WO2022199408A1 - 新型注射用阿比特龙衍生物的制备方法和用途 - Google Patents

新型注射用阿比特龙衍生物的制备方法和用途 Download PDF

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WO2022199408A1
WO2022199408A1 PCT/CN2022/080603 CN2022080603W WO2022199408A1 WO 2022199408 A1 WO2022199408 A1 WO 2022199408A1 CN 2022080603 W CN2022080603 W CN 2022080603W WO 2022199408 A1 WO2022199408 A1 WO 2022199408A1
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abiraterone
polyaminopolycarboxylic acid
acid modified
derivative
modified
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PCT/CN2022/080603
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French (fr)
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刘天军
朱娜
荣玉美
洪阁
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中国医学科学院生物医学工程研究所
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Priority to US18/280,132 priority Critical patent/US11944685B2/en
Priority to CA3208667A priority patent/CA3208667C/en
Priority to AU2022244858A priority patent/AU2022244858B2/en
Priority to EP22774070.1A priority patent/EP4282872A1/en
Priority to JP2023551172A priority patent/JP7506444B2/ja
Publication of WO2022199408A1 publication Critical patent/WO2022199408A1/zh
Priority to ZA2023/07833A priority patent/ZA202307833B/en

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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention belongs to the field of organic synthesis and medicine, and in particular relates to a preparation method and application of a novel polyaminopolycarboxylic acid-modified abiraterone derivative for injection used in the treatment of prostate tumors, in particular to the preparation and use of abiraterone by combining abiraterone with polyamino
  • a novel polyaminopolycarboxylic acid-modified abiraterone derivative for injection is prepared by the reaction of polycarboxylic acid monoacid anhydride, and the application of the polyaminopolycarboxylic acid-modified abiraterone derivative in the preparation of antitumor drugs.
  • PCa Prostate cancer
  • PSA prostate-specific antigen
  • Abiraterone acetate is a prodrug of abiraterone that is converted into abiraterone in the body.
  • the current clinical use is abiraterone acetate tablets, originally developed by Johnson & Johnson, and approved by the US Food and Drug Administration in 2011 to be used in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer. Approved for the treatment of newly diagnosed high-risk metastatic endocrine therapy-sensitive prostate cancer.
  • Abiraterone acetate has poor water solubility. According to the information disclosed by the FDA, the bioavailability of abiraterone acetate tablets is extremely low. Animal pharmacokinetic experiments revealed that the relative bioavailability in rats is 37%.
  • Bioavailability is only 1.6-1.7%.
  • the data disclosed in the clinical pharmacological mass balance experiment shows that after oral administration, 88% of the drug is excreted from the feces, and 5% of the drug is excreted from the urine, so the bioavailability of the human body is estimated to be less than 10%.
  • the absorption of abiraterone acetate tablets is greatly affected by food, so do not eat 2 hours before and 1 hour after taking the medicine. Compared to the fasted state, eating increased Cmax and AUC 0-24 by 7- and 5-fold, respectively, and eating a high-fat meal increased Cmax and AUC 0-24 by 17- and 10-fold, respectively.
  • abiraterone In addition, the inhibition of CYP17A1 activity by abiraterone leads to excessive mineralocorticoids, hypokalemia, hypertension, and water and sodium retention. Long-term clinical application may also lead to adverse reactions such as adrenal insufficiency, liver toxicity, and cardiotoxicity. Animal studies have also found that abiraterone may have toxic effects such as impaired reproductive or developmental function.
  • the current solutions mainly focus on changing the dosage form. For example: dissolving abiraterone, phospholipids and cholesterol in an organic solvent, and then adding surfactants such as polyethylene glycol, Tween 80, sodium carboxymethyl cellulose or polysorbate to obtain abiraterone flexible liposomes,
  • surfactants such as polyethylene glycol, Tween 80, sodium carboxymethyl cellulose or polysorbate
  • problems in the improved method such as the complex preparation process, the difficulty in realizing large-scale production, and the inability to effectively improve the activity of abiraterone and reduce the toxicity. Therefore, the development of a water-soluble abiraterone compound that is easy for industrial production and can effectively improve the anti-
  • the object of the present invention is to overcome the deficiencies of the prior art and provide a polyaminopolycarboxylic acid modified abiraterone derivative for injection.
  • the second object of the present invention is to provide a method for preparing a polyaminopolycarboxylic acid modified abiraterone derivative.
  • the third object of the present invention is to provide a pharmaceutical preparation of a polyaminopolycarboxylic acid-modified abiraterone derivative, which comprises a polyaminopolycarboxylic acid-modified abiraterone derivative as an active ingredient and an excipient and a solubilizer. , Solubilizer, emulsifier, antioxidant.
  • the fourth object of the present invention is to provide the use of a polyaminopolycarboxylic acid modified abiraterone derivative and its pharmaceutical preparation as an antitumor drug.
  • a polyaminopolycarboxylic acid modified abiraterone derivative for injection has the following structure:
  • a method for preparing a polyaminopolycarboxylic acid modified abiraterone derivative which is characterized in that abiraterone and polyaminopolycarboxylic acid monoacid anhydride are reacted under the action of an alkaline catalyst in a ratio of 1:1.1 to 1:3, A polyaminopolycarboxylic acid modified abiraterone derivative is obtained, and the polyaminopolycarboxylic acid modified abiraterone derivative has the following structure:
  • the above-mentioned method preferably is to dissolve abiraterone and polyaminopolycarboxylic acid monoacid anhydride (molar equivalent is 1.1 to 3 times of abiraterone) in N,N-dimethylformamide or N-methylpyrrolidone or dimethylformamide.
  • a pharmaceutical preparation of polyaminopolycarboxylic acid modified abiraterone derivative characterized in that the active ingredient is polyaminopolycarboxylic acid modified abiraterone derivative, the lyophilized excipient is mannitol or glucose, and the cosolvent is carbonic acid Sodium hydrogen or sodium carbonate or potassium carbonate or sodium hydroxide or potassium hydroxide, emulsifying co-solvent is glycerol or polyethylene glycol (molecular weight 300 or 400) or propylene glycol, antioxidant is sodium hydrogen sulfite or sodium sulfite or sodium thiosulfate .
  • the polyaminopolycarboxylic acid modified abiraterone derivative of the invention has good water solubility, can be completely dissolved in sodium bicarbonate aqueous solution, and has a simple and convenient preparation method with high yield, is suitable for large-scale production, and has advantages in anti-tumor aspects. Significant effect, can be used for the treatment of prostate cancer tumor, has the characteristics of high efficiency and low toxicity.
  • Fig. 1 is the synthetic route of triethylenetetraminehexaacetic acid modified abiraterone derivative AA-TTHA in Example 1 of the present invention.
  • Fig. 2 is the synthetic route of diethylenetriaminepentaacetic acid modified abiraterone derivative AA-DTPA in Example 2 of the present invention.
  • Example 3 is a high-resolution mass spectrogram of diethylenetriaminepentaacetic acid-modified abiraterone derivative AA-DTPA in Example 2 of the present invention.
  • Fig. 4 is the hydrogen nuclear magnetic resonance spectrum of diethylenetriaminepentaacetic acid modified abiraterone derivative AA-DTPA in Example 2 of the present invention.
  • Fig. 5 is the synthetic route of the EDTA modified abiraterone derivative AA-EDTA of Example 3 of the present invention.
  • Example 6 is a high-resolution mass spectrogram of the EDTA-modified abiraterone derivative AA-EDTA of Example 3 of the present invention.
  • Figure 7 shows the antitumor effect of the polyaminopolycarboxylic acid modified abiraterone derivative of Example 13 of the present invention on human prostate cancer cell LNCaP.
  • Figure 8 shows the antitumor effect of the polyaminopolycarboxylic acid modified abiraterone derivative of Example 14 of the present invention on human prostate cancer cell DU145.
  • Figure 9 is a photo of the experimental results of the in vivo antitumor effect of polyaminopolycarboxylic acid modified abiraterone derivatives on LNCaP prostate cancer tumor-bearing mice in Example 15 of the present invention.
  • Fig. 10 is a graph showing the experimental results of the effect of polyaminopolycarboxylic acid modified abiraterone derivatives on the body weight of LNCaP prostate cancer-bearing mice in Example 15 of the present invention.
  • FIG. 11 is a graph showing the experimental results of in vivo antitumor effect of polyaminopolycarboxylic acid modified abiraterone derivatives on LNCaP prostate cancer tumor-bearing mice in Example 15 of the present invention.
  • Figure 12 is a graph showing the experimental results of the effect of polyaminopolycarboxylic acid modified abiraterone derivatives on the organ index of LNCaP prostate cancer-bearing mice in Example 15 of the present invention.
  • Figure 13 is a graph showing the experimental results of the effect of polyaminopolycarboxylic acid modified abiraterone derivatives on blood routine of healthy ICR male mice in Example 16 of the present invention.
  • Figure 14 is a graph showing the experimental results of the effect of polyaminopolycarboxylic acid modified abiraterone derivatives on blood biochemistry of healthy ICR male mice in Example 16 of the present invention.
  • Figure 15 is a graph showing the experimental results of the effects of polyaminopolycarboxylic acid modified abiraterone derivatives on the histopathology of healthy ICR male mice in Example 16 of the present invention.
  • Figure 16 is a blood concentration-time curve diagram of a polyaminopolycarboxylic acid modified abiraterone derivative in rats in Example 17 of the present invention.
  • Fig. 17 is a graph showing the plasma concentration-time curve of abiraterone in rats in Example 17 of the present invention.
  • the precipitate was completely dissolved in water and acetonitrile, extracted with ether, the aqueous phase was collected, and lyophilized to obtain 1.64 g of EDTA-modified abiraterone derivative AA-EDTA with a yield of 87.7%.
  • AA-TTHA prepared in Example 1, 6 g of mannitol, and 0.01 g of sodium bisulfite, dissolve in 40 ml of water for injection, add 1 g of medicinal activated carbon, stir at room temperature for 20 min, filter to remove the activated carbon, and then filter with 0.22 ⁇ m.
  • AA-DTPA prepared in Example 2
  • 8 g of glucose, 0.2 ml of glycerol, and 0.01 g of sodium sulfite dissolve it in 80 ml of water for injection, add 1 g of medicinal activated carbon, stir at room temperature for 20 min, filter out the activated carbon, and then filter it with 0.22 ⁇ m.
  • AA-EDTA prepared in Example 3, 8g of mannitol, 0.5ml of polyethylene glycol (molecular weight 300), and 0.01g of sodium thiosulfate, dissolve in 40ml of water for injection, add 1g of medicinal activated carbon, and stir at room temperature After 20 min, the activated carbon was filtered off, then sterilized by filtration with a 0.22 ⁇ m filter membrane, and then packed into 5 ml vials, 2 ml per bottle, and freeze-dried.
  • AA-EDTA prepared in Example 6, 30 g of glucose, 0.45 g of potassium carbonate, and 0.01 g of sodium sulfite, dissolve in 200 ml of water for injection, add 10 g of medicinal activated carbon, stir at room temperature for 20 min, filter out the activated carbon, and then use 0.22 ⁇ m Filter and sterilize, aliquot into 10ml vials, 5ml each, and freeze-dried.
  • Example 13 In vitro antitumor effect of polyaminopolycarboxylic acid modified abiraterone derivatives (LNCaP)
  • the in vitro anti-tumor evaluation of AA-EDTA, AA-DTPA and AA-TTHA prepared in Examples 1-6 on human prostate cancer cell LNCaP includes the following steps:
  • Human prostate cancer cell LNCaP in logarithmic growth phase was taken, digested with trypsin, resuspended in RPMI 1640 medium containing 15% fetal bovine serum, and seeded in a 96-well plate at a density of 1 ⁇ 10 4 cells/well, and then The 96-well plate was placed in a cell incubator for 24 h.
  • the culture medium was discarded, and 100 ⁇ l of drug solutions with different concentrations were added to each well.
  • the drug concentrations were 2.5 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, 40 ⁇ M, 80 ⁇ M, and 160 ⁇ M in sequence.
  • CCK8 method to detect cell viability aspirate the liquid in the well, add 10 ⁇ l of CCK8 reagent and 100 ⁇ l of serum-free medium to each well, and continue to culture for 4 h.
  • the microplate reader detects the light absorption value of each well at 450 nm. The cells incubated with no compound were used as blank control, and the cell viability was calculated. The results are shown in Figure 7.
  • the in vitro anti-tumor evaluation of AA-EDTA, AA-DTPA and AA-TTHA prepared in Examples 1-6 on human prostate cancer cell DU145 includes the following steps:
  • Human prostate cancer cell DU145 in logarithmic growth phase was taken, digested with trypsin, resuspended in RPMI 1640 medium containing 15% fetal bovine serum, and seeded in a 96-well plate at a density of 4 ⁇ 10 3 cells/well.
  • the 96-well plate was placed in a cell incubator for 24 h.
  • the culture medium was discarded, and 100 ⁇ l of drug solutions with different concentrations were added to each well.
  • the drug concentrations were 2.5 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, 40 ⁇ M, 80 ⁇ M, and 160 ⁇ M in sequence.
  • CCK8 method to detect cell viability aspirate the liquid in the well, add 10 ⁇ l of CCK8 reagent and 100 ⁇ l of serum-free medium to each well, and continue to culture for 4 h.
  • the microplate reader detects the light absorption value of each well at 450 nm. The cells incubated without compound were used as blank control, and the cell viability was calculated. The results are shown in Figure 8.
  • Example 15 Inhibitory effect of polyaminopolycarboxylic acid modified abiraterone derivatives on tumor growth of human prostate cancer LNCaP nude mice xenografts
  • the in vivo experimental process of the AA-DTPA prepared in Example 2 for the treatment of transplanted prostate cancer LNCaP tumor-bearing mice includes the following steps:
  • the diameter of the transplanted tumor in nude mice was measured with a vernier caliper, and the anti-tumor effect of abiraterone was dynamically observed.
  • organ index organ weight/(body weight-tumor weight) , unit: mg/g]
  • mice There were 20 ICR mice, 5 in each group, in a total of 4 groups (NS group, positive control group AA 150mg/kg/d p.o., experimental group AA-DTPA 35mg/kg/w and 52.5mg/kg/w i.v.).
  • the microscopic examination results of pathological sections showed no abnormal changes in the heart, spleen, kidney, and testis.
  • the positive control group AA and the experimental group AA-DTPA 52.5mg/kg/w had mild disease symptoms in the lungs, and the AA group had mild symptoms in the liver. Lesion symptoms, suggesting that AA-DTPA has no obvious organ toxicity, and the toxicity is lower than AA.
  • the pharmacokinetic experiment of the polyaminopolycarboxylic acid modified abiraterone derivative AA-DTPA prepared in Example 2 in rats includes the following steps:
  • 8 healthy male SD rats weighing 220 ⁇ 20g, were randomly divided into 2 groups with 4 rats in each group; one group received 0.2ml/200g rat tail vein AA-DTPA at a dose of 8mg/kg; the other group According to the dose of 30mg/kg, 0.2ml/200g rats were given AA by gavage; the blood collection time of the two groups were before administration, 5, 15, 30 min and 1, 2, 4, 6, 12, and 24 h after administration. At each time point, 0.5 ml of blood was collected from the eye canthus, placed in a heparinized plastic centrifuge tube, and centrifuged at 3000 r/min for 10 min to separate serum.
  • AA-DTPA exhibits bi-exponential decay after intravenous injection, the half-life is 0.26h, and the average clearance rate is 0.513L/h/kg; AA concentration in plasma reaches a peak value (15.28 ⁇ 1.24 0.5h after AA gavage administration). ng/ml), the half-life is 8.46h, the drug is absorbed slowly in the body and the individual absorption varies greatly. Meanwhile, the bioavailability of AA-DTPA is much higher than that of AA.

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Abstract

本发明公开了用于前列腺肿瘤治疗的新型注射用多氨基多羧酸修饰阿比特龙衍生物、含多氨基多羧酸修饰阿比特龙衍生物的药物制剂、制备方法及用途。所述的多氨基多羧酸修饰阿比特龙衍生物具有下述结构(I) 。本发明的多氨基多羧酸修饰阿比特龙衍生物水溶性好，在碳酸氢钠水溶液中可完全溶解，且制备方式简单、便捷、收率高，适用于规模化生产，在抗肿瘤方面有显著的效果，可用于治疗前列腺癌肿瘤，具有高效低毒的特点。

Description

新型注射用阿比特龙衍生物的制备方法和用途 技术领域
本发明属于有机合成和药物领域，具体涉及一种用于前列腺肿瘤治疗的新型注射用多氨基多羧酸修饰阿比特龙衍生物的制备方法和用途，特别是涉及通过将阿比特龙与多氨基多羧酸单酸酐反应制备新型注射用多氨基多羧酸修饰阿比特龙衍生物，以及此多氨基多羧酸修饰阿比特龙衍生物在制备抗肿瘤药物中的应用。
背景技术
前列腺癌(Prostate cancer，PCa)是雄激素依赖性疾病，位居全球男性恶性肿瘤的第二位，其致死性仅次于肺癌，具有很强的病理异质性，5年生存率仅28％。近年来随着人口老龄化的进展、生活方式的改变及前列腺特异抗原(PSA)筛查的普及，PCa发病率呈直线型上升趋势，且其中大多数患者已发展成晚期前列腺癌，成为严重影响男性健康的恶性泌尿系肿瘤。
醋酸阿比特龙是阿比特龙的前药，可在体内转化成阿比特龙。目前在临床上使用的是醋酸阿比特龙片，最初由强生公司开发，并在2011年被美国药监局批准与泼尼松或泼尼松龙合用治疗转移性去势抵抗前列腺癌，后续又被批准用于治疗新诊断的高危转移性内分泌治疗敏感性前列腺癌。醋酸阿比特龙水溶性差，根据FDA公开的资料，醋酸阿比特龙片生物利用度极低，动物药代实验披露，在大鼠体内的相对生物利用度为37％，猴及迷你猪的体内相对生物利用度只有1.6-1.7％。临床药理质量平衡实验披露的数据表明，口服后88％的药物从粪便排出，5％的药物从尿液排出，以此推算人体生物利用度低于10％。醋酸阿比特龙片的吸收受食物影响非常大，在服药前2小时及服药后1小时内不能进食。与禁食状态相比，进食可分别使C max和AUC 0-24提高7倍和5倍，进食高脂肪餐则可分别使C max和AUC 0-24提高17倍和10倍。此外，阿比特龙抑制CYP17A1的活性导致盐皮质激素过多，出现低钾血症、高血压和水钠潴留，长期的临床应用也可能导致肾上腺皮质机能不全、肝脏毒性、心脏毒性等不良反应。动物研究也发现，阿比特龙可能具有致生殖或发育功能受损等毒性反应。
针对阿比特龙生物利用度极低以及毒副作用等现状，目前解决的方法主要集中在改变剂型方面。例如：将阿比特龙、磷脂和胆固醇溶于有机溶剂中，再加入聚乙二醇、吐温80、羧甲基纤维素钠或聚山梨酯等表面活性剂得到阿比特龙柔性脂质体，从而提高阿比特龙的跨膜转运，增加渗透性以提高阿比特龙生物利用度；或将阿比特龙包封或键合在血清白蛋白等生物材料上，提高水溶性；但这一系列制剂改良方式存在诸多问题，如制备工艺复杂、难以实现规模化生产，且无法有效提高阿比特龙的活性以及降低毒性。因此， 开发易于工业化生产、且有效提高抗前列腺肿瘤效果的水溶性阿比特龙化合物，具有重要的学术价值和社会意义。
本实验室长期致力于水溶性化合物的研究，前期开发了氨基多羧酸修饰紫杉醇类化合物，提高了紫杉醇、多烯紫杉醇和卡巴他赛的水溶性，同时其抗肿瘤活性也优于前体化合物紫杉醇、多烯紫杉醇和卡巴他赛，并申请了相关专利。因此，从多氨基多羧酸修饰阿比特龙衍生物开发高效、低毒、水溶性好的可注射阿比特龙类化合物，可以极大丰富治疗前列腺癌肿瘤的药物和途径。
发明内容
本发明的目的在于克服现有技术的不足，提供一种注射用多氨基多羧酸修饰阿比特龙衍生物。
本发明的第二个目的是提供一种多氨基多羧酸修饰阿比特龙衍生物的制备方法。
本发明的第三个目的是提供一种多氨基多羧酸修饰阿比特龙衍生物的药物制剂，其中包含作为活性成分的多氨基多羧酸修饰阿比特龙衍生物和赋形剂、增溶剂、增溶乳化剂、抗氧化剂。
本发明的第四个目的是提供一种多氨基多羧酸修饰阿比特龙衍生物及其药物制剂作为抗肿瘤药物的用途。
本发明的技术方案概述如下：
一种注射用多氨基多羧酸修饰阿比特龙衍生物，具有下述结构：
Figure PCTCN2022080603-appb-000001
其中，
Figure PCTCN2022080603-appb-000002
Figure PCTCN2022080603-appb-000003
一种多氨基多羧酸修饰阿比特龙衍生物的制备方法，其特征是按照1:1.1～1:3的比例将阿比特龙和多氨基多羧酸单酸酐在碱性催化剂作用下反应，得到多氨基多羧酸修饰阿比特龙衍生物，所述的多氨基多羧酸修饰阿比特龙衍生物具有下述结构：
Figure PCTCN2022080603-appb-000004
其中，
Figure PCTCN2022080603-appb-000005
Figure PCTCN2022080603-appb-000006
上述方法优选的是将阿比特龙和多氨基多羧酸单酸酐(摩尔当量为阿比特龙的1.1～3倍)溶于N,N-二甲基甲酰胺或N-甲基吡咯烷酮或二甲基亚砜中，在碱性催化剂条件下，-10～40℃反应5～48h，反应完全后抽滤去除不溶物，滤液加入冰乙醚，-40℃静置2h以上，待沉淀完全析出，离心收集沉淀，溶解于水和乙腈混合液中，乙醚萃取，收集水相并冷冻干燥，得到所述的多氨基多羧酸修饰阿比特龙衍生物。
一种多氨基多羧酸修饰阿比特龙衍生物的药物制剂，其特征是活性成分为多氨基多羧酸修饰阿比特龙衍生物，冻干赋形剂为甘露醇或葡萄糖，助溶剂为碳酸氢钠或碳酸钠或碳酸钾或氢氧化钠或氢氧化钾，乳化助溶剂为甘油或聚乙二醇(分子量300或400)或丙二醇，抗氧化剂为亚硫酸氢钠或亚硫酸钠或硫代硫酸钠。
一种多氨基多羧酸修饰阿比特龙衍生物及其药物制剂在制备抗肿瘤药物中的应用。
本发明的多氨基多羧酸修饰阿比特龙衍生物水溶性好，在碳酸氢钠水溶液中可完全溶解，且制备方式简单、便捷、收率高，适用于规模化生产，在抗肿瘤方面有显著的效果，可用于治疗前列腺癌肿瘤，具有高效低毒的特点。
附图说明
图1为本发明实施例1的三乙烯四胺六乙酸修饰阿比特龙衍生物AA-TTHA的合成路线。
图2为本发明实施例2的二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA的合成路线。
图3为本发明实施例2的二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA的高分辨质谱图。
图4为本发明实施例2的二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA的核磁共振氢谱图。
图5为本发明实施例3的乙二胺四乙酸修饰阿比特龙衍生物AA-EDTA的合成路线。
图6为本发明实施例3的乙二胺四乙酸修饰阿比特龙衍生物AA-EDTA的高分辨质谱图。
图7为本发明实施例13的多氨基多羧酸修饰阿比特龙衍生物对人前列腺癌细胞LNCaP的抗肿瘤作用。
图8为本发明实施例14的多氨基多羧酸修饰阿比特龙衍生物对人前列腺癌细胞DU145的抗肿瘤作用。
图9为本发明实施例15多氨基多羧酸修饰阿比特龙衍生物对LNCaP前列腺癌荷瘤小鼠的体内抗肿瘤作用实验结果照片。
图10为本发明实施例15多氨基多羧酸修饰阿比特龙衍生物对LNCaP前列腺癌荷瘤小鼠的体重影响实验结果图。
图11为本发明实施例15多氨基多羧酸修饰阿比特龙衍生物对LNCaP前列腺癌荷瘤小鼠的体内抗肿瘤作用实验结果图。
图12为本发明实施例15多氨基多羧酸修饰阿比特龙衍生物对LNCaP前列腺癌荷瘤小鼠的脏器指数影响实验结果图。
图13为本发明实施例16多氨基多羧酸修饰阿比特龙衍生物对健康ICR雄性小鼠血常规影响的实验结果图。
图14为本发明实施例16多氨基多羧酸修饰阿比特龙衍生物对健康ICR雄性小鼠血生化影响的实验结果图。
图15为本发明实施例16多氨基多羧酸修饰阿比特龙衍生物对健康ICR雄性小鼠组织病理影响的实验结果图。
图16为本发明实施例17多氨基多羧酸修饰阿比特龙衍生物在大鼠体内的血药浓度-时间曲线图。
图17为本发明实施例17阿比特龙在大鼠体内的血药浓度-时间曲线图。
本发明的最好实施方式
下面通过实施例对本发明作进一步说明，其目的仅在于更好的理解本发明的内容而非限制本发明的保护范围：
实施例1三乙烯四胺六乙酸修饰阿比特龙衍生物AA-TTHA的合成
将1mmol阿比特龙及3mmol三乙烯四胺六乙酸单酸酐溶于30ml N,N-二甲基甲酰胺中，加入1.5mmol N-二甲氨基吡啶及3mmol三乙胺，40℃搅拌反应5h。反应完毕后，抽滤去除体系中的不溶物，滤液用200ml冰乙醚沉淀，-40℃放置过夜，待沉淀析出完全，离心收集固体物质。沉淀用水和乙腈完全溶解，乙醚萃取，收集水相，冷冻干燥，得到三乙烯四胺六乙酸修饰阿比特龙衍生物AA-TTHA 0.79g，产率72.1％(合成路线见图1)。
实施例2二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA的合成
将1mmol阿比特龙及2mmol二乙烯三胺五乙酸单酸酐溶于30ml N-甲基吡咯烷酮中，加入1.5mmol N-二甲氨基吡啶及2mmol三乙胺，-10℃搅拌反应48h。反应完毕后，抽滤去除体系中的不溶物，滤液用300ml冰乙醚沉淀，-40℃放置过夜，待沉淀析出完全，离心收集固体物质。沉淀用水和乙腈完全溶解，乙醚萃取，收集水相，冷冻干燥，得到二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA 1.13g，产率87.5％。(合成路线见图2，高分辨质谱见图3，核磁共振氢谱见图4)。
实施例3乙二胺四乙酸修饰阿比特龙衍生物AA-EDTA的合成
将1mmol阿比特龙及1.5mmol乙二胺四乙酸单酸酐溶于30ml二甲基亚砜中，加入1mmol N-二甲氨基吡啶及1.5mmol三乙胺，25℃搅拌反应24h。反应完毕后，抽滤去除体系中的不溶物，滤液用300ml冰乙醚沉淀，-40℃放置过夜，待沉淀析出完全，离心收集固体物质。沉淀用水和乙腈完全溶解，乙醚萃取，收集水相，冷冻干燥，得到乙二胺四乙酸修饰卡巴阿比特龙衍生物AA-EDTA 0.91g，产率75.6％(合成路线见图5，高分辨质谱见图6)。
实施例4三乙烯四胺六乙酸修饰阿比特龙衍生物AA-TTHA的合成
将3mmol阿比特龙及6mmol三乙烯四胺六乙酸单酸酐溶于60ml二甲基亚砜中，加入3mmol N-二甲氨基吡啶及6mmol三乙胺，40℃搅拌反应10h。反应完毕后，抽滤去除体系中的不溶物，滤液用400ml冰乙醚沉淀，-40℃放置6h，待沉淀析出完全， 离心收集固体物质。沉淀用水和乙腈完全溶解，乙醚萃取，收集水相，冷冻干燥，得到三乙烯四胺六乙酸修饰阿比特龙衍生物AA-TTHA 2.16g，产率87.2％。
实施例5二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA的合成
将3mmol阿比特龙及9mmol二乙烯三胺五乙酸单酸酐溶于100ml N,N-二甲基甲酰胺中，加入4mmol N-二甲氨基吡啶及9mmol三乙胺，25℃搅拌反应36h。反应完毕后，抽滤去除体系中的不溶物，滤液用500ml冰乙醚沉淀，-40℃放置4h，待沉淀析出完全，离心收集固体物质。沉淀用水和乙腈完全溶解，乙醚萃取，收集水相，冷冻干燥，得到二乙烯三胺五乙酸修饰阿比特龙衍生物AA-DTPA 1.87g，产率86.1％。
实施例6乙二胺四乙酸修饰阿比特龙衍生物AA-EDTA的合成
将3mmol阿比特龙及7.5mmol乙二胺四乙酸单酸酐溶于60ml N-甲基吡咯烷酮中，加入3mmol N-二甲氨基吡啶及7.5mmol三乙胺，10℃搅拌反应48h。反应完毕后，抽滤去除体系中的不溶物，滤液用400ml冰乙醚沉淀，-40℃放置2h，待沉淀析出完全，离心收集固体物质。沉淀用水和乙腈完全溶解，乙醚萃取，收集水相，冷冻干燥，得到乙二胺四乙酸修饰阿比特龙衍生物AA-EDTA 1.64g，产率87.7％。
实施例7 AA-TTHA冻干粉针剂的制备
取实施例1制备的AA-TTHA 0.2g，甘露醇6g，亚硫酸氢钠0.01g，溶于40ml注射用水中，再加入1g药用活性炭，室温搅拌20min，过滤除活性炭，再用0.22μm滤膜过滤除菌，分装到5ml的西林瓶中，每瓶2ml，冷冻干燥。
实施例8 AA-TTHA冻干粉针剂的制备
取实施例4制备的AA-TTHA 2.0g，葡萄糖20g，碳酸氢钠0.4g，亚硫酸钠0.03g，溶于100ml注射用水中，再加入10g药用活性炭，室温搅拌20min，过滤除活性炭，再用0.22μm滤膜过滤除菌，分装到10ml的西林瓶中，每瓶5ml，冷冻干燥。
实施例9 AA-DTPA冻干粉针剂的制备
取实施例2制备的AA-DTPA 0.2g，葡萄糖8g，甘油0.2ml，亚硫酸钠0.01g，溶于80ml注射用水中，再加入1g药用活性炭，室温搅拌20min，过滤除活性炭，再用0.22μm滤膜过滤除菌，分装到5ml的西林瓶中，每瓶2ml，冷冻干燥。
实施例10 AA-DTPA冻干粉针剂的制备
取实施例5制备的AA-DTPA 2.0g，甘露醇30g，碳酸钠0.6g，亚硫酸钠0.05g，溶于200ml注射用水中，再加入10g药用活性炭，室温搅拌20min，过滤除活性炭，再用0.22μm滤膜过滤除菌，分装到10ml的安西林瓶中，每瓶5ml，冷冻干燥。
实施例11 AA-EDTA冻干粉针剂的制备
取实施例3制备的AA-EDTA 0.2g，甘露醇8g，聚乙二醇(分子量300)0.5ml，硫代硫酸钠0.01g，溶于40ml注射用水中，再加入1g药用活性炭，室温搅拌20min，过滤除活性炭，再用0.22μm滤膜过滤除菌，分装到5ml的西林瓶中，每瓶2ml，冷冻干燥。
实施例12 AA-EDTA冻干粉针剂的制备
取实施例6制备的AA-EDTA 2.0g，葡萄糖30g，碳酸钾0.45g，亚硫酸钠0.01g，溶于200ml注射用水中，再加入10g药用活性炭，室温搅拌20min，过滤除活性炭，再用0.22μm滤膜过滤除菌，分装到10ml的西林瓶中，每瓶5ml，冷冻干燥。
实施例13多氨基多羧酸修饰阿比特龙衍生物的体外抗肿瘤效果(LNCaP)
由实施例1-6制备的AA-EDTA，AA-DTPA，AA-TTHA对人前列腺癌细胞LNCaP的体外抗肿瘤评价，包括如下步骤：
取对数生长期的人前列腺癌细胞LNCaP，胰蛋白酶消化后，重悬在含15％胎牛血清的RPMI 1640培养基中，以密度为1×10 4细胞/孔接种于96孔板，然后将96孔板放入细胞孵育箱中培养24h。
弃去培养基，每孔中加入不同浓度的药物溶液100μl，药物浓度依次为2.5μM、5μM、10μM、20μM、40μM、80μM及160μM，重复5个复孔，放入培养箱中孵育48h。
CCK8法检测细胞存活率：吸出孔中液体，每孔中加入10μl CCK8试剂及100μl无血清培养基，继续培养4h。酶标仪检测各孔在450nm处的光吸收值。以无化合物孵育培养的细胞作为空白对照，计算细胞存活率，结果见图7。
由图7可知，多氨基多羧酸修饰阿比特龙衍生物AA-EDTA，AA-DTPA，AA-TTHA的体外抗肿瘤效果(LNCaP)优于阿比特龙AA。
实施例14多氨基多羧酸修饰阿比特龙衍生物的体外抗肿瘤效果(DU145)
由实施例1-6制备的AA-EDTA，AA-DTPA，AA-TTHA对人前列腺癌细胞DU145的体外抗肿瘤评价，包括如下步骤：
取对数生长期的人前列腺癌细胞DU145，胰蛋白酶消化后，重悬在含15％胎牛血清的RPMI 1640培养基中，以密度为4×10 3细胞/孔接种于96孔板，然后将96孔板放入细胞孵育箱中培养24h。
弃去培养基，每孔中加入不同浓度的药物溶液100μl，药物浓度依次为2.5μM、5μM、10μM、20μM、40μM、80μM及160μM，重复5个复孔，放入培养箱中孵育48h。
CCK8法检测细胞存活率：吸出孔中液体，每孔中加入10μl CCK8试剂及100μl无血清培养基，继续培养4h。酶标仪检测各孔在450nm处的光吸收值。以无化合物孵育 培养的细胞作为空白对照，计算细胞存活率，结果见图8。
由图8可知，多氨基多羧酸修饰阿比特龙衍生物AA-EDTA，AA-DTPA，AA-TTHA的体外抗肿瘤效果(DU145)优于阿比特龙AA。
实施例15多氨基多羧酸修饰阿比特龙衍生物对人前列腺癌LNCaP裸鼠异种移植肿瘤生长的抑制作用
由实施例2制备的AA-DTPA治疗移植性前列腺癌LNCaP荷瘤小鼠的在体实验过程，包括如下步骤：
取对数生长期的人前列腺癌LNCaP细胞株，在无菌条件下制备成5×10 7个/ml的细胞悬液，以0.1ml每只接种于裸鼠右侧腋窝皮下，待肿瘤生长至100-200mm 3后，将动物随机分组。
正常组Normal不给予任何治疗；模型组NS注射等量生理盐水，每天1次；AA组(150mg/kg/d p.o.)，每天灌胃给药1次；AA-DTPA组(35mg/kg/w i.v.)和AA-DTPA组(52.5mg/kg/w i.v.)，均每周尾静脉给药1次。治疗28天后，处死小鼠，手术剥取瘤块称重，实验结果见图9。
用游标卡尺测量裸鼠移植瘤直径，动态观察阿比特龙抗肿瘤效果。小鼠体重和肿瘤大小的测量：肿瘤直径的测量次数为每周2次，测量肿瘤长、宽，根据公式：肿瘤体积(mm 3)＝1/2×长×宽 2，绘制小鼠体重增长曲线和肿瘤生长曲线，结果见图10-11。
最后一次给药两天后，处死小鼠，解剖取出心、肝、脾、肺、肾以及睾丸，并称取其重量，计算脏器指数[脏器指数＝脏器重量/(体重-肿瘤重量)，单位：mg/g]，脏器指数实验结果见图12。
由图9和图11可知，经过28天对比治疗，在相同条件下，AA组和多氨基多羧酸修饰阿比特龙衍生物AA-DTPA组(35mg/kg/w)和AA-DTPA组(52.5mg/kg/w)肿瘤生长得到显著抑制，且AA-DTPA组(35mg/kg/w)和AA-DTPA组(52.5mg/kg/w)组肿瘤抑制效果优于AA组。
由图12可知，经过28天对比治疗，在相同条件下，模型组脾脏指数明显增加，脾脏增大，表明模型组小鼠机体免疫能力降低；相比于正常组和模型组，AA组小鼠睾丸萎缩，睾丸指数显著降低，表明AA药物存在生殖毒性；除此之外，AA组小鼠心脏指数也略有降低，其他脏器指数，如肝、肺、肾，AA组和模型组之间未发现显著性差异；相比于模型组，AA-DTPA治疗组其他脏器指数，如心、肝、肺、肾、睾丸未发现显著性差异，说明AA-DTPA在治疗剂量下的脏器毒性低于AA。
由图10可知，经过28天对比治疗，在相同条件下，多氨基多羧酸修饰阿比特龙衍生物AA-DTPA组(35mg/kg)和AA-DTPA组(52.5mg/kg)组动物体重和正常组相当，表明其对动物的生长无明显影响。
实施例16多氨基多羧酸修饰阿比特龙衍生物的毒性研究
由实施例5制备的多氨基多羧酸修饰阿比特龙衍生物AA-DTPA对ICR健康雄性小鼠给药28天后血常规、血生化及病理组织的影响，包括如下步骤：
ICR小鼠20只，每组5只，共4组(NS组、阳性对照组AA 150mg/kg/d p.o.、实验组AA-DTPA 35mg/kg/w和52.5mg/kg/w i.v.)。
灌胃每天给药1次，静脉每隔1天给药1次，治疗28天后取血送检；脱颈处死所有小鼠，解剖收集心、肝、脾、肺、肾、睾丸，10％甲醛固定脏器，石蜡包埋后切片，HE染色后进行组织病理学检查(血常规实验结果见图13，血生化实验结果见图14，组织病理学实验结果见图15)。
由图13可知，多氨基多羧酸修饰阿比特龙衍生物AA-DTPA对健康雄性ICR小鼠血常规的影响较小；相比于阿比特龙AA组，AA-DTPA对健康雄性ICR小鼠的淋巴细胞数目和单核细胞数目影响较小，提示AA-DTPA的毒性低于AA。
由图14可知，多氨基多羧酸修饰阿比特龙衍生物AA-DTPA对健康雄性ICR小鼠血生化的影响较小；相比于阿比特龙AA组，AA-DTPA对健康雄性ICR小鼠的丙氨酸氨基转移酶和天冬氨酸氨基转氨酶的影响更小，提示AA-DTPA的毒性低于AA。
由图15可知，病理切片镜检结果，心、脾、肾、睾丸未见异常改变，阳性对照组AA与实验组AA-DTPA 52.5mg/kg/w肺脏出现轻微病变症状，AA组肝脏出现轻微病变症状，提示AA-DTPA无明显的器官毒性，且毒性低于AA。
实施例17多氨基多羧酸修饰阿比特龙衍生物在大鼠体内的药代动力学研究
由实施例2制备的多氨基多羧酸修饰阿比特龙衍生物AA-DTPA在大鼠体内的药代动力学实验，包括如下步骤：
健康雄性SD大鼠8只，体重220±20g，随机分为2组，每组4只；其中一组按照8mg/kg的剂量，以0.2ml/200g大鼠尾静脉AA-DTPA；另一组按照30mg/kg的剂量，以0.2ml/200g大鼠灌胃AA；两组取血时间均为给药前、给药后5、15、30min及1、2、4、6、12、24h，各时间点眼眦取血0.5ml，置于肝素化的塑料离心管中，3000r/min离心10min，分离血清。
取50μl大鼠血浆样品+5μl甲醇/水(1:1，v/v)+150μl沉淀剂，充分涡旋震荡3min，4℃、12000r/min离心10min，取上清，LC-MS/MS进样分析，实验结果见图16。
由图16可知，AA-DTPA静脉注射后呈双指数衰减，半衰期为0.26h，平均清除率为0.513L/h/kg；AA灌胃给药后0.5h血浆中AA浓度达到峰值(15.28±1.24ng/ml)，半衰期为8.46h，药物在体内吸收较慢且个体吸收差异较大。同时，AA-DTPA的生物利用度远远高于AA。

Claims (8)

  1. 一种注射用多氨基多羧酸修饰阿比特龙衍生物，具有下述结构：
    Figure PCTCN2022080603-appb-100001
    其中，
    Figure PCTCN2022080603-appb-100002
    Figure PCTCN2022080603-appb-100003
  2. 根据权利要求1所述的一种多氨基多羧酸修饰阿比特龙衍生物的制备方法，其特征是按照1:1.1～1:3的比例将阿比特龙和多氨基多羧酸单酸酐在碱性催化剂作用下反应，得到多氨基多羧酸修饰阿比特龙衍生物，所述的多氨基多羧酸修饰阿比特龙衍生物具有下述结构：
    Figure PCTCN2022080603-appb-100004
    其中，
    Figure PCTCN2022080603-appb-100005
    Figure PCTCN2022080603-appb-100006
  3. 根据权利要求2所述的制备方法，其特征是包括如下步骤：阿比特龙和多氨基多羧酸单酸酐(摩尔当量为阿比特龙的1.1～3倍)溶于N,N-二甲基甲酰胺或N-甲基吡咯烷酮或二甲基亚砜中，在碱性催化剂条件下，-10～40℃反应5～48h，反应完全后抽滤去除不溶 物，滤液加入冰乙醚，-40℃静置2h以上，待沉淀完全析出，离心收集沉淀，溶解于水和乙腈混合液中，乙醚萃取，收集水相并冷冻干燥，得到所述的多氨基多羧酸修饰阿比特龙衍生物。
  4. 一种多氨基多羧酸修饰阿比特龙衍生物的药物制剂，其特征在是将权利要求1-3所述的多氨基多羧酸修饰阿比特龙衍生物制成可用于静脉注射的冻干粉针。
  5. 根据权利要求4所述的多氨基多羧酸修饰阿比特龙衍生物的药物制剂，其特征是包括以下组分：活性成分多氨基多羧酸修饰阿比特龙衍生物，冻干赋形剂，助溶剂，乳化助溶剂，抗氧化剂。
  6. 根据权利要求5所述的多氨基多羧酸修饰阿比特龙衍生物的药物制剂，其特征是所述的冻干赋形剂为甘露醇或葡萄糖；所述的助溶剂为碳酸氢钠或碳酸钠或碳酸钾或氢氧化钠或氢氧化钾；所述的乳化助溶剂为甘油或聚乙二醇(分子量300或400)或丙二醇；所述的抗氧剂为亚硫酸氢钠或亚硫酸钠或硫代硫酸钠。
  7. 根据权利要求1-6所述的多氨基多羧酸修饰阿比特龙衍生物及其药物制剂在制备抗肿瘤药物中的应用。
  8. 根据权利要求7所述的应用，其特征是所述的肿瘤包括但不限于前列腺癌。
PCT/CN2022/080603 2021-03-25 2022-03-14 新型注射用阿比特龙衍生物的制备方法和用途 WO2022199408A1 (zh)

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