WO2003089448A1 - Ester d'ibuprofene-ribavirine, procede d'elaboration et utilisation - Google Patents

Ester d'ibuprofene-ribavirine, procede d'elaboration et utilisation Download PDF

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Publication number
WO2003089448A1
WO2003089448A1 PCT/CN2003/000292 CN0300292W WO03089448A1 WO 2003089448 A1 WO2003089448 A1 WO 2003089448A1 CN 0300292 W CN0300292 W CN 0300292W WO 03089448 A1 WO03089448 A1 WO 03089448A1
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Prior art keywords
ibuprofen
ribavirin
triazole
type
riboside
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PCT/CN2003/000292
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English (en)
French (fr)
Inventor
Hualu Wang
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Hualu Wang
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Priority claimed from CN 02109536 external-priority patent/CN1379037A/zh
Application filed by Hualu Wang filed Critical Hualu Wang
Priority to AU2003236149A priority Critical patent/AU2003236149A1/en
Publication of WO2003089448A1 publication Critical patent/WO2003089448A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to a phenylpropionate derivative of a nucleoside and a preparation method and application thereof, and more particularly, to a ibuprofen triazole riboside ester and a preparation method and application thereof.
  • Glycosides are used for anti-inflammatory, antipyretic, analgesic and antiviral. Background technique
  • Antipyretic and analgesics commonly used in clinical practice are mainly paracetamol, aspirin, ibuprofen, and traditional antipyretic and analgesic drugs such as annaimicin, antipyrine, phenacetin, and aminopyrine. Because of its toxic and side effects are gradually withdrawing from this rank. Due to its toxicity, phenacetin has been rarely used in developed countries. Aminopyrine is used less and less because of its damage to hematopoietic granulocytes, which can cause aplastic anemia. Parkresh pain has a strong antipyretic and analgesic effect, but it does not have an anti-inflammatory effect. Usually, while using Parkresh Pain, other anti-inflammatory drugs must be added.
  • ibuprofen is surpassing aspirin, and is expected to replace Parkrexam as the drug of choice, due to its strong antipyretic and analgesic effects and fewer side effects.
  • Ibuprofen is an arylpropionic acid and was initially marketed as a non-steroidal anti-inflammatory drug. In recent years, it has been increasingly used in the treatment of fever and pain caused by inflammation and infection due to foreign countries. Western European countries such as the United Kingdom have replaced Parkrexam as the drug of choice for this indication, and there is also a trend to replace Parkrexam in the United States. China also has many single or compound preparations based on ibuprofen for antipyretics. Pain. For fever and pain caused by the virus, ibuprofen alone is not enough. Other antiviral drugs are also needed.
  • the ⁇ carbon connected to the carboxyl group is a chiral carbon and can have two configurations, R and S.
  • Compounds that can have this general structural formula can have three optical isomers, namely R-cloth Ibuprofen, a mixture of S-ibuprofen, R-ibuprofen and S-ibuprofen include the racemic ibuprofen.
  • Ibuprofen is currently used as a medicinal active ingredient, two of which are racemic ibuprofen and ibuprofen with chiral carbon in the S configuration. Among them, the racemic ibuprofen is the most commonly used, and the S configuration of ibuprofen is less commonly used.
  • Viruses are the smallest of pathogenic microorganisms.
  • the core is a nucleic acid and the shell is a protein. Has a cellular structure. According to its core composition, it can be divided into two types, a type of DNA virus and a type of RNA virus.
  • RNA viruses There are many types of RNA viruses, RNA viruses, which can cause a variety of diseases, such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever and so on.
  • RNA viruses which can cause a variety of diseases, such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever and so on.
  • drugs used for anti-RNA virus such as virin, amantadine, ribavirin and so on. Due to the uncertainty of its efficacy, Wei Lin Ling has been rarely used clinically.
  • Ribavirin is a monophosphate hypoxanthine dehydrogenase inhibitor, which can block the synthesis of viral nucleic acids, has a broad-spectrum antiviral effect, and is effective against influenza, adenoviral pneumonia, measles, herpes, liver dysentery, epidemic bleeding Fever has clinical effects and is widely used.
  • ester compounds There are many methods for preparing ester compounds, and different preparation methods are used according to different acid and alcohol reactants.
  • the object of the present invention is to provide an anti-inflammatory, analgesic, antipyretic and antiviral pharmacological effect, for treating flu, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other diseases, high fever and pain, etc.
  • Yet another object of the present invention is to provide a method for treating a disease selected from the group consisting of influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other diseases and high fever pain, including administering to a patient to be treated Drug ibuprofen triazole riboside compound.
  • Another object of the present invention is to provide a pharmaceutical composition for the use of ibuprofen ribavirin in the treatment of symptoms such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other symptoms, and high fever and pain.
  • symptoms such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other symptoms, and high fever and pain.
  • the present invention relates to a ibuprofen triazolyl ester, which has the structural formula:
  • the present invention also relates to a method for preparing the ibuprofen triazoloside described above, which comprises mixing 2- (4'-isobutylphenyl) -propionyl chloride and ribavirin in a basic organic solvent such as pyridine Made in the reaction.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising ibuprofen ribavirin and a pharmaceutically acceptable carrier thereof.
  • the present invention relates to a method for treating a disease selected from the group consisting of influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other diseases, including high fever pain.
  • a disease selected from the group consisting of influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other diseases, including high fever pain.
  • a disease selected from the group consisting of influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other diseases, including high fever pain.
  • a disease selected from the group consisting of influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other diseases, including high fever pain.
  • ibuprofen ribavirin Of patients were administered ibupro
  • the present invention relates to the preparation of ibuprofen ribavirin for the treatment of symptoms such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other symptoms and high fever pain.
  • symptoms such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other symptoms and high fever pain.
  • symptoms such as influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever, hepatitis A and other symptoms and high fever pain.
  • the ibuprofen ribavirin of the present invention has a structure of the following general formula I:
  • the molecular formula is C 21 H 28 N 4 0 6 and the molecular weight is 432.48.
  • the ibuprofen triazole riboside is a combination of ibuprofen and ribavirin, which is characterized by the OH on ibuprofen The root is replaced with ribavirin. At the same time, the ribavirin loses one H.
  • the ibuprofen ribavirin ester of the present invention is made up of the structure of ibuprofen and ribavirin through a carbonyl group (-CO) and an oxy group (0).
  • the optical characteristics of the ibuprofen triazole riboside structure are the same as the optical characteristics of the ibuprofen and ribavirin structure, that is, the structural properties of the ibuprofen triazole riboside include ibuprofen Characteristics of the Fen Structure and Ribavirin Structure.
  • the ⁇ -carbon linked to the carbonyl group in the ibuprofen ribavirin structure of the present invention is a chiral carbon and may have two configurations of R and S.
  • the ibuprofen triazole riboside in the present invention includes R-ibuprofen triazole riboside 10 glycoside ester, S-ibuprofen triazole riboside, R-ibuprofen triazole riboside And S-ibuprofen ribavirin (including racemic ibuprofen ribavirin) and other optical isomers.
  • racemic ibuprofen triazolidine riboside refers to a compound of ibuprofen triazole riboside that has a chiral carbon atom adjacent to the benzene ring of R-type and S-type. An equal amount of mixture, 15 is hereinafter referred to as "racemic ibuprofen ribavirin.”
  • the racemic ibuprofen triazole riboside can be obtained, for example, by reacting the acid chloride of racemic ibuprofen with ribavirin.
  • the present invention may adopt the reaction of ibuprofen's acid chloride with ribavirin, that is, 2- (4'-isobutylbenzene) Group)-propionyl chloride reacts with ribavirin.
  • 2-. (4 '-. Isobutylphenyl) -propionyl chloride can be prepared from ibuprofen and thionyl chloride under reflux by methods known in the art.
  • the chemical reaction characteristics of the carboxyl group of S-type ibuprofen are similar to those of the mixture of R-type ibuprofen and S-type ibuprofen (including the racemic ibuprofen).
  • S-type ibuprofen triazole riboside can be prepared by reacting S-type 2- (4'-isobutylphenyl) -propionyl chloride with ribavirin in basic hydrolysis, such as pyridine, and further Made into a medicinal dosage form.
  • S-type ibuprofen ribavirin has a structure of the following general formula 11:
  • the S-type 2- (4'-isobutylphenyl) -propionyl chloride used in the above reaction can be prepared by refluxing S-type ibuprofen and sulfoxide in benzene.
  • the raw materials used in the preparation of the ibuprofen triazole riboside can be 2- (4'-isobutylphenyl) -propionyl chloride and triazole riboside, where 2- (4'- Isobutylphenyl) -propionyl chloride can be a mixture of R-type and S-type 2- (4'-isobutylphenyl) -propionyl chloride (including 2- (4'-isobutylphenyl) -propionyl chloride racemic Body), or a single S-type 2- (4'-isobutylphenyl) -propionyl chloride.
  • the raw materials used in the preparation of the compound of the present invention may be ibuprofen, sulfoxide, and ribavirin, where ibuprofen may be a mixture of S and R-type ibuprofen Rotobuprofen) or a single S-type ibuprofen.
  • the chemical reaction in the preparation process of the present invention is as follows:
  • the reaction temperature of the reaction between 2- (4'-isobutylphenyl) -propionyl chloride and ribavirin is preferably 0 ° C to 30 ° C, and more preferably 0 ° C to 10 C.
  • the molar ratio of the two reactants is preferably 1: 1 to 2, and more preferably 1: 1.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formulae 1 and II and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention may be in the form of solid preparations such as tablets, capsules, granules, and the like, and liquid preparations such as solutions and injections.
  • the pharmaceutical composition may be administered orally,
  • composition of the present invention is in the form of a liquid formulation, it preferably includes a co-solvent, which includes, but is not limited to, polyethylene glycol, diamidinofluoramide, difluorenylsulfoxide, and the like.
  • a co-solvent includes, but is not limited to, polyethylene glycol, diamidinofluoramide, difluorenylsulfoxide, and the like.
  • the pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are well known in the art and include, but are not limited to, such as fillers, lubricants, disintegrants, and adhesives.
  • the pharmaceutical composition of the present invention may also contain other active ingredients such as antihistamine drugs, nasal mucosal decongestants, antitussives, and the like.
  • the pharmaceutical composition according to the present invention may further contain another active ingredient such as pseudoephedrine, puermin, dextromethorphan hydrobromide, etc., which has a synergistic activity with the compounds of the general formulae I and II of the present invention.
  • another active ingredient such as pseudoephedrine, puermin, dextromethorphan hydrobromide, etc.
  • the compounds of the general formulae I and II according to the present invention have anti-inflammatory, antipyretic, analgesic and antiviral effects, and can be made into pharmaceutical dosage forms for oral, intravenous administration, subcutaneous intramuscular injection or external application.
  • the compounds and pharmaceutical compositions of the present invention are capable of treating influenza, common cold, measles, herpes, adenoviral pneumonia, hemorrhagic fever and liver dysentery.
  • the carboxyl group of ibuprofen exists in the form of an ester, which reduces the damage to the organism, which is manifested in the reduction of its acute toxicity, that is, the half lethal dose (LI) 5 () ) Zenglikou.
  • the modified Rundall Selitto method was used to study the analgesic effect of the racemic ibuprofen ribavirin ribose ester of general formula I in the present invention on rats: three groups of rats, eight in each group, and a control group, The positive control group used racemic ibuprofen (30 mg / kg body weight), and the experimental group used racemic ibuprofen ribavirin (63 mg / kg body weight).
  • the results show that the analgesic effect of the racemic ibuprofen ribavirin ribose esters of the general formula I is similar to that of the ibuprofen racemate.
  • the antipyretic effect of the racemic ibuprofen ribavirin ribozylate according to the present invention was studied by a rat yeast fever test: three groups of rats, eight in each group, and a control group and a positive control group Racemic ibuprofen (30 mg / kg body weight) was used, and the experimental group used racemic ibuprofen ribavirin (63 mg / kg body weight).
  • the results show that the antipyretic effect of the racemic ibuprofen ribavirin ester of the general formula I is similar to that of the racemic ibuprofen.
  • the anti-inflammatory effect of the racemic ibuprofen ribavirin ribose ester of the general formula I according to the present invention was tested using the carrageenan edema method in rats: three groups of eight rats, Control group The group used racemic ibuprofen (30 mg / kg body weight) and the experimental group used racemic ibuprofen ribavirin (63 mg / kg body weight). The results show that the anti-inflammatory effect of the racemic ibuprofen ribavirin is similar to that of the ibuprofen racemate.
  • the modified Rundall Selitto method was used to study the analgesic effect of the compound of the general formula II of the present invention on rats: three groups of rats, eight in each group, with a control group, and the positive control group was given S-type ibuprofen (30 Mg / kg body weight), and the experimental group was administered a compound of the general formula II of the present invention (63 mg / kg body weight).
  • the results show that the analgesic effect of the compound of the general formula II of the present invention is similar to that of S-type ibuprofen.
  • the rat yeast fever test was used to study the antipyretic effect of the compound of the general formula II of the present invention: three groups of rats, eight in each group, with a control group, and a positive control group was given S-type ibuprofen (30 mg / kg Body weight); The experimental group was given a compound of Formula II according to the present invention (63 mg / kg body weight). The results show that the compound of the general formula II of the present invention has an antipyretic effect similar to that of S-type ibuprofen.
  • the anti-inflammatory effect of the compound of the general formula II described in the present invention was studied by rat foot carrageenan edema method: three groups of rats, eight in each group, a control group, and a positive control group was given S-type bromide Fen (30 mg / kg body weight); the experimental group was given a compound of general formula II (63 mg / kg body weight). The results show that the anti-inflammatory effect of the compound of formula II is similar to that of S-type ibuprofen.
  • mice The acute toxicity test in mice shows that the damage of the ibuprofen ribavirin to the organism is reduced.
  • 100 healthy mice weighing 18-22 grams were randomly divided into 10 groups.
  • the test drugs were: racemic ibuprofen ribavirin, and an equimolar mixture of ibuprofen racemate and Ribavirin (206: 244 weight ratio).
  • Five dose groups of each test drug were administered orally.
  • the test results showed that the racemic ibuprofen triazole riboside LD 5 was the dead weight. It was 3592 mg / kg body weight.
  • the equimolar LD 50 of the racemic mixture of ibuprofen and ribavirin was 2683 mg / kg body weight.
  • the in vitro anti-viral test of the compounds of the general formulae I and II of the present invention shows that its antiviral effect is similar to ribavirin.
  • the dose of ribavirin in the control group was 50mg / kg.day, and the dose of racemic ibuprofen ribavirin in the test group was 35mg. /kg.day, for five consecutive days, the inhibition rate in the control group was 22.5%, and the test group was 25%.
  • the activity of the ibuprofen ribavirin-resistant influenza virus-adapted strain of the general formula I of the present invention is better than that of the control group. Examples
  • the resulting insoluble matter was dissolved in ethyl acetate, and the resulting ethyl acetate solution was washed with 0.01 N diluted hydrochloric acid, and then washed with saturated sodium chloride solution to neutrality, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue. Recrystallization from ethyl acetate to obtain the racemic ibuprofen triazolium riboside compound according to the present invention.
  • the melting point determined by capillary method is: 169-172 ° C.
  • Elemental analyzer determination (, H, N content were C: 58.30%, H: 6.52%, N: 12.93%.
  • KBr tablet was used to measure the infrared spectrum, and there was a strong absorption peak at 1733.
  • Example 1 "the acidification of the reaction solution to a slightly acidic pH (3.5-4.5) with a cold hydrochloric acid solution” was performed as follows:
  • the resulting insoluble matter was recrystallized from ethanol to obtain a racemic ibuprofen triazole riboside compound of the general formula I according to the present invention.
  • the melting point was 179-181 C as measured by the capillary method.
  • Example 3 In a reaction flask equipped with a condenser with a drying tube, a thermometer and a stirring device, add 300 ml of benzene and 20.6 g of S-type ibuprofen. After it is completely dissolved, add 50 ml of sulfoxide and heat to reflux to maintain the reaction temperature. Benzene and unreacted sulfoxide were distilled off under reduced pressure at 80-82 ° C for 4 hours, and the resulting (S) -2- (4'_isobutylphenyl) -propionyl chloride was cooled and dried with 50 ml of water. Pyridine was mixed and cooled to room temperature.
  • the resulting insoluble matter is recrystallized from ethanol to obtain a compound of the general formula II according to the present invention.
  • the melting point determined by the capillary method is 177-] 8rC, and the specific rotation is [a] D 2 () -2.4 80 mg / nil dimethylformamide solution.
  • the contents of (, H, and N determined by elemental analyzer are: C: 58.38%, II: 6.53%, N: 12.97%.
  • the infrared spectrum of KBr tablet has a strong absorption peak at 1732.
  • DMSO is a solvent and 500MHz NMR Resonance measurement of hydrogen spectrum, chemical shift results are as follows:
  • a pharmaceutical composition containing a compound of the general formulae I and II of the present invention is formulated using the components described below:
  • the mixture of ibuprofen ribavirin, starch, and low-substituted hydroxypropyl cellulose of the present invention is sieved, and a soft material is made with 15% starch slurry, and granulated through an 18-mesh sieve, 70-80 degrees After drying, add talc and magnesium stearate to make 1000 tablets.

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Description

布洛芬三氮唑核苷酯及
制备方法和用途 技术领域
本发明涉及核苷的苯丙酸酯衍生物及其制备方法和用途， 更具体地说， 涉及布洛芬三氮唑核苷酯及其制备方法和用途， 所述布洛芬三氮唑核苷酯 用于抗炎解热镇痛和抗病毒。 背景技术
临床上常用的解热镇痛药主要有朴热息痛、 阿司匹林、 布洛芬等， 传 统的象安乃近、 安替比林、 非那西丁、 氨基比林类等解热镇痛药物， 因其 毒副作用正逐渐退出这一行列。 非那西丁因为有毒性， 在发达国家已经很 少使用， 氨基比林类因其对造血粒细胞的损伤， 如可引起再生障碍性贫血， 使用越来越少。 朴热息痛有较强的解热镇痛作用， 但不具有抗炎作用， 通 常在使用朴热息痛的同时， 还要加进其它抗炎药物。 阿司匹林则有较强的 消化系统和抗凝血副作用， 也不是非常理想的解热镇痛药物。 布洛芬作为 这一领域的新军， 正在超越阿司匹林， 并且有望取代朴热息痛成为首选药 物， 因其较强的解热镇痛作用、 较少的副作用受到人们的日益重视。 布洛 芬 (Ibuprofen)是一种芳基丙酸类药物， 最初作为一种非留体抗炎药上市。 近 年来因国外已经越来越多地将其应用于由炎症及感染引起的发热疼痛等方 面的治疗。 在英国等西欧国家已取代朴热息痛成为此适应症的首选药物， 在美国也有取代朴热息痛的趋势， 中国也有很多以布洛芬为主药的单方或 复方制剂用于解热镇痛方面。 对于由病毒引起的发热疼痛， 光使用布洛芬 是不够的， 还要使用其它抗病毒类药物。
从布洛芬的结构式看， 与羧基相连的 α碳是个手性碳， 可以有 R、 S两 种构型， 可以具有这一通用结构式的化合物可以有三种光学异构体存在， 即 R-布洛芬， S-布洛芬， R-布洛芬和 S-布洛芬的混合物包括外消旋体布洛 芬。 目前作为药用活性成分的布洛芬为其中的两种， 即外消旋体布洛芬和 手性碳为 S构型的布洛芬。 其中， 以外消旋体布洛芬为最常用的， S构型的 布洛芬较少用。
病毒是病原微生物中最小的一种， 其核心是核酸， 外壳是蛋白质， 不 具有细胞结构。 按其核心组成可分为两类， 一类 DNA型病毒， 一类 RNA 病毒。 RNA病毒即核糖核酸型病毒有很多种， 相应地可引起多种疾病， 如 流感、 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热等等。 临床上用于抗 RNA病毒的药物不多， 有病毒灵、 金刚烷胺、 三氮唑核苷等。 病毒灵因其 疗效的不确定性， 临床上已经很少使用。 金刚烷胺因其抗病毒谱较窄， 仅 对亚洲 A-III型流感病毒起作用， 使其使用范围很窄。 三氮唑核苷为一种单 磷酸次黄嘌呤脱氢酶抑制剂， 能阻碍病毒核酸的合成， 有广谱抗病毒作用， 对流感、 腺病毒肺炎、 麻疹、 疱疹、 曱肝、 流行性出血热均有临床疗效， 被广泛应用。
酯类化合物的制备有很多种方法， 根据不同的酸和醇反应物， 采用不 同的制备方法。
本发明的目的是提供一种既具有抗炎、 镇痛、 解热作用又具有抗病毒 药学作用， 治疗流感、 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热、 甲 肝等疾病和高烧疼痛等症状的酯类化合物， 即布洛芬三氮唑核苷酯。
本发明的另一目的是提供布洛芬三氮唑核苷酯化合物的制备方法。 本发明的另一个目的是提供一种药物组合物， 该药物组合物包含布洛 芬三氮唑核苷酯及其可药用的载体。
本发明的再一个目的是提供一种治疗疾病的方法， 所述疾病选自流感、 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热、 甲肝等疾病和高烧疼痛， 包括给待治的患者给药布洛芬三氮唑核苷酯化合物。
本发明的再一个目的是提供布洛芬三氮唑核苷酯在制备用于治疗流 感、 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热、 甲肝等疾病和高烧疼 痛等症状的药物组合物中的用途。 发明内容
本发明涉及一种布洛芬三氮唑苷酯， 其结构式为
Figure imgf000003_0001
2
替换页（细则第 26条) 本发明还涉及上文所述的布洛芬三氮唑苷酯的制备方法， 包括将 2- (4'- 异丁苯基)-丙酰氯与三氮唑核苷在碱性有机溶剂如吡啶中反应制得。
根据本发明的另一方面， 本发明涉及一种药物组合物， 该药物组合物 包含布洛芬三氮唑核苷酯及其可药用的载体。
根据本发明的再一方面， 本发明涉及一种治疗疾病的方法， 所述疾病 选自流感、 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热、 甲肝等疾病和 高烧疼痛， 包括给待治的患者给药布洛芬三氮唑核苷酯化合物。
根据本发明的再一方面， 本发明涉及布洛芬三氮唑核苷酯在制备用于 治疗流感、 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热、 甲肝等疾病和 高烧疼痛等症状的药物组合物中的用途。 具体实施方式
尽管本发明的权利要求书具体指出并明确要求了本发明的保护范围， 但是根据下文的详细描述能够更好地理解本发明。
布洛芬三氮唑核苷酯的一般描述
本发明的布洛芬三氮唑核苷酯具有如下通式 I的结构：
(】 ）
Figure imgf000004_0001
分子式为 C21H28N406， 分子量为 432.48。
从本发明布洛芬三氮唑核苷酯的结构式可以看出， 布洛芬三氮唑核苷 酯是由布洛芬和三氮唑核苷化合而成，其特征是布洛芬上的 OH根被三氮唑 核苷所取代， 取代的同时三氮唑核苷失掉一个 H。
为便于
Figure imgf000004_0002
3
替换页（细则第 26条) 其中（1 )为布洛芬的结构式， （2)为三氮唑核苷的结构式， 布洛芬取代三氮唑 核苷中的 H , 或者三氮唑核苷取代布洛芬中的 OH , 就构成了本发明的布洛 芬三氮唑核苷酯。
本发明的布洛芬三氮唑核苷酯是由布洛芬的结构和三氮唑核苷结构通 5 过羰基 (-CO)和氧基 (0)连接而成的。 布洛芬三氮唑核苷酯结构上的光学特 性与布洛芬和三氮唑核苷结构的光学特性相同， 也就是说布洛芬三氮唑核 苷酯结构上的特性包含了布洛芬结构和三氮唑核苷结构的特性。 具体说， 本发明的布洛芬三氮唑核苷酯结构中与羰基相连的 α碳是一个手性碳， 可 以有 R、 S 两种构型。 本发明的布洛芬三氮唑核苷酯以 R-布洛芬三氮唑核 1 0 苷酯、 S-布洛芬三氮唑核苷酯、 R-布洛芬三氮唑核苷酯和 S-布洛芬三氮唑 核苷酯的混合物（包括外消旋布洛芬三氮唑核苷酯）等光学异构体的形式存 在。
本发明中所用的术语 "外消旋布洛芬三氮唑核苷酯" 是指与苯环相邻 的手性碳原子为 R型和 S型的布洛芬三氮唑核苷酯化合物的等量混合物， 1 5 下文称为 "外消旋布洛芬三氮唑核苷酯"。 该外消旋布洛芬三氮唑核苷酯例 如可以由外消旋布洛芬的酰氯与三氮唑核苷反应而得到。 布洛芬三氮唑核苷酯的制备方法
由于布洛芬的酸性较弱， 不能直接同醇发生酯化反应， 因此本发明可 20 以采取用布洛芬的酰氯同三氮唑核苷反应， 即用 2-(4'-异丁苯基) -丙酰氯同 三氮唑核苷反应。
其中， 2-.(4'-.异丁苯基) -丙酰氯可通过本领域公知的方法， 由布洛芬和 氯化亚砜在笨中回流制得。
S型布洛芬的羧基的化学反应特性与 R型布洛芬和 S型布洛芬的混合 25 物（包括布洛芬外消旋体)的羧基的化学反应特性是类似的。
S型布洛芬三氮唑核苷酯可以由 S型 2-(4'-异丁苯基) -丙酰氯与三氮唑 核苷在碱性溶削如吡啶中反应制得， 并可进一步制成可供药用的剂型。 S型 布洛芬三氮唑核苷酯具有如下通式 11的结构：
?0
Figure imgf000006_0001
分子式 C21H28N406， 分子量为 432.48。
从这一结构中可以看出通式 1和 II的化合物的差别在于 C*的构型， 通 式 I的化合物为 R型和 S型布洛芬三氮唑核苷酯的混合物（包括外消旋布洛 芬三氮唑核苷酯)， 通式 II为 S型布洛芬三氮唑核苷酯。
在上述反应中所用的 S型 2-(4'-异丁苯基) -丙酰氯可由 S型布洛芬和氯 化亚砜在苯中回流制得。
在制备本发明的布洛芬三氮唑核苷酯的过程中所用的原料可以是 2- (4'- 异丁苯基)-丙酰氯和三氮唑核苷，其中 2-(4'-异丁苯基)-丙酰氯可以是 R型和 S 型 2-(4'-异丁苯基) -丙酰氯的混合物（包括 2- (4'-异丁苯基)-丙酰氯外消旋 体)， 也可以是单一的 S型 2- (4'-异丁苯基) -丙酰氯。
另一方面， 本发明的化合物制备过程中所用的原料可以是布洛芬、 氯 化亚砜和三氮唑核苷， 其中布洛芬可以是 S和 R型布洛芬的混合物（包括外 消旋体布洛芬）， 也可以是单一的 S型布洛芬。
由 R型和 S型 2-(4'-异丁苯基) -丙酰氯的混合物和三氮唑核苷制得的或 由 R型和 S型布洛芬的混合物、 氯化亚砜和三氮唑核苷制得的布洛芬三氮 唑核苷酯具有 R型和 S型的混合物的光学特性； 由 S型 2-(4'-异丁苯基) -丙 酰氯与三'氮唑核苷制得的或由 S型布洛芬、 氯化亚硯和三氯唑核苷制得的 布洛芬三氮唑核苷酯具有 S型光学特性。 所用的原料布洛芬和三氮唑核苷 可以使用符合中国药典 2000年版的原料药， S型布洛芬的含量在 98 %以上。
本发明制备过程的化学反应如下：
Figure imgf000006_0002
5
替换页（细则第 26条)
Figure imgf000007_0001
Figure imgf000007_0002
在 2- (4'-异丁苯基) -丙酰氯与三氮唑核苷的反应中， 由于三氮唑核苷的核糖 环上有三个羟基，一个伯醇和两个仲醇，本发明制备过程中 2-(4'-异丁苯基) - 丙酰氯与三氮唑核苷的酯化反应的目的是使反应发生在伯醇的羟基上， 通 过控制酯化反应过程中的反应条件可以确保既有较高的收率， 又有较好的 纯度。
本发明制备过程中， 2- (4'-异丁苯基)-丙酰氯与三氮唑核苷反应的反应 温度优选为 0 °C ~ 30 °C , 更优选为 0 °C ~ 10 C。 上述两反应物的用量摩尔比 优选为 1 : 1 ~ 2, 更优选为 1 : 1.1。 药物组合物
因此， 本发明还涉及包含通式 1和 II的化合物和可药用的栽体的药物 组合物。
本发明所述的药物组合物可以呈固体制剂如片剂、 胶囊剂和颗粒剂 等， 以及液体制剂如溶液和注射液等形式。 所述药物组合物可以通过口服、
6
替换页（细则第 26条) 静脉给药、 皮下肌肉注射或外用涂抹等途径给药。 当本发明的药物组合物 呈液体制剂形式时， 其优选包含助溶剂， 所述助溶剂包括但不限于聚乙二 醇、 二曱基曱酰胺和二曱基亚砜等。
本发明所述的药物组合物中所包含的可药用的栽体是本领域公知的， 包括但不限于如填充剂、 润滑剂、 崩解剂和粘合剂等。
本发明所述的药物组合物还可以包含其它活性成分如抗组胺药物、 鼻 粘膜减充血剂及镇咳药等。
本发明所述的药物组合物还可以包含另一活性成分如伪麻黄碱、 朴尔 敏和氢溴酸右美沙芬等， 该活性成分与本发明的通式 I和 II 的化合物在活 性上有协同作用。
本发明所述的通式 I和 II的化合物具有抗炎、 解热、 镇痛及抗病毒作 用， 可以制成可供口服、 静脉给药、 皮下肌肉注射或外用涂抹等药物剂型。
本发明所述的化合物和药物组合物能治疗流感、 普通感冒、 麻疹、 疱 疹、 腺病毒肺炎、 出血热和曱肝。
本发明所述的布洛芬三氮唑核苷酯结构中， 布洛芬的羧基以酯的形式 存在，其对生物体的损伤降低，表现在其急性毒性降低，即半数致死量 (LI)5()) 增力口。 药学实验
用改良的 Rundall Selitto方法研究本发明所述的通式 I的外消旋布洛芬 三氮唑核苷酯对大鼠的镇痛作用： 三组大鼠， 每组八只， 设对照组， 阳性 对照组使用布洛芬外消旋体 (30毫克 /千克体重）， 实验组使用通式 I 的外消 旋布洛芬三氮唑核苷酯 (63 毫克 /千克体重）。 结果表明通式 I 的外消旋布洛 芬三氮唑核苷酯的镇痛作用与布洛芬外消旋体相近。
用大鼠酵母发热试验研究本发明所述的通式 I 的外消旋布洛芬三氮唑 核苷酯的解热作用： 三组大鼠， 每组八只， 设对照组， 阳性对照组使用外 消旋体布洛芬 (30毫克 /千克体重）， 实验组使用通式 I 的外消旋布洛芬三氮 唑核苷酯 (63 毫克 /千克体重）。 结果表明通式 I 的外消旋布洛芬三氮唑核苷 酯的解热作用与布洛芬外消旋体相近。
用大鼠足角叉菜胶致肿法试验研究本发明所述的通式 I 的外消旋布洛 芬三氮唑核苷酯的抗炎作用： 三组大鼠， 每组八只， 设对照组， 阳性对照 组使用布洛芬外消旋体 (30毫克 /千克体重）， 实验组使用通式 I 的外消旋布 洛芬三氮唑核苷酯 (63 毫克 /千克体重)。 结果表明通式】 的外消旋布洛芬三 氮唑核苷酯的抗炎作用与布洛芬外消旋体相近。
用改良的 Rundall Stlitto方法研究包含本发明所述的通式】的外消旋布 洛芬三氮唑核苷酯和伪麻黄碱、 朴尔敏、 氢溴酸右美沙芬的药物组合物对 大鼠的镇痛作用： 四组大鼠， 每组八只， 阳性对照药物为通式】的外消旋布 洛芬三氮唑核苷酯，试验用药物：药物组合物 1(外消旋布洛芬三氮唑核苷酯： 伪麻黄城 =500:30); 药物组合物 11(外消旋布洛芬三氮唑核苷酯： 伪麻黄碱： 朴尔敏 =500:30:2); 药物组合物 ΙΠ (外消旋布洛芬三氮唑核苷酯： 伪麻黄碱： 朴尔敏： 氢溴酸右美沙芬 =500:30:2: 15)。 结果表明试验组效果优于对照组。
用改良的 Rundall Selitto方法研究本发明所述的通式 II的化合物对大鼠 的镇痛作用： 三组大鼠， 每组八只， 设对照组， 阳性对照组给予 S 型布洛 芬 (30毫克 /千克体重）， 实验组给予本发明的通式 II的化合物 (63毫克 /千克 体重）。 结果表明本发明的通式 II的化合物的镇痛作用与 S型布洛芬相近。
用大鼠酵母发热试验研究本发明所述的通式 II的化合物的解热作用： 三组大鼠， 每组八只， 设对照组， 阳性对照组给予 S型布洛芬 (30毫克 /千克 体重)； 实验组给予本发明所述的通式 II的化合物 (63毫克 /千克体重）。 结果 表明本发明的通式 II的化合物的解热作用与 S型布洛芬相近。
用大鼠足角叉菜胶致肿法试验研究本发明所述的通式 II的化合物的抗 炎作用： 三组大鼠， 每组八只， 设对照组， 阳性对照组给予 S型布洛芬 (30 毫克 /千克体重)； 实验组给予通式 II 的化合物 (63 毫克 /千克体重)。 结果表 明通式 II的化合物的抗炎作用与 S型布洛芬相近。
通过小鼠急性毒性试验表明本发明所述的布洛芬三氮唑核苷酯对生物 体的损伤减小。 把体重为 18-22克健康小鼠 100只， 随机分成 10组， 受试 药物为： 外消旋布洛芬三氮唑核苷酯、 和等摩尔均匀混合的布洛芬外消旋 体和三氮唑核苷 (重量比为 206:244)。 每种受试药物五个剂量组， 灌胃给药， 试验结果，外消旋布洛芬三氮唑核苷酯的半数死量 LD5。为 3592mg/kg体重。 等摩尔均勾混合布洛芬外消旋体与三氮唑核苷酯的 LD50为 2683mg/kg 体 重。
本发明的通式 I和 II的化合物的体外细胞病变抑制法抗病毒试验研究 表明， 其抗病毒作用与三氮唑核苷相近。 在流感病毒的鼠肺适应株抗病毒试验中， 对照组三氮唑核苷的给药剂 量为 50mg/kg.day , 试验组外消旋布洛芬三氮唑核苷酯给药剂量为 35mg/kg.day, 连续给药五天， 对照组抑制率为 22.5%, 试验组为 25%。 这 表明本发明的通式 I 的布洛芬三氮唑核苷酯抗流感病毒适应株的活性优于 对照组。 实施例
采用以下非限制性的实施例来说明本发明的布洛芬三氮唑核苷酯及其 药物组合物的制备。
实施例 1
在装有带干燥管的冷凝器， 温度计及搅拌装置的反应瓶内， 加入 100 毫升无水吡啶， 26.8克（约 1 10毫摩尔）三氮唑核苷。 在冷却下加入溶于 50 毫升无水吡啶的 22.4克 (约 100毫摩尔 )2-(4'-异丁苯基) -丙酰氯外消旋体。反 应温度控制在 0°C〜10°C。 完毕后， 室温反应 1 小时。 用冷的盐酸溶液将反 应液酸化至微酸性 (pH3.5-4.5)。 产生的不溶物溶于乙酸乙酯中， 将所得到的 乙酸乙酯溶液用 0.01N 稀盐酸洗涤， 再用饱和氯化钠溶液洗至中性， 无水 硫酸钠干燥， 过滤， 浓缩， 残留物用乙酸乙酯重结晶， 得到本发明所述的 化合物外消旋布洛芬三氮唑核苷酯。 毛细管法测定的熔点为： 169-172°C。
元素分析仪测定（ 、 H、 N含量分别为 C: 58.30 % , H: 6.52 % , N: 12.93 %。
KBr压片测定红外光谱， 在 1733处有强吸收峰。
DMSO为溶剂， 500MHz核磁共振测定氢谱， 化学位移结果如下： 8.80(1 H); 7.85(1 H); 7.65(1 H); 7.06-7.16(4H), 5.88(1H); 5.64(111); 5.34(1 H); 3.99-4.44(5H); 3.77(1 H); 2.40(2H); 1.79(1 H); 1.28-1.37(311); 0.83-0.85(6H)„
实施例 2
实施例 1中"用冷的盐酸溶液将反应液酸化至微酸性 (pH3.5-4.5)"以后按 如下操作进行：
产生的不溶物用乙醇重结晶， 得到本发明所述的通式 I 的外消旋布洛 芬三氮唑核苷酯化合物， 毛细管法测熔点为 179-181 C。
实施例 3 在装有带干燥管的冷凝器、 温度计及搅拌装置的反应瓶内， 加入 300 毫升苯， 20.6克 S型布洛芬， 完全溶解后加入 50ml氯化亚砜，加热至回流， 维持在反应温度 80-82 °C下 4小时， 减压蒸去苯及未反应的氧化亚砜， 将所 得的 (S)-2-(4'_异丁苯基) -丙酰氯冷却后与 50 毫升无水吡啶混合， 并冷至室 温。
在装有带干燥管的冷凝器、 温度计及搅拌装置的反应瓶内， 加入 100 毫升无水吡啶和 26.8 克三氮唑核苷。 此反应 在冰水冷却下滴加前述的 (S)-2-(4'_异丁苯基) -丙酰氯与吡啶的混合物， 反应温度控制在 0°C〜10°C。 滴 加完毕后， 室温反应 1 小时。 用冷的盐酸溶液将反应液酸调至微酸性 (pH3.5-4.5)。 产生的不溶物用乙醇重结晶，得到本发明所述的通式 II的化合 物。 毛细管法测定的熔点为 177-】8rC， 比旋度为 [a]D 2()-2.4 80mg/nil二甲 基甲酰胺溶液。 通过元素分析仪测定的（ 、 H、 N含量分别为： C: 58.38 %， I I： 6.53 % , N: 12.97 %。 KBr压片测定红外光谱在 1732处有强吸收峰。 DMSO 为溶剂， 500MHz核磁共振测定氢谱， 化学位移结果如下：
8.80(111); 7.85(1 H); 7.65(1 H); 7.06-7.16(4H), 5.88(1 H); 5.64(111);
5.34(1 H); 3.99-4.44(5H); 3.77(1 H); 2.40(2H); 1.79(1 H); 1.28- 1 .37(311); 0.83-0.85(6H)„
实施例 4
采用下文所述的组分， 配制含本发明的通式 I和 II的化合物的药物组 合物：
Figure imgf000011_0001
450.0克
淀粉 14.0克
15%淀粉浆 27.0克
低取代羟丙基纤维素 14.0克
滑石粉 2.7克
硬脂酸镁 2.7克
将上述本发明的布洛芬三氮唑核苷酯、 淀粉、 低取代羟丙基纤维素的 混合物过筛， 用 15%淀粉浆制成软材， 过 18 目筛制粒， 70-80度干燥后加 滑石粉、 硬脂酸镁压片， 共制成 1000片。

Claims

权 利 要 求 书 布洛芬三氮唑苷酯， 其结构式为
Figure imgf000012_0001
2. 根据权利要求 1 所述的布洛芬三氮唑核苷酯， 其为与苯环相邻的手 性碳原子为 R型和 S型的混合物。
3. 根据权利要求 2所述的布洛芬三氮唑核苷酯， 其为与苯环相邻的手 性碳原子为 R型和 S型的等量混合物。
4. 根据权利要求 1 所述的布洛芬三氮唑核苷酯， 其中， 与苯环相邻的 手性碳原子为 S型。
5. 制备权利要求 1 4中任一项所述的布洛芬三氮唑核苷酯的方法，包 括将 2- (4'-异丁苯基)-丙酰氯与三氮唑核苷在碱性有机溶剂， 优选为吡啶中 于反应。
6. 根据权利要求 5所述的布洛芬三氮唑核苷酯的制备方法， 其特征是 2-(4'-异丁笨基) -丙酰氯与三氮唑核苷的反应温度为 0°C ~ 30 C , 优选为
0°C ~ 10°C, 两者用量的摩尔比为 1:1 ~2, 优选为 1:1上
7. 一种药物组合物，包含权利要求】 - 4中任一项的布洛芬三氮唑核苷 酯及可药用的载体。
8. 根据权利要求 7所述的药物组合物， 还包含一种或多种其它活性成 分， 所述活性成分选自鼻粘膜减充血 、 抗组胺药和镇咳药
9. 根据权利要求 8所述的药物组合物， 其中所述其它活性成分为伪麻 黄碱、 朴尔敏或氢溴酸右美沙芬。
10. 一种治疗疾病的方法， 所述疾病选自流感 , 普通感冒， 麻疹， 疱疹， 腺病毒肺炎， 出血热和甲肝， 包括给待治的患者给药权利要求 1 4屮任 - 项的布洛芬三氮唑核苷酯化合物。
11. 根据权利要求 1 - 4 屮任一项所述的布洛芬三氮唑核苷 在制 ; I] 于抗炎、 解热、 镇痛和抗病毒的药物组合物中的用途。
1 2. 根据权利要求 1 1所述的用途，其中所述药物组合物用于治疗 -;, 普通感冒、 麻疹、 疱疹、 腺病毒肺炎、 出血热和甲肝。
PCT/CN2003/000292 2002-04-22 2003-04-22 Ester d'ibuprofene-ribavirine, procede d'elaboration et utilisation WO2003089448A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0531700A2 (de) * 1991-08-14 1993-03-17 Bayer Ag Diastereomerenreine Zwischenprodukte und ihre Verwendung bei der Herstellung von (R)- oder (S)-Ketoprofen
CN1257860A (zh) * 1999-08-20 2000-06-28 复旦大学 酮基布洛芬的合成方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0531700A2 (de) * 1991-08-14 1993-03-17 Bayer Ag Diastereomerenreine Zwischenprodukte und ihre Verwendung bei der Herstellung von (R)- oder (S)-Ketoprofen
CN1257860A (zh) * 1999-08-20 2000-06-28 复旦大学 酮基布洛芬的合成方法

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