WO2020103924A1 - 一种乙肝表面抗原抑制剂的晶型 - Google Patents

一种乙肝表面抗原抑制剂的晶型

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WO2020103924A1
WO2020103924A1 PCT/CN2019/120169 CN2019120169W WO2020103924A1 WO 2020103924 A1 WO2020103924 A1 WO 2020103924A1 CN 2019120169 W CN2019120169 W CN 2019120169W WO 2020103924 A1 WO2020103924 A1 WO 2020103924A1
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Prior art keywords
compound
hepatitis
crystal form
mmol
surface antigen
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PCT/CN2019/120169
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English (en)
French (fr)
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胡彦宾
孙飞
施沈一
苏艳晓
丁照中
Original Assignee
福建广生堂药业股份有限公司
南京明德新药研发有限公司
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Application filed by 福建广生堂药业股份有限公司, 南京明德新药研发有限公司 filed Critical 福建广生堂药业股份有限公司
Priority to CA3120532A priority Critical patent/CA3120532C/en
Priority to AU2019382521A priority patent/AU2019382521B2/en
Priority to KR1020217019055A priority patent/KR102606946B1/ko
Priority to BR112021009770-8A priority patent/BR112021009770A2/pt
Priority to EP19887009.9A priority patent/EP3885349B1/en
Priority to JP2021529057A priority patent/JP7138246B2/ja
Priority to CN201980042359.6A priority patent/CN112368288B/zh
Priority to ES19887009T priority patent/ES2961520T3/es
Priority to US17/293,479 priority patent/US20220017536A1/en
Publication of WO2020103924A1 publication Critical patent/WO2020103924A1/zh
Priority to ZA2021/03974A priority patent/ZA202103974B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a crystal form of a hepatitis B surface antigen inhibitor and a preparation method thereof, and further includes the application of the crystal form in preparing a hepatitis B surface antigen inhibitor.
  • Hepatitis B is a disease caused by hepatitis B virus (Hepatitis B Virus, HBV for short).
  • Hepatitis B virus is a hepatotropic virus, which mainly exists in liver cells and damages liver cells, causing inflammation, necrosis, and fibrosis of liver cells.
  • Acute hepatitis B in most adults can heal itself through its own immune mechanism.
  • chronic hepatitis B (CHB) has become a great challenge for global health care, and it is also the main cause of chronic liver disease, cirrhosis and liver cancer (HCC).
  • HBsAg hepatitis B virus surface antigen
  • the surface antigen protein of hepatitis B virus plays a very important role in the process of HBV invading liver cells, and is of great significance for the prevention and treatment of HBV infection.
  • Surface antigen proteins include large (L), medium (M) and small (S) surface antigen proteins, sharing a common C-terminal S region. They are expressed in an open reading frame, and their different lengths are determined by the three AUG start codons in the reading frame. These three surface antigen proteins include pre-S1 / pre-S2 / S, pre-S2 / S and S domains.
  • the HBV surface antigen protein is integrated into the endoplasmic reticulum (ER) membrane and is initiated by the N-terminal signal sequence.
  • SVPs spherical and filamentous subviral particles
  • HBsAg spherical and filamentous subviral particles
  • SVP contains most S surface antigen proteins.
  • the L protein is crucial in the interaction between viral morphogenesis and nucleocapsid, but it is not necessary for the formation of SVP. Due to their lack of nucleocapsid, the SVPs are non-infectious. SVPs are greatly involved in disease progression, especially the immune response to hepatitis B virus.
  • HBsAg can also inhibit human innate immunity, can inhibit the production of cytokines induced by polysaccharides (LPS) and IL-2, inhibit the DC function of dendritic cells, and LPS interferes with ERK-1 / 2 and c-Jun N-terminal interference kinase-1 / 2 Inducing activity in monocytes. It is worth noting that the disease progression of cirrhosis and hepatocellular carcinoma is also largely related to the persistent secretion of HBsAg. These findings indicate that HBsAg plays an important role in the development of chronic hepatitis.
  • anti-HBV drugs are mainly immunomodulators (interferon- ⁇ and pegylated interferon- ⁇ -2 ⁇ ) and antiviral drugs (lamivudine, adefovir dipivoxil, entecavir, and Bifudine, Tenofovir, Kravudine, etc.).
  • antiviral drugs belong to the class of nucleotide drugs, and their mechanism of action is to inhibit the synthesis of HBV DNA, and cannot directly reduce the level of HBsAg.
  • nucleotide drugs show HBsAg clearance rate similar to natural observations.
  • RG7834 a surface antigen inhibitor
  • Roche has developed a surface antigen inhibitor called RG7834 for the treatment of hepatitis B, and reported the drug efficacy of the compound in the model of woodchuck anti-hepatitis B: when using RG7834 as a single drug, it can reduce the surface of 2.57 Logs Antigen, reducing HBV-DNA by 1.7 Logs.
  • the compound has good activity, but in the process of molecular synthesis, the isomers need to be resolved, which reduces the yield and increases the cost.
  • WO2017013046A1 discloses a series of 2-oxo-7,8-dihydro-6H-pyrido [2,1, a] [2] benzodiazepine-3-for the treatment or prevention of hepatitis B virus infection Carboxylic acid derivatives.
  • the IC 50 of Example 3 the highest activity of this series of fused ring compounds, is 419 nM, and there is much room for improvement in activity.
  • the chiral centers contained in this series of compounds are difficult to synthesize asymmetrically.
  • the 7-membered carbocyclic ring has poor water solubility and is prone to oxidative metabolism.
  • the present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.04 ° ⁇ 0.2 °, 16.52 ° ⁇ 0.2 °, 19.52 ° ⁇ 0.2 °,
  • the X-ray powder diffraction pattern of Form A above has characteristic diffraction peaks at the following 2 ⁇ angles: 8.04 ° ⁇ 0.2 °, 10.47 ° ⁇ 0.2 °, 11.90 ° ⁇ 0.2 °, 16.52 ° ⁇ 0.2 °, 18.06 ° ⁇ 0.2 °, 19.52 ° ⁇ 0.2 °, 22.02 ° ⁇ 0.2 °, 25.28 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A above is shown in FIG. 1.
  • the above differential scanning calorimetry curve of Form A has a starting point of an endothermic peak at 139.64 ⁇ 5 ° C.
  • the above differential scanning calorimetry curve of Form A is shown in FIG. 2.
  • thermogravimetric analysis curve of Form A above has a weight loss of 0.4757% at 125.23 ⁇ 3 ° C.
  • thermogravimetric analysis curve of Form A is shown in FIG. 3.
  • the invention also provides the application of the above crystal form A in the preparation of medicines for treating hepatitis B.
  • the compound of the present invention has significant anti-hepatitis B virus activity.
  • the compound of the present invention has a moderate plasma protein binding rate, does not inhibit cytochrome P450 isoenzymes, and shows a low risk of drug-drug interaction; liver microsomes in three species of rats, humans, and mice
  • the stability is excellent, indicating that the compound is not easily metabolized; it has good exposure and bioavailability; it is well tolerated in neurotoxicity studies with a single administration.
  • the compound synthesis process of the invention is simple and economical.
  • the crystal form of the invention has good solubility, easy availability, and good physical stability and chemical stability.
  • intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • Test method about 10 ⁇ 20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 30mA
  • Step size 0.5 seconds
  • DSC Differential Scanning Calorimeter
  • Test method Take a sample (2 ⁇ 6mg) and place it in a 30UL DSC gold-plated high-pressure crucible for testing. Heat the sample from 40 °C to 350 °C at a heating rate of 10 °C / min.
  • Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 10mg) in an aluminum crucible, and then place it in a platinum hanging basket for testing. Under nitrogen (N 2 ) conditions, with a gas flow rate of 40mL / min and a temperature rise of 10 ° C / min Rate, heating the sample from 40 ° C to 500 ° C.
  • Fig. 1 is an XRPD spectrum of Cu-K ⁇ radiation of the crystalline form A of compound (I).
  • Fig. 2 is a DSC spectrum of the crystal form of compound A of formula (I).
  • Fig. 3 is a TGA spectrum of the crystal form A of the compound of formula (I).
  • Figure 4 shows the HBsAg content (IU / mL) at different days after the administration of the mice.
  • Figure 5 shows the changes in body weight of mice after administration on different days.
  • Step A Maintaining 0 degree Celsius, to a solution of compound 1 (100.00 g, 762.36 mmol, 1.00 equiv) in tetrahydrofuran (400.00 mL) was added lithium aluminum hydride (80.00 g, 2.11 mol, 2.77 equiv). The solution was stirred at 10 degrees Celsius for 10 hours. Then, 80.00 ml of water was added to the reaction solution with stirring, and 240.00 ml of 15% aqueous sodium hydroxide solution was added, and then 80.00 ml of water was added. The resulting suspension was stirred at 10 degrees Celsius for 20 minutes, and filtered to obtain a colorless clear liquid. Concentrate under reduced pressure to obtain compound 2.
  • Step B Dissolve compound 2 (50.00 g, 426.66 mmol) and triethylamine (59.39 mL, 426.66 mmol) in dichloromethane (500.00 mL), di-tert-butyl dicarbonate (92.19 g, 422.40 mmol) ) was dissolved in dichloromethane (100.00 ml) and added dropwise to the previous reaction solution at 0 degrees Celsius. The reaction solution was then stirred at 25 degrees Celsius for 12 hours.
  • reaction solution was washed with saturated brine (600.00 ml), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and spin-dried, and then recrystallized from methyl tert-butyl ether / petroleum ether (50.00 / 100.00) to obtain compound 3.
  • Step C Dissolve thionyl chloride (100.98 ml, 1.39 mmol) in acetonitrile (707.50 ml), compound 3 (121.00 g, 556.82 mmol) in acetonitrile (282.90 ml), and add dropwise at minus 40 degrees Celsius To the last reaction solution, after the dropwise addition, pyridine (224.72 mL, 2.78 mol) was added to the reaction solution in one portion. The ice bath was removed, and the reaction solution was stirred at 5-10 degrees Celsius for 1 hour.
  • Step 2 The obtained oil and water and ruthenium trichloride (12.55 g, 55.68 mmol) were dissolved in acetonitrile (153.80 ml), and sodium periodate (142.92 g, 668.19 mmol) was suspended in water (153.80 ml ), Slowly add to the above reaction solution, and the final reaction mixture is stirred at 5-10 degrees Celsius for 0.15 hours.
  • Step D Dissolve compound 5 (100.00 g, 657.26 mmol) in acetonitrile (1300.00 mL), add potassium carbonate (227.10 g, 1.64 mol) and 1-bromo-3-methoxypropane (110.63 g, 722.99 mmol) Moore). The reaction solution was stirred at 85 degrees Celsius for 6 hours. The reaction solution was extracted with ethyl acetate 600.00 ml (200.00 ml ⁇ 3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain compound 6.
  • Step E Compound 6 (70.00 g, 312.15 mmol) was dissolved in methylene chloride, m-chloroperoxybenzoic acid (94.27 g, 437.01 mmol) was added, and the reaction was stirred at 50 degrees Celsius for 2 hours. After cooling the reaction solution, it was filtered, the filtrate was extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution 2000.00 ml (400.00 ml ⁇ 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A brown oil was obtained. After dissolving with as little methanol as possible, a solution of 2 mol per liter of potassium hydroxide (350.00 ml) was slowly added (exothermic).
  • reaction solution was stirred at room temperature for 20 minutes, and the reaction solution was adjusted to pH 5 with 37% hydrochloric acid. It was extracted with ethyl acetate 400.00 ml (200.00 ml ⁇ 2), the organic phase was washed with saturated brine 200.00 ml (100.00 ml ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7.
  • Step F Dissolve compound 7 (33.00 g, 155.48 mmol) in tetrahydrofuran (330.00 mL), add paraformaldehyde (42.02 g, 466.45 mmol), magnesium chloride (29.61 g, 310.97 mmol), triethylamine ( 47.20 g, 466.45 mmol, 64.92 mL). The reaction solution was stirred at 80 degrees Celsius for 8 hours.
  • Step G Dissolve compound 8 (8.70 g, 36.21 mmol) in N, N-dimethylformamide (80.00 mL), add potassium carbonate (10.01 g, 72.42 mmol) and compound 4 (11.13 g, 39.83 Mmol), the reaction solution was stirred at 50 degrees Celsius for 2 hours. The reaction solution was quenched with 1.00 mol / L aqueous hydrochloric acid solution (200.00 mL), and extracted with ethyl acetate (150.00 mL ⁇ 2). The combined organic phase was washed with water (150.00 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 9.
  • Step H Compound 9 (15.80 g, 35.95 mmol) was dissolved in dichloromethane (150.00 mL), and trifluoroacetic acid (43.91 mL, 593.12 mmol) was added. The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10.
  • Step I Compound 10 (5.00 g, 15.56 mmol) was dissolved in toluene (20.00 mL), and compound 11 (8.04 g, 31.11 mmol) was added. The reaction solution was stirred at 120 ° C for 12 hours under nitrogen protection. The reaction solution was quenched with water (100.00 mL), extracted with ethyl acetate (100.00 mL ⁇ 2), the combined organic phases were washed with water (80.00 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column.
  • Step J Compound 12 (875.00 mg, 1.90 mmol) was dissolved in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and tetrachlorobenzoquinone (1.40 g, 5.69 mmol) was added. The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase.
  • Mobile phase methanol (0.05% diethylamine) in carbon dioxide, from 5% to 40%.
  • Step A The compound of formula (I) (1.89Kg) was added to ethanol (9.5L), then heated to reflux to dissolve, and then the gradient temperature was lowered, when the temperature of the reaction system was lowered to about 25 degrees Celsius, a large amount of solid precipitated, and then filtered A solid is obtained.
  • Step B Add the solid obtained in Step A to water (9.5 L), stir at room temperature for 3 to 5 hours, and then filter to obtain a solid.
  • Step C The solid obtained in Step B is baked in an oven at 45 to 50 degrees Celsius for 48 to 72 hours to obtain Form A of the compound of formula (I).
  • HepG2.2.15 cell culture medium (DMEM / F12, Invitrogen-11330032; 10% serum, Invitrogen-10099141; 100 units of penicillin and 100 ⁇ g / mL streptomycin per ml, Hyclone-SV30010; 1% non-essential amino acids, Invitrogen-11140050; 2 mm L-GLUTAMINE, Invitrogen-25030081; 300 ⁇ g / mL Geneticin, Invitrogen-10131027)
  • DMEM / F12 Invitrogen-11330032
  • 10% serum Invitrogen-10099141
  • 100 units of penicillin and 100 ⁇ g / mL streptomycin per ml Hyclone-SV30010; 1% non-essential amino acids, Invitrogen-11140050; 2 mm L-GLUTAMINE, Invitrogen-25030081; 300 ⁇ g / mL Geneticin, Invitrogen-10131027
  • Probe sequence 5 '+ FAM + CCTCTKCATCCTGCTGCTATGCCTCATC (SEQ ID NO.3) + TAMRA-3'
  • the reaction conditions of PCR are: heating at 95 ° C for 10 minutes, then denaturing at 95 ° C for 15 seconds, and extending at 60 ° C for 1 minute for a total of 40 cycles.
  • the compound of formula (I) of the present invention can effectively inhibit HBV-DNA and hepatitis B surface antigen (HBsAg).
  • the main reagents of this project include QIAamp96 DNA kit and Universal PCR Master Mix, Hepatitis B virus surface antigen detection kit.
  • Instruments include: centrifuge (Beckman Allegra X-15R), tissue grinding machine (QIAGEN-Tissue Lyser II) and spectrophotometer (Thermo-NANODROP 1000).
  • mice started oral administration on the 28th day after virus injection, and this day was set as the 0th day. All mice were submandibular blood collected before administration to collect serum. Give the medicine once a day for four consecutive weeks. See Table 3 for the specific dosing schedule.
  • mice All mice are subject to submandibular blood collection twice a week for serum collection, each time the blood collection volume is about 100 ⁇ L.
  • the specific blood collection time is shown in Table 3.
  • mice On day 28, all mice were euthanized, and blood was collected from the heart to collect serum.
  • the serum HBsAg content was detected to evaluate the anti-HBV activity of the test compound in the AAV / HBV mouse model.
  • the results are shown in Table 4 and Figure 4.
  • the change in body weight of mice is shown in Figure 5.
  • the compound of the present invention can significantly reduce HBsAg in AAV / HBV mouse model experiments, and the mice show good tolerance.

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Abstract

本发明公开了一种乙肝表面抗原抑制剂的晶型及其制备方法，还包括所述晶型在制备乙肝表面抗原抑制剂中的应用。

Description

一种乙肝表面抗原抑制剂的晶型
本申请要求申请日为2018年11月22日的中国专利申请CN2018113995143的优先权。本申请引用该中国专利申请的全文。
技术领域
本发明涉及一种乙肝表面抗原抑制剂的晶型及其制备方法，还包括所述晶型在制备乙肝表面抗原抑制剂中的应用。
背景技术
乙型病毒性肝炎，简称乙肝，是一种由乙型肝炎病毒(Hepatitis B Virus，简称HBV)感染机体后所引起的疾病。乙型肝炎病毒是一种嗜肝病毒，主要存在于肝细胞内并损害肝细胞，引起肝细胞炎症、坏死、纤维化。乙型病毒性肝炎分急性和慢性两种。急性乙型肝炎在成年人中大多数可通过其自身的免疫机制而自愈。但是慢性乙型肝炎(CHB)已成为全球健康保健所面临的极大挑战，同时也是引起慢性肝病，肝硬化(cirrhosis)和肝癌(HCC)的主要原因。据估计，全球有20亿人感染了慢性乙型肝炎病毒，超过3亿5千万人口已发展成为了乙型肝炎，每年近60万人死于慢性乙型肝炎的并发症。我国是乙肝高发区，乙型肝炎累积病人多，危害严重。据资料显示，我国现有乙型肝炎病毒感染者约9300万，而其中约2000万患者确诊为慢性乙型肝炎，当中10％-20％可演变成肝硬化，1％-5％可发展成肝癌。
乙肝功能性治愈的关键是清除HBsAg(乙型肝炎病毒表面抗原)，产生表面抗体。HBsAg量化是一个非常重要的生物指标。在慢性感染病人中，很少能观察到HBsAg的减少和血清转化，这是目前治疗的终点。
乙型肝炎病毒(HBV)的表面抗原蛋白在HBV侵入肝细胞的过程中起非常重要的作用，对于防治HBV的感染有重要意义。表面抗原蛋白包括大(L)、中(M)和小(S)的表面抗原蛋白，共享共同的C端S区。它们从一个开放读码框中表达，其不同的长度是由 读码框三个AUG起始密码子决定的。这三个表面抗原蛋白包括前S1/前S2/S，前S2/S和S域。HBV表面抗原蛋白被整合到内质网(ER)膜，由N端信号序列启动。它们不仅构成了病毒体的基本结构，而且还形成球状和丝状亚病毒颗粒(SVPs，HBsAg)，聚集在ER，宿主ER和前高尔基体器，SVP包含大多S表面抗原蛋白。L蛋白，在病毒的形态发生与核衣壳相互作用方面是至关重要的，但对于SVP的形成是没有必要的。由于它们缺乏核衣壳，所述的SVPs是非感染性的。SVPs大大参与了疾病进展，尤其是对乙肝病毒的免疫应答，在感染者的血液里，SVPs的量至少是病毒数量的10,000倍，诱捕了免疫系统，削弱人体对乙肝病毒的免疫反应。HBsAg也可抑制人的天然免疫，能够抑制多糖(LPS)和IL-2诱导的细胞因子产生，抑制树状细胞DC功能以及LPS对ERK-1/2和c-Jun N端的干扰激酶-1/2在单核细胞的诱导活性。值得注意的是，肝硬化和肝细胞癌的疾病进展很大程度也与持续分泌的HBsAg相关。这些研究结果表明HBsAg在慢性肝炎的发展中起重要作用。
目前被批准上市的抗HBV药物主要是免疫调节剂(干扰素-α和聚乙二醇干扰素-α-2α)和抗病毒治疗药物(拉米夫定、阿德福韦酯、恩替卡韦、替比夫定、替诺福韦、克拉夫定等)。其中，抗病毒治疗药物属于核苷酸类药物，其作用机制是抑制HBV DNA的合成，并不能直接减少HBsAg水平。与延长治疗一样，核苷酸类药物显示HBsAg清除速度类似于自然观察结果。
临床已有疗法降低HBsAg疗效不佳，因此，开发能够有效降低HBsAg的小分子口服抑制剂是目前临床用药所亟需的。
罗氏公司开发了一个名为RG7834的表面抗原抑制剂用于治疗乙肝，并报道了该化合物在土拨鼠抗乙肝模型中的药效：在以RG7834作为单药使用时可以降低2.57个Log的表面抗原，降低1.7个Log的HBV-DNA。该化合物活性较好，但是分子合成过程中，需要拆分异构体，降低了产率，增加了成本。
WO2017013046A1公开了一系列用于治疗或者预防乙型肝炎病毒感染的2-氧代-7，8-二氢-6H-吡啶并[2,1,a][2]苯并氮杂卓-3-羧酸衍生物。该系列稠环化合物最高活性实施例3的IC 50为419nM，活性有很大提高空间。该系列化合物含有的手性中心，不对称合成 难度较大。通常7元碳环的水溶性不佳，易于氧化代谢。
发明内容
本发明提供式(I)化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.04°±0.2°、16.52°±0.2°、19.52°±0.2°，
Figure PCTCN2019120169-appb-000001
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.04°±0.2°、10.47°±0.2°、11.90°±0.2°、16.52°±0.2°、18.06°±0.2°、19.52°±0.2°、22.02°±0.2°、25.28°±0.2°。
在本发明的一些方案中，上述A晶型的X射线粉末衍射图谱如图1所示。
在本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示。
表1 式(I)化合物A晶型的XRPD图谱解析数据
Figure PCTCN2019120169-appb-000002
Figure PCTCN2019120169-appb-000003
在本发明的一些方案中，上述A晶型的差示扫描量热曲线在139.64±5℃处具有吸热峰的起始点。
在本发明的一些方案中，上述A晶型的差示扫描量热曲线图谱如图2所示。
在本发明的一些方案中，上述A晶型的热重分析曲线在125.23±3℃处失重达0.4757％。
在本发明的一些方案中，上述A晶型的热重分析曲线图谱如图3所示。
本发明还提供上述A晶型在制备治疗乙肝药物中的应用。
技术效果
本发明化合物有显著的抗乙肝病毒活性。本发明化合物具有适中的血浆蛋白结合率，对细胞色素P450同工酶没有抑制，显示药物-药物相互作用的风险较低；在大鼠、人和小鼠这三个种属中的肝微粒体稳定性优秀，显示化合物不易被代谢；具有较好的暴露量和生物利用度；在单次给药的神经毒性研究中耐受性较好。本发明化合物合成工艺简洁、经济。
本发明晶型溶解性好、易于获得、物理稳定性和化学稳定性均较好。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
化合物经手工或者
Figure PCTCN2019120169-appb-000004
软件命名，市售化合物采用供应商目录名称。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：丹东浩元DX-2700BH X-射线衍射仪
测试方法：大约10～20mg样品用于XRPD检测。
详细的XRPD参数如下：
光管：Cu,kα,
Figure PCTCN2019120169-appb-000005
光管电压：40kV，光管电流：30mA
发散狭缝：1mm
探测器狭缝：0.3mm
防散射狭缝：1mm
扫描范围：3-40deg
步径：0.02deg
步长：0.5秒
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号：METTLER TOLEDO DSC1差示扫描量热仪
测试方法：取样品(2～6mg)置于30UL的DSC镀金高压坩锅内进行测试，以10℃/min的升温速率，加热样品从40℃到350℃。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号：TA TGA550热重分析仪
测试方法：取样品(2～10mg)置于铝坩埚内，然后放置于铂金吊篮内进行测试，在氮气(N 2)条件下，以40mL/min的气体流速，以10℃/min的升温速率，加热样品从40℃到500℃。
附图说明
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图。
图2为式(I)化合物A晶型的DSC谱图。
图3为式(I)化合物A晶型的TGA谱图。
图4为小鼠给药后不同日期的HBsAg含量(IU/mL)。
图5为小鼠给药后不同日期的体重变化。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1式(I)化合物的制备
Figure PCTCN2019120169-appb-000006
Figure PCTCN2019120169-appb-000007
步骤A:保持0摄氏度下，向化合物1(100.00克，762.36毫摩尔，1.00当量)的四氢呋喃(400.00毫升)溶液中加入四氢锂铝(80.00克，2.11摩尔，2.77当量)。溶液在10摄氏度下搅拌10小时。然后在搅拌下向反应液中加入80.00毫升水，并加入240.00毫升15％氢氧化钠水溶液，再加入80.00毫升水。得到的悬浮液在10摄氏度下搅拌20分钟，过滤得到无色清液。减压浓缩得到化合物2。
步骤B:将化合物2(50.00克，426.66毫摩尔)和三乙胺(59.39毫升，426.66毫摩尔)溶解在二氯甲烷(500.00毫升)中，二碳酸二叔丁酯(92.19克，422.40毫摩尔)溶解在二氯甲烷(100.00毫升)中，在0摄氏度下逐滴加入到上一反应液中。然后反应液在25摄氏度下搅拌12小时。反应液用饱和食盐水(600.00毫升)洗涤，无水硫酸钠干燥，有机相减压浓缩旋干，然后用甲基叔丁基醚/石油醚(50.00/100.00)重结晶，得到化合物3。
步骤C：将氯化亚砜(100.98毫升，1.39毫摩尔)溶解在乙腈(707.50毫升)，化合物3(121.00克，556.82毫摩尔)溶解在乙腈(282.90毫升)中，与零下40摄氏度下滴加到上一反应液，滴加完后，吡啶(224.72毫升，2.78摩尔)一次性加入反应液中。移去冰浴，反应液在5-10摄氏度下搅拌1小时。减压旋干溶剂后，加入乙酸乙酯(800.00毫升)，有固体析出，过滤，减压浓缩滤液。第二步：得到的油和水和三氯化钌(12.55克，55.68毫摩尔)溶解在乙腈(153.80毫升)中，将高碘酸钠(142.92克，668.19毫摩尔)悬浮在水(153.80毫升)中，缓慢加入上述反应液中，最终的反应混合液在5-10摄氏度下搅拌0.15小时。过滤反应混合液，得到滤液，用乙酸乙酯(800.00毫升×2)萃取，有机相用饱和食盐水(800.00毫升)洗涤，无水硫酸钠干燥，过滤并减压浓缩旋干。过柱纯化(二氧化硅，石油醚/乙酸乙酯＝50/1至20/1)得到化合物4。
步骤D：将化合物5(100.00克，657.26毫摩尔)溶解在乙腈(1300.00毫升)中，加入碳酸钾(227.10克，1.64摩尔)和1-溴-3-甲氧基丙烷(110.63克，722.99毫摩尔)。反应液在85摄氏度搅拌6小时。反应液用乙酸乙酯600.00毫升(200.00毫升×3)萃取，用无水硫酸钠进行干燥，然后过滤，减压浓缩，得到化合物6。
步骤E：将化合物6(70.00克，312.15毫摩尔)溶解在二氯甲烷中，加入间氯过氧苯甲酸(94.27克，437.01毫摩尔)，反应物在50摄氏度搅拌2小时。待冷却反应液后，过滤，滤液用二氯甲烷进行萃取，有机相用饱和碳酸氢钠溶液洗涤2000.00毫升(400.00毫升×5)，无水硫酸钠干燥，减压浓缩。得到棕色的油状物，用尽量少的甲醇溶解后，缓慢加入2摩尔每升的氢氧化钾(350.00毫升)溶液(会放热)。深色的反应液在室温搅拌20分钟，用37％的盐酸将反应液调酸碱度至5。用乙酸乙酯400.00毫升(200.00毫升×2)进行萃取，有机相用饱和食盐水200.00毫升(100.00毫升×2)进行洗涤，无水硫酸钠干燥，减压浓缩得到化合物7。
步骤F：将化合物7(33.00克，155.48毫摩尔)溶于四氢呋喃中(330.00毫升)，加入多聚甲醛(42.02克，466.45毫摩尔)，氯化镁(29.61克，310.97毫摩尔)，三乙胺(47.20克，466.45毫摩尔，64.92毫升)。反应液在80摄氏度搅拌8小时。反应完后，在25摄氏度用2摩尔盐酸溶液(200.00毫升)淬灭，然后用乙酸乙酯600.00毫升(200.00毫升×3)萃 取，有机相用饱和食盐水400.00毫升(200.00毫升×2)洗涤，无水硫酸钠干燥，过滤减压浓缩得残渣。残渣用乙醇(30.00毫升)洗涤，过滤，得滤饼。从而获得化合物8。
步骤G：将化合物8(8.70克，36.21毫摩尔)溶解在N,N-二甲基甲酰胺(80.00毫升)中，加入碳酸钾(10.01克，72.42毫摩尔)和化合物4(11.13克，39.83毫摩尔)，反应液在50摄氏度下搅拌2小时。反应液用1.00摩尔/升盐酸水溶液(200.00毫升)淬灭，乙酸乙酯(150.00毫升×2)萃取。合并有机相用水(150.00毫升×3)洗涤，无水硫酸钠干燥，过滤减压浓缩，得到化合物9。
步骤H：将化合物9(15.80克，35.95毫摩尔)溶解在二氯甲烷(150.00毫升)中，加入三氟乙酸(43.91毫升，593.12毫摩尔)。反应液在10摄氏度下搅拌3小时。反应液减压浓缩旋干，加入碳酸氢钠水溶液(100.00毫升)，二氯甲烷(100.00毫升)萃取。有机相用无水硫酸钠干燥，过滤减压浓缩，得到化合物10。
步骤I：将化合物10(5.00克，15.56毫摩尔)溶解在甲苯(20.00毫升)中加入化合物11(8.04克，31.11毫摩尔)反应液在氮气保护下于120摄氏度下搅拌12小时。反应液用水(100.00毫升)淬灭，乙酸乙酯(100.00毫升×2)萃取，合并有机相用水(80.00毫升×2)洗涤，无水硫酸钠干燥，过滤减压浓缩。残渣通过反相柱纯化。再经高效液相制备色谱法纯化(柱子：Phenomenex luna C18 250×50毫米×10微米；流动相:[水(0.225％甲酸)-乙腈]；洗脱梯度:35％-70％,25分钟)得到化合物12。
步骤J：将化合物12(875.00毫克，1.90毫摩尔)溶解在甲苯(20.00毫升)和乙二醇二甲醚(20.00毫升)中，加入四氯苯醌(1.40克，5.69毫摩尔)。反应液在120摄氏度下搅拌12小时。反应液冷却到室温，加入饱和碳酸钠水溶液(50.00毫升)和乙酸乙酯(60.00毫升)。将混合液在10-15摄氏度下搅拌20分钟，分液得到有机相。有机相加入2.00摩尔/升盐酸水溶液(60.00毫升)，在10-15摄氏度下搅拌20分钟，分液，有机相再用2摩尔/升盐酸水溶液(60.00毫升×2)洗涤，分液，水相中加入2摩尔/升氢氧化钠水溶液(200.00毫升)和二氯甲烷(200.00毫升)。分液，有机相用无水硫酸钠干燥，过滤减压浓缩，得到化合物13。
步骤K：将化合物13(600.00毫克，1.31毫摩尔)溶解在甲醇(6.00毫升)，加入 4.00摩尔/升的氢氧化钠水溶液(2.00毫升，6.39当量)。反应液在15摄氏度下搅拌0.25小时。将反应液用1.00摩尔/升的盐酸水溶液调节pH＝3-4，然后用二氯甲烷(50.00毫升×3)萃取，合并有机相，用饱和食盐水洗涤(50.00毫升)，无水硫酸钠干燥，过滤减压浓缩，得到式(I)化合物。ee值(对映体过量)：100％。
SFC(超临界流体色谱)方法：
柱子:Chiralcel OD-3 100毫米×4.6毫米 规格,3微米。
流动相:甲醇(0.05％二乙胺)在二氧化碳中，从5％到40％。
流速:3毫升每分钟。
波长:220纳米。
实施例2式(I)化合物A晶型的制备
步骤A：将式(I)化合物(1.89Kg)加入到乙醇(9.5L)中，然后加热回流至溶解，然后梯度降温，将反应体系温度下降到25摄氏度左右时，有大量固体析出，然后过滤得到固体。
步骤B：将步骤A所得到的固体加入到水(9.5L)中，在室温下搅拌3～5h，然后过滤得到固体。
步骤C：将步骤B所得到的固体在45～50摄氏度的烘箱中，烘48～72h，得到式(I)化合物的A晶型。质谱：[M+H] +＝432.2。 1H NMR(400MHz,氘代氯仿)δ15.72(br s,1H),8.32-8.93(m,1H),6.60-6.93(m,2H),6.51(br s,1H),4.38-4.63(m,2H),4.11(br dd,J＝4.52,12.23Hz,3H),3.79-3.87(m,3H),3.46-3.54(m,2H),3.29(s,3H),2.07(quin,J＝6.24Hz,2H),0.77-1.21(m,9H)。
实施例3式(I)化合物的HBV体外活性测试
实验材料：
1.细胞系：HepG2.2.15细胞
HepG2.2.15细胞培养基(DMEM/F12，Invitrogen-11330032；10％血清，Invitrogen- 10099141；每毫升100单位青霉素和100μg/mL链霉素，Hyclone-SV30010；1％非必需氨基酸，Invitrogen-11140050；2毫米L-GLUTAMINE，Invitrogen-25030081；300μg/mL Geneticin，Invitrogen-10131027)
2.试剂：
胰酶(Invitrogen-25300062)
DPBS(Corning-21031CVR)
二甲基亚砜(Sigma-D2650-100ML)
高通量DNA纯化试剂盒(QIAamp 96 DNA Blood Kit，Qiagen-51162)
定量快速启动通用探针试剂(FastStart Universal Probe Master，Roche-04914058001)
乙型肝炎表面抗原定量检测试剂盒(安图生物，CL 0310)
3.耗材与仪器：
96孔细胞培养板(Corning-3599)
CO 2培养箱(HERA-CELL-240)
光学封板膜(ABI-4311971)
定量PCR 96孔板(Applied Biosystems-4306737)
荧光定量PCR仪(Applied Biosystems-7500real time PCR system)
实验方法：
1.种HepG2.2.15细胞(4x10 4细胞/孔)到96孔板，在37℃，5％CO 2培养过夜。
2.第二天，稀释化合物，共8个浓度，3倍梯度稀释。加不同浓度化合物到培养孔中，双复孔。培养液中二甲基亚砜的终浓度为0.5％。10μM ETV(恩替卡韦)作为100％抑制对照；0.5％的二甲基亚砜作为0％抑制对照。
3.第五天，更换含有化合物的新鲜培养液。
4.第八天收取培养孔中的培养液，取部分样品ELISA测定乙肝病毒S抗原的含量；取部分样品使用高通量DNA纯化试剂盒(Qiagen-51162)提取DNA。
5.PCR反应液的配制如表1所示：
表2 PCR反应液的配制
Figure PCTCN2019120169-appb-000008
前引物序列：GTGTCTGCGGCGTTTTATCA(SEQ ID NO.1)
后引物序列：GACAAACGGGCAACATACCTT(SEQ ID NO.2)
探针序列：5'+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC(SEQ ID NO.3)+TAMRA-3'
6.在96孔PCR板中每孔加入15μL的反应混合液，然后每孔加入10μL的样品DNA或HBV DNA的标准品。
7.PCR的反应条件为：95℃加热10分钟，然后95℃变性15秒，60℃延伸1分钟，共40个循环。
8.ELISA测定乙肝病毒S抗原的含量
取50μL样品和标准品分别加入到反应板中，再每孔分别加入50μL酶结合物，震荡混匀，37℃温浴60分钟，然后用洗液洗板5次，再每孔加入50μL发光底物，混匀，室温避光反应10分钟，最后用酶标仪检测化学发光强度。
9.数据分析：
计算抑制百分比：％Inh.＝(1-样品中的值/二甲基亚砜对照值)×100。
计算EC 50：使用GraphPad Prism软件计算化合物对HBV的50％抑制浓度(EC 50)值。
实验结果：式(I)化合物作用于HBV-DNA和HBsAg的EC 50分别是2.55nM和3.88nM。
实验结论：本发明式(I)化合物能有效抑制HBV-DNA和乙肝表面抗原(HBsAg)。
实施例4式(I)化合物的体内药效研究
实验材料：
C57BL/6小鼠、10％HP-β-CD作为溶媒、参考化合物TDF(替诺福韦酯)、式(I)化合物、重组病毒rAAV8-1.3HBV。
本项目主要试剂包括QIAamp96 DNA试剂盒和
Figure PCTCN2019120169-appb-000009
Universal PCR Master Mix，乙型肝炎病毒表面抗原检测试剂盒。
仪器包括：离心机(Beckman Allegra X-15R)，组织研磨机(QIAGEN-Tissue lyser II)和分光光度仪(Thermo-NANODROP 1000)。
实验方法：
a)所有小鼠在病毒注射后第28天开始口服给药，将该天设为第0天。给药前所有小鼠颌下采血收集血清。每天给一次药，连续给四周。具体给药方案见表3。
b)所有小鼠每周进行两次颌下采血用于收集血清，每次采血量为约100μL。具体采血时间见表3。
c)第28天，将所有小鼠安乐死，心脏采血收集血清。
d)所有血清样品送至检测。
表3 体内实验方案
Figure PCTCN2019120169-appb-000010
Figure PCTCN2019120169-appb-000011
实验结果：
检测血清中HBsAg含量评价受试化合物在AAV/HBV小鼠模型中抗HBV活性。结果见表4和图4。小鼠体重变化见图5。
表4 小鼠给药后不同日期的HBsAg含量(IU/mL)
Figure PCTCN2019120169-appb-000012
实验结论：
本发明化合物在AAV/HBV小鼠模型实验中，能够极显著降低HBsAg，且小鼠表现出良好的耐受性。

Claims (8)

  1. 式(I)化合物的A晶型，其特征在于，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.04°±0.2°、16.52°±0.2°、19.52°±0.2°，
    Figure PCTCN2019120169-appb-100001
  2. 根据权利要求1所述的A晶型，其特征在于，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.04°±0.2°、10.47°±0.2°、11.90°±0.2°、16.52°±0.2°、18.06°±0.2°、19.52°±0.2°、22.02°±0.2°、25.28°±0.2°。
  3. 根据权利要求2所述的A晶型，其X射线粉末衍射图谱如图1所示。
  4. 根据权利要求1-3任意一项所述的A晶型，其差示扫描量热曲线在139.64±5℃处具有吸热峰的起始点。
  5. 根据权利要求4所述的A晶型，其差示扫描量热曲线图谱如图2所示。
  6. 根据权利要求1-3任意一项所述的A晶型，其热重分析曲线在125.23±3℃处失重达0.4757％。
  7. 根据权利要求6所述的A晶型，其热重分析曲线图谱如图3所示。
  8. 根据权利要求1-7任意一项所述A晶型在制备治疗乙肝药物中的应用。
PCT/CN2019/120169 2018-11-22 2019-11-22 一种乙肝表面抗原抑制剂的晶型 WO2020103924A1 (zh)

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