WO2023087611A1 - Sel d'ébastine, procédé de préparation associé et son application - Google Patents

Sel d'ébastine, procédé de préparation associé et son application Download PDF

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Publication number
WO2023087611A1
WO2023087611A1 PCT/CN2022/086801 CN2022086801W WO2023087611A1 WO 2023087611 A1 WO2023087611 A1 WO 2023087611A1 CN 2022086801 W CN2022086801 W CN 2022086801W WO 2023087611 A1 WO2023087611 A1 WO 2023087611A1
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WO
WIPO (PCT)
Prior art keywords
ebastine
salt
acid
preparation
piperidinyl
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PCT/CN2022/086801
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English (en)
Chinese (zh)
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钟林睿
牛犇
李家慧
黄坤
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江苏联环药业股份有限公司
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Publication of WO2023087611A1 publication Critical patent/WO2023087611A1/fr

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    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention belongs to the technical field of pharmacy and relates to a class of salts of ebastine, in particular to 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethyl) Oxygen)-1-piperidinyl]-1-butanone pharmaceutically acceptable salt and its preparation method and application.
  • Ebastine is a long-acting, non-sedating second-generation histamine H1 receptor antagonist, which is highly selective for H1 receptors without central inhibitory effect.
  • Clinically used for the treatment of allergic diseases including seasonal, allergic rhinitis and chronic idiopathic urticaria, eczema, skin itching and other diseases; compared with cetirizine, the effect is more significant, and the drowsiness effect is less .
  • ebastine preparations are oral tablets. Because ebastine contains multiple hydrophobic groups in its molecular structure, it is insoluble in water, and the dissolution rate of the tablet is poor, and its bioavailability is low. Absorption, limiting the therapeutic effect of ebastine.
  • the symptoms of allergic diseases are mostly in the skin, nasopharynx, eyes, etc., and are directly administered through pharmaceutical preparations such as solutions, sprays, lotions, liniments, ointments, eye drops, ointments, and ophthalmic gels. In the symptomatic area, it has the advantages of rapid absorption, quick onset, low dose, and small side effects; however, this type of preparation also puts forward certain requirements for the water solubility of the raw material drug.
  • Patents WO2009157006A1 and CN112574097A describe the preparation method of the fumarate of ebastine.
  • the fumarate of ebastine is used as an intermediate in the synthesis of ebastine. Its water solubility and biological activity were measured and described.
  • Patent WO2011/121099A2 describes the preparation method of p-toluenesulfonate, phosphate and oxalate of ebastine, and the water solubility of these salts of ebastine is described, but its biological activity is not Determination and description.
  • the technical problem to be solved by the present invention lies in a class of ebastine salt (formula II), which is a pharmaceutically acceptable salt with certain water solubility, and has good drug activity.
  • Another technical problem to be solved by the present invention is to provide a preparation method for the above-mentioned salt of ebastine, which has the advantages of simplicity, high yield, good purity, and suitability for industrialized production.
  • a technical problem to be solved by the present invention is to provide the pharmaceutical use of the salt of ebastine.
  • a class of salt of ebastine, structural formula (formula II) is as follows:
  • H-A is selected from hydrochloric acid, sulfuric acid, benzenesulfonic acid, maleic acid and malic acid.
  • the preparation method of the salt of ebastine 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piper Pyridyl]-1-butanone is dissolved in a solvent, and acid or acid solution is added at 20-90°C, stirred and reacted, and then purified by column chromatography, thin-layer chromatography, recrystallization or beating 1-[4-(1,1-Dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone salt.
  • the reaction formula is as follows:
  • the solvent is selected from methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, methyl tert-butyl ketone, ethyl acetate, ether, tetrahydrofuran, dichloromethane, chloroform, toluene, water, dimethyl Any one or more mixtures of sulfoxide or dimethylformamide. Preference is given to ethanol or acetone.
  • the solvent and 1-[4-(1,1-dimethylethyl) phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone The dosage ratio is 1.5-6.0mL: 1g; the preferred dosage ratio is 1.5-4.0mL: 1g (the solvent usage refers to the dosage for dissolving ebastine).
  • the acid and 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone The molar ratio is 1-2:1; the preferred molar ratio is 1.05-1.6:1.
  • the reaction temperature is 20-50°C.
  • the preparation method of the salt of ebastine, the purification method is recrystallization or beating.
  • salt of ebastine refers to 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1 -Piperidinyl]-1-butanone reacts with an acid to form a product represented by structural formula "II".
  • the “acid” refers to a Bronsted acid, namely a proton donor, represented by "H-A” in the structural formula.
  • the "pharmaceutically acceptable salt” refers to a kind of salt of ebastine, which is 1-[4-(1,1-dimethylethyl)phenyl]- 4-[4-(Diphenylmethoxy)-1-piperidinyl]-1-butanone obtained by reacting with Bronsted acid, among which the acid is optimally selected but not limited to hydrochloric acid, sulfuric acid, p-toluenesulfonate acid, methanesulfonic acid, benzenesulfonic acid, thiocyanic acid, cyanic acid, dodecylbenzenesulfonic acid, 2-naphthalenesulfonic acid, 2,2-ethanedisulfonic acid, oxalic acid, 2-hydroxyethylsulfonic acid, Orotic acid, glycerophosphoric acid, malic acid, maleic acid, ethanesulfonic acid, phosphoric acid, glutamic acid, rapcyclic acid
  • the “solvent” refers to a liquid or a mixture of liquids, which can make 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy Base)-1-piperidinyl]-1-butanone is dissolved therein, or partially dissolved, or forms a suspension, wherein the liquid is preferably but not limited to water, methanol, ethanol, propanol, isopropanol, butanol Alcohol, tert-butanol, acetonitrile, acetone, 2-butanone, cyclohexanone, methyl tert-butyl ketone, methyl acetate, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, three Chloromethane, 1,2-dichloroethane, carbon tetrachloride, benzene, tolu
  • the “purification” refers to the means of separating the ebastine salt generated by the reaction from the reaction system. This means is preferably but not limited to column chromatography, thin layer chromatography, recrystallization, and beating.
  • the "histamine H1 receptor antagonist” refers to a drug or pharmaceutical composition that can selectively bind to the H1 receptor on histamine target cells and block the histamine H1 receptor to exert an antihistamine effect.
  • the present invention has the following advantages:
  • the preparation method of the salt of ebastine provided by the present invention has the advantages of simplicity, high yield and good purity, and is suitable for industrial production.
  • the salt of ebastine prepared by the present invention can effectively improve the water solubility of ebastine, and has good drug activity.
  • the salt of a class of ebastine provided by the present invention has better histamine H1 receptor antagonistic biological activity and water solubility, and is convenient for preparing various liquid preparations, so that the range of preparations of ebastine It has been expanded and can be better applied to the preparation of various allergic disease drugs.
  • the main detection methods adopted in the following examples are:
  • High-performance liquid chromatography liquid chromatograph: Agilent 1260; chromatographic column: Agilent Eclipse Plus C18 100 ⁇ 4.6mm 3.5 ⁇ m; mobile phase: mobile phase A is phosphate buffer (take 3.58g of disodium hydrogen phosphate dodecahydrate, Add water to dissolve and dilute to 1000mL, adjust the pH value to 6.3 with phosphoric acid, add 1.92g sodium lauryl sulfate, mix well) – acetonitrile (80:20), mobile phase B is acetonitrile. Linear gradient elution was performed according to Table 1. Solvent: acetonitrile-water (75:25) Detection wavelength: 210nm Column temperature: 40°C Flow rate: 1.0mL/min, injection volume: 10 ⁇ L.
  • Liquid mass spectrometry The molecular weight of the sample is tested by electrospray mass spectrometry, and the instrument is Agilent 1290-6460 liquid mass spectrometry.
  • Embodiment 6 Water Solubility Determination
  • the salt of ebastine prepared according to the method provided by the present invention is tested according to the given experimental method in Article 15 of the "Pharmacopoeia of the People's Republic of China" 2020 Edition, and the water solubility data at room temperature (25°C) are shown in the table 2.
  • the Chinese hamster ovary cells were stably transfected with human recombinant H1 receptor, and the ability of ebastine and its salt to bind to H1 receptor competitively with [ 3 H]-mepyramine was detected.
  • Membrane protein (0.2 to 0.3 mg) was co-incubated with 4nM [ 3 H]-mepyramine in 50mM Tris/HCl, pH 7.4, 2mM MgCl 2 buffer, and different concentrations of test substances (5.72nM to 6mM) were added, Among them, 10 ⁇ M cetirizine was added to the non-specific binding well. Incubate at 37° C.
  • % inhibition rate 100 ⁇ [1-(sample well value-low signal well average)/(high signal well average-low signal well average)], use "log(inhibitor) vs.response” in GraphPad Prism 5.0 -Variable slope” model was fitted, and the IC 50 and Ki values were calculated. Two repetitions were set for each test substance in each test, and the average value was obtained by repeating 3 times. The results are shown in Table 4 below.
  • guinea pigs were sacrificed by headbutting, and the abdominal cavity was immediately opened, and a section of ileum with a length of about 8 cm was taken out, placed in Tyrode's solution at 4°C, the fatty tissue around the ileum was removed, rinsed with Tyrode's solution, and a section of ileum about 1.5 cm in length was cut. Put it into a bath containing 20 mL of 37°C preheated and oxygenated (95% O 2 /5% CO 2 ) Tyrode equilibrium solution, fix one end of each ileum segment to a ventilation hook, and connect the other end to a tension transducer.
  • a multi-channel biological signal acquisition and processing system records tension changes.
  • pA2 negative logarithm of the antagonist concentration (mol/L) required to reduce the response of a double dose of agonist to a single dose (for competitive antagonism).
  • Guinea pigs 400 to 500 g, Weitong Lihua Experimental Animal Technology Co., Ltd. were killed, and the whole trachea from the thyroid cartilage to the bifurcation of the trachea was taken, preheated at 37°C and oxygenated (95% O 2 /5% CO 2 )
  • the Krebs balance solution gently and quickly separate the muscular layer, prepare a tracheal ring with a length of about 0.5 cm, connect the tracheal ring to the muscle tone transducer, place it in Krebs balance solution at 37°C for incubation, and continue to give 1g initial tension.
  • the formal experiment was started when the tracheal ring reached an optimal and stable contraction state.
  • the guinea pigs were intravenously injected with corresponding doses of ebastine salt injection prepared in Example 7 according to the groups, and 10 ⁇ g/kg of 0.1% histamine was intravenously injected 1 hour later.
  • Volume scanners were used before and after histamine induction Monitor the tidal volume, and use the electrophysiological monitor to monitor the waveform of each lead.
  • $ is the equimolar dose of ebastine, and the molecular weights are: 469.30, 505.27, 567.27, 627.30, 585.31, 603.32.
  • #The negative control group is an equal volume of water for injection containing 0.004% mannitol, and the bronchoconstriction induced by histamine is recorded as 100%.
  • 35 SD rats (180 to 220 g, Weitong Lihua Experimental Animal Technology Co., Ltd.) were placed in the experimental environment for adaptive feeding for 4 days. Before the experiment, the animals were weighed and grouped, with 5 rats in each group. See Table 8 for the grouping information.
  • cyclophosphamide + 1mg OVA (dissolved in normal saline containing 10mg alum) was injected intraperitoneally.
  • Day 8 was stimulated intranasally with 1% OVA, and Day 15 and Day 22 were stimulated intranasally with 2% OVA once respectively.
  • the animals were given the corresponding dose of the test substance by intragastric administration 1 h before the stimulation on Day 22.
  • the number of sneezing and nasal rubbing of rats was recorded within 10 min.
  • 35 SD rats (180 to 220 g, Weitong Lihua Experimental Animal Technology Co., Ltd.) were placed in the experimental environment for adaptive feeding for 4 days.
  • the Day-1 rats were weighed, shaved and grouped one day before the experiment, with 5 rats in each group.
  • the grouping information is shown in Table 10.
  • Evans Blue was injected intravenously at a dose of 30 mg/kg on Day 1; 45 minutes later, the rabbits were eye-dropped for prophylaxis; 30 minutes after the test substance was instilled, all groups of rabbits were injected with 25 ⁇ L of histamine under the conjunctiva of both eyes for model induction. , the concentration was 30ng/ ⁇ L; 1 hour after the injection of histamine, all the experimental animals were euthanized and the conjunctival tissue was taken to detect the content of Evans Blue to evaluate the effect of each test substance on the vascular permeability of the conjunctiva.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Dermatology (AREA)
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Abstract

La présente invention divulgue un sel d'ébastine, un procédé de préparation associé et une application de ce sel. Le sel de l'ébastine est un sel de 1-[4-(1,1-diméthyléthyl)phényl]-4-[4-(diphénylméthoxy)-1-pipéridinyl]-1-butanone, et le procédé de préparation de ce sel comprend la dissolution de 1-[4-(1,1-diméthyléthyl)phényl]-4-[4-(diphénylméthoxy)-1-pipéridinyl]-1-butanone dans un solvant, l'addition d'un acide ou d'une solution acide à 20 à 90 °C, l'agitation pour permettre une réaction, puis la mise en œuvre d'une purification par chromatographie sur colonne, chromatographie sur couche mince, recristallisation ou mise en suspension pour obtenir le sel. Le procédé de préparation est simple et facile à mettre en œuvre, son rendement est élevé, sa pureté est bonne et il convient à une production industrielle. Le sel d'ébastine a une bonne activité biologique antagoniste du récepteur H1 de l'histamine et une bonne solubilité dans l'eau, il facilite la préparation de différentes préparations liquides et se caractérise par une grande valeur en médication clinique.
PCT/CN2022/086801 2021-11-16 2022-04-14 Sel d'ébastine, procédé de préparation associé et son application WO2023087611A1 (fr)

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CN202111357396.1A CN114014796A (zh) 2021-11-16 2021-11-16 一类依巴斯汀的盐及其制备方法和应用

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CN114014796A (zh) * 2021-11-16 2022-02-08 江苏联环药业股份有限公司 一类依巴斯汀的盐及其制备方法和应用
CN114712322A (zh) * 2022-04-01 2022-07-08 南京联智医药科技有限公司 一种依巴斯汀的盐的片剂及其制备方法
CN114681400A (zh) * 2022-04-01 2022-07-01 南京联智医药科技有限公司 一种含依巴斯汀的盐类口服溶液制剂及其制备方法
CN114671802B (zh) * 2022-04-14 2024-05-17 江苏联环药业股份有限公司 一种高纯度依巴斯汀的制备方法
WO2024146022A1 (fr) * 2023-01-03 2024-07-11 成都施贝康生物医药科技有限公司 Forme cristalline et forme amorphe de p-toluènesulfonate de carébastine

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CN109593058A (zh) * 2019-01-23 2019-04-09 江苏联环药业股份有限公司 一种依巴斯汀的制备方法
CN114014796A (zh) * 2021-11-16 2022-02-08 江苏联环药业股份有限公司 一类依巴斯汀的盐及其制备方法和应用

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CN109593058A (zh) * 2019-01-23 2019-04-09 江苏联环药业股份有限公司 一种依巴斯汀的制备方法
CN114014796A (zh) * 2021-11-16 2022-02-08 江苏联环药业股份有限公司 一类依巴斯汀的盐及其制备方法和应用

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