WO2023151164A1 - 一种具有协同增效效应的药物组合物及其其抗病毒用途 - Google Patents

一种具有协同增效效应的药物组合物及其其抗病毒用途 Download PDF

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WO2023151164A1
WO2023151164A1 PCT/CN2022/084724 CN2022084724W WO2023151164A1 WO 2023151164 A1 WO2023151164 A1 WO 2023151164A1 CN 2022084724 W CN2022084724 W CN 2022084724W WO 2023151164 A1 WO2023151164 A1 WO 2023151164A1
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virus
deuterated
pharmaceutically acceptable
pharmaceutical composition
solvate
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French (fr)
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黄才古
庄鸿达
孙辉
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广州谷森制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

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  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a novel deuterated cyano compound or its isomer or its prodrug or its solvate or a pharmaceutically acceptable salt thereof, and a deuterated cytidine derivative or its isomer A pharmaceutical composition composed of a body or its prodrug or its solvate or a pharmaceutically acceptable salt thereof and its antiviral application.
  • the coronavirus in the human body was first isolated in the UK in the 1960s.
  • the virus got its name from the crown-shaped protrusions on its surface. It may be associated with respiratory infections in humans, pigs, cats, dogs, rats and chickens.
  • the SARS virus belongs to the order Nesting Viridae, Coronaviridae, and the genus Coronaviridae, and is a subgroup B coronavirus of the genus Beta. Most of the virus particles are round, with a capsule, and there are coronal-arranged fibers around the periphery. They are distributed in the cytoplasm and are round. The diameter of the virus is between 80 and 120nm. SARS is an infectious disease with rapid onset, rapid spread and high fatality rate. Most of the infected patients have direct or indirect contact with patients, or live in endemic areas.
  • MERS virus is a ⁇ genus C subgroup coronavirus, its full name is Middle East Respiratory Syndrome Coronavirus (MERS-CoV for short), and it causes Middle East Respiratory Syndrome (Middle East Respiratory Syndrome, MERS for short) after infection. ).
  • MERS-CoV was first discovered in Saudi Arabia in September 2012. It was named "SARS-like virus” because of its similar clinical symptoms to SARS. It also became the sixth known human coronavirus and the first isolated in the past 10 years. 3 types.
  • the new coronavirus SARS-CoV-2 is a new strain of coronavirus that has never been found in humans before. It was discovered and reported for the first time in 2019. It is still prevalent in many countries around the world and has not been well received in many countries and regions. good control.
  • coronavirus Common signs after human infection with coronavirus include respiratory symptoms, fever, cough, shortness of breath and dyspnea. In more severe cases, infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death, and there is currently no specific treatment for the illness caused by the novel coronavirus.
  • the new deuterated cyano compound is a small molecule 3CL protease inhibitor independently developed by Shanghai Gusen Pharmaceutical Co., Ltd. Its structure is: In vitro experiments have confirmed that it has excellent anti-SARS-CoV-2 activity and can effectively inhibit the replication of the virus. On the basis of comparable antibacterial activity of the virus, the compound has achieved better pharmacokinetic properties than other oral anti-new crown drugs. Shanghai Gusen Pharmaceutical Co., Ltd. has applied for an invention patent (application number CN202111234708X) for the above-mentioned novel deuterated cyano compounds.
  • Deuterated cytidine derivatives are also a small-molecule neocytidine oral antiviral drug independently developed by Shanghai Gusen Pharmaceutical Co., Ltd.
  • the drug is a SARS-CoV-2 polymerase inhibitor. In vitro experiments have confirmed that it has strong anti-SARS-CoV-2 activity and can effectively inhibit virus replication.
  • the chemical name of the compound deuterated cytidine derivative is : ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxylamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)deuteromethyl Isobutyl ester, its chemical formula is: And has applied for an invention patent (application number CN2021110245289).
  • the object of the present invention is to provide a novel deuterated cyano compound or its isomer or its prodrug or its solvate or its pharmaceutically acceptable salt, and deuterated cytidine derivative or its isomer or its prodrug or its solvate or its pharmaceutically acceptable salt composition and its antiviral use.
  • the present invention provides a pharmaceutical composition, characterized in that: it is composed of novel deuterated cyano compound or its isomer or its prodrug or its solvate or its pharmaceutically acceptable salt, and deuterated Cytidine derivatives or isomers or prodrugs or solvates or pharmaceutically acceptable salts thereof.
  • novel deuterated cyano compound structure that the present invention relates to is as follows:
  • the pharmaceutically acceptable salts of the present invention include organic salts and inorganic salts of the corresponding compounds, which can be all salts well known to those skilled in the art, preferred but non-limiting examples are hydrochloride, hydrobromide, sulfate, nitric acid salt, acetate, adipate, aspartate, benzoate, etc.
  • the compounds may be administered in the form of prodrugs.
  • Prodrugs may comprise covalently bonded carriers that release the active parent drug when administered to a mammalian subject.
  • Prodrugs can be modified by modifying functional groups present in the compound in such a way that the modification is cleaved to the parent compound during routine manipulation or in vivo.
  • the solvate of the present invention refers to the association formed by one or more solvent molecules and the present invention, and the solvents forming the solvate include but not limited to water, isopropanol, ethanol, methanol, dimethyl sulfoxide and the like.
  • the isomers of the present invention include stereoisomers and tautomers.
  • the compounds of the present invention include crystalline and non-crystalline forms thereof, wherein crystals include single crystals, polycrystals and co-crystals.
  • the weight ratio of the solvate or its pharmaceutically acceptable salt is (100-300):(200-400), preferably, their mass ratio is 100:200, 100:300, 100:400, 200:300, 200: 400, 300: 400.
  • their mass ratio is 200:300.
  • the pharmaceutical composition disclosed herein comprises about 100 mg to about 300 mg of the novel deuterated cyano compound and 200 mg to 400 mg of the deuterated cytidine derivative.
  • the pharmaceutical composition comprises about 200 mg of novel deuterated cyano compounds and 200 mg-300 mg of deuterated cytidine derivatives, preferably, the pharmaceutical composition comprises approximately 200 mg of novel deuterated cyano compounds and 300 mg of deuterated cytidine derivatives things.
  • the pharmaceutical composition of the present invention can be administered simultaneously in the same or different pharmaceutical compositions, or can be administered sequentially, that is, the novel deuterated cyano compounds and deuterated cytidine derivatives can be mixed together to form a single
  • the dosage units can also be independently formed into dosage units. If administered separately, the time between administration of the second active ingredient should not be such that the synergistic therapeutic benefit of the combination of active ingredients can be lost.
  • the novel deuterated cyano compound and the deuterated cytidine derivative independently form administration units.
  • composition also includes a pharmaceutically acceptable carrier consisting of materials considered safe and effective, and which can be administered to an individual without causing adverse biological side effects or undesired interactions.
  • a carrier is all ingredients present in a pharmaceutical formulation other than the active ingredient.
  • carrier includes, but is not limited to, regulators, binders, lubricants, disintegrants, fillers, colorants, plasticizers, film coating materials, organic solvents, solubilizers, flavoring agents, Surfactant etc.
  • Diluents also known as "fillers,” are often necessary to increase the bulk of solid dosage forms to provide a practical size for compressing tablets or forming beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pre- Gelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesion to a solid dosage form, thereby ensuring that the tablet or beads or granules remain intact after the dosage form has been formed.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycols, waxes, natural and synthetic gums.
  • Lubricants are used to facilitate tablet manufacturing.
  • suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate disintegration or "breakdown" of the dosage form after administration, and typically include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pre- Gelatinized starch, clay, cellulose, alginate, gum or cross-linked polymer.
  • Stabilizers are used to inhibit or delay drug decomposition reactions, including, for example, oxidation reactions.
  • the surfactant may be anionic, cationic, amphoteric or nonionic.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • Examples of anionic surfactants include sodium, potassium, ammonium salts of long chain alkyl sulfonic acids and alkylaryl sulfonic acids, eg sodium dodecylbenzene sulfonate; sodium dialkyl sulfosuccinate.
  • plasticizers examples include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, Triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides.
  • the organic solvent can be alcohols, such as isopropanol, propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and polyoxyethylene alcohol.
  • compositions described herein can be formulated for modified or controlled release.
  • controlled release dosage forms include extended release dosage forms, delayed release dosage forms, pulsed release dosage forms, and combinations thereof.
  • the compound or pharmaceutical composition is administered orally, intravenously, including tablets or oral solutions.
  • the present invention provides the application of a pharmaceutical composition in the preparation of medicines for the treatment or prevention of virus infection
  • the virus can be the new coronavirus SARS-CoV-2, SARS coronavirus, MERS coronavirus, eastern horse Encephalitis virus, western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, Orthomyxoviridae or Paramyxoviridae, RSV, influenza A and B viruses, Bora virus.
  • the virus is the new coronavirus SARS-CoV-2, SARS coronavirus and MERS coronavirus.
  • the virus is the new coronavirus SARS-CoV-2.
  • the active ingredients in the pharmaceutical composition of the present invention are novel deuterated cyano compounds and deuterated cytidine derivatives, respectively a small molecule 3CL protease inhibitor and neocytidine independently developed by Shanghai Gusen Pharmaceutical Co., Ltd. Glycoside antiviral oral drugs, they all exhibit excellent antiviral activity.
  • composition of the present invention is obviously better than single administration, has a significant synergistic effect, and reduces cytotoxicity.
  • the new deuterated cyano compound is aimed at the protease of the virus, while the deuterated cytidine derivative is aimed at the RNA polymerase of the virus.
  • Combining drugs for different targets can solve the problem of drug resistance, Thereby improving drug safety.
  • Fig. 1 is the influence of pharmaceutical composition on cytotoxicity
  • Figure 2 is the antiviral activity of the pharmaceutical composition
  • Fig. 3 is the cellular antiviral activity of drug composition contrast drug alone
  • Embodiment 1 the synthetic route of novel deuterated cyano compound (hereinafter referred to as compound 1)
  • TLC detects that the reaction conversion is substantially complete, adding water (80ml) and extracting three times with EA, combining the organic phases, using 0.5mol/L HCl, 5% NaHCO successively Washing with water, drying over anhydrous magnesium sulfate, concentrating to dryness to obtain crude product 1,
  • Column chromatography obtained 8.4 g of an off-white solid product, which is a novel deuterated cyano compound (hereinafter referred to as compound 1).
  • Example 2 The synthetic route of deuterated cytidine derivatives (hereinafter referred to as compound 2)
  • Embodiment 3 cytotoxicity test
  • Vero-E6 cells were digested and passaged, and the cell density was adjusted to 1 ⁇ 105 cells/mL with DMEM containing 10% FBS, inoculated in a 96-well plate, 100 ⁇ L/well, and cultured at 35°C and 6% CO2 Cultivate in box for 20h;
  • Embodiment 4 In vitro antiviral activity EC 50 test
  • Vero-E6 cells were digested and passaged, and the cell density was adjusted to 1 ⁇ 105 cells/mL with 10% FBS-containing DMEM, inoculated in a 96-well plate, 100 ⁇ L/well, and placed in a 35°C, 6% CO2 incubator Cultivate for 20 hours;
  • composition comprising Compound 1 and Compound 2 at a molar ratio of 1:1 with DMEM containing 1% FBS, so that the concentration of the composition is 200 ⁇ M, 60 ⁇ M, 20 ⁇ M, 6 ⁇ M, 2 ⁇ M, 0.6 ⁇ M, 0.2 ⁇ M, 0.06 ⁇ M , 0.02 ⁇ M;
  • the results are shown in Table 1.
  • the half maximal effect concentration (EC50) of the composition of the present invention is: 0.241 ⁇ M, significantly lower than compound 1 (1.716 ⁇ M) and compound 2 (1.563 ⁇ M) used alone.
  • Vero-E6 cells were digested and passaged, and the cell density was adjusted to 1 ⁇ 10 5 /mL with cell culture medium, inoculated in a 96-well plate, 100 ⁇ L/well, and placed in a 35°C, 6% CO2 incubator for 20 hours;
  • composition containing compound 1 and compound 2 Dilute the composition containing compound 1 and compound 2 with DMEM containing 1% FBS according to the molar ratio of 1:1, so that the concentration of the composition is 200 ⁇ M, 60 ⁇ M, 20 ⁇ M, 6 ⁇ M, 2 ⁇ M, 0.6 ⁇ M, 0.2 ⁇ M, 0.06 ⁇ M, 0.02 ⁇ M;
  • the TCID50 when the concentration of the composition is 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M and 0 ⁇ M are 0, 0, 0, 0, 0, 10-2.58/mL, 10-3.87/mL, 10- 6.8/mL, at 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, and 1 ⁇ M, no virus was detected, and the proliferation of the virus could be completely inhibited.
  • the titer could be reduced by about 4.22 titers, and at 0.1 ⁇ M, the titer could be reduced by about 2.93 titers.
  • the TCID50 of 0.3 ⁇ M compound 2 or compound 1 administered alone was 10-5.07/mL and 10-3.84/mL, while the TCID50 of the composition of the present invention at 0.3 ⁇ M was 10-2.58/mL, which was 2.49% lower than that of compound 1 administered alone titer, which was 1.26 titer lower than compound 2 alone.
  • the TCID50 of 0.1 ⁇ M Compound 2 and Compound 1 administered alone were 10-5.596/mL and 10-4.67/mL, respectively, and the TCID50 of 0.1 ⁇ M Compound 1 was 10-3.87/mL, which was 3.016 units lower than that of Compound 1 administered alone The titer was 2.09 lower than that of compound 2 alone.
  • the antiviral effect of the composition of the present invention is obviously better than that of single administration, and has a significant synergistic effect.
  • the new deuterated cyano compounds target the protease of the virus, while the deuterated cytidine derivatives target the RNA polymerase of the virus. Combining drugs targeting different targets can solve the problem of drug resistance, thereby Improve drug safety.

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Abstract

一种由新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、以及氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐组成的药物组合物及其抗病毒用途。所述组合物的抗病毒效果明显优于单独给药，具有显著的协同增效效应，且还具有安全性高、耐药性低、毒副作用小等优点。

Description

一种具有协同增效效应的药物组合物及其其抗病毒用途 技术领域
本发明属于药物制剂领域，具体涉及由新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、以及氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐组成的药物组合物及其抗病毒用途。
背景技术
人体内的冠状病毒最早于1960年代在英国被分离出来，病毒因其表面皇冠状的突起物而得名。它可能与人、猪、猫、狗、鼠和鸡的呼吸系统感染相关。
SARS病毒属于套式病毒目、冠状病毒科、冠状病毒属，为β属B亚群冠状病毒。病毒粒子多呈圆形，有囊膜，外周有冠状排列的纤突,分布于细胞浆中，呈圆形，病毒直径在80～120nm之间。SARS是一种起病急、传播快、病死率高的传染病，被传染的病人多数都与患者直接或间接接触，或生活在流行区内。
MERS病毒是一种β属C亚群冠状病毒，全名为中东呼吸综合征冠状病毒(Middle East Respiratory Syndrome Coronavirus，简称MERS-CoV)，感染后引发中东呼吸综合征(Middle East Respiratory Syndrome，简称MERS)。MERS-CoV最早于2012年9月在沙特被发现，早期因与SARS临床症状相似得名“类SARS病毒”，也成为第6种已知的人类冠状病毒，也是过去10年内被分离出来的第3种。
新型冠状病毒SARS-CoV-2是以前从未在人体中发现的冠状病毒新毒株，2019年首次被发现并报道，至今仍然在全球多个国家流行肆虐，并在很多国家区域并未得到很好的控制。
人感染冠状病毒后常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等。在较严重病例中，感染可导致肺炎、严重急性呼吸综合征、肾衰竭，甚至死亡，而且目前对于新型冠状病毒所致疾病没有特异治疗方法。
新型氘代氰基类化合物是由上海谷森医药有限公司独自研发的一种小分子3CL蛋白酶抑制剂，其结构为：
Figure PCTCN2022084724-appb-000001
体外实验证实其具有优良的抗SARS-CoV-2活性，能有效抑制病毒的复制，该化合物在病毒抑菌活性相当的基础上，实现了比其他口服抗新冠药更优的药动学性质，上海谷森医药有限公司针对上述新型氘代氰基类化合物是申请了发明专利(申请号CN202111234708X)。
氘代胞苷衍生物也是由上海谷森医药有限公司独自研发的一种小分子新胞苷类抗病毒口服药物。该药物是一种SARS-CoV-2聚合酶抑制剂，体外实验证实，其具有很强的抗SARS-CoV-2活性，能有效抑制病毒的复制，化合物氘代胞苷衍生物的化学名为：((2R,3S,4R,5R)-3,4-二羟基-5-(4-(羟胺基)-2-氧代嘧啶-1(2H)-基)四氢呋喃-2-基)氘甲基异丁酯，其化学式为：
Figure PCTCN2022084724-appb-000002
并已申请了发明专利(申请号CN2021110245289)。
尽管新型氘代氰基类化合物和氘代胞苷衍生物在体外具有较好的抗病毒活性，但其安全性和耐药性有待提升。基于此，迫切需要开发切实有效的药物组合物，以改善药物的抗病毒活性、耐药性和安全性。而本发明公开的药物组合 物恰好解决了上述问题。
发明内容
本发明的目的是提供一种包含新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、以及氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐组成的药物组合物及其抗病毒用途。
一方面，本发明提供了一种药物组合物，其特征在于：由新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、以及氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐组成。
本发明涉及的新型氘代氰基类化合物结构如下：
Figure PCTCN2022084724-appb-000003
氘代胞苷衍生物的结构如下：
Figure PCTCN2022084724-appb-000004
本发明药学上可接受的盐包括相应化合物的有机盐和无机盐，可以是本领域技术人员所熟知的所有盐，优选但非限制性实例是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐等。
进一步地，化合物可以以前药的形式施用。前药可包含共价键合的载体，其施用于哺乳动物对象时释放活性母体药物。前药可以通过以这种方式修饰化合物中存在的功能基团使得修饰在例行操作中或在体内裂解为母体化合物。
本发明的溶剂化物是指一个或多个溶剂分子与本发明形成的缔合物，形成溶剂化物的溶剂包括但不限于水、异丙醇、乙醇、甲醇、二甲亚砜等。
本发明的异构体包括立体异构、互变异构体。
此外，本发明的化合物包括其晶体和非晶体形式，其中晶体包括单晶、多晶和共晶。
优选地，新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、与氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐的重量比为(100-300):(200-400)，优选地，它们的质量比为100：200、100：300、100：400、200：300、200：400、300：400。优选地，它们的质量比为200：300。
优选地，本文公开的药物组合物包含约100mg至约300mg新型氘代氰基类化合物和200mg-400mg氘代胞苷衍生物。优选地，药物组合物包含约200mg新型氘代氰基类化合物和200mg-300mg氘代胞苷衍生物，优选地，药物组合物包含约200mg新型氘代氰基类化合物和300mg氘代胞苷衍生物。
应当理解，本发明药物组合物可以在相同或不同药物组合物中同时给药，或者可按顺序给药，也即新型氘代氰基类化合物与氘代胞苷衍生物可以混合在一起形成单一的给药单元，也可以分别独立形成给药单元。如果是独立给药，给第二种活性组分的间隔时间不应当使活性组分联合所能产生的协同疗效的益处失去。优选新型氘代氰基类化合物与氘代胞苷衍生物分别独立形成给药单元。
所述组合物还包括药学上可接受的载体，所述载体由被认为是安全且有效的材料组成，并且可以对个体施用而不会引起不良的生物学副作用或不期望的相互作用。载体是药物制剂中存在的除活性成分以外的所有成分。如本文通常所使用的，“载体”包括但不限于调节剂、黏合剂、润滑剂、崩解剂、填充剂、 着色剂、增塑剂、膜衣材料、有机溶剂、增溶剂、调味剂、表面活性剂等。
稀释剂，也被称为“填充剂”，其通常是增加固体剂型的体积从而提供用于压制片剂或形成珠子和颗粒的实用大小所必需的。合适的稀释剂包括但不限于磷酸二钙二水合物、硫酸钙、乳糖、蔗糖、甘露醇、山梨糖醇、纤维素、微晶纤维素、高岭土、氯化钠、干淀粉、水解淀粉、预胶化淀粉、二氧化硅、氧化钛、硅酸铝镁和糖粉。
黏合剂被用于赋予固体剂型黏结性，从而确保剂型形成后片剂或珠子或颗粒保持完整。合适的黏合剂材料包括但不限于淀粉、预胶化淀粉、明胶、糖类(包括蔗糖、葡萄糖、右旋糖、乳糖和山梨糖醇)、聚乙二醇、蜡、天然树胶和合成树胶。
润滑剂用于促进片剂的制造。合适的润滑剂的实例包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸、山嵛酸甘油酯、聚乙二醇、滑石粉和矿物油。
崩解剂用于在施用后促进剂型崩解或“分解”，并且通常包括但不限于淀粉、淀粉乙醇酸钠、羧甲基淀粉钠、羧甲基纤维素钠、羟丙基纤维素、预胶化淀粉、黏土、纤维素、海藻酸盐、胶或交联的聚合物。
稳定剂用于抑制或延缓药物分解反应，例如包括氧化反应。
表面活性剂可以是阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂或非离子表面活性剂。合适的阴离子表面活性剂包括但不限于含有羧酸根、磺酸根和硫酸根离子的那些。阴离子表面活性剂的实例包括长链烷基磺酸和烷基芳基磺酸的钠盐、钾盐、铵盐，例如十二烷基苯磺酸钠；二烷基磺基琥珀酸钠。
典型的增塑剂的实例包括聚乙二醇、丙二醇、三醋精、邻苯二甲酸二甲酯、邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、癸二酸二丁酯、柠檬酸三乙酯、柠檬 酸三丁酯、乙酰柠檬酸三乙酯、蓖麻油和乙酰化的单甘油酯。
有机溶剂可以为醇类，如异丙醇，丙二醇，聚乙二醇，聚丙烯乙二醇，甘油和聚氧乙烯醇等。
可以配制本文所述的组合物以用于调节释放或控制释放。控释剂型的实例包括延长释放剂型、延迟释放剂型、脉冲释放剂型及其组合。
优选地，化合物或药物组合物通过口服施用、静脉内施用，口服包括片剂或者口服液。
另一方面，本发明提供一种药物组合物在制备用于治疗或预防病毒感染的药物中的用途，所述病毒可以为新冠病毒SARS-CoV-2、SARS冠状病毒、MERS冠状病毒、东部马脑炎病毒、西部马脑炎病毒、委内瑞拉马脑炎病毒、奇昆古尼亚热病毒、正黏病毒科病毒或副黏病毒科病毒、RSV病毒、甲型流感病毒和乙型流感病毒、埃博拉病毒。优选地，所述病毒为新冠病毒SARS-CoV-2、SARS冠状病毒和MERS冠状病毒。优选地，所述病毒为新冠病毒SARS-CoV-2。
本发明的药物组合物具有以下优点和有益效果：
(1)本发明所述药物组合物中的活性成分新型氘代氰基类化合物和氘代胞苷衍生物分别是由上海谷森医药有限公司独自研发的一种小分子3CL蛋白酶抑制剂和新胞苷类抗病毒口服药物，它们均展现出优异的抗病毒活性。
(2)本发明所述组合物的抗病毒效果明显优于单独给药，具有显著的协同增效效应，并降低了细胞毒性。
(3)新型氘代氰基类化合物针对的是病毒的蛋白酶，而氘代胞苷衍生物针对的是病毒的RNA聚合酶，将针对不同靶点的药物组合在一起可以解决耐药性问题，从而提高药物的安全性。
说明书附图
图1为药物组合物对细胞毒性的影响
图2为药物组合物的抗病毒活性
图3为药物组合物对比单独用药的细胞抗病毒活性
具体实施方式：
以下结合具体实施例对本发明做进一步详细的说明。
以下详细的说明都仅是示例性和解释性的，而非限制性的。
以下实施例，除非另外指出，否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
实施例1：新型氘代氰基类化合物(以下简称化合物1)的合成路线
Figure PCTCN2022084724-appb-000005
1)中间体H、K、M的制备方法可参见发明人在先申请CN202111234708.X。
2)新型氘代氰基类化合物(以下简称化合物1)的合成
在室温下，将M(8g，21.1mmol)溶于THF(80ml)和MeOH(80ml)中。加入氢氧化锂(1.5g，62.8mmol)的水溶液(15ml)，室温搅拌2小时。调温至0-10℃，加入乙酸乙酯后使用1N HCl调反应液至酸性，分层，水相使用EA萃取两次，合并有机相后无水硫酸镁干燥，浓缩至干得到粗品，柱层析纯化得到M水解化合物。
将上一步所得的水解化合物和DMF(100ml)投入反应瓶中，调温至0-10℃。在此温度下，依次加入EDCI(4.9g，25.6mmol)，HOBt(3.4g，25.2mmol)，NMM(4.3g，42.5mmol)，并在此温度下搅拌30分钟。在此温度下，分批加入H(4.0g，21mmol)，加完后在室温下搅拌过夜。TLC检测反应转化基本完全，加入水(80ml)后用EA萃取三次，合并有机相，依次使用0.5mol/L HCl，5％NaHCO3，水洗涤，无水硫酸镁干燥，浓缩至干得到粗品1，柱层析得到类白色固体产物8.4g，即新型氘代氰基类化合物(以下简称化合物1)。
实施例2：氘代胞苷衍生物(以下简称化合物2)的合成路线
Figure PCTCN2022084724-appb-000006
具体操作步骤可参见发明人在先申请CN202111479537.7。
实施例3：细胞毒性试验
试验方法：
1)将Vero-E6细胞进行消化传代，用含10％FBS的DMEM调整细胞密度为1×10 5个细胞/mL接种96孔板，100μL/孔，放置于温度为35℃、6％CO2培养箱培养20h；
2)将孔中的培养基去除，1×PBS洗涤2次，甩干后加入含1％FBS的DMEM，同时加入实施例1-2所述新型氘代氰基类化合物(以下简称化合物1)和氘代胞苷衍生物(以下简称化合物2)(摩尔比为1：1)，使孔内组合物的终浓度为1000μM、300μM、100μM、30μM，设置细胞对照组，放置于35℃、6％CO2培养箱培养；
3)48h后，用CCK8试剂盒进行细胞活力检测。
试验结果：
结果见图1。由图可知，该组合物对Vero-E6细胞的毒性作用小，其CC50 大于100μM。
实施例4：体外抗病毒活性EC 50试验
试验方法：
1)将Vero-E6细胞进行消化传代，用含10％FBS的DMEM调整细胞密度为1×10 5个细胞/mL接种于96孔板，100μL/孔，放置于35℃、6％CO2培养箱培养20h；
2)用含1％FBS的DMEM按照1:1的摩尔比稀释包含化合物1和化合物2的组合物，使组合物浓度为200μM、60μM、20μM、6μM、2μM、0.6μM、0.2μM、0.06μM、0.02μM；
3)弃去孔中培养基，并在96孔板盖子上做好标记，1×PBS洗三次，按序每孔加入100μL稀释好的组合物，接着每孔加入100μL 0.01MOI病毒液，使组合物的终浓度为100μM、30μM、10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM，设置细胞对照组和病毒对照组，放置于35℃、6％CO2培养箱培养；
4)48h后，用CCK8试剂盒进行细胞活力检测。
试验结果：
结果见表1。本发明的组合物半数最大效应浓度(EC50)为：0.241μM，显著低于单独使用化合物1(1.716μM)与化合物2(1.563μM)。
表1 药物组合物体外抗病5毒活性(EC50)对比
组别 EC50(μM)
化合物2 1.716±0.585μM
化合物1 1.563±0.576μM
化合物1+化合物2 0.241±0.084μM
实施例5：抗病毒活性(TCID 50)的测定
试验方法：
1)将Vero-E6细胞进行消化传代，用细胞培养液调整细胞密度为1×10 5/mL接种96孔板，100μL/孔，放置于35℃、6％CO2培养箱培养20h；
2)用含1％FBS的DMEM按照按照1:1的摩尔比稀释包含化合物1和化合物2的组合物，使组合物浓度分别为200μM、60μM、20μM、6μM、2μM、0.6μM、0.2μM、0.06μM、0.02μM；
3)弃去96孔板孔中培养基，用1×PBS洗三次，每孔对应加入100μL已经稀释好的组合物，每孔接种100μL 0.01MOI的病毒，使组合物的终浓度为100μM、30μM、10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM，于35℃、6％CO2培养箱培养；
4)约80h后，收集每孔上清测毒价。
试验结果：
由图2可知，病毒毒价随着组合物浓度增加而降低。组合物浓度大于0.3μM时抑制效果最明显。组合物浓度为100μM、30μM、10μM、3μM、1μM、0.3μM、0.1μM、0μM时的TCID50分别为0、0、0、0、0、10-2.58/mL、10-3.87/mL、10-6.8/mL，在100μM、30μM、10μM、3μM、1μM时，没有检测到病毒，能完全抑制病毒的增殖，0.3μM时可以降低约4.22个滴度，0.1μM时可以降低约2.93个滴度。
组合物与单独用药的比较结果见图3。单独用药0.3μM化合物2或化合物1的TCID50分别为10-5.07/mL、10-3.84/mL，而本发明组合物0.3μM的TCID50为10-2.58/mL，组合物较化合物1单独用药降低2.49个滴度，较化合物2单独用药降低1.26个滴度。单独用药0.1μM化合物2和化合物1的 TCID50分别为10-5.596/mL、10-4.67/mL，组合物0.1μM的TCID50为10-3.87/mL，组合物相较于化合物1单独用药降低3.016个滴度，较化合物2单独用药降低2.09个滴度。
综上，本发明所述组合物的抗病毒效果明显优于单独给药，具有显著的协同增效效应。此外，新型氘代氰基类化合物针对的是病毒的蛋白酶，而氘代胞苷衍生物针对的是病毒的RNA聚合酶，将针对不同靶点的药物组合在一起可以解决耐药性问题，从而提高药物的安全性。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种药物组合物，其特征在于：由新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、以及氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐组成；
    其中，新型氘代氰基类化合物的结构如下：
    Figure PCTCN2022084724-appb-100001
    氘代胞苷衍生物的结构如下：
    Figure PCTCN2022084724-appb-100002
  2. 根据权利要求1所述的药物组合物，其特征在于：新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、与氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐的重量比为(100-300)mg:(200-400)mg。
  3. 根据权利要求2所述的药物组合物，其特征在于：新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、与氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐的重量比为200mg：300mg。
  4. 根据权利要求1-3任一项所述的药物组合物，其特征在于：还包括一种或多种药学上可接受的载体。
  5. 根据权利要求4所述的药物组合物，其特征在于：药学上可接受的载体包括调节剂、黏合剂、润滑剂、崩解剂、填充剂、着色剂、增塑剂、膜衣材料、 有机溶剂、增溶剂、调味剂。
  6. 根据权利要求1-5任一项所述的药物组合物，其特征在于：新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、与氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐可以混合在一起形成单一的给药单元，也可以分别独立形成给药单元。
  7. 根据权利要求6所述的药物组合物，其特征在于：新型氘代氰基类化合物或其异构体或其前药或其溶剂化物或其药学上可接受的盐、与氘代胞苷衍生物或其异构体或其前药或其溶剂化物或其药学上可接受的盐分别独立形成给药单元。
  8. 权利要求1-7任一项所述药物组合物在制备抗新冠病毒SARS-CoV-2、SARS冠状病毒、MERS冠状病毒、甲型流感病毒和乙型流感病毒、东部马脑炎病毒、西部马脑炎病毒、委内瑞拉马脑炎病毒、奇昆古尼亚热病毒、正黏病毒科病毒或副黏病毒科病毒、RSV病毒、埃博拉病毒的药物中的用途。
  9. 根据权利要求8所述的用途，其特征在于：病毒为新冠病毒SARS-CoV-2、SARS冠状病毒和MERS冠状病毒、甲型流感病毒和乙型流感病毒。
  10. 根据权利要求9所述的用途，其特征在于：病毒为新冠病毒SARS-CoV-2。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210252033A1 (en) * 2020-02-07 2021-08-19 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
CN113735928A (zh) * 2021-10-21 2021-12-03 药康众拓(江苏)医药科技有限公司 一种n4-羟基胞苷衍生物及其制备方法和用途
CN113929724A (zh) * 2021-11-02 2022-01-14 周雨恬 一种核苷类化合物及其药物组合物和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210252033A1 (en) * 2020-02-07 2021-08-19 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
CN113735928A (zh) * 2021-10-21 2021-12-03 药康众拓(江苏)医药科技有限公司 一种n4-羟基胞苷衍生物及其制备方法和用途
CN113929724A (zh) * 2021-11-02 2022-01-14 周雨恬 一种核苷类化合物及其药物组合物和用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DAMPALLA CHAMANDI S., ZHENG JIAN, PERERA KRISHANI DINALI, WONG LOK-YIN ROY, MEYERHOLZ DAVID K., NGUYEN HARRY NHAT, KASHIPATHY MAIT: "Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 118, no. 29, 20 July 2021 (2021-07-20), pages e2101555118, XP093082965, ISSN: 0027-8424, DOI: 10.1073/pnas.2101555118 *
LI, PENGFEI ET AL.: ""SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination"", CELL RESEARCH, vol. 32, 20 January 2022 (2022-01-20), XP037706409, DOI: 10.1038/s41422-022-00618-w *
VANGEEL, L. ET AL.: ""Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern"", ANTIVIRAL RESEARCH, vol. 198, 24 January 2022 (2022-01-24), XP086953055, DOI: 10.1016/j.antiviral.2022.105252 *

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