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 PDFInfo
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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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- 239000008367 deionised water Substances 0.000 description 2
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- 238000004821 distillation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
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- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
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- AJLYOHLKYFSFSE-UHFFFAOYSA-N 3-benzhydryloxy-3-oxopropanoic acid Chemical compound C=1C=CC=CC=1C(OC(=O)CC(=O)O)C1=CC=CC=C1 AJLYOHLKYFSFSE-UHFFFAOYSA-N 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 150000007942 carboxylates Chemical class 0.000 description 1
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- 239000012930 cell culture fluid Substances 0.000 description 1
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- IYYVTOXOSQYWKJ-UHFFFAOYSA-N diethyl 2-(6-phenylmethoxyhexyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CCCCCCOCC1=CC=CC=C1 IYYVTOXOSQYWKJ-UHFFFAOYSA-N 0.000 description 1
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- HCWOVPZEAFLXPL-UHFFFAOYSA-N diphenyl propanedioate Chemical compound C=1C=CC=CC=1OC(=O)CC(=O)OC1=CC=CC=C1 HCWOVPZEAFLXPL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 229930182478 glucoside Natural products 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
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- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 150000002641 lithium Chemical group 0.000 description 1
- 208000016848 malignant germ cell tumor Diseases 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
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- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- PQTLYDQECILMMB-UHFFFAOYSA-L platinum(2+);sulfate Chemical compound [Pt+2].[O-]S([O-])(=O)=O PQTLYDQECILMMB-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Images
Classifications
-
- 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
Description
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 |
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 |
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 |
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 |
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 |
Claims (10)
- 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: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: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: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,
- 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。
- 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。
- 一种式(III)所示的化合物,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:可选地,所述式(III)选自下述化合物: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。
- 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: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: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:
- 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。
- 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。
- 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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