WO2024016640A1 - 抗组胺类化合物及其制备方法和用途 - Google Patents

抗组胺类化合物及其制备方法和用途 Download PDF

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WO2024016640A1
WO2024016640A1 PCT/CN2023/075594 CN2023075594W WO2024016640A1 WO 2024016640 A1 WO2024016640 A1 WO 2024016640A1 CN 2023075594 W CN2023075594 W CN 2023075594W WO 2024016640 A1 WO2024016640 A1 WO 2024016640A1
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compound
salt
preparation
pharmaceutically acceptable
prepared
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杨成
张起愿
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华创合成制药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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 present invention belongs to the field of medical technology, and more specifically, relates to a class of antihistamine compounds, their preparation methods and their use in the medical field.
  • H1 receptor antagonists are the main drugs used in the clinical treatment of allergic diseases. Structure-activity relationship studies show that H 1 receptor antagonists generally consist of an aromatic ring region, a connecting segment and a basic amine region. According to their structural types, they can be roughly divided into ethylenediamines, aminoalkyl ethers, propylamines and tricyclic drugs. During the clinical application of H 1 receptor antagonists, the main adverse reactions focus on central depression and cardiotoxicity.
  • H1 receptor antagonist molecules have high fat solubility and easily penetrate the blood-cerebrospinal fluid barrier, thereby causing sedation and hypnosis.
  • certain H 1 receptor antagonists can inhibit the delayed rectifier potassium current potassium channel on human cardiomyocytes, resulting in prolongation of the QT interval in the electrocardiogram and induction of torsades de pointes (TdP). , causing fatal arrhythmias.
  • the H 1 receptor antagonists astemizole and terfiladine have been withdrawn from the market due to cardiotoxicity issues.
  • desloratadine Although many tricyclic antihistamine derivatives have been synthesized, including the highly active desloratadine. But as research deepens, its side effects gradually become apparent. At lower concentrations, desloratadine's affinity for M-type choline receptors is similar to that of histamine H receptors, so symptoms such as fatigue, dry mouth, dizziness, and headaches may inevitably occur. Sedation may also occur in patients with brain barrier resistance. In addition, desloratadine has a certain inhibitory effect on potassium channels at high concentrations, which may also have an impact on the cardiovascular system. Therefore, it is of great research value to modify the structure of desloratadine and screen out new drugs with stronger antihistamine activity, better physical and chemical properties, and better stability.
  • An object of the present invention is to provide a class of antihistamine compounds and pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a preparation method for such compounds.
  • Another object of the present invention is to provide the medicinal use of such compounds, which are generally useful in treating seasonal and perennial allergic rhinitis, allergic conjunctivitis, urticaria and other diseases.
  • Another object of the present invention is to disclose pharmaceutical compositions containing such compounds and their pharmaceutically acceptable salts as main active ingredients.
  • the present invention specifically relates to compounds having the structure of formula I and pharmaceutically acceptable salts thereof;
  • R 1 is halogen
  • X 1 is H, alkali metal, amino acid, meglumine, and choline; is an integer from 1 to 3.
  • the present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, wherein the compounds are selected from the following:
  • the present invention also provides the use of compounds of formula I, pharmaceutically acceptable salts or pharmaceutical compositions containing such substances for the treatment of seasonal and perennial allergic rhinitis, allergic conjunctivitis, urticaria and other diseases.
  • R 1 , X 1 , X 2 and n are defined as above.
  • Dissolve M1 in aprotic solvents such as dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine or toluene, add dropwise a solution of halohydrin or its corresponding organic solvent, and add triethylamine, pyridine , potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide and other organic or inorganic bases are acid binding agents, react at -5 ⁇ 60°C Compound I was prepared.
  • the molar ratio of M1 to halohydrin is 1: (1-10).
  • the compounds of the present invention are used in the form of pharmaceutical preparations, and the administration route can be parenteral route (such as intravenous, intramuscular administration) and oral administration.
  • compositions of the compounds of the present invention are prepared as follows: using standard and conventional techniques, the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable auxiliaries and excipients. The excipients are combined to prepare microparticles or microspheres.
  • Solid dosage forms include tablets, dispersible granules, capsules, sustained-release tablets, sustained-release pellets, etc.
  • a solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, disintegrating agent, and encapsulating agent.
  • Inert solid carriers include magnesium phosphate, magnesium stearate, talc, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methyl cellulose, microcrystalline cellulose, Low melting point paraffin, polyethylene glycol, mannitol, cocoa butter, etc.
  • Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.
  • the amount of active ingredients (compounds of the present invention) contained in pharmaceutical compositions and unit dosage forms can be specifically applied according to the patient's condition and the situation diagnosed by the doctor.
  • the amount or concentration of the compound used can be adjusted within a wide range, usually , the amount of active compound ranges from 0.5% to 90% by weight of the composition. Another preferred range is 0.5-70%.
  • Compound III-2 was prepared in the same way as compound III-1 in Example 24, replacing intermediate 1 with intermediate 2, and keeping other materials unchanged.
  • Compound III-3 was prepared in the same manner as compound III-1 in Example 24, except that intermediate 1 was replaced by intermediate 3, and other materials remained unchanged.
  • Compound III-4 was prepared in the same way as compound III-1 in Example 24, except that intermediate 1 was replaced by intermediate 4, and other materials remained unchanged.
  • Compound III-5 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 5, and other materials remained unchanged.
  • Compound III-6 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 6, and other materials remained unchanged.
  • Compound III-7 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 7, and other materials remained unchanged.
  • Compound III-8 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 8, and other materials remained unchanged.
  • Compound III-9 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 9, and other materials remained unchanged.
  • Compound III-10 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 10, and other materials remained unchanged.
  • Compound III-11 was prepared using the same method as the preparation method of compound III-1 in Example 24, replacing intermediate 1 with intermediate 11, and keeping other materials unchanged.
  • Compound III-12 was prepared in the same manner as compound III-1 in Example 24, replacing intermediate 1 with intermediate 12, and keeping other materials unchanged.
  • Compound III-13 was prepared in the same way as compound III-1 in Example 24, except that intermediate 1 was replaced by intermediate 13, and other materials remained unchanged.
  • Compound III-14 was prepared in the same manner as compound III-1 in Example 24, except that intermediate 1 was replaced by intermediate 14, and other materials remained unchanged.
  • Compound III-15 was prepared in the same manner as in Example 24 for compound III-1, except that intermediate 1 was replaced by intermediate 15, and other materials remained unchanged.
  • Compound III-16 was prepared using the same preparation method as compound III-1 in Example 24. Intermediate 1 was replaced with intermediate 20. Other materials were not used. Change.
  • Compound III-17 was prepared using the same method as compound III-1 in Example 24, replacing intermediate 1 with intermediate 21, and keeping other materials unchanged.
  • Compound III-18 was prepared in the same manner as compound III-1 in Example 24, except that intermediate 1 was replaced by intermediate 22, and other materials remained unchanged.
  • Compound III-19 was prepared in the same manner as compound III-1 in Example 24, except that intermediate 1 was replaced by intermediate 23, and other materials remained unchanged.
  • Compound IV-2 was prepared in the same manner as in Example 43, except that compound III-1 was replaced with III-4, sodium hydroxide was replaced with potassium hydroxide, and other materials remained unchanged.
  • Compound IV-3 was prepared in the same manner as in Example 43, except that compound III-1 was replaced with III-7, sodium hydroxide was replaced with choline hydroxide, and other materials remained unchanged.
  • Compound IV-4 was prepared in the same way as compound IV-1 in Example 43, except that compound III-1 was replaced with III-10, and other materials remained unchanged.
  • Compound IV-5 was prepared in the same manner as in Example 43, except that compound III-1 was replaced with III-10, sodium hydroxide was replaced with choline hydroxide, and other materials remained unchanged.
  • Compound IV-6 was prepared in the same manner as in Example 43, except that compound III-1 was replaced with III-13, sodium hydroxide was replaced with choline hydroxide, and other materials remained unchanged.
  • Compound IV-7 was prepared in the same manner as in Example 43, except that compound III-1 was replaced with III-13, sodium hydroxide was replaced with choline hydroxide, and other materials remained unchanged.
  • Compound IV-8 was prepared in the same manner as in Example 43, except that compound III-1 was replaced with III-16, sodium hydroxide was replaced with arginine, and other materials remained unchanged.
  • Compound IV-9 was prepared in the same manner as compound IV-1 in Example 43, except that compound III-1 was replaced with III-17, and other materials remained unchanged.
  • Compound IV-10 was prepared in the same way as compound IV-1 in Example 43, except that compound III-1 was replaced with III-18, and other materials remained unchanged.
  • Compound IV-11 was prepared in the same manner as in Example 43, except that compound III-1 was replaced by III-19, and other materials remained unchanged.
  • solubility of the compound of the present invention in water is better than that of desloratadine and hydroxyethylloratadine series compounds, especially It is more soluble in water after forming a sodium salt, and is more suitable for preparing intravenous administration preparations.
  • the solubility of the compound of the present invention in methanol and isopropyl alcohol is equivalent to that of desloratadine.
  • Example 55 Antiasthmatic effect of compounds of the present invention on histamine-induced asthma in guinea pigs
  • guinea pig Take the guinea pig, place it in a plexiglass bell jar, spray ultrasonic atomization salt histamine solution (0.8 mg/mL) for 40 seconds, record the time when the guinea pig develops asthma, and use the time of convulsions and falls as the incubation period. Guinea pigs that exceed 180 seconds will not be treated For selection, 185 selected guinea pigs were randomly divided into 37 groups: normal control group, desloratadine group (1 mg/kg), and loratadine group (1 mg/kg).
  • loratadine hydroxypropyl base group (1mg/kg), loratadine hydroxypropyl base group (1mg/kg), loratadine hydroxypropyl base group (1mg/kg), loratadine hydroxypropyl base group (1mg/kg), loratadine hydroxypropyl base group (1mg/kg), loratadine hydroxypropyl base group (1mg/kg)
  • a certain group (1 mg/kg) and a compound group of the present invention (1 mg/kg).
  • test results show that the post-drug incubation period of the compound of the present invention is significantly longer than that of the normal control group, desloratadine group and hydroxyethylloratadine series group, indicating that the compound of the present invention inhibits asthma better than the control group and normal group.
  • Example 56 Effect on muscle tone of isolated ileal smooth muscle of guinea pigs
  • the guinea pig was knocked unconscious with a wooden stick, and its abdomen was immediately opened. An approximately 15 cm long ileum was isolated. The contents of the intestinal segment were washed with Tyrode's solution and placed in Tyrode's solution at a constant temperature of 37°C for later use, while supplying oxygen. Cut the experimental intestinal tube (length 1cm) and put it into 20ml Tyrode's solution at a constant temperature of 37°C. Continuously aerate it with oxygen. One end is fixed on the ventilation hook, and the other end is connected and fixed on the muscle tension transducer and led to the computer interface. Use BL The system records the muscle tension value of the ileal smooth muscle, and the experiment is conducted after the contraction of the intestinal segment has stabilized.
  • test results show that compared with the desloratadine group and the hydroxyethyl-loratadine series group, the compound of the present invention has higher antihistamine activity.
  • Preparation method Take 500ml of water for injection, add sucrose, stir and dissolve; add compound IV-16g to the solution, stir to dissolve, add citric acid and ethyl 4-hydroxybenzoate to the solution, stir to dissolve, add water to 1000ml, filter and aliquot , sterilize at 105°C for 30 minutes and it is ready.
  • Preparation method Take 700ml of water for injection, add compound IV-4, stir and dissolve, add glucose to the solution, stir and dissolve, adjust the pH of the solution to 8-9 with hydrochloric acid, filter, pour into a 7ml vial, add half a stopper, and freeze In the dryer, freeze drying, plugging, and capping.
  • Preparation method Take the prescribed amount of starch, microcrystalline cellulose and compound III-12, mix them evenly; use 4% povidone K30 solution to make the materials into soft materials, granulate with a 20-mesh screen, and dry at 40-50°C Until the moisture content is qualified, pass through a 20-mesh sieve to make the tablets whole, add the prescribed amount of magnesium stearate, final mix, measure the intermediate content, determine the tablet weight, and press the tablets.
  • the compound of the present invention was placed for 6 months at a temperature of 40°C ⁇ 2°C and a relative humidity of 75% ⁇ 5%. Samples were taken to determine the properties, related substances and content. The results are shown in Table 5 below.

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Abstract

本发明涉及一类抗组胺化合物及其制备方法和用途。具体地，涉及一类具有式Ⅰ结构的抗组胺化合物及其药学上可接受的盐及其制备方法，式Ⅰ结构的抗组胺化合物及其药学上可接受的盐作为活性有效成分的药物组合物及其在治疗季节性和常年性过敏性鼻炎、过敏性结膜炎和荨麻疹等疾病中的用途。

Description

抗组胺类化合物及其制备方法和用途
本申请要求于2022年07月21日提交中国专利局、申请号为202210874033.3、发明名称为“抗组胺类化合物及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药技术领域，更确切地说，涉及一类抗组胺化合物、其制备方法和在医药领域的用途。
背景技术
过敏性疾病是影响人类健康的主要疾病，开发并获得药效更强、不良反应更低的抗过敏药物一直是全世界药物工作者的研究重点之一。H1受体拮抗剂是临床治疗过敏性疾病的主要药物。构效关系研究表明：H1受体拮抗剂一般由芳环区、连接段与碱性胺区域构成。根据其结构类型可大致分为乙二胺类、氨烷基醚类、丙胺类和三环类药物。H1受体拮抗剂在临床应用的过程中主要不良反应集中在中枢抑制以及心脏毒性这两个方面。前者是因为H1受体拮抗剂分子的脂溶性较高，容易透过血脑脊液屏障从而引起镇静催眠作用。后者是因为某些H1受体拮抗剂可以抑制人心肌细胞上的延迟整流钾电流钾离子通道，导致心电图QT间期延长，同时诱发尖端扭转型室性心动过速(torsadesde pointes，TdP)，引发致命性心律失常。其中H1受体拮抗剂阿司咪唑与特非拉定由于心脏毒性的问题已经撤出市场。
尽管许多三环类抗组胺衍生物已被合成，其中包括活性很好的地氯雷他定。但随着研究的深入，其副作用逐渐显现出来。在较低浓度下，地氯雷他定对M型胆碱受体的亲和力与组胺H受体类似，因此不可避免地可能出现疲劳、口干、眩晕、头痛等症状，同时其对缺乏血脑屏障抵抗力的患者也可能引起镇静作用。另外，地氯雷他定在高浓度下对钾通道有一定的抑制作用，由此也可能对心血管系统产生影响。因此对地氯雷他定进行结构修饰进而筛选出抗组胺活性更强、理化性质更优，稳定性更好的新药具有重要的研究价值。
发明内容
本发明的一个目的是提供一类抗组胺化合物及其药学上可接受的盐。
本发明的另一目的是提供该类化合物的制备方法。
本发明的又一目的是提供该类化合物的医药用途，这类化合物通常具有治疗季节性和常年性过敏性鼻炎、过敏性结膜炎和荨麻疹等疾病。
本发明的再一个目的在于，公开以该类化合物及其药学上可接受的盐为主要活性成分的药物组合物。
现结合本发明目的，对本发明内容进行详细阐述。
本发明具体涉及具有式I结构的化合物及其药学上可接受的盐；
其中，R1为卤素；X1为H、碱金属、氨基酸、葡甲胺、胆碱；X2为H、碱金属、氨基酸、葡甲胺、胆碱；n1为1-5的整数；n2为1-3的整数。
本发明提供了式Ⅰ化合物及其药学上可接受的盐，其中所述化合物选自如下：






本发明也提供了应用式I化合物、药学上可接受的盐或者包含这种物质的药物组合物，用以季节性和常年性过敏性鼻炎、过敏性结膜炎和荨麻疹等疾病。
式I化合物的制备如下：
其中，R1、X1、X2和n的定义如上面所述。
其中，M1的合成已见于文献报道，按报道方法本领域技术人员均可制得。
将M1溶于二氯甲烷、三氯甲烷、丙酮、乙睛、四氢呋喃、DMF、吡啶或甲苯等非质子性溶剂，滴加卤代醇或其对应的有机溶媒的溶液，以三乙胺、吡啶、叔丁醇钾、甲醇钠、乙醇钠、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠或氢氧化钾等有机碱或无机碱为缚酸剂，-5～60℃反应制得化合物Ⅰ。M1与卤代醇的摩尔比为1：(1-10)。
将M1或化合物Ⅰ溶于二氯甲烷、三氯甲烷、丙酮、乙睛、四氢呋喃、DMF、吡啶或甲苯等非质子性溶剂，滴加氯溴烷烃或其对应的有机溶媒的溶液，以三乙胺、吡啶、叔丁醇钾、甲醇钠、乙醇钠、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠或氢氧化钾等有机碱或无机碱为缚酸剂，-5～60℃反应 制得化合物Ⅱ。M1或化合物Ⅰ与氯溴烷烃的摩尔比为1：(1-10)。
将上述所得产物化合物Ⅱ溶于乙腈、丙酮、甲醇、乙醇或四氢呋喃中，在加入三乙胺搅拌均匀，滴加磷酸，25～80℃反应制得化合物Ⅲ。
将上述所得产物化合物Ⅲ溶于乙腈、丙酮、甲醇、乙醇或四氢呋喃中，在加入氢氧化钠或氢氧化钾或氢氧化胆碱或精氨酸或脯氨酸，25～80℃反应制得化合物Ⅳ，即药学上可接受的盐。
本发明的化合物以药物制剂的形式使用，给药途径可以是非肠道途径(如静脉、肌肉给药)及口服给药。
本发明化合物的药物组合物制备如下：使用标准和常规的技术，使本发明化合物与制剂学上可接受的固体或液体载体结合，以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质，其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖，果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。
药物组合物以及单元剂型中含有的活性成份(本发明化合物)的量可以根据患者的病情、医生诊断的情况特定地加以应用，所用的化合物的量或浓度在一个较宽的范围内调节，通常，活性化合物的量范围为组合物的0.5％-90％(重量)。另一优选的范围0.5-70％。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但不限制本发明。
制备实施例
实施例1：中间体1的制备
向反应瓶中加入四氢呋喃100ml、M110g、氯溴甲烷33.3g、氢氧化钠2.57g，慢慢升温至60℃，搅拌6h反应，反应完成后过滤反应液，滤液减压蒸除溶剂，得中间体1 8.67g，收率75％。
实施例2：中间体2的制备
同实施例1中间体1的制备方法制备中间体2，将M1替换为M2，其他物料不变。
实施例3：中间体3的制备
同实施例1中间体1的制备方法制备中间体3，将M1替换为M3，其他物料不变。
实施例4：中间体4的制备
同实施例1中间体1的制备方法制备中间体4，将氯溴甲烷替换为氯溴乙烷，其他物料不变。
实施例5：中间体5的制备
同实施例1中间体1的制备方法制备中间体5，将氯溴甲烷替换为氯溴乙烷，M1替换为M2，其他物料不变。
实施例6：中间体6的制备
同实施例1中间体1的制备方法制备中间体6，将氯溴甲烷替换为氯溴乙烷，M1替换为M3，其他物料不变。
实施例7：中间体7的制备
同实施例1中间体1的制备方法制备中间体7，将氯溴甲烷替换为1，3-氯溴丙烷，其他物料不变。
实施例8：中间体8制备
同实施例1中间体1的制备方法制备中间体8，将氯溴甲烷替换为1，3-氯溴丙烷，M1替换为M2，其他物料不变。
实施例9：中间体9的制备
同实施例1中间体1的制备方法制备中间体9，将氯溴甲烷替换为1，3-氯溴丙烷，M1替换为M3，其他物料不变。
实施例10：中间体10的制备
同实施例1中间体1的制备方法制备中间体10，将氯溴甲烷替换为1,4-氯溴丁烷，其他物料不变。
实施例11：中间体11的制备
同实施例1中间体1的制备方法制备中间体11，将氯溴甲烷替换为1,4-氯溴丁烷，M1替换为M2，其他物料不变。
实施例12：中间体12的制备
同实施例1中间体1的制备方法制备中间体12，将氯溴甲烷替换为1,4氯溴丁烷，M1替换为M3，其他物料不变。
实施例13：中间体13的制备
同实施例1中间体1的制备方法制备中间体13，将氯溴甲烷替换为1，5-氯溴戊烷，其他物料不变。
实施例14：中间体14的制备
同实施例1中间体1的制备方法制备中间体14，将氯溴甲烷替换为1，5-氯溴戊烷，M1替换为M2，其他物料不变。
实施例15：中间体15的制备
同实施例1中间体1的制备方法制备中间体15，将氯溴甲烷替换为1，5-氯溴戊烷，M1替换为M3，其他物料不变。
实施例16：中间体16的制备
同实施例1中间体1的制备方法制备中间体16，将氯溴甲烷替换为1-氯乙醇，其他物料不变。
实施例17：中间体17的制备
同实施例1中间体1的制备方法制备中间体17，将氯溴甲烷替换为1-氯丙醇，其他物料不变。
实施例18：中间体18的制备
同实施例1中间体1的制备方法制备中间体18，将氯溴甲烷替换为1-氯丁醇，其他物料不变。
实施例19：中间体19的制备
同实施例1中间体1的制备方法制备中间体19，将氯溴甲烷替换为1-氯戊醇，其他物料不变。
实施例20：中间体20的制备
同实施例1中间体1的制备方法制备中间体20，将M1替换为中间体16，其他物料不变。
实施例21：中间体21的制备
同实施例1中间体1的制备方法制备中间体21，将M1替换为中间体17，其他物料不变。
实施例22：中间体22的制备
同实施例1中间体1的制备方法制备中间体22，将M1替换为中间体18，其他物料不变。
实施例23：中间体23的制备
同实施例1中间体1的制备方法制备中间体23，将M1替换为中间体19，其他物料不变。
实施例24：化合物Ⅲ-1的制备
取30ml的乙腈置的反应瓶中，加入三乙胺7.0g和磷酸8.0g，搅拌加热至60℃溶解，慢慢加入中间体1，加完后60℃保温6小时，停止结束后，60℃减压蒸除溶剂，蒸干后，加入20ml水搅拌，慢慢滴加浓盐酸调pH至1.5，加入50ml(25ml×2次)乙酸乙酯萃取水层，去掉水层，然后50℃减压蒸除乙酸乙酯，得化合物Ⅲ-19.8g，收率83.7％。
实施例25：化合物Ⅲ-2的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-2，将中间体1替换为中间体2，其他物料不变。
实施例26：化合物Ⅲ-3的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-3，将中间体1替换为中间体3，其他物料不变。
实施例27：化合物Ⅲ-4的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-4，将中间体1替换为中间体4，其他物料不变。
实施例28：化合物Ⅲ-5的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-5，将中间体1替换为中间体5，其他物料不变。
实施例29：化合物Ⅲ-6的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-6，将中间体1替换为中间体6，其他物料不变。
实施例30：化合物Ⅲ-7的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-7，将中间体1替换为中间体7，其他物料不变。
实施例31：化合物Ⅲ-8的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-8，将中间体1替换为中间体8，其他物料不变。
实施例32：化合物Ⅲ-9的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-9，将中间体1替换为中间体9，其他物料不变。
实施例33：化合物Ⅲ-10的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-10，将中间体1替换为中间体10，其他物料不变。
实施例34：化合物Ⅲ-11的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-11，将中间体1替换为中间体11，其他物料不变。
实施例35：化合物Ⅲ-12的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-12，将中间体1替换为中间体12，其他物料不变。
实施例36：化合物Ⅲ-13的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-13，将中间体1替换为中间体13，其他物料不变。
实施例37：化合物Ⅲ-14的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-14，将中间体1替换为中间体14，其他物料不变。
实施例38：化合物Ⅲ-15的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-15，将中间体1替换为中间体15，其他物料不变。
实施例39：化合物Ⅲ-16的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-16，将中间体1替换为中间体20，其他物料不 变。
实施例40：化合物Ⅲ-17的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-17，将中间体1替换为中间体21，其他物料不变。
实施例41：化合物Ⅲ-18的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-18，将中间体1替换为中间体22，其他物料不变。
实施例42：化合物Ⅲ-19的制备
同实施例24化合物Ⅲ-1的制备方法制备化合物Ⅲ-19，将中间体1替换为中间体23，其他物料不变。
实施例43：化合物Ⅳ-1的制备
取化合物Ⅲ-110g加入反应瓶中，再加入50ml乙醇加热至50℃搅拌溶解，加入氢氧化钠1.91g搅 拌使溶解，保温搅拌20分钟，过滤，滤液降温至0～5℃，保温析晶4小时，过滤，滤饼鼓风干燥，得化合物Ⅳ-1 9.9g，收率89.7％。
实施例44：化合物Ⅳ-2的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-2，将化合物Ⅲ-1替换为Ⅲ-4，氢氧化钠替换为氢氧化钾，其他物料不变。
实施例45：化合物Ⅳ-3的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-3，将化合物Ⅲ-1替换为Ⅲ-7，氢氧化钠替换为氢氧化胆碱，其他物料不变。
实施例46：化合物Ⅳ-4的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-4，将化合物Ⅲ-1替换为Ⅲ-10，其他物料不变。
实施例47：化合物Ⅳ-5的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-5，将化合物Ⅲ-1替换为Ⅲ-10，氢氧化钠替换为氢氧化胆碱，其他物料不变。
实施例48：化合物Ⅳ-6的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-6，将化合物Ⅲ-1替换为Ⅲ-13，氢氧化钠替换为氢氧化胆碱，其他物料不变。
实施例49：化合物Ⅳ-7的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-7，将化合物Ⅲ-1替换为Ⅲ-13，氢氧化钠替换为氢氧化胆碱，其他物料不变。
实施例50：化合物Ⅳ-8的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-8，将化合物Ⅲ-1替换为Ⅲ-16，氢氧化钠替换为精氨酸，其他物料不变。
实施例51：化合物Ⅳ-9的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-9，将化合物Ⅲ-1替换为Ⅲ-17，其他物料不变。
实施例52：化合物Ⅳ-10的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-10，将化合物Ⅲ-1替换为Ⅲ-18，其他物料不变。
实施例53：化合物Ⅳ-11的制备
同实施例43化合物Ⅳ-1的制备方法制备化合物Ⅳ-11，将化合物Ⅲ-1替换为Ⅲ-19，其他物料不变。
理化性质考察
实施例54：本发明化合物溶解度的考察
分别测试本发明化合物和对比化合物在水、甲醇、异丙醇中的溶解度。
对比化合物1：羟己基地氯雷他定
对比化合物2：羟戊基地氯雷他定
对比化合物3：羟丁基地氯雷他定
对比化合物4：羟丙基地氯雷他定
对比化合物5：羟乙基地氯雷他定
对比化合物6：地氯雷他定。
测试结果见下表1所示。
表1：溶解度测试结果
结果表明，本发明化合物在水中溶解度优于地氯雷他定和羟乙基地氯雷他定系列化合物，尤其 是成钠盐后在水中溶解更大，更适合制备静脉给药制剂，在甲醇和异丙醇中本发明化合物与地氯雷他定溶解度相当。
药效研究
实施例55：本发明化合物对组胺所致哮喘豚鼠的平喘作用
取豚鼠，置于有机玻璃钟罩内，超声雾化喷入盐组胺溶液(0.8mg/mL)40s，记录豚鼠产生哮喘的时间，以抽搐、跌倒的时间为潜伏期，超过180s的豚鼠不予选用，将选出的豚鼠185只随机分组，每组5只，分为37组:正常对照组、地氯雷他定组(lmg/kg)、羟乙基地氯雷他定组(1mg/kg)、羟丙基地氯雷他定组(1mg/kg)、羟丁基地氯雷他定组(1mg/kg)、羟戊基地氯雷他定组(1mg/kg)、羟己基地氯雷他定组(1mg/kg)、本发明化合物组(1mg/kg)。以2mL/kg bw灌胃给药，给药后60min，分别放入玻璃钟罩内，按预选时的同样条件喷雾盐酸组胺溶液，记录哮喘出现的潜伏期，若超过8min仍未出现哮喘者，以8min计，结果进行统计学处理。
其结果如表2所示
表2为测试化合物拮抗组胺的作用结果(n＝5)

试验结果表明，本发明的化合物药后潜伏期明显长于正常对照组、地氯雷他定组和羟乙基地氯雷他定系列组，说明本发明的化合物哮喘抑制优于对照组和正常组。
实施例56：对豚鼠离体回肠平滑肌的肌张力的作用
将豚鼠用木棍击昏，立即开腹，分离出约15cm长的回肠，用台氏液冲洗肠段中的内容物，放入37℃恒温的台氏液中备用，同时供氧。剪取实验肠管(长度1cm)放入37℃恒温的20ml台氏液中，持续通氧，一端固定于通气钩上，另一端连接固定于肌张力换能器上并引至计算机接口，用BL系统记录回肠平滑肌的肌张力值，待肠段收缩稳定后进行实验。
待回肠收缩曲线稳定后，记录加药前的张力值，再分别加入药物或DMSO，5分钟后记录回肠收缩曲线在该点的平均张力值，平行操作8次。按以下公式计算其解痉百分率。
结果如表3所示：
表3为测试化合物拮抗组胺的作用结果(n＝8)

待回肠蠕动曲线稳定后，记录加化合物前的张力值，再加入组胺0.05mL，当达最大收缩时，分别加入不同化合物或DMS0各0.05mL，观察并记录加组胺时以及给化合物后3min的平均张力值，平行操作8次，求出解痉百分率。
结果如表4所示
表4为测试化合物拮抗组胺的作用结果(n＝8)

试验结果表明与地氯雷他定组和羟乙基地氯雷他定系列组相比，本发明的化合物具有较高的抗组胺活性。
制剂制备
实施例57：口服液的制备
处方：
制法：取注射用水500ml，加入蔗糖搅拌溶解；取化合物Ⅳ-16g加入溶液中搅拌溶解，再取柠檬酸和4-羟基苯甲酸乙酯加入溶液中搅拌溶解，加水至1000ml，过滤，分装，105℃灭菌30分钟，即得。
实施例58：冻干制剂的制备
处方：
制法：取注射用水700ml，加入化合物Ⅳ-4搅拌溶解，再取葡萄糖加入溶液中搅拌溶解，用盐酸调节溶液pH至8-9，过滤，灌装置7ml西林瓶中，加半塞，置冷冻干燥机中，冷冻干燥，压塞，轧盖。
实施例59：片剂的制备
处方：
制法：取处方量的淀粉、微晶纤维素和化合物Ⅲ-12，混合均匀；用4％聚维酮K30溶液将物料制软材，用20目筛网制粒，与40-50℃干燥至水分合格，过20目筛整粒，加处方量的硬脂酸镁，终混，测中间体含量，定片重；压片。
稳定性研究
实施例60：本发明化合物稳定性考察
本发明化合物在温度40℃±2℃，相对湿度75％±5％条件下放置6个月，取样测定性状、有关物质和含量，结果见下表5。
表5：本发明化合物加速稳定性试验结果

结果表明本发明化合物在加速条件稳定性良好，尤其是钠盐化合物稳定性明显优于其他化合物。

Claims (8)

  1. 一种抗组胺化合物及其药学上可接受的盐，其结构如式Ⅰ所示：
    其中，R1为卤素；X1为H、碱金属、氨基酸、葡甲胺、胆碱；X2为H、碱金属、氨基酸、葡甲胺、胆碱；n1为1-5的整数；n2为1-3的整数。
  2. 如权利要求l所述的抗组胺化合物及其药学上可接受的盐，其特征在于，所述药学上可接受的盐包括与无机碱或有机碱形成的盐。
  3. 如权利要求2所述的抗组胺化合物及其药学上可接受的盐，其特征在于，所述有机碱选自氢氧化胆碱、葡甲胺或二异丙基乙基胺。
  4. 如权利要求1所述的抗组胺化合物及其药学上可接受的盐，其特征在于，所述药学上可接受的盐包括金属盐或与碱性氨基酸盐。
  5. 如权利要求4所述的抗组胺化合物及其药学上可接受的盐，其特征在于，所述金属盐选自碱金属盐、碱土金属盐，所述碱金属盐选自钠盐或钾盐，所述碱土金属盐选自钙盐、镁盐或钡盐，所述碱性氨基酸盐选自赖氨酸盐、精氨酸盐。
  6. 如权利要求l所述的抗组胺化合物及其药学上可接受的盐，其特征在于，所述抗组胺化合物及其药学上可接受的盐选自如下化合物：






  7. 一种药物组合物，其包括治疗量的如权利要求l～6任一项所述的抗组胺化合物和/或其药学上可接受的盐，以及其他药学上可接受的辅料。
  8. 如权利要求l～6任一项所述的抗组胺类化合物或其药学上可接受的盐在制备抗过敏药物中的用途。
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