CN110218231B - Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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CN110218231B
CN110218231B CN201910158841.8A CN201910158841A CN110218231B CN 110218231 B CN110218231 B CN 110218231B CN 201910158841 A CN201910158841 A CN 201910158841A CN 110218231 B CN110218231 B CN 110218231B
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高清志
高香倩
韩建斌
杨金娜
杨柳
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Abstract

A cyclobutane dicarboxylic acid platinum complex shown as a formula (I), an intermediate thereof, a preparation method thereof, a pharmaceutical composition and application thereof. The cyclobutane dicarboxylic acid platinum complex has good antitumor activity. Compared with the existing platinum antineoplastic drugs, the complex provided by the invention has the advantages that the water solubility is improved by more than dozens of times, the high water solubility characteristic can increase and improve the excretion of the drugs in the kidney, the general high renal toxic and side effects of the platinum drugs are reduced, and the compounds are easy to prepare and are more convenient to apply clinically.
Figure DDA0001982753660000011

Description

Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to a water-soluble platinum complex, an intermediate thereof, a preparation method thereof, a pharmaceutical composition and application thereof.
Background
Platinum anticancer drugs are a representative class of drugs in the field of tumor therapy. It belongs to a cell cycle nonspecific drug, and has therapeutic effects on sarcoma, malignant epithelial tumors, lymphoma and germ cell tumors. Currently, the representative platinum anticancer drugs widely used in clinical treatment in the world mainly include: cisplatin, carboplatin, and oxaliplatin. The fatal defects of platinum anticancer drugs are extremely strong toxic and side effects and the problems of inherent and subsequently formed drug resistance. In addition, as the medicaments are metal organic compounds, all platinum medicaments on the market generally have the characteristic of extremely low water solubility, and the water solubility of cisplatin, carboplatin and oxaliplatin is 1.0, 17.0 and 6.0mg/ml respectively.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a cyclobutane dicarboxylic acid platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has good water solubility and good antitumor activity.
The invention provides a cyclobutane dicarboxylic acid platinum complex shown as a formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
Figure BDA0001982753640000011
wherein:
x and Y are ligands, each independently selected from NH 3 、C 1 -C 8 Straight or branched chain alkyl primary amine (optionally C) 1 -C 6 A linear or branched primary alkyl amine of (1), optionally C 1 -C 3 Linear or branched alkyl primary amine) of C 3 -C 8 A cyclic alkyl primary amine (optionally C) 3 -C 6 Cyclic alkyl primary amine), aromatic primary amine, one or more C 1 -C 4 A linear or branched alkyl substituted primary aromatic amine of the formula R 1 -NH-R 2 Of (a) wherein R is 1 And R 2 Are the same or different and are each represented by C 1 -C 8 Linear or branched alkyl (optionally C) 1 -C 6 Is straight or branched alkyl, optionally C 1 -C 3 Linear or branched alkyl groups of (a); or R 1 -NH-R 2 Together form C 4 -C 8 Alicyclic secondary amine (optionally C) 5 -C 6 Alicyclic secondary amine) nitrogen-containing aromatic heterocyclic compound, one or more C 1 -C 4 A straight-chain or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compound, sulfur-containing aromatic heterocyclic compound, or sulfur-containing non-aromatic heterocyclic compound; wherein, the aryl in the aromatic primary amine is a 5-10 membered monocyclic or fused bicyclic aromatic group, and the aromatic heterocycle is a 5-10 membered monocyclic or fused bicyclic aromatic heterocycle; the non-aromatic heterocycle is a 4-10 membered monocyclic or polycyclic aliphatic heterocycle;
or X and Y together form a structure of formula (IV):
Figure BDA0001982753640000012
in the formula (IV), D is C 0 Or C 1 An alkylene group of (a); b is C 2 -C 8 Alkylene (optionally C) 2 -C 6 Alkylene of (2), optionally C 3 -C 5 Alkylene groups of (a);
n =0, 1,2,3,4, 5 or 6 (alternatively, n =0, 1,2,3 or 6, alternatively, n =0, 1,2 or 3);
r is selected from the following monosaccharide groups, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure BDA0001982753640000021
alternatively, R is selected from the following monosaccharide groups, the 1-position substitution of the monosaccharide is alpha substitution or beta substitution,
Figure BDA0001982753640000022
optionally, X and Y are each NH 3 Or X, Y together are trans- (1R, 2R) -cyclohexanediamine, trans- (1S, 2S) -cyclohexanediamine, cis- (1R, 2S) -cyclohexanediamine, cis- (1S, 2R) -cyclohexanediamine, racemic trans-1, 2-cyclohexanediamine or racemic cis-1, 2-cyclohexanediamine.
Optionally, X and Y are each NH 3 (ii) a Or X, Y together are trans- (1R, 2R) -cyclohexanediamine.
n =0, 1,2,3 or 6; r is selected from the following monosaccharide groups, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure BDA0001982753640000031
alternatively, the formula (I) is selected from the following complexes,
Figure BDA0001982753640000032
/>
Figure BDA0001982753640000041
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Figure BDA0001982753640000051
in another aspect of the present invention, there is provided a compound represented by the formula (III) which is useful as an intermediate for the preparation of a cyclobutanedicarboxylic acid platinum complex represented by the formula (I),
Figure BDA0001982753640000052
in the formula (III):
each M independently represents a hydrogen atom, or a metal atom of group IA of the periodic Table of the elements, or two M together represent a metal atom of group IIA of the periodic Table of the elements; optionally M independently represents H, na, K, li, cs or both M together represent Ba;
n =0, 1,2,3,4, 5 or 6 (alternatively, n =0, 1,2,3 or 6, alternatively, n =0, 1,2 or 3);
r is selected from hydrogen or the following monosaccharide groups, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure BDA0001982753640000061
alternatively, the formula (III) is selected from the following compounds:
Figure BDA0001982753640000062
in the formula (III-1), the formula (III-2) and the formula (III-3),
n =0, 1,2,3, or 6 (alternatively, n =0, 1,2, or 3);
m independently represents H, na, K, li, cs or two M together represent Ba.
In another aspect of the present invention, there is provided a method for preparing the above cyclobutane dicarboxylic acid platinum complex, or its optical isomer, or its pharmaceutically acceptable salt, or solvate, comprising the steps of adding water to the compound of formula (II) and the compound of formula (III) to adjust them into an aqueous solution for reaction; optionally, adding alkali into the reaction aqueous solution to adjust the pH value to 7-9,
optionally, the base is an inorganic base, optionally, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, cesium hydroxide, or barium hydroxide;
the structural formula of the (II) is as follows:
Figure BDA0001982753640000071
in the formula (II):
x and Y are ligands, each independently selected from NH 3 、C 1 -C 8 Straight or branched chain alkyl primary amine (optionally C) 1 -C 6 A linear or branched primary alkyl amine of (1), optionally C 1 -C 3 Linear or branched alkyl primary amine) of C 3 -C 8 A cyclic alkyl primary amine (optionally C) 3 -C 6 Cyclic alkyl primary amine), aromatic primary amine, one or more C 1 -C 4 A linear or branched alkyl substituted primary aromatic amine of the formula R 1 -NH-R 2 Of (a) wherein R is 1 And R 2 Are the same or different and are each represented by C 1 -C 8 Linear or branched alkyl (optionally C) 1 -C 6 Is straight or branched alkyl, optionally C 1 -C 3 Straight or branched alkyl groups of (ii); or R 1 -NH-R 2 Together form C 4 -C 8 Alicyclic secondary amine (optionally C) 5 -C 6 Alicyclic secondary amine of (a), nitrogen-containing aromatic heterocyclic compound, one or more C 1 -C 4 A straight-chain or branched alkyl-substituted nitrogen-containing aromatic heterocyclic compound, sulfur-containing aromatic heterocyclic compound, or sulfur-containing non-aromatic heterocyclic compound; wherein, the aryl in the aromatic primary amine is a 5-10 membered monocyclic or fused bicyclic aromatic group, and the aromatic heterocycle is a 5-10 membered monocyclic or fused bicyclic aromatic heterocycle; the non-aromatic heterocycle is a 4-10 membered monocyclic or polycyclic aliphatic heterocycle;
or X and Y are represented together by structural formula (IV):
Figure BDA0001982753640000072
in the formula (IV), D is C 0 Or C 1 An alkylene group of (a); b is C 2 -C 8 Alkylene (optionally C) 2 -C 6 Alkylene of (2), optionally C 3 -C 5 Alkylene groups of (a);
A 1 and A 2 Identical or different, each independently of the others, represents hydroxyl, nitrate or perchlorate, or A 1 And A 2 Together represent sulfate or carbonate;
the structural formula of the (III) is as follows:
Figure BDA0001982753640000073
in the formula (III):
each M independently represents a hydrogen atom, or a metal atom of group TA of the periodic Table of the elements, or two M together represent a metal atom of group IIA of the periodic Table of the elements; optionally M independently represents H, na, K, li, cs or two M together represent Ba;
n =0, 1,2,3,4, 5 or 6 (alternatively, n =0, 1,2,3 or 6);
r is selected from hydrogen, or R is selected from the following monosaccharide groups, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure BDA0001982753640000081
alternatively, in the above reaction, 0.5 to 4 equivalents of compound (II) are used per equivalent of compound (III), preferably 1 to 2 equivalents.
Optionally, the inorganic base concentration is 0.1N to 5N, preferably 1N.
Alternatively, the reaction may be carried out over a relatively wide temperature range, for example, a temperature in the range of 0 to 100℃, preferably 25 to 90℃, more preferably 60 to 90℃, with stirring. The time required for the reaction may vary depending on the target product. Depending on the nature of the various reactants, it generally takes from 1 hour to 30 days to complete. More often, it takes from 10 hours to 15 days.
Alternatively, the water used in the above reaction to adjust the reaction compound to an aqueous solution is preferably deionized water.
The specific preparation can be completed by the following method and reaction formula:
the method A comprises the following steps:
Figure BDA0001982753640000082
the method B comprises the following steps:
Figure BDA0001982753640000091
in the method a, when M is a hydrogen atom in the formula (III), the reaction can be carried out by adjusting the pH of the reaction aqueous solution to be maintained between 7 and 9 using an appropriate inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, cesium hydroxide and the like to complete the preparation of the complex represented by the formula (I); when M is a metal atom, for example: sodium atom, potassium atom, lithium atom, barium atom or cesium atom, the reaction can be smoothly carried out in an aqueous solution, and if necessary, the synthesis of the complex represented by the formula (I) can be completed by maintaining the pH of the reaction solution at 7 to 9 using a small amount of an aqueous solution of the above inorganic base.
In the method B, when M is a hydrogen atom, the reaction can be carried out by carrying out a condensation reaction with the metal platinum sulfate compound represented by the formula (II) in an aqueous solution using an equivalent amount of barium hydroxide as an inorganic base to prepare the complex represented by the formula (I). When preparing the complex of the invention by the method B, the complex can also be prepared by reacting a barium salt prepared in advance, namely two M together represent a barium atom, with the metal platinum sulfate complex shown in the formula (II) in an aqueous solution.
The compounds represented by the formula (II) in the processes A and B can be prepared by reacting the corresponding cis-platinum dichloride complex with X and Y (e.g., cis-dichloro- (1, 2-diaminocyclohexane) platinum) with 2 equivalents of silver nitrate or 1 equivalent of silver sulfate. The reaction is preferably carried out in aqueous solution, the water used preferably being deionized water. The reaction temperature is suitably at room temperature.
The method for purifying the product (I) prepared by the above method is not particularly limited, and the product (I) can be purified by a method conventionally used in the art, for example, a mixture after completion of the reaction may be first filtered to remove a precipitate which may be formed, then concentrated by distillation under reduced pressure, and then an organic solvent (alternatively, the organic solvent is preferably an organic solvent miscible with water, such as alcohols (e.g., methanol, ethanol, propanol, butanol, isopropanol, etc.) or ethers miscible with water (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, etc.) is added to precipitate the target compound (I), and finally the obtained precipitate is collected, for example, by filtration, to obtain the desired compound represented by formula (I). The product (I) obtained by the above reaction may be purified and purified by a method such as chromatography, for example, by using an ion exchange resin or by preparative liquid chromatography. Liquid chromatography separation and purification is generally performed using methanol and water as mobile phases.
The compound (III) of the present invention can be prepared by any of the glucose-exemplified methods C, D or methods E, F given by the following reaction scheme:
the method C comprises the following steps:
Figure BDA0001982753640000101
the method D comprises the following steps:
Figure BDA0001982753640000102
the method E comprises the following steps:
Figure BDA0001982753640000103
method F:
Figure BDA0001982753640000111
in methods C and D, the hydroxy-containing cyclobutanedicarboxylate derivatives reacted with the sugar can be prepared by a general method known in the literature (e.g., molecules2016, 21 (5), 612) using a hydroxy-containing 1, 3-dihaloalkane derivative and a malonate compound such as dimethyl malonate, diethyl malonate, diphenylmethyl malonate, cyclodisolide malonate, etc., as exemplified by glucose. The obtained hydroxyl-containing cyclobutane dicarboxylate derivative and glucose can be subjected to condensation reaction in a solvent in the presence of Lewis acid, so as to obtain the glucoside compound of cyclobutane dicarboxylate. The conditions of the condensation reaction are such that 0.1 to 50 equivalents of the hydroxyl-containing cyclobutanedicarboxylate are used with respect to the glucose compound, or conversely 0.1 to 50 equivalents of glucose are used with respect to the hydroxyl-containing cyclobutanedicarboxylate. The Lewis acid used may be BF 3 ，SnCl 4 ，FeCl 3 ，AlCl 3 Hydrochloric acid, p-toluenesulfonic acid, camphorsulfonic acid, etc., and the amount of the Lewis acid may be 0.1 to 10 equivalents relative to glucose. The solvent used may be tetrahydrofuran, dichloromethane, toluene, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, or the like, and the reaction may be carried out using either one of the two reactants as a solvent. The reaction temperature can be from 0 ℃ to 100 ℃, and the reaction can be completed by heating at 60-80 ℃ generally. The time required for the reaction varies depending on the reactants, and may be generally 1 hour to 7 days. The reaction product obtained can be purified by a series of purification conditions, and silica gel chromatography or liquid chromatography can be generally used. The product thus obtained is subjected to removal of the protecting group of malonic acid to finally obtain the desired compound represented by the formula (III). Deprotection methods depending on the protection usedDepending on the group, when diphenylmethyl malonate is used, deprotection can be carried out by hydrogenation reduction, when diethyl malonate or cyclodiolactone malonate is used, deprotection can be carried out in methanol-water or THF-water solvent using an inorganic base, and the ratio of the organic solvent to water is generally 1: 1 to 4: 1. The inorganic base used may be sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc. The reaction temperature is generally room temperature and the reaction time is generally 1 to 24 hours. Purification of the deprotected compound can be accomplished by silica gel chromatography or ion exchange resin filtration, or by liquid chromatography, and if the reaction solvent is directly removed by distillation, the resulting product will be the corresponding metal carboxylate.
The preparation methods shown in methods C and D are preparation routes using acetyl protected sugar, or directly using unprotected sugar and hydroxyl-containing cyclobutane dicarboxylate derivative to condense in the presence of Lewis acid and then perform deprotection to obtain the target product (III).
The preparation method shown in the methods E and F is a preparation route that firstly, the hydroxyl-containing 1, 3-dihalogenated alkane derivative and acetyl protected or unprotected sugar form glucoside derivative, then the glucoside derivative is condensed with malonate to form cyclobutane dicarboxylate, and finally the target product (III) is obtained by removing the protecting group.
In methods C and F, glucose may be first converted to the corresponding acetylated glucose and then subjected to a condensation reaction with the corresponding hydroxyl-containing intermediate, and the acetylation of glucose may be carried out according to literature reported methods, for example, in pyridine using acetic anhydride as the acetylation reagent, by heating at room temperature or at 60 ℃ for 1-24 hours.
In another aspect of the present invention, a pharmaceutical composition is provided, which comprises one or more of the above-mentioned complexes, or optical isomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, and optionally a pharmaceutically acceptable carrier.
In another aspect of the present invention, there is provided a use of the above-mentioned complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutical composition thereof in the preparation of an anti-tumor cell drug.
Alternatively, the tumor cell is human lung cancer, human liver cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymphoma, human skin cancer, human pancreatic cancer, human bladder cancer, human esophageal cancer, human stomach cancer, human male genital cancer, human thyroid cancer, human bone cancer, human melanoma, or human oral cancer.
Optionally, the tumor cell is human colon cancer cell HT29, human non-small cell lung cancer cell A549, human liver cancer cell SMMC7721, human breast cancer cell MCF-7, human ovarian cancer cell SKOV3, human esophageal cancer cell ECA109, human prostate cancer cell DU145, human cervical cancer cell Hela, human melanoma cell A375, human oral epidermoid carcinoma cell KB, human gastric cancer cell HGC27, human thyroid cancer cell SW579, human bladder cancer cell 5637, human pancreatic cancer cell Panc-1, human large cell lung cancer cell H460, human plasma cell leukemia cell H929, human liver cancer cell HepG2, human monocytic leukemia THP-1.
The route of administration of the antitumor agent of the present invention is not particularly limited, and the dose thereof depends not only on the age, body weight and condition of the patient, but also on the kind, nature and severity of the tumor. However, in general, it is preferred to use between 10 mg and 1g of the compound per day for adult patients. Typically once or several times every one to three weeks.
The compound provided by the invention has good antitumor activity. Compared with the existing platinum antineoplastic drugs, the complex provided by the invention has the advantages that the water solubility is improved by more than dozens of times, the high water solubility characteristic can increase the excretion of drugs in the kidney, reduce the accumulation of the drugs in the body, reduce the general high renal toxic and side effects of the platinum drugs, and simultaneously make the compounds easy to formulate, improve the stability of the preparation and be more convenient for clinical application.
Drawings
FIG. 1 shows compounds 1, 4, 7, 10 of the present invention in combination with a disclosed compoundIC of substance-1, compound-2 and Carboplatin in H460/Hela/5637 tumor cells 50 A comparison graph of values;
FIG. 2 shows the IC of compounds 1, 4, 7, 10 of the present invention with disclosed compound-1, disclosed compound-2 and carboplatin in HGC27/DU145/KB tumor cells 50 A comparison graph of values;
FIG. 3 is a graph showing the IC of compounds 1, 4, 7, 10 of the present invention with disclosed compound-1, disclosed compound-2 and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells 50 A comparison graph of values;
FIG. 4 is a graph showing the IC of compounds 11 and 12 of the present invention with disclosed Compound-1, compound-2 and carboplatin in H460/Hela/5637 tumor cells 50 A comparison graph of values;
FIG. 5 shows the IC of compounds 11 and 12 of the present invention with disclosed compound-1, disclosed compound-2 and carboplatin in HGC27/DU145/KB tumor cells 50 A comparison graph of values;
FIG. 6 is a graph showing the IC of compounds 11, 12 of the present invention with disclosed compound-1, disclosed compound-2 in ECA-109/SMMC7721/THP-1/A549 tumor cells 50 A comparison graph of values;
FIG. 7 is a graph showing the comparison of IC50 values of compounds 13, 16, 19, 22 of the present invention with those of compound-1, compound-2 and carboplatin in H460/Hela/5637 tumor cells;
FIG. 8 shows the IC of compounds 13, 16, 19, 22 of the present invention with disclosed Compound-1, compound-2 and carboplatin in HGC27/DU145/KB tumor cells 50 A comparison graph of values;
FIG. 9 is a graph showing the IC of compounds 13, 16, 19, 22 of the present invention with disclosed compound-1, disclosed compound-2 and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells 50 A comparison graph of values;
FIG. 10 is a graph showing the IC's of compounds 23 and 24 of the present invention with disclosed Compound-1, compound-2 and carboplatin in H460/Hela/5637 tumor cells 50 A comparison graph of values;
FIG. 11 shows compounds 23, 24 andIC of disclosing Compound-1, disclosing Compound-2 and Carboplatin in HGC27/DU145/KB tumor cells 50 A comparison graph of values;
FIG. 12 is a graph showing the IC of compounds 23, 24 of the invention with disclosed compound-1, disclosed compound-2 and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells 50 A comparison graph of values;
FIG. 13 is a graph showing the IC of compound 25 of the present invention with disclosed Compound-1, compound-2 and carboplatin in H460/Hela/5637 tumor cells 50 A comparison graph of values;
FIG. 14 shows the IC of compound 25 of the present invention with disclosed Compound-1, compound-2 and carboplatin in HGC27/DU145/KB tumor cells 50 A value comparison graph;
FIG. 15 is a graph showing the IC of compound 25 of the present invention with disclosed compound-1, disclosed compound-2 and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells 50 A comparison graph of values;
FIG. 16 is a graph showing the IC's of compounds 15, 18, and 20 of the present invention with disclosed Compound-1, compound-2, and Carboplatin in H460/Hela/5637 tumor cells 50 A comparison graph of values;
FIG. 17 shows the IC of compounds 15, 18, 20 of the present invention with disclosed Compound-1, compound-2 and carboplatin in HGC27/DU145/KB tumor cells 50 A value comparison graph;
FIG. 18 is a graph showing the IC of compounds 15, 18, 20 of the present invention with disclosed compound-1, disclosed compound-2 and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells 50 Comparison of values.
Detailed Description
The invention is further illustrated by the following specific examples. Representative examples of preferred compounds of the platinum complex for tumor therapy represented by formula (I) provided in the present invention can also be listed in table 1 below, but the platinum complex encompassed by the present invention is not limited to the following examples.
Table 1 list of compounds of the examples
Figure BDA0001982753640000131
/>
Figure BDA0001982753640000141
/>
Figure BDA0001982753640000151
/>
Figure BDA0001982753640000161
Example 1: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000162
/>
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-acetoxy-cyclobutane
Figure BDA0001982753640000171
60% sodium hydride (0.8 g) was dissolved in a solution of N, N-dimethylformamide (15 ml) in diethyl malonate (1.6 g). The mixture was stirred at room temperature for 30 minutes. Then, an N, N-dimethylformamide solution (10 ml) containing 1, 3-dibromo-2-ester-ylpropane (1.3 g) was added to the reaction solution, and the mixture was stirred at 80 ℃ for 6 hours. The solvent was removed by rotary evaporation, and the residue was redissolved in a mixed solution of ethyl acetate (150 ml) and saturated ammonium chloride (150 ml), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate: 50/1) to give a colorless oily product (0.66 g).
1 H NMR(400MHz，CDCl 3 )δ5.02(dt，J＝10.0，7.4Hz，1H)，4.29-4.07(m，4H)，2.93(dt，J＝17.6，6.3Hz，2H)，2.64-2.52(m，2H)，2.05-1.95(m，3H)，1.24(dt，J＝14.3，4.3Hz，6H).MS(m/z)：281.0[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-hydroxy-cyclobutane
Figure BDA0001982753640000172
The product of the above step (1.29 g) was dissolved in 0.1M sodium ethoxide solution (10 ml), stirred at room temperature for 2 hours, the residue was dissolved in ethyl acetate solution (100 ml) and ammonium chloride solution (100 ml), liquid-separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give a colorless oil (0.75 g).
1 H NMR(400MHz，CDCl 3 )δ5.02(dt，J＝10.0，7.4Hz，1H)，4.29-4.07(m，4H)，2.92(dt，J＝17.6，6.3Hz，2H)，2.62-2.49(m，2H)，1.24(dt，J＝14.3，4.3Hz，6H).MS(m/z)：239.0[M+Na] +
(3) Preparation of 1, 1-dicarboxylic acid ethyl ester-3- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000173
1,2,3,4, 6-O-Pentaacetyl-D-glucose (1.84 g) was added to a solution of ethyl 1, 1-dicarboxylate-3-hydroxycyclobutane (1.02 g) in methylene chloride (20 ml) at room temperature, cooled to 0 ℃ and the atmosphere in the flask was replaced with nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and simple purification was performed by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.71g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.16(t，J＝9.5Hz，1H)，5.05(t，J＝9.7Hz，1H)，4.95(dd，J＝9.5，8.1Hz，1H)，4.46(d，J＝8.0Hz，1H)，4.41-4.28(m，1H)，4.20(qd，J＝12.6，5.8Hz，5H)，4.09(dd，J＝12.3，2.2Hz，1H)，3.65(ddd，J＝9.9，4.8，2.3Hz，1H)，2.87-2.73(m，2H)，2.59(dd，J＝12.1，7.2Hz，1H)，2.49(dd，J＝11.7，7.3Hz，1H)，2.07(s，3H)，2.05(s，3H)，2.01(s，3H)，1.99(s，3H)，1.24(td，J＝7.1，2.3Hz，6H).
MS(m/z)：569.1[M+Na] +
(4) Preparation of 1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000181
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane (1.09 g), and stirred at 90 ℃ for 8h while elevating the temperature. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.93g of a white solid.
(5) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000182
1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (0.9 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. About.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and separated by semi-preparative high pressure liquid chromatography to give 0.54g of the final product.
1 H NMR(400MHz，D 2 O)δ5.76(s，1H)，5.06(s，1H)，4.46(d，J＝8.0Hz，1H)，4.42-4.35(m，1H)，3.89(dd，J＝12.3，1.7Hz，1H)，3.70(dd，J＝12.4，5.7Hz，1H)，3.52-3.28(m，5H)，3.24(t，J＝8.6Hz，1H)，2.81(dd，J＝12.1，7.3Hz，1H)，2.72(dd，J＝11.9，7.3Hz，1H)，2.42-2.30(m，2H)，1.99(d，J＝11.9Hz，2H)，1.53(d，J＝8.3Hz，2H)，1.29-1.18(m，2H)，1.08(t，J＝10.0Hz，2H)。
Example 2: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000183
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] -cyclobutane
Figure BDA0001982753640000184
1,2,3,4, 6-O-Pentaacetyl-D-mannose (1.84 g) was added to a dichloromethane (20 ml) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxycyclobutane (1.02 g) at room temperature, cooled to 0 ℃ and the atmosphere in the flask was replaced with nitrogen, and a boron trifluoride ether solution (98%, 1.19 ml) was slowly dropped under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and simple purification was performed by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.39g of a crude product.
1 H NMR(400MHz，CDCl 3 )65.38-5.16(m，3H)，4.81(d，J＝1.1Hz，1H)，4.36-4.14(m，6H)，4.09(dd，J＝12.2，2.1Hz，1H)，4.04-3.97(m，1H)，2.82(ddd，J＝9.3，7.3，3.7Hz，2H)，2.69-2.51(m，2H)，2.14(s，3H)，2.10(s，3H)，2.04(s，3H)，1.99(s，3H)，1.26(q，J＝7.2Hz，6H).MS(m/z)：569.1[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane
Figure BDA0001982753640000191
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, and then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] -cyclobutane (1.09 g), and the temperature was raised and stirred at 90 ℃ for 8 hours. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.95g of a white solid.
(3) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000192
1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (0.9 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. About.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.39g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ5.79(s，1H)，5.07(d，J＝9.3Hz，1H)，4.94(s，1H)，4.29(m，1H)，4.00-3.88(m，2H)，3.87-3.57(m，4H)，3.51-3.40(m，1H)，3.37(dd，J＝11.2，6.3Hz，1H)，2.87(dd，J＝11.9，7.4Hz，1H)，2.77(dd，J＝11.8，7.4Hz，1H)，2.41(d，J＝6.0Hz，2H)，2.02(d，J＝11.3Hz，2H)，1.56(d，J＝7.6Hz，2H)，1.25(d，J＝8.6Hz，2H)，1.11(d，J＝9.9Hz，2H).
Example 3: cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ] preparation
Figure BDA0001982753640000193
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(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000194
1,2,3,4, 6-O-Pentaacetyl-D-galactose (1.84 g) was added to a solution of ethyl 1, 1-dicarboxylate-3-hydroxycyclobutane (1.02 g) in methylene chloride (20 ml) at room temperature, cooled to 0 ℃ and the atmosphere in the flask was replaced with nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.55g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.35(d，J＝2.7Hz，1H)，5.16(dd，J＝10.4，8.0Hz，1H)，4.97(dd，J＝10.5，3.4Hz，1H)，4.45-4.29(m，2H)，4.23-4.03(m，6H)，3.86(dd，J＝6.8，6.1Hz，1H)，2.88-2.71(m，2H)，2.59(dd，J＝12.2，7.2Hz，1H)，2.49(dd，J＝11.8，7.3Hz，1H)，2.12(s，3H)，2.05(s，3H)，2.03(s，3H)，1.96(s，3H)，1.23(td，J＝7.1，2.9Hz，6H).MS(m/z)：569.1[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane
Figure BDA0001982753640000201
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, and then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] cyclobutane (1.09 g), the temperature was raised, and stirred at 90 ℃ for 8 hours. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.95g of a white solid.
(3) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000202
1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] -cyclobutane (0.9 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.54g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.46-4.35(m，2H)，3.90(d，J＝3.2Hz，1H)，3.81-3.59(m，4H)，3.52-3.44(m，1H)，3.39(dd，J＝11.9，7.1Hz，1H)，3.31(dd，J＝11.4，6.3Hz，1H)，2.81(dd，J＝12.1，7.3Hz，1H)，2.70(dd，J＝12.0，7.3Hz，1H)，2.40-2.29(m，2H)，1.99(d，J＝12.0Hz，2H)，1.53(d，J＝8.2Hz，2H)，1.24(d，J＝8.9Hz，2H)，1.09(t，J＝10.1Hz，2H).
Example 4: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-methylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000203
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-benzyloxymethyl-cyclobutane
Figure BDA0001982753640000204
Sodium hydride (60%) (1.01 g) as a solid was slowly added to a DMF (10 ml) solution containing diethyl malonate (2.02 g) under cooling in an ice bath, and the mixture solution was stirred at room temperature for 30 minutes. Then, a DMF (15 ml) solution containing ((4-bromo-3- (methyl) butoxy) methyl) benzene (2.03 g) was further added to the reaction solution at room temperature, and the reaction solution was stirred at 80 ℃ for 12 hours. The solvent was removed by rotary evaporation. To the reaction solution was added 100ml of ethyl acetate, which was then washed with a saturated aqueous solution of ammonium chloride (1X 50 ml), the aqueous phase was extracted with ethyl acetate (2X 25 ml), and the organic phases were combined. The organic phase was washed successively with a saturated aqueous solution of ammonium chloride (1 × 100 ml), distilled water (1 × 100 ml), and a saturated aqueous solution of sodium chloride (1 × 100 ml), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to give 1.64g of a colorless oily product.
1 H NMR(400MHz，CDCl 3 )δ7.37-7.27(m，5H)，4.49(d，J＝6.9Hz，2H)，4.19(dq，J＝17.9，7.1Hz，4H)，3.44(d，J＝5.8Hz，2H)，2.76-2.54(m，3H)，2.43-2.27(m，2H)，1.25(ddd，J＝14.5，8.5，4.5Hz，6H).MS(m/z)：343.1[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-hydroxymethyl-cyclobutane
Figure BDA0001982753640000211
Palladium on carbon (0.11 g) was added to a methanol solution containing the product of the above step (1.16 g), and hydrogen was replaced under vacuum at room temperature, followed by stirring the reaction solution under hydrogen conditions for 36 hours. The excess residue was removed by celite filtration to give a filtrate, the solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give 0.813g of a colorless oily product.
1 H NMR(400MHz，CDCl 3 )δ4.21(dq，J＝14.3，6.9Hz，4H)，3.49(t，J＝6.5Hz，2H)，2.58(ddd，J＝9.1，8.3，2.3Hz，2H)，2.51-2.35(m，1H)，2.30-2.16(m，2H)，1.23(td，J＝7.5，5.4Hz，6H).MS(m/z)：253.0[M+Na] +
(3) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-methylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000212
1,2,3,4, 6-O-Pentaacetyl-D-glucose (1.84 g) was added to a dichloromethane (20 ml) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxymethyl-cyclobutane (1.08 g) at room temperature, cooled to 0 ℃ in an ice bath, the flask was purged with nitrogen, and a boron trifluoride ether solution (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1), to obtain 1.71g of a crude product.
1 HNMR(400MHz，CDCl 3 )δ5.14(t，J＝9.5Hz，1H)，5.02(t，J＝9.7Hz，1H)，4.92(dd，J＝9.6，8.0Hz，1H)，4.45(d，J＝8.0Hz，1H)，4.21-4.05(m，6H)，3.80(dd，J＝9.9，5.7Hz，1H)，3.64(ddd，J＝9.9，4.7，2.3Hz，1H)，3.41(dd，J＝9.9，6.2Hz，1H)，2.64-2.48(m，3H)，2.28(ddd，J＝19.9，10.1，5.1Hz，2H)，2.04(s，3H)，2.00(s，3H)，1.97(s，3H)，1.95(s，3H)，1.20(td，J＝7.1，3.7Hz，6H).MS(m/z)：583.1[M+Na] +
(4) Preparation of 1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000213
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-methylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane (1.12 g), and the temperature was raised and stirred at 90 ℃ for 8h. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.96g of a white solid.
(5) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-methylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000221
1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (0.93 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH approximately 8 with a saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.49g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ5.71(d，J＝14.9Hz，2H)，4.88(s，2H)，4.32(d，J＝7.9Hz，1H)，3.86(m，2H)，3.77-3.52(m，5H)，3.44(dd，J＝9.7，8.1Hz，1H)，3.05(dd，J＝20.1，10.3Hz，2H)，2.53(ddd，J＝22.8，17.2，9.2Hz，3H)，2.32(d，J＝5.9Hz，2H)，1.91(d，J＝11.2Hz，2H)，1.45(d，J＝7.3Hz，2H)，1.14(s，2H)，1.05-0.93(m，2H).
Example 5: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-methylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000222
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-methylene- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] -cyclobutane
Figure BDA0001982753640000223
1,2,3,4, 6-O-Pentaacetyl-D-mannose (1.84 g) was added to a dichloromethane (20 ml) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxymethyl-cyclobutane (1.08 g) at room temperature, cooled to 0 ℃ in an ice bath, the atmosphere in the flask was replaced with nitrogen, and a boron trifluoride ether solution (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.39g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.37-5.17(m，4H)，4.78(s，1H)，4.23(ddt，J＝14.2，10.2，6.2Hz，5H)，4.02-3.92(m，1H)，3.66(dd，J＝9.9，5.6 Hz，1H)，3.46(dd，J＝9.8，5.4Hz，1H)，2.71-2.59(m，3H)，2.33(dd，J＝8.4，5.4Hz，2H)，2.15(s，3H)，2.11(s，3H)，2.04(s，3H)，1.98(s，3H)，1.25(s，6H).MS(m/z)：583.1[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane
Figure BDA0001982753640000224
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-methylene- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] -cyclobutane (1.12 g), and the temperature was raised and stirred at 90 ℃ for 8 hours. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.95g of a white solid.
(3) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-methylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000231
1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] -cyclobutane (0.93 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.44g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ5.76(d，J＝25.8Hz，2H)，4.94(s，2H)，4.79(s，1H)，3.91-3.78(m，2H)，3.77-3.48(m，5H)，3.44(dd，J＝9.8，5.5Hz，1H)，3.13-2.91(m，2H)，2.62(dd，J＝18.9，10.9Hz，2H)，2.50(dd，J＝14.0，7.2Hz，1H)，2.33(s，2H)，1.91(d，J＝10.8Hz，2H)，1.45(d，J＝7.1Hz，2H)，1.12(dd，J＝15.0，8.2Hz，2H)，1.00(d，J＝9.8Hz，2H).
Example 6: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-methylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000232
(1) Preparation of 1, 1-Diformic acid Ethyl ester-3-methylene- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000233
1,2,3,4, 6-O-Pentaacetyl-D-galactose (1.84 g) was added to a dichloromethane (20 ml) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxymethyl-cyclobutane (1.08 g) at room temperature, cooled to 0 ℃ in an ice bath, the flask was purged with nitrogen, and a boron trifluoride ether solution (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.57g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.36(d，J＝2.8Hz，1H)，5.17(dd，J＝10.5，8.0Hz，1H)，4.98(dd，J＝10.5，3.4Hz，1H)，4.43(d，J＝7.9Hz，1H)，4.23-4.09(m，6H)，3.91-3.78(m，2H)，3.44(dd，J＝9.9，6.4Hz，1H)，2.73-2.50(m，3H)，2.31(ddd，J＝18.5，10.0，4.6Hz，2H)，2.13(s，3H)，2.05(s，3H)，2.03(s，3H)，1.96(s，3H)，1.23(td，J＝7.1，2.8Hz，6H).MS(m/z)：583.1[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000241
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-methylene- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane (1.12 g), and stirred at 90 ℃ for 8h while elevating the temperature. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.98g of a white solid.
(3) Cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-methylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000242
1, 1-Dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (0.93 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.48g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.32(d，J＝8.1Hz，1H)，3.92-3.79(m，2H)，3.77-3.52(m，5H)，3.44(dd，J＝9.7，8.1Hz，1H)，3.03(dd，J＝20.1，10.7Hz，2H)，2.55(ddd，J＝22.8，17.2，9.3Hz，3H)，2.32(d，J＝5.9Hz，2H)，1.91(d，J＝11.2Hz，2H)，1.45(d，J＝7.3Hz，2H)，1.12(s，2H)，1.05-0.93(m，2H).
Example 7: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-ethylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000243
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-benzyloxyethyl-cyclobutane
Figure BDA0001982753640000244
Sodium hydride (60%) (1.01 g) as a solid was slowly added to a DMF (10 ml) solution containing diethyl malonate (2.02 g) under cooling in an ice bath, and the mixture solution was stirred at room temperature for 30 minutes. Then, a DMF (15 ml) solution containing ((4-bromo-3- (methyl) butoxy) methyl) benzene (2.12 g) was added to the reaction solution at room temperature, and the reaction solution was stirred at 80 ℃ for 12 hours. The solvent was removed by rotary evaporation. To the reaction mixture was added 100ml of ethyl acetate, which was then washed with saturated aqueous ammonium chloride solution (1X 50 ml), the aqueous phase was extracted with ethyl acetate (2X 25 ml), and the organic phases were combined. The organic phase was washed successively with a saturated aqueous solution of ammonium chloride (1 × 100 mL), distilled water (1 × 100 mL), and a saturated aqueous solution of sodium chloride (1 × 100 mL), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to give 1.69g of a colorless oily product.
1 H NMR(400MHz，CDCl 3 )δ7.24(dd，J＝19.1，7.5Hz，5H)，4.40(s，2H)，4.20-4.05(m，4H)，3.34(dd，J＝8.3，4.1Hz，2H)，2.58(dd，J＝13.4，5.4Hz，2H)，2.43(dd，J＝15.4，7.7Hz，1H)，2.16(dd，J＝14.3，6.3Hz，2H)，1.68(dd，J＝12.0，5.4Hz，2H)，1.23-1.13(m，6H).MS(m/z)：357.1[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-hydroxyethyl-cyclobutane
Figure BDA0001982753640000251
Palladium on carbon (0.11 g) was added to a methanol solution containing the product of the above step (1.21 g), hydrogen was replaced under vacuum at room temperature, and the reaction solution was stirred under hydrogen for 36 hours. The excess residue was removed by celite filtration to give a filtrate, the solvent was removed by rotary evaporation, and the product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give 0.830g of a colorless oily product.
1 H NMR(400MHz，CDCl 3 )δ4.17(dq，J＝14.2，7.1Hz，4H)，3.55(t，J＝6.5Hz，2H)，2.63(ddd，J＝9.0，8.3，2.4Hz，2H)，2.52-2.38(m，1H)，2.25-2.14(m，2H)，1.66(dd，J＝13.8，6.7Hz，2H)，1.22(td，J＝7.1，5.8Hz，6H).MS(m/z)：267.0[M+Na] +
(3) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-ethylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000252
1,2,3,4, 6-O-pentaacetyl-D-glucose (1.84 g) was added to a dichloromethane (20 ml) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxyethyl-cyclobutane (1.15 g) at room temperature, cooled to 0 ℃, the atmosphere in the flask was replaced with nitrogen, and a boron trifluoride ether solution (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.71g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.18(t，J＝9.5Hz，1H)，5.07(t，J＝9.7Hz，1H)，4.99-4.92(m，1H)，4.45(d，J＝8.0Hz，1H)，4.30-4.08(m，6H)，3.82(dt，J＝9.8，6.0Hz，1H)，3.67(ddd，J＝9.7，4.5，2.3Hz，1H)，3.40(dt，J＝9.5，6.7Hz，1H)，2.65-2.55(m，2H)，2.41(dt，J＝16.2，8.1Hz，1H)，2.20(dd，J＝11.2，6.3Hz，2H)，2.08(s，3H)，2.05(s，3H)，2.01(s，3H)，1.99(s，3H)，1.68(pd，J＝13.6，6.6Hz，2H)，1.24(td，J＝7.1，5.3Hz，6H).
MS(m/z)：597.2[M+Na] +
(4) Preparation of 1, 1-dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000253
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-ethylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane (1.15 g), and the temperature was raised and stirred at 90 ℃ for 8h. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 1.0g of a white solid.
(5) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-ethylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000261
1, 1-dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.52g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.76(s，1H)，3.89-3.77(m，3H)，3.68(dd，J＝11.7，5.1Hz，2H)，3.57(d，J＝8.5Hz，2H)，3.50-3.42(m，1H)，3.24(d，J＝12.1Hz，1H)，3.02(s，1H)，2.50-2.34(m，4H)，2.31-2.23(m，1H)，1.89(d，J＝7.8Hz，2H)，1.70(d，J＝5.3Hz，2H)，1.43(s，2H)，0.98(d，J＝8.0Hz，4H).
Example 8: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-ethylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000262
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-ethylene- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] cyclobutane
Figure BDA0001982753640000263
1,2,3,4, 6-O-Pentaacetyl-D-mannose (1.84 g) was added to a dichloromethane (20 ml) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxyethyl-cyclobutane (1.15 g) at room temperature, cooled to 0 ℃, the atmosphere in the flask was replaced with nitrogen, and a boron trifluoride ether solution (98%, 1.19 ml) was slowly dropped under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.39g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.31-5.24(m，2H)，5.20(dd，J＝3.1，1.8Hz，1H)，4.76(d，J＝1.4Hz，1H)，4.31-4.14(m，5H)，4.08(dd，J＝12.2，2.3Hz，1H)，3.97-3.89(m，1H)，3.62(dt，J＝9.7，6.6Hz，1H)，3.38(dt，J＝9.7，6.4Hz，1H)，2.73-2.59(m，2H)，2.45(dt，J＝16.1，8.1Hz，1H)，2.28-2.18(m，2H)，2.14(s，3H)，2.09(s，3H)，2.04(s，3H)，1.98(s，3H)，1.74(ddd，J＝13.8，8.5，5.2Hz，2H)，1.25(q，J＝7.0Hz，6H).
MS(m/z)：597.2[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] -cyclobutane
Figure BDA0001982753640000271
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-ethylene- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] -cyclobutane (1.15 g), and the temperature was raised and stirred at 90 ℃ for 8 hours. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 0.98g of a white solid.
(3) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-ethylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000272
1, 1-dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] -cyclobutane (0.95 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.50g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.83(s，1H)，3.97-3.85(m，2H)，3.82(d，J＝6.5Hz，1H)，3.73(dd，J＝19.4，8.5Hz，2H)，3.63(d，J＝7.1Hz，2H)，3.53(dd，J＝10.1，5.4Hz，1H)，3.19(d，J＝8.0Hz，1H)，3.07(t，J＝9.5Hz，1H)，2.57-2.41(m，2H)，2.34(dd，J＝17.6，8.5Hz，3H)，2.00(d，J＝11.5Hz，2H)，1.79-1.64(m，2H)，1.54(d，J＝7.2Hz，2H)，1.25(s，2H)，1.11(d，J＝10.1Hz，2H).
Example 9: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-ethylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000273
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-ethylene- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000274
1,2,3,4, 6-O-Pentaacetyl-D-galactose (1.84 g) was added to a solution of 1, 1-dicarboxylic acid ethyl ester-3-hydroxyethyl-cyclobutane (1.15 g) in dichloromethane (20 ml) at room temperature, cooled to 0 ℃ and the atmosphere in the flask was replaced with nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 1.54g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.34(d，J＝3.0Hz，1H)，5.14(dd，J＝10.4，8.0Hz，1H)，4.97(dd，J＝10.5，3.4Hz，1H)，4.39(d，J＝7.9Hz，1H)，4.21-4.07(m，6H)，3.93-3.73(m，2H)，3.47-3.31(m，1H)，2.64-2.52(m，2H)，2.40(dt，J＝16.1，8.1Hz，1H)，2.17(dd，J＝11.6，9.3Hz，2H)，2.11(s，3H)，2.04(s，3H)，2.01(s，3H)，1.94(s，3H)，1.68(ddd，J＝19.7，13.7，6.5Hz，2H)，1.21(dd，J＝12.6，7.0Hz，6H).MS(m/z)：597.2[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000281
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, and then slowly added to an aqueous solution (7 ml) containing the 1, 1-dicarboxylic acid ethyl ester-3-ethylene- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane compound (1.15 g) obtained in step (1), and stirred at elevated temperature at 90 ℃ for 8 hours. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 1.0g of a white solid.
(3) Cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-ethylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000282
1, 1-Dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (0.95 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH.approx.8 with a saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and separated by semi-preparative high pressure liquid chromatography to give 0.54g of the final product.
1 H NMR(600MHz，D 2 O)δ5.93-5.63(m，2H)，5.02(d，J＝8.1Hz，2H)，，4.36(d，J＝7.7Hz，1H)，3.89(s，2H)，3.74(dt，J＝22.3，11.2Hz，2H)，3.67-3.58(m，3H)，3.47(t，J＝8.7Hz，1H)，3.16-3.03(m，2H)，2.40(dd，J＝21.1，10.3Hz，3H)，2.28-2.17(m，1H)，1.98(d，J＝10.8Hz，2H)，1.50(dd，J＝45.9，22.0Hz，5H)，1.19(s，2H)，1.06(s，2H).
Example 10: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-propylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000283
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-benzyloxypropyl-cyclobutane
Figure BDA0001982753640000291
Sodium hydride (60%) (1.01 g) as a solid was slowly added to a DMF (10 ml) solution containing diethyl malonate (2.02 g) under cooling in an ice bath, and the mixture solution was stirred at room temperature for 30 minutes. Then, a DMF (15 ml) solution containing ((4-bromo-3- (methyl) butoxy) methyl) benzene (2.21 g) was further added to the reaction solution at room temperature, and the reaction solution was stirred at 80 ℃ for 12 hours. The solvent was removed by rotary evaporation. To the reaction solution was added 100ml of ethyl acetate, which was then washed with a saturated aqueous solution of ammonium chloride (1X 50 ml), the aqueous phase was extracted with ethyl acetate (2X 25 ml), and the organic phases were combined. The organic phase was washed successively with a saturated aqueous solution of ammonium chloride (1 × 100 ml), distilled water (1 × 100 ml), and a saturated aqueous solution of sodium chloride (1 × 100 ml), followed by drying over anhydrous sodium sulfate, and the solvent was evaporated to dryness with a rotary evaporator to obtain a pale yellow oil, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to obtain 1.74g of a colorless oily product.
1 H NMR(400MHz，CDCl 3 )δ7.38-7.26(m，5H)，4.48(s，2H)，4.19(dd，J＝14.4，7.2Hz，4H)，3.43(t，J＝6.1Hz，2H)，2.67-2.54(m，2H)，2.34(dt，J＝16.0，7.9Hz，1H)，2.22-2.12(m，2H)，1.62-1.40(m，4H)，1.24(dd，J＝13.4，7.0Hz，6H).
(2) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-hydroxypropyl-cyclobutane
Figure BDA0001982753640000292
Palladium on carbon (0.11 g) was added to a methanol solution containing the reaction product (1.26 g) of the above step, and hydrogen was replaced under vacuum at room temperature, followed by stirring the reaction solution under hydrogen conditions for 36 hours. The excess residue was removed by celite filtration to obtain a filtrate, the solvent was removed by rotary evaporation, and the resulting pale yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain 0.868g of a colorless oily product.
1 H NMR(400MHz，CDCl 3 )δ4.17(dq，J＝14.2，7.1Hz，4H)，3.61-3.53(m，2H)，2.67-2.51(m，2H)，2.39-2.25(m，1H)，2.20-2.05(m，2H)，1.70(s，1H)，1.45(dd，J＝6.6，3.1Hz，4H)，1.22(dd，J＝13.2，7.1Hz，6H).MS(m/z)：281.0[M+Na] +
(3) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-propylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000293
1,2,3,4, 6-O-Pentaacetyl-D-glucose (1.84 g) was added to a solution of 1, 1-dicarboxylic acid ethyl ester-3-hydroxypropyl-cyclobutane (1.22 g) in dichloromethane (20 ml) at room temperature, cooled to 0 ℃ and the flask was purged with nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.72g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.19(t，J＝9.5Hz，1H)，5.08(t，J＝9.7Hz，1H)，4.97(dd，J＝9.5，8.1Hz，1H)，4.48(t，J＝8.0Hz，1H)，4.30-4.09(m，6H)，3.83(dd，J＝9.8，6.1Hz，1H)，3.68(ddd，J＝9.8，4.6，2.4Hz，1H)，3.48-3.37(m，1H)，2.67-2.55(m，2H)，2.31(dt，J＝15.1，7.5Hz，1H)，2.16(dd，J＝10.0，8.0Hz，2H)，2.08(s，3H)，2.04(s，3H)，2.02(s，3H)，2.00(s，3H)，1.45(dt，J＝17.6，9.7Hz，4H)，1.27-1.21(m，6H).
MS(m/z)：611.2[M+Na] +
(4) Preparation of 1, 1-dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] cyclobutane
Figure BDA0001982753640000301
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-propylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane (1.18 g), and the temperature was raised and stirred at 90 ℃ for 8h. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 1.0g of a white solid.
(5) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-propylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000302
1, 1-Dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH 8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.52g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ5.71(s，1H)，5.05(s，1H)，4.91(d，J＝3.5Hz，1H)，4.37(d，J＝7.9Hz，1H)，3.98-3.85(m，2H)，3.85-3.69(m，2H)，3.64(ddd，J＝13.2，8.7，3.8Hz，2H)，3.52-3.42(m，1H)，3.15-3.01(m，2H)，2.38(dd，J＝23.2，10.4Hz，4H)，2.22(dt，J＝15.8，7.8Hz，1H)，2.00(d，J＝12.0Hz，2H)，1.56(dd，J＝15.6，7.9Hz，4H)，1.46(dd，J＝14.7，7.1Hz，2H)，1.25(d，J＝8.9Hz，2H)，1.12(dd，J＝19.5，8.9Hz，2H).
Example 11: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-propylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000303
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-propylene- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] cyclobutane
Figure BDA0001982753640000304
1,2,3,4, 6-O-Pentaacetyl-D-mannose (1.84 g) was added to a dichloromethane (20 mL) solution containing 1, 1-dicarboxylic acid ethyl ester-3-hydroxypropyl-cyclobutane (1.22 g) at room temperature, cooled to 0 ℃, the atmosphere in the flask was replaced with nitrogen, and a boron trifluoride ether solution (98%, 1.19 mL) was slowly dropped under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.41g of a crude product.
1 H NMR(400MHz，CDCl 3 )δ5.36-5.21(m，3H)，4.79(s，1H)，4.33-4.07(m，6H)，4.02-3.92(m，1H)，3.65(d，J＝9.3Hz，1H)，3.49-3.36(m，1H)，2.72-2.58(m，2H)，2.41-2.30(m，1H)，2.16(s，5H)，2.11(s，3H)，2.05(s，3H)，1.99(s，3H)，1.57-1.44(m，4H)，1.28-1.24(m，6H).MS(m/z)：611.2[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane
Figure BDA0001982753640000311
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-propylene- [ 2,3,4, 6-O-acetyl-1-O-D-mannoside ] cyclobutane (1.18 g), and the temperature was raised and stirred at 90 ℃ for 8 hours. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 1.0g of a white solid.
(3) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-propylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000312
1, 1-Dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.50g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.35(d，J＝7.9Hz，1H)，3.83(dd，J＝8.1，4.2Hz，2H)，3.65-3.60(m，2H)，3.42-3.34(m，3H)，3.16(t，J＝8.6Hz，1H)，3.06(dd，J＝18.6，9.3Hz，2H)，2.49-2.22(m，5H)，1.91(d，J＝10.7Hz，2H)，1.67(d，J＝6.6Hz，2H)，1.45(d，J＝6.1Hz，2H)，1.12(s，2H)，1.00(d，J＝9.1Hz，2H).
Example 12: cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 1, 1-dicarboxylic acid-3-propylene- (1-O-D-galactoside) cyclobutane ]
Figure BDA0001982753640000313
(1) Preparation of 1, 1-dicarboxylic acid ethyl ester-3-propylene- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000321
1,2,3,4, 6-O-Pentaacetyl-D-galactose (1.84 g) was added to a solution of 1, 1-dicarboxylic acid ethyl ester-3-hydroxypropyl-cyclobutane (1.22 g) in dichloromethane (20 ml) at room temperature, cooled to 0 ℃ and the atmosphere in the flask was replaced with nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under nitrogen. The reaction was stirred at 0 ℃ for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction product was subjected to simple purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 1.57g of a crude product.
1 H NMR(400MHz，CDCl 3 )65.42-5.30(m，1H)，5.18(d，J＝7.9Hz，1H)，5.01(dd，J＝9.9，2.9Hz，1H)，4.44(d，J＝7.2Hz，1H)，4.27-4.04(m，6H)，3.87(dt，J＝10.7，6.0Hz，2H)，3.43(s，1H)，2.70-2.53(m，2H)，2.36-2.26(m，1H)，2.15(s，6H)，2.05(s，5H)，1.99(s，3H)，1.56-1.38(m，4H)，1.27-1.20(m，6H).MS(m/z)：611.2[M+Na] +
(2) Preparation of 1, 1-dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane
Figure BDA0001982753640000322
NaOH (0.72 g) was dissolved in 15ml of water at room temperature, which was then slowly added to an aqueous solution (7 ml) containing 1, 1-dicarboxylic acid ethyl ester-3-propylene- [ 2,3,4, 6-O-acetyl-1-O-D-galactoside ] cyclobutane (1.18 g), and stirred at 90 ℃ for 8h while elevating the temperature. After the reaction solution was cooled, an aqueous solution (10 ml) of the desired acid was obtained by passing through a strongly acidic cation exchange resin, and freeze-dried to obtain 1.0g of a white solid.
(3) Preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-propylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000323
1, 1-Dicarboxylic acid 3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum cyclohexanediaminesulfate (0.82 g) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.55g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ5.62(s，1H)，4.96(s，1H)，4.34(d，J＝8.0Hz，1H)，3.87-3.49(m，4H)，3.46-3.25(m，3H)，3.14(t，J＝8.6Hz，1H)，3.05-2.94(m，2H)，2.29(dd，J＝22.7，10.1Hz，4H)，2.13(dt，J＝15.6，7.9Hz，1H)，1.91(d，J＝12.1Hz，2H)，1.47(t，J＝11.3Hz，4H)，1.40-1.29(m，2H)，1.22-1.10(m，2H)，1.02(d，J＝9.7Hz，2H).
Example 13: preparation of diamidoplatinum (II) [ 1, 1-dicarboxylic acid-3- (1-O-D-glucoside) cyclobutane ]
Figure BDA0001982753640000331
1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (0.9 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. About.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.41g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(600MHz，D 2 O)δ4.40(d，J＝8.0Hz，1H)，4.37-4.29(m，1H)，4.14(brs，6H)，3.84(d，J＝12.1Hz，1H)，3.65(dd，J＝12.5，5.9Hz，1H)，3.43-3.25(m，5H)，3.19(t，J＝8.7Hz，1H)，2.79-2.70(m，1H)，2.70-2.61(m，1H).
Example 14: preparation of diamidoplatinum (II) [ 3- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000332
1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] -cyclobutane (0.9 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.42g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(600MHz，D 2 O)δ4.37-4.31(m，2H)，4.16(s，6H)，3.85(d，J＝3.2Hz，1H)，3.69(m，1H)，3.46-3.24(m，6H)，2.76(dd，J＝12.1，7.4Hz，1H)，2.66(dd，J＝11.9，7.3Hz，1H).
Example 15: preparation of diaminoplatinum (II) [ 3- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000333
1, 1-dicarboxylic acid-3- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (0.9 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.44g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1H NMR(400MHz，D 2 O)δ4.91(d，J＝13.8Hz，1H)，3.96-3.60(m，6H)，3.45-3.25(m，2H)，2.91-2.57(m，2H).
Example 16: preparation of diaminoplatinum (II) [ 3-methylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000334
1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (0.93 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.41g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.83(d，J＝3.7Hz，0.4H)，4.37(d，J＝8.0Hz，0.6H)，4.11(s，5H)，3.87-3.74(m，2H)，3.71-3.55(m，3H)，3.49-3.29(m，3H)，3.23-3.16(m，2H)，2.68-2.41(m，3H).
Example 17: preparation of diamidoplatinum (II) [ 3-methylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000341
1, 1-dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] -cyclobutane (0.93 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.40g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.71(d，J＝1.4Hz，1H)，4.04(s，5H)，3.83-3.46(m，7H)，3.35(dd，J＝9.9，5.7Hz，1H)，2.99-2.83(m，2H)，2.61-2.32(m，3H).
Example 18: preparation of diaminoplatinum (II) [ 3-methylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000342
1, 1-Dicarboxylic acid-3-methylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (0.93 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Approx.8 with a saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.40g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(600MHz，D 2 O)δ4.87(d，J＝3.2Hz，0.4H)，4.32(d，J＝7.9Hz，0.6H)，4.15(s，5H)，3.92-3.56(m，7H)，3.44(t，J＝8.9Hz，1H)，3.01(s，2H)，2.59(dd，J＝24.8，12.1Hz，2H)，2.50(dd，J＝14.8，7.3Hz，1H).
Example 19: preparation of diaminoplatinum (II) [ 3-ethylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000343
1, 1-dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH 8 with a saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.44g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.34(d，J＝8.0Hz，1H)，4.09(s，5H)，3.87-3.71(m，2H)，3.66-3.52(m，2H)，3.46-3.31(m，2H)，3.31-3.22(m，1H)，3.15(dd，J＝9.1，8.2Hz，1H)，3.11-2.96(m，2H)，2.49-2.33(m，2H)，2.26(dd，J＝16.2，7.8Hz，1H)，1.65(dd，J＝13.7，6.7Hz，2H).
Example 20: preparation of diaminoplatinum (II) [ 3-ethylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000351
1, 1-Dicarboxylic acid-3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane (0.95 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH.approx.8 with a saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.41g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.86(s，1H)，3.99-3.86(m，2H)，3.86-3.70(m，3H)，3.69-3.59(m，2H)，3.54(d，J＝4.1Hz，1H)，3.23-3.05(m，2H)，2.50(dd，J＝21.3，12.1Hz，2H)，2.41-2.29(m，1H)，1.85-1.64(m，2H).
Example 21: preparation of diaminoplatinum (II) [ 3-ethylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000352
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1, 1-Dicarboxylic acid 3-ethylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (0.95 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.40g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.91(d，J＝3.6Hz，1H)，3.97(d，J＝2.7Hz，1H)，3.91(t，J＝6.1Hz，1H)，3.82(ddd，J＝21.5，10.3，3.4Hz，2H)，3.71(dd，J＝19.2，6.6Hz，3H)，3.54-3.44(m，1H)，3.17-3.05(m，2H)，2.48(dt，J＝12.2，7.8Hz，2H)，2.34(dt，J＝16.1，8.0Hz，1H)，1.84-1.65(m，2H).
Example 22: preparation of diaminoplatinum (II) [ 3-propylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000353
1, 1-Dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-glucoside ] -cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.46g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.81(d，J＝3.5Hz，0.6H)，4.36(d，J＝7.9Hz，0.4H)，4.09(s，5H)，3.85-3.52(m，5H)，3.47-3.26(m，3H)，3.01(dd，J＝11.4，8.8Hz，2H)，2.40-2.24(m，2H)，2.14(dt，J＝15.8，7.9Hz，1H)，1.62-1.27(m，4H).
Example 23: preparation of diaminoplatinum (II) [ 3-propylene- (1-O-D-mannoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000361
1, 1-Dicarboxylic acid-3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-mannoside ] cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.40g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.88(s，1H)，3.99-3.86(m，2H)，3.74(dd，J＝23.3，12.7Hz，3H)，3.70-3.61(m，2H)，3.56(d，J＝4.7Hz，1H)，3.12(t，J＝9.4Hz，2H)，2.51-2.34(m，2H)，2.32-2.18(m，1H)，1.54(dd，J＝32.5，5.6Hz，4H).
Example 24: preparation of diaminoplatinum (II) [ 3-propylene- (1-O-D-galactoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000362
1, 1-Dicarboxylic acid 3-propylene- [ 2,3,4, 6-tetrahydroxy-1-O-D-galactoside ] cyclobutane (1.0 g) was dissolved in 20mL of water, and the pH of the solution was adjusted to pH. Apprxeq.8 with saturated barium hydroxide solution. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing diamineplatinum sulfate (0.65 g) was added to the reaction solution obtained above under a nitrogen blanket, and the mixture was stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, the supernatant was collected, lyophilized using a lyophilizer, and 0.43g of the final product was obtained by semi-preparative high pressure liquid chromatography.
1 H NMR(400MHz，D 2 O)δ4.78(d，J＝3.4Hz，0.8H)，4.23(d，J＝7.9Hz，0.2H)，3.83-3.46(m，7H)，3.44-3.29(m，1H)，3.03-2.87(m，2H)，2.32-2.20(m，2H)，2.15-2.00(m，1H)，1.51-1.18(m，4H).
Example 25: preparation of diaminoplatinum (II) [ 3-hexylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
Figure BDA0001982753640000363
Figure BDA0001982753640000371
(1) Preparation of 6-benzyloxy-1-hexanol
1, 6-hexanediol (2.36 g) was dissolved in 60mL of dry N, N-dimethylformamide, 60% sodium hydride (920 mg) was slowly added to the reaction mixture in portions at 0 ℃, after stirring for 30 minutes, benzyl bromide (2.38 mL) was slowly added, and the reaction mixture was slowly warmed to room temperature and stirred overnight. The end of the reaction was monitored by TLC, after completion of the reaction, excess solvent was removed by rotary evaporation under reduced pressure, 100mL of ethyl acetate was added to the residue, which was then washed with saturated aqueous ammonium chloride (1 × 50 mL), the aqueous phase was extracted with ethyl acetate (100 mL), the two organic phases were combined and successively purified with saturated aqueous ammonium chloride (1 × 100 mL), distilled water (1 × 100 mL), saturated sodium chloride solution (1 × 100 mL), which was then dried over anhydrous sodium sulfate, the solvent was evaporated to dryness with a rotary evaporator, and the resulting pale yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give 1.8g of a colorless transparent oily product.
(2) Preparation of benzyl-6-bromohexyl ether
6-benzyloxy-1-hexanol (1.5 g) was dissolved in 20mL of dry dichloromethane, the reaction solution was cooled to 0 ℃, a dichloromethane solution (10 mL) of carbon tetrabromide (3.5 g) was slowly added dropwise, then a dichloromethane solution (10 mL) of triphenyl phosphorus (2.8 g) was slowly added, the reaction solution was stirred at 0 ℃ for 1 hour, the end point of the reaction was monitored by TLC, after the completion of the reaction, the excess solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain 1.7g of a colorless transparent oily product.
(3) Preparation of diethyl 2- (6-benzyloxyhexyl) malonate
60% sodium hydride (222 mg) was suspended in 5mL of a dry tetrahydrofuran solution in an ice-water bath, the air in the flask was replaced with nitrogen, diethyl malonate (1.3 mL) was slowly added dropwise under nitrogen protection, the reaction was stirred in an ice-water bath for 0.5 hour, then a dry tetrahydrofuran solution (2 mL) of benzyl-6-bromohexylether (1.5 g) was slowly added dropwise to the reaction solution, and then the reaction solution was heated to 70 ℃ and stirred for 5 hours. The end of the reaction was monitored by TLC, after completion of the reaction, the reaction was cooled to room temperature, 100mL of ethyl acetate was added to the reaction solution, followed by washing with a saturated aqueous ammonium chloride solution (1 × 50 mL), the aqueous phase was extracted with ethyl acetate (2 × 50 mL), the two organic phases were combined, the organic phase was successively washed with a saturated aqueous ammonium chloride solution (1 × 100 mL), distilled water (1 × 100 mL), a saturated sodium chloride solution (1 × 100 mL), followed by drying with anhydrous sodium sulfate, the solvent was evaporated to dryness with a rotary evaporator, and the resulting pale yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to give 1.5g of a colorless transparent oily product.
(4) Preparation of 2- (6-benzyloxyhexyl) -1, 3-propanediol
Lithium aluminum hydride (282 mg) is suspended in 15mL of anhydrous ether in an ice-water bath, a solution (10 mL) of diethyl 2- (6-benzyloxyhexyl) malonate (1.3 g) in anhydrous ether is slowly added dropwise under the protection of nitrogen, the reaction endpoint is monitored by TLC, sodium sulfate decahydrate is slowly added into the reaction liquid until no gas is generated in the reaction liquid after the reaction is completed, the solid is filtered, the filtrate is collected, the solvent is evaporated by a rotary evaporator to dryness, and the obtained light yellow oily substance is purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain 0.8g of a colorless transparent oily product.
(5) Preparation of 6-benzyloxyhexyl-1, 3-dibromopropane
2- (6-benzyloxyhexyl) -1, 3-propanediol (0.6 g) was dissolved in 8mL of dry dichloromethane, the reaction solution was cooled to 0 ℃ and a solution of carbon tetrabromide (2.2 g) in dichloromethane (4 mL) was slowly added dropwise, then a solution of triphenylphosphine (1.8 g) in dichloromethane (4 mL) was slowly added thereto, the reaction was carried out at 0 ℃ for 1 hour, the end point of the reaction was monitored by TLC, after the completion of the reaction, the excess solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain 0.8g of a colorless transparent oily product.
(6) Preparation of 1, 1-dicarboxylic acid diethyl ester-3-benzyloxyhexyl-cyclobutane
60% sodium hydride (142 mg) was suspended in 3mL of dry N, N-dimethylformamide under ice-water bath conditions, diethyl malonate (0.54 mL) was slowly added dropwise under nitrogen protection, after stirring for half an hour, a solution of 2-benzyloxyhexyl-1, 3-dibromopropane (0.7 g) in N, N-dimethylformamide (3 mL) was slowly added dropwise to the reaction solution, and then the reaction solution was heated to 70 ℃ and stirred for 7 hours. The end of the reaction was monitored by TLC, after completion of the reaction, the reaction was cooled to room temperature, 100mL of ethyl acetate was added to the reaction solution, which was then washed with a saturated aqueous solution of ammonium chloride (1 × 50 mL), the aqueous phase was extracted with ethyl acetate (2 × 50 mL), the two organic phases were combined and successively purified with a saturated aqueous solution of ammonium chloride (1 × 100 mL), distilled water (1 × 100 mL), a saturated solution of sodium chloride (1 × 100 mL), which was then dried over anhydrous sodium sulfate, the solvent was evaporated to dryness with a rotary evaporator, and the resulting pale yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to give 0.5g of a colorless transparent oily product.
(7) Preparation of 1, 1-dicarboxylic acid diethyl ester-3-hydroxyhexyl-cyclobutane
Diethyl 3-benzyloxyhexyl-cyclobutane-1, 1-dicarboxylate (0.4 g) was dissolved in 10mL of methanol, 10% palladium on carbon (0.1 g) was added, the air in the reaction flask was replaced with nitrogen gas 3 times, then the nitrogen gas in the reaction flask was replaced with hydrogen gas 3 times, and the reaction mixture was stirred at room temperature overnight. Monitoring the reaction end point by TLC, after the reaction is finished, replacing hydrogen in the reaction bottle with nitrogen, filtering palladium carbon, collecting filtrate, and evaporating the solvent to dryness by using a rotary evaporator to obtain 0.3g of a colorless transparent oily product.
(8) Preparation of 1, 1-dicarboxylic acid diethyl ester 3-hexylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] cyclobutane
Diethyl 3-hydroxyhexyl-cyclobutane-1, 1-dicarboxylate (200 mg) and 1,2,3,4, 6-pentaacetyl- β -D-glucopyranosate (286 mg) were dissolved in 5mL of dry dichloromethane, the reaction was cooled to 0 ℃ and then a solution of boron trifluoride in diethyl ether (1 mL) was slowly added dropwise, the reaction was slowly warmed from 0 ℃ to room temperature and stirred overnight. The end of the reaction was monitored by TLC, after completion of the reaction, dichloromethane (100 mL) was added to the reaction solution, and the organic phase was washed successively with distilled water (1 × 100 mL), saturated sodium bicarbonate solution (1 × 100 mL), then dried with anhydrous sodium sulfate, the solvent was evaporated to dryness with a rotary evaporator, and the resulting pale yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 60mg of the product as a colorless transparent oil.
(9) Preparation of 1, 1-dicarboxylic acid-3-hexylene- [ 1-O-D-glucoside ] cyclobutane
1, 1-diethyl phthalate 3-hexylene- [ 2,3,4, 6-O-acetyl-1-O-D-glucoside ] (60 mg) is dissolved in 1mL of methanol, then an aqueous solution (2 mL) of sodium hydroxide (34 mg) is added, the reaction solution is heated to 90 ℃ for 5 hours of reaction, the TLC is used for monitoring the reaction endpoint, after the reaction is completed, the reaction solution is cooled to room temperature, a rotary evaporator is used for removing the methanol, then strong acid cation exchange resin is added into the reaction solution and stirred for half an hour, the resin is filtered, the filtrate is collected and dried by a freeze dryer, 35mg of colorless viscous liquid is obtained, and the crude product is directly used for the next reaction.
(10) Preparation of diaminoplatinum (II) [ 3-hexylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
1, 1-dicarboxylic acid-3-hexylene- [ 1-O-D-glucoside ] cyclobutane crude product (35 mg) was dissolved in 2mL of water, and then an aqueous solution of sodium hydroxide was added to adjust the pH of the reaction mixture to 7, followed by stirring at room temperature in the dark for 30min. Diamineplatinum nitrate (30 mg) was dissolved in 1mL of water under nitrogen protection, and the resulting solution was added dropwise to the reaction solution, followed by stirring at room temperature in the dark for 1 hour. Detecting the reaction by HPLC, after the reaction is completed, removing the precipitate by using a centrifuge, collecting the supernatant, separating and purifying by using semi-preparative high pressure liquid chromatography, and drying by using a low temperature freeze dryer to obtain 20mg of a final product which is a white solid.
1 H NMR(400MHz，D 2 O)δ4.91(d，J＝3.7Hz，1H)，3.85(dd，J＝12.2，2.2Hz，1H)，3.79-3.66(m，4H)，3.56-3.51(m，2H)，3.39(dd，J＝21.2，11.2Hz，1H)，3.08(dd，J＝11.4，9.5Hz，2H)，2.40(dd，J＝11.6，9.6Hz，2H)，2.25-2.17(m，1H)，1.68-1.59(m，2H)，1.44-1.29(m，8H).
Example 26: preparation of cis- [ trans- (1R, 2R) -diaminocyclohexane ] platinum (II) [ 3-hexylene- (1-O-D-glucoside) cyclobutane-1, 1-dicarboxylic acid ]
2mL of 1, 1-dicarboxylic acid-3-hexamethylene- [ 1-O-D-glucoside ] cyclobutane (35 mg) prepared in example 25 was added to water, and then an aqueous solution of sodium hydroxide was added to adjust the pH of the reaction mixture to 7, followed by stirring at room temperature in the dark for 30min. 1mL of an aqueous solution containing platinum cyclohexanediaminesulfate (40 mg) was added dropwise to the reaction solution under nitrogen protection, and the mixture was stirred at room temperature for 1 hour in the dark. Detecting the reaction by HPLC, after the reaction is completed, removing the precipitate by using a centrifuge, collecting the supernatant, separating and purifying by using a semi-preparative high pressure liquid chromatography, and drying by using a low temperature freeze dryer to obtain 30mg of a final product, namely a white solid.
1 H NMR(400MHz，D 2 O)δ5.75(s，1H)，5.03(d，J＝9.7Hz，1H)，4.83(s，1H)，3.79-3.63(m，4H)，3.55-3.50(m，2H)，3.38(dd，J＝21.2，11.2Hz，1H)，3.07(dd，J＝11.4，9.5Hz，2H)，2.41(dd，JJ＝11.6，9.6Hz，2H)，2.25-2.15(m，1H)，1.68-1.59(m，2H)，1.44-1.29(m，8H).
Test example 1: solubility test
The experimental method comprises the following steps: approximately 0.5mL of distilled water was taken in a 5mL EP tube and the dried compound was slowly added until it could not dissolve (turbidity still appeared with 25 ℃ sonication). The solution was filtered into another 5mL clean and weighed EP tube, reweighed, and the weight of the solution calculated. The filtrate was lyophilized, weighed and the mass of solute of the remaining solid calculated, so that the weight of solvent and mass of solute were known and the solubility of the compound in water was calculated.
Table 2 solubility data in water for the samples of the examples
Figure BDA0001982753640000391
Figure BDA0001982753640000401
The solubility of the platinum complex in water is far greater than that of cisplatin, carboplatin and oxaliplatin on the market, and the water solubility can be improved by dozens to thousands of times.
Test example 2: antitumor effect
The following experiments were conducted to experimentally verify the proliferation inhibitory effect of the cyclobutane dicarboxylic acid platinum complex for tumor therapy of the present invention on different kinds of human tumor cells.
(1) The test method comprises the following steps:
cell culture solution:
cell culture medium containing 10% fetal bovine serum (total bovine serum) was used.
Main experimental apparatus:
HERACell150i type carbon dioxide incubator (Thermo), research grade inverted fluorescence microscope (Nikon, japan), multifunctional microplate reader (Thermo), ultra low temperature refrigerator (Thermo), biological safety cabinet (1300SeriesA2, thermo), micropipettor (eppendorf, germany), ultra pure water system (Milli-Q, USA).
Experimental reagent:
MTT: sigma-Aldrich Co
DMSO, DMSO: jiangtian chemical technology Limited of Tianjin
Tumor cells:
TABLE 3 MTT test cell List
Figure BDA0001982753640000402
Figure BDA0001982753640000411
Cytotoxicity test:
cytotoxicity experiments were tested using the MTT method. Tumor cells in log phase are collected, cell suspension concentration is adjusted, 100. Mu.l of cell suspension is added to each well, and the density of cells to be tested is adjusted to 1000-10000 cells/well by plating (the marginal wells are filled with sterile PBS). In 5% of CO 2 Incubating at 37 ℃ until cells adhere to the wall (96-hole flat bottom plate), adding drugs with different concentration gradients, and arranging 4 multiple wells in each 100-mountain hole. In 5% of CO 2 And incubating for 72 hours at 37 ℃ and observing under an inverted microscope. Adding reagent to 96-well plateThe prepared MTT solution (5 mg/ml) was mixed in 20. Mu.l per well, and the content of CO was determined at 37 ℃ by 5% 2 After incubation for 4h under these conditions, the plate contents were discarded, 150. Mu.l DMSO was added to each well, the microplate reader was shaken for 3 minutes, and the OD (optical density) was measured at 490 nm.
Control group:
under the same conditions as above, no active ingredient to be detected was added, and finally, the OD of the tumor cells at 490nm was measured.
Inhibitory Activity of drugs on tumor cells IC 50 ：
Calculating the cell inhibition rate: the inhibition rate of the drug on the growth of tumor cells is calculated according to the following formula:
1) Cell survival rate (%) = (treatment group OD value/control group OD value) × 100
2) The cell viability was determined for each drug concentration, and this was plotted against the drug concentration. Therefore, the drug effects of different drug concentrations on the tumor cell proliferation inhibition are judged.
3) The drug concentration corresponding to the cell survival rate of 50% of the control group is the half inhibitory concentration of the drug on tumor cells, namely the IC of the drug 50 The value is obtained.
The above experiment for each drug concentration was repeated for 4 groups, and the average OD value was taken to calculate the cell survival rate.
(2) The experimental results are as follows: (IC) 50 (test result value)
TABLE 4 MTT test results (I)
Figure BDA0001982753640000412
Figure BDA0001982753640000421
TABLE 5 MTT test results (two)
IC 50 Value of (. Mu.M) 11 12 13 14 15 16 17 18 19 20 Carboplatin
HT29 18.83 19.41 9.89 19.30 10.44 24.73 31.73 9.36 23.96 9.65 53.20
SMMC7721 4.95 4.70 1.76 5.23 2.23 4.96 8.04 2.17 4.13 2.23 12.03
MCF-7 84.56 85.36 47.05 97.64 40.16 85.26 152.47 44.70 78.81 47.31 282.81
A549 37.83 35.80 14.00 35.49 15.34 41.97 67.49 17.98 36.9 16.62 95.26
SKOV3 88.11 98.42 56.89 79.94 53.47 72.89 167.16 42.09 81.25 47.30 318.37
ECA109 12.54 10.05 4.56 12.58 5.15 10.99 20.21 4.66 10.34 5.36 26.88
DU145 65.67 56.22 26.13 63.15 19.18 60.43 90.00 17.11 58.89 21.61 135.10
Hela 11.34 10.56 6.17 16.34 6.46 12.22 24.56 5.68 15.43 6.28 34.13
A375 14.77 13.54 10.67 11.72 10.46 15.71 10.44 21.68 18.89 28.84 31.24
KB 10.11 15.00 5.73 15.27 5.65 14.16 27.33 5.59 17.23 5.54 33.51
HGC27 32.23 25.21 12.53 31.94 13.04 31.95 44.89 12.94 30.11 11.36 68.31
SW579 73.34 75.11 30.04 77.41 24.05 75.38 91.45 29.89 72.22 27.18 170.46
5637 13.44 11.78 5.53 12.99 5.42 13.21 19.09 5.07 9.67 5.18 27.90
Panc-1 78.55 70.22 40.42 92.12 42.48 75.98 122.23 41.45 76.78 40.55 213.94
H929 9.33 8.11 4.09 9.71 3.65 9.43 15.55 8.88 9.67 3.81 23.14
HepG2 10.99 12.55 5.81 13.89 5.70 12.50 19.90 4.75 11.91 5.36 29.70
THP-1 7.12 7.11 3.68 6.47 2.94 7.15 9.59 3.33 7.29 3.23 15.01
TABLE 6 MTT test results (III)
Figure BDA0001982753640000422
Figure BDA0001982753640000431
Note: "- -" represents no testing.
Test example 3 antitumor Effect of the Compound of the present invention and known Compound
The comparison document wO2008086783A2 discloses the following platinum complexes of cyclobutanedicarboxylic acid coupled in the 3-position of the sugar molecule: in order to verify that the antitumor effect of the complex is superior to that of the disclosed compound, the following efficacy comparison experiment is carried out:
Figure BDA0001982753640000432
(1) The test method comprises the following steps:
the test method is the same as the test method of the antitumor drug effect of the experimental example 2, and the compounds selected for comparison are the compounds (compound-1, 4, 7, 10, 13, 16, 19, 22 and 25) containing the same glucose molecular structure as the disclosed compounds and the compounds (compound-11, 20 and 23: mannose; compound-12, 15, 18 and 24: galactose) containing non-glucose molecular structure, and the antitumor drug effect of the disclosed compounds is compared to respectively obtain the half inhibitory concentration of the drug on tumor cells, namely the IC of the drug 50 The value is obtained.
(2) And (3) test results:
TABLE 7 MTT pharmacodynamic comparative test results
Figure BDA0001982753640000433
/>
Figure BDA0001982753640000441
Figure BDA0001982753640000451
The results show that: compared with the public compound, the anti-tumor effect of the compound in various tumor cells is obviously superior to that of the public compound.

Claims (21)

1. A cyclobutanedicarboxylic acid platinum complex represented by formula (I), or a pharmaceutically acceptable salt thereof:
Figure FDA0004019158580000011
wherein:
x and Y are ligands, each independently selected from NH 3 Or C 1 -C 8 A linear or branched primary alkyl amine;
or X, Y together are trans- (1R, 2R) -cyclohexanediamine, trans- (1S, 2S) -cyclohexanediamine, cis- (1R, 2S) -cyclohexanediamine, cis- (1S, 2R) -cyclohexanediamine, rac-trans-1, 2-cyclohexanediamine or rac-cis-1, 2-cyclohexanediamine;
n =0, 1,2,3,4, 5 or 6;
r is selected from the following monosaccharide groups, the 1-position substitution of monosaccharide is alpha substitution or beta substitution,
Figure FDA0004019158580000012
2. the cyclobutanedicarboxylic acid platinum complex of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that C is 1 -C 8 Straight-chain or branched primary alkyl amines C 1 -C 6 Linear or branched primary alkyl amines of (a).
3. The cyclobutanedicarboxylic acid platinum complex of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that C is 1 -C 8 Straight or branched primary alkyl amines C 1 -C 3 Linear or branched primary alkyl amines of (a).
4. The cyclobutanedicarboxylic acid platinum complex of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that n =0, 1,2,3 or 6.
5. The cyclobutanedicarboxylic acid platinum complex of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that n =0, 1,2 or 3.
6. The cyclobutanedicarboxylic acid platinum complex of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of X and Y is NH 3 (ii) a Or X, Y together are trans- (1R, 2R) -cyclohexanediamine.
7. The cyclobutanedicarboxylic acid platinum complex of claim 1, or a pharmaceutically acceptable salt thereof,
x and Y are respectively NH 3 (ii) a Or X, Y together are trans- (1R, 2R) -cyclohexanediamine;
n =0, 1,2,3 or 6;
r is selected from the following monosaccharide groups, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure FDA0004019158580000021
8. the cyclobutanedicarboxylic acid platinum complex of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, said formula (I) being selected from the group consisting of,
Figure FDA0004019158580000022
Figure FDA0004019158580000031
Figure FDA0004019158580000041
9. a compound of formula (III),
Figure FDA0004019158580000042
in the formula (III):
each M independently represents a hydrogen atom, or a metal atom of group IA of the periodic Table of the elements, or two M together represent a metal atom of group IIA of the periodic Table of the elements;
n =0, 1,2,3,4, 5 or 6;
r is the following monosaccharide group, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure FDA0004019158580000043
10. a compound of formula (III) according to claim 9, characterized in that M each independently represents H, na, K, li, cs or both M together represent Ba.
11. The compound of formula (III) according to claim 9, characterized in that n =0, 1,2,3 or 6.
12. A compound of formula (III) according to claim 9, characterized in that n =0, 1,2 or 3.
13. A compound of formula (III) according to claim 9, selected from the following compounds:
Figure FDA0004019158580000051
in the formula (III-1), the formula (III-2) and the formula (III-3),
n =0, 1,2,3 or 6;
m independently represents H, na, K, li, cs or two M together represent Ba.
14. A compound of formula (III) according to claim 9, characterized in that n =0, 1,2 or 3.
15. The process for producing a cyclobutanedicarboxylic acid platinum complex compound, or its pharmaceutically acceptable salt, according to any one of claims 1 to 8, characterized by comprising the step of reacting the compound of formula (II) with the compound of formula (III) with water to adjust the reaction mixture to an aqueous solution; adding alkali into the reaction water solution to adjust the pH value to 7-9,
the alkali is inorganic alkali, and the inorganic alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, cesium hydroxide or barium hydroxide;
the structural formula of the (II) is as follows:
Figure FDA0004019158580000052
in the formula (II):
x and Y are as defined for formula (I),
A 1 and A 2 Identical or different, each independently of the others, represents hydroxyl, nitrate or perchlorate, or A 1 And A 2 Together represent sulfate or carbonate;
the structural formula of the (III) is as follows:
Figure FDA0004019158580000053
in the formula (III):
each M independently represents a hydrogen atom, or a metal atom of group IA of the periodic Table of the elements, or two M together represent a metal atom of group IIA of the periodic Table of the elements;
n =0, 1,2,3,4, 5 or 6;
r is selected from the following monosaccharide groups, and the 1-position substitution of the monosaccharide is alpha substitution or beta substitution:
Figure FDA0004019158580000061
16. the method according to claim 15, wherein each M independently represents H, na, K, li, cs or both M together represent Ba.
17. The method of claim 15, wherein n =0, 1,2,3, or 6.
18. A pharmaceutical composition comprising one or more of the cyclobutanedicarboxylic acid platinum complexes of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
19. Use of the complex of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, in the preparation of an anti-neoplastic drug.
20. The use according to claim 19, characterized in that the tumor is human lung cancer, human liver cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymph cancer, human skin cancer, human pancreatic cancer, human bladder cancer, human esophageal cancer, human stomach cancer, human male genital cancer, human thyroid cancer, human bone cancer, human melanin cancer, or human oral cancer.
21. The use according to claim 20, characterized in that the cells of said tumor are human colon cancer cells HT29, human non-small cell lung cancer cells a549, human hepatoma cells SMMC7721, human breast cancer cells MCF-7, human ovarian cancer cells SKOV3, human esophageal cancer cells ECA109, human prostate cancer cells DU145, human cervical cancer cells Hela, human melanoma cells a375, human oral epidermoid cancer cells KB, human gastric cancer cells HGC27, human thyroid cancer cells SW579, human bladder cancer cells 563-7, human pancreatic cancer cells Panc-1, human large cell lung cancer cells H460, human plasma cell leukemia cells H929, human hepatoma cells HepG2, human monocytic leukemia THP-1.
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