WO2015192672A1 - Dérivé de benzofurane, son procédé de préparation, et son utilisation - Google Patents

Dérivé de benzofurane, son procédé de préparation, et son utilisation Download PDF

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Publication number
WO2015192672A1
WO2015192672A1 PCT/CN2015/074370 CN2015074370W WO2015192672A1 WO 2015192672 A1 WO2015192672 A1 WO 2015192672A1 CN 2015074370 W CN2015074370 W CN 2015074370W WO 2015192672 A1 WO2015192672 A1 WO 2015192672A1
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WO
WIPO (PCT)
Prior art keywords
butyl
benzoyl
methanesulfonylaminobenzofuran
propoxy
piperidin
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2015/074370
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English (en)
Chinese (zh)
Inventor
王文峰
杨琰
李日东
郑满冬
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Resources Saike Pharmaceutical Co Ltd
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China Resources Saike Pharmaceutical Co Ltd
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Publication of WO2015192672A1 publication Critical patent/WO2015192672A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention relates to a benzofuran derivative or a pharmaceutically acceptable salt thereof, a process for producing the derivative, a pharmaceutical composition comprising the derivative, and the derivative and Use of a pharmaceutical composition for the preparation of an antiarrhythmic drug and a treatment related disorder.
  • Amiodarone is a benzofuran derivative and is used for the prevention and treatment of ventricular arrhythmia and atrial fibrillation. It has been used as an antiarrhythmic drug for more than 40 years. Since the molecular structure of amiodarone contains 2 iodine atoms, accounting for 37.2% of its relative molecular mass, about 5% to 28% of patients have thyroid dysfunction after 2 to 3 months of treatment. The long-term use of amiodarone increases the risk of adverse reactions, among which lung toxicity is the most common, the incidence rate is 1% to 17%, and interstitial pneumonia or allergic pneumonia occurs after 3 to 12 months of continuous medication.
  • Dronedarone (SR33589) is a Class III antiarrhythmic drug developed by Sanofi-Aventis, France. It was approved for marketing in the United States on July 1, 2009 and approved by the European Union EMEA on December 16, 2009. It is suitable for heart rhythm control, maintenance of sinus rhythm and slowing ventricular rhythm in patients with atrial fibrillation (AF) and atrial flutter (AFL). It is mainly used for the treatment of arrhythmia. Dronedarone is a derivative of benzofuran similar in structure to Amiodarone and has an electrophysiological effect similar to that of amiodarone.
  • dronedarone has certain effects of class I, class II and class IV antiarrhythmic drugs, inhibiting sodium, potassium and calcium influx, and also antagonizing alpha and beta adrenergic receptors. Unlike amiodarone, dronedarone rarely affects thyroid receptors, treats atrial fibrillation and atrial flutter, maintains sinus rhythm, and is well tolerated. This has been a large-scale clinical practice. Test confirmed.
  • Dronedarone hydrochloride is almost insoluble in water, and its bioavailability is relatively poor, only 15% to 20%. This is due to the obvious first-pass effect of the liver, which can increase the blood concentration by 2 to 3 times with food. Druidron hydrochloride is widely metabolized in the human body after oral administration, mainly by CYP3A4 metabolism.
  • Debutyl butyl dronedarone (SR35021) is the main metabolite, which is equivalent to the blood concentration of dronedarone.
  • SR35021 has antiarrhythmic, electrophysiological and hemodynamic activities similar to that of dronedarone, but its activity is 3 to 10 times weaker than that of dronedarone. Recent studies have shown heart failure with severe heart failure or new hospitalization The risk of death from dronedarone hydrochloride was at least doubled in patients; in addition, dronedarone hydrochloride may cause severe liver damage.
  • the present invention has modified the structure of dronedarone hydrochloride by using a five- or six-membered ring.
  • the amine replaces the dibutylamine group of dronedarone hydrochloride.
  • a first object of the present invention is to provide a benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 are a hydrogen atom, a halogen, a cyano group or a trifluoromethyl group
  • n 2 or 3;
  • A is -(CH 2 ) m - or -(CH 2 ) m -O-, wherein m is 1 or 2;
  • R 4 is a hydrogen atom, a hydroxyl group, a C 1-4 alkyl group or a halogen-substituted C 1-4 alkyl group.
  • the R 1 , R 2 and R 3 groups are a hydrogen atom, a fluorine atom, a cyano group or a trifluoromethyl group;
  • the R 4 group is a hydrogen atom, a hydroxyl group or a methyl group.
  • the group A is -CH 2 -, -CH 2 CH 2 - or -CH 2 -O-;
  • the compounds of the invention are:
  • the salt of the benzofuran derivative of the present invention is a salt of a benzofuran derivative of the above formula I and an organic acid or an inorganic acid.
  • the compound represented by the formula I may form a pharmaceutically acceptable salt with a mineral acid, such as a sulfate, a phosphate, a hydrochloride or a hydrobromide salt; or may form a pharmaceutically acceptable salt with an organic acid, such as an acetate or an oxalate.
  • a mineral acid such as a sulfate, a phosphate, a hydrochloride or a hydrobromide salt
  • an organic acid such as an acetate or an oxalate.
  • Preferred is the hydrochloride salt.
  • a second object of the present invention is to provide a process for producing a benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof.
  • the benzofuran derivative of the present invention or a pharmaceutically acceptable salt thereof the preparation method comprises the following steps:
  • R 1 , R 2 and R 3 are a hydrogen atom, a halogen, a cyano group or a trifluoromethyl group
  • n 2 or 3;
  • A is -(CH 2 ) m - or -(CH 2 ) m -O-, wherein m is 1 or 2;
  • R 4 is a hydrogen atom, a hydroxyl group, a C 1-4 alkyl group or a halogen-substituted C 1-4 alkyl group.
  • a third object of the present invention is to provide a pharmaceutical composition comprising at least one benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof.
  • composition of the present invention may also be added with one or more pharmaceutically acceptable carriers or excipients as needed.
  • the pharmaceutical composition of the present invention may be in an amount of from 0.1 to 99.9% by weight, the balance being a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form, including: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, orally. Liquid, buccal, granules, granules, pills, powders, ointments, dans, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches .
  • the preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, an agent, a paste or the like.
  • the route of administration of the present invention may be oral, parenteral or topical, preferably oral and injectable.
  • the pharmaceutically acceptable oral administration preparation may be in the form of a tablet, a capsule, a granule or other pharmaceutically acceptable liquid form preparation such as a solution, an emulsion, a suspension or the like.
  • Preferred oral formulations are tablets, and the tablets may be in the form of a coating, enteric, sustained release or quantitative release.
  • the pharmaceutical composition of the present invention may contain conventional excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a moisturizing agent.
  • a binder such as a polyethylene glycol dimethacrylate, polyethylene glycol dimethacrylate, polypropylene glycol dimethacrylate, a steaglycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, a talct, talct, talct, talct, talct, talct copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer, graft copolymer,
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
  • Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of filler.
  • the oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats.
  • Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carriers (they may include edible Oil), for example, almond oil, fractionated coconut oil, an oily ester of an ester such as glycerol, propylene glycol or ethanol; a preservative such as p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may be conventional Aroma or colorant.
  • edible Oil for example, almond oil, fractionated coconut oil, an oily ester of an ester such as glycerol, propylene glycol or ethanol
  • a preservative such as p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may be conventional Aroma or colorant.
  • the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle.
  • This compound can be suspended or dissolved depending on the carrier and concentration.
  • the solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier.
  • the composition can be frozen after filling the vial and the water removed under vacuum.
  • the pharmaceutical composition of the present invention may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sulfur Sodium sulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid , phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and their derivatives , alginate, gelatin, polyvinylpyrrolidone, glycerin,
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention can be formulated into various suitable dosage forms depending on the route of administration.
  • the use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which may be employed in pharmaceutical compositions.
  • the appropriate form of formulation will depend on the route of administration chosen and may be prepared according to common general knowledge in the art.
  • a fourth object of the present invention is to provide a use of a benzofuran derivative or a pharmaceutically acceptable salt thereof for the preparation of an antiarrhythmic drug.
  • a fifth object of the present invention is to provide a pharmaceutical composition using a benzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient for the preparation of an antiarrhythmic drug.
  • the benzofuran derivative or the pharmaceutically acceptable salt thereof of the invention has better water solubility than dronedarone hydrochloride, and has better in vitro stability and antiarrhythmic effect than dronedarone hydrochloride.
  • 2-butyl-5-nitrobenzofuran (8.77 g, 40 mmol) was dissolved in 50 ml of dichloromethane, 3-fluoro-4-methoxybenzoyl chloride (7.55 g, 40 mmol) and anhydrous Aluminum chloride (8.00 g, 40 mmol) was reacted at room temperature for 12 h, and anhydrous aluminum trichloride (8.00 g, 40 mmol) was added to the reaction mixture, and the mixture was heated to reflux. The reaction mixture was poured into water (100 ml), evaporated, evaporated, evaporated.
  • Example 20 The solubility of the compound described in Examples 1 to 19 and dronedarone hydrochloride in water
  • the solubility of the compound of the present invention in water is significantly better than that of the marketed drug dronedarone hydrochloride.
  • Mobile phase 0.1% aqueous formic acid (A) and 0.1% formic acid-acetonitrile (B); elution procedure is 0-0.5 min, maintaining mobile phase B is 5%; 0.5-1.0 min, mobile phase B is 5% to 95 %; 1.0 ⁇ 1.5min, maintain mobile phase B is 95%; 1.5 ⁇ 2.0min, equilibrated to mobile phase B is 5%.
  • the running time was 2 min, the flow rate was 1 mL/min, and the loading volume was 5 ⁇ L.
  • Example 21 The inhibitory effects of the compounds described in Examples 1 to 19 and dronedarone hydrochloride on the potassium channel of hERG
  • the collected cells (recombinant HEK293 cell line express human hERG (ether-a-go-go related gene) potassium channel) suspension is placed in the cell pool, and the cells are sucked once every 30s to avoid cell sedimentation or agglomeration .
  • the robotic arm automatically injects intracellular fluid, extracellular fluid and injects the cell suspension into the sealing chip.
  • the cells were randomly attached to the well under the suction of negative pressure, and then the membrane attached to the well was ruptured by suction to form a whole cell recording mode.
  • the leakage current is less than 100pA.
  • the current before administration is greater than 400 pA.
  • A represents an IC 50 value in the range 1nM to 1 ⁇ M
  • B Representative IC 50 values in the range of 1 ⁇ M to 5 ⁇ M.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé de benzofurane, dont la structure est représentée par la formule générale I, ou un sel pharmaceutiquement acceptable de celui-ci. Elle concerne un procédé de préparation de celui-ci, et une utilisation de celui-ci dans la préparation de médicaments anti-arythmiques. Les définitions des groupes sont telles que décrites dans la description.
PCT/CN2015/074370 2014-06-16 2015-03-17 Dérivé de benzofurane, son procédé de préparation, et son utilisation Ceased WO2015192672A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410267113.8 2014-06-16
CN201410267113.8A CN105315245B (zh) 2014-06-16 2014-06-16 苯并呋喃类衍生物、其制备方法和应用

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WO2015192672A1 true WO2015192672A1 (fr) 2015-12-23

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PCT/CN2015/074370 Ceased WO2015192672A1 (fr) 2014-06-16 2015-03-17 Dérivé de benzofurane, son procédé de préparation, et son utilisation

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CN (1) CN105315245B (fr)
WO (1) WO2015192672A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117024383A (zh) * 2023-07-28 2023-11-10 广州瑞尔医药科技有限公司 一种盐酸胺碘酮的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753822B (zh) * 2016-02-24 2018-04-03 华润赛科药业有限责任公司 一种苯并呋喃类衍生物、其制备方法和应用
CN106432159B (zh) * 2016-07-14 2019-07-12 华润赛科药业有限责任公司 一种新型苯并呋喃类衍生物、其制备方法和应用
CN112442003B (zh) * 2020-12-17 2022-04-19 南京方生和医药科技有限公司 一种决奈达隆中间体杂质及其制备方法

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WO1990007330A1 (fr) * 1989-01-06 1990-07-12 The Regents Of The University Of California Procede de selection de composes pharmaceutiques specifiques utiles
US5223510A (en) * 1990-08-06 1993-06-29 Sanofi Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them
CN1471521A (zh) * 2000-08-23 2004-01-28 ʥŵ��-�ϳ�ʵ���ҹ�˾ 氨基烷基苯甲酰基-苯并呋喃或苯并噻吩类,它们的制备方法与含有它们的组合物
CN101993427A (zh) * 2009-08-26 2011-03-30 成都伊诺达博医药科技有限公司 一种制备决奈达隆(Dronedarone)的新方法
CN102321058A (zh) * 2011-07-20 2012-01-18 北京赛科药业有限责任公司 一种合成盐酸决奈达隆的方法
CN102653530A (zh) * 2011-03-04 2012-09-05 浙江省医学科学院 一种苯并呋喃衍生物的制备方法及其应用
CN103450124A (zh) * 2013-08-30 2013-12-18 江苏九九久科技股份有限公司 决奈达隆合成方法

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CN101642451B (zh) * 2008-08-08 2013-04-24 湘北威尔曼制药股份有限公司 胺碘酮及其衍生物的新用途
EP2452938A1 (fr) * 2010-11-12 2012-05-16 LEK Pharmaceuticals d.d. Procédé pour la préparation de dérivés de 3-aroyl-5-aminobenzofurane
CN105753822B (zh) * 2016-02-24 2018-04-03 华润赛科药业有限责任公司 一种苯并呋喃类衍生物、其制备方法和应用

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WO1990007330A1 (fr) * 1989-01-06 1990-07-12 The Regents Of The University Of California Procede de selection de composes pharmaceutiques specifiques utiles
US5223510A (en) * 1990-08-06 1993-06-29 Sanofi Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them
CN1471521A (zh) * 2000-08-23 2004-01-28 ʥŵ��-�ϳ�ʵ���ҹ�˾ 氨基烷基苯甲酰基-苯并呋喃或苯并噻吩类,它们的制备方法与含有它们的组合物
CN101993427A (zh) * 2009-08-26 2011-03-30 成都伊诺达博医药科技有限公司 一种制备决奈达隆(Dronedarone)的新方法
CN102653530A (zh) * 2011-03-04 2012-09-05 浙江省医学科学院 一种苯并呋喃衍生物的制备方法及其应用
CN102321058A (zh) * 2011-07-20 2012-01-18 北京赛科药业有限责任公司 一种合成盐酸决奈达隆的方法
CN103450124A (zh) * 2013-08-30 2013-12-18 江苏九九久科技股份有限公司 决奈达隆合成方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117024383A (zh) * 2023-07-28 2023-11-10 广州瑞尔医药科技有限公司 一种盐酸胺碘酮的制备方法

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CN105315245B (zh) 2018-10-12

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