WO2017215188A1 - 新型紫杉类化合物及其制备方法和应用 - Google Patents

新型紫杉类化合物及其制备方法和应用 Download PDF

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WO2017215188A1
WO2017215188A1 PCT/CN2016/105692 CN2016105692W WO2017215188A1 WO 2017215188 A1 WO2017215188 A1 WO 2017215188A1 CN 2016105692 W CN2016105692 W CN 2016105692W WO 2017215188 A1 WO2017215188 A1 WO 2017215188A1
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cancer
group
protecting
taxane compound
novel taxane
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PCT/CN2016/105692
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French (fr)
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杨达丽亚
王慧娟
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内蒙古普因药业有限公司
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Priority to EP16905300.6A priority Critical patent/EP3470403B1/en
Priority to JP2018565744A priority patent/JP6801011B2/ja
Priority to CA3043895A priority patent/CA3043895C/en
Priority to US16/310,403 priority patent/US10676497B2/en
Publication of WO2017215188A1 publication Critical patent/WO2017215188A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a novel taxane compound and a preparation method and application thereof.
  • taxane compounds have deficiencies such as high toxicity and low antitumor activity, especially for solid tumors such as gastrointestinal cancer, lung cancer, breast cancer and leukemia.
  • the object of the present invention is to solve the deficiencies of the prior art and to provide a novel type with less toxicity, higher anti-tumor activity, especially for solid tumors such as gastrointestinal cancer, lung cancer, breast cancer and leukemia. Taxane compounds and preparation methods and applications thereof.
  • a technical solution for achieving the above object of the present invention is: a novel taxane compound having a structure as shown in the general formula (I):
  • R 1 is a C 1 -C 6 alkyl group or a substituted alkyl group, preferably an ethyl group, an n-butyl group or a n-hexyl group, and more preferably an n-butyl group.
  • n is 0 to 6, preferably 0 to 2, and more preferably 1.
  • the preparation method of the above novel taxane compound has the following steps:
  • the hydroxy protecting reagent used in the above step S1 is hexamethyldisilazane, hexamethyldisiloxane, trimethylchlorosilane or trimethyliodosilane, preferably hexamethyldisilazane.
  • the alkyl chloroformate described in the above step S1 is methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, n-amyl chloroformate, chloroformic acid.
  • One of the esters is preferably ethyl chloroformate, n-butyl chloroformate or n-hexyl chloroformate, more preferably n-butyl chloroformate.
  • the protective reagent used in the first hydroxy protection in the above step S2 is tert-butyldimethylchlorosilane, isopropyldimethylchlorosilane, ethyldimethylchlorosilane or trimethylchlorosilane, preferably tert-butyl Dimethylchlorosilane.
  • the protective reagent for the second hydroxyl protection in the above step S2 is 2,2,2-trichloroethyl chloroformate.
  • the dianhydride used in the above step S3 is succinic anhydride, glutaric anhydride or adipic anhydride, preferably glutaric anhydride.
  • the condensation reagent used in the above step S4 is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC) or N,N-diisopropylcarbodiimide (DIC), preferably 1-(3-dimethylaminopropane) 3-ethylcarbodiimide hydrochloride or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, more preferably 1-(3-dimethylaminopropane) 3-ethylcarbodiimide hydrochloride.
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EDC 1-ethyl-(3-d
  • the condensation reaction of the above step S4 is preferably carried out in the presence of 4-dimethylaminopyridine.
  • the hydroxy deprotection of the above step S5 is carried out in the presence of zinc powder and sodium acetate.
  • the above tumor is a hematoma or a malignant solid tumor; specifically, the above tumor includes colon cancer, rectal cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, liver cancer, esophageal cancer, brain tumor, ovarian cancer, uterine cancer, Kidney cancer, head and neck cancer, skin cancer, bladder cancer, vulvar cancer, testicular tumor, villus cancer, germ cell tumor, malignant lymph Tumor, leukemia and multiple myeloma; preferably including colon cancer, rectal cancer, gastric cancer, lung cancer, breast cancer, and leukemia.
  • a pharmaceutical composition comprising as an active ingredient the above novel taxane compound and one or more pharmaceutically acceptable carriers/excipients.
  • the dosage form of the above pharmaceutical composition is an injection dosage form or an oral dosage form, wherein the injection dosage form is a solution injection, a suspension injection, an emulsion injection, or a sterile powder for injection; the oral dosage form is a tablet, a powder, a granule, a capsule. Agents, pellet preparations, solutions, suspensions, emulsions, syrups or elixirs.
  • the positive effect of the invention is that the novel taxane compound of the invention has less toxicity (MTD dose only 250mg/kg) and has high anti-tumor activity, especially for solid tumors such as gastrointestinal cancer, lung cancer, breast cancer and leukemia. Has a good inhibition rate (colon cancer TGI up to 85.69%).
  • Fig. 1 is a 1 H-NMR chart of the intermediate G1.
  • Fig. 2 is a 1 H-NMR chart of the intermediate G2.
  • Fig. 3 is a 1 H-NMR chart of the intermediate D1.
  • Fig. 4 is a 1 H-NMR chart of the intermediate D2.
  • Fig. 5 is a 1 H-NMR chart of the novel taxane Z1.
  • Fig. 6 is a 13 C-NMR chart of the novel taxane Z1.
  • Figure 7 is an HSQC diagram (heteronuclear single quantum correlation spectrum) of the novel taxane Z1.
  • the preparation method of the novel taxane Z1 has the following steps:
  • reaction mixture was evaporated to dryness, and the residue was dissolved in 500 mL of ethyl acetate/dichloromethane mixture (1:3), and then shaken with 300 mL of citric acid solution (containing 42 g of citric acid) in a separating funnel.
  • citric acid solution containing 42 g of citric acid
  • the organic layer was directly poured into a filter funnel containing 100 g of silica gel, and the aqueous phase was extracted three times with 200 mL of ethyl acetate/dichloromethane mixed solvent (1:3), followed by 100 mL of ethyl acetate/dichloromethane.
  • the reaction mixture was shaken with 3.90 g of citric acid (18.6 mmol, 4.5 eq.), and the extract after evaporation of the solvent did not need to be dried.
  • the residue was dried under high vacuum at 40 ° C, and then dissolved in 27 mL of tetrahydrofuran.
  • the solution was cooled to 0 ° C, triethylamine and 3 times hydrofluoric acid were added, the solution was placed in a refrigerator at 5 ° C overnight, and the reaction mixture was placed at 20 ° C for 3 h the next day, and then distilled off at this temperature.
  • Solvent 3.90 g of citric acid (18.6 mmol, 4.5 eq.
  • the pyridine was distilled off at 30 ° C, and the residue was dried under vacuum at this temperature, and the residue was dissolved in a solution of 5.5 g of citric acid (26 mmol, 32 eq.), then extracted with dichloromethane, and the extract was poured directly.
  • the silica gel column (containing 20 g of silica gel) was used, and the impurities were washed away with 110 mL of a methanol/methylene chloride mixed solvent (1:100), and the product was mixed with 143 mL of methanol/dichloromethane (1:100) and 102 mL of methanol. The mixture was washed with a methylene chloride mixed solvent (1:50), and evaporated to dryness.
  • the crude product was subjected to silica gel column chromatography (35 g silica gel), and then 50 mL of dichloromethane, 210 mL of ethyl acetate / dichloromethane mixed solvent (1:20) and 220 mL of ethyl acetate / dichloromethane mixed solvent
  • the impurities were washed away (1:10), and the eluted fractions were collected in a test tube, and subjected to column elution with an ethyl acetate/dichloromethane mixed solvent (1:5).
  • the same fractions were combined, and the solvent was evaporated, and then dried in vacuo at 40 ° C to give 0.623 g of white solid intermediate D1, yield 60%.
  • the reaction mixture was poured directly into a silica gel column (containing 35 g of silica gel), and then mixed with 50 mL of dichloromethane, 205 mL of ethyl acetate / dichloromethane mixed solvent (1:40), 210 mL of ethyl acetate / dichloromethane
  • the solvent (1:20) and 220 mL of a mixed solvent of ethyl acetate/dichloromethane (1:10) were used to wash away the impurities, and the eluted fractions were collected in a test tube using 360 mL of ethyl acetate/dichloromethane.
  • the mixed solvent (1:5) was subjected to column elution, the same fractions were combined, and the solvent was evaporated, and then dried under vacuum at 40 ° C to give 0.636 g of colorless transparent intermediate D2 with a yield of 76%.
  • TLC showed that the intermediate D2 disappeared, only a trace amount of di(trichloroethane)
  • the oxyformyl) product and an amount of the mono(trichloroethoxycarbonyl) product are mostly the target product.
  • Ultrasonic vibration was continued and vigorously shaken for 15 min.
  • TLC showed no bis(trichloroethoxycarbonyl) product, but a part of mono(trichloroethoxycarbonyl) was still present, and the reaction mixture was ultrasonically shaken for the third time.
  • the 1 H-NMR spectrum, the 13 C-NMR spectrum, and the HSQC spectrum of the target product Z1 are shown in Figures 5 to 7, respectively.
  • the preparation method of each example is basically the same as that of Example 1, except that the alkyl chloroformate used in the step S1, the dianhydride used in the step S3, and the finally obtained novel taxane compound are shown in Table 1.
  • This example is a method for preparing a pharmaceutical composition containing the novel taxoid compound Z1 of Example 1.
  • the injection type is lyophilized powder injection, including: 30g of new taxane Z1, mannitol (20%, w/v) 300g, buffer sodium dihydrogen phosphate dihydrate 7g, surfactant Polan Sham 188 (F68) 4.0g.
  • Sodium dihydrogen phosphate dihydrate, poloxamer 188 (F68), mannitol (20%, w/v) accurately weighed according to the above prescription amount is added to 300 g of water for injection precooled to below 10 ° C to dissolve. Adjust the pH of the solution to 7.3-7.5 with 0.1 mol/L NaOH; add 30 g of the new taxane compound Z1 to the above solution.
  • the novel taxane compound of the present invention can be prepared into other forms of injection preparations such as a solution injection, a suspension injection, and an emulsion injection.
  • Suitable dosage forms of the pharmaceutical composition may be formulated into oral powders, granules, capsules, pellets, solutions, suspensions, emulsions, syrups or elixirs, in addition to the tablet forms mentioned above, or It is a sustained-release and controlled-release preparation in oral form, or a pharmaceutical composition in other oral forms.
  • These oral dosage forms contain common corresponding excipients (additives, add-ons, etc. according to different effects), such as additives with drug grades. Mannitol, lactose, starch, magnesium stearate, saccharin salt, cellulose or magnesium sulfate.
  • a pharmaceutically acceptable addenda may be selected as a carrier for the pharmaceutically active ingredient, including materials mature in the prior art, such as inert solid diluents, aqueous solvents, liposomes, microspheres or/and none.
  • Toxic organic solvents, etc. preferred additions are: moisturizer, emulsifier, pH buffer, human serum albumin, antioxidants, preservatives, bacteriostatic agents, glucose, sucrose, trehalose, maltose, lecithin, glycine, Sorbic acid, propylene alcohol, polyethylene, protamine, boric acid, sodium chloride, or potassium chloride, mineral oil, vegetable oil, etc.; one or several combinations may be selected as a pharmaceutical carrier.
  • Target tumors of the pharmaceutical compositions of the invention include hematomas or malignant solid tumors.
  • the target tumor includes colon cancer, rectal cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, liver cancer, esophageal cancer, brain tumor, ovarian cancer, uterine cancer, kidney cancer, head and neck cancer, skin cancer, bladder cancer.
  • vulvar cancer testicular tumor, villus cancer, germ cell tumor, malignant lymphoma, leukemia and multiple myeloma, and even more preferred target tumors may include colon cancer, rectal cancer, stomach cancer, lung cancer, pancreatic cancer, liver cancer, ovary Cancer, renal cancer, malignant lymphoma, breast cancer, and leukemia, but the present invention is not limited thereto.
  • This application example is to study the toxicity of single-time intraperitoneal administration of the novel taxane Z1 of Example 1 to ICR mice to determine the maximum tolerance dose (MTD).
  • the maximum tolerated dose means that the animal does not die, the animal's weight loss does not exceed 10% (compared to Day 0), or the dose does not produce significant toxic side effects.
  • the solvent used to dissolve the test substance is as follows:
  • Cremophor EL lot 27963, manufacturer: Sigma.
  • the animal room environment maintained a temperature of 18-26 ° C, relative humidity of 30-70%, 12 hours of light.
  • the experimental animals were filtered and sterilized with water, and the animals were free to eat and drink.
  • Mode of administration IP. If the animal dies, the dose is reduced until the animal survives, and if there is no animal death, the dose is increased; if the animal is normally alive at a given high dose, the experiment is over. Finally, the MTD of the test subject was determined according to the experimental results; the animals were continuously observed for 7 days after acute administration.
  • All animals in the experiment were subjected to detailed clinical observations of all the tested animals. Two times a day (10:00, 16:00 each), continuous observation for 14 days, including but not limited to: skin, Hair, eyes, ears, nose, mouth, chest, abdomen, external genitalia, limbs and feet, respiratory and circulatory systems, autonomic effects (such as salivation), nervous system (such as tremors, convulsions, stress reactions, and abnormal behavior).
  • 14 days including but not limited to: skin, Hair, eyes, ears, nose, mouth, chest, abdomen, external genitalia, limbs and feet, respiratory and circulatory systems, autonomic effects (such as salivation), nervous system (such as tremors, convulsions, stress reactions, and abnormal behavior).
  • the body weight of the animals was weighed before administration, and then the body weight of the animals was weighed and recorded at the same time every day.
  • the MTD dose of the novel taxane Z1 was 250 mg/kg.
  • This application example is to investigate the growth inhibitory effect of a single intravenous injection of the novel taxane Z1 of Example 1 on colon cancer HCT-116 tumor-bearing nude mice.
  • the solvent used to dissolve the test substance is as follows:
  • Cremophor EL lot 27963, manufacturer: Sigma.
  • the animal room environment maintained a temperature of 23 ⁇ 2 ° C, humidity of 40-70%, alternating 12 hours of light and dark.
  • Animal feed (SLAC-M01) was purchased from Beijing Keao Xieli Co., Ltd.
  • the experimental animals were filtered and sterilized with water, and the animals were free to eat and drink.
  • tumor cells colon cancer HCT-116 cells, purchased from the Institute of Cell Biology, Chinese Academy of Sciences. The cells were cultured in a carbon dioxide incubator at 37 ° C, saturated humidity, and containing a volume fraction of 5% CO 2 and 95% air using F-12 medium (containing 10% FBS). Logarithmic growth phase cells were taken before inoculation, digested with 0.25% trypsin, washed once with PBS, resuspended in PBS, resuspended in serum-free medium, and adjusted to a cell concentration of about 3 ⁇ 10 7 cells/mL. .
  • Each nude mouse was subcutaneously inoculated with 0.1 mL of cell suspension (3 ⁇ 10 6 cell/mouse) under sterile conditions. When the tumor grows to a volume of about 60-150 mm 3 , nude mice with similar tumor volume and good shape are selected (the shape is as single spherical as possible, no irregular shape or multiple tumors are gathered together), and each group has 6 rats.
  • V 3/4 ⁇ (D/2) 3 .
  • the evaluation index of antitumor activity is the tumor growth inhibition rate TGI (%), and its calculation formula is:
  • TGI (%) (V control - V Treatment ) / V control ) ⁇ 100%.
  • mice The body weight of the mice was weighed 3 times a week.
  • the weight loss is >20% after administration of the test substance, the sudden death of the animal or the tumor volume exceeds 2800 mm 3 , the CO 2 is sacrificed, the tumor is isolated and weighed, autopsy is performed, and the diseased organ is visually observed and recorded.
  • the growth inhibition rate (TGI%) of the novel taxane Z1 against human colon cancer HCT-116 tumor-bearing mice was 85.69%.

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Abstract

式（I）紫衫类化合物及其制备方法和应用，其制备方法具有以下步骤：先将吉西他滨中的两个羟基进行保护，然后与氯甲酸烷基酯缩合，接着脱除羟基保护基得到中间体G1；分别对G1的羟基进行保护，然后脱除第一个羟基保护基团，得到中间体G2；将7,10-二（三氯乙氧基甲酰）多西他赛与二酸酐反应得到中间体D1；D1与G2缩合得到中间体D2；D2的羧基脱保护得到目标产物。式I化合物可以用于抑制胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤。

Description

新型紫杉类化合物及其制备方法和应用 技术领域
本发明涉及一种新型紫杉类化合物及其制备方法和应用。
背景技术
现有的紫杉类化合物大多存在毒性较大、抗肿瘤活性较低等不足，尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤的抑制效果不佳。
发明内容
本发明的目的在于解决现有技术的不足，提供一种毒性较小、抗肿瘤活性较高、尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤具有很好的抑制率的新型紫杉类化合物及其制备方法和应用。
实现本发明上述目的的技术方案是：一种新型紫杉类化合物，其结构如通式(Ⅰ)所示：
Figure PCTCN2016105692-appb-000001
通式(Ⅰ)中，R1为C1～C6烷基或取代烷基，优选为乙基、正丁基或者正己基，更优选为正丁基。
n为0～6，优选为0～2，更优选为1。
上述新型紫杉类化合物的制备方法具有以下步骤：
S1：先对吉西他滨中的两个羟基进行保护，然后与氯甲酸烷基酯进行缩合反应，接着脱除羟基保护基团，得到中间体G1；
S2：先对步骤S1制得的中间体G1其中一个羟基进行保护，然后再对另一个羟基进行保护，接着脱除第一个羟基脱保基团，得到中间体G2；
S3：将7,10-二(三氯乙氧基甲酰)多西他赛与二酸酐反应得到中间体D1；
S4：将步骤S3制得的中间体D1与步骤S2制得的中间体G2进行缩合反应得到中间体D2；
S5：对步骤S4制得的中间体D2进行羟基脱保护得到目标产物。
上述步骤S1中采用的羟基保护试剂为六甲基二硅氮烷、六甲基二硅氧烷、三甲基氯硅烷或者三甲基碘硅烷，优选为六甲基二硅氮烷。
上述步骤S1中所述的氯甲酸烷基酯为氯甲酸甲酯、氯甲酸乙酯、氯甲酸正丙酯、氯甲酸异丙酯、氯甲酸正丁酯、氯甲酸正戊酯、氯甲酸正己酯中的一种，优选为氯甲酸乙酯、氯甲酸正丁酯或者氯甲酸正己酯，更优选为氯甲酸正丁酯。
上述步骤S2中第一个羟基保护采用的保护试剂为叔丁基二甲基氯硅烷、异丙基二甲基氯硅烷、乙基二甲基氯硅烷或者三甲基氯硅烷，优选为叔丁基二甲基氯硅烷。
上述步骤S2中第二个羟基保护采用的保护试剂为氯甲酸-2,2,2-三氯乙酯。
上述步骤S3中采用的二酸酐为丁二酸酐、戊二酸酐或者己二酸酐，优选为戊二酸酐。
上述步骤S4中采用的缩合试剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)、二环己基碳二亚胺(DCC)或者N,N-二异丙基碳二亚胺(DIC)，优选为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或者1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐，更优选为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
上述步骤S4的缩合反应优选在4-二甲氨基吡啶的存在下进行。
上述步骤S5的羟基脱保护是在锌粉和乙酸钠的存在下进行的。
上述新型紫杉类化合物在制备抗肿瘤药物中的应用。
上述肿瘤为血液瘤或者恶性实体瘤；具体来说，上述肿瘤包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌、前列腺癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、绒毛癌、生殖细胞瘤、恶性淋巴 瘤、白血病和多发性骨髓瘤；优选包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌以及白血病。
一种药物组合物，其含有作为活性成分的上述新型紫杉类化合物以及一种或者多种药用载体/赋形剂。
上述药物组合物的剂型为注射剂型或者是口服剂型，其中注射剂型为溶液型注射剂、混悬型注射剂、乳剂型注射剂、或注射用无菌粉末；口服剂型为片剂、散剂、颗粒剂、胶囊剂、微丸制剂、溶液剂、混悬剂、乳剂、糖浆剂或者酏剂。
本发明具有的积极效果：本发明的新型紫杉类化合物毒性较小(MTD剂量只有250mg/kg)，抗肿瘤活性较高，尤其是对于胃肠道癌、肺癌、乳腺癌以及白血病等实体肿瘤具有很好的抑制率(结肠癌TGI可达85.69％)。
附图说明
图1为中间体G1的1H-NMR谱图。
图2为中间体G2的1H-NMR谱图。
图3为中间体D1的1H-NMR谱图。
图4为中间体D2的1H-NMR谱图。
图5为新型紫杉类化合物Z1的1H-NMR谱图。
图6为新型紫杉类化合物Z1的13C-NMR谱图。
图7为新型紫杉类化合物Z1的HSQC图(异核单量子相关谱图)。
具体实施方式
(实施例1)
本实施例的新型紫杉类化合物Z1的结构式如下：
Figure PCTCN2016105692-appb-000002
该新型紫杉类化合物Z1的制备方法具有以下步骤：
S1：制备中间体G1，合成路线如下：
Figure PCTCN2016105692-appb-000003
具体方法如下：
S11：在1L的圆底烧瓶中加入30g的吉西他滨(0.114mol)、143mL的六甲基二硅氮烷(0.68mol、6eq.)、0.569g的硫酸铵(4mmol、0.038eq.)以及143mL的二氧六环，然后将混合物至于130℃的油浴中，回流1.5h，直至不再有氨气产生。
待挥发物蒸发后，先将半结晶固体真空干燥10min，剩余物用干燥的甲苯共蒸发二次后于60℃真空干燥，得到53.99g的白色结晶固体。
S12：0℃的温度下，向含有28.05g上述S11制得的白色结晶固体(59mmol)和8.02mL的N-甲基咪唑(101mmol、1.7eq.)的296mL二氯甲烷溶液中加入11.3mL的氯甲酸正丁酯(89mmol、1.5eq.)，此时无沉淀产生，将反应混合物室温(15～25℃， 下同)下搅拌4h，然后在30℃的温度下蒸除溶剂，向剩余物中加入197mL的甲醇和41mL的三乙胺(0.27mol、5eq)，将反应混合物室温下搅拌过夜，第二天TLC表明几乎都是产物。
将反应混合物蒸除溶剂，剩余物溶解在500mL的乙酸乙酯/二氯甲烷混合溶液(1∶3)中，然后与300mL的柠檬酸溶液(含42g柠檬酸)在分液漏斗中混合摇晃，将有机层直接倒入含有100g硅胶的过滤漏斗中，将水相用200mL的乙酸乙酯/二氯甲烷混合溶剂(1∶3)提取3次，再依次用100mL的乙酸乙酯/二氯甲烷混合溶剂(1∶3)和300mL的甲醇/二氯甲烷混合溶剂(1∶20)进行洗脱，产物用1300mL的甲醇/二氯甲烷混合溶剂(1∶20)洗脱。蒸除溶剂后于60℃真空干燥，得到19.8g白色固体泡沫中间体G1，收率为92.0％(以吉西他滨计)。
中间体G1的1H-NMR谱图见图1。
1H NMR(399.86MHz,DMSO-d6):δ＝0.90(t,3H,3J＝7.42Hz,CH3),1.30-1.41(m,2H,CH2CH2CH2CH3),1.54-1.64(m,2H,CH2CH2CH2CH3),3.65(dm,1H,2J＝12.69Hz,3J＝3.22Hz,H-5a'),3.81(dm,1H,2J＝12.69Hz,H-5b'),3.86-3.91(m,1H,H-4'),4.12(t,2H,3J＝6.64Hz,CH2CH2CH2CH3),4.13-4.25(m,1H,H-3'),5.30(t,1H,3J＝5.37Hz,OH-5'),6.17(t,1H,3J(H-F)＝7.52Hz,H-1'),6.32(d,1H,3J＝6.45Hz,OH-3'),7.10(d,1H,3J＝7.71Hz,H-5),8.22(d,1H,3J＝7.71Hz,H-6),10.84(br s,1H,NH)。
LC/MS(ESI)[M+H]+理论值：364.13，实测值：364.17。
S2：制备中间体G2，合成路线如下：
Figure PCTCN2016105692-appb-000004
具体方法如下：
将1.5g步骤S1制得的中间体G1(4.1mmol)、0.653g的叔丁基二甲基氯硅烷(4.3mmol、1.05eq.)和0.765mL的吡啶(9.5mmol，2.3eq.)溶解在15mL的二氯甲烷中，室温搅拌1h，TLC表明反应进行了一半。将反应混合物搅拌过夜，仍有较多中 间体G1存在，再添加0.187g的叔丁基二甲基氯硅烷(1.24mmol、0.3eq.)，将反应混合物室温搅拌6h，TLC表明仍然存在中间体G1，再加入0.124g的叔丁基二甲基氯硅烷(0.83mmol、0.2eq.)，继续搅拌过夜，第二天TLC表明没有中间体G1，随后加入0.2-33mL的吡啶(2.9mmol、0.7eq.)，接着在0℃下加入0.625mL的氯甲酸-2,2,2-三氯乙酯(4.5mmol、1.1eq.)，将反应混合物室温搅拌0.5h，TLC表明反应完全。
将反应混合物与3.90g的柠檬酸(18.6mmol，4.5eq.)一起摇晃，蒸除溶剂后的提取物无需干燥，将剩余物在40℃下进行高真空干燥，然后溶解在27mL的四氢呋喃中，将溶液冷却至0℃，加入三乙胺以及3倍的氢氟酸，将溶液置于5℃的冰箱中过夜，第二天将反应混合物置于20℃保持3h，然后在该温度下蒸除溶剂。将剩余物经硅胶柱层析(含55g硅胶)，然后依次用500mL的乙酸乙酯/二氯甲烷混合溶剂(1∶5)以及450mL的乙酸乙酯/二氯甲烷混合溶剂(1∶2)洗脱。合并相同组分，蒸除溶剂后于60℃真空干燥，得到1.904g的白色固体泡沫中间体G2，收率为86％。
中间体G2的1H-NMR谱图见图2。
1H NMR(399.86MHz,DMSO-d6):δ＝0.90(t,3H,3J＝7.32Hz,CH2CH2CH2CH3),1.30-1.41(m,2H,CH2CH2CH2CH3),1.55-1.64(m,2H,CH2CH2CH2CH3),3.68-3.76(m,1H,H-5a'),3.78-3.85(m,1H,H-5b'),4.12(t,2H,3J＝6.64Hz,CH2CH2CH2CH3),4.34-4.39(m,1H,H-4'),5.01(d,1H,2J＝12.20Hz,Troc),5.09(d,1H,2J＝12.20Hz,Troc),5.31-5.41(m,2H,H-3',OH-5'),6.34(t,1H,3J(H-F)＝8.60Hz,H-1'),7.13(d,1H,3J＝7.62Hz,H-5),8.15(d,1H,3J＝7.62Hz,H-6),10.87(br s,1H,NH)。
LC/MS(ESI)[M+H]+理论值：538.0，实测值：538.2。
S3：制备中间体D1，合成路线如下：
Figure PCTCN2016105692-appb-000005
具体方法如下：
将0.95g的7,10-二(三氯乙氧基甲酰)多西他赛(0.82mmol)和0.935g的戊二酸酐(8.2mmol、10eq.)溶解在10.6mL的吡啶(131mmol、160eq.)中，将反应混合物室温搅拌2.5h，然后置于-20℃的冰箱中过夜，第二天再将反应混合物室温搅拌3h以上，TLC表明反应基本完成。
在30℃下蒸除吡啶，并将剩余物在该温度下真空干燥，将剩余物溶解在5.5g的柠檬酸(26mmol、32eq.)溶液中，然后用二氯甲烷提取，将提取物直接倒入硅胶柱(含20g硅胶)，将杂质用110mL的甲醇/二氯甲烷混合溶剂(1∶100)洗去，将产物用143mL的甲醇/二氯甲烷混合溶剂(1∶100)以及102mL的甲醇/二氯甲烷混合溶剂(1∶50)洗出，蒸除溶剂后于40℃真空干燥，得到1.055g白色固体中间体D1粗品。
将粗品经硅胶柱层析(含35g硅胶)，然后依次用50mL的二氯甲烷、210mL的乙酸乙酯/二氯甲烷混合溶剂(1∶20)以及220mL的乙酸乙酯/二氯甲烷混合溶剂(1∶10)洗去杂质，将洗脱后的组分收集于试管中，并用乙酸乙酯/二氯甲烷混合溶剂(1∶5)进行柱洗脱。合并相同组分，蒸除溶剂后于40℃真空干燥，得到0.623g白色固体中间体D1成品，收率为60％。
中间体D1的1H-NMR谱图见图3。
1H NMR(399.86MHz,DMSO-d6):δ＝0.98(s,3H,CH3),1.03(s,3H,CH3),1.38(s,9H,BOC),1.51-1.65(m,1H),1.68(s,3H,CH3),1.72-1.91(m,4H),1.80(s,3H,CH3),2.26(s,3H,OAc),2.28(t,2H,3J＝7.42Hz,COCH2CH2CH2COOH),2.46(t,2H,3J＝7.23Hz,COCH2CH2CH2COOH),2.56-2.50(m,1H),3.65(d,1H,3J＝6.83Hz,CH),4.03-4.10(m,2H),4.77(d,1H,2J＝12.01Hz,Troc-a),4.81(s,1H),4.93(d,1H,2J＝12.01Hz,Troc-a),4.95(d,1H,2J＝12.10Hz,Troc-b),4.98-5.02(m,1H),5.00(d,1H,2J＝12.10Hz,Troc-b),5.01-5.07(m,1H),5.09(d,1H,3J＝8.40Hz),5.38-5.47(m,2H),5.79(t,1H,3J＝8.89Hz,CH),6.09(s,1H),7.18(t,1H,3J＝7.32Hz,CHp-Ph),7.37(d,2H,3J＝7.62Hz,CHo-Ph),7.41-7.47(m,2H,CHm-Ph),7.65-7.72(m,2H,CHm-Bz),7.76(t,1H,3J＝7.32Hz,CHp-Bz),7.88(d,1H,3J＝8.98Hz,NH-BOC),7.99(d,2H,3J＝7.22Hz,CHo-Bz),12.13(br s,1H,COOH)。
LC/MS(ESI)[M+Na]+理论值：1292.2，实测值：1292.2。
S4：制备中间体D2，合成路线如下：
Figure PCTCN2016105692-appb-000006
具体方法如下：
0℃的温度下，将0.277mg步骤S2制得的中间体G2(0.51mmol、1.1eq.)、0.594mg步骤S3制得的中间体D1(0.47mmol、1eq)、98mg的碳化二亚胺(0.51mmol、1.1eq.)以及11.4mg的4-二甲氨基吡啶(95·10–6mol、0.2eq.)溶解在0.934mL的二氯甲烷中，将反应混合物缓慢加热至室温，搅拌过夜，第二天，TLC表明为主要产品和一些轻微的杂质。
将反应混合物直接倒入硅胶柱(含35g硅胶)中，依次用50mL的二氯甲烷、205mL的乙酸乙酯/二氯甲烷混合溶剂(1∶40)、210mL的乙酸乙酯/二氯甲烷混合溶剂(1∶20)以及220mL的乙酸乙酯/二氯甲烷混合溶剂(1∶10)将杂质洗去，将洗脱后的组分收集于试管中，用360mL的乙酸乙酯/二氯甲烷混合溶剂(1∶5)进行柱洗脱，合并相同组分，蒸除溶剂后于40℃真空干燥，得到0.636g无色透明中间体D2，收率为76％。
中间体D2的1H-NMR谱图见图4。
1H NMR(399.86MHz,DMSO-d6):δ＝1H NMR(399.86MHz,DMSO-d6):δ＝0.90(t,3H,3J＝7.32Hz,CH2CH2CH2CH3),0.98(s,3H,CH3),1.02(s,3H,CH3),1.30-1.41(m,2H,CH2CH2CH2CH3),1.37(s,9H,BOC),1.51-1.66(m,4H,CH2CH2CH2CH3,CH2-a, CH2-a),1.68(s,3H,CH3),1.75-1.89(m,4H),1.80(s,3H,CH3),2.26(s,3H,OAc),2.43(t,2H,3J＝7.52Hz,COCH2CH2CH2CO),2.46(t,2H,3J＝8.01Hz,COCH2CH2CH2CO),3.65(d,1H,3J＝6.64Hz,CH),4.03-4.10(m,2H),4.12(t,2H,3J＝6.64Hz,CH2CH2CH2CH3),4.43(dd,1H,2J＝12.10Hz,3J＝6.25Hz,H-5'a),4.51(dd,1H,2J＝12.10Hz,3J＝2.84Hz,H-5'b),4.55-4.62(m,1H,H-4'),4.77(d,1H,2J＝12.11Hz,Troc-a),4.80(s,1H),4.93(d,1H,2J＝12.11Hz,Troc-a),4.94(d,1H,2J＝12.10Hz,Troc-b),4.97-5.20(m,3H),5.01-5.10(m,2H),5.09(d,1H,2J＝12.30Hz,Troc-c),5.37-5-57(m,3H),5.80(t,1H,3J＝8.98Hz,CH),6.09(s,1H),6.36(t,2H,3J(H-F)＝8.30Hz,H-1'),7.16(d,1H,3J＝7.61Hz,H-5),7.18(t,1H,3J＝7.42Hz,CHp-Ph),7.37(d,2H,3J＝7.62Hz,CHo-Ph),7.40-7.47(m,2H,CHm-Ph),7.65-7.72(m,2H,CHm-Bz),7.76(t,1H,3J＝7.42Hz,CHp-Bz),7.87(d,1H,3J＝8.98Hz,NH-BOC),7.99(d,2H,3J＝7.42Hz,CHo-Bz),8.07(d,1H,3J＝7.42Hz,H-6),10.90(br s,1H,NH)。
LC/MS(ESI)[M+H–Troc]+理论值：1617.3，实测值：1617.6。
S5：制备新型紫杉类化合物Z1，合成路线如下：
Figure PCTCN2016105692-appb-000007
具体方法如下：
将1.101g的乙酸钠(13.4mmol、40eq.)溶解在12mL甲醇和12mL醋酸的混合溶液中，然后将该溶液加入到装有0.602g步骤S4制得的中间体D2(0.34mmol)的烧 瓶中，待其完全溶解后，加入1.756g的锌粉(27mmol、40eq.)，将反应混合物在5℃超声振动15min并剧烈摇晃，TLC表明中间体D2消失，只有微量的二(三氯乙氧基甲酰)产物和一定量的单(三氯乙氧基甲酰)产物，绝大部分是目标产物。继续超声振动并剧烈摇晃持续15min，TLC显示没有二(三氯乙氧基甲酰)产物，但仍有一部分单(三氯乙氧基甲酰)存在，将反应混合物第三次超声振动并剧烈摇晃15min，然后倒入50mL含有19.44g的碳酸氢钠(0.23mol)水悬浮液中，接着加入乙酸乙酯，过滤，滤液用乙酸乙酯提取，提出物于25℃蒸干。
将剩余物溶于二氯甲烷后经硅胶柱层析(含35g硅胶)，然后依次用203.3mL的甲醇/二氯甲烷混合溶剂(1∶60)以及615mL的甲醇/二氯甲烷混合溶剂(1∶40)洗脱，将洗脱后的组分收集于试管中，依次用206.7mL的甲醇/二氯甲烷混合溶剂(1∶30)以及208mL的甲醇/二氯甲烷(1∶25)混合溶剂进行洗脱。合并相同组分，蒸除溶剂后于40℃真空干燥，得到0.244g无色透明目标产物Z1，收率为57％，纯度为95.0％(HPLC)。
目标产物Z1的1H-NMR谱图、13C-NMR谱图以及HSQC谱图分别见图5～图7。
1H NMR(399.86MHz,DMSO-d6):δ＝0.90(t,3H,3J＝7.13Hz,CH2CH2CH2CH3),0.97(s,6H,CH3×2),1.29-1.41(m,2H,CH2CH2CH2CH3),1.36(s,9H,BOC),1.51(s,3H,CH3),1.53-1.67(m,4H,CH2CH2CH2CH3,CH2-a,CH2-a),1.70(s,3H,CH3),1.76-1.89(m,3H,COCH2CH2CH2CO,CH2-b),2.23(s,3H,OAc),2.25-2.33(m,1H,CH2-b),2.38-2.48(m,4H,COCH2CH2CH2CO),3.63(d,1H,3J＝6.44Hz,CH),3.97-4.07(m,3H,CH,CH2O),4.06-4.12(m,1H,H-4'),4.12(t,2H,3J＝6.44Hz,CH2CH2CH2CH3),4.18-4.31(m,1H,H-3'),4.32-4.47(m,3H,H-5',t-OH),4.86-4.95(m,2H,CH,OH),5.00(d,1H,3J＝6.64Hz,OH),5.03-5.14(m,3H,CH×3),5.40(d,1H,3J＝6.83Hz,CH),5.77(t,1H,3J＝8.59Hz,CH),6.22(t,2H,3J(H-F)＝7.52Hz,H-1'),6.49(d,1H,3J＝6.06Hz,OH-3'),7.10-7.20(m,2H,H-5,Hp-Ph),7.31-7.45(m,4H,Ho-Ph×2,Hm-Ph×2),7.61-7.69(m,2H,Hm-Ph),7.73(t,1H,3J＝7.42Hz,Hp-Ph),7.85(d,1H,3J＝8.98Hz,NH-BOC),7.93-8.04(m,3H,Ho-Ph×2,H-6),10.86(br s,1H,NH)。
13C NMR(100.56MHz,DMSO-d6):δ＝9.8(CH3),13.5(CH2CH2CH2CH3),13.6(CH3),18.4(CH2CH2CH2CH3),19.7(COCH2CH2CH2CO),20.7(CH3),22.4(OAc),26.4(CH3),28.1(t-BOC,primary),30.2(CH2CH2CH2CH3),32.1(COCH2CH2CH2CO),32.3(COCH2CH2CH2CO),34.7(CH2),36.4(CH2),42.9,45.9(CH),55.1(CH),57.0,62.8(CH2-5'),65.1(CH2CH2CH2CH3),70.1(t,2J(C-F)＝23.0Hz,CH-3'),70.7(CH),71.2(CH), 73.7(CH),74.8(CH),75.0(CH),75.4(CH2),76.8,77.9(CH-4'),78.5,80.3(t-BOC,quaternary),83.7(CH),84.5(br s,CH-1'),95.2(CH-5),122.5(t,1J(C-F)＝259.2Hz,C-2'),127.3(CHo-Ph),128.0(CHp-Ph),128.5(CHm-Ph),128.6(CHm-Ph),129.5(CHo-Ph),130.0,133.3(CHp-Ph),135.9,136.9,137.5,144.9(CH-6),153.1(NHCOO),153.9(COAr),155.1(NHCOO),163.5(C-4),165.3(COO),169.0(COO),169.5(COO),171.8(COCH2CH2CO),172.1(COCH2CH2CO),209.3(CO)。
LC/MS(ESI)[M+H]+理论值：1267.5，实测值：1267.8。
(实施例2～实施例9)
各实施例的制备方法与实施例1基本相同，不同之处在于步骤S1中采用的氯甲酸烷基酯、步骤S3中采用的二酸酐以及最后得到的新型紫杉类化合物，具体见表1。
表1
Figure PCTCN2016105692-appb-000008
(实施例10)
本实施例为含有实施例1的新型紫杉类化合物Z1的药物组合物的制备方法。
其中，注射剂型以冻干粉针剂为例，包括：30g的新型紫杉类化合物Z1、甘露醇(20％，w/v)300g、缓冲剂二水合磷酸二氢钠7g、表面活性剂泊洛沙姆188(F68)4.0g。
将按照上述处方量准确称取的二水合磷酸二氢钠、泊洛沙姆188(F68)、甘露醇(20％，w/v)加入300g预冷至10℃以下的注射用水中溶解后，用0.1mol/L的NaOH调节溶液pH值为7.3～7.5；再向上述溶液中加入30g的新型紫杉类化合物Z1混合 均匀，用0.1mol/L的NaOH溶液或0.1mol/L的HCl调节pH值为7.3±0.2(本实施例为7.5)；加水至2000g，溶液用0.22μm微孔滤膜过滤除菌；按每瓶2.0g将滤液分装于管制瓶中，半加塞后置于冷冻干燥机中冻干，待干燥后真空压塞，轧盖，贴标签，即得冻干粉针剂1000支，保存在2～8℃温度下。
除了上述冻干粉针剂即注射用无菌粉末外，本发明的新型紫杉类化合物还可制备成其他形式的注射剂型，如溶液型注射剂、混悬型注射剂、乳剂型注射剂。
药物组合物的适用剂型除了上述涉及的片剂形式外，还可以被制成口服的散剂、颗粒剂、胶囊剂、微丸制剂、溶液剂、混悬剂、乳剂、糖浆剂或者酏剂，或者是口服形式的缓释及控释制剂，或者是其他口服形式的药物组合物，这些口服剂型含有常见的相应的辅料(根据不同的作用分为添加剂、附加物等)，如添加剂有药物等级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精盐、纤维素或硫酸镁等。
在实现上述口服剂型中，可以选择药学上的附加物作为药物活性组分的载体，包括已有技术成熟的物质，例如：惰性固体稀释液、水溶剂、脂质体、微球体或/和无毒有机溶剂等；优选的附加物有：加湿剂、乳化剂、pH缓冲液、人血清白蛋白、抗氧化剂、防腐剂、抑菌剂、葡萄糖、蔗糖、海藻糖、麦芽糖、卵磷脂、甘氨酸、山梨酸、丙烯醇、聚乙烯、鱼精蛋白、硼酸、氯化钠、或者氯化钾、矿物油、植物油等；可从中选择一种或几种组合作为药物载体。
本发明的药物组合物的靶肿瘤包括血液瘤或者恶性实体瘤。具体的，靶肿瘤包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌、前列腺癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、绒毛癌、生殖细胞瘤、恶性淋巴瘤、白血病和多发性骨髓瘤，并且甚至更优选的靶肿瘤可包括结肠癌、直肠癌、胃癌、肺癌、胰腺癌、肝癌、卵巢癌、肾癌、恶性淋巴瘤、乳腺癌以及白血病，但本发明不限于此。
(应用例1、单次腹腔给药新型紫杉类化合物在ICR小鼠的最大耐受量实验)
本应用例是研究实施例1的新型紫杉类化合物Z1单次腹腔给药对ICR小鼠的毒性反应，以确其最大耐受量(maximal tolerance dose，MTD)。
最大耐受量是指动物不会发生死亡，动物的体重降低不会超过10％(与Day 0相比)，或者不产生明显毒副作用的剂量。
1、受试物的配制。
受试物溶解所用溶剂来源如下：
无水乙醇，批号10009218，厂商：国药集团化学试剂有限公司。
Cremophor EL，批号27963，厂商：Sigma。
0.9％生理盐水，批号13083004，厂商：华裕制药有限公司。
称取定量对应的受试物于5mL玻璃试管中，在5mm的磁力搅拌子搅拌下溶解于乙醇中，全部溶解后加入Cremophor EL，保持搅拌，临用前加入标示量的生理盐水搅拌均匀，配置时乙醇、Cremophor EL、生理盐水的体积比为5∶5∶90。
2、实验动物。
品种和品系：ICR小鼠。
级别：SPF。
性别：雌性。
来源：上海斯莱克实验动物有限公司。
合格证号：0130749。
实验开始动物体重：18-20g。
数量和性别：41只。
适应环境时间：5-7天，与实验时相同饲养条件。
动物房环境保持温度18-26℃，相对湿度30-70％，12小时光照。
实验动物用水采用过滤灭菌水，动物自由饮食及饮水。
3、实验方法。
给药方式：IP。如动物死亡则减低剂量，直至动物存活，如无动物死亡，则增加剂量；如在给给定高剂量下动物正常存活则实验结束。最终根据实验结果确定小鼠对受试物的MTD；急性给药后连续观察动物7天。
实验过程中所有动物，对所有的受试动物进行详细临床观察，给药后每天两次(上10：00、下午16：00各一次)，连续观察14天，观察包括但不仅限于：皮肤，毛，眼，耳，鼻，口腔，胸腔，腹部，外生殖器，四肢和脚，呼吸道及循环系统，自主效应(如流涎)，神经系统(如震颤，抽搐，应激反应以及反常行为)。
给药前称重动物的体重，随后每天在同一时间称量动物的体重并记录。
每天详细记录观察结果、动物体重以及给药一周后动物存活情况。
4、实验结果。
新型紫杉类化合物Z1的MTD剂量为250mg/kg。
(应用例2、单次腹腔注射新型紫杉类化合物对肿瘤的生长抑制作用)
本应用例是研究单次腹腔注射实施例1的新型紫杉类化合物Z1对结肠癌HCT-116荷瘤裸小鼠移植瘤的生长抑制作用。
1、受试物的配制。
受试物溶解所用溶剂来源如下：
无水乙醇，批号10009218，厂商：国药集团化学试剂有限公司。
Cremophor EL，批号27963，厂商：Sigma。
0.9％生理盐水，批号13083004，厂商：华裕制药有限公司。
称取定量对应的受试物于5mL玻璃试管中，在5mm的磁力搅拌子搅拌下溶解于乙醇中，全部溶解后加入Cremophor EL，保持搅拌，临用前加入标示量的生理盐水搅拌均匀，配置时乙醇、Cremophor EL、生理盐水的体积比为5∶5∶90。
2、实验动物。
品种和品系：Balb/c Nude小鼠。
级别：SPF。
性别：雌性。
来源：上海西普尔-毕凯实验动物有限公司。
动物合格证号：0123627。
实验开始时动物年龄：7-9周龄。
实验开始时动物体重：18-22克。
适应环境时间：5-7天，与实验时相同饲养条件。
动物房环境保持温度23±2℃，湿度40-70％，12小时明暗交替。
动物饲料(SLAC-M01)购自北京科澳协力有限公司。
实验动物用水采用过滤灭菌水，动物自由饮食和饮水。
3、实验方法。
3.1、肿瘤细胞：结肠癌HCT-116细胞，购于中科院细胞生物研究所。用F-12培养基(含10％的FBS)培养在37℃，饱和湿度，含体积分数为5％CO2、95％空气的二氧化碳培养箱内。接种前取对数生长期细胞，以0.25％胰蛋白酶消化后，PBS洗涤1次，PBS重新悬浮计数，用不含血清的培养基重新悬浮细胞，调整细胞浓度至约3×107cell/mL。
3.2、动物接种及分组：每个裸鼠在无菌状态下，右侧后肢皮下接种0.1mL细胞悬液(3×106cell/mouse)。待肿瘤长至体积60-150mm3左右时，选出肿瘤体积相近、形状较好的裸鼠(形状尽量为单一圆球形，无不规则的形状或多个肿瘤聚在一起)，每组6只。
3.3、动物给药和观察。
(1)观察各组裸鼠接种部位肿瘤的形成状况，每周3次用圆洞尺测量肿瘤结节的直径(D)，并按如下公式计算肿瘤结节的体积(V)：
V＝3/4π(D/2)3。
(2)抗肿瘤活性的评价指标为肿瘤生长抑制率TGI(％)，其计算公式为：
TGI(％)＝(Vcontrol-VTreatment)/Vcontrol)×100％。
每周3次称量小鼠体重。
3.4、临床症状。
在实验开始和实验过程中每个动物所有的临床症状都应记录。观察应在每天的同一时间进行。
给予受试物后如出现体重减低＞20％，濒死动物或肿瘤体积超过2800mm3，则CO2处死，分离肿瘤并称重，尸检，肉眼观察是否有病变器官并记录。
3.5、数据统计。
实验数据除特别指出外，均以Mean±SEM表示；两组间数据采用非配对T检验，P＜0.05认为有显著性差异。
4、实验结果。
新型紫杉类化合物Z1对人结肠癌HCT-116荷瘤小鼠肿瘤的生长抑制率(TGI％)为85.69％。

Claims (10)

  1. 一种新型紫杉类化合物，其特征在于其结构如通式(Ⅰ)所示：
    Figure PCTCN2016105692-appb-100001
    通式(Ⅰ)中，R1为C1～C6烷基或取代烷基；n为0～6。
  2. 根据权利要求1所述的新型紫杉类化合物，其特征在于：通式(Ⅰ)中，R1为乙基、正丁基或者正己基；n为0～2。
  3. 根据权利要求2所述的新型紫杉类化合物，其特征在于：通式(Ⅰ)中，R1为正丁基；n为1。
  4. 权利要求1至3之一所述的新型紫杉类化合物的制备方法，其特征在于具有以下步骤：
    S1：先对吉西他滨中的两个羟基进行保护，然后与氯甲酸烷基酯进行缩合反应，接着脱除羟基保护基团，得到中间体G1；
    S2：先对步骤S1制得的中间体G1其中一个羟基进行保护，然后再对另一个羟基进行保护，接着脱除第一个羟基脱保基团，得到中间体G2；
    S3：将7,10-二(三氯乙氧基甲酰)多西他赛与二酸酐反应得到中间体D1；
    S4：将步骤S3制得的中间体D1与步骤S2制得的中间体G2进行缩合反应得到中间体D2；
    S5：对步骤S4制得的中间体D2进行羟基脱保护得到目标产物。
  5. 根据权利要求1所述的新型紫杉类化合物的制备方法，其特征在于：步骤S1中所述的氯甲酸烷基酯为氯甲酸正丁酯。
  6. 根据权利要求1所述的新型紫杉类化合物的制备方法，其特征在于：步骤S3中所述的二酸酐为戊二酸酐。
  7. 根据权利要求1所述的新型紫杉类化合物的制备方法，其特征在于：步骤S1中采用的羟基保护试剂为六甲基二硅氮烷；步骤S2中第一个羟基保护采用的保护试剂为叔丁基二甲基氯硅烷，第二个羟基保护采用的保护试剂为氯甲酸-2,2,2-三氯乙酯。
  8. 权利要求1至3之一所述的新型紫杉类化合物在制备抗肿瘤药物中的应用。
  9. 根据权利要求8所述的应用，其特征在于：所述肿瘤包括结肠癌、直肠癌、胃癌、肺癌、乳腺癌、前列腺癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、绒毛癌、生殖细胞瘤、恶性淋巴瘤、白血病和多发性骨髓瘤。
  10. 根据权利要求9所述的应用，其特征在于：所述肿瘤包括结肠癌、直肠癌、胃癌、肺癌、胰腺癌、肝癌、卵巢癌、肾癌、恶性淋巴瘤、乳腺癌以及白血病。
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