WO2008144956A1 - Nouveaux composés ambroxol, leurs procédés de préparation et leurs utilisations - Google Patents

Nouveaux composés ambroxol, leurs procédés de préparation et leurs utilisations Download PDF

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Publication number
WO2008144956A1
WO2008144956A1 PCT/CN2007/001719 CN2007001719W WO2008144956A1 WO 2008144956 A1 WO2008144956 A1 WO 2008144956A1 CN 2007001719 W CN2007001719 W CN 2007001719W WO 2008144956 A1 WO2008144956 A1 WO 2008144956A1
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WO
WIPO (PCT)
Prior art keywords
ambroxol
water
group
compound
solvent
Prior art date
Application number
PCT/CN2007/001719
Other languages
English (en)
Chinese (zh)
Inventor
Lida Tang
Meixiang Zou
Jialin Guo
Zhuanyou Zhao
Yiliang Li
Xinhui Sun
Caixia Zhang
Original Assignee
Tianjin Institute Of Pharmaceutical Research
Tianjin Kanghong Pharmaceutical Technology Development Co., Ltd.
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 Tianjin Institute Of Pharmaceutical Research, Tianjin Kanghong Pharmaceutical Technology Development Co., Ltd. filed Critical Tianjin Institute Of Pharmaceutical Research
Priority to PCT/CN2007/001719 priority Critical patent/WO2008144956A1/fr
Publication of WO2008144956A1 publication Critical patent/WO2008144956A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • A61P11/10—Expectorants
    • 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
    • A61P11/14—Antitussive agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system

Definitions

  • the invention relates to a novel ambroxol compound and a preparation method thereof, in particular to a salt of ambroxol thiazolidine propionic acid derivative and a preparation method thereof.
  • the invention further relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound, and to the use thereof for the preparation of antitussive and expectorant pharmaceutical preparations. Description of the prior art
  • Ambroxol is an active metabolite of bromhexine. Its chemical name is trans-4-[(2-amino-3, 5-dibromobenzyl)amino]cyclohexanol, a new generation of respiratory tract.
  • the mucus regulator has superior sputum performance, its sputum effect is stronger than that of bromide, and it has a significant promoting effect on the synthesis and secretion of alveolar surfactant.
  • Ambroxol stimulates the bronchial mucous glands to secrete more fluid mucus to dilute the sputum, reduce its viscosity, and increase the production and secretion of pulmonary surfactant, thereby reducing airway resistance and reducing mucus adhesion.
  • Ambroxol is safe to use, has good tolerance, and is re-used without drug accumulation. At present, ambroxol tablets, capsules, syrups, injections, sustained release capsules and the like have been marketed.
  • the structure of the compound is as follows:
  • Mojistein is a non-narcotic antitussive developed by Roche and is an acetylcholine antagonist. Its chemical name is: ( ⁇ ) -3-[2-(hydroxyethylcarbonyl)acetyl]-2-(2-decyloxyphenoxy)tetrahydrothiazole, which is a peripheral property developed and marketed in recent years.
  • Non-narcotic antitussive drugs can alleviate airway inflammation in guinea pigs caused by different stimuli.
  • patients with respiratory illness with cough symptoms reduced cough by 42%, while placebo reduced by only 14%. Compared with the two, the difference was significant, and there was no report of serious adverse reactions of this product.
  • the new compound of ambroxol and thiazolidine propionic acid derivatives has a strong antitussive effect, and its antitussive effect is stronger than that of mojistein alone; its sputum effect is similar to that of ambroxol alone.
  • the new compounds may be those having specific structural and physicochemical properties, as well as amorphous solid powders or lyophilized powders; they may be used in the preparation of various conventional dosage forms.
  • Another object of the present invention is to provide a process for preparing an ambroxol thiazolidine propionic acid derivative salt.
  • the method comprises reacting ambroxol and a thiazolidinepropionic acid derivative in a water or a water-soluble solvent or a mixed solvent to form a salt; and then using a concentrated, mixed solvent crystallization, crystal form conversion, filtration or freeze drying to obtain ammonia A crystalline or lyophilized powder of a bromsothiazolidine derivative salt.
  • thiazolidine derivatives see EP333080.
  • the mixed solvent as used herein refers to a mixture of a water-soluble solvent and a water-insoluble solvent, and the water-soluble solvent is selected from the group consisting of lower alcohols, acetone and mixtures thereof; From halocarbon solvents, ether solvents and mixtures thereof.
  • Lower alcohols include decyl alcohol, ethanol, propanol, isopropanol; ethers refer to diethyl ether, isopropyl ether; hydrocarbon solvents refer to dichlorodecane, trichlorodecane, dichloroethane.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the ambroxol thiazolidine derivative derivative salt of the present invention and a pharmaceutically acceptable carrier, excipient or diluent, etc. .
  • the pharmaceutical composition is a mixture of the ambroxol thiazolidine derivative salt of the present invention prepared by the above method and a pharmaceutically acceptable pharmaceutical adjuvant, and the desired preparation form is obtained according to a conventional preparation method.
  • Such compositions may be in the form of oral preparations such as tablets, capsules, granules, suspensions, pills, and the like, including sustained release preparations, immediate release preparations, and release release preparations.
  • the composition of the present invention can be administered orally or parenterally, and the route of administration, the dose and the number of administrations can be appropriately adjusted depending on the age, body weight and disease of the patient.
  • composition may also be in the form of a large or small volume injection, a lyophilized powder, a sterile powder, or the like.
  • the oral solid preparations include tablets, capsules, granules, pills, and the like, and contain conventional excipients such as a binder such as syrup, starch syrup, gum arabic, gelatin, tragacanth or polyvinylpyrrolidone; Agents such as starch, lactose, microcrystalline cellulose, sugar, calcium phosphate or sorbitol; disintegrants such as sodium carboxymethyl starch, cross-linked sodium cellulose; slips for tableting, such as magnesium stearate or talc Powder; or a surfactant such as sodium lauryl sulfate.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Tablets can be coated into tablets or tablets according to conventional preparation methods.
  • Oral liquid preparations include oral solutions, syrups, emulsions or suspensions, etc., or may be present as a dry product, which may be reconstituted with water or other suitable vehicle before use.
  • These liquid preparations contain conventional additives such as suspending agents such as sugar syrups, cellulosic excipients, gum adjuvants, aluminum stearate gels or hydrogenated food fats; emulsifiers such as lecithin, sorbitan monooleate Or gum arabic; a preservative such as methylparaben or sorbic acid; if desired, conventional flavoring, coloring and co-solvents may also be added.
  • compositions may be in the form of injectable preparations such as large or small volume injections, lyophilized powders, sterile powders and the like.
  • the two active ingredients can be used to prepare unit liquid preparations separately from the sterile vehicle, and are suspended or dissolved in the carrier depending on the concentration used.
  • the active ingredient can be dissolved in water for injection and sterilized by filtration, followed by infusion into a vial or ampoule for sealing.
  • the composition can also be frozen and then filled into a vial and removed under vacuum. Remove moisture. .
  • compositions may also be in the form of other administration formulations such as transdermal agents, sprays or aerosols.
  • Another object of the present invention is to provide the use of the ambroxol thiazolidine propionic acid derivative salt of the present invention or a composition thereof for the preparation of antitussive and expectorant drugs, and for the preparation of a pharmaceutical preparation. Best way to implement the invention
  • Ambroxol somicol hydrolysate 100g was dissolved in water for injection and 150g of mannitol was dissolved in water for injection.
  • the two solutions were mixed and diluted, and diluted with water for injection to 5000 ml, and filtered through a 0.22 um microporous membrane. Under aseptic conditions, they are separately placed in a vial, loaded, and placed in a freeze-drying box. After lyophilization, the box is removed and the lid is rolled.
  • Example 5 Preparation of MA-2 tablets
  • Example 7 MA-2 granules
  • Example 8 After mixing the above raw materials and auxiliary materials, granulation, drying and bagging according to conventional wet method, Example 8: MA-2 dropping pills
  • mice weighing 18.6 ⁇ 0.8 (17.0 ⁇ 20.7) g, were randomly divided into 4 groups according to body weight, 16-18 in each group. 0.5% CMC-Na was given to the control group, and 55 mg/kg was given to ambroxol hydrochloride. 45 mg/kg was administered to the sputum, and 100 mg/kg was administered to the MA-2; the administration volume was 20 ml/kg.
  • the animal was placed in a 500 ml bell jar, a cotton ball was placed in the bell jar, 0.3 ml of ammonia water was quickly injected into the cotton ball, and the cotton ball was taken out after 15 seconds to observe the incubation period of the cough and the number of coughs within 3 min. , compared with the blank control group to determine the effect of drugs on the cough of ammonia.
  • mice after inhalation of ammonia water, mice can induce strong cough, and administration of ambroxol hydrochloride 55mg/kg can prolong the incubation period of cough and reduce the number of coughs, which prolongs the incubation period of animal cough by 31.1%.
  • the administration of 45 mg/kg of mojistin significantly prolonged the incubation period of cough (46.6%, P ⁇ 0.01) and decreased the number of cough (48.9%, P ⁇ 0.01).
  • Administration of -2 100 mg / kg significantly prolonged the incubation period of cough in animals (59.4%, P ⁇ 0.01) and reduced the number of coughs (54.9%, P ⁇ 0.01).
  • the number of coughing results showed that the new compound MA-2 consisting of ambroxol hydrochloride and mojistan had a significant effect, about 2.1 times that of ambroxol hydrochloride and 1.1 times that of mojistan.
  • mice Male mice, weighing about 25 g, were randomly divided into 8 groups according to body weight, 12 rats in each group.
  • the control group was given 0.5% CMC-Na, ambroxol hydrochloride was administered 55 mg/kg, HOmg/kg, and momsettan was given 45 mg. /kg, 90mg/kg, MA-2 was given 100mg/kg, 200mg/kg, and the positive control group was given bromohexine 80mg/kg; the dosage volume was 20ml/kg.
  • 10 ml/kg of 5% citrus physiological saline solution was intraperitoneally injected.
  • the animals were sacrificed by necking, and a trachea from the larynx to the tracheal bifurcation was placed in a test tube supplemented with 2 ml of physiological saline. After shaking for 30 min, add 0. lml of 0. lmol/L NaHC0 3 and mix, measure the red concentration at 545 nm, and observe the effect of the drug on tracheal phenol red secretion.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés ambroxol de formule I, les procédés pour leur préparation et leurs utilisations pour la production d'apophlegmatiques, d'antitussifs ou de médicaments ayant des activités apophlegmatiques et antitussives. (formule I) où R est un hydrogène, un C1-C4 alkyle, un allyle or un propargyle et X est O, CH2 ou S.
PCT/CN2007/001719 2007-05-28 2007-05-28 Nouveaux composés ambroxol, leurs procédés de préparation et leurs utilisations WO2008144956A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/001719 WO2008144956A1 (fr) 2007-05-28 2007-05-28 Nouveaux composés ambroxol, leurs procédés de préparation et leurs utilisations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/001719 WO2008144956A1 (fr) 2007-05-28 2007-05-28 Nouveaux composés ambroxol, leurs procédés de préparation et leurs utilisations

Publications (1)

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WO2008144956A1 true WO2008144956A1 (fr) 2008-12-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104958317A (zh) * 2015-07-30 2015-10-07 青岛蓝盛洋医药生物科技有限责任公司 一种祛痰药物盐酸氨溴索组合物
CN105125530A (zh) * 2015-08-31 2015-12-09 青岛蓝盛洋医药生物科技有限责任公司 一种治疗呼吸***疾病的药物盐酸氨溴索组合物
CN105997903A (zh) * 2015-05-15 2016-10-12 苗怡文 一种治疗呼吸***疾病的药物盐酸氨溴索组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206254A (en) * 1988-03-17 1993-04-27 Boehringer Mannheim Italia S.P.A. β-carbonyl-carboxyamides of 1,3-thiazolidines
CN1699337A (zh) * 2004-05-20 2005-11-23 江苏豪森药业股份有限公司 氨溴索半胱氨酸类似物盐及其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206254A (en) * 1988-03-17 1993-04-27 Boehringer Mannheim Italia S.P.A. β-carbonyl-carboxyamides of 1,3-thiazolidines
CN1699337A (zh) * 2004-05-20 2005-11-23 江苏豪森药业股份有限公司 氨溴索半胱氨酸类似物盐及其制备方法和用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105997903A (zh) * 2015-05-15 2016-10-12 苗怡文 一种治疗呼吸***疾病的药物盐酸氨溴索组合物
CN105997905A (zh) * 2015-05-15 2016-10-12 苗怡文 一种制备治疗呼吸***疾病的盐酸氨溴索冻干粉针剂的方法
CN106265615A (zh) * 2015-05-15 2017-01-04 苗怡文 一种用于制备治疗呼吸***疾病的药物组合物的盐酸氨溴索化合物晶体
CN104958317A (zh) * 2015-07-30 2015-10-07 青岛蓝盛洋医药生物科技有限责任公司 一种祛痰药物盐酸氨溴索组合物
CN105125530A (zh) * 2015-08-31 2015-12-09 青岛蓝盛洋医药生物科技有限责任公司 一种治疗呼吸***疾病的药物盐酸氨溴索组合物

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