WO2016019845A1 - Hcv ns3蛋白酶抑制剂的钠盐 - Google Patents

Hcv ns3蛋白酶抑制剂的钠盐 Download PDF

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WO2016019845A1
WO2016019845A1 PCT/CN2015/086017 CN2015086017W WO2016019845A1 WO 2016019845 A1 WO2016019845 A1 WO 2016019845A1 CN 2015086017 W CN2015086017 W CN 2015086017W WO 2016019845 A1 WO2016019845 A1 WO 2016019845A1
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formula
compound
sodium salt
sodium
preparation
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杨玲
顾红梅
刘飞
陈智林
田心
彭岩
朱金蕾
吕鹏
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the present invention is in the field of medicinal chemistry, and in particular relates to the sodium salt of a compound of formula I, a process for its preparation, a pharmaceutical composition thereof and its use in the prevention or treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • Hepatitis C is a global epidemic. It is often chronic after infection with hepatitis C virus (HCV), and it is easy to further develop the disease into cirrhosis, liver failure or hepatocellular carcinoma. The ideal treatment drugs and programs are still lacking.
  • HCV hepatitis C virus
  • HCV infection primarily include recombinant interferon-alpha alone or immunotherapy in combination with the nucleoside analog ribavirin, which have limited clinical benefit.
  • Several viral-encoded enzymes are recognized as targets for the treatment of HCV infection.
  • HCV NS3 protease plays an important role in virion maturation and replication, and is an important target for the research of anti-HCV infection drugs.
  • Chinese patent application CN103328466 discloses a series of HCV NS3 protease inhibitors which are useful for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • the Applicant has found that among the series of HCV NS3 protease inhibitors disclosed in CN103328466, a compound of the formula I having the following structure is selected, and as a therapeutic agent after it is formed into a sodium salt, it can be a drug having better drug-forming properties.
  • the invention provides a sodium salt of a compound of formula I,
  • the sodium salt of the compound of formula I of the invention is a monosodium salt of a compound of formula I.
  • the invention provides a process for the preparation of a sodium salt of a compound of formula I, which comprises reacting a compound of formula I with a sodium-containing base in a solvent to isolate the sodium salt of the compound of formula I.
  • the sodium-containing base is sodium hydroxide.
  • the molar ratio of the compound of formula I to the sodium-containing base is from 1:1 to 5, preferably in a molar ratio of from 1:1 to 2, most preferably in a molar ratio of from 1:1 to 1.2.
  • the reaction temperature is from 0 ° C to the boiling point of the solvent system, preferably from 0 to 25 ° C.
  • the reaction can be carried out under the protection of an inert gas; in a particular embodiment of the invention, the inert gas is nitrogen.
  • the reaction time is 1-5 h.
  • the solvent is selected from the group consisting of water, ethers, alcohols, ketones, nitriles, esters, alkanes, and halogenated alkanes, and specific solvents such as water, diethyl ether, diisopropyl ether, ethanol, methanol, isopropanol, and butyl Alcohol, acetone, methyl ethyl ketone, acetonitrile, dichloromethane, chloroform, hexane, pentane, ethyl acetate, methyl acetate.
  • the pharmaceutically acceptable salts of the present invention can be isolated using techniques well known in the art, such as filtration, concentration, spray drying, and the like. Further drying can also be carried out using standard techniques, and the pharmaceutically acceptable salts of the present invention can also be purified.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a sodium salt of a compound of formula I and a pharmaceutically acceptable carrier.
  • the sodium salt of the compound of formula I may be a monosodium salt of a compound of formula I.
  • the present invention provides the use of a sodium salt of a compound of the formula I and a pharmaceutical composition containing the same for the preparation of a medicament for the prevention and/or treatment of hepatitis C virus infection.
  • the sodium salt of the compound of formula I may be a compound of formula I. Single sodium salt.
  • the present invention provides a method of preventing and/or treating a hepatitis C virus infection, wherein the method comprises administering to a patient a sodium salt of a compound of formula I or a pharmaceutical composition of the invention.
  • the sodium salt of the compound of formula I has good fluidity and is of great significance in the preparation and purification process as well as in the formulation process.
  • the sodium salt of the compound of formula I readily yields a salt of high purity during the preparation, while other salts, such as the lithium salt of a compound of formula I, require multiple recrystallizations to achieve the same purity as the sodium salt of the compound of formula I. It can effectively save costs in the future industrial production process.
  • the sodium salt of the compound of formula I has higher stability under different conditions.
  • the sodium salt of a compound of formula I has better pharmacokinetic parameters, such as a higher bioavailability in different animals.
  • the compound of formula I is prepared according to the method disclosed in Chinese patent application CN103328466.
  • Group A intravenous administration of 10 mg/kg of the compound injection group of formula I,
  • Group B intragastric administration of a single sodium salt solution of the compound of formula I in a gavage group of 60 mg/kg (based on the compound of formula I, wherein the solution is a 5% dextrose solution),
  • Group C Administration of a single potassium salt solution of the compound of formula I by intragastric administration of 60 mg/kg (based on the compound of formula I, wherein the solution is a 5% aqueous glucose solution),
  • Group D intragastric administration of a single lithium salt solution of the compound of formula I in a gavage group of 60 mg/kg (based on the compound of formula I, wherein the solution is a 5% dextrose solution),
  • the time points of blood collection after administration were: 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h.
  • the blood samples were collected and placed in an EDTA-K2 centrifuge tube, and the plasma was separated by centrifugation at 4 ° C, 4000 rpm, and 10 min.
  • the plasma was pretreated and the concentration of the compound of formula I was determined by LC-MS/MS.
  • the pharmacokinetic parameters were calculated using DAS software (version number: 3.1) according to the statistical moment theory.
  • Group A Oral administration of a single capsule sodium salt of the compound of formula I, 300 mg/caps (based on the compound of formula I, wherein the common capsule contains a monosodium salt of the compound of formula I and glucose powder in a weight ratio of 1:3.5),
  • Group B Oral administration of a compound of formula I, single lithium salt, 300 mg/capsule (based on the compound of formula I, wherein the common capsule contains a monosodium salt of the compound of formula I and glucose powder in a weight ratio of 1:3.5),
  • the time points of blood collection after administration were: 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h.
  • the blood samples were collected and placed in an EDTA-K2 centrifuge tube, and the plasma was separated by centrifugation at 4 ° C, 4000 rpm, and 10 min.
  • the plasma was pretreated and the concentration of the compound of formula I was determined by LC-MS/MS.
  • the pharmacokinetic parameters were calculated using DAS software (version number: 3.1) according to the statistical moment theory.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

本发明公开了HCV NS3蛋白酶抑制剂的钠盐、其制备方法、其药物组合物及其在预防或治疗丙型肝炎病毒（HCV）感染中的用途。本发明的HCV NS3蛋白酶抑制剂的钠盐与其他盐相比，具有较好的流动性、更高的稳定性、更好的药代动力学参数。

Description

HCV NS3蛋白酶抑制剂的钠盐 技术领域
本发明属于药物化学领域，具体涉及式Ⅰ化合物的钠盐、其制备方法、其药物组合物及其在预防或治疗丙型肝炎病毒(HCV)感染中的用途。
背景技术
丙型肝炎呈全球性流行，感染丙型肝炎病毒(HCV)后常呈慢性化，且易使病情进一步发展为肝硬化、肝功能衰竭或肝细胞癌，至今仍缺少理想的治疗药物和方案。
目前对于HCV感染的治疗主要包括单独用重组干扰素-α或其与核苷类似物利巴韦林组合的免疫治疗，这些治疗具有有限的临床益处。几种病毒编码的酶被公认为是治疗HCV感染的靶标，其中的HCV NS3蛋白酶在病毒体的成熟和复制中起着重要的作用，是目前抗HCV感染药物研究的重要靶点。
中国专利申请CN103328466公开了一系列HCV NS3蛋白酶抑制剂，它们可用于治疗HCV感染和/或降低HCV感染的可能性或症状严重性。申请人发现CN103328466公开的一系列HCV NS3蛋白酶抑制剂中，选择具有如下结构的式Ⅰ化合物，并在其成钠盐后作为治疗剂可成为更好成药特性的药物。
Figure PCTCN2015086017-appb-000001
发明内容
本发明一方面提供了一种式Ⅰ化合物的钠盐，
Figure PCTCN2015086017-appb-000002
作为本发明的一种实施方式，本发明的式Ⅰ化合物的钠盐为式Ⅰ化合物的单钠盐。
另一方面，本发明提供一种制备式Ⅰ化合物的钠盐的方法，包括将式Ⅰ化合物与含钠的碱在溶剂中反应，分离得到式Ⅰ化合物的钠盐。
作为本发明的一些实施方式，上述方法中：
含钠的碱为氢氧化钠。式Ⅰ化合物与含钠的碱的摩尔比为1:1-5，优选摩尔比为1:1-2，最优选摩尔比为1:1-1.2。
反应温度为从0℃至溶剂系统的沸点，优选为0-25℃。
反应可以在惰性气体的保护下进行；在本发明的一个具体实施方案中，惰性气体为氮气。
反应时间为1-5h。
所述溶剂选自水、醚类、醇类、酮类、腈类、酯类、烷烃类和卤代烷烃类，具体的溶剂例如水、乙醚、异丙醚、乙醇、甲醇、异丙醇、丁醇、丙酮、丁酮、乙腈、二氯甲烷、三氯甲烷、己烷、戊烷、乙酸乙酯、乙酸甲酯。
本发明的药学上可接受的盐可以使用本领域公知的技术进行分离，例如过滤、浓缩、喷雾干燥等。进一步地还可以使用标准技术进行干燥，还可以对本发明的药学上可接受的盐进行提纯。
再一方面，本发明提供一种药物组合物，其含有治疗有效量的式Ⅰ化合物钠盐和药学上可接受的载体。具体地，式Ⅰ化合物钠盐可以为式Ⅰ化合物单钠盐。
进一步地，本发明提供式Ⅰ化合物钠盐以及含有它们的药物组合物在制备预防和/或治疗丙型肝炎病毒感染药物中的用途。具体地，式Ⅰ化合物钠盐可以为式Ⅰ化合 物单钠盐。
进一步地，本发明提供一种预防和/或治疗丙型肝炎病毒感染的方法，其中，所述方法包括对患者给药式Ⅰ化合物的钠盐或本发明所述的药物组合物。
本发明的式Ⅰ化合物的钠盐与其他盐相比，具有出乎意料的优势：
1、式Ⅰ化合物的钠盐具有较好的流动性，在制备和提纯过程中、以及在制剂过程中具有重要的意义。
2、式Ⅰ化合物的钠盐在制备过程中很容易得到纯度高的盐，而其它盐例如式Ⅰ化合物的锂盐等则需多次重结晶才能达到与式Ⅰ化合物的钠盐同样的纯度，在未来的工业化生产过程中能有效节约成本。
3、式Ⅰ化合物的钠盐在不同条件下均具有更高的稳定性。
4、式Ⅰ化合物的钠盐具有更好的药代动力学参数，例如在不同动物体内均呈现较高的生物利用度。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
按照中国专利申请CN103328466中公开的方法，制备得到式Ⅰ化合物。
实施例1 式Ⅰ化合物单钠盐的制备
0-5℃，氮气保护下，氢氧化钠(8.51g)水溶液(21.2ml，10mol/L)于二氯甲烷(1800ml)中，搅拌10min。加入150g式Ⅰ化合物，缓慢升温至10-15℃，持续搅拌3h，直至反应液澄清。反应结束后，反应液经无水硫酸钠干燥，后45℃下减压蒸干至粉末状，转移至真空烘箱45℃减压干燥4h，得式Ⅰ化合物单钠盐(154.5g)。收率99.8％，纯度99.1％，钠含量：3.1％(质量)。
实施例2 在水中溶解度实验
表1式Ⅰ化合物单钠盐在pH为6.8水溶液(磷酸盐缓冲液调pH)中的溶解度
样品 含量(mg/ml)
式Ⅰ化合物单钠盐 2.926
实施例3 稳定性实验
1、式Ⅰ化合物单钠盐在室温下不同pH溶液中的稳定性(按归一化统计总杂，％)，下表为式Ⅰ化合物单钠盐在不同溶液中放置时的杂质含量：
Figure PCTCN2015086017-appb-000003
2、式Ⅰ化合物的不同盐在高温下的稳定性(按归一化统计总杂，％)，结果如下表所示：
考察项目 0天 高温60℃下10天后
式Ⅰ化合物单钠盐所含总杂质(％) 0.92 0.96(总杂增加了4％)
式Ⅰ化合物单钾盐所含总杂质(％) 0.93 1.10(总杂增加了18％)
式Ⅰ化合物单锂盐所含总杂质(％) 1.92 2.50(总杂增加了30％)
实施例4药代动力学研究
1、SD大鼠中的药代动力学研究
实验过程：
20只201-228g雄性大鼠随机分为4组，每组5只。其中，
A组：静脉注射给予式Ⅰ化合物注射液组10mg/kg，
B组：灌胃给予式Ⅰ化合物单钠盐溶液灌胃组60mg/kg(以式Ⅰ化合物计，其中溶液为5％葡萄糖水溶液)，
C组：灌胃给予式Ⅰ化合物单钾盐溶液灌胃组60mg/kg(以式Ⅰ化合物计，其中溶液为5％葡萄糖水溶液)，
D组：灌胃给予式Ⅰ化合物单锂盐溶液灌胃组60mg/kg(以式Ⅰ化合物计，其中溶液为5％葡萄糖水溶液)，
给药后采血时间点为：5min、10min、15min、30min、1h、2h、4h、6h、8h、12h及24h。血样采集后置EDTA-K2离心管中，在4℃，4000rpm，10min条件下离心分离血浆。血浆经过前处理后以LC-MS/MS测定其中式Ⅰ化合物的浓度。药代动力学参数采用DAS软件(版本号：3.1)，按统计矩理论计算。
实验结果：
Figure PCTCN2015086017-appb-000004
2、Beagle犬中的药代动力学研究
实验过程：
6只201-228g雄性Beagle犬随机分为2组，每组3只，其中
A组：灌胃给予式Ⅰ化合物单钠盐普通胶囊300mg/只(以式Ⅰ化合物计，其中普通胶囊含有重量比为1:3.5的式Ⅰ化合物单钠盐和葡萄糖粉)，
B组：灌胃给予式Ⅰ化合物单锂盐普通胶囊300mg/只(以式Ⅰ化合物计，其中普通胶囊含有重量比为1:3.5的式Ⅰ化合物单钠盐和葡萄糖粉)，
给药后采血时间点为：10min、30min、1h、2h、4h、6h、8h、10h及24h。血样采集后置EDTA-K2离心管中，在4℃，4000rpm，10min条件下离心分离血浆。血浆经过前处理后以LC-MS/MS测定其中式Ⅰ化合物的浓度。药代动力学参数采用DAS软件(版本号：3.1)，按统计矩理论计算。
实验结果：
Figure PCTCN2015086017-appb-000005

Claims (10)

  1. 式Ⅰ化合物的钠盐，
    Figure PCTCN2015086017-appb-100001
  2. 权利要求1所述的式Ⅰ化合物的钠盐，其中式Ⅰ化合物的钠盐为式Ⅰ化合物的单钠盐。
  3. 一种权利要求1或2所述的式Ⅰ化合物的钠盐的制备方法，包括将式Ⅰ化合物与含钠的碱在溶剂中反应，分离得到式Ⅰ化合物的钠盐。
  4. 权利要求3所述的式Ⅰ化合物的钠盐的制备方法，其中含钠的碱为氢氧化钠。
  5. 权利要求3所述的式Ⅰ化合物的钠盐的制备方法，其中式Ⅰ化合物与含钠的碱的摩尔比为1:5。
  6. 权利要求5所述的式Ⅰ化合物的钠盐的制备方法，其中式Ⅰ化合物与含钠的碱的摩尔比为1:2。
  7. 权利要求3所述的式Ⅰ化合物的钠盐的制备方法，其中所述溶剂选自水、醚类、醇类、酮类、腈类、酯类、烷烃类和卤代烷烃类。
  8. 一种药物组合物，其含有治疗有效量的式Ⅰ化合物的钠盐和药学上可 接受的载体。
  9. 权利要求1或2所述的式Ⅰ化合物的钠盐或权利要求8所述的药物组合物在制备预防和/或治疗丙型肝炎病毒感染药物中的用途。
  10. 一种预防和/或治疗丙型肝炎病毒感染的方法，其中，所述方法包括对患者给药权利要求1或2所述的式Ⅰ化合物的钠盐或权利要求8所述的药物组合物。
PCT/CN2015/086017 2014-08-04 2015-08-04 Hcv ns3蛋白酶抑制剂的钠盐 Ceased WO2016019845A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102140100A (zh) * 2010-01-27 2011-08-03 爱博新药研发(上海)有限公司 高效抑制丙型肝炎病毒的多环化合物及其制备方法和用途
WO2012176149A1 (en) * 2011-06-23 2012-12-27 Panmed Ltd. Treatment of hepatitis c virus
CN103328466A (zh) * 2010-11-01 2013-09-25 Rfs制药公司 Hcv ns3蛋白酶抑制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102140100A (zh) * 2010-01-27 2011-08-03 爱博新药研发(上海)有限公司 高效抑制丙型肝炎病毒的多环化合物及其制备方法和用途
CN103328466A (zh) * 2010-11-01 2013-09-25 Rfs制药公司 Hcv ns3蛋白酶抑制剂
WO2012176149A1 (en) * 2011-06-23 2012-12-27 Panmed Ltd. Treatment of hepatitis c virus

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