WO2016019845A1 - Sodium salt of hcv ns3 protease inhibitor - Google Patents
Sodium salt of hcv ns3 protease inhibitor Download PDFInfo
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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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- 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
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- 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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Abstract
Disclosed are a sodium salt of HCV NS3 protease inhibitor, preparation method therefor, pharmaceutical compositions thereof, and use thereof in preventing or treating the infection of Hepatitis C Virus (HCV). Compared with other salts, the sodium salt of HCV NS3 protease inhibitor of the present invention has better fluidity, higher stability and better pharmacokinetic parameters.
Description
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。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.
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。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.
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。Current treatments for 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. Among them, 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.
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。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.
发明内容Summary of the invention
本发明一方面提供了一种式Ⅰ化合物的钠盐，
In one aspect, the invention provides a sodium salt of a compound of formula I,
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。As an embodiment of the invention, the sodium salt of the compound of formula I of the invention is a monosodium salt of a compound of formula I.
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。In another aspect, 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.
作为本发明的一些实施方式，上述方法中：As some embodiments of the present invention, in the above method:
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。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.
反应温度为从0℃至溶剂系统的沸点，优选为0-25℃。The reaction temperature is from 0 ° C to the boiling point of the solvent system, preferably from 0 to 25 ° C.
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。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.
反应时间为1-5h。The reaction time is 1-5 h.
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。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.
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。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.
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。In a further aspect, 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. In particular, the sodium salt of the compound of formula I may be a monosodium salt of a compound of formula I.
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。Further, 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. Specifically, the sodium salt of the compound of formula I may be a compound of formula I.
Single sodium salt.
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。Further, 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.
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：The sodium salt of the compounds of formula I of the present invention has unexpected advantages over other salts:
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。1. 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.
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。2. 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.
3、式Ⅰ化合物的钠盐在不同条件下均具有更高的稳定性。3. The sodium salt of the compound of formula I has higher stability under different conditions.
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。4. The sodium salt of a compound of formula I has better pharmacokinetic parameters, such as a higher bioavailability in different animals.
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。The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.
按照中国专利申请CN103328466中公开的方法，制备得到式Ⅰ化合物。The compound of formula I is prepared according to the method disclosed in Chinese patent application CN103328466.
实施例1 式Ⅰ化合物单钠盐的制备Example 1 Preparation of a Monosodium Salt of a Compound of Formula I
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)。An aqueous solution of sodium hydroxide (8.51 g) (21.2 ml, 10 mol/L) was added to dichloromethane (1800 ml) with stirring under nitrogen for 10 min. 150 g of the compound of formula I were added and the temperature was slowly raised to 10-15 ° C and stirring was continued for 3 h until the reaction was clear. After completion of the reaction, the reaction solution was dried over anhydrous sodium sulfate, and evaporated to dryness, and then evaporated to dryness. The yield was 99.8%, the purity was 99.1%, and the sodium content was 3.1% (mass).
实施例2 在水中溶解度实验Example 2 Solubility Experiment in Water
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Table 1 Solubility of the monosodium salt of the compound of formula I in an aqueous solution of pH 6.8 (pH adjusted by phosphate buffer)
| 样品sample | 含量(mg/ml)Content (mg/ml) |
| 式Ⅰ化合物单钠盐Compound I monosodium salt of formula I | 2.9262.926 |
实施例3 稳定性实验Example 3 Stability Experiment
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：1. The stability of the monosodium salt of the compound of the formula I in different pH solutions at room temperature (according to the normalized total miscellaneous, %), the following table shows the impurity content of the monosodium salt of the compound of the formula I when placed in different solutions:
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：2. The stability of the different salts of the compound of formula I at high temperature (by normalization, total miscellaneous, %), the results are shown in the following table:
| 考察项目investigation | 0天0 days | 高温60℃下10天后10 days after high temperature 60 ° C |
| 式Ⅰ化合物单钠盐所含总杂质(％)Total impurities (%) of the monosodium salt of the compound of formula I | 0.920.92 | 0.96(总杂增加了4％)0.96 (total increase of 4%) |
| 式Ⅰ化合物单钾盐所含总杂质(％)Total impurities (%) of monopotassium salt of compound of formula I | 0.930.93 | 1.10(总杂增加了18％)1.10 (total increase of 18%) |
| 式Ⅰ化合物单锂盐所含总杂质(％)Total impurities (%) of the single lithium salt of the compound of formula I | 1.921.92 | 2.50(总杂增加了30％)2.50 (total increase of 30%) |
实施例4药代动力学研究Example 4 Pharmacokinetic Study
1、SD大鼠中的药代动力学研究1. Pharmacokinetics study in SD rats
实验过程：experiment procedure:
20只201-228g雄性大鼠随机分为4组，每组5只。其中，Twenty male rats of 201-228 g were randomly divided into 4 groups, 5 in each group. among them,
A组：静脉注射给予式Ⅰ化合物注射液组10mg/kg，Group A: intravenous administration of 10 mg/kg of the compound injection group of formula I,
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)，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),
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)，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),
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)，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),
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。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.
实验结果：
Experimental results:
2、Beagle犬中的药代动力学研究2. Pharmacokinetics in Beagle dogs
实验过程：experiment procedure:
6只201-228g雄性Beagle犬随机分为2组，每组3只，其中Six male 201-228g Beagle dogs were randomly divided into 2 groups, 3 in each group.
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)，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),
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)，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),
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。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.
实验结果：Experimental results:
Claims (10)
- 式Ⅰ化合物的钠盐，a sodium salt of a compound of formula I,
- 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。A sodium salt of a compound of formula I according to claim 1 wherein the sodium salt of the compound of formula I is a monosodium salt of a compound of formula I.
- 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。A process for the preparation of a sodium salt of a compound of formula I according to claim 1 or 2 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.
- 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。A process for the preparation of a sodium salt of a compound of formula I according to claim 3, wherein the sodium-containing base is sodium hydroxide.
- 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。A process for the preparation of a sodium salt of a compound of formula I according to claim 3 wherein the molar ratio of the compound of formula I to the sodium-containing base is 1:5.
- 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。A process for the preparation of a sodium salt of a compound of formula I according to claim 5 wherein the molar ratio of the compound of formula I to the sodium-containing base is 1:2.
- 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。A process for the preparation of a sodium salt of a compound of formula I according to claim 3, wherein the solvent is selected from the group consisting of water, ethers, alcohols, ketones, nitriles, esters, alkanes and halogenated alkanes.
- 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。A pharmaceutical composition comprising a therapeutically effective amount of a sodium salt of a compound of formula I and a pharmaceutically acceptable Accepted carrier.
- 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。Use of the sodium salt of a compound of the formula I according to claim 1 or 2 or the pharmaceutical composition according to claim 8 for the preparation of a medicament for the prophylaxis and/or treatment of hepatitis C virus infection.
- 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。 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 according to claim 1 or 2 or a pharmaceutical composition according to claim 8.
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| CN102140100A (en) * | 2010-01-27 | 2011-08-03 | 爱博新药研发(上海)有限公司 | Polycyclic compound for inhibiting hepatitis C virus efficiently, preparation method thereof and application thereof |
| WO2012176149A1 (en) * | 2011-06-23 | 2012-12-27 | Panmed Ltd. | Treatment of hepatitis c virus |
| CN103328466A (en) * | 2010-11-01 | 2013-09-25 | Rfs制药公司 | Novel specific HCV NS3 protease inhibitors |
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| CN102140100A (en) * | 2010-01-27 | 2011-08-03 | 爱博新药研发(上海)有限公司 | Polycyclic compound for inhibiting hepatitis C virus efficiently, preparation method thereof and application thereof |
| CN103328466A (en) * | 2010-11-01 | 2013-09-25 | Rfs制药公司 | Novel specific HCV NS3 protease inhibitors |
| WO2012176149A1 (en) * | 2011-06-23 | 2012-12-27 | Panmed Ltd. | Treatment of hepatitis c virus |
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