WO2021253954A1 - 镇痛剂 - Google Patents

镇痛剂 Download PDF

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Publication number
WO2021253954A1
WO2021253954A1 PCT/CN2021/087041 CN2021087041W WO2021253954A1 WO 2021253954 A1 WO2021253954 A1 WO 2021253954A1 CN 2021087041 W CN2021087041 W CN 2021087041W WO 2021253954 A1 WO2021253954 A1 WO 2021253954A1
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compound
injection
pharmaceutically acceptable
pharmaceutical composition
dosage form
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PCT/CN2021/087041
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English (en)
French (fr)
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徐奎
赵宏
刘逸凡
詹书胜
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安徽恒星制药有限公司
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Publication of WO2021253954A1 publication Critical patent/WO2021253954A1/zh

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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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This application relates to the field of medicine, in particular to a new type of analgesic.
  • the present disclosure aims to solve one of the existing technical problems at least to a certain extent.
  • the embodiment of the first aspect of the present disclosure provides a compound of the structure represented by formula (I) or a pharmaceutically acceptable salt thereof
  • R 1 is selected from -H; -F, -Cl, -Br; -CN; or -NO 2
  • R 2 is selected from -CF 3 ; -OCF 3 ; -CN or -NO 2 .
  • R 1 is -H, -F, or -Cl
  • R 2 is -CF 3 or -OCF 3 .
  • the compound is selected from the following structures:
  • the compound is in the form of a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrofluoride Acid salt, sulfate, nitrate, phosphate, formate, acetate, propionate, oxalate, malonate, butyrate, lactate, methanesulfonate, ethanesulfonic acid Salt, p-toluenesulfonate, maleate, benzoate, succinate, picrate, tartaric acid, citrate, fumarate.
  • a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrofluoride Acid salt, sulfate, nitrate, phosphate, formate, acetate, propionate, oxalate, malonate, butyrate, lactate, methanesulfonate, ethanesulfonic acid Salt, p-toluene
  • the embodiment of the second aspect of the present disclosure provides a pharmaceutical composition comprising the compound in the embodiment of the first aspect as described above and pharmaceutically acceptable excipients.
  • the pharmaceutical composition is formulated as an oral dosage form, an injection dosage form, or an inhalation dosage form.
  • the oral dosage form includes tablets, granules and capsules, preferably sustained-release tablets and sustained-release capsules.
  • the embodiment of the third aspect of the present disclosure provides the use of the compound in the embodiment of the first aspect as described above in the preparation of an analgesic drug for the prevention or treatment of neuropathic pain or inflammatory pain.
  • the compound is administered to a subject in need thereof by a route selected from the group consisting of oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal.
  • the parenteral route of administration includes subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection, and infusion.
  • the embodiment of the fourth aspect of the present disclosure provides the compound of the embodiment of the first aspect as described above, for use as an analgesic.
  • the embodiment of the fifth aspect of the present disclosure provides the compound of the embodiment of the first aspect as described above, for use in the prevention or treatment of neuropathic pain or inflammatory pain.
  • the compound is administered to a subject in need thereof by a route selected from the group consisting of oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal.
  • the parenteral route of administration includes subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection, and infusion.
  • the embodiment of the sixth aspect of the present disclosure provides a method for preventing or treating neuropathic pain or inflammatory pain, which comprises: administering the compound in the embodiment of the first aspect as described above to a subject in need thereof.
  • the compound is administered to a subject in need thereof by a route selected from the group consisting of oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal.
  • the parenteral route of administration includes subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intrasternal injection, and infusion.
  • Epoxide hydrolase inhibitors have the following pharmacological effects: anti-inflammatory, protect kidneys, protect nerves, protect myocardium, protect heart and lung function, treat pain, promote vasodilation, prevent arteriosclerosis, etc., but due to some toxic side effects Or the shortcomings of poor oral sex. Therefore, the inventors studied from the aspects of water solubility, stability, oral sex, etc., hoping to find a fast, efficient, and selective inhibitor, so as to achieve a better effect of treating related diseases. There are other alternatives for managing pain. Examples include non-steroidal anti-inflammatory drugs ((NSAID)) or narcotic analgesics (such as opioids).
  • NSAID non-steroidal anti-inflammatory drugs
  • opioids such as opioids
  • non-steroidal anti-inflammatory drugs causes adverse side effects such as gastrointestinal injury or kidney disease
  • narcotic analgesics causes Adverse side effects, such as constipation, drowsiness, nausea or vomiting.
  • neuropathic pain is treated with anticonvulsants, such as gabapentin or pregabalin, and central nervous system side effects such as dizziness, nausea or vomiting occur frequently. Therefore, there is an urgent need to develop new analgesics for neuropathic pain with few side effects.
  • This disclosure proposes for the first time that pregabalin and urea epoxide hydrolase inhibitors are cleverly connected to form a new derivative, and for the first time the compound's efficacy in preventing or treating pain is studied and disclosed. Therefore, this application provides another analgesic drug that can effectively prevent or treat pain (especially neuropathic pain drugs and inflammatory pain), which has better solubility, stability and fewer side effects.
  • administering (administering" a compound) of a compound and "administration of” compound” (“administration of” compound) shall be understood to mean providing a compound of the present invention, including a compound of the present invention, to an individual in need thereof Or the pharmaceutical composition of the prodrug of the compound. It is recognized that those skilled in the non-limiting field can use an effective amount of the compound of the present invention to treat patients currently suffering from neuropathic pain or inflammatory pain, or through preventive treatment of patients suffering from this disorder.
  • composition is intended to encompass products containing specified amounts of specified ingredients, as well as any product produced directly or indirectly from a combination of specified amounts of specified ingredients.
  • the term in relation to pharmaceutical compositions is intended to cover products containing active ingredients and inert ingredients that constitute carriers, as well as directly or indirectly composed of any combination, complexation or polymerization of two or more ingredients, or by other types of reactions or Any product resulting from an interaction (for example, causing one or more ingredients to break down). Therefore, the pharmaceutical composition of the present invention encompasses any composition made by mixing the compound of the present invention and a pharmaceutically acceptable carrier.
  • the term "subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the mammalian category: humans; non-human primates, such as chimpanzees, and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, pigs; domestic animals , Such as rabbits, dogs, and cats; and experimental animals including rodents, such as rats, mice, and guinea pigs.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • pharmaceutically acceptable excipients refer to pharmaceutically acceptable materials, compositions, or vehicles that participate in imparting the form or consistency of the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed. When administered to a patient, such interactions will drastically reduce the efficacy of the compounds of the invention and produce pharmaceutically unacceptable compositions.
  • each excipient must of course have a sufficiently high purity to make it pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable excipients will vary according to the particular dosage form selected.
  • suitable pharmaceutically acceptable excipients can be selected to achieve their specific functions in the composition.
  • certain pharmaceutically acceptable excipients can be selected because of their ability to promote uniform dosage forms.
  • Certain pharmaceutically acceptable excipients can be selected because of their ability to produce stable dosage forms.
  • Certain pharmaceutically acceptable excipients can be selected because once they are administered to the patient, they help to carry or transport the compound of the invention from one organ or part of the patient's body to another organ or part of the body.
  • Certain pharmaceutically acceptable excipients can be selected because of their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, auxiliary materials Solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, Surfactants and buffers.
  • certain pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions.
  • step 3 Dissolve the product of step 3 (32g, 0.1mol) and the product of step 1 (31g, 0.12mol) in 300ml of dichloromethane, add DCC (27g, 0.13mol) and DMAP (5g) while stirring, stir at room temperature for 15h, and filter Remove the insoluble DCHU, concentrate to dryness under reduced pressure, dissolve the product in toluene (300ml), add water, wash with saturated sodium bicarbonate solution (3 ⁇ 50ml), wash with saturated sodium chloride solution 50ml, dry with anhydrous sodium sulfate, reduce It was concentrated to dryness to obtain 4 g of off-white solid powder with a yield of 73% and an HPLC content of 94.3%, which was directly used in the next reaction.
  • Example 1 where 3-fluoro-4-(trifluoromethoxy)aniline was replaced with 3-fluoro-4-(trifluoromethyl)aniline in step 2 , compound I 2, 7.6 was conveniently prepared g, the total yield (calculated from step 2) is 33.6%, and the HPLC content is 98.2%.
  • Example 1 where 3-fluoro-4-(trifluoromethoxy)aniline was replaced with 4-trifluoromethoxyaniline in step 2, compound I 3 was conveniently prepared, 6.1g, total yield (Calculated from step 2) 38.2%, HPLC content 97.8%.
  • step 2 3-fluoro-4-(trifluoromethoxy)aniline was replaced with 3-chloro-4-(trifluoromethoxy)aniline, compound I 4 was conveniently prepared, 3.7 g, the total yield (calculated from step 2) is 29.3%, and the HPLC content is 99.1%.
  • step 4 replaced the product of step 1 with cyclohexyl carboxylic acid
  • compound I 5 was conveniently prepared, 2.4 g, HPLC content 98.3%, LC-MS: 416.7.
  • the solubility is determined according to the method of Chinese Pharmacopoeia 2015 at room temperature 23°C.
  • the DDY mice were grown under fasting conditions for at least 16 h while allowing free intake of water, and a solution or solvent of the test compound (0.1ml/5g) was orally administered to them.
  • a solvent for the test compound solution dimethyl sulfoxide: Tween 80: 27% hydroxypropyl ⁇ cyclodextrin (1:1:8) was used.
  • a solution of 0.6% acetic acid (0.1ml/5g) was intraperitoneally applied 45 minutes after the administration to induce a writhing response (ie, movement of stretching or arching the body).
  • the number of writhing reactions that occurred in the 10 min period after 10 minutes of applying the acetic acid solution was counted, and the number of writhing reactions was designated as an indicator of pain.
  • the number of writhing reactions in mice in the solvent group was designated as 100%, and the concentration of the test compound that inhibited 50% of the number of writhing reactions was designated as the ED 50 value.
  • the results are shown in
  • test results show that the compound I 1 -compound I 4 provided by the embodiments of the present disclosure exhibit significantly more outstanding analgesic effects than pregabalin or compound I 5.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

提供了式(I)所示结构的化合物或其药学上可接受的盐，及其作为镇痛剂预防或治疗神经性疼痛或炎症性疼痛的用途。

Description

镇痛剂
优先权信息
本申请请求2020年06月17日向中国国家知识产权局提交的、专利申请号为202010556427.5的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术背景
本申请涉及医药领域，特别涉及一种新型镇痛剂。
背景技术
在过去的几十年里，疼痛一直是医学上有待解决的一个难题，它给整个社会带来负担的同时还严重降低了人们的生活质量。目前虽然很多药物可以缓解疼痛，但是大多数这些药物具有剂量依赖或限制性使用的副作用。因此，迫切需要研究和开发新的药物来治疗疼痛。
发明内容
本公开旨在至少在一定程度上解决现有的技术问题之一。
本公开第一方面的实施方案提供了式(I)所示结构的化合物或其药学上可接受的盐
Figure PCTCN2021087041-appb-000001
其中R 1选自-H；-F、-Cl、-Br；-CN；或-NO 2，并且R 2选自-CF 3；-OCF 3；-CN或-NO 2。
在一些实施方案中，R 1为-H、-F或-Cl，R 2为-CF 3或-OCF 3。
在一些实施方案中，所述化合物选自以下结构：
Figure PCTCN2021087041-appb-000002
Figure PCTCN2021087041-appb-000003
在一些实施方案中，所述化合物为药学上可接受的盐的形式，所述药学上可接受的盐选自由以下组成的组：盐酸盐、氢溴酸盐、氢碘酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、乙二酸盐、丙二酸盐、丁酸盐、乳酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、苦味酸盐、酒石酸、柠檬酸盐、富马酸盐。
本公开第二方面的实施方案提供了药物组合物，包含如上所述第一方面实施方案中的化合物和药学上可接受的辅料。
在一些实施方案中，所述药物组合物被配制成口服剂型、注射剂型或吸入剂型。
在一些实施方案中，所述口服剂型包括片剂、颗粒剂和胶囊剂，优选地缓释片剂和缓释胶囊。
本公开第三方面的实施方案提供了如上所述第一方面实施方案中的化合物在制备镇痛药物中的用途，所述镇痛药物用于预防或治疗神经性疼痛或炎症性疼痛。
在一些实施方案中，通过选自以下的途径向有此需要的受试者施用所述化合物：口服、局部、肠胃外、舌下、直肠、阴道和鼻内。
在一些实施方案中，肠胃外途径施用包括皮下注射、静脉内注射、肌内注射、硬膜外注射、胸骨内注射和输注。
本公开第四方面的实施方案提供了如上所述第一方面实施方案中的化合物，用于作为镇痛药物。
本公开第五方面的实施方案提供了如上所述第一方面实施方案中的化合物，用于在预防或治疗神经性疼痛或炎症性疼痛中使用。
在一些实施方案中，通过选自以下的途径向有此需要的受试者施用所述化合物：口服、局部、肠胃外、舌下、直肠、阴道和鼻内。
在一些实施方案中，肠胃外途径施用包括皮下注射、静脉内注射、肌内注射、硬膜外注射、胸骨内注射和输注。
本公开的第六方面的实施方案提供了预防或治疗神经性疼痛或炎症性疼痛的方法，包括：向有此需要的受试者施用如上所述第一方面实施方案中的化合物。
在一些实施方案中，通过选自以下的途径向有此需要的受试者施用所述化合物：口服、局部、肠胃外、舌下、直肠、阴道和鼻内。
在一些实施方案中，肠胃外途径施用包括皮下注射、静脉内注射、肌内注射、硬膜外注射、胸骨内注射和输注。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
环氧化物水解酶抑制剂具有以下几种药理作用：抗炎、保护肾脏、保护神经、保护心肌、保护心肺功能、治疗镇痛、促使血管舒张、防止动脉硬化等作用，但是由于存在一些毒副作用或者口服性较差的缺点。因此发明人从水溶性、稳定性、口服性等这几个方面去研究，希望能找到一种快速、高效、选择性强的抑制剂，从而达到更好的治疗相关疾病的效果。还存在其他备选方案可用于处理疼痛。实例包括非甾类消炎药品((NSAID)或麻醉镇痛药(例如阿片类)。但是，非甾类消炎药品的使用引起不良副作用，例如胃肠伤害或肾病，且麻醉镇痛药的使用引起不良副作用，例如便秘、磕睡、恶心或呕吐。另一方面，神经性疼痛通过使用抗惊厥剂治疗，例如加巴喷丁或普瑞巴林，出现了中枢神经系统副作用如眩晕、恶心或呕吐的频率高。因此，迫切需要研发出用于神经性疼痛且副作用少的新型镇痛药。
本公开首次提出将普瑞巴林与脲类环氧化物水解酶抑制剂巧妙地连接在一起，形成新型衍生物，并首次研究并公开该化合物在预防或治疗疼痛方面的功效。由此，本申请提供了另一种能够有效预防或治疗疼痛(尤其是神经性疼痛药以及炎症疼痛)镇痛药物，具有更好的可溶解性、稳定性和更少的副作用。
术语及其定义
如本文所用，术语“施用”("administering"a compound)化合物和化合物的“施用”("administration of"compound)应理解为是指向有此需要的个体提供本发明的化合物、包含本发明的化合物或化合物的前药的药物组合物。公认的是，非限制性领域的技术人员可以用有效量的本发明化合物治疗目前患有神经性疼痛或炎症性疼痛的患者，或者通过在预防上治疗患有该障碍的患者。
如本文所用，术语“组合物”旨在涵盖包含指定量的指定成分的产品，以及直接或间接地由指定量的指定成分的组合产生的任何产品。与药物组合物有关的该术语旨在涵盖包含构成载体的活性成分和惰性成分的产品，以及直接或间接由任何两种或多种成分的组合、络合或聚合，或者由其他类型的反应或相互作用(例如导致一种或多种成分分解)产生的任何产品。因此，本发明的药物组合物涵盖通过混合本发明的化合物和药学上可接受的载 体制成的任何组合物。
如本文所用，术语“受试者”涵盖哺乳动物和非哺乳动物。哺乳动物的示例包括但不限于哺乳动物类别的任何成员：人类；非人类灵长类动物，例如黑猩猩，以及其他猿类和猴子物种；农畜，例如牛、马、绵羊、山羊、猪；家畜，例如兔、狗和猫；以及包括啮齿动物的实验动物，例如大鼠、小鼠和豚鼠等。非哺乳动物的示例包括但不限于鸟类、鱼类等。在本发明的一个实施方案中，哺乳动物是人。
如本文所用，“药学上可接受的辅料”是指参与赋予药物组合物形式或稠度的药学上可接受的材料、组合物或媒介物。每种辅料在混合时必须与药物组合物的其他成分兼容。当向患者施用时，这样相互作用将大幅度降低本发明化合物的药效，并产生药物学上不可接受的组合物。另外，每种辅料当然必须具有足够高的纯度以使其在药学上可接受。
合适的药学上可接受的辅料将根据所选的特定剂型而变化。另外，可以选择合适的药学上可接受的辅料以实现它们在组合物中的特定功能。例如，可以选择某些药学上可接受的辅料，因为它们具有促进产生均匀剂型的能力。可以选择某些药学上可接受的辅料，因为它们具有产生稳定剂型的能力。可以选择某些药学上可接受的辅料，因为一旦向患者施用它们，便有助于携带或运输本发明的化合物从患者的一个器官或身体的一部分到另一器官或身体的一部分。可以选择某些药学上可接受的辅料，因为它们具有增强患者依从性的能力。
合适的药学上可接受的辅料包括以下类型的辅料：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、助溶剂、悬浮剂、乳化剂、甜味剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员将理解，取决于制剂中存在多少辅料和制剂中存在什么其他成分，某些药学上可接受的辅料可以发挥一种以上的功能并且可以发挥替代的功能。
技术人员具有本领域的知识和技能，以使他们能够选择适当量的合适的药学上可接受的辅料用于本发明。另外，本领域技术人员可获得描述药学上可接受的辅料的资源，并且这些资源可用于选择合适的药学上可接受的辅料。示例包括《雷明顿药物科学》(Remington's Pharmaceutical Sciences)(Mack Publishing Company)、《药物添加剂手册》(The Handbook of Pharmaceutical Additives)(Gower Publishing Limited)，以及《药物辅料手册》(The Handbook of Pharmaceutical Excipients)(the American Pharmaceutical Association and the Pharmaceutical Press).
在“《雷明顿：药学的科学与实践》(Remington:The Science and Practice of Pharmacy),第21版,2005,D.B.Troy编,Lippincott Williams&Wilkins,费城”和“《医药技术百科全书》 (Encyclopedia of Pharmaceutical Technology),J.Swarbrick和J.C.Boylan编,1988-1999,Marcel Dekker,纽约”中公开了用于配制药学上可接受的组合物的各种载体及其制备的已知技术，其每个的内容通过引用并入本文。除非任何常规载体介质与本发明化合物不兼容，例如通过产生任何不良的生物学作用或以有害的方式与药学上可接受的组合物的任何其他组分相互作用，否则其用途是预期在本发明的范围内的。
除非另外定义，否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。如果发生冲突，以本说明书(包括定义)为准。在整个说明书和权利要求书中，词语“包括”或诸如“包含”或“含有”的变体将被理解为暗示包含所述整体或整体的组但不排除任何其它整体或整体的组。除非上下文另有要求，否则未用数量词限定的名词包括单数和复数指示对象。术语“例如”或“如”之后的任何实例并不意味着穷举或限制。
实施例
下面的实施例可以对本公开实施方案进行进一步的描述，然而这些实施例不应作为对本发明范围的限制。
实施例1(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(3-氟-4-(三氟甲氧基)苯基)脲(化合物I 1)的合成
Figure PCTCN2021087041-appb-000004
制备工艺反应流程：
Figure PCTCN2021087041-appb-000005
1、步骤1
在500ml三口瓶中，依次加入S(+)氨己烯酸(24g，0.15mol)、二恶烷170ml及去离子水170ml，室温搅拌下加入氢氧化钠(18g，0.45mol)，完毕后搅拌5min，加入BOC酸酐(43.6g，0.2mol)的50ml二恶烷溶液，将得到的混合液在室温搅拌1.5h，TLC鉴别反应完毕后，减压浓缩除去大部分二恶烷，剩余物用乙醚(3×100ml)萃取，除去有机相，水层用10％枸橼酸水溶液调节pH酯至1～2，静置20min，析出大量白色固体，过滤，固体用适量水洗，55℃～60℃真空干燥4h，得白色固体粉末33.6g，收率86％，HPLC含量97.2％，直接用于下一步反应。
2、步骤2
将3-氟-4-(三氟甲氧基)苯胺(68g，0.35mol)、甲苯(400ml)及吡啶31ml加入到1000ml反应釜中，搅拌溶解，冷却至-5～0℃，滴入固体光气(60g，0.2mol)的120ml甲苯溶液，滴入完毕保持温度在-5～0℃搅拌1.5h，TLC(乙酸乙酯:石油醚＝1:10)鉴别反应完毕后，冷却至-10℃，分批加入4-氨基哌啶-1-羧酸叔丁酯(80g，0.4mol)，加入过程中检测反应体系pH，维持在8-9，若pH偏低，加入适量的吡啶，加入完毕，维持温度反应0.5h，再升温至室温搅拌反应3h，TLC(乙酸乙酯-石油醚＝1:10)鉴别反应完毕后，加入冷水200ml，搅拌20min，静置分层，水层用甲苯(3×200ml)萃取，合并有机层，无水硫酸镁干燥，减压浓缩至干，直接用于下一步。
3、步骤3
步骤2产品，加入二恶烷450ml及6N盐酸溶液45ml，室温搅拌反应混合物1.5h，TLC鉴别反应[展开剂:乙酸乙酯:甲醇＝10:1]，反应完毕，加入乙醚300ml，搅拌1h，过滤，固体用乙醚适量洗涤，35℃～40℃真空干燥6h，得白色固体粉末76.5g，两步总收率68％，HPLC含量96.9％，直接用于下一步反应。
4、步骤4
将步骤3产物(32g，0.1mol)、步骤1产物(31g，0.12mol)溶于二氯甲烷300ml中，搅拌下，加入DCC(27g，0.13mol)及DMAP(5g)，室温搅拌15h，过滤出去不溶物DCHU，减压浓缩至干，将产物溶于甲苯(300ml)，加水，用饱和碳酸氢钠溶液(3×50ml)洗涤，饱和氯化钠溶液50ml洗涤，无水硫酸钠干燥，减压浓缩至干，得类白色固体粉末4g，收率73％，HPLC含量94.3％，直接用于下一步反应。
5、步骤5
步骤4产品，加入二恶烷410ml及6N盐酸溶液12ml，室温搅拌反应混合物2h，TLC鉴别反应[展开剂:乙酸乙酯:甲醇＝10:1]，反应完毕，加入异丙醚350ml，搅拌1h，过滤，固体用异丙醚适量洗涤，55℃～60℃真空干燥4h，所得固体用乙腈重结晶，得白色结晶性 固体粉末27.5g，收率81.1％，HPLC含量98.7％。
Figure PCTCN2021087041-appb-000006
1H-NMR(500MHz,CDCl 3/TMS，ppm)：
δ8.53(s，1H)；7.84(s，1H)；7.33(d，J＝7.8Hz，1H)；7.01(d，J＝7.8Hz，1H)；6.45(s，1H)；3.68(m，1H)；3.52～3.59(t，J＝6.3Hz，4H)；1.76～2.04(t，J＝6.3Hz，4H)；1.99～2.31(d，J＝7.8Hz，2H)；1.66(m，1H)；2.46～2.72(t，J＝6.3Hz，2H)；1.37(t，J＝6.3Hz，2H)；1.74(m，1H)；0.93(s，6H)。
MS：m/z(M+H +)463.5。
实施例2(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(3-氟-4-(三氟甲基)苯基)脲(化合物I 2)的合成
Figure PCTCN2021087041-appb-000007
参照实施例1，其中步骤2中将3-氟-4-(三氟甲氧基)苯胺替换为将3-氟-4-(三氟甲基)苯胺，方便地制得了化合物I 2，7.6g，总收率(从步骤2开始计)33.6％，HPLC含量98.2％。
Figure PCTCN2021087041-appb-000008
1H-NMR(500MHz,CDCl 3/TMS，ppm)：
δ8.54(s，1H)；7.85(s，1H)；7.33(d，J＝7.8Hz，1H)；7.02(d，J＝7.8Hz，1H)；6.44(s，1H)；3.68(m，1H)；3.50～3.58(t，J＝6.3Hz，4H)；1.77～2.06(t，J＝6.3Hz，4H)；1.99～2.33(d，J＝7.8Hz，2H)；1.65(m，1H)；2.43～2.70(t，J＝6.3Hz，2H)；1.35(t，J＝6.3Hz，2H)；1.71(m，1H)；0.95(s，6H)。
MS：m/z(M+H +)447.5。
实施例3(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(4-(三氟甲氧基)苯基)脲(化合物I 3)的合成
Figure PCTCN2021087041-appb-000009
参照实施例1，其中步骤2中将3-氟-4-(三氟甲氧基)苯胺替换为将4-三氟甲氧基苯胺，方便地制得了化合物I 3，6.1g，总收率(从步骤2开始计)38.2％，HPLC含量97.8％。
Figure PCTCN2021087041-appb-000010
1H-NMR(500MHz,CDCl 3/TMS，ppm)：
δ8.56(s，1H)；7.28(d，J＝7.8Hz，2H)；6.87(d，J＝7.8Hz，2H)；6.53(s，1H)；3.70(m，1H)；3.53～3.62(t，J＝6.3Hz，4H)；1.79～2.08(t，J＝6.3Hz，4H)；1.94～2.30(d，J＝7.8Hz，2H)；1.65(m，1H)；2.41～2.74(t，J＝6.3Hz，2H)；1.37(t，J＝6.3Hz，2H)；1.72(m，1H)；0.94(s，6H)。
MS：m/z(M+H +)445.3。
实施例4(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(3-氯-4-(三氟甲氧基)苯基)脲(化合物I 4)的合成
Figure PCTCN2021087041-appb-000011
参照实施例1，其中步骤2中将3-氟-4-(三氟甲氧基)苯胺替换为将3-氯-4-(三氟甲氧基)苯胺，方便地制得了化合物I 4，3.7g，总收率(从步骤2开始计)29.3％，HPLC含量99.1％。
Figure PCTCN2021087041-appb-000012
1H-NMR(500MHz,CDCl 3/TMS，ppm)：
δ8.54(s，1H)；7.56(s，1H)；7.33(d，J＝7.8Hz，1H)；7.01(d，J＝7.8Hz，1H)；6.43(s，1H)；3.68(m，1H)；3.50～3.59(t，J＝6.3Hz，4H)；1.73～2.06(t，J＝6.3Hz， 4H)；1.99～2.35(d，J＝7.8Hz，2H)；1.64(m，1H)；2.44～2.70(t，J＝6.3Hz，2H)；1.36(t，J＝6.3Hz，2H)；1.70(m，1H)；0.93(s，6H)。
MS：m/z(M+H +)479.3。
对比实施例化合物I 5的合成
Figure PCTCN2021087041-appb-000013
参照实施例1，其中步骤4用环己基甲酸替换步骤1产物，方便地制得了化合物I 5，2.4g，HPLC含量98.3％，LC-MS：416.7。
实施例5溶解度试验
溶解度是依据中国药典2015版方法在室温23℃条件下测定所得。
项目 pH1.2 pH4.0 pH6.8 水
化合物I 1 262mg/ml 87mg/ml 11.7mg/ml 6.3mg/ml
化合物I 2 213mg/ml 65mg/ml 9.3mg/ml 4.9mg/ml
化合物I 3 355mg/ml 97mg/ml 15.8mg/ml 8.1mg/ml
化合物I 4 248mg/ml 76mg/ml 8.6mg/ml 5.6mg/ml
化合物I 5 0.84mg/ml 0.81mg/ml 0.80mg/ml 0.8mg/ml
实验结果显示，本公开实施方案提供的化合物I 1-化合物I 4在水中的溶解度是化合物I 5的6倍至10倍，并且具有pH依赖性。
实施例6化学稳定性试验
将样品置于80℃热水中恒温6h取样，HPLC分析：
项目 母体化合物(％) 步骤3产物(％) 普瑞巴林(％)
化合物I 1 98.6 0.7 0.7
化合物I 2 99.1 0.4 0.4
化合物I 3 99.3 0.3 0.3
化合物I 4 98.6 0.2 0.2
化合物I 5 97.2 1.4 ——
实验结果显示，本公开实施方案提供的化合物I 1-化合物I 4在水溶液中的稳定性显著高于 化合物I 5。
实施例7镇痛效果评估
使DDY小鼠在禁食状况下生长至少16h同时允许自由摄入水，并向其口服施用测试化合物的溶液或溶剂(0.1ml/5g)。作为用于测试化合物溶液的溶剂，使用二甲亚砜:吐温80:27％羟丙基β环糊精(1:1:8)。给药45min以后腹膜内施加0.6％乙酸的溶液(0.1ml/5g)以引起扭体反应(即，伸展或拱起身体的运动)。对从施加乙酸溶液10min以后的10min时间段内出现的扭体反应的次数进行计数，将扭体反应次数被指定为疼痛的指标。施用溶剂组小鼠出现的扭体反应次数指定为100％，并将抑制50％扭体反应次数的测试化合物的浓度指定为ED 50值，结果见下表：
化合物 ED 50(mg/kg)[90％置信区间]
化合物I 1 0.12[0.09-0.20]
化合物I 2 0.19[0.11-0.25]
化合物I 3 0.16[0.13-0.27]
化合物I 4 0.27[0.16-0.42]
化合物I 5 8.67[6.57-10.23]
普瑞巴林 2.42[1.62-3.95]
测试结果表明本公开实施方案提供的化合物I 1-化合物I 4相对于普瑞巴林或化合物I 5表现出明显更加杰出的镇痛效果。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (17)

  1. 具有式(I)所示结构的化合物或其药学上可接受的盐
    Figure PCTCN2021087041-appb-100001
    其中R 1选自-H；-F或-Cl或-Br；-CN；或-NO 2，并且R 2选自-CF 3；-OCF 3；-CN或-NO 2。
  2. 根据权利要求1所述的化合物，其中R 1为-H、-F或-Cl，R 2为-CF 3或-OCF 3。
  3. 根据权利要求1或2所述的化合物，其中所述化合物选自以下结构：
    Figure PCTCN2021087041-appb-100002
  4. 根据权利要求1至3中任一项所述的化合物，其中所述化合物为药学上可接受的盐的形式，所述药学上可接受的盐选自由以下组成的组：盐酸盐、氢溴酸盐、氢碘酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、乙二酸盐、丙二酸盐、丁酸盐、乳酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、苦味酸盐、酒石酸、柠檬酸盐、富马酸盐。
  5. 药物组合物，包含如权利要求1至4中任一项所述的化合物和药学上可接受的辅料。
  6. 根据权利要求5所述的药物组合物，其中所述药物组合物被配制成口服剂型、注射剂型或吸入剂型。
  7. 根据权利要求6所述的药物组合物，其中所述口服剂型包括片剂、颗粒剂和胶囊剂，优选地缓释片剂和缓释胶囊。
  8. 根据权利要求1至4中任一项所述的化合物在制备镇痛药物中的用途，所述镇痛药物用于预防或治疗神经性疼痛或炎症性疼痛。
  9. 根据权利要求8所述的用途，其中通过选自以下的途径向有此需要的受试者施用所述化合物：口服、局部、肠胃外、舌下、直肠、阴道和鼻内。
  10. 根据权利要求9所述的用途，其中肠胃外途径施用包括皮下注射、静脉内注射、肌内注射、硬膜外注射、胸骨内注射和输注。
  11. 根据权利要求1至4中任一项所述的化合物，用于作为镇痛药。
  12. 根据权利要求1至4中任一项所述的化合物，用于在预防或治疗神经性疼痛或炎症性疼痛中使用。
  13. 根据权利要求11或12使用的所述化合物，其中通过口服、局部、肠胃外、舌下、直肠、阴道和鼻内施用所述化合物。
  14. 根据权利要求13使用的所述化合物，其中肠胃外途径施用包括皮下注射、静脉内注射、肌内注射、硬膜外注射、胸骨内注射和输注。
  15. 一种预防或治疗神经性疼痛或炎症性疼痛的方法，包括：向有此需要的受试者施用权利要求1所述的化合物。
  16. 根据权利要求15所述的方法，其中通过口服、局部、肠胃外、舌下、直肠、阴道和鼻内施用所述化合物。
  17. 根据权利要求16所述的方法，其中肠胃外途径施用包括皮下注射、静脉内注射、肌内注射、硬膜外注射、胸骨内注射和输注。
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