WO2019165964A1 - 环丁烷二羧酸铂配合物、其中间体、其制备方法、药物组合物及用途 - Google Patents

环丁烷二羧酸铂配合物、其中间体、其制备方法、药物组合物及用途 Download PDF

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WO2019165964A1
WO2019165964A1 PCT/CN2019/076236 CN2019076236W WO2019165964A1 WO 2019165964 A1 WO2019165964 A1 WO 2019165964A1 CN 2019076236 W CN2019076236 W CN 2019076236W WO 2019165964 A1 WO2019165964 A1 WO 2019165964A1
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human
optionally
formula
cancer
group
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French (fr)
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高香倩
韩建斌
杨金娜
杨柳
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天津谷堆生物医药科技有限公司
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Priority to JP2020568584A priority Critical patent/JP2022517885A/ja
Priority to KR1020207025356A priority patent/KR102640022B1/ko
Publication of WO2019165964A1 publication Critical patent/WO2019165964A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Definitions

  • the present invention relates to a water-soluble platinum complex, an intermediate thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • Platinum anticancer drugs are a representative class of drugs in the field of cancer therapy. It belongs to the cell cycle non-specific drug and has therapeutic effects on sarcoma, malignant epithelial tumor, lymphoma and germ cell tumor.
  • representative platinum-based anticancer drugs widely used in clinical treatment in the world are: cisplatin, carboplatin and oxaliplatin.
  • the fatal shortcoming of platinum-based anticancer drugs is the extremely toxic side effects and the inherent and subsequent resistance problems.
  • all platinum-listed drugs generally have extremely low water solubility characteristics, and the water solubility of cisplatin, carboplatin and oxaliplatin are 1.0, 17.0, and 6.0 mg/ml, respectively.
  • the object of the present invention is to overcome the deficiencies in the prior art and to provide a cyclobutanedicarboxylic acid platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has good Water solubility as well as good anti-tumor activity.
  • the present invention provides a platinum complex of cyclobutanedicarboxylate represented by the formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
  • X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 straight or branched) Alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkyl group) An amine), a primary aromatic amine, one or more C 1 -C 4 linear or branched alkyl substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 The same or different each is represented by a linear or branched alkyl group of C 1 -C 8 (optionally a linear or branched alkyl group of C 1 -C 6 , optionally a linear or branched C 1 -C 3 ) Alkyl group; or R 1
  • D is C 0 or C 1 alkylene
  • B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
  • R is selected from the group consisting of a monosaccharide group substituted with an alpha substitution or a beta substitution:
  • R is selected from the group consisting of a monosaccharide group in which a 1-position substitution of a monosaccharide is an alpha substitution or a beta substitution,
  • the X and Y are respectively 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-ring Hexamethylenediamine.
  • the X and Y are each NH 3 ; or X, Y together are trans-(1R, 2R)-cyclohexanediamine.
  • n 0, 1, 2, 3 or 6;
  • R is selected from the group consisting of a monosaccharide group substituted with an alpha substitution or a beta substitution:
  • formula (I) is selected from the following complexes,
  • Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
  • R is selected from hydrogen, or a monosaccharide group as described below, and the 1-position substitution of the monosaccharide is an alpha substitution or a beta substitution:
  • formula (III) is selected from the group consisting of:
  • M each independently represents H, Na, K, Li, Cs or two M together to represent Ba.
  • the present invention provides a method for producing a cyclobutane dicarboxylic acid platinum complex, or an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, which comprises the compound of the formula (II) a step of reacting the compound of the formula (III) with water to adjust the reaction to an aqueous solution; optionally, the reaction solution is added with a base to adjust the pH to 7-9,
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide, barium hydroxide or barium hydroxide.
  • X and Y are ligands, each of which is independently selected from NH 3 , C 1 -C 8 linear or branched alkyl primary amines (optionally C 1 -C 6 straight or branched) Alkyl primary amine, optionally a C 1 -C 3 linear or branched alkyl primary amine), a C 3 -C 8 cyclic alkyl primary amine (optionally a C 3 -C 6 cyclic alkyl group) An amine), a primary aromatic amine, one or more C 1 -C 4 linear or branched alkyl substituted aromatic primary amines, a secondary amine of the formula R 1 -NH-R 2 wherein R 1 and R 2 The same or different each is represented by a linear or branched alkyl group of C 1 -C 8 (optionally a linear or branched alkyl group of C 1 -C 6 , optionally a linear or branched C 1 -C 3 ) Alkyl group; or R 1
  • D is C 0 or C 1 alkylene
  • B is C 2 -C 8 alkylene (optionally C 2 -C 6 alkylene, optionally C 3 -C 5 alkylene);
  • a 1 and A 2 are the same or different and each independently represents a hydroxyl group, a nitrate or a perchlorate, or A 1 and A 2 together represent a sulfate or a carbonate;
  • Each M independently represents a hydrogen atom, or a metal atom of Group IA of the periodic table, or two M atoms collectively represent a metal atom of Group IIA of the periodic table; optionally M independently represents H, Na, K , Li, Cs or two M together represent Ba;
  • R is selected from hydrogen, or R is selected from the group consisting of the following monosaccharide groups, and the monosaccharide 1-position substitution is an alpha substitution or a beta substitution:
  • the inorganic base concentration is from 0.1 N to 5 N, preferably 1 N.
  • the above reaction may be carried out in a relatively wide temperature range, for example, at a temperature ranging from 0 to 100 ° C to carry out the above reaction, preferably 25 to 90 ° C, more preferably 60 to 90 ° C, and simultaneously It is good with stirring.
  • the time required for the reaction depending on the target product may vary. Depending on the nature of the different reactants, it usually takes from 1 hour to 30 days to complete. In more cases, it takes 10 hours to 15 days.
  • the water used for the above reaction to adjust the reaction compound to an aqueous solution is preferably deionized water.
  • the reaction can be carried out by using a suitable inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide and hydrogen. Oxide or the like to adjust the pH of the aqueous solution to be maintained between 7 and 9 to complete the preparation of the complex represented by the formula (I); when M is a metal atom, for example, a sodium atom, a potassium atom, a lithium atom, a hafnium atom or The ruthenium atom can be smoothly carried out in an aqueous solution. If necessary, a small amount of an aqueous solution of the above inorganic base is used to maintain the pH of the reaction solution between 7 and 9 to complete the synthesis of the complex represented by the formula (I).
  • a suitable inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, lithium hydroxide and hydrogen.
  • Oxide or the like to adjust the pH of the aqueous solution to be
  • the reaction when M is a hydrogen atom, the reaction can be carried out by using an equivalent amount of cesium hydroxide as an inorganic base, and a condensation reaction with a metal platinum sulfate compound represented by the formula (II) is carried out in an aqueous solution to prepare a formula ( I) the complex shown.
  • a condensation reaction with a metal platinum sulfate compound represented by the formula (II) is carried out in an aqueous solution to prepare a formula ( I) the complex shown.
  • the complex of the present invention is prepared by the method B, it is also possible to use a previously prepared phosphonium salt, that is, two M together represent a deuterium atom, and the metal platinum sulfate complex represented by the formula (II) is reacted in an aqueous solution. The preparation process of the complex is completed.
  • the compounds represented by the formula (II) in the methods A and B may be a complex of X and Y (for example, cis-dichloro-(1,2-diaminocyclohexane) platinum by the corresponding cis-platinum dichloride.
  • X and Y for example, cis-dichloro-(1,2-diaminocyclohexane) platinum by the corresponding cis-platinum dichloride.
  • X and Y for example, cis-dichloro-(1,2-diaminocyclohexane) platinum by the corresponding cis-platinum dichloride.
  • Y for example, cis-dichloro-(1,2-diaminocyclohexane
  • the reaction is preferably carried out in an aqueous solution, and the water used is preferably 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 may be purified by a conventional method in the prior art.
  • the mixture after the completion of the reaction may be first removed by filtration to remove precipitates which may be formed. Then, it is concentrated by distillation under reduced pressure, and then an organic solvent is added (optionally, the organic solvent is preferably an organic solvent miscible with water, such as an alcohol (for example, methanol, ethanol, propanol, butanol, isopropanol).
  • the product (I) obtained by purifying and purifying the above reaction can also be subjected to a method such as chromatography, for example, using an ion exchange resin, or by preparative liquid chromatography. Liquid chromatography separation and purification are generally carried out using methanol and water as mobile phases.
  • the compound (III) of the present invention can be produced by any one of the methods C, D or the methods E and F which are given by the following reaction formula:
  • hydroxyl group-containing cyclobutanedicarboxylate derivative which reacts with a sugar by using a hydroxy-containing 1,3-dihalogenated alkane derivative and a malonic ester compound, for example Dimethyl malonate, diethyl malonate, diphenyl malonate, cycloalcooractate, etc. according to general methods known in the literature (for example: Molecules 2016, 21 (5), 612) To prepare.
  • the obtained hydroxycyclobutanedicarboxylate derivative and glucose can be subjected to a condensation reaction in a solvent in the presence of a Lewis acid to obtain a glucoside compound of a cyclobutanedicarboxylate.
  • the conditions of the condensation reaction are from 0.1 to 50 equivalents of the hydroxy-containing cyclobutanedicarboxylate for the glucose compound or 0.1 to 50 equivalents of glucose for the hydroxy-containing cyclobutanedicarboxylate.
  • the Lewis acid used may be BF 3 , SnCl 4 , FeCl 3 , AlCl 3 , hydrochloric acid, p-toluenesulfonic acid, camphorsulfonic acid or the like, and the amount of Lewis acid may be 0.1 to 10 equivalents relative to glucose.
  • the solvent to be 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 of the two reactants as a solvent.
  • the temperature of the reaction can be from 0 ° C to 100 ° C, and the reaction can generally be completed by heating at 60-80 ° C.
  • the time required for the reaction varies depending on the reactants, and can usually be completed in 1 hour to 7 days.
  • the obtained reaction product can be purified by a series of purification conditions, and generally, a silica gel chromatography method or a liquid chromatography column separation method can be used.
  • the obtained product can be finally subjected to the desired compound represented by the formula (III) by removing the protective group of malonic acid.
  • the method of deprotection varies depending on the protecting group used. If diphenylmethyl malonate is used, deprotection can be carried out by hydroreduction, if diethyl malonate or malonate is used.
  • the deprotection reaction can be carried out using an inorganic base in methanol-water or a THF-water solvent, and the ratio of the organic solvent to water is generally from 1:1 to 4:1.
  • the inorganic base to be used may be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide or the like.
  • the reaction temperature is usually room temperature, and the reaction time is usually from 1 to 24 hours.
  • the purification of the compound formed by deprotection can be carried out by silica gel chromatography or ion exchange resin filtration, or by liquid chromatography. If the reaction solvent is directly removed by distillation, the resulting product will be the corresponding metal carboxylate. Acid salt.
  • the preparation methods shown in the methods C and D are carried out using an acetyl-protected sugar, or directly using an unprotected sugar and a hydroxy-containing cyclobutanedicarboxylate derivative in the presence of a Lewis acid, followed by deprotection to obtain a target product (III). Preparation route.
  • the preparation methods shown in the methods E and F are first to form a hydroxy-1,3-1,3-haloalkane derivative with an acetyl-protected or unprotected sugar to form a glycoside derivative, and then condense with the malonate to form a cyclobutane II.
  • the carboxylic acid ester is finally subjected to removal of the protecting group to obtain a preparation route of the target product (III).
  • glucose can be first converted to the corresponding acetylated glucose, followed by a condensation reaction with the corresponding hydroxyl-containing intermediate.
  • the acetylation of glucose can be carried out according to methods reported in the literature, for example, using pyridine in pyridine.
  • the anhydride is completed as an acetylating agent by heating at room temperature or at 60 ° C for 1 to 24 hours.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the above complexes, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and optionally A pharmaceutically acceptable carrier is present.
  • the tumor cells are 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 gastric cancer, human male genital cancer, human thyroid cancer, human bone cancer, human melanoma, or human oral cancer.
  • the tumor cells are human colon cancer cell line 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 line Hela, human melanoma cell line A375, human oral epidermoid carcinoma cell line KB, human gastric cancer cell line HGC27, human thyroid cancer cell line SW579, human bladder cancer cell line 5637, human pancreatic cancer cell line 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 antitumor agent of the present invention is not particularly limited in its administration route, and its dose depends not only on the age, weight and condition of the patient but also on the type, nature and severity of the tumor. In general, however, it is preferred for adult patients to use between 10 mg and 1 gram of the compound per day. It is usually administered once or three times a week or several times.
  • the compounds provided by the present invention have good antitumor activity.
  • the complex provided by the invention has an increase in water solubility compared with the existing platinum antitumor drugs, and the high water solubility characteristic can increase the excretion of the drug in the kidney and reduce the drug in the body.
  • the savings can alleviate the high renal toxicity side effects of platinum drugs, and make these compounds easy to formulate, improve the stability of the preparation, and are more convenient for clinical application.
  • 1 is a graph showing the comparison of IC 50 values of Compound 1, 4, 7, 10 and disclosed Compound-1, Compound Compound-2, and carboplatin in H460/Hela/5637 tumor cells;
  • FIG. 2 is a graph showing the comparison of IC 50 values of Compound 1, 4, 7, 10 and disclosed Compound-1, disclosed Compound-2, and carboplatin in HGC27/DU145/KB tumor cells;
  • Figure 3 is a graph showing the IC 50 values of Compounds 1, 4, 7, 10 and disclosed Compound-1, Compound Compound-2, and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells of the present invention.
  • FIG 4 is a compound of the present invention discloses compounds 11 and 12 -1, -2 compounds disclosed and the comparative IC 50 values carboplatin H460 / Hela / 5637 tumor cells;
  • FIG 5 is a compound of the present invention discloses compounds 11 and 12 -1, -2 compounds disclosed and the comparative IC 50 values carboplatin HGC27 / DU145 / KB tumor cells;
  • Figure 6 is a graph showing the comparison of IC 50 values of Compounds 11 and 12 of the present invention and disclosed Compound-1, Compound Compound-2 in ECA-109/SMMC7721/THP-1/A549 tumor cells;
  • Figure 7 is a graph showing the comparison of IC50 values of Compounds 13, 16, 19, 22 of the present invention with disclosed Compound-1, Compound Compound-2, and carboplatin in H460/Hela/5637 tumor cells;
  • FIG 8 is a compound of the present invention with compounds disclosed 13,16,19,22-1, -2 and comparative compounds disclosed in FIG IC 50 values carboplatin HGC27 / DU145 / KB tumor cells;
  • Figure 9 is a graph showing the IC 50 values of Compounds 13, 16, 19, 22 of the present invention and disclosed Compound-1, Compound Compound-2, and carboplatin in ECA-109/SMMC7721/THP-1/A549 tumor cells.
  • FIG 10 is a compound of the present invention discloses compounds 23, 24 -1, -2 compounds disclosed and the comparative IC 50 values carboplatin H460 / Hela / 5637 tumor cells;
  • FIG 11 is a compound of the present invention discloses compounds 23, 24 -1, -2 compounds disclosed and the comparative IC 50 values carboplatin HGC27 / DU145 / KB tumor cells;
  • FIG 12 is a compound of the present invention discloses compounds 23 and 24 -1, -2 compounds disclosed and the comparative IC 50 values carboplatin ECA-109 / SMMC7721 / THP- 1 / A549 tumor cells;
  • FIG 13 is a compound of the present invention discloses compounds with a 25 -1, -2 compounds disclosed and the comparative IC 50 values carboplatin H460 / Hela / 5637 tumor cells;
  • Figure 14 is a graph showing the IC 50 values of Compound 25 of the present invention and disclosed Compound-1, Compound Compound-2, and carboplatin in HGC27/DU145/KB tumor cells;
  • FIG 15 is a compound of the present invention discloses compounds with a 25 -1, -2 and comparative compounds disclosed in FIG IC 50 values carboplatin ECA-109 / SMMC7721 / THP- 1 / A549 tumor cells;
  • FIG 16 is a compound of the present invention discloses compounds and 15,18,20-1, -2 and comparative compounds disclosed in FIG IC 50 values carboplatin H460 / Hela / 5637 tumor cells;
  • Figure 17 is a graph showing the comparison of IC 50 values of Compounds 15, 18, 20 and disclosed Compound-1, disclosed Compound-2, and carboplatin in HGC27/DU145/KB tumor cells of the present invention
  • FIG 18 is a compound of the present invention discloses compounds and 15,18,20-1, -2 and compounds disclosed in FIG carboplatin comparison ECA-109 / SMMC7721 / THP- 1 50 values of tumor cells IC / A549 of.
  • Example 1 Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-(1-O-D-glucoside)cyclobutane-1,1-dicarboxylic acid]
  • 1,2,3,4,6-O-pentaacetyl-D-glucose (1.84 g) was added to ethyl 3-hydroxycyclobutane (1.02 g) containing 1,1-dicarboxylate at room temperature.
  • the solution of methylene chloride (20 ml) was cooled to 0 ° C, the air 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 a nitrogen atmosphere.
  • the reaction solution was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was evaporated to dryness, mjjjjjj
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.54 g of a final product.
  • 1,2,3,4,6-O-pentaacetyl-D-mannose (1.84 g) was added to ethyl 3-hydroxycyclobutane (1.02 g) containing 1,1-dicarboxylate at room temperature.
  • the solution of methylene chloride (20 ml) was cooled to 0 ° C, the air 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 a nitrogen atmosphere.
  • the reaction solution was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was evaporated to dryness, mjjjjjj
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.39 g of a final product.
  • Example 3 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-(1-OD-galactoside)cyclobutane-1,1-dicarboxylic acid] preparation
  • 1,2,3,4,6-O-pentaacetyl-D-galactose (1.84 g) was added to ethyl 3-hydroxycyclobutane (1.02 g) containing 1,1-dicarboxylate at room temperature.
  • the solution of methylene chloride (20 ml) was cooled to 0 ° C, the air 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 a nitrogen atmosphere.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.54 g of a final product.
  • 1,2,3,4,6-O-pentaacetyl-D-glucose (1.84 g) was added to ethyl 1,1-hydroxycarboxylate 3-hydroxymethyl-cyclobutane (1.08) at room temperature.
  • the solution of g) in dichloromethane (20 ml) was cooled to 0 ° C in an ice bath, and the air 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 a nitrogen atmosphere.
  • the reaction solution was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was evaporated to purified crystalljjjjjjjjjj
  • 1,1-Dicarboxylic acid-3-methylene-[2,3,4,6-tetrahydroxy-1-OD-glucoside]cyclobutane (0.93 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.49 g of a final product.
  • 1,2,3,4,6-O-pentaacetyl-D-mannose (1.84 g) was added to ethyl 1,1-dicarboxylate-3-hydroxymethyl-cyclobutane at room temperature (A solution of 1.08 g of methylene chloride (20 ml) was cooled to 0 ° C in an ice bath, and air was placed in the flask under nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under a nitrogen atmosphere. The reaction solution was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was evaporated to dryness crystalljjjjjjjjjj
  • 1,1-Dicarboxylic acid-3-methylene-[2,3,4,6-tetrahydroxy-1-OD-mannosidic]cyclobutane (0.93 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by high-pressure liquid chromatography to obtain 0.44 g of a final product.
  • Example 6 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-methylene-(1-OD-galactoside)cyclobutane-1,1 -dicarboxylic acid preparation
  • 1,2,3,4,6-O-pentaacetyl-D-galactose (1.84 g) was added to ethyl 1,1-dicarboxylate-3-hydroxymethyl-cyclobutane at room temperature (A solution of 1.08 g of methylene chloride (20 ml) was cooled to 0 ° C in an ice bath, and air was placed in the flask under nitrogen, and a solution of boron trifluoride in diethyl ether (98%, 1.19 ml) was slowly added dropwise under a nitrogen atmosphere. The reaction solution was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure.
  • 1,1-Dicarboxylic acid-3-methylene-[2,3,4,6-tetrahydroxy-1-OD-galactoside]cyclobutane (0.93 g) was dissolved in 20 mL of water and saturated with hydrogen The hydrazine solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.48 g of a final product.
  • Example 7 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-ethylidene-(1-OD-glucoside)cyclobutane-1,1- Dicarboxylic acid] preparation
  • 1,2,3,4,6-O-pentaacetyl-D-glucose (1.84 g) was added to ethyl 3-hydroxyethyl-cyclobutane (1.15) containing 1,1-dicarboxylate at room temperature.
  • the solution of g) in dichloromethane (20 ml) was cooled to 0 ° C, and the air 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 a nitrogen atmosphere.
  • 1,1-Dicarboxylic acid-3-ethylene-[2,3,4,6-tetrahydroxy-1-OD-glucoside]cyclobutane (1.0 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated into 0.52 g of a final product by semi-preparative high pressure liquid chromatography.
  • Example 8 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-ethylidene-(1-OD-mannosidyl)cyclobutane-1,1- Dicarboxylic acid] preparation
  • 1,2,3,4,6-O-pentaacetyl-D-mannose (1.84 g) was added to ethyl 3-hydroxyethyl-cyclobutane (1,1-dicarboxylate) at room temperature ( 1.15 g of a solution of dichloromethane (20 ml) was cooled to 0 ° C, and the air 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 a nitrogen atmosphere. The reaction solution was stirred at 0 ° C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours.
  • 1,1-Dicarboxylic acid-3-ethylene-[2,3,4,6-tetrahydroxy-1-OD-mannosidic]cyclobutane (0.95 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.50 g of a final product.
  • Example 9 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-ethylidene-(1-OD-galactoside)cyclobutane-1,1 -dicarboxylic acid] preparation
  • 1,1-Dicarboxylic acid-3-ethylene-[2,3,4,6-tetrahydroxy-1-OD-galactoside]cyclobutane (0.95 g) was dissolved in 20 mL of water and saturated with hydrogen The hydrazine solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.54 g of a final product.
  • Example 10 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-propylene-(1-OD-glucoside)cyclobutane-1,1- Dicarboxylic acid] preparation
  • the sodium hydride (60%) (1.01 g) solid was slowly added to a solution containing diethyl malonate (2.02 g) in DMF (10 ml), and the mixture was stirred at room temperature for 30 minutes. Then, a solution of ((4-bromo-3-(methyl)butoxy)methyl)benzene (2.21 g) in DMF (15 ml) was further added to the reaction solution at room temperature, and the reaction solution was stirred at 80 ° C. 12 hours. The solvent was removed by rotary evaporation.
  • 1,2,3,4,6-O-pentaacetyl-D-glucose (1.84 g) was added to ethyl 3-hydroxypropyl-cyclobutane (1.22) containing 1,1-dicarboxylate at room temperature.
  • the solution of g) in dichloromethane (20 ml) was cooled to 0 ° C, and the air 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 a nitrogen atmosphere.
  • 1,1-Dicarboxylic acid-3-propylene-[2,3,4,6-tetrahydroxy-1-OD-glucoside]cyclobutane (1.0 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated into 0.52 g of a final product by semi-preparative high pressure liquid chromatography.
  • Example 11 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-propylene-(1-OD-mannosidyl)cyclobutane-1,1- Dicarboxylic acid] preparation
  • 1,1-Dicarboxylic acid-3-propylene-[2,3,4,6-tetrahydroxy-1-OD-mannosidic]cyclobutane (1.0 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.50 g of a final product.
  • Example 12 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [1,1-dicarboxylic acid-3-propylene-(1-OD-galactoside) Cyclobutane] preparation
  • 1,1-Dicarboxylic acid-3-propylene-[2,3,4,6-tetrahydroxy-1-OD-galactoside]cyclobutane (1.0 g) was dissolved in 20 mL of water and saturated with hydrogen The hydrazine solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing cyclohexanediamine sulphate (0.82 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated into 0.55 g of a final product by semi-preparative high pressure liquid chromatography.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.41 g of a final product.
  • Example 14 Preparation of diaminoplatinum(II) [3-(1-O-D-mannosidic) cyclobutane-1,1-dicarboxylic acid]
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.42 g of a final product.
  • 1,1-Dicarboxylic acid-3-methylene-[2,3,4,6-tetrahydroxy-1-OD-glucoside]cyclobutane (0.93 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.41 g of a final product.
  • Example 17 Preparation of diaminoplatinum(II) [3-methylene-(1-O-D-mannosidyl)cyclobutane-1,1-dicarboxylic acid]
  • 1,1-Dicarboxylic acid-3-methylene-[2,3,4,6-tetrahydroxy-1-OD-mannosidic]cyclobutane (0.93 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.40 g of a final product.
  • 1,1-Dicarboxylic acid-3-methylene-[2,3,4,6-tetrahydroxy-1-OD-galactoside]cyclobutane (0.93 g) was dissolved in 20 mL of water and saturated with hydrogen The hydrazine solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.40 g of a final product.
  • 1,1-Dicarboxylic acid-3-ethylene-[2,3,4,6-tetrahydroxy-1-OD-glucoside]cyclobutane (1.0 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by high-pressure liquid chromatography to obtain 0.44 g of a final product.
  • Example 20 Preparation of diaminoplatinum(II) [3-ethylidene-(1-O-D-mannosidic) cyclobutane-1,1-dicarboxylic acid]
  • 1,1-Dicarboxylic acid-3-ethylene-[2,3,4,6-tetrahydroxy-1-OD-mannosidic]cyclobutane (0.95 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.41 g of a final product.
  • 1,1-Dicarboxylic acid-3-ethylene-[2,3,4,6-tetrahydroxy-1-OD-galactoside]cyclobutane (0.95 g) was dissolved in 20 mL of water and saturated with hydrogen The hydrazine solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.40 g of a final product.
  • 1,1-Dicarboxylic acid-3-propylene-[2,3,4,6-tetrahydroxy-1-OD-glucoside]cyclobutane (1.0 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.46 g of a final product.
  • 1,1-Dicarboxylic acid-3-propylene-[2,3,4,6-tetrahydroxy-1-OD-mannosidic]cyclobutane (1.0 g) was dissolved in 20 mL of water with saturated cesium hydroxide The solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.40 g of a final product.
  • 1,1-Dicarboxylic acid-3-propylene-[2,3,4,6-tetrahydroxy-1-OD-galactoside]cyclobutane (1.0 g) was dissolved in 20 mL of water and saturated with hydrogen The hydrazine solution adjusts the pH of the solution to pH ⁇ 8. The mixed solution was stirred at room temperature for 30 minutes. An aqueous solution (7 ml) containing platinum diamine sulfate (0.65 g) was added to the reaction mixture obtained above under a nitrogen atmosphere, and stirred at room temperature for 12 hours in the dark.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by a semi-preparative high-pressure liquid chromatography to obtain 0.43 g of a final product.
  • 1,6-hexanediol (2.36 g) was dissolved in 60 mL of dry N,N-dimethylformamide, and 60% sodium hydride (920 mg) was slowly added portionwise to the reaction mixture at 0 ° C, and stirred 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 reaction end point was monitored by TLC.
  • 6-Benzyloxy-1-hexanol (1.5 g) was dissolved in 20 mL of dry dichloromethane, the reaction solution was cooled to 0 ° C, and a solution of carbon tetrabromide (3.5 g) in dichloromethane was slowly added dropwise. 10 mL), then slowly added a solution of triphenylphosphine (2.8 g) in dichloromethane (10 mL). The reaction mixture was stirred at 0 ° C for 1 hour. The reaction was quenched by TLC. The solvent was purified by silica gel column chromatography (EtOAc(EtOAc)
  • the reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1 ⁇ 50 mL), and the aqueous phase was extracted with ethyl acetate. (2 ⁇ 50 mL), the organic phase was combined twice, and the organic phase was washed successively with saturated aqueous ammonium chloride (1 ⁇ 100 mL), distilled water (1 ⁇ 100 mL), saturated sodium chloride solution (1 ⁇ 100 mL), and then used After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness crystals crystals
  • Lithium tetrahydrogen aluminum (282 mg) was suspended in 15 mL of anhydrous diethyl ether in an ice water bath, and 2-(6-benzyloxyhexyl)malonate (1.3 g) was slowly added dropwise under a nitrogen atmosphere.
  • Water diethyl ether solution (10 mL), the reaction end point was monitored by TLC.
  • sodium sulfate decahydrate was slowly added to the reaction liquid until no more gas was generated in the reaction liquid.
  • the solid was filtered, and the filtrate was collected and rotated by a rotary evaporator. The solvent was evaporated to dryness.
  • the reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added to the reaction mixture, and then washed with a saturated aqueous solution of ammonium chloride (1 ⁇ 50 mL), and the aqueous phase was extracted with ethyl acetate. (2 ⁇ 50 mL), the organic phases were combined twice and washed successively with saturated aqueous ammonium chloride (1 ⁇ 100 mL), distilled water (1 ⁇ 100 mL), saturated sodium chloride solution (1 ⁇ 100 mL), and then anhydrous sulfuric acid The sodium was dried, and the solvent was evaporated to dryness.
  • dichloromethane 100 mL was added to the reaction mixture, and the organic phase was washed successively with distilled water (1 ⁇ 100 mL), saturated sodium hydrogen carbonate solution (1 ⁇ 100 mL), and then anhydrous The mixture was dried over sodium sulfate and evaporated to dryness.
  • a strong acidic cation exchange resin was added to the solution and stirred for half an hour, and the resin was filtered, and the filtrate was collected and dried using a freeze dryer to obtain 35 mg of a colorless viscous liquid, and the crude product was directly used for the next reaction.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated and purified by preparative high pressure liquid chromatography, and then dried using a low temperature freeze dryer to obtain 20 mg of a final product, a white solid.
  • Example 26 cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II) [3-hexylene-(1-OD-glucoside)cyclobutane-1,1-di Preparation of formic acid
  • the 1,1-dicarboxylic acid-3-hexylene-[1-OD-glucoside]cyclobutane (35 mg) prepared in the above 25 examples was added to 2 mL of water, and the pH of the reaction solution was adjusted to 7 by adding an aqueous sodium hydroxide solution. Stir at room temperature for 30 min in the dark. Under a nitrogen atmosphere, 1 mL of an aqueous solution containing cyclohexanediamine sulfate (40 m) was added dropwise to the above reaction solution, and the mixture was stirred at room temperature for 1 hour in the dark. The reaction was detected by HPLC.
  • the precipitate was removed using a centrifuge, and the supernatant was collected, separated and purified by preparative high pressure liquid chromatography, and then dried using a low temperature freeze dryer to obtain 30 mg of a final product, a white solid.
  • Compound Solubility (mg/mL) Compound Solubility (mg/mL) 1 512.11 14 842.05 2 246.92 15 1089.40 3 459.38 16 1211.51 4 507.75 17 732.82 5 235.35 18 1080.72 6 443.30 19 1105.96 7 490.79 20 687.09 8 225.83 twenty one 1038.69 9 430.29 twenty two 1100.37 10 483.54 twenty three 669.92 11 223.12 twenty four 958.3 12 418.76 25 764.66 13 1357.68 26 684.67 Cisplatin 1.0 Carboplatin 17.0 Oxaliplatin 6.0
  • the solubility of the platinum complex of the present invention in water is much greater than that of cisplatin, carboplatin and oxaliplatin which have been marketed, and the water solubility can be increased by several tens to several thousand times.
  • a cell culture medium containing 10% fetal bovine serum was used.
  • HERAcell150i carbon dioxide incubator (Thermo), research-grade inverted fluorescence microscope (Nikon, Japan), multi-function microplate reader (Thermo), ultra-low temperature refrigerator (Thermo), biosafety cabinet (1300 Series A2, Thermo), micropipette (Eppendorf, Germany), ultrapure water system (Milli-Q, USA).
  • the cytotoxicity test was tested by the MTT method.
  • the log phase tumor cells were collected, the cell suspension concentration was adjusted, 100 ⁇ l was added to each well, and the density of the cells to be tested was adjusted to 1000-10000 cells/well (the edge cells were filled with sterile PBS).
  • the cell survival rate is 50% of the control group, and the drug concentration is the half inhibitory concentration of the drug on the tumor cells, that is, the IC 50 value of the drug.
  • the test method is the same as that of Experimental Example 2, and the compound selected for comparison is a compound having the same glucose molecular structure as the disclosed compound in the present invention (Compound-1, 4, 7, 10, 13, 16, 19, 22, 25), and a compound of the invention containing a non-glucose molecular structure (compound-11, 20, 23: mannose; compound-12, 15, 18, 24: galactose), compared with the disclosed compounds for antitumor efficacy
  • the half-inhibitory concentration of the drug on the tumor cells that is, the IC 50 value of the drug, was obtained.

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Abstract

一种式(I)所示的环丁烷二羧酸铂配合物、其中间体、其制备方法、药物组合物及用途。所述环丁烷二羧酸铂配合物具有良好的抗肿瘤活性。本发明所提供的配合物在水溶性方面与现有铂类抗肿瘤药品相比，都具有几十倍以上的提高，这种高水溶性特点能够增加和提高药物在肾脏的排泄，减轻铂类药物一般存在的高肾毒副作用，同时使这些化合物容易制剂化，在临床上的应用更方便。

Description

环丁烷二羧酸铂配合物、其中间体、其制备方法、药物组合物及用途 技术领域
本发明涉及一种水溶性铂配合物、其中间体、其制备方法、药物组合物及用途。
背景技术
铂类抗癌药是肿瘤治疗领域具有代表性的一类药物。其属于细胞周期非特异性药物，对肉瘤，恶性上皮肿瘤，淋巴瘤以及生殖细胞肿瘤都具有治疗功效。目前世界上广泛应用于临床治疗的具有代表性的铂类抗癌药主要有：顺铂、卡铂和奥沙利铂。铂类抗癌药物的致命缺点是具有极强的毒副作用以及固有的和后续形成的耐药性问题。另外由于此类药物是金属有机化合物，所有铂类上市药物普遍存在水溶性极低的特性，顺铂、卡铂和奥沙利铂的水溶性分别为1.0、17.0、6.0mg/ml。
发明内容
本发明的目的是克服现有技术中的不足，提供一种环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物，其具有良好的水溶性以及良好的抗肿瘤活性。
本发明提供一种式(I)所示的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物：
Figure PCTCN2019076236-appb-000001
其中：
X和Y是配位体，所述X和Y各自独立地选自NH 3、C 1-C 8直链或支链烷基伯胺(可选为C 1-C 6的直链或支链烷基伯胺，可选为C 1-C 3的直链或支链烷基伯胺)、C 3-C 8环状烷基伯胺(可选为C 3-C 6环状烷基伯胺)、芳香族伯胺、一个或多个C 1-C 4直链或支链烷基取代的芳香族伯胺、分子式为R 1-NH-R 2的仲胺，其中R 1和R 2相同或者不同各自表示为C 1-C 8的直链或支链烷基(可选为C 1-C 6的直链或支链烷基，可选为C 1-C 3的直链或支链烷基)；或R 1-NH-R 2共同组成C 4-C 8的脂环仲胺(可选为C 5-C 6的脂环仲胺)、含氮芳香族杂环化合物、一个或多个C 1-C 4直链或支链烷基取代的含氮芳香族杂环化合物、含硫芳香族杂环化合物或含硫非芳香族杂环化合物；其中，所述“芳香族伯胺”中的芳基为5～10元单环或稠合双环芳香基团，所述“芳香族杂环”为5～10 元单环或稠合双环芳香杂环；所述“非芳香族杂环”为4～10元单环或多环脂杂环；
或者X和Y一起构成式(IV)结构：
Figure PCTCN2019076236-appb-000002
式(IV)中，D为C 0或C 1的亚烷基；B为C 2-C 8的亚烷基(可选为C 2-C 6的亚烷基、可选为C 3-C 5的亚烷基)；
n＝0、1、2、3、4、5或6(可选地，n＝0、1、2、3或6，可选地，n＝0、1、2或3)；
R选自下述单糖基，所述单糖1-位取代为α取代或者β取代：
Figure PCTCN2019076236-appb-000003
可选地，R选自下述单糖基，单糖1-位取代为α取代或者β取代，
Figure PCTCN2019076236-appb-000004
可选地，所述X和Y分别为NH 3，或X,Y一起为反式-(1R，2R)-环己二胺，反式-(1S，2S)-环己二胺，顺式-(1R，2S)-环己二胺，顺式-(1S，2R)-环己二胺，消旋反式-1，2-环己二胺或消旋顺式-1，2-环己二胺。
可选地，所述X和Y分别为NH 3；或X,Y一起为反式-(1R，2R)-环己二胺。
n＝0、1、2、3或6；R选自下述单糖基，所述单糖1-位取代为α取代或者β取代：
Figure PCTCN2019076236-appb-000005
可选地，所述式(I)选自下述配合物，
Figure PCTCN2019076236-appb-000006
Figure PCTCN2019076236-appb-000007
Figure PCTCN2019076236-appb-000008
本发明另一方面，提供式(III)所示的化合物，其可以用作为制备式(I)所示的环丁烷二羧酸铂配合物的中间体，
Figure PCTCN2019076236-appb-000009
式(III)中：
各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；
n＝0、1、2、3、4、5或6(可选地，n＝0、1、2、3或6，可选地，n＝0、1、2或3)；
R选自氢，或下述单糖基，单糖1-位取代为α取代或者β取代：
Figure PCTCN2019076236-appb-000010
可选地，所述式(III)选自下述化合物：
Figure PCTCN2019076236-appb-000011
式(III-1)，式(III-2)，式(III-3)中，
n＝0、1、2、3或6(可选地，n＝0、1、2或3)；
M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba。
本发明另一方面，提供上述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、溶剂化物的制备方法，其包括将式(II)化合物与式(III)化合物加水调节为水溶液进行反应的步骤；可选地，反应水溶液加碱调节pH为7-9，
可选地，所述碱为无机碱，可选地，所述无机碱选自氢氧化钠，氢氧化钾，碳酸钠，碳酸氢 钠，碳酸钾，氢氧化锂，氢氧化铯或氢氧化钡中的一种或多种；
所述(II)的结构式为：
Figure PCTCN2019076236-appb-000012
式(II)中：
X和Y是配位体，所述X和Y各自独立地选自NH 3、C 1-C 8直链或支链烷基伯胺(可选为C 1-C 6的直链或支链烷基伯胺，可选为C 1-C 3的直链或支链烷基伯胺)、C 3-C 8环状烷基伯胺(可选为C 3-C 6环状烷基伯胺)、芳香族伯胺、一个或多个C 1-C 4直链或支链烷基取代的芳香族伯胺、分子式为R 1-NH-R 2的仲胺，其中R 1和R 2相同或者不同各自表示为C 1-C 8的直链或支链烷基(可选为C 1-C 6的直链或支链烷基，可选为C 1-C 3的直链或支链烷基)；或R 1-NH-R 2共同组成C 4-C 8的脂环仲胺(可选为C 5-C 6的脂环仲胺)、含氮芳香族杂环化合物、一个或多个C 1-C 4直链或支链烷基取代的含氮芳香族杂环化合物、含硫芳香族杂环化合物或含硫非芳香族杂环化合物；其中，所述“芳香族伯胺”中的芳基为5～10元单环或稠合双环芳香基团，所述“芳香族杂环”为5～10元单环或稠合双环芳香杂环；所述“非芳香族杂环”为4～10元单环或多环脂杂环；
或者X和Y一起用结构式(Ⅳ)表示：
Figure PCTCN2019076236-appb-000013
式(Ⅳ)中，D为C 0或C 1的亚烷基；B为C 2-C 8的亚烷基(可选为C 2-C 6的亚烷基、可选为C 3-C 5的亚烷基)；
A 1和A 2相同或者不同，各自独立地代表羟基，硝酸根或高氯酸根，或者A 1和A 2共同代表硫酸根或碳酸根；
所述(III)的结构式为：
Figure PCTCN2019076236-appb-000014
式(III)中：
各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；
n＝0、1、2、3、4、5或6(可选地，n＝0、1、2、3或6)；
R选自氢，或R选自下述单糖基，单糖1-位取代为α取代或者β取代：
Figure PCTCN2019076236-appb-000015
可选地，上述反应中，每当量的化合物(III)选用0.5-4当量的化合物(II)，优选1至2当量。
可选地，所述无机碱浓度为0.1N-5N，优选为1N。
可选地，上述反应可以在一个比较宽的温度范围内来进行，例如选择在0-100℃的温度范围来进行上述反应，优选为25-90℃，更优选为60-90℃，并同时伴随搅拌为好。根据不同的目标产物反应需要的时间可以不同。根据不同反应物的性质，一般需要1小时到30天来完成。更多的 情况下需要10小时至15天的时间。
可选地，上述反应将反应化合物调节为水溶液所用的水优选使用去离子水。
其具体的制备可以利用下述的方法和反应式来完成：
方法A：
Figure PCTCN2019076236-appb-000016
方法B：
Figure PCTCN2019076236-appb-000017
在方法A中，当式(III)中M是氢原子时，反应可以通过使用适当的无机碱，例如氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，碳酸钾，氢氧化锂以及氢氧化铯等来调节反应水溶液的pH维持在7-9之间来完成式(I)所示配合物的制备；当M为金属原子时，例如：钠原子、钾原子、锂原子、钡原子或铯原子，反应可在水溶液中顺利进行，必要时使用少量的上述无机碱的水溶液维持反应溶液的pH在7-9之间即可完成式(I)所示配合物的合成。
在方法B中，当M是氢原子时，反应可以通过使用等当量的氢氧化钡作为无机碱，在水溶液中完成与式(II)所示的金属铂硫酸盐化合物的缩合反应来制备式(I)所示配合物。由方法B制备本发明配合物时，亦可以使用事先制得的钡盐，即两个M共同代表一个钡原子，与式(II)所示的金属铂硫酸盐配合物在水溶液中进行反应来完成配合物的制备过程。
方法A和B中式(II)所表示的化合物可以通过相应的顺-二氯化铂与X和Y的配合物(例如：顺-二氯-(1，2-二氨基环己烷)合铂)与2当量的硝酸银或1当量的硫酸银反应而制备。该反应最好在水溶液中进行，使用的水最好是去离子水。反应温度在室温比较合适。
本发明对采用上述方法制备所得的生成物(I)进行提纯的方法并没有特别的限制，可以采用现有技术常规的方法进行提纯，例如反应完成后的混合物可以先通过过滤除去可能生成的沉淀物，然后通过减压蒸馏浓缩，然后加入有机溶剂(可选地，所述有机溶剂优选采用能够与水互溶 的有机溶剂，例如醇类(例如甲醇，乙醇，丙醇，丁醇，异丙醇等)，或者与水有一定互溶性的醚类(例如二乙醚，甲基叔丁基醚，四氢呋喃，乙二醇二乙醚，乙二醇二甲醚等))，使目标化合物(I)沉淀析出，最后将得到的沉淀收集起来，例如通过过滤，就可以得到所需要的式(I)所表示的化合物。另外，提纯和精制上述反应中得到的生成物(I)也可以用色谱等的方法，例如用离子交换树脂，或者用制备液相色谱。液相色谱分离精制一般使用甲醇和水作为流动相来进行。
本发明化合物(III)，可以由下述的反应式所给出的以葡萄糖为例的方法C，D或者方法E，F中的任意一种来进行制备：
方法C:
Figure PCTCN2019076236-appb-000018
方法D:
Figure PCTCN2019076236-appb-000019
方法E:
Figure PCTCN2019076236-appb-000020
方法F:
Figure PCTCN2019076236-appb-000021
以葡萄糖为例，在方法C和D中，作为与糖反应的含羟基环丁烷二羧酸酯衍生物，可以通过使用含羟基1,3-二卤代烷烃衍生物与丙二酸酯化合物例如丙二酸二甲酯，丙二酸二乙酯，丙二酸二苯甲酯，丙二酸环异内酯等按照文献已知的一般方法(例如：Molecules 2016,21(5),612)来制备。得到的含羟基环丁烷二羧酸酯衍生物与葡萄糖可以在路易斯酸存在下在溶剂中进行缩合反应，从而得到环丁烷二羧酸酯的葡萄糖苷化合物。缩合反应的条件是针对葡萄糖化合物使用0.1-50当量的含羟基环丁烷二羧酸酯，或者相反针对含羟基环丁烷二羧酸酯使用0.1-50当量的葡萄糖。使用的路易斯酸可以是BF 3，SnCl 4，FeCl 3，AlCl 3，盐酸，对甲苯磺酸，樟脑磺酸等，路易斯酸的量相对于葡萄糖可以是0.1-10当量。所使用的溶剂可以是四氢呋喃，二氯甲烷，甲苯，乙二醇二甲醚，乙二醇二乙醚等，也可以使用两种反应物中的任意一种当作溶剂来进行该反应。反应的温度可以从0℃到100℃，一般可以在60-80℃加热完成该反应。反应所需要的时间根据反 应物的不同而不同，一般1小时至7天可以完成。得到的反应产物可以通过一系列的提纯条件来进行精制，一般可以使用硅胶层析分离法，或者液相色谱柱分离法。得到的该产物，经过除去丙二酸的保护基就可以最后得到所需要的式(III)所表示的化合物。脱保护的方法根据使用的保护基的不同而不同，如果使用丙二酸二苯甲基酯，可以使用加氢还原的方法进行脱保护，如果使用丙二酸二乙酯或者丙二酸环异内酯进行反应时，脱保护反应可以使用无机碱在甲醇-水，或者THF-水溶剂中来进行，有机溶剂与水的比例一般为1:1-4:1。所使用的无机碱可以是氢氧化钠，氢氧化钾，氢氧化钡，氢氧化锂等。反应温度一般为室温，反应时间一般为1-24小时。脱保护生成的化合物的提纯可以使用硅胶层析法或者离子交换树脂过滤法，或者使用液相色谱法来完成，如果用蒸馏法直接除去反应溶剂，所得到的生成物将会是相应的金属羧酸盐。
方法C和D所示的制备方法是使用乙酰基保护的糖，或者直接使用非保护的糖与含羟基环丁烷二羧酸酯衍生物在路易斯酸存在下缩合然后脱保护获得目标产物(III)的制备路线。
方法E和F所示的制备方法是先将含羟基1,3-二卤代烷烃衍生物与乙酰基保护或者非保护的糖形成糖苷衍生物，然后再与丙二酸酯缩合形成环丁烷二羧酸酯，最后经过脱除保护基获得目标产物(III)的制备路线。
在方法C和F中，葡萄糖可以先转化成相应的乙酰化葡萄糖，然后再实施与相应的含羟基中间体的缩合反应，葡萄糖的乙酰化可以按照文献报道的方法实施，例如在吡啶中采用乙酸酐作为乙酰化试剂在室温或者在60℃加热1-24小时即可完成。
本发明另一方面，提供一种药物组合物，其包括上述的配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物中的一种或多种以及任选存在的药学上可接受的载体。
本发明另一方面，提供一种上述的配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或者上述的药物组合物在制备抗肿瘤细胞药物中的用途。
可选地，所述肿瘤细胞为人肺癌，人肝癌，人大肠癌，人头颈癌，人前列腺癌，人乳腺癌，人卵巢癌，人子宫颈癌，人白血病，人淋巴癌，人皮肤癌，人胰腺癌，人膀胱癌，人食道癌，人胃癌，人男性生殖器癌，人甲状腺癌，人骨癌，人黑色素癌，或人口腔癌。
可选地，所述肿瘤细胞为人结肠癌细胞HT29，人非小细胞肺癌细胞A549，人肝癌细胞SMMC7721，人乳腺癌细胞MCF-7，人卵巢癌细胞SKOV3，人食管癌细胞ECA109，人前列腺癌细胞DU145，人宫颈癌细胞Hela，人黑色素瘤细胞A375，人口腔表皮样癌细胞KB，人胃癌细胞HGC27，人甲状腺癌细胞SW579，人膀胱癌细胞5637，人胰腺癌细胞Panc-1，人大细胞肺癌细胞H460，人浆细胞白血病细胞H929，人肝癌细胞HepG2，人单核细胞白血病THP-1。
本发明的抗肿瘤药物，其给药途径没有特别的限制，其剂量不仅取决于病人的年龄，体重以 及病情，还取决于肿瘤的种类，性质和严重程度。但一般来说，对于成年病人，最好每天使用的该化合物的量为10毫克至1克之间。一般为每一至三周一次或几次用药。
本发明提供的化合物具有良好的抗肿瘤活性。本发明所提供的配合物在水溶性方面与现有铂类抗肿瘤药品相比，都具有几十倍以上的提高，这种高水溶性特点能够增加药物在肾脏的排泄，减少药物在身体内的积蓄，减轻铂类药物一般存在的高肾毒副作用，同时使这些化合物容易制剂化，提高制剂的稳定性，在临床上的应用更方便。
附图说明
图1是显示本发明中的化合物1、4、7、10与公开化合物-1、公开化合物-2以及卡铂在H460/Hela/5637肿瘤细胞中的IC 50值的对比图；
图2是显示本发明中的化合物1、4、7、10与公开化合物-1、公开化合物-2以及卡铂在HGC27/DU145/KB肿瘤细胞中的IC 50值的对比图；
图3是显示本发明中的化合物1、4、7、10与公开化合物-1、公开化合物-2以及卡铂在ECA-109/SMMC7721/THP-1/A549肿瘤细胞中的IC 50值的对比图；
图4是显示本发明中的化合物11、12与公开化合物-1、公开化合物-2以及卡铂在H460/Hela/5637肿瘤细胞中的IC 50值的对比图；
图5是显示本发明中的化合物11、12与公开化合物-1、公开化合物-2以及卡铂在HGC27/DU145/KB肿瘤细胞中的IC 50值的对比图；
图6是显示本发明中的化合物11、12与公开化合物-1、公开化合物-2在ECA-109/SMMC7721/THP-1/A549肿瘤细胞中的IC 50值的对比图；
图7是显示本发明中的化合物13、16、19、22与公开化合物-1、公开化合物-2以及卡铂在H460/Hela/5637肿瘤细胞中的IC50值的对比图；
图8是显示本发明中的化合物13、16、19、22与公开化合物-1、公开化合物-2以及卡铂在HGC27/DU145/KB肿瘤细胞中的IC 50值的对比图；
图9是显示本发明中的化合物13、16、19、22与公开化合物-1、公开化合物-2以及卡铂在ECA-109/SMMC7721/THP-1/A549肿瘤细胞中的IC 50值的对比图；
图10是显示本发明中的化合物23、24与公开化合物-1、公开化合物-2以及卡铂在H460/Hela/5637肿瘤细胞中的IC 50值的对比图；
图11是显示本发明中的化合物23、24与公开化合物-1、公开化合物-2以及卡铂在HGC27/DU145/KB肿瘤细胞中的IC 50值的对比图；
图12是显示本发明化合物23、24与公开化合物-1、公开化合物-2以及卡铂在ECA-109/SMMC7721/THP-1/A549肿瘤细胞中的IC 50值的对比图；
图13是显示本发明中的化合物25与公开化合物-1、公开化合物-2以及卡铂在H460/Hela/5637肿瘤细胞中的IC 50值的对比图；
图14是显示本发明中的化合物25与公开化合物-1、公开化合物-2以及卡铂在HGC27/DU145/KB肿瘤细胞中的IC 50值对比图；
图15是显示本发明中的化合物25与公开化合物-1、公开化合物-2以及卡铂在ECA-109/SMMC7721/THP-1/A549肿瘤细胞中的IC 50值的对比图；
图16是显示本发明中的化合物15、18、20与公开化合物-1、公开化合物-2以及卡铂在H460/Hela/5637肿瘤细胞中的IC 50值的对比图；
图17是显示本发明中的化合物15、18、20与公开化合物-1、公开化合物-2以及卡铂在HGC27/DU145/KB肿瘤细胞中的IC 50值对比图；
图18是显示本发明中的化合物15、18、20与公开化合物-1、公开化合物-2以及卡铂在ECA-109/SMMC7721/THP-1/A549肿瘤细胞中的IC 50值的对比图。
具体实施方式
以下用具体的实施例来进一步说明本发明。作为本发明所提供的由式(I)所表示的用于肿瘤治疗的铂配合物，其优选化合物的代表性举例亦可以由下述表1列出，但本发明所涵盖的铂配合物不限于以下的举例。
表1 实施例化合物列表
Figure PCTCN2019076236-appb-000022
Figure PCTCN2019076236-appb-000023
Figure PCTCN2019076236-appb-000024
Figure PCTCN2019076236-appb-000025
Figure PCTCN2019076236-appb-000026
实施例1：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000027
(1)1,1-二甲酸乙酯-3-乙酰氧基-环丁烷的制备
Figure PCTCN2019076236-appb-000028
将60％氢化钠(0.8g)溶于N，N-二甲基甲酰胺(15ml)的丙二酸二乙酯(1.6g)溶液中。混合物在室温下搅拌30分钟。然后将含有1,3-二溴-2-酯基丙烷(1.3g)的N，N-二甲基甲酰胺溶液(10ml)加入到反应溶液中，混合物在80℃搅拌6小时。旋蒸除去溶剂，残余物重新溶解在乙酸乙酯(150ml)和饱和氯化铵(150ml)的混合溶液中，分液。有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析(石油醚/乙酸乙酯：50/1)纯化，得到无色油状产物(0.66g)。
1H 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)1,1-二甲酸乙酯-3-羟基-环丁烷的制备
Figure PCTCN2019076236-appb-000029
将上步产物(1.29g)溶解于0.1M的乙醇钠溶液(10ml)中，室温搅拌2小时，将残余物溶解于乙酸乙酯溶液(100ml)和氯化铵溶液(100ml)中，分液，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化，得无色油状物(0.75g)。
1H 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)1,1-二甲酸乙酯-3-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000030
在室温条件下将1,2,3,4,6-O-五乙酰基-D-葡萄糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟基环丁烷(1.02g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，硅胶柱层析(石油醚/乙酸乙酯＝5/1)实施简单纯化，得到粗产品1.71g。
1H 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)1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000031
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷(1.09g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.93g。
(5)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】 的制备
Figure PCTCN2019076236-appb-000032
将1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(0.9g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.54g最终产品。
1H NMR(400MHz,D 2O)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)。
实施例2：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000033
(1)1,1-二甲酸乙酯-3-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000034
在室温条件下将1,2,3,4,6-O-五乙酰-D-甘露糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟基环丁烷(1.02g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，硅胶柱层析(石油醚/乙酸乙酯＝5/1)实施简单纯化，得到粗产品1.39g。
1H NMR(400MHz,CDCl 3)δ5.38–5.16(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)1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000035
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷(1.09g)的水溶液(7ml)当中，升高温度，在90°C下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.95g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000036
将1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(0.9g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.39g最终产品。
1H NMR(400MHz,D 2O)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).
实施例3：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000037
(1)1,1-二甲酸乙酯-3-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000038
在室温条件下将1,2,3,4,6-O-五乙酰-D-半乳糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟基环丁烷(1.02g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚/乙酸乙酯＝5/1)对反应生成物实施简单纯化，得到粗产品1.55g。
1H 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)1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000039
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷(1.09g)的水溶液(7ml)当中，升高温度，在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.95g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000040
将1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(0.9g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.54g最终产品。
1H NMR(400MHz,D 2O)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).
实施例4：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚甲基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000041
(1)1,1-二甲酸乙酯-3-苄氧甲基-环丁烷的制备
Figure PCTCN2019076236-appb-000042
冰浴冷却下，将氢化钠(60％)(1.01g)固体缓慢加入到含有丙二酸二乙酯(2.02g)的DMF(10ml)溶液当中，混合物溶液室温搅拌30分钟。然后在室温下将含有((4-溴-3-(甲基)丁氧基)甲基)苯(2.03g)的DMF(15ml)溶液进一步加入到反应溶液中，在80℃下反应液搅拌12小时。旋蒸除去溶剂。向反应液中加入100ml乙酸乙酯，然后用饱和氯化铵水溶液(1×50ml)洗涤，将水相用乙酸乙酯萃取(2×25ml)，合并有机相。将有机相依次用饱和氯化铵水溶液(1×100ml)，蒸馏水(1×100ml)，饱和氯化钠水溶液(1×100ml)洗涤，然后用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色油状产物1.64g。
1H 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)1,1-二甲酸乙酯-3-羟甲基-环丁烷的制备
Figure PCTCN2019076236-appb-000043
将钯碳(0.11g)加入到含有上步产物(1.16g)的甲醇溶液当中，室温下真空置换氢气，然后在氢气条件下反应液搅拌36小时。硅藻土过滤去除多余残渣得滤液，旋蒸除去溶剂，硅胶柱层析纯化(石油醚/乙酸乙酯＝4/1)，得到无色油状产物0.813g。
1H 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)1,1-二甲酸乙酯-3-亚甲基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000044
在室温条件下将1,2,3,4,6-O-五乙酰-D-葡萄糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟甲基-环丁烷(1.08g)的二氯甲烷(20ml)溶液当中，冰浴冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化,得到粗产品1.71g。
1H NMR(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)1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000045
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚甲基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷(1.12g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.96g。
(5)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚甲基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000046
将1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(0.93g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.49g最终产品。
1H NMR(400MHz,D 2O)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).
实施例5：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚甲基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000047
(1)1,1-二甲酸乙酯-3-亚甲基-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000048
在室温条件下将1,2,3,4,6-O-五乙酰-D-甘露糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟甲基-环丁烷(1.08g)的二氯甲烷(20ml)溶液当中，冰浴冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，硅胶柱层析(石油醚/乙酸乙酯＝5/1)分离纯化，得到粗产品1.39g。
1H 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＝9.9,5.6Hz,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)1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000049
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚甲基-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷(1.12g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.95g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚甲基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000050
将1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(0.93g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.44g最终产品。
1H NMR(400MHz,D 2O)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).
实施例6：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚甲基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000051
(1)1,1-二甲酸乙酯-3-亚甲基-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000052
在室温条件下将1,2,3,4,6-O-五乙酰-D-半乳糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟甲基-环丁烷(1.08g)的二氯甲烷(20ml)溶液当中，冰浴冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，减压除去溶剂，硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到粗产品1.57g。
1H 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)1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000053
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚甲基-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷(1.12g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.98g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚甲基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000054
将1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(0.93g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.48g最终产品。
1H NMR(400MHz,D 2O)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).
实施例7：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚乙基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000055
(1)1,1-二甲酸乙酯-3-苄氧乙基-环丁烷的制备
Figure PCTCN2019076236-appb-000056
冰浴冷却下，将氢化钠(60％)(1.01g)固体缓慢加入到含有丙二酸二乙酯(2.02g)的DMF(10ml)溶液当中，混合物溶液室温搅拌30分钟。然后在室温下将含有((4-溴-3-(甲基)丁氧基)甲基)苯(2.12g)的DMF(15ml)溶液加入到反应溶液中，在80℃下反应液搅拌12小时。旋蒸除去溶剂。向反应液中加入100ml乙酸乙酯，然后用饱和氯化铵水溶液(1×50ml)洗涤， 将水相用乙酸乙酯萃取(2×25ml)，合并有机相。将有机相依次用饱和氯化铵水溶液(1×100ml)，蒸馏水(1×100ml)，饱和氯化钠水溶液(1×100ml)洗涤，然后用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1)，得到无色油状产物1.69g。
1H 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)1,1-二甲酸乙酯-3-羟乙基-环丁烷的制备
Figure PCTCN2019076236-appb-000057
将钯/碳(0.11g)加入到含有上步产物(1.21g)的甲醇溶液当中，室温下真空置换氢气，然后在氢气条件下反应液搅拌36小时。硅藻土过滤去除多余残渣得滤液，旋蒸除去溶剂，硅胶柱层析纯化(石油醚/乙酸乙酯＝4/1)，得到无色油状产物0.830g。
1H 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)1,1-二甲酸乙酯-3-亚乙基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000058
在室温条件下将1,2,3,4,6-O-五乙酰-D-葡萄糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟乙基-环丁烷(1.15g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚/乙酸乙酯＝5/1)对反应生成物实施简单纯化,得到粗产品1.71g。
1H 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)1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000059
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚乙基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷(1.15g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体1.0g。
(5)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚乙基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000060
将1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.52g最终产品。
1H NMR(400MHz,D 2O)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).
实施例8：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚乙基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000061
(1)1,1-二甲酸乙酯-3-亚乙基-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000062
在室温条件下将1,2,3,4,6-O-五乙酰-D-甘露糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟乙基-环丁烷(1.15g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚/乙酸乙酯＝5/1)对反应生成物实施简单纯化，得到粗产品1.39g。
1H 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)1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000063
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚乙基-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷(1.15g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体0.98g。(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚乙基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000064
将1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(0.95g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.50g最终产品。
1H NMR(400MHz,D 2O)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).
实施例9：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚乙基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000065
(1)1,1-二甲酸乙酯-3-亚乙基-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000066
在室温条件下将1,2,3,4,6-O-五乙酰-D-半乳糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟乙基-环丁烷(1.15g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚∶乙酸乙酯＝5∶1)对反应生成物实施简单纯化,得到粗产品1.54g。
1H 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)1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000067
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有步骤(1)所得1,1-二甲酸乙酯-3-亚乙基-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷化合物(1.15g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体1.0g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚乙基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000068
将1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(0.95g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.54g最终产品。
1H NMR(600MHz,D 2O)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).
实施例10：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚丙基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000069
(1)1,1-二甲酸乙酯-3-苄氧丙基-环丁烷的制备
Figure PCTCN2019076236-appb-000070
冰浴冷却下，将氢化钠(60％)(1.01g)固体缓慢加入到含有丙二酸二乙酯(2.02g)的DMF(10ml)溶液当中，混合物溶液室温搅拌30分钟。然后在室温下将含有((4-溴-3-(甲基)丁氧基)甲基)苯(2.21g)的DMF(15ml)溶液进一步加入到反应溶液中，在80℃下反应液搅拌12小时。旋蒸除去溶剂。向反应液中加入100ml乙酸乙酯，然后用饱和氯化铵水溶液(1×50ml)洗涤，将水相用乙酸乙酯萃取(2×25ml)，合并有机相。将有机相依次用饱和氯化铵水溶液(1×100ml)，蒸馏水(1×100ml)，饱和氯化钠水溶液(1×100ml)洗涤，然后用无水硫酸钠干燥，用旋转蒸发仪将溶剂蒸干，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝50/1)，得到无色油状产物1.74g。
1H 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)1,1-二甲酸乙酯-3-羟丙基-环丁烷的制备
Figure PCTCN2019076236-appb-000071
将钯/碳(0.11g)加入到含有上步反应产物(1.26g)的甲醇溶液当中，室温下真空置换氢气，然后在氢气条件下反应液搅拌36小时。硅藻土过滤去除多余残渣得滤液，旋蒸除去溶剂，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)，得到无色油状产物0.868g。
1H 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)1,1-二甲酸乙酯-3-亚丙基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000072
在室温条件下将1,2,3,4,6-O-五乙酰-D-葡萄糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟丙基-环丁烷(1.22g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚/乙酸乙酯＝5/1)对反应生成物实施简单纯化,得到粗产品1.72g。
1H 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)1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000073
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚丙基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷(1.18g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体1.0g。
(5)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚丙基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000074
将1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.52g最终产品。
1H NMR(400MHz,D 2O)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).
实施例11：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚丙基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000075
(1)1,1-二甲酸乙酯-3-亚丙基-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000076
在室温条件下将1,2,3,4,6-O-五乙酰-D-甘露糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟丙基-环丁烷(1.22g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚/乙酸乙酯＝5/1)对反应生成物实施简单纯化，得到粗产品1.41g。
1H 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)1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000077
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚丙基-【2,3,4,6-O-乙酰基-1-O-D-甘露糖苷】环丁烷(1.18g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体1.0g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚丙基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000078
将1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.50g最终产品。
1H NMR(400MHz,D 2O)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).
实施例12：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【1,1-二甲酸-3-亚丙基-(1-O-D-半乳糖苷)环丁烷】制备
Figure PCTCN2019076236-appb-000079
(1)1,1-二甲酸乙酯-3-亚丙基-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000080
在室温条件下将1,2,3,4,6-O-五乙酰-D-半乳糖(1.84g)加入到含有1,1-二甲酸乙酯-3-羟丙基-环丁烷(1.22g)的二氯甲烷(20ml)溶液当中，冷却到0℃，用氮气置换烧瓶内空气，在氮气保护下慢慢滴加三氟化硼的乙醚溶液(98％，1.19ml)。将反应液在0℃搅拌15分钟，然后慢慢升温到室温并搅拌12小时。反应完成后，旋蒸除去溶剂，使用硅胶柱色谱(石油醚/乙酸乙酯＝5/1)对反应生成物实施简单纯化，得到粗产品1.57g。
1H NMR(400MHz,CDCl 3)δ5.42–5.30(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)1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷的制备
Figure PCTCN2019076236-appb-000081
室温下将NaOH(0.72g)溶解在15ml的水中，然后将其缓慢加入到含有1,1-二甲酸乙酯-3-亚丙基-【2,3,4,6-O-乙酰基-1-O-D-半乳糖苷】环丁烷(1.18g)的水溶液(7ml)当中，升高温度在90℃下搅拌8h。待反应溶液冷却后通过强酸性阳离子树脂获得所需的酸的水溶液(10ml)，冷冻干燥得到白色固体1.0g。
(3)顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚丙基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000082
将1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有环己二胺硫酸铂(0.82g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.55g最终产品。
1H NMR(400MHz,D 2O)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).
实施例13：二氨基铂(Ⅱ)【1,1-二甲酸-3-(1-O-D-葡萄糖苷)环丁烷】制备
Figure PCTCN2019076236-appb-000083
将1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(0.9g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.41g最终产品。
1H NMR(600MHz,D 2O)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).
实施例14：二氨基铂(Ⅱ)【3-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000084
将1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(0.9g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱 分离得到0.42g最终产品。
1H NMR(600MHz,D 2O)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).
实施例15：二氨基铂(Ⅱ)【3-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000085
将1,1-二甲酸-3-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(0.9g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.44g最终产品。
1H NMR(400MHz,D 2O)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).
实施例16：二氨基铂(Ⅱ)【3-亚甲基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000086
将1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(0.93g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.41g最终产品。
1H NMR(400MHz,D 2O)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).
实施例17：二氨基铂(Ⅱ)【3-亚甲基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000087
将1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(0.93g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.40g最终产品。
1H NMR(400MHz,D 2O)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).
实施例18：二氨基铂(Ⅱ)【3-亚甲基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000088
将1,1-二甲酸-3-亚甲基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(0.93g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.40g最终产品。
1H NMR(600MHz,D 2O)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).
实施例19：二氨基铂(Ⅱ)【3-亚乙基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000089
将1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.44g最终产品。
1H NMR(400MHz,D 2O)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).
实施例20：二氨基铂(Ⅱ)【3-亚乙基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000090
将1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(0.95g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.41g最终产品。
1H NMR(400MHz,D 2O)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).
实施例21：二氨基铂(Ⅱ)【3-亚乙基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000091
将1,1-二甲酸-3-亚乙基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(0.95g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液 相色谱分离得到0.40g最终产品。
1H NMR(400MHz,D 2O)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).
实施例22：二氨基铂(Ⅱ)【3-亚丙基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000092
将1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-葡萄糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.46g最终产品。
1H NMR(400MHz,D 2O)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).
实施例23：二氨基铂(Ⅱ)【3-亚丙基-(1-O-D-甘露糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000093
将1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-甘露糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.40g最终产品。
1H NMR(400MHz,D 2O)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).
实施例24：二氨基铂(Ⅱ)【3-亚丙基-(1-O-D-半乳糖苷)环丁烷-1,1-二甲酸】制备
Figure PCTCN2019076236-appb-000094
将1,1-二甲酸-3-亚丙基-【2,3,4,6-四羟基-1-O-D-半乳糖苷】环丁烷(1.0g)溶于20mL水中，用饱和氢氧化钡溶液调节溶液酸碱度到pH≈8。该混合溶液在室温下搅拌30分钟。在氮气保护下将含有二胺硫酸铂(0.65g)的水溶液(7ml)加入到上述所得反应液中，室温避光搅拌12小时。待反应完成后，使用离心机除去沉淀，收集上清液，使用冷冻干燥机冻干，用半制备高压液相色谱分离得到0.43g最终产品。
1H NMR(400MHz,D 2O)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).
实施例25：二氨基铂(Ⅱ)【3-亚己基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】的制备
Figure PCTCN2019076236-appb-000095
Figure PCTCN2019076236-appb-000096
(1)6-苄氧基-1-己醇的制备
将1,6-己二醇(2.36g)溶解于60mL干燥的N,N-二甲基甲酰胺中，在0℃向反应液缓慢分批加入60％氢化钠(920mg)，搅拌30分钟后缓慢加入溴化苄(2.38mL)，反应液缓慢升至室温并搅拌过夜。用TLC监测反应终点，待反应完成后，用减压旋蒸除去多余的溶剂，向残留物中加入100mL乙酸乙酯，然后用饱和氯化铵水溶液(1×50mL)洗涤，将水相用乙酸乙酯萃取(100mL)，合并两次的有机相，并依次用饱和氯化铵水溶液(1×100mL)，蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，用旋转蒸发仪将溶剂蒸干，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝4/1)，得到无色透明油状产物1.8g。
(2)苄基-6-溴己醚的制备
将6-苄氧基-1-己醇(1.5g)溶解于20mL干燥的二氯甲烷中，将反应液冷却到0℃，缓慢滴加四溴化碳(3.5g)的二氯甲烷溶液(10mL)，然后缓慢加入三苯基磷(2.8g)的二氯甲烷溶液(10mL)，反应液在0℃下搅拌1小时，用TLC监测反应终点，待反应完成后，减压旋蒸除去 多余的溶剂，残留物经硅胶柱色谱纯化(石油醚/乙酸乙酯＝20/1)，得到无色透明油状产物1.7g。
(3)2-(6-苄氧基己基)丙二酸二乙酯的制备
在冰水浴中将60％氢化钠(222mg)混悬于5mL干燥四氢呋喃溶液中，用氮气置换烧瓶内空气，在氮气保护下缓慢滴加丙二酸二乙酯(1.3mL)，反应在冰水浴中搅拌0.5小时后，向反应液中缓慢滴加苄基-6-溴己醚(1.5g)的干燥四氢呋喃溶液(2mL)，然后将反应液升温至70℃并搅拌5小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入100mL乙酸乙酯，然后用饱和氯化铵水溶液(1×50mL)洗涤，将水相用乙酸乙酯萃取(2×50mL)，合并两次的有机相，将有机相依次用饱和氯化铵水溶液(1×100mL)，蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，用旋转蒸发仪将溶剂蒸干，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝20/1)，得到无色透明油状产物1.5g。
(4)2-(6-苄氧基己基)-1,3-丙二醇的制备
在冰水浴中将四氢锂铝(282mg)混悬于15mL无水乙醚中，在氮气保护下缓慢滴加2-(6-苄氧基己基)丙二酸二乙酯(1.3g)的无水乙醚溶液(10mL)，用TLC监测反应终点，待反应完成后，向反应液中缓慢加入十水硫酸钠至反应液中不再有气体产生，将固体过滤，收集滤液，用旋转蒸发仪将溶剂蒸干，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝2/1)，得到无色透明油状产物0.8g。
(5)6-苄氧己基-1,3-二溴丙烷的制备
将2-(6-苄氧基己基)-1,3-丙二醇(0.6g)溶解于8mL干燥的二氯甲烷中，将反应液冷却至0℃，缓慢滴加四溴化碳(2.2g)的二氯甲烷溶液(4mL)，然后缓慢加入三苯基膦(1.8g)的二氯甲烷溶液(4mL)，0℃下反应1小时，用TLC监测反应终点，待反应完成后，减压旋蒸除去多余的溶剂，残留物经硅胶柱色谱纯化(石油醚/乙酸乙酯＝20/1)，得到无色透明油状产物0.8g。
(6)1,1-二甲酸二乙酯-3-苄氧己基-环丁烷的制备
在冰水浴条件下，将60％氢化钠(142mg)混悬于3mL干燥的N,N-二甲基甲酰胺中，在氮气保护下缓慢滴加丙二酸二乙酯(0.54mL)，搅拌半小时后，向反应液中缓慢滴加2-苄氧己基-1,3-二溴丙烷(0.7g)的N,N-二甲基甲酰胺(3mL)溶液，然后将反应液升温至70℃并搅拌7小时。用TLC监测反应终点，待反应完成后，将反应液冷却至室温，向反应液中加入100mL乙酸乙酯，然后用饱和氯化铵水溶液(1×50mL)洗涤，将水相用乙酸乙酯萃取(2×50mL)，合并两次的有机相并依次用饱和氯化铵水溶液(1×100mL)，蒸馏水(1×100mL)，饱和氯化钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，用旋转蒸发仪将溶剂蒸干，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝20/1)，得到无色透明油状产物0.5g。
(7)1,1-二甲酸二乙酯-3-羟己基-环丁烷的制备
将3-苄氧己基-环丁烷-1,1-二甲酸二乙酯(0.4g)溶解在于10mL甲醇中，加入10％钯碳(0.1g)，用氮气将反应瓶中的空气置换3次，然后用氢气将反应瓶中的氮气置换3次，反应液在室温下搅拌过夜。用TLC监测反应终点，待反应完成后，用氮气置换反应瓶中的氢气，将钯碳过滤，收集滤液，然后用旋转蒸发仪将溶剂蒸干，得到无色透明油状的产物0.3g。
(8)1,1-二甲酸二乙酯3-亚己基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷的制备
将3-羟己基-环丁烷-1,1-二甲酸二乙酯(200mg)和1，2，3，4，6-五乙酰-β-D-吡喃葡萄糖酯(286mg)溶解于5mL干燥二氯甲烷中，反应液冷却至0℃，然后缓慢滴加三氟化硼的乙醚溶液(1mL)，反应液由0℃缓慢升至室温并搅拌过夜。用TLC监测反应终点，待反应完成后，向反应液中加入二氯甲烷(100mL)，有机相依次用蒸馏水(1×100mL)，饱和碳酸氢钠溶液(1×100mL)洗涤，然后用无水硫酸钠干燥，用旋转蒸发仪将溶剂蒸干，得到的淡黄色油状物用硅胶柱色谱纯化(石油醚/乙酸乙酯＝5/1)，得到无色透明油状的产物60mg。
(9)1,1-二甲酸-3-亚己基-【1-O-D-葡萄糖苷】环丁烷的制备
1,1-二甲酸二乙酯3-亚己基-【2,3,4,6-O-乙酰基-1-O-D-葡萄糖苷】环丁烷(60mg)溶解于1mL甲醇中，然后加入氢氧化钠(34mg)的水溶液(2mL)，将反应液升温至90℃反应5小时，用TLC监测反应终点，待反应完成后，将反应液冷却至室温，用旋转蒸发仪除去甲醇，然后向反应液中加入强酸性阳离子交换树脂并搅拌半小时，将树脂进行过滤，收集滤液使用冷冻干燥机进行干燥，得到无色粘稠状液体35mg，粗产品直接用于下一步反应。
(10)二氨基铂(Ⅱ)【3-亚己基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】制备
将1,1-二甲酸-3-亚己基-【1-O-D-葡萄糖苷】环丁烷粗产品(35mg)溶解于2mL水中，加入氢氧化钠水溶液调节反应液pH到7，室温避光条件下搅拌30min。在氮气保护下将二胺硝酸铂(30mg)溶解于1mL水中，逐滴滴加入至上述反应液中，室温避光搅拌1小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相制备色谱进行分离纯化，然后使用低温冷冻干燥机进行干燥，得到20mg终产品，白色固体。
1H NMR(400MHz,D 2O)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).
实施例26：顺-【反式-(1R,2R)-二胺基环己烷】铂(Ⅱ)【3-亚己基-(1-O-D-葡萄糖苷)环丁烷-1,1-二甲酸】的制备
将上述实施例25种所制备的1,1-二甲酸-3-亚己基-【1-O-D-葡萄糖苷】环丁烷(35mg)2mL 水中，加入氢氧化钠水溶液调节反应液pH到7，室温避光条件下搅拌30min。在氮气保护下将将含有环己二胺硫酸铂(40m g)的水溶液1mL，逐滴滴加入至上述反应液中，室温避光搅拌1小时。用HPLC检测反应，待反应完成后，使用离心机除去沉淀，收集上清液，用半制备高压液相制备色谱进行分离纯化，然后使用低温冷冻干燥机进行干燥，得到30mg终产品，白色固体。
1H NMR(400MHz,D 2O)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,J＝11.6,9.6Hz,2H),2.25–2.15(m,1H),1.68–1.59(m,2H),1.44–1.29(m,8H).
试验例1：溶解度试验
实验方法：用5mL的EP管取大约0.5mL蒸馏水，慢慢加入干燥的化合物至不能溶解(25℃超声震荡，仍出现浑浊)。将溶液过滤至另一个5mL干净且已称重的EP管中，再称重，计算出溶液的重量。将滤液冻干，称重并计算出所剩固体的溶质质量，这样就可以知道溶剂的重量和溶质的质量，从而计算出化合物在水中的溶解度。
表2 实施例样品在水中的溶解度数据
化合物 溶解度(mg/mL) 化合物 溶解度(mg/mL)
1 512.11 14 842.05
2 246.92 15 1089.40
3 459.38 16 1211.51
4 507.75 17 732.82
5 235.35 18 1080.72
6 443.30 19 1105.96
7 490.79 20 687.09
8 225.83 21 1038.69
9 430.29 22 1100.37
10 483.54 23 669.92
11 223.12 24 958.3
12 418.76 25 764.66
13 1357.68 26 684.67
顺铂 1.0 卡铂 17.0
奥沙利铂 6.0    
本发明铂类配合物在水中的溶解度远远大于已经上市的顺铂、卡铂和奥沙利铂，水溶性能够提高几十至上千倍。
试验例2：抗肿瘤药效
以下实验针对本发明的用于肿瘤治疗的环丁烷二羧酸铂配合物对不同种类的人肿瘤细胞的增殖抑制效果进行了实验验证。
(1)试验方法：
细胞培养液：
使用含有10％胎牛血清(fetal bovine serum)的细胞培养液。
主要实验仪器：
HERAcell150i型二氧化碳培养箱(Thermo)、研究级倒置荧光显微镜(Nikon,日本)、多功能酶标仪(Thermo)、超低温冰箱(Thermo)、生物安全柜(1300 Series A2,Thermo)、微量移液器(德国eppendorf)、超纯水系统(美国Milli-Q)。
实验试剂：
MTT:Sigma-Aldrich公司
DMSO:天津市江天化工技术有限公司
肿瘤细胞：
表3 MTT试验细胞列表
细胞编号 细胞类型
HT29 人结肠癌细胞
A549 人非小细胞肺癌细胞
SMMC7721 人肝癌细胞
MCF-7 人乳腺癌细胞
SKOV3 人卵巢癌细胞
ECA109 人食管癌细胞
DU145 人前列腺癌细胞
Hela 人宫颈癌细胞
A375 人黑色素瘤细胞
KB 人口腔表皮样癌细胞
HGC27 人胃癌细胞
SW579 人甲状腺癌细胞
5637 人膀胱癌细胞
Panc-1 人胰腺癌细胞
H460 人大细胞肺癌细胞
H929 人浆细胞白血病细胞
HepG2 人肝癌细胞
THP-1 人单核细胞白血病
细胞毒性测试：
细胞毒性实验采用MTT法测试。收集对数期肿瘤细胞，调整细胞悬液浓度，每孔加入100μl， 铺板调整待测细胞密度至1000-10000个/孔，(边缘孔用无菌PBS填充)。在5％CO 2，37℃孵育，至细胞贴壁(96孔平底板)，加入不同浓度梯度的药物，每孔100μl，设4个复孔。在5％CO 2，37℃条件下孵育72小时，倒置显微镜下观察。向96孔板中加入配制好的MTT溶液(5mg/ml),每孔20μl，混匀，在37℃，5％CO 2条件下孵育4h后，弃掉板内液体，每孔加入150μl DMSO，酶标仪振荡3分钟，在490nm处检测OD值(光密度值)。
对照组：
在上述同样条件下不添加被测活性成分，最后取得肿瘤细胞在490nm处检测OD值。药物对肿瘤细胞的抑制活性IC 50：
细胞抑制率计算：按下列公式计算药物对肿瘤细胞生长的抑制率：
1)细胞存活率(％)＝(治疗组OD值/对照组OD值)×100
2)求出各药物浓度下的细胞存活率，用此对药物浓度作图。以此判断不同药物浓度对肿瘤细胞增殖抑制的药效。
3)细胞存活率为对照组的50％时所对应的药物浓度，为药物对肿瘤细胞的半数抑制浓度，即药物的IC 50值。
上述每个药物浓度的实验重复4组，取平均OD值计算细胞存活率。
(2)实验结果：(IC 50(验结果值)
表4 MTT试验结果(一)
化合物 1 2 3 4 5 6 7 8 9 10 卡铂
HT29 16.44 37.37 33.67 16.68 38.93 36.68 17.31 37.12 32.23 15.42 53.20
SMMC7721 4.96 8.12 7.24 5.02 6.91 6.87 4.90 8.91 8.71 4.68 12.03
MCF-7 93.95 153.47 154.17 85.26 155.46 144.89 86.02 146.35 140.31 86.49 282.81
A549 35.87 66.27 64.81 38.18 68.54 68.46 31.19 63.3 60.09 40.78 95.26
SKOV3 99.32 155.63 173.37 97.73 175.55 182.32 81.68 169.05 165.07 87.35 318.37
ECA109 11.62 19.18 20.10 9.39 20.21 20.36 11.31 19.33 17.44 10.11 26.88
DU145 56.14 93.65 99.18 60.03 97.00 97.11 58.80 91.71 93.22 64.33 135.10
Hela 13.13 19.04 24.43 15.26 19.56 19.28 15.40 16.28 22.66 15.11 34.13
A375 14.62 21.12 20.46 13.79 20.41 21.00 14.19 23.84 22.55 14.44 31.24
KB 16.13 25.33 26.15 15.16 25.31 17.59 14.24 18.14 22.43 14.30 33.51
HGC27 26.53 34.95 43.44 31.96 54.59 50.94 30.16 51.36 58.23 30.11 68.31
SW579 50.01 97.41 84.05 75.55 91.40 89.89 72.22 97.12 99.00 83.55 170.46
5637 10.93 15.11 15.02 13.33 19.02 18.07 12.64 18.18 19.33 12.11 27.90
Panc-1 94.42 132.12 132.49 95.58 122.23 121.43 93.70 127.57 152.23 98.22 213.94
H929 10.03 15.71 16.65 7.45 15.95 13.80 7.67 17.11 14.66 8.89 23.14
HepG2 11.83 17.89 15.20 9.03 16.90 16.73 11.93 16.33 18.99 9.90 29.70
THP-1 6.68 8.43 8.14 6.15 10.53 10.30 6.29 9.25 8.66 7.01 15.01
表5 MTT试验结果(二)
IC 50(μM)值 11 12 13 14 15 16 17 18 19 20 卡铂
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
表6 MTT试验结果(三)
IC 50(μM)值 21 22 23 24 25 26 卡铂
HT29 20.27 25.07 24.52 19.26 20.21 40.34 53.20
SMMC7721 4.91 4.67 4.55 5.06 5.54 8.11 12.03
MCF-7 94.23 98.92 72.53 87.96 90.23 145.32 282.81
A549 38.31 41.79 37.14 36.25 33.31 63.67 95.26
SKOV3 91.40 101.68 108.11 120.39 91.42 170.44 318.37
ECA109 11.52 12.45 10.77 10.52 10.99 20.11 26.88
DU145 57.31 54.90 54.65 52.70 53.43 88.99 135.10
Hela 16.39 15.22 14.22 15.09 16.11 20.56 34.13
A375 14.62 14.22 12.31 13.71 11.62 22.01 31.24
KB 14.09 13.91 12.77 11.43 14.77 19.23 33.51
HGC27 27.80 24.34 25.78 25.04 20.34 42.54 68.31
SW579 77.54 73.21 77.54 80.99 81.52 92.22 170.46
5637 11.34 11.89 11.99 12.25 11.78 15.45 27.90
Panc-1 74.08 91.87 80.98 94.03 80.01 145.66 213.94
H929 11.34 10.32 10.34 9.01 10.11 17.88 23.14
HepG2 10.56 11.88 12.23 13.06 12.11 19.50 29.70
THP-1 7.22 7.21 6.91 6.65 6.55 10.21 15.01
注：“--”代表未测试。
试验例3本发明化合物与已知化合物的抗肿瘤药效比较
对比文件WO2008086783A2中公开了如下糖分子3-位偶联的环丁烷二羧酸铂配合物：公开化合物-1和公开化合物-2.为了验证本发明配合物的抗肿瘤药效优于公开化合物，实施了如下药效对比实验：
Figure PCTCN2019076236-appb-000097
(1)试验方法：
试验方法与实验例2抗肿瘤药效实验方法相同，选择进行对比的化合物为本发明中与公开化合物含有相同葡萄糖分子结构的化合物(化合物-1、4、7、10、13、16、19、22、25)，以及含有非葡萄糖分子结构的本发明化合物(化合物-11、20、23：甘露糖；化合物-12、15、18、24：半乳糖)，与公开化合物进行抗肿瘤药效对比，分别获得药物对肿瘤细胞的半数抑制浓度，即药物的IC 50值。
(2)试验结果：
表7 MTT药效对比试验结果
Figure PCTCN2019076236-appb-000098
Figure PCTCN2019076236-appb-000099
Figure PCTCN2019076236-appb-000100
结果表明：与公开化合物相比，本发明化合物在各种不同肿瘤细胞中的抗肿瘤药效，均明显优于公开化合物。

Claims (10)

  1. 一种式(I)所示的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物：
    Figure PCTCN2019076236-appb-100001
    其中：
    X和Y是配位体，所述X和Y各自独立地选自NH 3、C 1-C 8直链或支链烷基伯胺(可选为C 1-C 6的直链或支链烷基伯胺，可选为C 1-C 3的直链或支链烷基伯胺)、C 3-C 8环状烷基伯胺(可选为C 3-C 6环状烷基伯胺)、芳香族伯胺、一个或多个C 1-C 4直链或支链烷基取代的芳香族伯胺、分子式为R 1-NH-R 2的仲胺，其中R 1和R 2相同或者不同各自表示为C 1-C 8的直链或支链烷基(可选为C 1-C 6的直链或支链烷基，可选为C 1-C 3的直链或支链烷基)；或R 1-NH-R 2共同组成C 4-C 8的脂环仲胺(可选为C 5-C 6的脂环仲胺)、含氮芳香族杂环化合物、一个或多个C 1-C 4直链或支链烷基取代的含氮芳香族杂环化合物、含硫芳香族杂环化合物或含硫非芳香族杂环化合物；其中，所述“芳香族伯胺”中的芳基为5～10元单环或稠合双环芳香基团，所述“芳香族杂环”为5～10元单环或稠合双环芳香杂环，所述“非芳香族杂环”为4～10元单环或多环脂杂环；
    或者X和Y一起构成式(IV)结构：
    Figure PCTCN2019076236-appb-100002
    式(IV)中，D为C 0或C 1的亚烷基；B为C 2-C 8的亚烷基(可选为C 2-C 6的亚烷基、可选为C 3-C 5的亚烷基)；
    n＝0、1、2、3、4、5或6(可选地，n＝0、1、2、3或6，可选地，n＝0、1、2或3)；
    R选自下述单糖基，所述单糖1-位取代为α取代或者β取代：
    Figure PCTCN2019076236-appb-100003
    可选地，R选自下述单糖基，单糖1-位取代为α取代或者β取代，
    Figure PCTCN2019076236-appb-100004
  2. 根据权利要求1所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物，其特征在于所述X和Y分别为NH 3，或X,Y一起为反式-(1R，2R)-环己二胺，反式-(1S，2S)-环己二胺，顺式-(1R，2S)-环己二胺，顺式-(1S，2R)-环己二胺，消旋反式-1，2-环己二胺或消旋顺式-1，2-环己二胺。
  3. 根据权利要求1或2所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物，其特征在于所述X和Y分别为NH 3；或X,Y一起为反式-(1R，2R)-环己二胺。
  4. 根据权利要求1-3任一项所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可 接受的盐、或其溶剂化物，其中，
    所述X和Y分别为NH 3；或X,Y一起为反式-(1R，2R)-环己二胺；
    n＝0、1、2、3或6；
    R选自下述单糖基，所述单糖1-位取代为α取代或者β取代：
    Figure PCTCN2019076236-appb-100005
  5. 根据权利要求1-4任一项所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物，所述式(I)选自下述配合物，
    Figure PCTCN2019076236-appb-100006
    Figure PCTCN2019076236-appb-100007
    Figure PCTCN2019076236-appb-100008
  6. 一种式(III)所示的化合物，
    Figure PCTCN2019076236-appb-100009
    式(III)中：
    各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；
    n＝0、1、2、3、4、5或6(可选地，n＝0、1、2、3或6，可选地，n＝0、1、2或3)；
    R选自氢，或下述单糖基，单糖1-位取代为α取代或者β取代：
    Figure PCTCN2019076236-appb-100010
    可选地，所述式(III)选自下述化合物：
    Figure PCTCN2019076236-appb-100011
    式(III-1)，式(III-2)，式(III-3)中，
    n＝0、1、2、3或6(可选地，n＝0、1、2或3)；
    M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba。
  7. 权利要求1-5任一项所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、溶剂化物的制备方法，其特征在于包括将式(II)化合物与式(III)化合物加水调节为水溶液进行反应的步骤；可选地，反应水溶液加碱调节pH为7-9，
    可选地，所述碱为无机碱，可选地，所述无机碱选自氢氧化钠，氢氧化钾，碳酸钠，碳酸氢 钠，碳酸钾，氢氧化锂，氢氧化铯或氢氧化钡中的一种或多种；
    所述(II)的结构式为：
    Figure PCTCN2019076236-appb-100012
    式(II)中：
    X和Y的定义与式(I)中的相同，
    A 1和A 2相同或者不同，各自独立地代表羟基，硝酸根或高氯酸根，或者A 1和A 2共同代表硫酸根或碳酸根；
    所述(III)的结构式为：
    Figure PCTCN2019076236-appb-100013
    式(III)中：
    各个M各自独立地代表氢原子，或者元素周期表第IA族的金属原子，或者两个M共同代表元素周期表中第IIA族的金属原子；可选的M各自独立地代表H、Na、K、Li、Cs或两个M共同代表Ba；
    n＝0、1、2、3、4、5或6(可选地，n＝0、1、2、3或6)；
    R选自氢，或R选自下述单糖基，单糖1-位取代为α取代或者β取代：
    Figure PCTCN2019076236-appb-100014
    Figure PCTCN2019076236-appb-100015
  8. 一种药物组合物，其包括权利要求1-5任一项所述的环丁烷二羧酸铂配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物中的一种或多种以及任选存在的药学上可接受的载体。
  9. 权利要求1-5任一项所述的配合物、或其光学异构体、或其药学上可接受的盐、或其溶剂化物、或者权利要求7所述的药物组合物在制备抗肿瘤药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于所述肿瘤为人肺癌，人肝癌，人大肠癌，人头颈癌，人前列腺癌，人乳腺癌，人卵巢癌，人子宫颈癌，人白血病，人淋巴癌，人皮肤癌，人胰腺癌，人膀胱癌，人食道癌，人胃癌，人男性生殖器癌，人甲状腺癌，人骨癌，人黑色素癌，或人口腔癌。
    可选地，所述肿瘤的细胞为人结肠癌细胞HT29，人非小细胞肺癌细胞A549，人肝癌细胞SMMC7721，人乳腺癌细胞MCF-7，人卵巢癌细胞SKOV3，人食管癌细胞ECA109，人前列腺癌细胞DU145，人宫颈癌细胞Hela，人黑色素瘤细胞A375，人口腔表皮样癌细胞KB，人胃癌细胞HGC27，人甲状腺癌细胞SW579，人膀胱癌细胞5637，人胰腺癌细胞Panc-1，人大细胞肺癌细胞H460，人浆细胞白血病细胞H929，人肝癌细胞HepG2，人单核细胞白血病THP-1。
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