu), δ 1.49 (m, 4Η, CH ₂ of DACH), δ 1.95 (m, 3H, NHCH and CH of camphorato), δ 3.40 (m, 2Η, NHCH ₂ of n-Bu), δ 4.80-6.80 (m, 3Η, CHNHand CHNH ₂ ); ESI-MS: m/z [M+H] ⁺ = 564 (50%), [M+Na+CH ₃ OH] += 619 (20%).

Note: Camphorate is converted from natural camphoric acid. Example 31. Preparation of Compound 1x (C _1Q H ₂₂ Cl ₂ N ₂ Pt)

Prepared as follows: Potassium tetrachloroplatinate (6.00 mmol) and N-n-butyl-1R, 2R-trans cyclohexanediamine (6.00 mmol) were mixed in 50 mL of water, and kept at room temperature in the dark. After overnight, a large amount of a yellow precipitate formed, which was filtered, washed repeatedly with water, anhydrous ethanol and diethyl ether, and dried to yield a yellow powder. Yield: 89%. IR (KBr, cm- ¹ ): 3490(br), 3187, 3117, 2935, 2863, 1582, 1451, 1380, 1239, 1192, 1157, 1068, 1038, 1014, 908; 1H NMR (J ₆ -DMSO/ TMS, ppm): δ 0.90 (t, 3H, CH ₂ CH ₃ ), δ 1.02-1.97 (m, 12H, CH ₂ of DACH and CH ₃ CH ₂ CH ₂ ), δ 2.12 (m, 2H, NHCH ₂ ) , δ 2.48-2.50(m, 2Η, NHCH), δ 5.37(m, 1Η, CH ₂ NH), δ 6.10-6.45(dd, 2Η, CHNH ₂ ) ; ESI-MS: m/z [M+Na] ⁺ = 459 (100%) Example 32 compound _{_{_{2x (C 9 H 2Q Cl 2}}} N 2 Pt) preparation of

The preparation method was the same as that in Example 31, yellow powder, yield: 90%. IR (KBr, cm-3474(br), 3258, 3194, 2924, 2867, 1594, 1451, 1423, 1390, 1267, 1190, 1157, 1124, 1068, 1006, 920, 797; 1H NMR (J6-DMSO/ TMS, ppm): δ 1.07-1.35 (m, 6H, CH(CH ₃ ) ₂ ), δ 1.04-2.17 (m, 9H, CH ₂ of DACH and CH(CH ₃ ) ₂ ), δ 3.01-3.45 (m , 2H, NHCH), δ 5.38 (m, 1 Η, CH ₂ NH), δ 6.05-6.14 (dd, 2Η, CHNH ₂ ) ; ESI-MS: m/z [M+Na] ⁺ = 445 (100%) Example 33. Preparation of Compound 3x (C _1Q H ₂₂ Cl ₂ N ₂ Pt)

The preparation was carried out in the same manner as in Example 31, yellow powder, yield: 88%. n^KBr' cm- ¹ ): 3495(br), 3249, 3186, 3117, 2936, 2864, 1581, 1450, 1392, 1368, 1186, 1156, 1132, 1070, 1032, 997; 1H NMR (J ₆ - DMSO/TMS ppm): δ 0.90-1.07 (m, 6H, CH ₂ CH(CH ₃ ) ₂ ), δ 1.10-2.15 (m, 9H, CH(CH ₃ ) ₂ and CH ₂ of DACH), δ 2.12- 2.44 (m, 4H, NHCH ₂ and NHCH and NH ₂ CH), δ 5.31-6.10 (m, 3 Η, CH ₂ NH and CHNH ₂ ); ESI-MS: m/z [M+Na] ⁺ = 459 (100 %) Example 34. Preparation of compound 4x (C _u H ₂₂ Cl ₂ N ₂ Pt)

The preparation method was the same as that in Example 31, yellow powder, yield: 88 o IR (KBr, cm" ¹ ): 3257, 3178, 3142, 2938, 2864, 1591, 1566, 1447, 1127, 1066; 1H NMR (J ₆ - DMSO/TMS, ppm): δ 1.00-1.21 (m, 4H, CH ₂ of DACH), δ 1.37-1.50 (m, 4H, CH ₂ of cyclopentyl), δ 1.59- 1.60 (m, 1H, CH ₂ of DACH ), δ 1.65-1.70 (m, 1H, CH ₂ of cyclopentyl), δ 1.79-2.18 (m, 6H, CH ₂ of DACH and cyclopentyl), δ 2.20-2.25 (m, 1H, CHNH of DACH), δ 2.30 -2.37 (m, 1H, CHNH of DACH), δ 3.09-3.12 (m, 1H, CHNH of cyclopentyl); ESI-MS: m/z [M+Na] ⁺ = 471 (100%) o Example 35. Preparation of single Boc protected trans 1,2-cyclohexanediamine

Measure 500 mL of methanol, put it into a 2 L flask, add 500 mmol of 1R, 2R-trans cyclohexanediamine or 12 2 trans-cyclohexanediamine, stir to dissolve at room temperature, and slowly add 2.5 mol/L hydrogen chloride/methanol under stirring. The solution was 200 mL and the control temperature did not exceed 5 °C. After the addition was completed, the temperature was returned to room temperature, 200 mL of water was added, and the mixture was stirred at room temperature for 30 min. The 550 mmol (Boc) _{20 was} dissolved in 250 mL of methanol, and added to the above solution at room temperature, and the addition was completed in about 30 minutes, and then stirred at room temperature for 1 hour. The reaction was stopped, 250 mL of methanol was removed under reduced pressure, 300 mL of water was added, and extracted with diethyl ether three times (250 mIJ). The aqueous phase was adjusted to pH 10 with 5M aqueous sodium hydroxide solution, extracted 4 times with dichloromethane (250 mIJ times), the organic phase was combined, washed twice with saturated sodium chloride solution (100 ml J times), and the organic phase was treated with anhydrous sulfuric acid. The sodium was dried overnight and filtered. The filtrate was concentrated under reduced pressure to about 200 mL, and recrystallized from 400 mL of petroleum ether (60-90 ° C) to give white white solid (83.0 g, 77.0%). IR (KBr, cm" ¹ ): 3350, 3291, 3183 (br), 2978, 2931, 2857, 1695, 1592, 1554, 1445, 1183, 1041, 849, 761 ; 1H-NMR (CDC1 ₃ /TMS): δ 1.45 (S, 9H, C(CH ₃ ) ₃ ), 52.01-1.02 (m, 8H, CH ₂ of DACH), 53.14-2.28 (m, 2H, NH ₂ CH), 54.49 (br, lH, CONH) ESI-MS m/z: [M+H] ⁺ = 215 (100%). Example 36. Synthesis of Ligand 1-R.2HC1 (Line I)

Weighed 17.12g (80mmol) of SM-R, placed in a 500mL three-necked flask, dissolved in 350mL of methanol, added 17.28g (240mmol) of n-butyraldehyde, stirred at room temperature for about 20min, and added 9.00g (240mmol) of sodium borohydride in batches. After that, stir for another 3 hours. The solvent was removed under reduced pressure, and the residue was crystallised eluted with ethyl acetate (300 mL), and the organic phase was washed twice with 150 mL of brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. After dissolving in 200 mL of anhydrous diethyl ether, 150 mL of 4 M hydrogen chloride / ethyl acetate was added, and after stirring for about 10 min, a gas appeared, and a white solid gradually precipitated, and stirred at room temperature for about 6 h. Filtration, the filter cake was washed 3 times with dry diethyl ether and dried in vacuo to give a white solid 15.6 g (80.1 IR (KBr, cm" ¹ ): 3416 (br), 2942, 2870, 1607, 1458, 1027; 1H-NMR ( D ₂ 0/TMS) : δ 0.94 (t, 3H, CH ₂ C3⁄4), 51.41-1.39 (m, 4H, CH ₃ CH ₂ CH ₂ ), 52.32-1.52 (m, 8H, CH ₂ of DACH), 53.26 -3.04 (m, 2H, NHCH ₂ ), 53.50-3.40 (m, 2 Η, NHCH); ESI-MS m/z: [M-2HC1+H] ⁺ = 171 (100%). Example 37. Ligand Synthesis of 2-R.2HC1 (Route I)

Using SM-R as the starting material and isobutyraldehyde as the reactant, a white solid 15.0 g (77.0 (KBr, cm" ¹ ) : 3430 (br), 2945, 2871, 1027, 1001; 1H was obtained as in Example 36. - NMR (D ₂ O rMS) : δ 1.02 (d, 6H, C3⁄4CHC3⁄4), 52.34-1.38 (m, 8H, CH ₂ of DACH), 52.09 (m, 1H, CH(CH ₃ ) ₂ ), 53.11-2.94 (d, 2H, NH CH ₂ ), 53.52-3.41 (m, 2H, CHNH); ESI-MS m/z: [M-2HC1+H] ⁺ = 171 (100%). Example 38. Ligand 3 Synthesis of -R.2HC1 (Route I)

Using SM-R as the starting material and methyl ethyl ketone as the reactant, 14.5 g (74.5%) of white solid was obtained by the method of Example 36. IR (KBr, cm" ¹ ) : 3428 (br), 2942, 2986, 1096, 1024 1H-NMR(D ₂ 0/TMS) : δ 1.01-0.95 (m, 3H, C3⁄4CH ₂ ), 52.32-1.37 (m, 8H, CH ₂ of DACH), 51.37-1.30 (m, 3H, CHC3⁄4), 51.38-1.30 (m, 2H, CH ₃ CH ₂ ), 53.39-3.38 (m, 1Η, NHCHCH ₃ ), 53.48-3.40 (m, 2H, CHNH) ; ESI-MS m/z: [M-2HC1+H ] ⁺ = 171 (100%) Example 39. Synthesis of Ligand 4-R.2HC1 (Route I)

Using SM-R as the starting material and acetone as the reactant, a white solid (13.0 g (70.9%) of IR (KBr, cm" ¹ ): 3431 (br), 2975, 2946, 1098, 1032 was obtained as in Example 36; 1H-NMR (D ₂ 0/TMS) : δΙ .38-1.25 (m, 6H, CH(CH ₃ ) ₂ ), 52.26-1.38 (m, 8H, CH ₂ of DACH), 53.67-3.58 (m, 1H , NHCHCH ₃ ), 53.41-3.35 (m, 2H, NHCH); ESI-MS m/z: [M-2HC1+H] ⁺ = 157 (100%). Example 40. Ligand 5-R.2HC1 Synthesis (route I)

Using SM-R as the starting material and cyclohexanone as the reactant, a white solid 18.0 g (84.0 ) dR (KBr, cm" ¹ ) was obtained as in Example 36: 3429 (br), 2939, 2860, 1030; 1H -NMR (D ₂ 0/TMS): 52.27-1.13 (m, 18H, CH ₂ of DACH and CHX), 53.45-3.32 (m, 3H, NHCH); ESI-MS m/z: [M-2HC1+H ] ⁺ = 197 (100%).

Note: CHX stands for cyclohexyl. Example 41. Synthesis of Ligand 6-R.2HC1 (Route I)

Using SM-R as the starting material and cyclopentanone as the reactant, a white solid 16.1 g (79.1) dR (KBr, cm" ¹ ) was obtained as in Example 36: 3430 (br), 2940, 2869, 2814, 1030 1H-NMR(D ₂ O rMS) : 52.36-1.37 (m, 16H, CH ₂ of DACH and CPX), 53.47-3.40 (m, 3H, NHCH) ; ESI-MS m/z: [M-2HC1+ H] ⁺ = 183 (100%).

Note: CPX stands for cyclopentyl. Example 42. In vitro antitumor activity assay of typical compounds

Some typical platinum (Π) complexes represented by formula (la) and formula (lb) were tested for in vitro antitumor activity. The cancer cells used were human hepatoma cells HepG-2, human breast cancer cells MCF-7, human body. The positive control used for lung cancer cell A549 and human colon cancer cell HCT-116 is the existing drug cisplatin, oxaliplatin or carboplatin. The specific experimental methods are as follows: The cell viability is detected by MTT assay, and the cells growing in the logarithmic growth phase are counted by 0.01% trypsin, counted, and inoculated in a 96-well plate at a cell density of 2.0×10 3 /well, Cultured in a 5% C0 ₂ incubator at 37 °C Night. Six concentration gradients were set for each compound, three wells were set for each concentration, and each concentration was added to the corresponding wells, cultured in a 5% C0 ₂ 37 °C incubator for 72 hours, and 20 mL of 5 mg/mL MTT was added. . After incubating for 3 hours at 37 ° C, the supernatant was aspirated, dissolved in 100 mL of DMSO, and the absorbance at 550 nm (Ll) was measured using a SpectraMAX 340. The reference wavelength was 690 nm (L2), and the (LI-L2) value was compared to the inhibitor. Drawing at different concentrations, the IC ₅ o value was fitted by the formula.

Table 1. IC ₅₀ values for platinum ( II ) complexes

Claims

Claim

A platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, characterized in that the structure is as shown in formula (la) or formula (lb):

Y in the formula (la) is an organic carboxylic acid anion, Z in the formula (lb) is an organic dicarboxylic acid dianion, and in the formula (la) and the formula (lb), R is a C ₃ - C ₈ alkyl group. The asterisk * represents a chiral carbon atom, and the compound of the formula (la) and the formula (lb) is a chiral isomer having a 1R, 2R-configuration and/or a 2 configuration.

2. The platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine according to claim 1 is a ligand, wherein Y in the formula (la) is -C _{Alkoxyacetate of 16} or C ₂ -C ₁₈ alkylcarboxylate; Z in formula (lb) is oxalate, malonate, 1,1-cyclosuccinate, 3-hydroxy-1,1 - cyclosuccinate, 3-alkoxy-1,1-cyclosuccinate, 3-aza-1, 1-cyclobutuccinate, N-substituted 3-aza-1, 1-cyclobutane Diacid or camphoric acid, N-substituted 3-aza-1, 1-cyclosuccinate, the substituent is benzyl, -C ₄ alkyl substituted benzyl, -C ₄ alkoxy substituted a benzyl group or a halogen atom substituted benzyl group.

The platinum (ruthenium) complex in which the N-alkyl-substituted trans 1,2-cyclohexanediamine according to claim 2 is a ligand, wherein the structure is as shown in the formula (lb). Wherein R is butyl, cyclopentyl, and Z is oxalate, malonate, 1,1-cyclosuccinate.

The platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine according to claim 3 is a ligand, wherein R is a sec-butyl group, a cyclopentyl group, Z is oxalate, malonate, 1,1-cyclosuccinate.

The platinum (ruthenium) complex in which the N-alkyl-substituted trans 1,2-cyclohexanediamine according to claim 2 is a ligand, which has a structure of the formula (la) or formula ( Shown in lb), wherein R is propyl, Y is C ₂ -C ₄ alkoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3 In the aza-1,1-cyclosuccinate, the substituent is a benzyl group, a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group.

6. The platinum (ruthenium) complex of the N-alkyl substituted trans 1,2-cyclohexanediamine according to claim 5, wherein R is an isopropyl group and Y is an isopropyl group. Oxyacetate or tert-butoxyacetate, Z is an N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1,1-cyclosuccinate The substituent is a methyl substituted benzyl or a methoxy substituted benzyl.

7. A platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, characterized in that the structure is as shown in formula (2);

Wherein, Hal represents Cl—, Br— or Γ, R is a C ₃ -C ₈ alkyl group according to any one of claims 1 to 6, and the asterisk * represents a chiral carbon atom, 2) The compound is a chiral isomer having a 1R, 2R-configuration and/or a 1^, 2^-configuration.

A method for preparing a platinum (ruthenium) complex in which an N-alkyl-substituted trans 1,2-cyclohexanediamine is a ligand, comprising the steps of: trans-protected by a single Boc , 2-cyclohexanediamine as a starting material, the compound represented by the formula (3) is obtained by the following scheme I, and then the compound represented by the formula (3) is reacted with potassium tetrahalide (potassium)ate to obtain a formula ( 2) the compound;

^ (3) The single Boc protected trans 1,2-cyclohexanediamine is represented by the formula (4):

a trip (X

Formula (4)

Wherein Boc represents a tert-butoxycarbonyl group; Route I is as follows: —曰

T)

In the route I, R is a C ₃ -C ₈ alkyl group according to any one of claims 1 to 6, the fatty aldehyde is a C ₃ - C ₈ chain alkyl aldehyde, and the aliphatic ketone is ₈ A chain or cyclic alkyl ketone, when R is a chain alkyl group, a chain alkyl aldehyde or a chain alkyl ketone is used, and when a chain alkyl aldehyde is used, R1 is. _{2 7} alkyl, R ₂ is a hydrogen atom; when a chain alkyl ketone is used, R 1 and R 2 are respectively a linear alkyl group of dC ₆ , the sum of the carbon atoms of the two should be less than 7 or equal to 7; In the case of a cyclic alkyl group, a cyclic alkyl ketone is used, wherein X is a C ₂ - C ₇ alkylene group.

The method for producing a platinum (II) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand according to claim 7, wherein the method is represented by the formula (2) The compound is reacted to form a compound of formula (la) or formula (lb).

The method for producing a platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand according to claim 8, wherein the method is represented by the formula (2) The method of reacting a compound to form a compound of formula (la) or formula (lb) is:

The halogen ion in the formula (2) is removed by silver ions in an aqueous solution under light shielding conditions, and then reacted with an alkali metal salt or an ammonium salt of Y defined by the formula (la) to form a platinum represented by the formula (la). (Π) complex, or reacted with an alkali metal salt or ammonium salt of Z as defined by formula (lb) to form a platinum (II) complex of formula (lb);

Or,

In a light-protected condition, a silver salt of Y defined by the formula (la) is reacted with a platinum (ruthenium) complex represented by the formula (2) in an aqueous solution to form a platinum (II) complex represented by the formula (la). The platinum salt of the formula (b) is reacted with a platinum (II) complex represented by the formula (2) to form a platinum (II) complex represented by the formula (lb).