WO2015106636A1 - 去甲伊伐布雷定盐及其制备方法和应用 - Google Patents

去甲伊伐布雷定盐及其制备方法和应用 Download PDF

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WO2015106636A1
WO2015106636A1 PCT/CN2015/000026 CN2015000026W WO2015106636A1 WO 2015106636 A1 WO2015106636 A1 WO 2015106636A1 CN 2015000026 W CN2015000026 W CN 2015000026W WO 2015106636 A1 WO2015106636 A1 WO 2015106636A1
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acid
pharmaceutically acceptable
salt
acceptable salt
preparation
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French (fr)
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王志刚
娄红祥
李文保
马恩龙
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山东诚创医药技术开发有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a mevabricated salt and a preparation method and application thereof.
  • Patent ivabradine published in EP 0534859, was approved by the European Union EMA in 2005, tablet, 5 mg, for the treatment of chronic stable angina with normal sinus rhythm that is banned or intolerant to beta blockers. Treatment of patients; treatment of patients with chronic stable angina pectoris who have been treated with beta blockers but with poorly controlled symptoms; and treatment of chronic heart failure (heart failure) with systolic dysfunction.
  • the structure of ivabradine is as follows:
  • Mebubricidine is the main active metabolite of ivabradine, and its chemical name is: 3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0] Octyl-1,3,5-triene]-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepine-4-one, chemical formula :C 26 H 34 N 2 O 5 ,Structural formula:
  • Ivabradine is mainly metabolized in the body by the liver CYP3A4 enzyme.
  • CYP3A4 is polymorphism, which is significantly different in different populations. Factors such as race, gender, age, pathological state, diet and drug interaction may affect the production and elimination of active metabolites. The concentrations of ivabradine and norvavirabride in different metabolites are significantly different. The above may lead to significant differences in efficacy and adverse reactions. In some specific populations, dose adjustments are needed to avoid treatment failure or emergence. Significant adverse reactions.
  • the rate of decomposition during in vivo administration may limit the speed of the absorption process, resulting in poor bioavailability.
  • Humidity is also a An important property is that compounds with low wettability are relatively stable and easy to process.
  • the object of the present invention is to provide a desifibrate salt which has good stability and solubility, and has low hygroscopicity and has a remarkable advantage in order to overcome the deficiencies of the prior art described above.
  • the invention also provides a preparation method of the above salt and application thereof.
  • Mevafloxadine salt which is a pharmaceutically acceptable salt, characterized in that the pharmaceutically acceptable salt comprises citrate, hydrobromide, sulfate, phosphate, acetate, three Fluoroacetate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, tartrate, maleate, ascorbate, oxalate, methanesulfonic acid Salt, besylate and camphorate.
  • the pharmaceutically acceptable salt is a decanoate, a fumarate, a maleate, a tartrate, a phosphate or a sulfate.
  • the pharmaceutically acceptable salt is a decanoate or a fumarate.
  • the pharmaceutically acceptable salt is a decanoate having the structural formula:
  • the above-mentioned method for preparing a mevafloxacin salt, a pharmaceutically acceptable salt is specifically prepared by dissolving 1.0 mmol of eswavride in 10 mL of a hot organic solvent, adding 1.0 to 1.1 mmol of acid, and stirring at room temperature 2 Hour, after the end of the reaction, obtained by post-treatment; wherein the temperature of the hot organic solvent is from room temperature to the boiling point of the solvent; the acid includes tannic acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid , pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid.
  • the acid is capric acid, fumaric acid, maleic acid, tartaric acid, phosphoric acid or sulfuric acid.
  • the temperature of the hot organic solvent is from 30 ° C to the boiling point of the solvent.
  • the room temperature according to the present invention is 10 to 30 °C.
  • the acid is capric acid or fumaric acid.
  • the acid is citric acid.
  • the organic solvent is methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane Any of them.
  • the organic solvent is acetone, ethyl acetate, ethanol, dichloromethane or tetrahydrofuran.
  • the organic solvent is acetone.
  • the post-treatment includes a crystallization, suction filtration, dipping and vacuum drying steps, or evaporation of the organic solvent under vacuum, immersion and vacuum drying steps, or decolorization of the adsorbent material, filtration, evaporation of the organic solvent under reduced pressure, dipping and vacuum.
  • the adsorbent material is activated carbon, silica gel or diatomaceous earth.
  • An oral preparation comprising a therapeutically effective amount of a pharmaceutically acceptable salt of desifibrate, and a pharmaceutically acceptable carrier;
  • the pharmaceutically acceptable salt comprising a decanoate, a hydrobromide salt, Sulfate, phosphate, acetate, trifluoroacetate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, tartrate, maleate , ascorbate, oxalate, methanesulfonate, besylate and camphorate;
  • the pharmaceutically acceptable salt is a decanoate, a fumarate, a maleate, a tartrate, Phosphate or sulfate.
  • the pharmaceutically acceptable salt is a decanoate or a fumarate.
  • the pharmaceutically acceptable salt is a decanoate.
  • the preparation is a tablet or capsule.
  • the above-mentioned pharmaceutically acceptable salt of efavirel is useful for the preparation of a chronic stable angina drug for treating a banned or intolerant beta blocker, sinus rhythm.
  • the norvavirabride salt of the present invention has good stability and solubility, and has weak wettability, and the advantages are remarkable, as follows:
  • the performance of citrate is the most superior, and the effect is remarkable.
  • the stability and solubility of various salts were found to be superior to other salts in the stability of citrate and in the pH range of the human gastrointestinal tract.
  • the hygroscopicity of the citrate is significantly lower than that of other salts, which is more conducive to the preparation and preservation of the preparation.
  • the pharmaceutically acceptable salt prepared by the present invention can also be used as a starting reagent to further react with other corresponding acids to form other addition salts, thereby obtaining a product having a high purity.
  • the pharmaceutically acceptable salt of the present invention can be used for the preparation of a chronic stable angina pectoris drug for treating a banned or intolerant beta blocker and a sinus rhythm.
  • Devafloxacin in Examples 1-12 was prepared according to the method disclosed in EP 2241554B.
  • the physicochemical properties and identification data of the prepared nevirapride decanoate are as follows:
  • Examples 1 to 6 were prepared under different experimental conditions for the preparation of yumvabradine citrate, and the methods of these examples all gave high-purity deevirapide citrate.
  • Devafloxacin fumarate was prepared from norvaribratin.
  • the chemical reaction formula is as follows:
  • the physicochemical properties and identification data of the prepared nevabradine fumarate are as follows:
  • Defibricabate maleate was prepared from norvaribratin.
  • the chemical reaction formula is as follows:
  • Devafloxacin sulfate is prepared from norvavirabride, and the chemical reaction formula is as follows:
  • Devafloxadine is prepared from norvavirabride hydrochloride, and the chemical reaction formula is as follows:
  • the salt of desipribide obtained by the present invention has a higher free base release, which is very important in the preparation of the drug.
  • the base for releasing the free base is not limited to the sodium hydroxide of the present embodiment, and potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, pyridine or the like can also be used.
  • Example 14 A salt prepared by the method of the present invention was used as a starting reagent to further react with other corresponding acids to form other addition salts, thereby obtaining a product having a high purity.
  • Example 1 The stability test of the salt of nevafleuride obtained in Example 1 and Examples 7 to 12 was carried out, and the test method was carried out in accordance with the guidelines of the stability test "Chinese Pharmacopoeia 2010 Edition". The results are shown in Table 1-1 to Table 1-5.
  • Solvent Hydrochloride Citrate Fumarate pH 1.0 Slightly soluble Soluble Soluble pH 2.5 Very slightly soluble Dissolve Dissolve pH 4.0 Dissolve Soluble Slightly soluble pH 5.5 Slightly soluble Soluble Slightly soluble pH 6.2 Slightly soluble Soluble Slightly soluble pH 6.8 Slightly soluble Soluble Slightly soluble pH 8.2 Slightly soluble Dissolve Slightly soluble water Dissolve Soluble Slightly soluble Methanol Dissolve Slightly soluble Slightly soluble Dichloromethane Soluble Slightly soluble Slightly soluble acetone Almost insoluble Almost insoluble Almost insoluble Almost insoluble
  • citrate pKa6.2, fumarate pKa8.2, hydrochloride pKa9.6 (using spectrophotometry, see the literature "Microscale Titrimetric and Spectrophotometric Methods for Determination of Ionization Constants and Partition Coefficients of New Drug Candidates , MICHAEL E. MORGAN, KUI LIU, BRADLEYD. ANDERSON, Journal of Pharmaceutical Sciences, Vol. 87, No. 2, February 1998").
  • the citrate has the best solubility in the pH range of the human gastrointestinal tract (1.0-6.8), which is beneficial to the absorption of the gastrointestinal tract.
  • Examples 15, 17, 19 are dry direct compression or capsules.
  • Preparation method Weighed with ezepride citrate, lactose, starch, maltodextrin, silica for 5 minutes according to the prescription amount, added magnesium stearate and mixed for 2 minutes, and tableted by tableting machine (Examples 15 and 17 were pressed at 10,000 sheets, and Example 19 was pressed at 5,000 sheets), and purified water was added to a coating premix of Opadry 03b28796 to obtain a concentration of 10%, and the coating weight gain was 2 to 4%. Or capsules were poured into the capsule shell (Examples 15 and 17 were filled with 10,000 capsules, and Example 19 was filled with 5000 capsules).
  • Examples 16, 18, and 20 are wet granulation tablets or capsules.
  • the ezepride citrate is pulverized through a 100 mesh sieve, and the microcrystalline cellulose, lactose, and croscarmellose sodium are passed through a 60 mesh sieve; the hypromellose is dissolved in purified water to prepare 2% hypromellose aqueous solution, spare.
  • Example 6 tableting (Examples 16 and 18 pressure 10000 tablets, Example 20 pressure 5000 tablets), using Opadry 03b28796 coating premix into the purified water to obtain a concentration of 10%, coating weight gain 2-4% Or a capsule obtained by pouring into a capsule shell (10,000 pellets for Examples 16 and 18 and 5000 pellets for Example 20).
  • the frog heart cannula was fixed on the iron stent, and the apex was clamped in the ventricular diastolic period to clamp the apex, and the wire tip of the frog heart clip was connected to the tension transducer through a pulley to adjust the preload to 1 g.
  • the normal frog heart beat curve was traced, and the heart rate, ventricular contraction and relaxation were observed and recorded. After stabilization, different concentrations of the test solution were added, and the changes of heart rate, ventricular contraction and diastolicity were recorded, and continuous recording was performed for 30 minutes to calculate the heart rate and the maximum inhibition rate of ventricular contraction and relaxation.
  • Sample norfivide citrate citrate, ivabradine hydrochloride, when used in physiological saline to the corresponding concentration of the drug solution, and physiological saline as a blank control group;
  • Wistar rats were divided into 6 groups: high, medium and low doses of desifibrate citrate, high and medium dose groups of ivabradine hydrochloride and normal saline group.
  • Ten rats were anesthetized by intraperitoneal injection of 20% urethane (4 mL/kg) and fixed in the dorsal position. Collect and record heart rate.
  • the rats in each group were anesthetized and the normal electrocardiogram was recorded for 5 min. The heart rate was recorded. Then, the test solutions were administered at different concentrations (10 mL/kg). After the administration, the electrocardiogram was continuously recorded and the heart rate was recorded for 8 hours. The maximum heart rate was inhibited. The rate reflects the effect of heart rate on drug anesthetized rats.
  • the results are shown in Table 5.
  • the maximum heart rate inhibition was produced in the hour, and the mevaflurane citrate was stronger than the same dose of the control drug.

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Abstract

去甲伊伐布雷定盐及其制备方法和应用。该去甲伊伐布雷定盐，为药学上可接受的盐，所述药学上可接受的盐包括枸橼酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、乳酸盐、丙酮酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、富马酸盐、酒石酸盐、马来酸盐、抗坏血酸盐、草酸盐、甲磺酸盐、苯磺酸盐和樟脑酸盐。

Description

去甲伊伐布雷定盐及其制备方法和应用 技术领域
本发明属于医药技术领域，具体涉及去甲伊伐布雷定盐及其制备方法和应用。
背景技术
专利EP 0534859公开的伊伐布雷定(ivabradine)于2005年获得欧盟EMA批准，片剂，规格5mg，用于治疗禁用或不耐受β受体阻滞剂的窦性心律正常的慢性稳定型心绞痛患者的治疗；已使用β受体阻滞剂但症状控制不佳慢性稳定型心绞痛患者的治疗；以及合并收缩功能异常的慢性心力衰竭(心衰)治疗。伊伐布雷定的结构如下：
Figure PCTCN2015000026-appb-000001
去甲伊伐布雷定是伊伐布雷定的主要活性代谢产物，其化学名称为：3-[3-[[(8S)-3，4-二甲氧基-8-双环[4.2.0]辛-1，3，5-三烯]-甲氨基]丙基]-7，8-二甲氧基-2，5-二氢-1H-3-苯并氮杂卓-4-酮，化学式：C26H34N2O5，结构式：
Figure PCTCN2015000026-appb-000002
伊伐布雷定在体内主要经肝脏CYP3A4酶代谢。CYP3A4主要特征之一为其具有多态性，在不同人群中表达差异显著，人种、性别、年龄、病理状态、饮食及药物相互作用等因素都有可能影响活性代谢物的生成及消除，因而不同代谢型人群服用药物后伊伐布雷定及去甲伊伐布雷定的浓度个体差异明显，以上可导致药效及不良反应个体差异明显，在某些特定人群需要调整剂量以避免治疗无效或出现明显的不良反应。
申请人研究了去甲伊伐布雷定体内外生理活性，发现其药效活性和有效作用时间均显著优于伊伐布雷定，并有望弥补伊伐布雷定临床治疗中的前述缺陷。由于去甲伊伐布雷定在水中难溶，申请人进一步将水溶性差的药物转变成盐，从而增加其水溶性。盐的形成会改变药物理化性质及生物学特性而不改变其基本的化学结构。盐的形式可能对药物的性质产生一定程度的影响，它的引湿性、稳定性、溶解性和加工特性等都是非常重要的考察指标。溶解性是盐的一个重要特性，可能影响其是否适合用于制备药品。当水溶性低，即小于10mg/mL时，体内给药时的分解速度可能限制吸收过程的速度，导致生物利用度差。引湿性也是一个 重要的特性，引湿性低的化合物比较稳定并易于加工。
因此，如何选择将去甲伊伐布雷定转变成合适的盐，对于获得药物的性质有着非常重大的影响。
但是，申请人通过初步研究发现去甲伊伐布雷定的盐在稳定性、引湿性、溶解性等方面存在较大差异，这些差异可能影响药品生产、质量、吸收和疗效。
发明内容
本发明的目的是为克服上述现有技术的不足，提供去甲伊伐布雷定盐，其具有良好的稳定性和溶解性，并且具有较低的引湿性，优势显著。
本发明还提供了上述盐的制备方法及其应用。
为实现上述目的，本发明采用下述技术方案：
去甲伊伐布雷定盐，为药学上可接受的盐，其特征在于，所述药学上可接受的盐包括枸橼酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、乳酸盐、丙酮酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、富马酸盐、酒石酸盐、马来酸盐、抗坏血酸盐、草酸盐、甲磺酸盐、苯磺酸盐和樟脑酸盐。
所述药学上可接受的盐为枸橼酸盐、富马酸盐、马来酸盐、酒石酸盐、磷酸盐或硫酸盐。
所述药学上可接受的盐为枸橼酸盐或富马酸盐。
所述药学上可接受的盐为枸橼酸盐，其结构式为：
Figure PCTCN2015000026-appb-000003
上述去甲伊伐布雷定盐，药学上可接受的盐的制备方法，具体步骤是：将1.0mmol去甲伊伐布雷定溶解于10mL热有机溶剂中，加入1.0～1.1mmol酸，室温搅拌2小时，反应结束后经后处理即得；其中，所述热有机溶剂的温度为室温至溶剂沸点；所述的酸包括枸橼酸、氢溴酸、硫酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、抗坏血酸、草酸、甲磺酸、苯磺酸和樟脑酸。
所述的酸为枸橼酸、富马酸、马来酸、酒石酸、磷酸或硫酸。
作为优选，所述热有机溶剂的温度为30℃至溶剂沸点。
本发明所述的室温为10～30℃。
优选的，所述的酸为枸橼酸或富马酸。
优选的，所述的酸为枸橼酸。
所述的有机溶剂为甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、二氯甲烷、氯仿、四氯化碳、1，2-二氯乙烷、四氢呋喃、1，4-二氧六环中的任一种。
优选的，所述的有机溶剂为丙酮、乙酸乙酯、乙醇、二氯甲烷或四氢呋喃。
优选的，所述的有机溶剂为丙酮。
所述的后处理包括析晶、抽滤、浸洗和真空干燥步骤，或者减压蒸发有机溶剂、浸洗和真空干燥步骤，或者吸附材料脱色、过滤、减压蒸发有机溶剂、浸洗和真空干燥步骤，或者吸附材料脱色、过滤、析晶、抽滤、浸洗和真空干燥步骤。
所述的吸附材料为活性炭、硅胶或者硅藻土。
一种口服制剂，含有治疗有效量的去甲伊伐布雷定药学上可接受的盐，以及药学上可接受的载体；所述药学上可接受的盐包括枸橼酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、乳酸盐、丙酮酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、富马酸盐、酒石酸盐、马来酸盐、抗坏血酸盐、草酸盐、甲磺酸盐、苯磺酸盐和樟脑酸盐；所述药学上可接受的盐优选为枸橼酸盐、富马酸盐、马来酸盐、酒石酸盐、磷酸盐或硫酸盐。
所述药学上可接受的盐为枸橼酸盐或富马酸盐。
所述药学上可接受的盐为枸橼酸盐。
所述的制剂为片剂或胶囊。
上述去甲伊伐布雷定药学上可接受的盐在制备用于治疗禁用或不耐受β受体阻断剂、窦性心律正常的慢性稳定型心绞痛药物中的应用。
本发明的有益效果：
(1)本发明的去甲伊伐布雷定盐，具有良好的稳定性和溶解性，并且具有较弱的引湿性，优势显著，具体如下：
(a)具有良好的稳定性，在高温、高湿及光照条件下最大单杂的变化小；
(b)在人体胃肠道pH值范围内溶解性好；
(c)具有较低的引湿性，对储存环境和生产设备的要求低，更利于制剂的制备和保存。
其中，以枸橼酸盐的性能最优越，并且效果显著。对各种盐的稳定性及溶解性考察发现，枸橼酸盐的稳定性和在人体胃肠道pH值范围内的溶解性明显优于其他盐。并且，枸橼酸盐的引湿性与其他盐相比明显较低，更利于制剂的制备和保存。
(2)本发明的去甲伊伐布雷定盐的制备方法简单，对设备没有特殊要求，并且，获得产品纯度高，最高可达99.7324％。
(3)本发明制备得到的药学上可接受的盐还可以作为起始试剂，进一步与其他相应的酸反应，生成其他的加成盐，从而获得纯度高的产品。
(4)本发明的药学上可接受的盐可以用于制备治疗禁用或不耐受β受体阻断剂、窦性心律正常的慢性稳定型心绞痛药物。
(5)体外药理试验结果表明，去甲伊伐布雷定枸橼酸盐及伊伐布雷定盐酸盐均可减慢体外蛙心心跳频率，且去甲伊伐布雷定枸橼酸盐心率抑制作用强于伊伐布雷定盐酸盐。在试验考察浓度范围内，二者对蛙离体心脏心室收缩和舒张程度均无明显影响。体内药理试验结果表明，受试药去甲伊伐布雷定枸橼酸盐及对照药伊伐布雷定盐酸盐在给药后4～5小时产生最大心率抑制作用，去甲伊伐布雷定枸橼酸盐与同剂量对照药相比，心率抑制作用强。体外离体蛙心的活性研究以及大鼠体内试验表明，本发明的去甲伊伐布雷定枸橼酸盐的生理活性优于已上市的伊伐布雷定盐酸盐，并且，去甲伊伐布雷定枸橼酸盐具有药效学个体差异小的优点。
具体实施方式
下面结合实施例对本发明进行进一步的阐述，应该说明的是，下述说明仅是为了解释本发明，并不对其内容进行限定。
实施例1～12中的去甲伊伐布雷定均按照EP 2241554B公开的方法制备。
实施例1去甲伊伐布雷定枸橼酸盐的制备
由去甲伊伐布雷定制备去甲伊伐布雷定枸橼酸盐，化学反应式如下：
Figure PCTCN2015000026-appb-000004
将45.4g(100mmol)去甲伊伐布雷定溶解在30℃的1000mL丙酮中，加入21.1g(110mmol)枸橼酸。将混合物在室温下搅拌反应2小时，将析出的晶体抽滤，用200mL丙酮浸洗，真空干燥得到去甲伊伐布雷定枸橼酸盐52.4g，收率81％，HPLC：99.734％。
制备得到的去甲伊伐布雷定枸橼酸盐理化性质及鉴别数据如下：
M.p.141-143℃：
DSC曲线(封闭盘10℃/分钟)：始于143.6℃。
IR光谱(KBr，以cm-1计算)：417，432，460，491，516，543，570，613，639，657，677，696，723，758，789，827，860，871，885，917，937，962，980，1005，1029，1072，1107，1161，1178，1207，1220，1248，1261，1284，1313，1349，1379，1404，1429，1446，1484，1518，1567，1599，1628，1697，1747，1933，2488，2644，2833，2921，2935，2969，3384。
1H-NMR(ppm)：1.88(m，2H)；2.08(s，1H)；2.53(s，2H)；2.57(s，2H)；2.59(s，1H)；2.85～2.93(m，3H)；2.99(m，2H)；3.00～3.09(m，1H)；3.20～3.28(dd，1H)；3.42(m，2H)；3.60(m，1H)；3.7(s，12H)；3.74(t，2H)；3.79(s，3H)；6.68(s，1H)；6.72(s，1H)；6.80(s，1H)；6.90(s，1H)；9.9～10.9(s，3H)。
13C-NMR(ppm)：25.12；31.96；34.51；38.93；41.92；43.32；44.85；45.20；45.83；50.83；55.89；55.92；55.98；56.27；56.28；71.86；108.16；108.47；114.27；114.76；123.76；128.24；134.56；135.94；147.16；147.91；149.71；150.66；172.01；172.89；177.37。
实施例2去甲伊伐布雷定枸橼酸盐的制备
将4.54g(10mmol)去甲伊伐布雷定溶解在30℃的100mL乙酸乙酯中，加入2.11g(11mmol)枸橼酸。将混合物在室温下搅拌反应2小时，将析出的晶体抽滤，用20mL乙酸乙酯浸洗，真空干燥得到去甲伊伐布雷定枸橼酸盐5.56g，收率86％，HPLC：99.644％。
实施例3去甲伊伐布雷定枸橼酸盐的制备
将4.54g(10mmol)去甲伊伐布雷定溶解在40℃的100mL乙醇中，加入2.11g(11mmol)枸橼酸。将混合物在室温下搅拌反应2小时，升高温度至55℃，加入0.3g活性炭脱色10分钟，趁热过滤。放置在20～25℃析晶3小时。将析出的晶体抽滤，用20mL乙醇浸洗，真空干燥得到去甲伊伐布雷定枸橼酸盐5.36g，收率83％，HPLC：99.840％。
实施例4去甲伊伐布雷定枸橼酸盐的制备
将4.54g(10mmol)去甲伊伐布雷定溶解在25℃的二氯甲烷中，加入2.11g(11mmol)枸橼酸。将混合物在室温下搅拌反应2小时，升高温度至回流，加入0.3g活性炭脱色10分钟，趁热过滤。放置在15～20℃析晶4小时。将析出的晶体抽滤，用20mL二氯甲烷浸洗，真空干燥得到去甲伊伐布雷定枸橼酸盐5.15g，收率79.7％，HPLC：99.751％。
实施例5去甲伊伐布雷定枸橼酸盐的制备
将4.54g(10mmol)去甲伊伐布雷定溶解在25℃的60mL四氢呋喃中，加入2.11g(11mmol)枸橼酸。将混合物在室温下搅拌反应2小时，升高温度至回流，加入0.3g硅藻土吸附10分 钟，趁热过滤。放置在15～20℃析晶4小时。将析出的晶体抽滤，用10mL四氢呋喃浸洗，真空干燥得到去甲伊伐布雷定枸橼酸盐5.05g，收率78％，HPLC：99.721％。
实施例6去甲伊伐布雷定枸橼酸盐的制备
将4.54g(10mmol)去甲伊伐布雷定溶解在35℃的100mL乙腈中，加入1.91g(10mmol)枸橼酸。将混合物在室温下搅拌反应2小时，升高温度至回流，加入0.3g硅胶吸附10分钟，趁热过滤。放置在15～20℃析晶4小时。将析出的晶体抽滤，用10mL四氢呋喃浸洗，真空干燥得到去甲伊伐布雷定枸橼酸盐5.65g，收率87％，HPLC：99.922％。
实施例1～6为不同实验条件下去甲伊伐布雷定枸橼酸盐的制备，通过这些实施例的方法均得到高纯度的去甲伊伐布雷定枸橼酸盐。
实施例7去甲伊伐布雷定富马酸盐的制备
由去甲伊伐布雷定制备去甲伊伐布雷定富马酸盐，化学反应式如下：
Figure PCTCN2015000026-appb-000005
将45.4g(100mmol)去甲伊伐布雷定溶解在30℃的1000mL丙酮中，加入12.8g(110mmol)富马酸。将混合物在室温下搅拌反应2小时，将析出的晶体抽滤，用200mL丙酮浸洗，真空干燥得到去甲伊伐布雷定富马酸盐43.6g，收率76.4％。HPLC：99.725％。
制备得到的去甲伊伐布雷定富马酸盐理化性质及鉴别数据如下：
M.p.177℃-179℃：
DSC曲线(封闭盘10℃/分钟)：始于179.8℃。
IR光谱(KBr，以cm-1计算)：432，457，472，502，555，576，663，697，723，742，762，774，804，827，858，893，910，955，981，1001，1043，1066，1079，1101，1157，1178，1209，1222，1247，1260，1313，1357，1405，1422，1463，1489，1519，1572，1627，1657，1709，2465，2830，2853，2938，2964，3007，3074，3282，3538。
1H-NMR(ppm)：1.78～1.80(m，2H)；2.08(s，1H)；2.71(t，2H)；2.76～2.79(d，1H)；2.86～2.89(m，1H)；2.95～2.97(m，2H)；3.02～3.05(dd，1H)；3.13～3.16(dd，1H)；3.36～3.44(m，2H)；3.68～3.70(s，12H)；3.71～3.76(t，2H)；3.80(s，2H)；3.81(s，1H)；6.45 (s，2H)；6.66(s，1H)；6.71(s，1H)；6.76(s，1H)；6.88(s，1H)。
13C-NMR(ppm)：26.45；32.11；34.38；40.44；42.03；43.68；45.65；45.66；51.89；55.85；55.95；56.21；56.25；108.07；108.47；110.00；114.22；114.75；123.89；128.26；134.69；135.83；135.97；137.59；147.10；147.86；149.58；150.28；169.29；172.31。
实施例8去甲伊伐布雷定马来酸盐的制备
由去甲伊伐布雷定制备去甲伊伐布雷定马来酸盐，化学反应式如下：
Figure PCTCN2015000026-appb-000006
将45.4g(100mmol)去甲伊伐布雷定溶解在40℃的1000mL乙醇中，加入11.6g(100mmol)马来酸。将混合物在室温下搅拌反应2小时，减压蒸发掉溶剂，残余物用100mL四氯化碳浸洗，得到去甲伊伐布雷定马来酸盐的油状物53.6g，收率94％。HPLC：99.526％。
实施例9去甲伊伐布雷定酒石酸盐的制备
由去甲伊伐布雷定制备L-(+)-酒石酸去甲伊伐布雷定盐，化学反应式如下：
Figure PCTCN2015000026-appb-000007
将45.4g(100mmol)去甲伊伐布雷定溶解在45℃的1000mL四氢呋喃中，加入16.5g(110mmol)L-(+)-酒石酸。将混合物在室温下搅拌反应2小时，减压蒸发掉溶剂，残余物用200mL丙酮浸洗，真空干燥得到L-(+)-酒石酸去甲伊伐布雷定盐53.6g，收率94％。HPLC：99.637％。
实施例10去甲伊伐布雷定磷酸盐的制备
由去甲伊伐布雷定制备去甲伊伐布雷定磷酸盐，化学反应式如下：
Figure PCTCN2015000026-appb-000008
将45.4g(100mmol)去甲伊伐布雷定溶解在35℃的1000mL乙腈中，加入10.8g(110mmol)磷酸。将混合物在室温下搅拌反应2小时，加入10.0g活性炭脱色10分钟，过滤。减压蒸发掉溶剂，残余物用200mL丙酮浸洗，真空干燥得到去甲伊伐布雷定磷酸盐43.8g，收率79％。HPLC：99.547％。
实施例11去甲伊伐布雷定硫酸盐的制备
由去甲伊伐布雷定制备去甲伊伐布雷定硫酸盐，化学反应式如下：
Figure PCTCN2015000026-appb-000009
将45.4g(100mmol)去甲伊伐布雷定溶解在30℃的1000mL丙酮中，加入10.8g(110mmol)硫酸。将混合物在室温下搅拌反应2小时，减压蒸发掉溶剂，残余物用200mL丙酮浸洗，真空干燥得到去甲伊伐布雷定硫酸盐40.2g，收率73％。HPLC：99.602％。
实施例12去甲伊伐布雷定盐酸盐的制备
将45.4g(100mmol)去甲伊伐布雷定溶解在30℃的1000mL乙酸乙酯中，加入110mL的1mol/L的盐酸溶液。将混合物在室温下搅拌反应2小时，将析出的晶体抽滤，用200mL乙酸乙酯浸洗，真空干燥得到去甲伊伐布雷定盐酸盐41.7g，收率85％，HPLC：99.558％。
实施例13去甲伊伐布雷定的制备
由去甲伊伐布雷定盐酸盐制备去甲伊伐布雷定，化学反应式如下：
Figure PCTCN2015000026-appb-000010
将49.1g(100mmol)去甲伊伐布雷定盐酸盐(按照实施例12的方法制备得到)溶解在1000mL蒸馏水中，加入4.4g(110mmol)氢氧化钠。将混合物在室温下搅拌反应1小时，加入1000mL二氯甲烷萃取。分离出有机相，用无水硫酸钠0.5g干燥1小时，过滤、减压蒸发掉溶剂，残余物加入丙酮1000mL，控制温度5～10℃，析晶2小时，过滤，真空干燥得到去甲伊伐布雷定38.5g，收率85％。HPLC：99.814％。
采用本发明获得的去甲伊伐布雷定的盐，释放出的游离碱纯度更高，这在药物制备中非常重要。用于释放游离碱的碱不局限于本实施例的氢氧化钠，还可以采用氢氧化钾、氢氧化钙、氢氧化铵、碳酸钠、甲胺、二甲胺、三乙胺、吡啶等。
实施例14由去甲伊伐布雷定枸橼酸盐制备去甲伊伐布雷定富马酸盐
将实施例1制备得到的323.1mg(0.5mmol)去甲伊伐布雷定枸橼酸盐，加入到30℃的10mL丙酮中，加入64mg(0.55mmol)富马酸。搅拌反应5小时，室温析晶5小时。将析出的晶体抽滤，用2mL丙酮浸洗，真空干燥得到去甲伊伐布雷定富马酸盐220mg，收率80％。HPLC：99.876％。
实施例14将根据本发明方法制备得到的盐作为起始试剂，进一步与其他相应的酸反应，生成其他的加成盐，从而获得纯度高的产品。
对实施例1和实施例7～12获得的去甲伊伐布雷定的盐进行了稳定性试验，试验方法参照稳定性试验指导原则《中国药典2010版》进行。结果见表1-1至表1-5。
表1-1.去甲伊伐布雷定不同盐的性状
Figure PCTCN2015000026-appb-000011
表1-2.去甲伊伐布雷定不同盐的熔点
Figure PCTCN2015000026-appb-000012
表1-3.去甲伊伐布雷定不同盐的有关物质
Figure PCTCN2015000026-appb-000013
表1-4.去甲伊伐布雷定不同盐的异构体
Figure PCTCN2015000026-appb-000014
表1-5.去甲伊伐布雷定不同盐的引湿性
Figure PCTCN2015000026-appb-000015
结论：
由表1-1至表1-5可以看出枸橼酸盐稳定性好，特别是有关物质以及引湿性等指标具有显著的优势。
对去甲伊伐布雷定盐酸盐、枸橼酸盐和富马酸盐进行了溶解度试验，试验方法参照《中国药典2010版》进行。结果见表2。
表2.去甲伊伐布雷定不同盐的溶解度试验结果
溶剂 盐酸盐 枸橼酸盐 富马酸盐
pH 1.0 微溶 易溶 易溶
pH 2.5 极微溶解 溶解 溶解
pH 4.0 溶解 易溶 略溶
pH 5.5 微溶 易溶 略溶
pH 6.2 微溶 易溶 微溶
pH 6.8 略溶 易溶 微溶
pH 8.2 略溶 溶解 略溶
水 溶解 易溶 略溶
甲醇 溶解 略溶 微溶
二氯甲烷 易溶 微溶 略溶
丙酮 几乎不溶 几乎不溶 几乎不溶
结论：
枸橼酸盐pKa6.2、富马酸盐pKa8.2、盐酸盐pKa9.6(采用分光光度法，测定方法见文献“Microscale Titrimetric and Spectrophotometric Methods for Determination of Ionization Constants and Partition Coefficients of New Drug Candidates，MICHAEL E.MORGAN，KUI LIU，BRADLEYD.ANDERSON，Journal ofPharmaceutical Sciences，Vol.87，No.2，February1998”)。枸橼酸盐在人体胃肠道pH值范围(1.0～6.8)内溶解性最好，有利于胃肠道吸收。
通过以上实验发现，去甲伊伐布雷定的盐酸盐、富马酸盐、酒石酸盐、磷酸盐和硫酸盐在高温、高湿和光照条件下的最大单杂变化大，稳定性较差，而枸橼酸盐的最大单杂变化小，稳定性好。在引湿性方面，硫酸盐易潮解，高湿环境下为液态，磷酸盐(19.3％)、酒石酸盐(16.3％)和盐酸盐(10％)的引湿性较强，富马酸盐引湿性一般(4.02％)，枸橼酸盐的引湿性最低p(1.13％)。在溶解性方面，枸橼酸盐在人体胃肠道pH值范围内溶解性最好。
由此可以看出，与去甲伊伐布雷定的其他盐相比，枸橼酸盐的稳定性、引湿性及溶解性 等均具有明显的优势。
本发明所述的制剂通过实施例15-20(表3)得到，其中的去甲伊伐布雷定枸橼酸盐由实施例1制备得到：
表3
Figure PCTCN2015000026-appb-000016
实施例15，17，19为干法直接压片或灌胶囊。制备方法：按处方量称取去甲伊伐布雷定枸橼酸盐、乳糖、淀粉、麦芽糊精、二氧化硅混合5分钟，加入硬脂酸镁并混合2分钟，用压片机压片(实施例15和17压10000片，实施例19压5000片)，用欧巴代03b28796的包衣预混剂加入纯化水得10％的浓度，包衣增重2～4％。或灌入胶囊壳中得胶囊(实施例15和17灌装10000粒胶囊，实施例19灌装5000粒胶囊)。
实施例16，18，20为湿法制粒压片或灌胶囊
将去甲伊伐布雷定枸橼酸盐粉碎过100目筛，微晶纤维素、乳糖、交联羧甲基纤维素钠过60目筛；将羟丙甲纤维素溶解于纯化水中，制成2％羟丙甲纤维素水溶液，备用。
2、按处方量称取去甲伊伐布雷定枸橼酸盐、微晶纤维素、乳糖、交联羧甲基纤维素钠，用一个高效湿法混合制粒机，干混合10分钟。
3、加入配制好的2％羟丙甲纤维素水溶液，使用高剪切制粒将混粉制成湿颗粒。
4、用流化床干燥器或热风循环烘箱将湿颗粒干燥至水分低于3％。
5、干燥颗粒经30目尼龙筛网或不锈钢筛网整粒，加入二氧化硅，混合10分钟，加入硬脂酸镁并混合2分钟。
6、压片(实施例16和18压10000片，实施例20压5000片)，用欧巴代03b28796的包衣预混剂加入纯化水得10％的浓度，包衣增重2～4％；或灌入胶囊壳中得胶囊(实施例16和18灌装10000粒，实施例20灌装5000粒)。
试验例
以下涉及的去甲伊伐布雷定枸橼酸盐由实施例1制备得到，伊伐布雷定盐酸盐由济南健丰化工有限公司购得。
1.体外试验
【材料】
去甲伊伐布雷定枸橼酸盐，伊伐布雷定盐酸盐，用时以任氏液配置成相应浓度药液，并以任氏液作为空白对照组；
【方法】
1、调节RM1640生物信号处理系统相应参数。
2、离体蛙心制备：
取蟾蜍一只，破坏脑和脊髓后，仰卧固定在蛙板上，手术暴露心脏，分离左、右主动脉，在左主动脉下方穿线备用。用眼科剪在左主动脉根部剪一小斜口，将盛有任氏液蛙心插管由此切口处插入动脉圆锥并转向心室中央方向，心室收缩期时将插管插入心室，蛙心插管用备线固定后剪断主动脉左右分支。用新鲜任氏液反复换洗蛙心插管内含血的任氏液，直至蛙心插管内无血液残留为止。将蛙心插管固定在铁支架上，用蛙心夹在心室舒张期夹住心尖，并将蛙心夹的线头通过滑轮连至张力换能器，调节前负荷至1g。
3、药物处置：
描记正常的蛙心搏动曲线，观察并记录心跳频率、心室的收缩和舒张程度。待稳定后加入不同浓度受试药液，记录心跳频率、心室的收缩和舒张程度的变化，连续记录30分钟，计算心跳频率及心室的收缩和舒张程度最大抑制率。
抑制率％(心跳频率及心室的收缩和舒张程度)＝【(给药前-给药后)/给药前】×100。
【结果】
结果见表4(每个浓度设置10个平行组)，去甲伊伐布雷定枸橼酸盐及伊伐布雷定盐酸盐均可减慢体外蛙心心跳频率，且去甲伊伐布雷定枸橼酸盐心率抑制作用强于伊伐布雷定盐酸盐。在试验考察浓度范围内，二者对蛙离体心脏心室收缩和舒张程度均无明显影响。
表4.去甲伊伐布雷定枸橼酸盐、伊伐布雷定盐酸盐对离体蛙心的影响(均值±标准差，n＝10)
Figure PCTCN2015000026-appb-000017
2.体内试验：
【材料】
样品：去甲伊伐布雷定枸橼酸盐，伊伐布雷定盐酸盐，用时以生理盐水配置成相应浓度药液，并以生理盐水作为空白对照组；
【方法】
将Wistar大鼠分为6组，分别为去甲伊伐布雷定枸橼酸盐的高、中、低剂量组，伊伐布雷定盐酸盐的高、中剂量组及生理盐水组，每组10只，腹腔注射质量浓度20％乌拉坦(4mL/kg)使其麻醉，背位固定。采集并记录心率。
各组试验大鼠麻醉后描记正常心电图5min.，记录心率，然后分别灌胃给药(10mL/kg)不同浓度受试药液，给药后连续描记心电图并记录心率8小时，以心率最大抑制率反映药物麻醉大鼠心率的影响。
心率最大抑制率％＝【(给药前心率-给药后心率最低值)/给药前心率】×100
【结果】
结果见表5，受试药去甲伊伐布雷定枸橼酸盐及对照药伊伐布雷定盐酸盐在给药后4～5 小时产生最大心率抑制作用，去甲伊伐布雷定枸橼酸盐与同剂量对照药相比心率抑制作用强。
表5.受试药和对照药对麻醉大鼠心率的影响(均值±标准差，n＝10)
Figure PCTCN2015000026-appb-000018
体外离体蛙心的活性研究以及大鼠体内试验表明，本发明的去甲伊伐布雷定枸橼酸盐的生理活性优于已上市的伊伐布雷定盐酸盐，并且，去甲伊伐布雷定枸橼酸盐具有药效学个体差异小的优点。
上述虽然对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。

Claims (10)

  1. 去甲伊伐布雷定盐，为药学上可接受的盐，其特征在于，所述药学上可接受的盐包括枸橼酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、乳酸盐、丙酮酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、富马酸盐、酒石酸盐、马来酸盐、抗坏血酸盐、草酸盐、甲磺酸盐、苯磺酸盐和樟脑酸盐。
  2. 根据权利要求1所述的去甲伊伐布雷定盐，其特征在于，所述药学上可接受的盐为枸橼酸盐、富马酸盐、马来酸盐、酒石酸盐、磷酸盐或硫酸盐；优选为枸橼酸盐或富马酸盐。
  3. 根据权利要求2所述的去甲伊伐布雷定盐，其特征在于，所述药学上可接受的盐为枸橼酸盐，其结构式为：
    Figure PCTCN2015000026-appb-100001
  4. 根据权利要求1所述的去甲伊伐布雷定盐的制备方法，具体步骤是：将1.0mmol去甲伊伐布雷定溶解于10mL热有机溶剂中，加入1.0～1.1mmol酸，室温搅拌2小时，反应结束后经后处理即得；其中，所述热有机溶剂的温度为室温至溶剂沸点；所述的酸包括枸橼酸、氢溴酸、硫酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、抗坏血酸、草酸、甲磺酸、苯磺酸和樟脑酸；所述的酸优选为枸橼酸、富马酸、马来酸、酒石酸、磷酸或硫酸；所述的酸进一步优选为枸橼酸或富马酸。
  5. 根据权利要求4所述的制备方法，其特征在于，所述热有机溶剂的温度为30℃至溶剂沸；所述的室温为10～30℃。
  6. 根据权利要求4所述的制备方法，其特征在于，所述的酸为枸橼酸。
  7. 根据权利要求4所述的制备方法，其特征在于，所述的有机溶剂为甲醇、乙醇、异丙醇、丙酮、乙酸乙酯、二氯甲烷、氯仿、四氯化碳、1，2-二氯乙烷、四氢呋喃、1，4-二氧六环中的任一种；所述的有机溶剂优选为丙酮、乙酸乙酯、乙醇、二氯甲烷或四氢呋喃；所述的有机溶剂进一步优选为丙酮。
  8. 根据权利要求4所述的制备方法，其特征在于，所述的后处理包括析晶、抽滤、浸洗和真空干燥步骤，或者减压蒸发有机溶剂、浸洗和真空干燥步骤，或者吸附材料脱色、过滤、减压蒸发有机溶剂、浸洗和真空干燥步骤，或者吸附材料脱色、过滤、析晶、抽滤、浸洗和真空干燥步骤；所述的吸附材料为活性炭、硅胶或者硅藻土。
  9. 一种口服制剂，含有治疗有效量的去甲伊伐布雷定药学上可接受的盐，以及药学上可接受的载体；所述药学上可接受的盐包括枸橼酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、乳酸盐、丙酮酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、富马酸盐、酒石酸盐、马来酸盐、抗坏血酸盐、草酸盐、甲磺酸盐、苯磺酸盐和樟脑酸盐；所述药学上可接受的盐优选为枸橼酸盐、富马酸盐、马来酸盐、酒石酸盐、磷酸盐或硫酸盐；所述药学上可接受的盐优选为枸橼酸盐或富马酸盐；所述药学上可接受的盐进一步优选为枸橼酸盐；所述的制剂为片剂或胶囊。
  10. 根据权利要求1所述的去甲伊伐布雷定药学上可接受的盐在制备用于治疗禁用或不耐受β受体阻断剂、窦性心律正常的慢性稳定型心绞痛药物中的应用。
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