WO2017133429A1 - 一种萜品烯醇类化合物及其制备方法和应用 - Google Patents

一种萜品烯醇类化合物及其制备方法和应用 Download PDF

Info

Publication number
WO2017133429A1
WO2017133429A1 PCT/CN2017/071217 CN2017071217W WO2017133429A1 WO 2017133429 A1 WO2017133429 A1 WO 2017133429A1 CN 2017071217 W CN2017071217 W CN 2017071217W WO 2017133429 A1 WO2017133429 A1 WO 2017133429A1
Authority
WO
WIPO (PCT)
Prior art keywords
terpineol
compound
compound according
membered
alkyl
Prior art date
Application number
PCT/CN2017/071217
Other languages
English (en)
French (fr)
Inventor
朱婉萍
胡永洲
刘霞
孔繁智
王昱霁
Original Assignee
浙江省中医药研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江省中医药研究院 filed Critical 浙江省中医药研究院
Priority to JP2018558468A priority Critical patent/JP6668508B2/ja
Priority to US16/074,403 priority patent/US11117866B2/en
Priority to EP17746749.5A priority patent/EP3412649B1/en
Publication of WO2017133429A1 publication Critical patent/WO2017133429A1/zh

Links

Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
    • C07C29/172—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds with the obtention of a fully saturated alcohol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/13—Monohydroxylic alcohols containing saturated rings
    • C07C31/133—Monohydroxylic alcohols containing saturated rings monocyclic
    • C07C31/135—Monohydroxylic alcohols containing saturated rings monocyclic with a five or six-membered rings; Naphthenic alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to a terpene enol compound and a preparation method and application thereof.
  • Ai leaf oil is a volatile oil contained in the dry leaves or fresh leaves of Artemisia argyi. It can directly relax the smooth muscle of the trachea and has protective effects on antigen, acetylcholine and histamine-induced tracheal smooth muscle spasm and asthma. It also has anti-allergic effects, can inhibit the release of allergic slow-reactive substances (SRS-A) in sensitized lung tissue, and can antagonize the effects of SRS-A and serotonin. It also has a certain expectorant and antitussive effect. No excitatory effects on the heart, mainly used for bronchial asthma and asthma-type chronic bronchitis.
  • SRS-A allergic slow-reactive substances
  • ⁇ -terpineol is an antiasthmatic active ingredient extracted from eucalyptus oil, and its chemical name is ⁇ , ⁇ ,4-trimethyl--3-cyclohexene-1-methanol.
  • Ru Ru et al. reported the pharmacological effects of ⁇ -terpineol ("Pharmacological action of new antiasthmatic drug- ⁇ -terpineol", Chinese Journal of Pharmacology, vol. 3, No. 6, 1987, pp. 323 ⁇ Page 328), it was found that ⁇ -terpineol has airway relaxation in guinea pig whole and ex vivo experiments, can increase cAMP content in tracheal smooth muscle, anti-allergic, antitussive and expectorant effects, and low toxicity. A safe and effective new antiasthmatic drug.
  • ⁇ -terpineol is different from the beta agonist and has an inhibitory effect on the isolated atrium of guinea pigs.
  • Chinese Patent Application Publication No. CN 103922927 A discloses an ⁇ -terpene enol derivative and a preparation method and application thereof, and the structure of the ⁇ -terpene enol derivative is as follows:
  • R is selected from a C 1 -C 5 alkyl group, and the anti-asthmatic activity is enhanced to a certain extent by derivatization of ⁇ -nonanol, but the antiasthmatic activity is still not good enough.
  • the invention provides a terpene enol compound and a preparation method and application thereof, the terpene enol compound having better anti-asthmatic activity and having certain anti-inflammatory activity.
  • R is independently selected from C 12 -C 16 alkyl, -NR 1 R 2 , -SR 3 or -OR 4 ;
  • R 1 , R 2 , R 3 and R 4 are independently selected from C 1 -C 6 alkyl or -NO 2 , and the C 1 -C 6 alkyl group may be substituted by OH;
  • the activity test shows that the terpineol compound of the present invention can effectively relax bronchial smooth muscle, reduce inflammatory cells, and effectively relieve pulmonary hypertension.
  • the R is -NR 1 R 2 , and in this case, the terpineol compound can form a pharmaceutically acceptable salt with an acid, is more easily dissolved in water, and is convenient for pharmaceutical applications.
  • said R is one of C 12 H 25 , C 16 H 33 or the like:
  • the present invention also provides a process for preparing the terpene enol compound.
  • the preparation method comprises the following steps:
  • the ⁇ -terpineol is reacted with alkanoyl chloride in dichloromethane under the action of pyridine, and the terpene enol compound is obtained after completion of the reaction;
  • the alkanoyl chloride is a C 14 -C 16 alkanoyl chloride.
  • the esterification intermediate obtained in the step (1) and a nucleophilic reagent are subjected to a substitution reaction in acetonitrile to obtain the terpinenol compound;
  • the nucleophile is HNR 1 R 2 , HSR 3 or HOR 4 .
  • the preparation method comprises the following steps:
  • the ⁇ -terpineol is subjected to hydrogenation reaction in methanol under a hydrogen atmosphere of Pd/C to obtain the terpene enol compound.
  • the invention also provides the use of the terpene enol compound in the pharmaceutical field.
  • the terpineol compound is used for preparing an anti-asthma drug
  • the anti-asthmatic drug is used to relax the bronchi.
  • the test results show that the terpineol compound can also effectively reduce the number of inflammatory cells.
  • the terpineol compound is used for the preparation of an anti-inflammatory drug.
  • the terpineol compound is used for the preparation of a medicament for treating or ameliorating pulmonary hypertension.
  • the present invention effectively enhances the anti-asthmatic action and anti-pulmonary hypertension effect of such compounds by derivatizing the terpineol compounds;
  • the terpineol compound of the present invention can reduce inflammatory cells and has good anti-inflammatory activity.
  • a rat asthma model was established. After the last administration, the trachea was isolated bluntly, bronchoalveolar lavage was performed, bronchial cell lavage fluid (BALF) was collected, and the total number of nucleated cells was counted. The results are shown in Table 2.
  • compound N is the product structure.
  • ⁇ ⁇ indicates that compared with the blank group, P ⁇ 0.01; ⁇ indicates that compared with the blank group, P ⁇ 0.05;
  • Each compound group can expand the relaxation rate of tracheal smooth muscle at different doses, and has an inhibitory effect on inflammation. It can be used for inflammation treatment of asthma, chronic obstructive pulmonary disease and various other diseases, such as arthritis, rheumatoid arthritis, bronchitis, allergic rhinitis, allergic dermatitis and the like.
  • the normal control group was given an equal volume of normal saline.
  • drug intervention was given, and each compound was administered 200 mg/Kg daily; the normal control group and the model group were given an equal volume of normal saline per day.
  • the right ventricular systolic pressure was measured by right heart catheterization under anesthesia, and the results are shown in Table 3.
  • each compound had a protective effect on monocrotaline-induced pulmonary hypertension in rats, which could improve hemodynamic parameters, reduce right ventricular systolic pressure, reduce right ventricular load, reduce right heart hypertrophy index, and relieve pulmonary vascular remodeling. .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明公开了一种萜品烯醇类化合物及其制备方法和应用，该萜品烯醇类化合物的结构如式(Ⅰ)或(Ⅱ)所示，式(Ⅰ)中，R独立地选自C12～C16烷基、-NR1R2、-SR3或-OR4；R1、R2、R3和R4独立地选自C1～C6烷基或-NO2，所述的C1～C6烷基可被OH取代；或者所述的R1、R2与连接它们的N共同形成五元环或者六元环，所述的五元环或者六元环可以含有一个O或者C＝O。活性测试结果表明，该萜品烯醇类化合物具有较好的抗哮喘作用、抗炎作用和抗肺动脉高压作用，具有重要的药学意义。

Description

一种萜品烯醇类化合物及其制备方法和应用 技术领域
本发明属于生物医药领域，具体涉及一种萜品烯醇类化合物及其制备方法和应用。
背景技术
艾叶油为菊科植物艾(Artemisia argyi)的干叶或鲜叶中所含的挥发油，能直接松弛气管平滑肌，对抗原、乙酰胆碱和组胺诱发的气管平滑肌痉挛和哮喘均有保护作用。还具有抗过敏作用，可抑制致敏肺组织释放过敏的慢反应物质(SRS-A)，并能拮抗SRS-A和5-羟色胺的作用。亦具有一定的祛痰、镇咳作用。对心脏无兴奋作用，主要用于支气管哮喘和哮喘型慢性支气管炎。
α-萜品烯醇是从艾叶油中提取的一种平喘有效成分，化学名称为：α,α,4-三甲基--3-环己烯-1-甲醇。卞如濂等人报道了α-萜品烯醇的药理作用(“新平喘药—α-萜品烯醇的药理作用”，《中国药理学通报》，1987年第3卷第6期，323页～328页)，发现α-萜品烯醇在豚鼠整体和离体实验中具有气道松弛作用，能升高气管平滑肌内cAMP含量，还有抗过敏、镇咳和祛痰作用,并且毒性低，为一安全有效的新平喘药。α-萜品烯醇不同于β受体激动剂，对豚鼠离体心房具有抑制作用。
公开号为CN 103922927 A的中国专利申请公开了一种α-萜品烯醇衍生物及其制备方法和应用，该α-萜品烯醇衍生物的结构如下：
Figure PCTCN2017071217-appb-000001
其中，R选自C1～C5烷基，通过对α-萜品烯醇的衍生化，使得平喘活性有了一定程度的增强，然而平喘活性仍然不够好。
发明内容
本发明提供了一种萜品烯醇类化合物及其制备方法和应用，该萜品烯醇类化合物具有更好的抗哮喘活性，同时还具有一定的抗炎活性。
一种抗哮喘化合物，结构如式(Ⅰ)或(Ⅱ)所示：
Figure PCTCN2017071217-appb-000002
式(Ⅰ)中，R独立地选自C12～C16烷基、-NR1R2、-SR3或-OR4；
R1、R2、R3和R4独立地选自C1～C6烷基或-NO2，所述的C1～C6烷基可被OH取代；
或者所述的R1、R2与连接它们的N共同形成五元环或者六元环，所述的五元环或者六元环可以含有一个O或者C＝O。
经过活性测试表明，本发明的萜品烯醇类化合物可以有效舒张支气管平滑肌、减少炎症细胞，同时有效地缓解肺动脉高压。
作为优选，所述的R为-NR1R2，此时，所述的萜品烯醇类化合物可以与酸形成药学上可接受的盐，更容易被水溶解，便于制药应用。
作为优选，所述的R为C12H25、C16H33或以下基团中的一种：
Figure PCTCN2017071217-appb-000003
其中，
Figure PCTCN2017071217-appb-000004
表示连接位置。
采用这些基团时，化合物活性较好，并且更容易获得。
本发明还提供了一种所述的萜品烯醇类化合物的制备方法。
当萜品烯醇类化合物为式(Ⅰ)所示的化合物，且R为C12～C16烷基时，该制备方法包括以下步骤：
在吡啶的作用下，将α-萜品烯醇与烷酰氯在二氯甲烷中进行反应，反应完成后得到所述的萜品烯醇类化合物；
所述的烷酰氯为C14～C16烷酰氯。
当萜品烯醇类化合物为式(Ⅰ)所示的化合物，且R为-NR1R2、-SR3或-OR4时，该制备方法包括以下步骤：
(1)在吡啶的作用下，α-萜品烯醇与溴乙酰溴在二氯甲烷中发生酯化反应，得到酯化中间体；
(2)在无机碱的作用下，步骤(1)得到的酯化中间体与亲核试剂在乙腈中发生取代反应，得到所述的萜品烯醇类化合物；
所述的亲核试剂为HNR1R2、HSR3或HOR4。
当萜品烯醇类化合物为式(Ⅱ)所示的化合物，该制备方法包括以下步骤：
在Pd/C和氢气氛围下，α-萜品烯醇在甲醇中进行加氢反应，得到所述的萜品烯醇类化合物。
本发明还提供了一种所述的萜品烯醇类化合物在制药领域中的应用。
作为优选，所述的萜品烯醇类化合物用于制备抗哮喘药物；
所述的抗哮喘药物用于舒张支气管。
试验结果表明，所述的萜品烯醇类化合物还可以有效地减少炎症细胞的数量，作为另外的优选，所述的萜品烯醇类化合物用于制备抗炎药物。
作为另外的优选，所述的萜品烯醇类化合物用于制备治疗或者缓解肺动脉高压的药物。
同现有技术相比，本发明的有益效果体现在：
(1)本发明通过对萜品烯醇类化合物的进行衍生化，有效地提高了这类化合物的抗哮喘作用和抗肺动脉高压作用；
(2)本发明的萜品烯醇类化合物可以减少炎症细胞，具有较好的抗炎活性。
具体实施方式
实施例1
精密称取原料α-萜品烯醇(4mmol)溶于10ml二氯甲烷中，加入吡啶(6mmol)，冰浴下滴加十四烷酰氯(6mmol)，室温反应8小时得终产物2a(3.74mmol,产率93.5％)。产物结构如下：
Figure PCTCN2017071217-appb-000005
实施例2
精密称取原料α-萜品烯醇(4mmol)溶于10ml二氯甲烷中，加入吡啶(6mmol)，冰浴下滴加十八烷酰氯(6mmol)，室温反应8小时得终产物2b(3.86mmol,产率96.5％)。
Figure PCTCN2017071217-appb-000006
实施例3～12
(1)称取原料α-萜品烯醇1.85g(10mmol)置于50ml圆底烧瓶内，加入30ml二氯甲烷，吡啶1.91ml(20mmol),冰浴下加入溴乙酰溴2.09ml(20mmol)，室温反应7小时得中间体3(5.9mmol,产率48.2％)。
反应式如下：
Figure PCTCN2017071217-appb-000007
(2)将中间体3(274mg,1mmol)溶于10mL乙腈中，室温下加入无水碳酸钾(276.4mg,2mmol)和中间体4(2mmol)，得到产物5，中 间体4的结构和收率见表1。
表1 实施例3～12的底物与结果
Figure PCTCN2017071217-appb-000008
实施例13
将α-萜品烯醇(400mg)加入到10mL甲醇中，加入Pd/C(40mg)，氢气环境下搅拌8h。分离得到无色油状物6(38mg,93.5％)，反应式如下：
Figure PCTCN2017071217-appb-000009
部分化合物的结构表征数据如下：
化合物A：
Figure PCTCN2017071217-appb-000010
1H NMR(500MHz,CDCl3)：δ5.37(s,1H),2.25–2.16(m,2H),2.07–1.90(m,4H),1.89–1.76(m,2H),1.64(s,3H),1.61–1.52(m,2H),1.43(s,3H),1.41(s,3H),1.25(s,21H),0.91–0.82(m,3H).
化合物B
Figure PCTCN2017071217-appb-000011
1H NMR(500MHz,CDCl3)：δ5.36(dd,J＝8.3,6.9Hz,1H),2.20(t,J＝7.5Hz,2H),2.08–1.91(m,4H),1.88–1.75(m,2H),1.64(s,3H),1.58–1.53(m,2H),1.44(s,3H),1.41(s,3H),1.34–1.19(m,29H),0.88(t,J＝7.0Hz,3H).
化合物C
Figure PCTCN2017071217-appb-000012
1H NMR(500MHz,CDCl3)：δ5.38(d,J＝2.0Hz,1H),3.62–3.58(m,2H),3.24(s,2H),2.73–2.69(m,2H),2.44(s,3H),2.13–1.93(m,4H),1.89–1.76(m,2H),1.66(s,3H),1.49(s,3H),1.46(s,3H),1.32(tt,J＝10.4,5.3 Hz,1H).
化合物D
Figure PCTCN2017071217-appb-000013
1H NMR(500MHz,CDCl3)：δ5.38(dd,J＝3.1,1.7Hz,1H),3.78(dd,J＝8.3,3.6Hz,4H),3.13(d,J＝1.3Hz,2H),2.64–2.56(m,4H),2.12–1.92(m,4H),1.89–1.76(m,2H),1.66(s,3H),1.48(s,3H),1.45(s,3H),1.36–1.26(m,1H).
化合物E
Figure PCTCN2017071217-appb-000014
1H NMR(500MHz,CDCl3)：δ5.36(s,1H),3.75(s,2H),2.13–1.94(m,4H),1.92–1.76(m,2H),1.64(s,3H),1.45(s,3H),1.36(s,3H),1.33(qd,J＝12.3,5.6Hz,1H).
化合物F
Figure PCTCN2017071217-appb-000015
1H NMR(500MHz,CDCl3)：5.38(dd,J＝2.9,1.5Hz,1H),3.23(s,2H),2.67(q,J＝7.3Hz,4H),2.10–1.93(m,4H),1.88–1.76(m,2H),1.65(s,3H),1.47(s,3H),1.44(s,3H),1.35–1.25(m,1H),1.08(td,J＝7.2,4.1Hz,6H).
化合物G
Figure PCTCN2017071217-appb-000016
1H NMR(500MHz,CDCl3)：δ5.37–5.34(m,1H),3.75(t,J＝5.6Hz,2H),3.18(s,2H),2.81(t,J＝5.5Hz,2H),2.09–1.94(m,4H),1.86–1.76(m,2H),1.63(s,3H),1.45(s,3H),1.43(s,3H),1.35–1.25(m,1H)；
化合物H
Figure PCTCN2017071217-appb-000017
1H NMR(500MHz,CDCl3)：δ5.33(t,J＝8.9Hz,1H),3.24(s,2H),2.87(t,J＝6.1Hz,4H),2.48(t,J＝6.1Hz,4H),2.09–1.89(m,4H),1.86–1.73(m,2H),1.63(s,3H),1.46(s,3H),1.43(s,3H),1.34–1.25(m,1H)；
化合物J
Figure PCTCN2017071217-appb-000018
1H NMR(500MHz,CDCl3)：δ5.35(d,J＝2.1Hz,1H),3.73–3.66(m,1H),3.11(s,2H),2.81(td,J＝8.9,3.8Hz,2H),2.38–2.30(m,2H),2.10–1.88(m,4H),1.85–1.74(m,2H),1.68–1.58(m,6H),1.45(s,3H),1.42(s,3H),1.33–1.26(m,1H)；
化合物K
Figure PCTCN2017071217-appb-000019
1H NMR(500MHz,CDCl3)：δ5.35(s,1H),3.81(s,1H),3.71(d,J＝11.0Hz,1H),3.60–3.46(m,1H),3.27–3.15(m,2H),2.85–2.77(m,1H),2.68(dd,J＝14.0,8.4Hz,1H),2.09–1.90(m,4H),1.86–1.75(m,2H),1.63(s,3H),1.45(s,3H),1.43(s,3H),1.33–1.25(m,1H)；
化合物L
Figure PCTCN2017071217-appb-000020
1H NMR(500MHz,CDCl3)：δ5.42–5.33(m,1H),3.06(d,J＝1.2Hz,2H),2.55–2.43(m,4H),2.10–1.89(m,4H),1.86–1.71(m,2H),1.62(s,3H),1.59(dd,J＝11.3,5.7Hz,4H),1.43(d,J＝5.8Hz,3H),1.42–1.37(m,5H),1.27(ddd,J＝24.4,12.2,5.7Hz,1H)；
化合物M
Figure PCTCN2017071217-appb-000021
1H NMR(500MHz,CDCl3)：δ5.33(s,1H),3.56–3.54(m,1H),3.11(s,2H),2.81(td,J＝8.9,3.8Hz,2H),2.38–2.30(m,2H),2.10–1.88(m,4H),1.85–1.74(m,2H),1.68–1.58(m,6H),1.45(s,3H),1.42(s,3H),1.33–1.26(m,1H)；
化合物N
Figure PCTCN2017071217-appb-000022
1H NMR(500MHz,CDCl3)：δ1.75(ddd,J＝16.6,10.2,4.5Hz,4H),1.43–1.42(m,1H),1.29–1.17(m,2H),1.13(s,6H),1.07–0.96(m,2H),0.89(dd,J＝12.0,2.9Hz,1H),0.85(d,J＝6.5Hz,3H).
扩张支气管及抗炎作用试验：
方法：制作离体气管条置于气管离体试验装置中，调张力，平衡后加入氯化乙酰胆碱100μL诱导气管收缩，使气管张力升高，待张力升高到最高值且张力趋于平衡后给予相应的受试药拮抗收缩的气管，描记等长肌张力变化曲线，计算平滑肌舒张率。舒张率＝(造模后张力-给药后张力)/(造模后张力)*100％
建立大鼠哮喘模型，末次给药后钝性分离气管，进行支气管肺泡灌洗，收集支气管细胞灌洗液(BALF)，计数有核细胞总数。结果如表2所示。
表2
Figure PCTCN2017071217-appb-000023
aCN 103922927 A中具体实施方式中的几个化合物，舒张率的计算公式有改进，同时，不同批次的测定结果有一定的误差，因此，舒张率数据有所差别。
Figure PCTCN2017071217-appb-000024
表示取代位置，化合物N为产物结构。
**表示与a-萜品烯醇组比较，P＜0.01；*表示与a-萜品烯醇组比较P＜0.05
△△表示与空白组比较，P＜0.01；△表示与空白组比较，P＜0.05；
与模型组比较，#P＜0.05，##P＜0.01
各化合物组在不同剂量下都能扩大气管平滑肌的舒张率，且有抑制炎症的作用。可应用于哮喘，慢性阻塞性肺疾病及其他各种疾病的炎症治疗，如关节炎，类风湿性关节炎，支气管炎、过敏性鼻炎、过敏性皮炎等。
对野百合碱诱导大鼠肺动脉高压的影响
方法：制作大鼠肺动脉高压模型，正常对照组给予注射等体积生理盐水。造模后第2天给予药物干预，每日给予各个化合物200mg/Kg；正常对照组及模型组每日给予等体积生理盐水灌胃。于第30天，在麻醉状态下以右心导管法测定大鼠右心室收缩压，结果见表3。
表3 不同组别大鼠右心室收缩压
Figure PCTCN2017071217-appb-000025
Figure PCTCN2017071217-appb-000026
与模型组相比，△P＜0.05，△△P＜0.01；与a-萜品烯醇组比较，#P＜0.05，##P＜0.01
试验结果表明，各化合物对野百合碱诱导大鼠肺动脉高压有一定保护作用，能改善血流动力学指标，降低右心室收缩压，减轻右心室负荷，降低右心肥厚指数，缓解肺血管重塑。

Claims (9)

  1. 一种萜品烯醇类化合物，其特征在于，结构如式(Ⅰ)或(Ⅱ)所示：
    Figure PCTCN2017071217-appb-100001
    式(Ⅰ)中，R独立地选自C12～C16烷基、-NR1R2、-SR3或-OR4；
    R1、R2、R3和R4独立地选自C1～C6烷基或-NO2，所述的C1～C6烷基可被OH取代；
    或者所述的R1、R2与连接它们的N共同形成五元环或者六元环，所述的五元环或者六元环可以含有一个O或者C＝O。
  2. 根据权利要求1所述的萜品烯醇类化合物，其特征在于，所述的R为C12H25、C16H33或以下基团中的一种：
    Figure PCTCN2017071217-appb-100002
    其中，
    Figure PCTCN2017071217-appb-100003
    表示连接位置。
  3. 一种如权利要求1所述的萜品烯醇类化合物的制备方法，其特征在于，包括以下步骤：
    在吡啶的作用下，将α-萜品烯醇与烷酰氯在二氯甲烷中进行反应，反应完成后得到所述的萜品烯醇类化合物；
    所述的烷酰氯为C14～C16烷酰氯，所述的R为C12～C16烷基。
  4. 一种如权利要求1所述的萜品烯醇类化合物的制备方法，其特征 在于，包括以下步骤：
    (1)在吡啶的作用下，α-萜品烯醇与溴乙酰溴在二氯甲烷中发生酯化反应，得到酯化中间体；
    (2)在无机碱的作用下，步骤(1)得到的酯化中间体与亲核试剂在乙腈中发生取代反应，得到所述的萜品烯醇类化合物；
    所述的亲核试剂为HNR1R2、HSR3或HOR4。
  5. 一种如权利要求1所述的萜品烯醇类化合物的制备方法，其特征在于，包括以下步骤：
    在Pd/C和氢气氛围下，α-萜品烯醇在甲醇中进行加氢反应，得到所述的萜品烯醇类化合物；
    所述的萜品烯醇类化合物为式(Ⅱ)所示的化合物。
  6. 一种如权利要求1或2所述的萜品烯醇类化合物在制药领域中的应用。
  7. 根据权利要求6所述的萜品烯醇类化合物在制药领域中的应用，其特征在于，所述的萜品烯醇类化合物用于制备抗哮喘药物；
    所述的抗哮喘药物用于舒张支气管。
  8. 根据权利要求6所述的萜品烯醇类化合物在制药领域中的应用，其特征在于，所述的萜品烯醇类化合物用于制备抗炎药物。
  9. 根据权利要求6所述的萜品烯醇类化合物在制药领域中的应用，其特征在于，所述的萜品烯醇类化合物用于制备治疗或者缓解肺动脉高压的药物。
PCT/CN2017/071217 2016-02-04 2017-01-16 一种萜品烯醇类化合物及其制备方法和应用 WO2017133429A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2018558468A JP6668508B2 (ja) 2016-02-04 2017-01-16 テルピネオール類化合物およびその調製方法と使用
US16/074,403 US11117866B2 (en) 2016-02-04 2017-01-16 Terpineol and preparation method and application thereof
EP17746749.5A EP3412649B1 (en) 2016-02-04 2017-01-16 Terpineol and preparation method and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610079970.4A CN106380400B (zh) 2016-02-04 2016-02-04 一种萜品烯醇类化合物及其制备方法和应用
CN201610079970.4 2016-02-04

Publications (1)

Publication Number Publication Date
WO2017133429A1 true WO2017133429A1 (zh) 2017-08-10

Family

ID=57916542

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/071217 WO2017133429A1 (zh) 2016-02-04 2017-01-16 一种萜品烯醇类化合物及其制备方法和应用

Country Status (5)

Country Link
US (1) US11117866B2 (zh)
EP (1) EP3412649B1 (zh)
JP (1) JP6668508B2 (zh)
CN (1) CN106380400B (zh)
WO (1) WO2017133429A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102416154A (zh) * 2011-12-08 2012-04-18 汪科元 一种沉香保健香囊
WO2013034416A1 (en) * 2011-09-09 2013-03-14 Unilever N.V. Antimicrobial method and composition
CN103922927A (zh) * 2014-04-01 2014-07-16 浙江省中医药研究院 α-萜品烯醇衍生物及其制备方法和应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733656A (ja) * 1993-07-23 1995-02-03 Sagami Chem Res Center 免疫賦活剤
JP3572115B2 (ja) * 1994-06-02 2004-09-29 塩野義製薬株式会社 ２−ピラノン誘導体及びそれを含有する免疫抑制剤
JPH0952854A (ja) * 1995-08-09 1997-02-25 Kao Corp α−ジヒドロテルピネオールの製造方法
JP2003212763A (ja) * 2002-01-16 2003-07-30 Toyama Prefecture 気管支拡張剤
JP4662134B2 (ja) * 2005-05-09 2011-03-30 ヤスハラケミカル株式会社 導電性ペースト
EA016931B1 (ru) * 2007-07-20 2012-08-30 Тойо Суйсан Кайся, Лтд. Новое сульфированное соединение сахара и его применение в качестве лекарственного средства
CN104447313B (zh) * 2015-01-07 2016-04-13 河北联合大学 α-萜品醇脂肪酸酯衍生物及应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013034416A1 (en) * 2011-09-09 2013-03-14 Unilever N.V. Antimicrobial method and composition
CN102416154A (zh) * 2011-12-08 2012-04-18 汪科元 一种沉香保健香囊
CN103922927A (zh) * 2014-04-01 2014-07-16 浙江省中医药研究院 α-萜品烯醇衍生物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIAN, RULIAN ET AL.: "THE PHARMACOLOGICAL PROPERTIES OF A NEW ANTIASTHMATIC DRUG, a-TERPINEOL", CHINESE PHARMACOLOGICAL BULLETIN, vol. 3, no. 6, 31 December 1987 (1987-12-31), pages 323 and 326, XP009507861, ISSN: 1001-1978 *
See also references of EP3412649A4 *

Also Published As

Publication number Publication date
JP2019506452A (ja) 2019-03-07
CN106380400B (zh) 2018-12-11
EP3412649A1 (en) 2018-12-12
US11117866B2 (en) 2021-09-14
EP3412649A4 (en) 2019-02-20
EP3412649B1 (en) 2020-03-04
CN106380400A (zh) 2017-02-08
US20190337900A1 (en) 2019-11-07
JP6668508B2 (ja) 2020-03-18

Similar Documents

Publication Publication Date Title
EP1339717A1 (de) Neue carbamat-substituierte pyrazolopyridinderivate
PT92303B (pt) Processo para a preparacao de derivados de xantina
WO2016015479A1 (zh) β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途
NO325685B1 (no) Substituerte (1,3-bis(cycloheksylmetyl)-1,2,3,6-tetrahydro-2,6-diokso-9H-purin-8-yl)fenylderivater, fremstilling og anvendelse derav samt farmasoytisk blanding.
JPS63502179A (ja) 新規なアリ−ル誘導体類
CN107118250B (zh) 一种no供体型齐墩果酸衍生物及其制备方法和用途
JP6126204B2 (ja) プロスタグランジンを主成分とした気管支拡張剤
WO2017133429A1 (zh) 一种萜品烯醇类化合物及其制备方法和应用
JP2010526812A (ja) 炎症性疾患の治療のためのスピロ化合物
JP2019504178A (ja) シクロデキストリンを主体とするポリマー、その方法、組成物、及び応用
JPS6246554B2 (zh)
CN104311622B (zh) 一种积雪草酸酰胺类衍生物
US11447522B2 (en) Potent soft anti-inflammatory corticosteroid compounds and uses thereof
CN115746079B (zh) 一种薯蓣皂苷元衍生物及其制备方法与用途
JP7348214B2 (ja) Ｈｄａｃ６選択的阻害剤の結晶形及びその使用
JPH0386824A (ja) ジテルペン系化合物及びこれを有効成分とする抗炎症剤
CN109928986A (zh) 1-o-乙酰基大花旋覆花内酯螺芳基异恶唑啉衍生物及其医药用途
WO2018050099A1 (zh) 二醇型人参皂苷衍生物及其制备方法和应用
WO2022022678A1 (zh) 一种吡嗪类化合物及其制备方法和应用
WO2022228577A1 (zh) 一种新型苯并酮类衍生物及其制备方法和应用
JP2002536454A (ja) 新規ギムネマ酸誘導体、その製造、それらを含む医薬組成物、およびそれらの医薬的使用
JP2016017062A (ja) 抗癌剤
CN117756798A (zh) 一种异丙托溴铵新晶体及其制备方法
JP2021531343A (ja) Ａｓｋ１阻害剤としての結晶形、その製造方法及び利用
CN108383838A (zh) 一种酰胺类衍生物及其在高血压、高血脂和动脉粥样硬化中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17746749

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2018558468

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2017746749

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017746749

Country of ref document: EP

Effective date: 20180904