WO2022095950A1 - 包含衣壳蛋白抑制剂和核苷类似物的药物组合 - Google Patents

包含衣壳蛋白抑制剂和核苷类似物的药物组合 Download PDF

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Publication number
WO2022095950A1
WO2022095950A1 PCT/CN2021/128892 CN2021128892W WO2022095950A1 WO 2022095950 A1 WO2022095950 A1 WO 2022095950A1 CN 2021128892 W CN2021128892 W CN 2021128892W WO 2022095950 A1 WO2022095950 A1 WO 2022095950A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
tenofovir
entecavir
compound
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PCT/CN2021/128892
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English (en)
French (fr)
Inventor
徐中南
霍丹丹
张弘
于雅楠
夏建华
贺海鹰
Original Assignee
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to US18/033,897 priority Critical patent/US20230404976A1/en
Priority to JP2023524733A priority patent/JP2023547150A/ja
Priority to CN202180070949.7A priority patent/CN116367834A/zh
Priority to EP21888642.2A priority patent/EP4241770A1/en
Publication of WO2022095950A1 publication Critical patent/WO2022095950A1/zh

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    • 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
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present application belongs to the field of medicinal chemistry, and relates to a pharmaceutical combination comprising capsid protein inhibitors and nucleoside analogs.
  • HBV hepatitis B virus
  • cccDNA a stable covalently closed circular DNA, cccDNA, is formed in the nucleus of the host's hepatocytes, serving as a template for HBV's continuous replication.
  • All subgenomic RNAs (sgRNAs) and pregenomic RNAs (pgRNAs) were transcribed from cccDNA. After exiting the nucleus, the sgRNA is translated into the X protein and three other envelope proteins, and the pgRNA is translated into the core protein and viral polymerase. Under the action of polymerase, pgRNA and core protein self-assemble to form RNA wrapped with nucleocapsid.
  • nucleocapsid In the nucleocapsid, pgRNA is reverse transcribed into negative-strand DNA, from which the plus-strand DNA is further synthesized to form rcDNA.
  • the rcDNA encapsulated by the nucleocapsid re-decapsulates into the nucleus to further amplify the cccDNA; on the other hand, it re-combines with the envelope protein and releases the cell through the endoplasmic reticulum to form a new HBV.
  • the synthesis of nucleocapsid is a key step in the process of HBV genome replication, and the synthesis of viral DNA can only occur specifically inside the nucleocapsid.
  • Nucleocapsid assembly is an evolutionarily constrained process limiting HBV diversity and is highly sensitive to even subtle molecular perturbations. Targets acting on the synthesis and degradation processes of the nucleocapsid are very promising for the development of new therapeutics against different HBV genotypes and drug-resistant strains.
  • nucleoside (acid) compounds and interferons.
  • Nucleoside (acid) drugs such as entecavir and tenofovir, can inhibit HBV DNA replication.
  • the application provides a pharmaceutical combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a reverse transcriptase inhibitor or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof,
  • the reverse transcriptase inhibitor is selected from entecavir or a pharmaceutically acceptable salt or solvate thereof, or tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof.
  • the application provides a pharmaceutical combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof.
  • the application provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir, or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof.
  • the present application also provides the use of the pharmaceutical combination of the present application in preparing a medicament for treating hepatitis B virus infection.
  • the present application also provides a method of treating hepatitis B virus infection comprising administering to an individual in need thereof an effective amount of the pharmaceutical combination of the present application.
  • the present application also provides pharmaceutical combinations for the treatment of hepatitis B virus infection.
  • the present application also provides the use of the pharmaceutical combination of the present application for treating hepatitis B virus infection.
  • the application provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of formula I is shown below:
  • the entecavir solvate is selected from entecavir hydrate. In some embodiments, the entecavir hydrate is selected from entecavir 0.5-2 hydrate. In some embodiments, the entecavir hydrate is selected from entecavir monohydrate.
  • the pharmaceutically acceptable salt of entecavir is selected from the maleate salt. In some embodiments of the present application, the pharmaceutically acceptable salt of entecavir is selected from a maleate salt.
  • entecavir or a pharmaceutically acceptable salt or solvate thereof is selected from entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.
  • the pharmaceutical combination described herein comprises a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or hydrate thereof.
  • the pharmaceutical combinations described herein include a compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir, or a monohydrate thereof.
  • the pharmaceutical combinations described herein include a compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir-maleate monohydrate.
  • the pharmaceutically acceptable prodrugs of tenofovir include tenofovir disoproxil, tenofovir alafenamide, or tenofovir.
  • the pharmaceutically acceptable salt of tenofovir or a pharmaceutically acceptable prodrug thereof is selected from the group consisting of fumarate, orotate, disulfonate, phosphate, succinic acid or Aspartate. In some embodiments of the present application, the pharmaceutically acceptable salt of tenofovir or a pharmaceutically acceptable prodrug thereof is selected from fumarate salts.
  • tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of tenofovir, tenofovir alafenamide fumarate, tenofovir Verdipirate fumarate, tenofovir disoproxil orotate, tenofovir disoproxil hemi-disulfonate, tenofovir disoproxil phosphate, tenofovir disoproxil Fosvir disoproxil succinate, tenofovir disoproxil aspartate, or tenofovir fumarate.
  • the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from tenofovir disoproxil fumarate or tenofovir alain Phenamine fumarate. In some embodiments of the present application, tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof is selected from tenofovir disoproxil fumarate.
  • tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof is selected from the following structures:
  • the pharmaceutical combination described herein comprises a compound of formula I or a pharmaceutically acceptable salt thereof and tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combinations described herein include a compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir alafenamide or tenofovir disoproxil, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combinations described herein include a compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir disoproxil fumarate or tenofovir alafenamide fumarate.
  • the compound of formula I or a pharmaceutically acceptable salt thereof of the pharmaceutical combination may be administered once a day, twice a day, once every two days, once every three days, every four days Administration is once, once every five days, once every six days, once every week, once every two weeks, or once every three weeks.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, of the pharmaceutical combination is administered at a dose of 10 mg or 50 mg per administration (calculated by weight of the compound of formula I).
  • the compound of formula I or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 0.0001 to 20 mg/kg weight (calculated by weight of the compound of formula I) per administration.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, of the pharmaceutical combination is 1-1500 mg or 10-1000 mg per administration.
  • the tenofovir or pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof of the pharmaceutical combination may be administered once daily, twice daily, or once every two days, or Administration is once every three days, or once every four days, or once every five days, or once every six days, or once every seven days. In some embodiments of the present application, the tenofovir or pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof of the pharmaceutical combination may be administered once a day.
  • tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable prodrug thereof every 24 hours Salt; in patients with creatinine clearance (mL/min) ⁇ 30-49, tenofovir or its pharmaceutically acceptable prodrug or its pharmaceutically acceptable salt every 48 hours; in creatinine clearance (mL/min)
  • tenofovir or its pharmaceutically acceptable prodrug or its pharmaceutically acceptable salt every 72 to 96 hours; for hemodialysis patients, every 7 days or about 12 hours after dialysis. Nofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof.
  • tenofovir disoproxil fumarate is 300 mg per administration. In some embodiments of the present application, tenofovir alafenamide 25 mg or tenofovir alafenamide fumarate 28 mg per administration.
  • the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 0.05 mg to 500 mg (by weight of tenofovir). In some embodiments of the present application, the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 0.1 mg to 400 mg (by weight of tenofovir). In some embodiments of the present application, the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 1 mg to 300 mg (by weight of tenofovir).
  • the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 5 mg to 200 mg (by weight of tenofovir). In some embodiments of the present application, the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 8 mg to 190 mg (by weight of tenofovir). In some embodiments of the present application, the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 10 mg to 185 mg (by weight of tenofovir). In some embodiments of the present application, the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 14 mg to 140 mg (by weight of tenofovir).
  • the entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination may be administered once a day, twice a day, or once every two days.
  • the entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination is administered at a dose of 0.5 mg or 1.0 mg (by weight of entecavir) per administration.
  • the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination is 0.005 mg to 10.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination is 0.05 mg to 5.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination is 0.10 mg to 2.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination is 0.25 mg to 2.0 mg. In some embodiments of the present application, the average daily dose of entecavir or a pharmaceutically acceptable salt or solvate thereof of the pharmaceutical combination is 0.5 mg to 1.0 mg.
  • the compound of formula I or a pharmaceutically acceptable salt thereof of the pharmaceutical combination is 1-1500 mg or 10-1000 mg (calculated by weight of the compound of formula I) per administration, the tenofovir or its
  • the average daily dose of a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is 0.05 mg to 500 mg (by weight of tenofovir).
  • the ratio of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is selected from 500:1 to 1:1000.
  • the ratio (in weight units) of the compound of formula I, or a pharmaceutically acceptable salt thereof, to the average daily dose of tenofovir, or a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable salt thereof is selected from 500: 1, 450:1, 400:1, 350:1, 300:1, 250:1, 200:1, 150:1, 100:1, 95:1, 90:1, 85:1, 80:1, 79:1, 78:1, 77:1, 76:1, 75:1, 74:1, 73:1, 72:1, 71:1, 70:1, 69:1, 68:1, 67: 1, 66:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 1:1, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1: 12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:30, 1:40, 1:
  • the ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the average daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof in the pharmaceutical combination (as free compound) molar ratio) is selected from 100:1 to 1:100.
  • the ratio of the average daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, to tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from: 100:1, 98:1, 96:1, 94:1, 92:1, 90:1, 88:1, 86:1, 84:1, 82:1 , 80:1, 78:1, 76:1, 74:1, 72:1, 70:1, 68:1, 66:1, 64:1, 62:1, 60:1, 58:1, 56 :1, 54:1, 52:1, 50:1, 48:1, 46:1, 45:1, 44:1, 43:1, 42:1, 41:1, 40:1, 39:1 , 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 30:1, 29:1, 28:1, 27:1, 26 :1, 25:1, 24:1, 23:1, 22
  • the pharmaceutical combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I as a free compound) and an average daily dose of tenofovir disoproxil fumarate (by weight) The ratio of units) is selected from 1:300 ⁇ 1500:300 or 10:300 ⁇ 1000:300.
  • the pharmaceutical combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I calculated as free compound) and tenofovir disoproxil fumarate average daily dose (in weight units) Ratio selected from 10:300, 20:300, 30:300, 40:300, 50:300, 60:300, 70:300, 80:300, 90:300, 100:300, 110:300, 120:300 , 130:300, 140:300, 150:300, 160:300, 170:300, 180:300, 190:300, 200:300, 210:300, 220:300, 230:300, 240:300, 250 :300, 260:300, 270:300, 280:300, 290:300, 300:300, 310:300, 320:300, 330:300, 340:300, 350:300, 360:300, 370:300 , 380:300, 390:300, 400:300, 410:300, 420:300, 430:300,
  • the compound of formula I or a pharmaceutically acceptable salt thereof (the compound of formula I is calculated as free compound) and the average daily dose of tenofovir alafenamide (in weight units) in the pharmaceutical combination The ratio is selected from 1:25-1500:25 or 10:25-1000:25.
  • the ratio of the compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I as free compound) to the average daily dose of tenofovir alafenamide (in weight units) in the pharmaceutical combination is selected from 10 :25, 20:25, 30:25, 40:25, 50:25, 60:25, 70:25, 80:25, 90:25, 100:25, 110:25, 120:25, 130:25 , 140:25, 150:25, 160:25, 170:25, 180:25, 190:25, 200:25, 210:25, 220:25, 230:25, 240:25, 250:25, 260 :25, 270:25, 280:25, 290:25, 300:25, 310:25, 320:25, 330:25, 340:25, 350:25, 360:25, 370:25, 380:25 , 390:25, 400:25, 410:25, 420:25, 430:25,
  • the pharmaceutical combination is a compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I as free compound) and tenofovir alafenamide fumarate average daily dose (by weight) The ratio of units) is selected from 1:28 ⁇ 1500:28 or 10:28 ⁇ 1000:28.
  • the pharmaceutical combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I calculated as free compound) and tenofovir alafenamide fumarate average daily dose (in units of weight)
  • the ratio is selected from 10:28, 20:28, 30:28, 40:28, 50:28, 60:28, 70:28, 80:28, 90:28, 100:28, 110:28, 120:28 , 130:28, 140:28, 150:28, 160:28, 170:28, 180:28, 190:28, 200:28, 210:28, 220:28, 230:28, 240:28, 280 :28, 260:28, 270:28, 280:28, 290:28, 300:28, 310:28, 320:28, 330:28, 340:28, 350:28, 360:28, 370:28 , 380:28, 390:28, 400:28, 410:28, 420:28, 430
  • the compound of formula I or a pharmaceutically acceptable salt thereof and tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof in the pharmaceutical combination are administered in a single dose or in multiple doses, respectively medicine.
  • the compound of formula I of the pharmaceutical combination or a pharmaceutically acceptable salt thereof is 1-1500 mg or 10-1000 mg per administration, and the entecavir or a pharmaceutically acceptable salt or a solvate thereof has an average daily Doses are 0.005 mg to 10.0 mg.
  • the ratio (in weight units) of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt or solvate thereof in the pharmaceutical combination is selected from 1000: 1 to 1:1000.
  • the ratio of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof is selected from 1000: 1, 950:1, 900:1, 850:1, 800:1, 750:1, 700:1, 650:1, 600:1, 550:1, 500:1, 450:1, 400:1, 350:1, 300:1, 250:1, 200:1, 150:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30: 1, 20:1, 10:1, 1:1., 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 , 1:100, 1:150, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:550, 1:600, 1:650, 1 :700, 1:750, 1:800, 1:850, 1
  • the ratio of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt or solvate thereof in the pharmaceutical combination is selected from From 100:1 to 1:100.
  • the ratio of the average daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof is selected From: 100:1, 98:1, 96:1, 94:1, 92:1, 90:1, 88:1, 86:1, 84:1, 82:1, 80:1, 78:1, 76:1, 74:1, 72:1, 70:1, 68:1, 66:1, 64:1, 62:1, 60:1, 58:1, 56:1, 54:1, 52: 1, 50:1, 48:1, 46:1, 44:1, 42:1, 40:1, 38:1, 36:1, 34:1, 32:1, 30:1, 28:1, 26:1, 24:1, 22:1, 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 8:1, 6:1, 4:1, 2: 1, 1:1, 1:2, 1:4, 1:6, 1:8, 1:10, 1:12, 1:12, 1:1
  • the ratio of the compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I as free compound) to the average daily dose of entecavir monohydrate (in weight units) in the pharmaceutical combination is selected from 1 :0.5 ⁇ 1500:0.5 or 10:0.5 ⁇ 1000:0.5.
  • the ratio of the compound of formula I or a pharmaceutically acceptable salt thereof (compound of formula I as free compound) to the average daily dose of entecavir monohydrate (in weight units) in the pharmaceutical combination is selected from the group consisting of 10:0.5, 20 :0.5, 30:0.5, 40:0.5, 50:0.5, 60:0.5, 70:0.5, 80:0.5, 90:0.5, 100:0.5, 110:0.5, 120:0.5, 130:0.5, 140:0.5 , 150:0.5, 160:0.5, 170:0.5, 180:0.5, 190:0.5, 200:0.5, 210:0.5, 220:0.5, 230:0.5, 240:0.5, 250:0.5, 260:0.5, 270 :0.5, 280:0.5, 290:0.5, 300:0.5, 310:0.5, 320:0.5, 330:0.5, 340:0.5, 350:0.5, 360:0.5, 370:0.5, 380:0.5, 390:0.5 , 400:0.5, 410:0.5, 420:0.5, 430:0.5,
  • the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the pharmaceutical combination are administered in a single dose or in multiple doses, respectively.
  • the drug combination is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir, or a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable salt thereof, in the fixed combination are present in the same solid pharmaceutical composition.
  • the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the fixed combination are present in the same solid pharmaceutical composition.
  • the drug combination is a non-fixed combination.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir, or a pharmaceutically acceptable salt, or solvate thereof, in the non-fixed combination are each in the form of a solid pharmaceutical composition.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir, or a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a solid pharmaceutical composition, and
  • the solid pharmaceutical composition of the compound of formula I, or a pharmaceutically acceptable salt thereof, and the solid pharmaceutical composition of tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, are present in the same sachet.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir, or a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a solid pharmaceutical composition, and
  • the solid pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof and the solid pharmaceutical composition of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof are not present in the same sachet.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir, or a pharmaceutically acceptable salt thereof, or a solvate thereof in the non-fixed combination are each in the form of a solid pharmaceutical composition, and the compound of formula I, or a pharmaceutically acceptable salt thereof, is each in the form of a solid pharmaceutical composition.
  • the solid pharmaceutical composition of the pharmaceutically acceptable salt and the solid pharmaceutical composition of entecavir or its pharmaceutically acceptable salt or its solvate are present in the same sachet.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir, or a pharmaceutically acceptable salt thereof, or a solvate thereof in the non-fixed combination are each in the form of a solid pharmaceutical composition, and the compound of formula I, or a pharmaceutically acceptable salt thereof, is each in the form of a solid pharmaceutical composition.
  • the solid pharmaceutical composition of the pharmaceutically acceptable salt and the solid pharmaceutical composition of entecavir or its pharmaceutically acceptable salt or its solvate are not present in the same sachet.
  • the solid pharmaceutical composition is selected from tablets or capsules.
  • the present application also provides the use of the pharmaceutical combination of the present application in preparing a medicament for treating hepatitis B virus infection.
  • the drug combination is as previously described.
  • the present application also provides a method of treating hepatitis B virus infection, comprising administering to an individual in need thereof an effective amount of the pharmaceutical combination of the present application.
  • the drug combination is as previously described.
  • the present application also provides the pharmaceutical combination of the present application for the treatment of hepatitis B virus infection.
  • the drug combination is as previously described.
  • the present application also provides the use of the pharmaceutical combination of the present application for treating hepatitis B virus infection.
  • the drug combination is as described above.
  • the present application also provides a kit for treating hepatitis B virus infection, comprising: (a) a first medicament comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient composition; and (b) a second pharmaceutical composition comprising a reverse transcriptase inhibitor or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient; and optionally (c) ) Instructions for the combined use of a compound of formula I or a pharmaceutically acceptable salt thereof and a reverse transcriptase inhibitor or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • the reverse transcriptase inhibitor or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is as previously described.
  • the present application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in preparation for the treatment of hepatitis B virus infection
  • a compound of formula I or a pharmaceutically acceptable salt thereof, and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in preparation for the treatment of hepatitis B virus infection
  • the application in medicine, wherein the compound of formula I or its pharmaceutically acceptable salt and tenofovir or its pharmaceutically acceptable prodrug or its pharmaceutically acceptable salt are respectively prepared into pharmaceutical compositions.
  • the present application also provides a kit for treating hepatitis B virus infection, comprising: (a) a first medicament comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient and (b) a second pharmaceutical composition comprising tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient; and optionally (c) a compound of formula I or a pharmaceutically acceptable salt thereof Instructions for the combined use of a pharmaceutically acceptable salt and tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof.
  • the present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of hepatitis B virus infection, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof are separately prepared into pharmaceutical compositions.
  • the present application also provides a kit for treating hepatitis B virus infection, comprising: (a) a first medicament comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient and (b) a second pharmaceutical composition comprising entecavir or a solvate thereof as an active ingredient; and optionally (c) a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt thereof or Instructions for the combined use of its solvates.
  • the compound of formula I belongs to the prior art, and its chemical name is 2-((1r,4r)-4-(2-(6-chloro-7-((3,4,5-trifluorophenyl)carbamate) acyl)-2,3-dihydro-1H-pyrrolin-5-yl)-2-oxalamido)-4-methylcyclohexyl)acetic acid, which has the following structural formula:
  • the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, preferably from tablets or capsules.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition
  • the single dose of the pharmaceutical composition is a pharmaceutical composition of 1 mg to 100 mg, preferably from a single dose of 1 mg, 2 mg, 3 mg, and 4 mg.
  • Entecavir or its pharmaceutically acceptable salt or its solvate described in this application includes entecavir or its pharmaceutically acceptable salt, entecavir or its pharmaceutically acceptable salt solvate, or any combination thereof.
  • Entecavir 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9- Dihydro-6H-purin-6-one, which has the following structural formula:
  • the pharmaceutically acceptable salt of entecavir is selected from the maleate salt. In some aspects, the pharmaceutically acceptable salt of entecavir is selected from a maleate salt.
  • the solvate of entecavir is selected from entecavir hydrate.
  • the entecavir hydrate is selected from entecavir 0.5-2 hydrate.
  • the entecavir hydrate is selected from entecavir monohydrate.
  • the entecavir or a pharmaceutically acceptable salt thereof, a solvate of entecavir or a pharmaceutically acceptable salt thereof is selected from entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate thing.
  • entecavir or a pharmaceutically acceptable salt or solvate thereof is in the form of a pharmaceutical composition.
  • the pharmaceutical composition is selected from solid pharmaceutical compositions.
  • the solid pharmaceutical composition is preferably selected from tablets or capsules.
  • the pharmaceutical composition of entecavir or its pharmaceutically acceptable salt or its solvate is selected from pharmaceutical compositions with a single dose of 0.01 mg to 5 mg, preferably from a single dose of 0.01 mg, 0.02 mg, and 0.05 mg. , 0.08mg, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6 mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg,
  • the entecavir or its pharmaceutically acceptable salt or its solvate, or its pharmaceutical composition can be selected from commercially available products (such as entecavir dispersible tablets: ).
  • Tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof described herein includes tenofovir free compound, or a pharmaceutically acceptable prodrug thereof, or tenofovir or a pharmaceutically acceptable prodrug thereof The pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the tenofovir chemical name is R-9-(2-phosphate methoxypropyl) adenine, which has the following structural formula:
  • the tenofovir pharmaceutically acceptable prodrug is selected from tenofovir alafenamide, tenofovir disoproxil or tenofovir emissive.
  • the pharmaceutically acceptable salts of the tenofovir free compound or prodrug include fumarate, orotate, disulfonate, phosphate, succinic acid, or aspartate.
  • the pharmaceutically acceptable salt of the tenofovir prodrug is selected from tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or tenofovir emirate Weifumarate.
  • the pharmaceutically acceptable salt of the tenofovir prodrug is selected from tenofovir alafenamide fumarate.
  • the number ratio of tenofovir alafenamide to fumaric acid in the pharmaceutically acceptable salt of the tenofovir prodrug is 2:1.
  • the tenofovir alafenamide fumarate is selected from the following structures
  • the pharmaceutically acceptable salt of the tenofovir prodrug is selected from tenofovir disoproxil fumarate.
  • the number ratio of tenofovir disoproxil to fumaric acid in the pharmaceutically acceptable salt of the tenofovir prodrug is 1:1.
  • the tenofovir disoproxil fumarate is selected from the following structures
  • the pharmaceutically acceptable salt of the tenofovir prodrug is selected from tenofovir fumarate emirate.
  • the number ratio of tenofovir to fumaric acid in the pharmaceutically acceptable salt of the tenofovir prodrug is 1:1.
  • the tenofovir fumarate is selected from the following structures
  • the pharmaceutically acceptable salt of the tenofovir prodrug is selected from tenofovir disoproxil orotate.
  • the number ratio of tenofovir disoproxil to orotic acid in the pharmaceutically acceptable salt of the tenofovir prodrug is 1:1.
  • the tenofovir disoproxil orotate is selected from the following structures
  • the pharmaceutically acceptable salt of the tenofovir prodrug is selected from tenofovir disoproxil succinate.
  • the number ratio of tenofovir disoproxil to succinic acid in the pharmaceutically acceptable salt of the tenofovir prodrug is 1:1.
  • the tenofovir disoproxil succinate is selected from the following structures
  • tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition.
  • the pharmaceutical composition is selected from solid pharmaceutical compositions.
  • the solid pharmaceutical composition is preferably selected from tablets or capsules.
  • the tenofovir or its pharmaceutically acceptable prodrug or its pharmaceutically acceptable salt is selected from the pharmaceutical composition with a single dose of 0.05 mg to 500 mg (based on the tenofovir free compound), preferably From a single dose of 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135
  • the pharmaceutical composition of tenofovir disoproxil fumarate is selected from the pharmaceutical composition in a single dose of 300 mg.
  • the pharmaceutical composition of tenofovir alafenamide is selected from the pharmaceutical composition in a single dose of 25 mg.
  • the pharmaceutical composition of tenofovir alafenamide fumarate is selected from the pharmaceutical composition in a single dose of 28 mg.
  • the tenofovir or its pharmaceutically acceptable prodrug or its pharmaceutically acceptable salt can be selected from commercially available products (such as tenofovir disoproxil fumarate tablets: Tenofovir Fumarate: ).
  • the individual is selected from a previously treated individual or a previously treatment naive individual.
  • the subject is selected from subjects previously treated with entecavir or a pharmaceutically acceptable salt or solvate thereof, or tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof.
  • the individual is selected from a treatment-na ⁇ ve individual. In some embodiments, the individual is selected from previously treated individuals.
  • the individual is selected from serum virological criteria: serum HBsAg positive for more than 24 weeks or evidence of chronic hepatitis B for 24 weeks, 1000IU/ml ⁇ HbsAg quantification ⁇ 40000IU/ml.
  • the individual is selected from previously treated individuals, subject to the following conditions:
  • HBV DNA inhibition recorded in the medical history 24 weeks before enrollment ⁇ lower limit of normal detection, and HBV DNA inhibition in the screening period was defined as ⁇ LLOQ;
  • the individual is selected from a previously untreated individual who meets the following conditions:
  • HBV DNA >10 4 copies/mL (or >2,000IU/mL) in HBeAg-negative patients;
  • the ratio of the amount of the compound to the solvent may be selected from the group consisting of 1:0.5, 1:1, 1:1.5, 1 :2 or a range formed by any endpoint, such as 1:0.5 to 1:2, 1:0.5 to 1:1.5, or 1:1 to 1:1.5.
  • the entecavir is in unsolvated form.
  • the entecavir solvate can be entecavir hydrate.
  • the entecavir hydrate may be entecavir monohydrate.
  • weight refers to the weight of the free form of the compound of formula I, entecavir or tenofovir.
  • administering or “administering” or “administering” refer to the physical introduction to a subject of a composition comprising a therapeutic agent using any of a variety of methods and delivery systems known to those skilled in the art.
  • treating generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treatment or prevention of a particular disease, condition or disorder, (ii) alleviation, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay herein
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • the term "individual" may be a mammal. In some embodiments, the subject is a mouse. In some embodiments, the subject is a human.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered by any suitable route and method, eg, orally or parenterally (eg, intravenously).
  • a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof includes, but is not limited to, from about 0.0001 to 20 mg/kg weight/day, such as from 0.001 to 10 mg/kg weight/day.
  • the dosage frequency of a compound of formula I or a pharmaceutically acceptable salt thereof is determined by the individual patient's needs, including severity, disease response, any treatment-related toxicity, patient's age and health status, for example once or twice a day, or daily more times.
  • Dosing can be intermittent, for example, wherein over a period of several days, the subject receives a daily dose of a compound of formula I or a pharmaceutically acceptable salt thereof, followed by a period of several or more days in which the patient does not receive formula I.
  • Daily dose of compound I or a pharmaceutically acceptable salt thereof can be intermittent, for example, wherein over a period of several days, the subject receives a daily dose of a compound of formula I or a pharmaceutically acceptable salt thereof, followed by a period of several or more days in which the patient does not receive formula I.
  • Entecavir or a pharmaceutically acceptable salt or solvate thereof can be administered by a variety of routes including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal , Buccal, Intranasal, Inhalation, Vaginal, Intraocular, Topical, Subcutaneous, Intralipid, Intraarticular, Intraperitoneal and Intrathecal.
  • administration is by oral route.
  • the amount of entecavir administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. For example, the daily dose of entecavir administered may range from 0.005 mg to 10.0 mg.
  • Entecavir can be administered one or more times daily. In some embodiments, entecavir is administered once daily in an oral solid formulation.
  • Tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, lingual Infrared, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal. In some specific embodiments, administration is by oral route.
  • the amount of tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof to be administered can be determined by the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • a daily dose of tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof may be administered from 0.05 mg to 500 mg.
  • Tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof can be administered one or more times per day.
  • tenofovir or a pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof is administered once daily in an oral solid formulation.
  • pharmaceutical combination refers to the simultaneous, concurrent or sequential use of two or more active ingredients in combination.
  • fixed combination refers to the simultaneous administration of the active ingredients (eg, a compound of formula I or entecavir or tenofovir) to a subject in a fixed total dose or dose ratio, or in a single entity, pharmaceutical composition or formulation. In some embodiments, for example, in the same tablet or the same capsule or the same sachet.
  • active ingredients eg, a compound of formula I or entecavir or tenofovir
  • non-fixed combination refers to the simultaneous, concurrent or sequential administration of two or more active ingredients as separate entities (eg, pharmaceutical compositions, pharmaceutical formulations) and without specific time constraints, wherein the active ingredients administered to the individual reach a level of A therapeutically effective dose level.
  • An example of a non-fixed combination may be a cocktail therapy, eg the administration of 2, 3 or more active ingredients.
  • the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the use of a combination between "fixed combination” or "fixed combination” with any one or more separate entities of the active ingredient.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the present application, or a pharmaceutical combination thereof, or a salt thereof, and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or a pharmaceutical combination thereof to a subject.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid preparations such as tablets, pills, capsules and the like.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to give tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” refers to a salt of a compound of the present application within the definition of “pharmaceutically acceptable”.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine, for example, a box of medicine contains seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • multi-dose consists of multiple single doses.
  • free compound means that the compound of the present application exists in a free state, and specifically refers to and
  • solvate refers to a substance formed by combining a compound of the present application with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, alcohols, and the like. Solvates include stoichiometric amounts and non-stoichiometric amounts of solvates.
  • the active ingredients in the pharmaceutical combination of the present application may be formulated separately, or some or all of them may be co-formulated.
  • the pharmaceutical combinations of the present application may be formulated as pharmaceutical compositions suitable for single or multiple administration.
  • the active ingredients in the pharmaceutical combination of the present application may each be administered alone, or some or all of them may be co-administered.
  • the components of the pharmaceutical combinations of the present application may not be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.
  • the active ingredients in the pharmaceutical combinations of the present application may be administered individually, or some or all of them together, by any suitable route, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). ).
  • the active components of the pharmaceutical combinations of the present application may each be administered independently, or some or all of them may be administered orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the active ingredients in the pharmaceutical combinations of the present application may each independently, or some or all of them together be in suitable dosage forms, including but not limited to: tablets, troches, pills, capsules (eg, hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), powders, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration
  • suitable dosage forms including but not limited to: tablets, troches, pills, capsules (eg, hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), powders, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration
  • suitable dosage forms including but not limited to: tablets, troches, pills, capsules (eg, hard
  • the active ingredients in the pharmaceutical combination of the present application may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical combinations of the present application may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a therapeutic agent known in the art for the treatment of hepatitis B virus infection.
  • an effective amount of a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, and entecavir, or a pharmaceutically acceptable salt thereof, or a solvate thereof may be administered to an individual in need thereof at the same time, sequentially or at intervals.
  • an individual in need thereof is administered an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and entecavir, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the same or different dosing regimens.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered three times per day, twice per day, once per day, once every two days, once every three days, once every four days, Administration is once every five days, once every six days, once every week, once every two weeks, or once every three weeks.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered at 1-1500 mg, or 1-1000 mg, or 1-800 mg, or 1-600 mg, or 1-400 mg, or 1-200 mg, or 1 mg per administration - Doses of 100 mg, preferably 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered once per day, at 1 to 400 mg, or 1 to 350 mg, or 1 to 300 mg, or 1 to 250 mg, or 1 to 200 mg, or 1 to 200 mg per administration.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered once a day, 1 to 100 mg per administration.
  • the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered three times a day, twice a day, once a day, every two days, every three days, every four days Administration is once, once every five days, once every six days, once every week, once every two weeks, or once every three weeks.
  • the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of 0.005 mg to 5.0 mg per administration, preferably 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg , 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg,
  • the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered once a day in a dose of 0.10 mg to 2.0 mg per administration. In some regimens, the entecavir or a pharmaceutically acceptable salt or solvate thereof may be administered once a day in a dose of 0.5 mg per administration. In some schemes, the compound of formula I is administered once a day, with a dose of 1 mg to 100 mg each time; the entecavir or a pharmaceutically acceptable salt or solvate thereof is administered once a day, with a dose of 0.10 mg to 2.0 mg each time. mg dose.
  • the tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or every two days, or every three days, or every Administration is once every four days, or once every five days, or once every six days, or once every seven days.
  • the tenofovir or pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof of the pharmaceutical combination may be administered once a day.
  • the tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is administered in a dose of 0.05 mg to 500 mg per administration, preferably 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 66mg, 67mg, 68mg, 70mg, 71mg, 72mg, 73mg, 74mg,
  • the tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is administered in a dose of 0.05 mg to 200 mg, 0.10 mg to 190 mg, 1 mg to 160 mg, 10 mg to 150 mg per administration.
  • the tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is administered once a day in a dose of 10 mg to 150 mg per administration. In some regimens, the tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof may be administered once a day at a dose of 15 mg or 135.5 mg per administration.
  • tenofovir disoproxil fumarate is administered at 300 mg once daily.
  • tenofovir alafenamide is administered at 25 mg once daily.
  • tenofovir alafenamide fumarate is administered once daily at 28 mg per dose.
  • the compound of formula I is administered once a day, with a dose of 1 mg to 100 mg each time; the tenofovir or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof is administered once a day, each time Administer doses of 10 mg to 150 mg at a time.
  • the drug combination of the present application can significantly reduce the level of HBV DNA or alleviate other HBV indicators; and compared with the single drug, the drug combination of the present application shows an enhancement effect, has good pharmacokinetic properties, and has less adverse reactions and is tolerated good sex. Compared with a single drug, the drug combination of the present application can more effectively reduce the level of HBV markers (including HBsAg, HBsAb, HBeAg, HBeAb, anti-HBc, HBV DNA quantification, HBV RNA and HbcrAg, etc.). It shows that the drug combination of the present application has good medicinal value.
  • the compound of formula I and entecavir were prepared with 100% DMSO, the mother liquor was stored in a nitrogen cabinet, and the compound concentrations were shown in Table 1.
  • HepG2.2.15 cell line was provided by WuXi AppTec.
  • the primary reagents used in this study included CellTiter-Glo (Promega, Cat. No. G7573), FastStart Universal Probe Mast Mix (Roche, Cat. No. 04914058001), and QIAamp 96 DNA Blood Kit (12) (Qiagen, Cat. No. 51162).
  • HepG2.2.15 cells were seeded into 96-well cell culture plates at a density of 60,000 cells/well, and then the cells were cultured overnight at 37°C under 5% CO 2 .
  • the compound of formula I and entecavir were formulated at 8 different concentrations (molar ratio 10:1), and a single drug control was set at the same time, and the compound was added to a 96-well plate, each concentration was 3 duplicate wells, and the final concentration of DMSO was 1%. .
  • the medium containing the compound was replaced with fresh medium, and the cells were cultured for 3 days under 5% CO 2 at 37°C.
  • the supernatant of the cell plate treated with the compound was collected, and DNA was extracted according to the instructions of the kit QIAamp 96 DNA Blood Kit (12). After the supernatant was collected, CellTiter-Glo was added to detect cell viability.
  • a1b1 represents the administration concentration of the compound of formula I (a) group 1 and the administration concentration of entecavir (b) group 1 in the compound of formula I combined with entecavir group. Others follow and so on.
  • HBV DNA Quantification of HBV DNA by qPCR method. Taking HBV plasmid DNA as the standard, the concentration of standard HBV plasmid DNA was diluted 7 points by 10-fold gradient starting from 10 7 copies/ ⁇ L. The HBV DNA copy number and CT value of each standard were fitted to the standard curve, and the HBV DNA copy number in each test sample was calculated.
  • the cytotoxicity of the compounds to HepG2.2.15 cells was detected by CellTiter-Glo kit.
  • the chemiluminescence intensity (RLU) of each cell well was detected with a multi-function microplate reader according to the kit instructions.
  • a mean combination index of 0.9-1.1 indicates an additive effect; a combination index of ⁇ 0.9 indicates a synergistic effect; a combination index of >1.1 indicates an antagonism.
  • Cell viability % (RLU of compound well-average RLU of culture medium control well)/(average RLU of DMSO control well
  • Inhibition rate% (1-HBV DNA content in sample/HBV DNA content in DMSO control group) ⁇ 100
  • the compound of formula I combined with entecavir has an average anti-HBV combination index of 0.85, showing a synergistic effect.
  • mice Male C57BL/6 mice, 5 weeks old, free of specific pathogens, were purchased from Shanghai Slack Laboratory Animal Co., Ltd. and housed in individually ventilated cages. Mice were injected with AAV/HBV virus after a 3-day acclimation period.
  • 10% Solutol preparation Take the preparation of 100mL as an example: Precisely extract 90mL of dd.water, and then add 10mL of solution-like solutol (in advance, put the solid Solutol in a 70-75°C oven for heating and dissolving for 15-30 minutes, until it is completely dissolved, use Syringe extraction), fully stirred and mixed to obtain 10% Solutol aqueous solution, which was prepared once a week. The prepared solution is stored at 2-8°C.
  • Compound of formula I Weigh an appropriate amount of compound of formula I, dissolve in 10% Solutol (no obvious particles exist), and store at 2-8° C. after preparation.
  • Entecavir Weigh an appropriate amount of entecavir, dissolve it in DMSO, prepare 1 mg/mL, and then gradually dilute it 1000 times with normal saline to 0.001 mg/mL, and store it as a stock solution in a -20°C refrigerator. Take 1 mg/mL every day. The tube was then diluted 10-fold with normal saline to obtain a concentration required for administration of 0.0001 mg/mL and stored at 2-8°C for daily administration.
  • rAAV8-1.3HBV (type D, ayw) was purchased from Beijing Wujiahe Institute of Molecular Medicine. Dilute to 5 x 1011 vg/mL with sterile PBS before experiment. Inject 200 ⁇ L per mouse, i.e. inject 1 ⁇ 10 11 vg per mouse
  • rAAV8-1.3HBV was pre-formulated with sterile PBS to a concentration of 1 ⁇ 10 11 vg/200 ⁇ L solution before injection. 200 ⁇ L of rAAV8-1.3HBV solution was injected into mice via tail vein.
  • Combination group (combo) compound of formula I 10mpk and entecavir.
  • Non-end-point blood collection On days -1, 3, 7, 14, 21, 28, 35 or 42, blood was collected through submandibular vein ⁇ 120 ⁇ L to collect serum for HBV DNA detection. If the drug was administered concurrently on the day of blood collection, blood collection was performed approximately 5 hours after the first dose of the day.
  • mice i-iv were euthanized on day 28. Serum was collected from mice by cardiac blood collection for HBV DNA detection. The experimental endpoints for groups v and vi were at day 42.
  • Compound of formula I prepared in 10 mg and 50 mg capsules.
  • Entecavir Entecavir tablet, specification 0.5mg/tablet (such as Chia Tai Tianqing Pharmaceutical Group Co., Ltd. ).
  • Placebo A placebo of a compound of formula I.
  • the age is 18-70 years old (including the boundary value), male and female are not limited.
  • Serum virological criteria serum HBeAg positive for more than 6 months or evidence of chronic hepatitis B for 6 months, 1000IU/mL ⁇ HBsAg quantitative ⁇ 30000IU/mL.
  • Liver biopsy within 1 year before or during screening without cirrhosis eg, Metavir score F0-F3, GS score S0-S3; or
  • the Fibroscan score within 6 months before screening was ⁇ 12.4kPa, and there was no liver cirrhosis on abdominal color Doppler ultrasound during the screening period.
  • liver biopsy results In the case of liver biopsy results, the liver biopsy results shall prevail.
  • Subjects must be na ⁇ ve patients at the time of screening, i.e.,
  • HBeAg-positive CHB patients HBV DNA > 10 5 copies/mL (or > 20,000 IU/mL); or HBeAg-negative patients with HBV DNA > 10 4 copies/mL (or > 2,000 IU/mL);
  • HBeAg-positive and All patients with negative chronic hepatitis B were determined by Roche second-generation Cobas Taqman real-time quantitative PCR method, and the lower limit of detection was 20IU/mL).
  • the compound of formula I capsule/placebo is administered once a day, under the condition of fasting (at least 2 hours before or after a meal), and the time of each administration should be approximately similar.
  • Entecavir is administered once a day. Entecavir is administered on an empty stomach (at least 2 hours before or after meals), and the time of each dose should be approximately similar.
  • Indicators include HBV markers (HBsAg, HBsAb, HBeAg, HBeAb, anti-HBc, HBV DNA quantification, HBV RNA, and HBcrAg.
  • Compound of formula I prepared in 10 mg and 50 mg capsules.
  • Entecavir Entecavir tablet, specification 0.5mg/tablet (such as Chia Tai Tianqing Pharmaceutical Group Co., Ltd. ).
  • Tenofovir Tenofovir disoproxil fumarate tablet, specification 300mg/tablet (such as Chia Tai Tianqing Pharmaceutical Group Co., Ltd. ).
  • Tenofovir Tenofovir alafenamide fumarate tablets, 25mg/tablet.
  • Placebo A placebo of a compound of formula I.
  • Serum virological criteria Serum HBsAg positive for more than 24 weeks or evidence of chronic hepatitis B for 24 weeks. 1000IU/ml ⁇ HbsAg quantitative ⁇ 40000IU/ml;
  • Subjects must receive the same dose of the same NA treatment (ETV/TDF) for ⁇ 48 weeks prior to screening;
  • HBV DNA inhibition recorded in the medical history 24 weeks before enrollment ⁇ lower limit of normal detection, and HBV DNA inhibition in the screening period was defined as ⁇ LLOQ;
  • HBeAg positive chronic hepatitis B patients HBV DNA>10 5 copies/mL (or>20,000IU/mL);
  • HBV DNA >10 4 copies/mL (or >2,000IU/mL) in HBeAg-negative patients;
  • the compound of formula I capsule/placebo is administered once a day, under the condition of fasting (at least 2 hours before or after a meal), and the time of each administration should be approximately similar.
  • Entecavir is administered once a day. Entecavir is administered on an empty stomach (at least 2 hours before or after meals), and the time of each dose should be approximately similar.
  • Tenofovir administered once a day, is administered on an empty stomach (at least 2 hours before or after meals), and the time of each dose should be roughly similar.
  • Indicators included HBV markers (HBsAg, HBsAb, HBeAg, HBeAb, anti-HBc, HBV DNA quantification, HBV RNA and HbcrAg).

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Abstract

一种包含衣壳蛋白抑制剂和核苷类似物的药物组合。具体而言，涉及衣壳蛋白抑制剂与选自恩替卡韦或其可药用盐或其溶剂合物、或替诺福韦或其可药用的前药或可药用的盐的核苷类似物的药物组合，以及上述药物组合在治疗乙型肝炎病毒感染中的用途。该药物组合具有良好的抗乙型肝炎病毒感染作用。

Description

包含衣壳蛋白抑制剂和核苷类似物的药物组合 技术领域
本申请属于医药化学领域，涉及包含衣壳蛋白抑制剂和核苷类似物的药物组合。具体而言，涉及作为衣壳蛋白抑制剂的式I化合物与恩替卡韦或替诺福韦的药物组合，或其在治疗乙型肝炎病毒感染中的用途。
背景技术
据世界卫生组织统计，全球约有2.57亿人感染有乙肝病毒(HBV)。如果肝炎病人无法得到救治，他们将面临长期致命的疾病，例如肝衰竭、肝硬化和肝癌等。
HBV感染的病人，在宿主的肝细胞核内形成稳定的共价闭合环状DNA，即cccDNA，作为HBV不断复制的模板。所有次基因组的RNA(sgRNA)和前基因组的RNA(pgRNA)均由cccDNA转录形成。出细胞核后，sgRNA翻译成X蛋白和其他三个包膜蛋白，pgRNA翻译成核心蛋白和病毒聚合酶。pgRNA与核心蛋白在聚合酶的作用下发生自组装，形成包裹了核衣壳的RNA。在核衣壳内，pgRNA逆转录成负链的DNA，并由此进一步合成出DNA正链，形成rcDNA。核衣壳包裹的rcDNA一方面重新脱壳进入细胞核，进一步使cccDNA扩增；另一方面重新与包膜蛋白结合，通过内质网释放出细胞，形成新的HBV。在HBV的复制循环中，核衣壳的的合成是HBV基因组复制过程中的关键一步，病毒DNA的合成只能特异性的发生在核衣壳的内部。核衣壳的组装是限制HBV多样性的一个进化制约过程，即使对细微的分子干扰也非常敏感。对于开发新的针对不同乙肝病毒基因型和耐药菌株的疗法，作用于核衣壳的合成和降解过程的靶标极具前景。
目前被许可用于治疗慢性乙肝的常规药物包括核苷(酸)类化合物和干扰素两类。核苷(酸)类药物，如恩替卡韦和替诺福韦，可以抑制HBV DNA复制。
尽管对乙型肝炎病毒感染患者而言有许多治疗选择，仍需要更为有效的治疗剂以供临床使用。
发明内容
一方面，本申请提供药物组合，其包括式I化合物或其可药用盐和逆转录酶抑制剂或其可药用的前药、或其可药用盐或其溶剂合物，
Figure PCTCN2021128892-appb-000001
在一些实施方案中，所述逆转录酶抑制剂选自恩替卡韦或其可药用盐或其溶剂合物、或替诺福韦或其可药用的前药或可药用的盐。
再一方面，本申请提供药物组合，其包括式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物。
再一方面，本申请提供药物组合，其包括式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐。
另一方面，本申请还提供本申请的药物组合在制备用于治疗乙型肝炎病毒感染的药物中的用途。本申请还提供治疗乙型肝炎病毒感染的方法，其包括向有需要的个体施用有效量的本申请的药物组合。本申请还提供用于治疗乙型肝炎病毒感染的药物组合。本申请还提供本申请的药物组合用于治疗乙型肝炎病毒感 染的用途。
再一方面，本申请提供药物组合，其包括式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物，所述式I化合物如下所示：
Figure PCTCN2021128892-appb-000002
在本申请的一些实施方案中，所述恩替卡韦溶剂合物选自恩替卡韦水合物。在一些实施方案中，所述恩替卡韦水合物选自恩替卡韦0.5～2水合物。在一些实施方案中，所述恩替卡韦水合物选自恩替卡韦一水合物。
在本申请的一些实施方案中，所述恩替卡韦的可药用盐选自马来酸盐。在本申请的一些实施方案中，所述恩替卡韦的可药用盐选自一马来酸盐。
在本申请的一些实施方案中，恩替卡韦或其可药用盐或其溶剂合物选自恩替卡韦一马来酸盐、恩替卡韦一水合物、或恩替卡韦一马来酸盐一水合物。
在本申请的一些实施方案中，本申请所述的药物组合包括式I化合物或其可药用盐和恩替卡韦或其可药用盐或其水合物。在一些实施方案中，本申请所述的药物组合包括式I化合物或其可药用盐和恩替卡韦或其一水合物。在一些实施方案中，本申请所述的药物组合包括式I化合物或其可药用盐和恩替卡韦一马来酸盐一水合物。
本申请的一些实施方案中，所述替诺福韦可药用的前药包括替诺福韦二吡呋酯、替诺福韦艾拉酚胺或艾米替诺福韦。
在本申请的一些实施方案中，所述替诺福韦或其可药用前药的可药用盐选自富马酸盐、乳清酸盐、二磺酸盐、磷酸盐、琥珀酸或天冬氨酸盐。在本申请的一些实施方案中，所述替诺福韦或其可药用前药的可药用盐选自富马酸盐。
在本申请的一些实施方案中，替诺福韦或其可药用前药或其可药用的盐选自替诺福韦、替诺福韦艾拉酚胺富马酸盐、替诺福韦二吡呋酯富马酸盐、替诺福韦二吡呋酯乳清酸盐、替诺福韦二吡呋酯半二磺酸盐、替诺福韦二吡呋酯磷酸盐、替诺福韦二吡呋酯琥珀酸盐、替诺福韦二吡呋酯天冬氨酸盐或艾米替诺福韦富马酸盐。在本申请的一些实施方案中，所述替诺福韦或其可药用前药或其可药用的盐选自替诺福韦二吡呋酯富马酸盐或替诺福韦艾拉酚胺富马酸盐。在本申请的一些实施方案中，替诺福韦或其可药用前药或其可药用的盐选自替诺福韦二吡呋酯富马酸盐。
在本申请的一些实施方案中，替诺福韦或其可药用前药或其可药用的盐选自以下结构：
Figure PCTCN2021128892-appb-000003
Figure PCTCN2021128892-appb-000004
在本申请的一些实施方案中，本申请所述的药物组合包括式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐。在一些实施方案中，本申请所述的药物组合包括式I化合物或其可药用盐和替诺福韦艾拉酚胺或替诺福韦二吡呋酯或其可药用的盐。在一些实施方案中，本申请所述的药物组合包括式I化合物或其可药用盐和替诺福韦二吡呋酯富马酸盐或替诺福韦艾拉酚胺富马酸盐。
在本申请的一些实施方案中，所述药物组合的式I化合物或其可药用盐可以每一天施用一次、每一天施用两次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次、或每三周施用一次。
在本申请的一些实施方案中，所述药物组合的式I化合物或其可药用盐每次施用10mg或50mg规格剂量(以式I化合物重量计算)。
在本申请的一些实施方案中，所述药物组合的式I化合物或其可药用盐每次施用0.0001到20mg/kg重量(以式I化合物重量计算)。
在本申请的一些实施方案中，所述药物组合的式I化合物或其可药用盐每次施用1-1500mg或10-1000mg。
在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐可以每天施用一次、每天施用两次、或每两天施用一次、或每三天施用一次、或每四天施用一次、或每五天施用一次、或每六天施用一次、或每七天施用一次。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐可以每天施用一次。
在本申请的一些实施方案中，对于肾功能损害患者，在肌酐清除率(mL/min)≥50的患者，每24小时一次替诺福韦或其可药用前药或其可药用的盐；在肌酐清除率(mL/min)≥30-49的患者，每48小时一次替诺福韦或其可药用前药或其可药用的盐；在肌酐清除率(mL/min)≥10-29的患者，每72～96小时一次替诺福韦或其可药用前药或其可药用的盐；对于血液透析患者，每7天一次或共透析约12小时后给予替诺福韦或其可药用前药或其可药用的盐。
在本申请的一些实施方案中，每次施用替诺福韦二吡呋酯富马酸盐300mg。在本申请的一些实施方案中，每次施用替诺福韦艾拉酚胺25mg或替诺福韦艾拉酚胺富马酸盐28mg。
在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐平均日剂量是0.05mg至500mg(以替诺福韦重量计算)。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可 药用前药或其可药用的盐平均日剂量是0.1mg至400mg(以替诺福韦重量计算)。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐平均日剂量是1mg至300mg(以替诺福韦重量计算)。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐平均日剂量是5mg至200mg(以替诺福韦重量计算)。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐平均日剂量是8mg至190mg(以替诺福韦重量计算)。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐平均日剂量是10mg至185mg(以替诺福韦重量计算)。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐平均日剂量是14mg至140mg(以替诺福韦重量计算)。
在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物可以每天施用一次、每天施用两次、或每两天施用一次。
在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物每次施用0.5mg或1.0mg规格剂量(以恩替卡韦重量计算)。
在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物平均日剂量是0.005mg至10.0mg。在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物平均日剂量是0.05mg至5.0mg。在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物平均日剂量是0.10mg至2.0mg。在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物平均日剂量是0.25mg至2.0mg。在本申请的一些实施方案中，所述药物组合的恩替卡韦或其可药用盐或其溶剂合物平均日剂量是0.5mg至1.0mg。
在本申请的一些实施方案中，所述药物组合的式I化合物或其可药用盐每次施用1-1500mg或10-1000mg(以式I化合物重量计算)，所述替诺福韦或其可药用前药或其可药用的盐平均日剂量是0.05mg至500mg(以替诺福韦重量计算)。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐与替诺福韦或其可药用前药或其可药用的盐平均日剂量之比(以对应的化合物的重量单位计，式I化合物：替诺福韦)选自500:1～1:1000。在一些方案中，所述式I化合物或其可药用盐与替诺福韦或其可药用前药或其可药用的盐平均日剂量之比(以重量单位计)选自500:1、450:1、400:1、350:1、300:1、250:1、200:1、150:1、100:1、95:1、90:1、85:1、80:1、79:1、78:1、77:1、76:1、75:1、74:1、73:1、72:1、71:1、70:1、69:1、68:1、67:1、66:1、65:1、60:1、55:1、50:1、45:1、40:1、35:1、30:1、25:1、30:1、25:1、20:1、15:1、10:1、5:1、1:1、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:30、1:40、1:50、1:60、1:70、1:80、1:90、1:100、1:150、1:200、1:250、1:300、1:350、1:400、1:450、1:500、1:550、1:600、1:650、1:700、1:750、1:800、1:850、1:900、1:950、1:1000或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐与替诺福韦或其可药用前药或其可药用的盐平均日剂量之比(以游离化合物的摩尔比计)选自100:1～1:100。在一些方案中，所述式I化合物或其可药用盐与替诺福韦或其可药用前药或其可药用的盐平均日剂量之比(以游离化合物的摩尔比计，式I化合物：替诺福韦)选自：100:1、98:1、96:1、94:1、92:1、90:1、88:1、86:1、84:1、82:1、80:1、78:1、76:1、74:1、72:1、70:1、68:1、66:1、64:1、62:1、60:1、58:1、56:1、54:1、52:1、50:1、48:1、46:1、45:1、44:1、43:1、42:1、41:1、40:1、39:1、38:1、37:1、36:1、35:1、34:1、33:1、32:1、31:1、30:1、29:1、28:1、27:1、26:1、25:1、24:1、23:1、22:1、21:1、20:1、18:1、16:1、14:1、12:1、10:1、8:1、6:1、4:1、2:1、1:1、1:2、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、1:24、1:25、1:26、1:27、1:28、1:29、1:30、1:31、1:32、1:33、1:34、1:35、 1:36、1:38、1:40、1:42、1:44、1:46、1:48、1:50、1:52、1:54、1:56、1:58、1:60、1:62、1:64、1:66、1:68、1:70、1:72、1:74、1:76、1:78、1:80、1:82、1:84、1:86、1:88、1:90、1:92、1:94、1:96、1:98、1:100或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与替诺福韦二吡呋酯富马酸盐平均日剂量(以重量单位计)之比选自1:300～1500:300或10:300～1000:300。在一些方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与替诺福韦二吡呋酯富马酸盐平均日剂量(以重量单位计)之比选自10:300、20:300、30:300、40:300、50:300、60:300、70:300、80:300、90:300、100:300、110:300、120:300、130:300、140:300、150:300、160:300、170:300、180:300、190:300、200:300、210:300、220:300、230:300、240:300、250:300、260:300、270:300、280:300、290:300、300:300、310:300、320:300、330:300、340:300、350:300、360:300、370:300、380:300、390:300、400:300、410:300、420:300、430:300、440:300、450:300、460:300、470:300、480:300、490:300、500:300、510:300、520:300、530:300、540:300、550:300、560:300、570:300、580:300、590:300、600:300、610:300、620:300、630:300、640:300、650:300、660:300、670:300、680:300、690:300、700:300、710:300、720:300、730:300、740:300、750:300、760:300、770:300、780:300、790:300、800:300或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与替诺福韦艾拉酚胺平均日剂量(以重量单位计)之比选自1:25～1500:25或10:25～1000:25。在一些方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与替诺福韦艾拉酚胺平均日剂量(以重量单位计)之比选自10:25、20:25、30:25、40:25、50:25、60:25、70:25、80:25、90:25、100:25、110:25、120:25、130:25、140:25、150:25、160:25、170:25、180:25、190:25、200:25、210:25、220:25、230:25、240:25、250:25、260:25、270:25、280:25、290:25、300:25、310:25、320:25、330:25、340:25、350:25、360:25、370:25、380:25、390:25、400:25、410:25、420:25、430:25、440:25、450:25、460:25、470:25、480:25、490:25、500:25、510:25、520:25、530:25、540:25、550:25、560:25、570:25、580:25、590:25、600:25、610:25、620:25、630:25、640:25、650:25、660:25、670:25、680:25、690:25、700:25、710:25、720:25、730:25、740:25、750:25、760:25、770:25、780:25、790:25、800:25或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与替诺福韦艾拉酚胺富马酸盐平均日剂量(以重量单位计)之比选自1:28～1500:28或10:28～1000:28。在一些方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与替诺福韦艾拉酚胺富马酸盐平均日剂量(以重量单位计)之比选自10:28、20:28、30:28、40:28、50:28、60:28、70:28、80:28、90:28、100:28、110:28、120:28、130:28、140:28、150:28、160:28、170:28、180:28、190:28、200:28、210:28、220:28、230:28、240:28、280:28、260:28、270:28、280:28、290:28、300:28、310:28、320:28、330:28、340:28、350:28、360:28、370:28、380:28、390:28、400:28、410:28、420:28、430:28、440:28、450:28、460:28、470:28、480:28、490:28、500:28、510:28、520:28、530:28、540:28、550:28、560:28、570:28、580:28、590:28、600:28、610:28、620:28、630:28、640:28、650:28、660:28、670:28、680:28、690:28、700:28、710:28、720:28、730:28、740:28、750:28、760:28、770:28、780:28、790:28、800:28或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐与替诺福韦或其可药用前药或其可药用的盐分别以单剂量或多剂量形式给药。
在本申请的一些实施方案中，所述药物组合的式I化合物或其可药用盐每次施用1-1500mg或10-1000mg，所述恩替卡韦或其可药用盐或其溶剂合物平均日剂量是0.005mg至10.0mg。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐与恩替卡韦或其可药用盐或其 溶剂合物平均日剂量之比(以重量单位计)选自1000:1～1:1000。在一些方案中，所述式I化合物或其可药用盐与恩替卡韦或其可药用盐或其溶剂合物平均日剂量之比(以重量单位计，式I化合物：恩替卡韦)选自1000:1、950:1、900:1、850:1、800:1、750:1、700:1、650:1、600:1、550:1、500:1、450:1、400:1、350:1、300:1、250:1、200:1、150:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、30:1、20:1、10:1、1:1.、1:10、1:20、1:30、1:40、1:50、1:60、1:70、1:80、1:90、1:100、1:150、1:200、1:250、1:300、1:350、1:400、1:450、1:500、1:550、1:600、1:650、1:700、1:750、1:800、1:850、1:900、1:950、1:1000或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐与恩替卡韦或其可药用盐或其溶剂合物平均日剂量之比(以游离化合物的摩尔比计)选自100:1～1:100。在一些方案中，所述式I化合物或其可药用盐与恩替卡韦或其可药用盐或其溶剂合物平均日剂量之比(以游离化合物的摩尔比计，式I化合物：恩替卡韦)选自：100:1、98:1、96:1、94:1、92:1、90:1、88:1、86:1、84:1、82:1、80:1、78:1、76:1、74:1、72:1、70:1、68:1、66:1、64:1、62:1、60:1、58:1、56:1、54:1、52:1、50:1、48:1、46:1、44:1、42:1、40:1、38:1、36:1、34:1、32:1、30:1、28:1、26:1、24:1、22:1、20:1、18:1、16:1、14:1、12:1、10:1、8:1、6:1、4:1、2:1、1:1、1:2、1:4、1:6、1:8、1:10、1:12、1:14、1:16、1:18、1:20、1:22、1:24、1:26、1:28、1:30、1:32、1:34、1:36、1:38、1:40、1:42、1:44、1:46、1:48、1:50、1:52、1:54、1:56、1:58、1:60、1:62、1:64、1:66、1:68、1:70、1:72、1:74、1:76、1:78、1:80、1:82、1:84、1:86、1:88、1:90、1:92、1:94、1:96、1:98、1:100或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与恩替卡韦一水合物平均日剂量(以重量单位计)之比选自1:0.5～1500:0.5或10:0.5～1000:0.5。在一些方案中，所述药物组合中式I化合物或其可药用盐(式I化合物以游离化合物计)与恩替卡韦一水合物平均日剂量(以重量单位计)之比选自10:0.5、20:0.5、30:0.5、40:0.5、50:0.5、60:0.5、70:0.5、80:0.5、90:0.5、100:0.5、110:0.5、120:0.5、130:0.5、140:0.5、150:0.5、160:0.5、170:0.5、180:0.5、190:0.5、200:0.5、210:0.5、220:0.5、230:0.5、240:0.5、250:0.5、260:0.5、270:0.5、280:0.5、290:0.5、300:0.5、310:0.5、320:0.5、330:0.5、340:0.5、350:0.5、360:0.5、370:0.5、380:0.5、390:0.5、400:0.5、410:0.5、420:0.5、430:0.5、440:0.5、450:0.5、460:0.5、470:0.5、480:0.5、490:0.5、500:0.5、510:0.5、520:0.5、530:0.5、540:0.5、550:0.5、560:0.5、570:0.5、580:0.5、590:0.5、600:0.5、610:0.5、620:0.5、630:0.5、640:0.5、650:0.5、660:0.5、670:0.5、680:0.5、690:0.5、700:0.5、710:0.5、720:0.5、730:0.5、740:0.5、750:0.5、760:0.5、770:0.5、780:0.5、790:0.5、800:0.5或任选上述比例形成的范围。
在本申请的一些实施方案中，所述药物组合中式I化合物或其可药用盐与恩替卡韦或其可药用盐或其溶剂合物分别以单剂量或多剂量形式给药。
在本申请的一些实施方案中，所述药物组合是固定组合。在一些实施方案中，所述固定组合呈固体药物组合物形式。
在一些实施方案中，所述固定组合中的式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐存在于同一固体药物组合物。
在一些实施方案中，所述固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物存在于同一固体药物组合物。
在本申请的一些实施方案中，所述药物组合是非固定组合。在一些实施方案中，所述非固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物各自呈固体药物组合物形式。
在一些实施方案中，所述非固定组合中的式I化合物或其可药用盐和替诺福韦或其可药用前药或其可 药用的盐各自呈固体药物组合物形式，且式I化合物或其可药用盐的固体药物组合物和替诺福韦或其可药用前药或其可药用的盐的固体药物组合物存在于同一个药袋。在一些实施方案中，所述非固定组合中的式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐各自呈固体药物组合物形式，且式I化合物或其可药用盐的固体药物组合物和替诺福韦或其可药用前药或其可药用的盐固体药物组合物不存在于同一个药袋。
在一些实施方案中，所述非固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物各自呈固体药物组合物形式，且式I化合物或其可药用盐的固体药物组合物和恩替卡韦或其可药用盐或其溶剂合物的固体药物组合物存在于同一个药袋。在一些实施方案中，所述非固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物各自呈固体药物组合物形式，且式I化合物或其可药用盐的固体药物组合物和恩替卡韦或其可药用盐或其溶剂合物的固体药物组合物不存在于同一个药袋。
在本申请的一些实施方案中，所述固体药物组合物选自片剂或胶囊。
另一方面，本申请还提供本申请的药物组合在制备用于治疗乙型肝炎病毒感染的药物中的用途。所述药物组合如前所述。
另一方面，本申请还提供治疗乙型肝炎病毒感染的方法，其包括向有需要的个体施用有效量的本申请的药物组合。所述药物组合如前所述。
另一方面，本申请还提供用于治疗乙型肝炎病毒感染的本申请的药物组合。所述药物组合如前所述。
另一方面，本申请还提供本申请的药物组合用于治疗乙型肝炎病毒感染的用途。所述药物组合如上所述。
在本申请的一些实施方案中，本申请还提供了用于治疗乙型肝炎病毒感染的试剂盒，其中包含：(a)含有式I化合物或其可药用盐作为活性成分的第一种药物组合物；和(b)含有逆转录酶抑制剂或其可药用前药、或其可药用的盐或其溶剂合物作为活性成分的第二种药物组合物；和任选的(c)式I化合物或其可药用盐和逆转录酶抑制剂或其可药用前药、或其可药用的盐或其溶剂合物联合使用的说明。
在本申请的一些实施方案中，逆转录酶抑制剂或其可药用前药或其可药用的盐如前所述。
在本申请的一些实施方案中，本申请提供了包括式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐在制备治疗乙型肝炎病毒感染的药物中的应用，其中式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐被分别制备成药物组合物。
在本申请的一些实施方案中，本申请还提供了用于治疗乙型肝炎病毒感染的试剂盒，其中包含：(a)含有式I化合物或其可药用盐作为活性成分的第一种药物组合物；和(b)含有替诺福韦或其可药用前药或其可药用的盐作为活性成分的第二种药物组合物；和任选的(c)式I化合物或其可药用盐和替诺福韦或其可药用前药或其可药用的盐联合使用的说明。
在本申请的一些实施方案中，本申请提供了包括式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物在制备治疗乙型肝炎病毒感染的药物中的应用，其中式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物被分别制备成药物组合物。
在本申请的一些实施方案中，本申请还提供了用于治疗乙型肝炎病毒感染的试剂盒，其中包含：(a)含有式I化合物或其可药用盐作为活性成分的第一种药物组合物；和(b)含有恩替卡韦或其溶剂合物作为活性成分的第二种药物组合物；和任选的(c)式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物联合使用的说明。
式I化合物或其可药用盐
所述式I化合物属于现有技术，其化学名为2-((1r,4r)-4-(2-(6-氯-7-((3,4,5-三氟苯基)氨甲酰基)-2,3-二氢-1H-吡咯啉-5-基)-2-草酰氨基)-4-甲基环己基)乙酸，其具有如下结构式：
Figure PCTCN2021128892-appb-000005
式I化合物或其可药用盐的制备方法和化学性质可参考WO2019223791。
在部分方案中，所述式I化合物或其可药用盐的药物组合物选自固体药物组合物，优选自片剂或胶囊。
在部分方案中，所述式I化合物或其可药用盐呈药物组合物形式，所述药物组合物单剂量为1mg～100mg的药物组合物，优选自单剂量为1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、95mg、96mg、97mg、98mg、99mg、100mg或上述任意值形成的范围的药物组合物。
恩替卡韦或其可药用盐、其溶剂合物，或其药物组合物
本申请中所述恩替卡韦或其可药用盐或其溶剂合物，包括恩替卡韦或其可药用盐、恩替卡韦或其可药用盐的溶剂合物、或其任意组合。
如本申请所用，所述恩替卡韦化学名为2-氨基-9-[(1S,3R,4S)-4-羟基-3-羟甲基-2-亚甲基环戊基]-1,9-二氢-6H-嘌呤-6-酮，其具有如下的结构式：
Figure PCTCN2021128892-appb-000006
在部分方案中，所述恩替卡韦的可药用盐选自马来酸盐。在部分方案中，所述恩替卡韦的可药用盐选自一马来酸盐。
在部分方案中，所述恩替卡韦的溶剂合物选自恩替卡韦水合物。在部分方案中，所述恩替卡韦水合物选自恩替卡韦0.5～2水合物。在部分方案中，所述恩替卡韦水合物选自恩替卡韦一水合物。
在部分方案中，所述恩替卡韦或其可药用盐、恩替卡韦或其可药用盐的溶剂合物，选自恩替卡韦一马来酸盐、恩替卡韦一水合物、或恩替卡韦一马来酸盐一水合物。
在部分方案中，恩替卡韦或其可药用盐或其溶剂合物呈药物组合物形式。优选地，所述药物组合物选自固体药物组合物。所述固体药物组合物优选选自片剂或胶囊。
在部分方案中，所述恩替卡韦或其可药用盐或其溶剂合物的药物组合物选自单剂量为0.01mg～5mg的药物组合物，优选自单剂量为0.01mg、0.02mg、0.05mg、0.08mg、0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、1.1mg、1.2mg、1.3mg、1.4mg、1.5mg、1.6mg、1.7mg、1.8mg、1.9mg、2.0mg、2.1mg、2.2mg、2.3mg、2.4mg、2.5mg、2.6mg、2.7mg、2.8mg、2.9mg、3.0mg、3.1mg、3.2mg、3.3mg、3.4mg、3.5mg、3.6mg、3.7mg、3.8mg、3.9mg、4.0mg、4.1mg、4.2mg、4.3mg、4.4mg、4.5mg、4.6mg、4.7mg、4.8mg、4.9mg、5.0mg或上述任意值形成的范围的药物组合物。
如本申请所用，所述恩替卡韦或其可药用盐或其溶剂合物、或其药物组合物可选自市售产品(如恩替卡韦分散片：
Figure PCTCN2021128892-appb-000007
)。
替诺福韦或其可药用前药或其可药用的盐
本申请所述替诺福韦或其可药用前药或其可药用的盐包括替诺福韦游离化合物、或其可药用前药、或替诺福韦或其可药用前药的药学上可接受的盐，或其药物组合物。
如本申请所用，所述替诺福韦化学名为R-9-(2-磷酸甲氧基丙基)腺嘌呤，其具有如下的结构式：
Figure PCTCN2021128892-appb-000008
在部分方案中，所述替诺福韦可药用前药选自替诺福韦艾拉酚胺、替诺福韦二吡呋酯或艾米替诺福韦。
在部分方案中，所述替诺福韦游离化合物或前药的可药用盐包括富马酸盐、乳清酸盐、二磺酸盐、磷酸盐、琥珀酸或天冬氨酸盐。
在部分方案中，替诺福韦前药的可药用的盐选自替诺福韦二吡呋酯富马酸盐、替诺福韦艾拉酚胺富马酸盐或艾米替诺福韦富马酸盐。
在部分方案中，所述替诺福韦前药的可药用的盐选自替诺福韦艾拉酚胺富马酸盐。在部分方案中，所述替诺福韦前药的可药用盐中替诺福韦艾拉酚胺与富马酸分子个数比为2:1。在部分方案中，所述替诺福韦艾拉酚胺富马酸盐选自以下结构
Figure PCTCN2021128892-appb-000009
在部分方案中，所述替诺福韦前药的可药用的盐选自替诺福韦二吡呋酯富马酸盐。在部分方案中，所述替诺福韦前药的可药用的盐中替诺福韦二吡呋酯与富马酸分子个数比为1:1。在部分方案中，所述替诺福韦二吡呋酯富马酸盐选自以下结构
Figure PCTCN2021128892-appb-000010
在部分方案中，所述替诺福韦前药的可药用的盐选自艾米替诺福韦富马酸盐。在部分方案中，所述替 诺福韦前药的可药用的盐中艾米替诺福韦与富马酸分子个数比为1:1。在部分方案中，所述艾米替诺福韦富马酸盐选自以下结构
Figure PCTCN2021128892-appb-000011
在部分方案中，所述替诺福韦前药的可药用的盐选自替诺福韦二吡呋酯乳清酸盐。在部分方案中，所述替诺福韦前药的可药用的盐中替诺福韦二吡呋酯与乳清酸分子个数比为1:1。在部分方案中，所述替诺福韦二吡呋酯乳清酸盐选自以下结构
Figure PCTCN2021128892-appb-000012
在部分方案中，所述替诺福韦前药的可药用的盐选自替诺福韦二吡呋酯琥珀酸盐。在部分方案中，所述替诺福韦前药的可药用的盐中替诺福韦二吡呋酯与琥珀酸分子个数比为1:1。在部分方案中，所述替诺福韦二吡呋酯琥珀酸盐选自以下结构
Figure PCTCN2021128892-appb-000013
在部分方案中，替诺福韦或其可药用前药或其可药用的盐呈药物组合物形式。优选地，所述药物组合物选自固体药物组合物。所述固体药物组合物优选选自片剂或胶囊。
在部分方案中，所述替诺福韦或其可药用前药或其可药用的盐选自(以替诺福韦游离化合物计)单剂量为0.05mg～500mg的药物组合物，优选自单剂量为0.1mg、0.5mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg或上述任意值形成的范围的药物组合物。
在部分方案中，替诺福韦二吡呋酯富马酸盐的药物组合物选自单剂量为300mg的药物组合物。
在部分方案中，替诺福韦艾拉酚胺的药物组合物选自单剂量为25mg的药物组合物。
在部分方案中，替诺福韦艾拉酚胺富马酸盐的药物组合物选自单剂量为28mg的药物组合物。
如本申请所用，所述替诺福韦或其可药用前药或其可药用的盐可选自市售产品(如富马酸替诺福韦二吡呋酯片：
Figure PCTCN2021128892-appb-000014
富马酸丙酚替诺福韦片：
Figure PCTCN2021128892-appb-000015
)。
在一些实施方案中，所述个体选自既往接受过治疗的个体或既往未接受过治疗的个体。在一些实施方案中，所述个体选自既往接受过恩替卡韦或其可药用盐或其溶剂合物、或者替诺福韦或其可药用前药或其可药用的盐治疗的个体。在一些实施方案中，所述个体选自既往未接受过治疗的个体。在一些实施方案中，所述个体选自既往接受过治疗的个体。
在部分方案中，所述个体选自血清病毒学标准：血清HBsAg阳性持续24周以上或有24周慢性乙型肝炎的证据，1000IU/ml≤HbsAg定量≤40000IU/ml。
在部分方案中，所述个体选自既往接受过治疗的个体，需满足以下条件：
1)受试者必须在筛选前接受相同剂量的相同NA治疗(ETV/TDF)≥48周；
2)入组24周前病史记录HBV DNA抑制<正常检测下限，筛选期HBV DNA抑制定义为<LLOQ；
3)ALT≤5×ULN。
在部分方案中，所述个体选自既往未接受过治疗的个体，需满足以下条件：
1)必须为初治个体，即
1.1从未接受过HBV抗病毒药物(NA)或干扰素(IFN)药物治疗，或者
1.2接受过HBV抗病毒药物(NA)或干扰素(IFN)治疗但已停用24周以上；
2)HBeAg阳性慢性乙肝患者，HBV DNA>10 5copies/mL(或者>20,000IU/mL)；
或者HBeAg阴性患者HBV DNA>10 4copies/mL(或者>2,000IU/mL)；
3)1.0×ULN≤ALT≤5×ULN。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的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，而应该按照本领域普通的含义去理解。
如本申请所用，当本申请所述逆转录酶抑制剂化合物选自其溶剂合物形式时，化合物与溶剂的物质的量之比可选自1:0.5、1:1、1:1.5、1:2或任意端点形成的范围，例如1:0.5～1:2、1:0.5～1:1.5、或1:1～1:1.5。例如，所述恩替卡韦是非溶剂合物的形式。例如，所述恩替卡韦溶剂合物可以是恩替卡韦水合物。例如，所述恩替卡韦水合物可以是恩替卡韦一水合物。
如本申请所用，除非另有指明，“以重量计”指以式I化合物、恩替卡韦或替诺福韦的游离形式的重量计。
术语“施用”或“给予”或“给药”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“个体”可为哺乳动物。在部分实施方案中，所述受试者是小鼠。在部分实施方案中，所述受试者是人。
如本申请所用，所述式I化合物或其可药用盐可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式I化合物或其可药用盐的治疗有效量为包括但不限于从约0.0001到20mg/kg重量/天，例如从0.001到10mg/kg重量/天。式I化合物或其可药用盐的剂量频率由患者个体的需求决定，包括严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态，例如每天1次或2次，或每天更多次。给药可以是间歇的，例如，其中在若干天的期间内，受试者接受式I化合物或其可药用盐的每日剂量，接着在若干天或更多天的期间，患者不接受式I化合物或其可药用盐的每日剂量。
恩替卡韦或其可药用盐或其溶剂合物可通过多种途径给药，该途径包括但不限于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。给予恩替卡韦的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予恩替卡韦的日剂量可为0.005mg至10.0mg。恩替卡韦可以每日施用一次或多次。在一些实施方案中，恩替卡韦以口服固体制剂每天给药一次。
替诺福韦或其可药用前药或其可药用的盐可通过多种途径给药，该途径包括但不限于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。给予替诺福韦或其可药用前药或其可药用的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予替诺福韦或其可药用前药或其可药用的盐的日剂量可为0.05mg至500mg。替诺福韦或其可药用前药或其可药用的盐可以每日施用一次或多次。在一些实施方案中，替诺福韦或其可药用前药或其可药用的盐以口服固体制剂每天给药一次。
术语“约”应理解为包括在平均值的三个标准偏差内或特定领域中的标准公差范围内。在某些实施方式中，约应理解为不超过0.5的变异。“约”修饰其后所有列举的值。例如，“约1、2、3”表示“约1”、“约2”、“约3”。
术语“药物组合”指两种以上活性组分同时、并行或依序组合使用。
术语“固定组合”指活性组分(例如式I化合物或恩替卡韦或替诺福韦)以固定总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。在部分实施方案中，例如存在于同一片剂或同一胶囊或同一药袋中。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、药物制剂)同时、并行或依序且无具体时间限制地给予个体，其中所述给予个体的活性成份达到治疗有效量水平。非固定组合可列举的实例是鸡尾酒疗法，例如给予2种、3种或以上的活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一种或多种活性组分的独立实体的联合使用。
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态制剂，如片剂、丸剂、胶囊剂等。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述 的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
术语“药学上可接受的盐”或“可药用盐”是指在“药学上可接受的”的定义范围内的本申请的化合物的盐。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
在本文中，除非另有说明，否则术语“包含、包括和含有”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。
术语“游离化合物”是指本申请化合物以游离态存在，具体是指
Figure PCTCN2021128892-appb-000016
Figure PCTCN2021128892-appb-000017
及
Figure PCTCN2021128892-appb-000018
术语“溶剂合物”是指本申请化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括水，醇等。溶剂化物包括化学计算量的溶剂合物和非化学计算量的溶剂合物。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
施用方式
下述内容并非限制本申请药物组合的施用方式。
本申请的药物组合中的活性组分可以各自分开配制，或者其中的部分或全部共同配制。在一个实施方案中，本申请的药物组合可以配制成适合于单次或多次施用的药物组合物。
本申请的药物组合中的活性组分可以各自单独施用，或者其中的部分或全部共同施用。本申请的药物组合中的组分可以基本上不同时施用，或者其中的部分或全部基本上同时施用。
本申请的药物组合中的活性组分可以各自独立地，或者其中的部分或全部共同以适合的各种途径施用，包括但不限于口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，本申请的药物组合的活性组分可以各自独立地，或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合中的活性组分可以各自独立地，或者其中的部分或全部共同是适合的剂型，包括但 不限于：片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌内、静脉内、腹腔内)、粉末、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的药物组合中的活性组分可以各自独立地，或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
本申请的药物组合还可以包含另外的治疗剂。在一个实施方案中，所述另外的治疗剂可以是本领域已知的治疗乙型肝炎病毒感染的治疗剂。
在部分方案中，可以同时、顺序或间隔向有需要的个体施用有效量的本申请的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物。
在部分方案中，可以相同或不同的给药方案向有需要的个体施用有效量的所述式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物。
在部分方案中，所述式I化合物或其可药用盐每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次、或每三周施用一次。
在部分方案中，所述式I化合物或其可药用盐每一次施用1-1500mg、或1-1000mg、或1-800mg、或1-600mg、或1-400mg、或者1-200mg、或者1mg-100mg的剂量，优选1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、95mg、96mg、97mg、98mg、99mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg或上述任意值形成的范围的剂量。
在部分方案中，所述式I化合物或其可药用盐每一天施用一次，每一次施用1至400mg、或1至350mg或1至300mg、或1至250mg、或1至200mg、或1至150mg、或10至150mg、或20至150mg、或50至150mg、或50至100mg。
在部分方案中，所述式I化合物或其可药用盐每一天施用一次，每一次施用1至100mg。
在部分方案中，所述恩替卡韦或其可药用盐或其溶剂合物每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次、或每三周施用一次。
在部分方案中，所述恩替卡韦或其可药用盐或其溶剂合物每一次施用0.005mg至5.0mg的剂量，优选0.01mg、0.05mg、0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、1.1mg、1.2mg、1.3mg、1.4mg、1.5mg、1.6mg、1.7mg、1.8mg、1.9mg、2.0mg、2.1mg、2.2mg、2.3mg、2.4mg、2.5mg、2.6mg、2.7mg、2.8mg、2.9mg、3.0mg、3.1mg、3.2mg、3.3mg、3.4mg、3.5mg、3.6mg、3.7mg、3.8mg、3.9mg、4.0mg、4.1mg、4.2mg、4.3mg、4.4mg、4.5mg、4.6mg、4.7mg、4.8mg、4.9mg、5.0mg或上述任意值形成的范围的剂量。在部分方案中，所述恩替卡韦或其可药用盐或其溶剂合物每一次施用0.05mg至5.0mg、0.10mg至2.0mg、0.25mg至2.0mg、0.5mg至1.0mg的剂量。
在部分方案中，所述恩替卡韦或其可药用盐或其溶剂合物每天施用一次，每次施用0.10mg至2.0mg的剂量。在部分方案中，所述恩替卡韦或其可药用盐或其溶剂合物可以每天施用一次，每次施用0.5mg的剂量。在部分方案中，所述式I化合物每一天给药一次，每次施用1mg～100mg的剂量；所述恩替卡韦或其可药用盐或其溶剂合物每天施用一次，每次施用0.10mg至2.0mg的剂量。
在部分方案中，所述替诺福韦或其可药用前药或其可药用的盐每天施用一次、每天施用两次、或每两天施用一次、或每三天施用一次、或每四天施用一次、或每五天施用一次、或每六天施用一次、或每七天施用一次。在本申请的一些实施方案中，所述药物组合的替诺福韦或其可药用前药或其可药用的盐可以每天施用一次。
在部分方案中，所述替诺福韦或其可药用前药或其可药用的盐每一次施用0.05mg至500mg的剂量，优选0.1mg、0.5mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、35mg、40mg、45mg、50mg、55mg、56mg、57mg、58mg、59mg、60mg、65mg、66mg、67mg、68mg、70mg、71mg、72mg、73mg、74mg、75mg、80mg、85mg、90mg、91mg、92mg、93mg、94mg、95mg、100mg、101mg、102mg、103mg、104mg、105mg、110mg、111mg、112mg、113mg、114mg、115mg、120mg、125mg、130mg、131mg、132mg、133mg、134mg、135mg、136mg、137mg、138mg、139mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、181mg、182mg、183mg、184mg、185mg、190mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg或上述任意值形成的范围的剂量。在部分方案中，所述替诺福韦或其可药用前药或其可药用的盐每一次施用0.05mg至200mg、0.10mg至190mg、1mg至160mg、10mg至150mg的剂量。
在部分方案中，所述替诺福韦或其可药用前药或其可药用的盐每天施用一次，每次施用10mg至150mg的剂量。在部分方案中，所述替诺福韦或其可药用前药或其可药用的盐可以每天施用一次，每次施用15mg或135.5mg的剂量。
在部分方案中，替诺福韦二吡呋酯富马酸盐每天施用一次，每次施用300mg。
在部分方案中，替诺福韦艾拉酚胺每天施用一次，每次施用25mg。
在部分方案中，替诺福韦艾拉酚胺富马酸盐每天施用一次，每次施用28mg。
在部分方案中，所述式I化合物每一天给药一次，每次施用1mg～100mg的剂量；所述替诺福韦或其可药用前药或其可药用的盐每天施用一次，每次施用10mg至150mg的剂量。
技术效果
本申请的药物组合可以显著降低HBV DNA水平或缓解其他HBV指标；并且与单药相比，本申请的药物组合表现出增强作用，具有良好的药代动力学性质，且不良反应小，耐受性好。与单药相比，本申请的药物组合能更有效降低HBV标志物(包括HBsAg、HBsAb、HBeAg、HBeAb、抗-HBc、HBV DNA定量、HBV RNA和HbcrAg等)水平。其说明本申请的药物组合具有良好的药用价值。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1 HepG2.2.15细胞实验
1.1实验材料
1.1.1化合物
式I化合物和恩替卡韦用100％DMSO配制，母液保存于氮气柜中，化合物浓度见表1。
1.1.2细胞株
HepG2.2.15细胞株由药明康德提供。
1.1.3试剂
本研究使用的主要试剂包括CellTiter-Glo(Promega，货号G7573)，FastStart Universal Probe Mast Mix(Roche，货号04914058001)和QIAamp 96 DNA Blood Kit(12)(Qiagen，货号51162)。
1.1.4仪器
实时荧光定量PCR仪(Applied Biosystems，型号7900HT Fast Real-Time PCR System)和多功能酶标仪(BioTek，型号Synergy2)。
1.2实验方法
将HepG2.2.15细胞以60,000个细胞/孔的密度种入96孔细胞培养板，然后将细胞在5％CO 2、37℃条件下培养过夜。将式I化合物与恩替卡韦以8个不同浓度进行配比(摩尔比10:1)，同时设置单药对照，将化合物加入96孔板中，每个浓度为3复孔，DMSO终浓度为1％。更换含有化合物的新鲜培养基，细胞在5％CO 2、37℃条件下培养3天。收集化合物处理后的细胞板上清液，按照试剂盒QIAamp 96 DNA Blood Kit(12)说明书抽提DNA。待收集上清后加入CellTiter-Glo检测细胞活力。
表1化合物测试浓度(nM)
Figure PCTCN2021128892-appb-000019
注：a1b1表示式I化合物联合恩替卡韦组中采用式I化合物(a)第1组的给药浓度和恩替卡韦(b)第1组的给药浓度。其他依次类推。
qPCR方法定量HBV DNA。以HBV质粒DNA为标准品，标准品HBV质粒DNA浓度从10 7copies/μL起始10倍梯度稀释7个点。利用各标准品的HBV DNA拷贝数和CT值拟合标准曲线，计算各检测样本中的HBV DNA拷贝数。
用CellTiter-Glo试剂盒检测化合物对HepG2.2.15细胞的细胞毒性。按试剂盒说明书方法，用多功能酶标仪检测各细胞孔的化学发光强度(RLU)。
应用CompuSyn软件对试验数据进行分析并计算联合指数。分别计算了50％、75％、90％和95％抑制率的联合指数，并计算平均联合指数(CIwt)。
平均联合指数(CIwt)＝【1×CI50+2×CI75+3×CI90+4CI95】/10
平均联合指数在0.9-1.1时表示相加作用；联合指数在<0.9时表示协同作用；联合指数在>1.1表示拮抗作用。
化合物细胞毒性数据(细胞活率％)计算公式和化合物抑制率(％)公式如下：
细胞活率％＝(化合物孔RLU-培养液对照孔RLU平均值)/(DMSO对照孔RLU平均值
-培养液对照孔RLU平均值)×100％
抑制率％＝(1-样品中的HBV DNA含量/DMSO对照组中的HBV DNA含量)×100
1.3结果
表2体外联合用药对HBV的抑制活性
Figure PCTCN2021128892-appb-000020
式I化合物与恩替卡韦联合用药抗HBV平均联合指数为0.85，显示协同效应。
实施例2 AAV/HBV小鼠模型实验
2.1.实验材料
2.1.1.动物
雄性C57BL/6小鼠，5周龄，无特定病原体，购于上海斯莱克实验动物有限公司，饲养于独立通风笼盒中。小鼠度过3天的环境适应期后注射AAV/HBV病毒。
2.1.2.溶剂和化合物
2.1.2.1溶剂
10％Solutol配制：以配制100mL为例：精密抽取90mL的dd.water，然后加入10mL溶液状的solutol(提前将固体Solutol放入70～75℃烘箱加热溶解15～30分钟，直至完全溶解，用注射器抽取)，充分搅拌混匀得到10％Solutol水溶液,每周配制一次。配好的溶液保存于2-8℃。
2.1.2.2化合物
式I化合物：称取适量式I化合物，溶于10％Solutol中(无明显颗粒存在)，配好后保存于2-8℃。
恩替卡韦：称取适量的恩替卡韦，溶解于DMSO中，配制成1mg/mL，再用生理盐水逐步稀释1000倍至0.001mg/mL，分装后作为储备液保存在-20℃冰箱中，每天取1管再用生理盐水稀释10倍得到给药需要浓度0.0001mg/mL，保存于2-8℃用于每天的给药。
2.1.3 rAAV8-1.3HBV
rAAV8-1.3HBV(D型，ayw)购于北京五加和分子医学研究所。实验前用无菌PBS稀释至5×10 11v.g./mL。每只小鼠注射200μL，即每只小鼠注射1×10 11v.g.
2.1.4试剂及仪器
QIAamp96 DNA试剂盒(货号：Qiagen-51162)、
Figure PCTCN2021128892-appb-000021
Universal PCR Master Mix(货号：Roche-04914058001)、乙型肝炎病毒e抗原检测试剂盒(货号：安图生物-CL 0312)和乙型肝炎病毒表面抗原检测试剂盒(货号：安图生物-CL 0310)。
离心机(Beckman Allegra X-15R)、酶标仪(BioTek-Synergy 2)、定量PCR仪(ABI-7900)和分光光度仪(Thermo-NANODROP 1000)。
2.2试验方法
2.2.1建立AAV/HBV小鼠模型建立
AAV/HBV注射：rAAV8-1.3HBV在注射前预先用无菌PBS配制成浓度为1×10 11v.g./200μL溶液。于小鼠经尾静脉注射200μL rAAV8-1.3HBV溶液。
分组前采血：病毒注射后第14和21天，感染的小鼠通过颌下静脉采血～120μL用于收集血清。全血置于37℃培养箱中孵育30分钟后，13,200×g，4℃离心3分钟收集血清。血清保存于-80℃，用于HBV DNA、HBeAg和HBsAg检测。
分组：病毒注射后第27天，根据第14和21天血清HBV DNA、HBeAg和HBsAg结果，随机分组，每组8只或4只，根据实验设计给予相应治疗处理。
组号：
i.溶剂组；
ii.单药组：恩替卡韦；
iii.单药组：式I化合物3mpk；
iv.联用组(combo)：式I化合物3mpk与恩替卡韦；
v.单药组：式I化合物10mpk；
vi.联用组(combo)：式I化合物10mpk与恩替卡韦。
2.2.2体内试验设计
化合物处理：感染后第28天，所有小鼠用溶剂或化合物进行灌胃给药。首次给药当天设为实验第0天，给药持续时间是第0-27天。恩替卡韦每天给药一次(QD)，式I化合物每天给药两次(BID，给药间隔时间为8hr/16hr)。给药体积为10mL/kg。
表3给药方案
Figure PCTCN2021128892-appb-000022
注：i.g.：灌胃；QD：每日给药一次。BID：每日给药两次。联用组给药方法和单药组给药方法保持一致。
非终点采血：在第-1，3，7，14，21，28，35或42天，通过颌下静脉采血～120μL收集血清，用于HBV DNA检测。若采血当天同时有给药，则采血在当天第一次给药后约5小时进行。
实验终点：组i-iv在第28天进行小鼠安乐死。小鼠经心脏采血收集血清，用于HBV DNA检测。组v和vi的实验终点在第42天。
2.2.3样品分析
qPCR定量小鼠血清中HBV DNA：提取血清中DNA，实验步骤参照QIAamp 96 DNA Blood Kit说明书。qPCR反应条件为95℃、10分钟1个循环；95℃、15秒，60℃、1分钟，40个循环。
2.2.4统计学分析
数据用平均值±标准误表示，统计学分析方法采用Student t test。
2.2.5结果
表4小鼠血清中HBV DNA检测结果1
Figure PCTCN2021128892-appb-000023
表5小鼠血清中HBV DNA检测结果2
Figure PCTCN2021128892-appb-000024
注：*平均值±标准误差。LLOQ为2.08log10copy/μL血清，低于LLOQ数值以2.08log10copy/μL表示。与溶剂组比较，p<0.01。
上述结果说明，与溶剂组相比，式I化合物与恩替卡韦联合用药对血清HBV DNA抑制效果显著，且优于单药。
实施例3
1.试验药物
式I化合物：制备成规格10mg和50mg胶囊。
恩替卡韦：恩替卡韦片剂，规格0.5mg/片(比如正大天晴药业集团股份有限公司的
Figure PCTCN2021128892-appb-000025
)。
安慰剂：式I化合物的安慰剂。
2.入组受试者
需满足以下标准：
1)年龄在18-70周岁(包括边界值)，男女不限。
2)血清病毒学标准：血清HBeAg阳性持续6个月以上或有6个月慢性乙型肝炎的证据，1000IU/mL≤HBsAg定量≤30000IU/mL。
3)无肝硬化，以下列方式证实：
在筛选前1年内或筛选期间的肝组织活检未见肝硬化(如Metavir评分为F0-F3，GS评分为S0-S3)；或
在筛选前在筛选前6个月内的Fibroscan评分<12.4kPa，同时筛选期腹部彩超无肝硬化表现。
在有肝活检结果的情况下，以肝活检结果为准。
4)筛选时受试者必须为初治患者，即，
从未接受过HBV抗病毒药物(NA)或干扰素(IFN)药物治疗，或者
接受过HBV抗病毒药物(NA)或干扰素(IFN)治疗但已停用6个月以上。
5)HBeAg阳性慢乙肝患者，HBV DNA＞10 5copies/mL(或者>20,000IU/mL)；或者HBeAg阴性患者HBV DNA＞10 4copies/mL(或者>2,000IU/mL)；(HBeAg阳性及阴慢乙肝患者均为罗氏二代Cobas  Taqman实时定量PCR法测定，检下限值为20IU/mL)。
6)1.0×ULN≤ALT≤5×ULN。
7)受试者能够和研究者进行良好的沟通，并且理解和遵守本项研究的各项要求，理解并签署知情同意书。
3.给药方案
式I化合物胶囊/安慰剂，每天给药一次，空腹(餐前或后至少2小时)条件下给药，每次服药时间应大致相近。
恩替卡韦，每天给药一次，恩替卡韦空腹(餐前或后至少2小时)条件下给药，每次服药时间应大致相近。
4.有效性指标
指标包括HBV标志物(HBsAg、HBsAb、HBeAg、HBeAb、抗-HBc、HBV DNA定量、HBV RNA和HBcrAg。
实施例4
1.试验药物
式I化合物：制备成规格10mg和50mg胶囊。
恩替卡韦：恩替卡韦片剂，规格0.5mg/片(比如正大天晴药业集团股份有限公司的
Figure PCTCN2021128892-appb-000026
)。
替诺福韦：替诺福韦二吡呋酯富马酸盐片剂，规格300mg/片(比如正大天晴药业集团股份有限公司的
Figure PCTCN2021128892-appb-000027
)。
替诺福韦：替诺福韦艾拉酚胺富马酸盐片剂，规格25mg/片。
安慰剂：式I化合物的安慰剂。
2.入组受试者
需满足以下标准：
1)18-70岁(包括边界值)，男女不限；
2)血清病毒学标准：血清HBsAg阳性持续24周以上或有24周慢性乙型肝炎的证据。1000IU/ml≤HbsAg定量≤40000IU/ml；
3)经研究者判断无肝硬化。
4)受试者能够和研究者进行良好的沟通，并且理解和遵守本项研究的各项要求，理解并签署知情同意书。
经治患者需满足以下条件：
5)受试者必须在筛选前接受相同剂量的相同NA治疗(ETV/TDF)≥48周；
6)入组24周前病史记录HBV DNA抑制<正常检测下限，筛选期HBV DNA抑制定义为<LLOQ；
7)ALT≤5×ULN；
初治患者需要满足以下条件：
8)筛选时受试者必须为初治患者，即
◆从未接受过HBV抗病毒药物(NA)或干扰素(IFN)药物治疗，或者
◆接受过HBV抗病毒药物(NA)或干扰素(IFN)治疗但已停用24周以上；
9)HBeAg阳性慢性乙肝患者，HBV DNA>10 5copies/mL(或者>20,000IU/mL)；
或者HBeAg阴性患者HBV DNA>10 4copies/mL(或者>2,000IU/mL)；
10)1.0×ULN≤ALT≤5×ULN。
3.给药方案
式I化合物胶囊/安慰剂，每天给药一次，空腹(餐前或后至少2小时)条件下给药，每次服药时间应大致相近。
恩替卡韦，每天给药一次，恩替卡韦空腹(餐前或后至少2小时)条件下给药，每次服药时间应大致相近。
替诺福韦，每天给药一次，替诺福韦空腹(餐前或后至少2小时)条件下给药，每次服药时间应大致相近。
4.有效性指标
指标包括HBV标志物(HBsAg、HBsAb、HBeAg、HBeAb、抗-HBc、HBV DNA定量、HBV RNA和HbcrAg)。

Claims (20)

  1. 药物组合，其包括式I化合物或其可药用盐和逆转录酶抑制剂或其可药用的前药、或其可药用盐或其溶剂合物，
    Figure PCTCN2021128892-appb-100001
  2. 如权利要求1所述的药物组合，所述逆转录酶抑制剂选自恩替卡韦或其可药用盐或其溶剂合物、或替诺福韦或其可药用的前药或可药用的盐。
  3. 如权利要求2所述的药物组合，其特征在于，所述恩替卡韦或其可药用盐或其溶剂合物选自恩替卡韦马来酸盐、恩替卡韦一马来酸盐、恩替卡韦水合物、恩替卡韦0.5～2水合物、或恩替卡韦一水合物；任选地，所述恩替卡韦或其可药用盐或其溶剂合物选自恩替卡韦一马来酸盐一水合物。
  4. 如权利要求2或3所述的药物组合，其特征在于，所述式I化合物或其可药用盐与恩替卡韦或其可药用盐或其溶剂合物的平均日剂量之比选自1000:1～1:1000；任选地，所述式I化合物或其可药用盐与恩替卡韦或其可药用盐或其溶剂合物的平均日剂量之比选自1000:1、950:1、900:1、850:1、800:1、750:1、700:1、650:1、600:1、550:1、500:1、450:1、400:1、350:1、300:1、250:1、200:1、150:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、30:1、20:1、10:1、1:1.、1:10、1:20、1:30、1:40、1:50、1:60、1:70、1:80、1:90、1:100、1:150、1:200、1:250、1:300、1:350、1:400、1:450、1:500、1:550、1:600、1:650、1:700、1:750、1:800、1:850、1:900、1:950、1:1000或任选上述比例形成的范围。
  5. 如权利要求2-4任一项所述的药物组合，其特征在于，所述恩替卡韦或其可药用盐或其溶剂合物每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次、或每三周施用一次。
  6. 如权利要求2-4任一项所述的药物组合，其特征在于，所述恩替卡韦或其可药用盐或其溶剂合物每一次施用0.005mg至5.0mg的剂量；任选地，所述恩替卡韦或其可药用盐或其溶剂合物每一次施用0.01mg、0.05mg、0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、1.1mg、1.2mg、1.3mg、1.4mg、1.5mg、1.6mg、1.7mg、1.8mg、1.9mg、2.0mg、2.1mg、2.2mg、2.3mg、2.4mg、2.5mg、2.6mg、2.7mg、2.8mg、2.9mg、3.0mg、3.1mg、3.2mg、3.3mg、3.4mg、3.5mg、3.6mg、3.7mg、3.8mg、3.9mg、4.0mg、4.1mg、4.2mg、4.3mg、4.4mg、4.5mg、4.6mg、4.7mg、4.8mg、4.9mg、5.0mg或上述任意值形成的范围的剂量。
  7. 如权利要求2所述的药物组合，所述替诺福韦可药用的前药包括替诺福韦二吡呋酯、替诺福韦艾拉酚胺或艾米替诺福韦；
    任选地，所述替诺福韦或其可药用前药的可药用盐选自富马酸盐、乳清酸盐、二磺酸盐、磷酸盐、琥珀酸或天冬氨酸盐；
    任选地，所述替诺福韦或其可药用前药或其可药用的盐选自替诺福韦、替诺福韦艾拉酚胺富马酸盐、替诺福韦二吡呋酯富马酸盐、替诺福韦二吡呋酯乳清酸盐、替诺福韦二吡呋酯半二磺酸盐、替诺福韦二吡呋酯磷酸盐、替诺福韦二吡呋酯琥珀酸盐、替诺福韦二吡呋酯天冬氨酸盐或艾米替诺福韦富马酸盐。
  8. 如权利要求2或7所述的药物组合，所述式I化合物或其可药用盐与替诺福韦或其可药用前药或其可 药用的盐平均日剂量之比选自500:1～1:1000；任选地，所述式I化合物或其可药用盐与替诺福韦或其可药用前药或其可药用的盐平均日剂量之比选自500:1、450:1、400:1、350:1、300:1、250:1、200:1、150:1、100:1、95:1、90:1、85:1、80:1、79:1、78:1、77:1、76:1、75:1、74:1、73:1、72:1、71:1、70:1、69:1、68:1、67:1、66:1、65:1、60:1、55:1、50:1、45:1、40:1、35:1、30:1、25:1、30:1、25:1、20:1、15:1、10:1、5:1、1:1、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:30、1:40、1:50、1:60、1:70、1:80、1:90、1:100、1:150、1:200、1:250、1:300、1:350、1:400、1:450、1:500、1:550、1:600、1:650、1:700、1:750、1:800、1:850、1:900、1:950、1:1000或任选上述比例形成的范围。
  9. 如权利要求2、7或8任一项所述的药物组合，所述替诺福韦或其可药用前药或其可药用的盐每天施用一次、或每天施用两次、或每两天施用一次、或每三天施用一次、或每四天施用一次、或每五天施用一次、或每六天施用一次、或每七天施用一次。
  10. 如权利要求2、7-9任一项所述的药物组合，所述替诺福韦或其可药用前药或其可药用的盐平均日剂量是0.05mg至500mg；或者，平均日剂量是0.1mg至400mg；或者，平均日剂量是1mg至300mg；或者，平均日剂量是5mg至200mg；或者，平均日剂量是8mg至190mg；或者，平均日剂量是10mg至185mg；或者，平均日剂量是14mg至140mg；
    任选地，每次施用替诺福韦二吡呋酯富马酸盐300mg；
    或者，每次施用替诺福韦艾拉酚胺25mg；
    或者，每次施用替诺福韦艾拉酚胺富马酸盐28mg。
  11. 如权利要求1-10任一项所述的药物组合，其特征在于，所述式I化合物或其可药用盐每一天施用一次、每一天施用两次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次、或每三周施用一次。
  12. 如权利要求1-11任一项所述的药物组合，其特征在于，所述式I化合物或其可药用盐每一次施用1mg-1500mg的剂量。
  13. 如权利要求1-12任一项所述的药物组合，其特征在于，所述药物组合是固定组合；任选地所述固定组合呈固体药物组合物形式；任选地，所述固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物、或和替诺福韦或其可药用前药或其可药用的盐存在于同一固体药物组合物。
  14. 如权利要求1-12任一项所述的药物组合，其特征在于，所述药物组合是非固定组合；
    任选地，所述非固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物、或和替诺福韦或其可药用前药或其可药用的盐各自呈固体药物组合物形式；
    任选地，所述非固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物、或和替诺福韦或其可药用前药或其可药用的盐各自呈固体药物组合物形式，且式I化合物或其可药用盐的固体药物组合物和恩替卡韦或其可药用盐或其溶剂合物、或和替诺福韦或其可药用前药或其可药用的盐的固体药物组合物存在于同一个药袋；
    任选地，所述非固定组合中的式I化合物或其可药用盐和恩替卡韦或其可药用盐或其溶剂合物、或和替诺福韦或其可药用前药或其可药用的盐各自呈固体药物组合物形式，且式I化合物或其可药用盐的固体药物组合物和恩替卡韦或其可药用盐或其溶剂合物、或和替诺福韦或其可药用前药或其可药用的盐的固体药物组合物不存在于同一个药袋。
  15. 如权利要求1-14任一项所述的药物组合在制备用于治疗乙型肝炎病毒感染的药物中的用途。
  16. 治疗乙型肝炎病毒感染的方法，其包括向所述个体施用有效量的如权利要求1-14任一项所述的药物组合。
  17. 用于治疗乙型肝炎病毒感染的药物组合，所述药物组合选自权利要求1-14任一项所述的药物组合。
  18. 权利要求1-14任一项所述的药物组合用于治疗乙型肝炎病毒感染的用途。
  19. 用于治疗乙型肝炎病毒感染的试剂盒，其中包含：(a)含有式I化合物或其可药用盐作为活性成分的第一种药物组合物；和(b)含有逆转录酶抑制剂或其可药用前药、或其可药用的盐或其溶剂合物作为活性成分的第二种药物组合物；和任选的(c)式I化合物或其可药用盐和逆转录酶抑制剂或其可药用前药、或其可药用的盐或其溶剂合物联合使用的说明，
    Figure PCTCN2021128892-appb-100002
  20. 如权利要求19所述的试剂盒，所述逆转录酶抑制剂或其可药用前药、或其可药用的盐或其溶剂合物选自恩替卡韦或其可药用盐或其溶剂合物、或替诺福韦或其可药用前药或其可药用的盐。
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