WO2009097774A1 - 芳基哌嗪衍生物在制备用于治疗疼痛的药物中的用途 - Google Patents

芳基哌嗪衍生物在制备用于治疗疼痛的药物中的用途 Download PDF

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WO2009097774A1
WO2009097774A1 PCT/CN2009/070162 CN2009070162W WO2009097774A1 WO 2009097774 A1 WO2009097774 A1 WO 2009097774A1 CN 2009070162 W CN2009070162 W CN 2009070162W WO 2009097774 A1 WO2009097774 A1 WO 2009097774A1
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phenylethanone
piperazin
group
pain
piperazine
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PCT/CN2009/070162
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English (en)
French (fr)
Inventor
Guisen Zhang
Lin Guo
Xiangping Yang
Xiangqing Xu
Jianqi Li
Guan Wang
Yanqin Ma
Shuming Hu
Shicheng Liu
Shixia Zhou
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Nhwa Pharma.Corporation
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Priority to EP09709122.7A priority Critical patent/EP2246055B1/en
Priority to US12/865,599 priority patent/US8420652B2/en
Publication of WO2009097774A1 publication Critical patent/WO2009097774A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an aryl piperazine derivative or a pharmaceutically acceptable salt thereof, alone or in combination with other analgesics, for the preparation of a medicament for the treatment of acute pain, neuropathic pain or nociceptive pain in a mammal including a human.
  • analgesics for the preparation of a medicament for the treatment of acute pain, neuropathic pain or nociceptive pain in a mammal including a human.
  • European Patent EP1627871 discloses compounds having the general formula used as intermediates in the preparation of body hormone sulfatase inhibitors:
  • R3 and R4 represent hydrogen, halogen, cyano, or lower hydrazine, respectively; and R6 represents a protecting group for hydrogen or hydroxy.
  • European Patent EP 1 123 926 discloses compounds having the general formula for the preparation of piperazine derivatives for the treatment of disorders of the central nervous system: Wherein R1 is a monocyclic or bicyclic aryl group, a heteroaryl group, R2 is an aryl group or a heteroaryl group, and A is -CH2- or -CH2CH2. The patent document does not describe the pharmacological activity of the above-mentioned compound.
  • the present invention provides one of the following aryl piperazine compounds of the general formula (I) and one of their pharmaceutically acceptable salts for the preparation of acute pain, neuropathic pain or for the treatment of mammals including humans
  • Ar is an aryl or heteroaryl group which is unsubstituted or substituted at one or more positions by a substituent selected from the group consisting of halogen, fluorenyl, d-4 fluorenyl and halo fluorenyl.
  • a method of treating acute pain, neuropathic or nociceptive pain in a mammal, including a human, with a compound of formula (I) above comprising administering to a subject in need of treatment a therapeutically effective The amount of this compound.
  • halogen means fluorine, chlorine, bromine and iodine, of which fluorine, chlorine or bromine is preferred.
  • a fluorenyl group is a straight-chain, branched or cyclic saturated hydrocarbon group containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, N-pentyl and n-hexyl, of which methyl is preferred.
  • a decyloxy group means a fluorenyl-0- group, wherein the fluorenyl group is a fluorenyl group containing 1, 2, 3 or 4 carbon atoms as defined above, such as methoxy, ethoxy, n-propoxy, Isopropoxy and n-butoxy, of which methoxy is preferred.
  • Halogenated fluorenyl refers to a fluorenyl group containing 1, 2, 3 or 4 carbon atoms as defined above, partially or completely substituted by halogen, preferably a trifluoromethyl group.
  • the aryl group means an aliphatic arene group containing 5 to 14 carbon atoms, such as a phenyl group or a naphthyl group, of which a phenyl group is preferable, and a phenyl group substituted by the above substituent is particularly preferable.
  • Heteroaryl refers to a 5-14 membered monocyclic or bicyclic aryl group containing from 1 to 4, preferably from 1 to 2, heteroatoms selected from 0, N and S, preferably benzothiazole, pyridine or pyrimidine. base.
  • the aryl group is a mono- or di-substituted phenyl group, wherein the substituent is preferably selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy and trifluoromethyl.
  • the heteroaryl represents benzothiazole, pyridine or pyrimidine Pyridine, and the substituted heteroaryl group contains no more than two substituents, preferably selected from the group consisting of fluorine, chlorine, bromine, methyl, methoxy and trifluoromethyl.
  • the compound of the formula (I) of the present invention can be produced in the form of a pharmaceutically acceptable salt according to a conventional method known in the art.
  • the pharmaceutically acceptable salt is a conventional salt used in the art, such as an acid addition salt.
  • the pharmaceutically acceptable acid addition salts include inorganic acid addition salts prepared with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or organic acid additions made with organic acids.
  • the organic acid such as acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerol phosphate, acetylsalicylic acid, decyl or aryl sulfonic acid
  • the organic acid such as acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerol phosphate, acetylsalicylic acid, decyl or aryl sulfonic acid
  • methanesulfonic acid benzenesulfonic acid or toluenesulfonic acid.
  • the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of pain refers to the use of an analgesic agent clinically.
  • the acute pain includes, but is not limited to, headache, joint pain, muscle tension or dysmenorrhea.
  • the neuralgia includes, but is not limited to, chronic back pain, postherpetic neuralgia, diabetic peripheral neuralgia, fibromyalgia, cancer-related pain, hallucinal limb pain, pain during childbirth, and opioid analgesics.
  • Neuralgia The nociceptive pain includes, but is not limited to, postoperative pain, toothache, pain caused by surgery, pain caused by severe burns.
  • the compounds of formula (I) should be formulated into pharmaceutical compositions according to conventional pharmaceutical standard methods.
  • the compound of formula (I) can be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injectable solutions.
  • Preferred carriers are, but not limited to, saline solutions, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, and the like.
  • the compounds of the invention may be formulated in the form of an ointment or cream.
  • the compound of the formula (I) can be dissolved, suspended or emulsified in an aqueous solution such as a common saline solution and a 5% glucose solution, or a non-aqueous solution such as a synthetic fatty acid glyceride, a higher fatty acid ester, and propylene glycol.
  • aqueous solution such as a common saline solution and a 5% glucose solution
  • non-aqueous solution such as a synthetic fatty acid glyceride, a higher fatty acid ester, and propylene glycol.
  • the formulations of the present invention may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives.
  • the preferred administration amount of the compound of the formula (I) may vary depending on factors such as the health condition and body weight of the patient, the severity of the disease, the formulation of the drug, the administration route and the time, but those skilled in the art can appropriately perform the measurement.
  • the compound of the present invention is administered in a daily dose of 1 to 200 mg / kg (body weight), preferably 1 to 100 mg / kg (body weight), which may be administered once or in divided doses.
  • the pharmaceutical composition of the present invention may comprise from 0.001 to 99 weights, depending on the method of administration.
  • the pharmaceutical composition of the present invention can be administered to mammals by various routes including rats, mice, livestock and humans. All routes of administration can be used, such as oral, transdermal, parenteral, subcutaneous, intranasal, intramuscular or intravenous.
  • the compound of the formula (I) may also be administered together with another analgesic, in a ratio of 1 part of the compound of the formula (I) to 1 to 10 parts of other analgesic agent.
  • the goal is to achieve synergy.
  • the other analgesic agents include, but are not limited to, non-anti-inflammatory analgesics such as aspirin, naproxen, narcotic analgesics such as morphine, dipyridamole, fentanyl, and the formula (I) of the present invention.
  • Compounds can be prepared by the methods shown in the following synthetic routes:
  • mice (18-22 g), half male and half female. They were divided into a negative control group, aspirin and morphine as positive control groups, and a compound administration group of the present invention. Each group of mice were intragastrically or subcutaneously (sc) The corresponding drug (0.2 ml/10 g) was received, and the negative control group was given an equal volume of distilled water. After 60 minutes (administered by gavage) or 30 minutes later (subcutaneous administration), mice in each group were intraperitoneally injected with 0.6% vinegar solution (0.4 ml), and the number of writhings within 15 minutes was immediately observed. The pharmacodynamic index of pain relief was made by its writhing inhibition rate. Negative pair array writhing times - drug treatment group writhing times
  • mice thermal stimulation model is also one of the commonly used physiological pain models. When the mice are stimulated by heat, they appear to be hind paws, jumps, and the like. Analgesic drugs acting on the central nervous system can increase the thermal pain threshold of mice and prolong the incubation period of protective reflexes.
  • mice 18-22 g of female Kunming mice were used, and the initial screening was performed before the experiment, and the animals were too slow (>30s) or too sensitive ( ⁇ 6s) to be removed.
  • the primary screened mice were divided into a negative control group, a morphine control group, and a compound administration group of the present invention.
  • the mice in each group were orally administered with the corresponding dose of the drug for 30 minutes, and then the hot plate experiment was performed to record the time of the first occurrence of hind paw and jump (60 for more than 60 s), and the incubation period of the control animals.
  • analgesic activity was calculated at each dose, and the ED50 value was calculated using the obtained results. The results are shown in Table 3.
  • Table 3 Analgesic activity of mouse hot plate test
  • intrathecal injection of the compound of the present invention can significantly reduce the total number of spontaneous contractions in rats within 1 hour (P ⁇ 0.05), and significantly inhibit the spontaneous pain response induced by bee venom, the inhibition rate is respectively It is 33.14% and 35.56%.
  • the analgesic effect was the strongest within half an hour after administration; it could significantly prolong the thermal stimulation latency (PO.05) and increase its thermal allodynia, but had no significant effect on mechanical allodynia.
  • Experimental Example 4 Rat neuropathic pain test
  • Neuropathic pain referred to as neuralgia
  • Pain is an abnormal state of pain caused by trauma or disease-induced damage to the peripheral or central nervous system. There is currently no effective treatment.
  • the sciatic nerve branch injury injury model (SNI) is an animal model of neuralgia established in 2000 (see: Spared nerve injury: an animal model of persistent peripheral neuropathic pain, Pain. 2000 Aug; 87(2): 149 -58), this model can produce significant abnormal mechanical allodynia and can better simulate clinical neuropathic pain.

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Description

芳基哌嗪衍生物在制备用于治疗疼痛的药物中的用途 技术领域
本发明涉及芳基哌嗪衍生物或其药学上可接受的盐单独或与其它止痛 剂合用在制备用于在包括人类在内的哺乳动物中治疗急性疼痛、 神经疼痛 或感受伤害性疼痛的药物方面的用途。 背景技术
欧洲专利 EP1627871公开了具有如下通式化合物， 其作为中间体用于 制备 体激素硫酸酯酶抑制剂：
Figure imgf000003_0001
其中 R3和 R4分别代表氢、 卤素、 氰基、 低级垸烃； R6代表氢或羟基的 保护基。 该专利文献未述及上述通式化合物药理活性。
欧洲专利 EP1123926公开了具有如下通式的化合物， 其作为中间体用 于制备治疗中枢神经系统失调的哌嗪衍生物：
Figure imgf000003_0002
其中 R1为单环或双环芳基、 杂芳基， R2为芳基或杂芳基， A为 -CH2- 或 -CH2CH2 该专利文献未述及上述通式化合物药理活性。
我们经研究发现以下式 （ I ) 化合物及其药学上可接受的盐单独或与 其它止痛剂合用 （在此情况下产生协同作用） 可用于在包括人类在内的哺 乳动物中治疗急性疼痛、 神经疼痛、 感受伤害性疼痛。 发明内容
本发明提供下列通式 （ I ) 的芳基哌嗪化合物及其药学上可接受的盐 类之一在制备用于治疗包括人类在内的哺乳动物的急性疼痛、 神经疼痛或 感受伤害性疼痛的药物方面的用途：
Figure imgf000004_0001
( I )
其中
Ar为未取代的或者被选自以下组中的取代基在一个或者多个位置上取代的 芳基或杂芳基： 卤素、 垸基、 d—4垸氧基和卤代 垸基。
根据本发明的另一个方面， 其还提供用上述式 （I)化合物治疗包括人 类在内的哺乳动物的急性疼痛、 神经疼痛或感受伤害性疼痛的方法， 包括 向需要治疗的个体给药治疗有效量的该化合物。 具体实施方式
在本发明中， 卤素是指氟、 氯、 溴和碘， 其中优选氟、 氯或溴。
垸基是指包含 1、 2、 3、 4、 5或 6个碳原子的直链、 支链或环状 的饱和烃基， 例如甲基、 乙基、 丙基、 异丙基、 正丁基、 正戊基和正己基， 其中优选的是甲基。
垸氧基是指垸基 -0-基团， 其中垸基为如上所定义的包含 1、 2、 3 或 4个碳原子的垸基， 如甲氧基、 乙氧基、 正丙氧基、 异丙氧基和正丁氧 基， 其中优选的是甲氧基。
卤代 垸基是指部分或者完全被卤素取代的如上所定义的包含 1、2、 3或 4个碳原子的垸基， 其中优选为三氟甲基。
芳基是指包含 5-14个碳原子的脂族芳烃基团， 如苯基或萘基， 其中优 选的是苯基， 尤其优选的是被上述取代基取代的苯基。
杂芳基是指其中包含 1-4个、 优选 1-2个选自 0、 N和 S的杂原子的 5-14元单环或二环芳基， 其中优选为苯并噻唑、 吡啶或嘧啶基。
在本发明的一个实施方案中， 所述芳基为一取代或二取代的苯基， 其 中取代基优选选自氟、 氯、 溴、 甲基、 甲氧基和三氟甲基。
在本发明的另一个实施方案中， 所述杂芳基代表苯并噻唑、 吡啶或嘧 啶， 而取代的杂芳基含有不超过二个取代基， 所述取代基优选选自氟、 氯、 溴、 甲基、 甲氧基和三氟甲基。
本发明的通式 （ I ) 化合物可根据本领域已知的常规方法以药物学可 接受的盐的形式制成。 该药物学可接受的盐是本领域所用的常规的盐， 如 酸加成盐。 药物学可接受的酸加成盐包括用无机酸制成的无机酸加成盐， 所述无机酸例如是盐酸、 氢溴酸、 磷酸或硫酸， 或者是用有机酸制成的有 机酸加成盐， 该有机酸例如是乙酸、 丙酸、 乳酸、 柠檬酸、 富马酸、 苹果 酸、 琥珀酸、 水杨酸、 马来酸、 甘油磷酸、 乙酰水杨酸、 垸基或芳基磺酸 如甲磺酸、 苯磺酸或甲苯磺酸。
通式 （ I ) 化合物或其药学上可接受的盐在制备治疗疼痛药物方面的 用途是指在临床上做为止痛剂的用途。所述的急性疼痛包括但不限于头疼、 关节疼、 肌肉紧张或痛经。 所述的神经痛包括但不限于慢性背疼、 疱疹后 遗神经痛、 糖尿病外周神经痛、 肌纤维痛、 与癌症有关的疼痛、 幻觉肢体 疼痛、 分娩过程中的疼痛以及耐阿片类镇痛药的神经痛。 所述感受伤害性 疼痛包括但不限于术后疼痛、 牙疼、 手术引起的疼痛、 严重烧伤引起的疼 痛。
为在治疗时给药所述式 （I) 的化合物， 这些化合物应根据常规的制药 标准方法配制成药物组合物。 例如， 该式 （I) 的化合物可溶解在油、 丙二 醇或者常用于制备注射液的其他溶剂中。优选的载体是但不限于盐水溶液、 聚乙二醇、 乙醇、 植物油、 肉豆蔻酸异丙基酯等。 对于局部给药， 本发明 的化合物可配制成软膏或者乳膏的形式。
所述式 （I) 的化合物可溶解、 悬浮或者乳化在含水溶液中， 如普通盐 水溶液和 5 %葡萄糖溶液， 或者非水溶液中， 如合成脂肪酸甘油酯、 高级 脂肪酸酯、 和丙二醇， 由此配制成注射剂。 本发明的制剂可包含常规的添 加剂如增溶剂、 等渗剂、 悬浮剂、 乳化剂、 稳定剂和防腐剂。
式 （I)化合物的优选给药量可根据以下因素变化： 患者的健康状况和 体重、 疾病的严重程度、 药物的制剂、 给药途径和时间， 但是本领域技术 人员可适当地进行测定。 然而， 为得到优选的效果， 本发明化合物的日给 药剂量为 1-200 mg /kg (体重)， 优选为 1一 100 mg/kg (体重)， 该剂量可一次 给药或者分数次给药。 根据给药方法， 本发明的药物组合物可包含 0.001— 99 重量
0.01— 60重量％的式 （I) 化合物。
本发明的药物组合物可通过各种途径给药于哺乳动物， 包括大鼠、 小 鼠、 家畜和人。 可以使用所有的给药途径， 例如口服、 透皮、 非胃肠道、 皮下、 鼻内、 肌肉或静脉内等途径。
根据本发明的另一个实施方案， 该式（I)的化合物也可与另一止痛剂 一起进行给药， 两者的比例为 1份的式 （ I ) 化合物对 1-10份的其它止痛 剂， 其目标是获得协同作用。 所述的其它止痛剂包括但不限于非 体消炎 镇痛药如阿斯匹林、 萘普生， 麻醉性镇痛药如吗啡、 度冷丁、 芬太尼类药 本发明所述式（ I )化合物可由根据以下合成路线中所示的方法制得:
Figure imgf000006_0001
例如， 将取代的芳基哌嗪或杂芳基哌嗪 0.24mol、 α-氯代苯乙酮 0.24mol、乙醇 480ml、碳酸钠 50.4g加入 1000ml 四口瓶中，搅拌回流 4 小 时后， 薄层层析法跟踪反应至主产物点不再变化， 指示反应完毕。 热滤、 滤液蒸干， 二氯甲垸溶解蒸干后的残留物， 水洗二氯甲垸溶液近中性， 加 无水硫酸钠干燥后， 用饱合的氯化氢乙酸乙酯溶液调 pH至 3-4， 过滤、 乙 醚洗涤， 无水乙醇重结晶， 50°C真空干燥， 得类白色固体。 实施例
以下将参考实施例对本发明做进一步的说明， 但本领域技术人员应理 解的是，这些实施例仅是用于说明本发明，而绝不应是对本发明范围的任 何限制。 制备例：
用相应的起始物按照上述通用方法制备以下表 1中所示的化合物。 表 1
Figure imgf000007_0001
实 施 Ar= HMNR(300MHz), δ (溶剂） MS (m/z)
例 号
7.95(d,J=7.2,2H), 7.72(t,J=7.2,lH) 310.3[M]+
1 2-甲氧基苯 7.55(t,J=7.6,2H), 7.16(t,J=7.6,lH) 205.2[Ci2Hi7N2O]+ 基 7.12(d,J=7.6,lH), 7.05(d,J=7.6,lH) 105.1 [C7H50]+
7.01(t,J=7.6,lH), 5.00(s,lH)
3.82(s,3H), (CDCL3 )
2 3-甲氧基苯 8.01(d,J=7.6,2H), 7.64 (t,J=7.6,lH) 310.3[M]+
基 7.53(t,J=7.6,2H), 7.10 (t，J=8.0，lH) 205.2[Ci2Hi7N2O]+
6.52(dd,J=2.0,7.6,lH),6.44(t,J=2.0,lH) 105.1 [C7H50]+ 6.36(dd,J=2.0,7.6,lH), 3.88(s,2H)
，3，71(s，3H )，(CDCL3 )
3 4-甲氧基苯 7.94(d,J=7.6,2H), 7.72(t,J=7.6,lH) 310.3[M]+
基 7.55(t,J=7.6,2H), 7.12(d,J=8.8,2H) 205.2[C12H17N2O]+
7.08(d,J=8.8,2H), 5.00(s,2H) 105.1 [C7H50]+ 3.76 (s,3H), (CDCL3 )
4 2-氯苯基 8.02(d,J=7.6,2H), 7.64 (t,J=7.6,lH) 314.1[M]+
7.53(t,J=7.6,2H), 7.39 (dd,J=l.2,7.6, 1H) 209.0 [C12H17N2CL]+ 7.28(td,J=1.2,7.6,lH),7.16(dd,J=1.2,7.6,l 105.1 [C7H50]+ H)， 7.03(td,J=1.2,7.6,lH), 3.93 (s,2H)
(CDCL3 )
5 3-氯苯基 8.01(d,J=7.6,2H), 7.64(t,J=7.2,lH) 314.1[M]+
7.53(t,J=8.0,2H), 7.20(t,J=8.0, 1H) 209.0 [C12H17N2CL]+ 6.93(t,J=2.0, lH),6.89(dd,J=1.2,7.6,lH) 105.1 [C7H50]+ 6.77(dd,J=1.2,7.6,lH), 3.92(s,2H)
(CDCL3 ) 4-氯苯基 8.01(d,J=7.6,2H), 7.64(t,J=7.2,lH) 314.1[M]+
7.53(t,J=7.6,2H), 7.22(d,J=8.8, 2H) 209.0 [C12H17CLN2]+ 6.94(d，J=8.8，2H)， 3.92(s,2H), (CDCL3 ) 105.1 [C7H50]+
2,3-二氯苯 8.01(d,J=7.6,2H), 7.59(tt,J=1.2,7.6,lH) 348.3 [M]+
基 7.53(t,J=7.6,2H), 7.17-7.13(m, 2H) 243.2 [C12H13CL2N2]+
6.97(dd,J=5.6,2.8,lH), 3.92(s,2H) 105.1 [C7H50]+ (CDCL3 )
4-氟苯基 8.01(d,J=7.2,2H), 7.64(t,J=7.2,lH) 298.1 [M]+
7.53(t,J=7.6,2H), 7.04(t,J=8.8, 2H) 193.0 [C12H13FN2]+ 6.95-6.93(m,2H), 3.92(s,2H), (CDCL3 ) 105.1 [C7H50]+
3-三氟甲基 7.99 (d,J=7.2,2H), 7.58(t,J=7.6,lH) 348.3 [M]+
苯基 7.43(t,J=7.6,2H), 7.32(t,J=8.0,lH) 243.2 [C12H14F3N2]+
7.14(br,lH), 7.04(d,J=8.0,lH) 105.1 [C7H50]+ 7.01(t,J=7.6,lH), 4.93(s,2H)
3.79-3.14(br,3H), (CDCL3 )
2，3-二甲基 7.92(d,J=7.2,2H), 7.59(t,J=7.6,lH) 308.3 [M]+
苯基 7.45(t,J=7.6,2H), 6.94(t,J=7.6,lH) 203.2 [C13H19N2]+
6.86(d,J=7.6,lH), 6.82(d,J=7.6,lH) 105.1 [C7H50]+ 4.94 (s,2H), 3.59-3.09(br,3H), (CDCL3 ) 132.2 [C9Hi0N]+
6-甲氧基 7.92(d,J=7.6,2H), 7.58(tt,J=l.2,7.2, 1H) 367.3 [M]+
-2-苯并噻 7.47 (t,J=7.6,2H),7.15(t,J=2.4,lH) 262.2 [C13H16N3OS]+ 唑基 7.45(s,lH), 3.90(s,2H), 105.1 [C7H50]+
6.90 (dd，J=2.4，7.6，lH)， 3.68((t,J=5.2,4H) 207.2 [CioHnN2OS]+
3.82 (s,2H), (CDCL3)
6-甲基 -2- 8.00 (d,J=7.6,2H), 7.64(t,J=7.6,lH) 351.3 [M]+
苯并噻唑 7.56-7.5 l(m,3H), 7.34(d,J=8.4,lH) 246.2 [C13H16N3S]+ 基 7.08(dd,J=0.8,7.6,lH), 3.97(s,2H) 105.1 [C7H50]+
3.55 (t, J=1.2,2H), (CDCL3) 191.2 [C10HnN2S]+ 13 4-甲基 -2- 8.00(m,2H), 7.58 (tt,J=l.2,7.2, 1H) 351.3 [M]+
苯并噻唑 7.49 -7.43(m,3H), 6.98(t,J=7.6,lH) 246.2 [C13H16N3S]+ 基 7.12(d,J=7.2,lH), 3.74(t,J=5.2,4H) 105.1 [C7H50]+
3.91(s,2H), (CDCL3) 191.2 [CioHnN2S]+
14 6-氯 -2-苯 7.98 (d,J=7.6,2H), 7.60(tt,J=1.2,7.2,lH) 371.3 [M]+
并噻唑基 7.57 (d,J=2.0,lH), 7.48 (t,J=7.6,2H) 266.2 [C12H14CLN3S]+
7.45 (d,J=8.8,lH), 7.25 (dd,J=2.0,8.8,lH) 105.1 [C7H50]+ 3.97(s,2H), (CDCL3) 211.2 [C9H8LN2S]+
15 4-氯 -2-苯 7.98 (d,J=7.6,2H), 7.59(t,J=7.6,lH) 371.3 [M]+
并噻唑基 7.49 -7.42 (br,3H), 7.31(dd,J=1.2,7.6,lH) 266.2 [C12H14CLN3S]+
6.98(t，J=8.0，lH)， 3.97(s,2H) 105.1 [C7H50]+ 3.72 (t,J=5.2,4H), (CDCL3) 211.2 [C9H8LN2S]+
16 2-嘧啶基 8.51 (d,J=5.2,2H), 7.91(d,J=7.6,2H) 282.2 [M]+
7.68 (t,J=7.6,2H), 7.51(t,J=8.0,lH) 177.1 [C9H13N4]+ 6.97 (t,J=5.2,lH), 5.00(s,2H) 105.1 [C7H50]+ 4.14-2.89 (br,8H), (CDCL3)
17 6-氯 -2-吡 8.01(d,J=7.6,2H), 7.64 (t,J=7.6,lH) 315.2 [M]+
啶基 7.53(t,J=7.6,2H), 7.10 (t，J=8.0，lH) 210.1 [C9H12CLN3]+
6.52(dd,J=2.0,7.6,lH),6.44(t,J=2.0,lH) 105.1 [C7H50]+ 6.36(dd,J=2.0,7.6,lH), 3.88(s,2H),
3,71(s,3H ),(CDCL3 ) 以下采用昆明小鼠和 SD大鼠作为实验动物， 通过醋酸扭体法、 蜂毒 刺激法、 热板法、 坐骨神经结扎法等疼痛模型对本发明化合进行止痛活性 的研究。 实验例 1: 小鼠醋酸扭体实验
KM小鼠 （18-22 g)， 雌雄各半。 分别分为阴性对照组、 阿司匹林及吗 啡为阳性对照组以及本发明化合物给药组。各组小鼠分别灌胃或皮下（s.c) 接受相应的药物 （0.2 ml/10g)， 阴性对照组给予等体积的蒸馏水。 60分 后 （灌胃给药） 或 30分钟后 （皮下给药）， 各组小鼠经腹腔注射 0.6%醋 溶液（0.4 ml) , 并立即观察记录 15分钟内扭体次数。 以其扭体抑制率做 止痛的药效学指标。 阴性对数组扭体次数-药物处理组扭体次数
扭体抑制率
Figure imgf000010_0001
阴性对照组扭体次数
利用所得到的结果， 可计算出半数最大效应量 （ED50)。 结果如表 所示。 表 2 小鼠醋酸扭体实验的止痛活性
ED50 ( mg/Kg)
供 试 品 灌 胃 皮 下 （S.C) 实施例 1 20 15
实施例 2 5 2
实施例 3 30 20
实施例 4 80 36
实施例 5 50 18
实施例 7 60 20
实施例 8 120 80
实施例 9 3 2
实施例 10 5 10
实施例 11 200 120
实施例 12 180 100
实施例 14 152 78
实施例 16 132 100
阿司匹林 100 80
吗 啡 4 1 由表 2的结果显示， 本发明的化合物可以明显抑制小鼠的扭体次数， 改善临床症状， 具有良好的镇痛效果。 实验例 2: 小鼠热刺激实验
小鼠热刺激模型也是常用的生理性疼痛模型之一。 小鼠在受到热刺激 时， 表现为舔后足、 跳起等动作。 作用于中枢神经系统的镇痛药物可以提 高小鼠的热痛阈， 延长其保护性反射的潜伏期。
采用 18-22g的雌性昆明小鼠， 实验前首先进行初筛， 将反应过于迟钝 (>30s)或过于敏感（<6s)动物去除。将初筛合格的小鼠分为阴性对照组、 吗啡对照组以及本发明化合物给药组。 各组小鼠灌胃或静注给予相应剂量 的药物 30分钟后进行热板实验， 记录第一次出现舔后足和跳起的时间（超 过 60s者记为 60)， 与对照组动物的潜伏期进行比较， 在每个剂量下计算 出止痛活性， 利用所得结果计算 ED50值。 结果如表 3所示。 表 3 小鼠热板实验的止痛活性
Figure imgf000011_0001
由以上表 3的结果可以看出， 在小鼠热板实验中， 本发明的式 （I) 化 合物显示了良好的镇痛效果。 实验例 3: 大鼠蜂毒实验
成年 SD大鼠， 雄性， 体重 200-250g， 饲养 1周适应环境后进行实验。 首先进行大鼠鞘内置管， 3-4天后， 观察动物状态良好者用于蜂毒实验。将 动物分为鞘内 DMSO对照组、 鞘内吗啡组、 鞘内本发明化合物给药组。 给 药后 5分钟各组大鼠于左侧后肢皮下注入蜜蜂毒 50 ul，立即观察并记录 60 分钟内每 5分钟自发缩足反射次数及 1小时内总的缩足次数； 并分别于鞘 内给药前和蜜蜂毒注射后 2小时测定各组大鼠双侧足底热刺激潜伏期和机 械刺激阈值。 实验结果如表 4所示。 表 4 小鼠蜂毒实验中的止痛活性
Figure imgf000012_0001
由表 4的结果可以看出， 鞘内注射本发明化合物能显著的减少大鼠 1 小时内自发缩足总次数（P<0.05 )， 明显抑制蜜蜂毒诱导的自发痛反应， 其 抑制率为分别为 33.14%和 35.56%。观察反应时程发现，给药后半小时内镇 痛作用最强； 能显著的延长大鼠热刺激潜伏期 （PO.05 ) , 提高其热痛敏， 但对机械痛敏没有明显影响。 实验例 4: 大鼠神经病理性疼痛实验
神经源性病理性疼痛 (neuropathic pain)简称神经痛， 是一种常见的慢性 痛， 是由创伤或疾病致外周或中枢神经受损所引起的异常的疼痛状态， 目 前尚缺乏有效的治疗措施。坐骨神经分支选择损伤模型 (spared nerve injury, SNI)是 2000年建立的一种神经痛动物模型 （参见： Spared nerve injury: an animal model of persistent peripheral neuropathic pain, Pain. 2000 Aug; 87(2): 149-58)， 该模型能产生显著的异常机械痛敏， 可以较好的模拟临床神经病 理性疼痛。
成年 SD大鼠 （徐州医学院实验动物中心）， 雄性， 体重 220〜280g。 饲养 1周适应环境后进行实验。首先，复制坐骨神经分支选择性损伤（SNI) 模型。 造模成功的大鼠于手术后第 12、 13、 14天灌胃给药 （Bid, 9AM和 3PM) o 每天上午给药后 60分钟测定其机械痛敏情况 （von Frey纤毛仪， 中国医学科学院生物工程研究所生产）。 实验结果如表 5所示。
Figure imgf000013_0001
Figure imgf000013_0002
由表 5 的结果可以看出， 各组造模大鼠第七天时机械阈值明显降低 (P<0.01 )， 说明该 SNI模型能造成大鼠机械痛敏， 本发明化合物给药组能 明显的提高大鼠的痛域值（P<0.01 )， 说明该化合物在该剂量下具有较好的 镇痛作用。

Claims

权 利 要 求 书
1、 一种通式 I所示的芳基哌嗪化合物或其药学上可接受的盐在制备 治疗包括人类在内的哺乳动物的急性疼痛、 神经疼痛、 感受伤害性疼痛的 药物中的用途，
Figure imgf000015_0001
其中
Ar为未取代的或者被选自以下组中的取代基在一个或者多个位置上取代的 芳基或杂芳基： 卤素、 垸基、 d—4垸氧基和卤代 d—4垸基。
2、 权利要求 1所述的用途， 其中 Ar为被以下取代基一取代或二取代 的苯基： 氟、 氯、 溴、 甲基、 甲氧基或三氟甲基。
3、 权利要求 1所述的用途， 其中 Ar为未取代或被一或二取代的杂芳 基。
4、权利要求 3所述的用途，其中所述杂芳基为苯并噻唑、吡啶或嘧啶。
5、 权利要求 3所述的用途， 其中所述杂芳基上的取代基选自氟、 氯、 溴、 甲基、 甲氧基和三氟甲基。
6、 权利要求 1所述的用途， 其中所述化合物选自以下组中：
1) 2- [4- (2-甲氧基苯基） 哌嗪 -1-基]小苯基乙酮
2) 2- [4- (3-甲氧基苯基） 哌嗪 -1-基] - 1-苯基乙酮
3) 2- [4- (4-甲氧基苯基） 哌嗪 -1-基] - 1-苯基乙酮
4) 2-[4- (2-氯苯基） 哌嗪 -1-基]- 1-苯基乙酮 5) 2-■[4- (3- .氯苯基） 哌嗪 -1-基]— 1-苯基乙酮
6) 2- ■[4- (4- .氯苯基） 哌嗪 -1-基]— 1-苯基乙酮
7) 2- ■[4- (2： ， 3-二氯苯基） 哌嗪 -1-基]- 1-苯基乙酮
8) 2- ■[4- (4- .氟苯基） 哌嗪 -1-基]— 1-苯基乙酮
9) 2- ■[4- (3- .三氟甲基苯基） 哌嗪 -1-基] - 1-苯基乙酮
10) 2- ■[4- (2： ， 3-二甲基苯基） 哌嗪 -1-基] - 1-苯基乙酮
11) 2- ■[4- (6- .甲氧基 -2-苯并噻唑基） 哌嗪 -1-基] - 1-苯基乙酮
12) 2- ■[4- (6- .甲基 2-苯并噻唑基） 哌嗪 -1-基] - 1-苯基乙酮
13) 2- ■[4- (4- .甲基 -2-苯并噻唑基） 哌嗪 -1-基] - 1-苯基乙酮
14) 2- ■[4- (6- .氯-2-苯并噻唑基） 哌嗪 -1-基] - 1-苯基乙酮
15) 2- ■[4- (4- .氯-2-苯并噻唑基） 哌嗪 -1-基] - 1-苯基乙酮
16) 2- ■[4- (2- .嘧啶基） 哌嗪 -1-基] - 1-苯基乙酮
17) 2- ■[4- (6- .氯-2-吡啶基） 哌嗪 -1-基] - 1-苯基乙酮
18) 2- ■[4- (3- .甲基吡啶基） 哌嗪 -1-基] - 1-苯基乙酮以及
19) 2- ■[4- (2- .甲基吡啶基） 哌嗪 -1-基] - 1-苯基乙酮。
7、权利要求 1的用途， 其中所述式 I的化合物或其药学上可接受的盐 可与另一种常用的止痛剂一起使用。
8、权利要求 1的式 I化合物， 其是用于治疗包括人类在内的哺乳动物 的急性疼痛、 神经疼痛或感受伤害性疼痛药物。
PCT/CN2009/070162 2008-01-31 2009-01-15 芳基哌嗪衍生物在制备用于治疗疼痛的药物中的用途 WO2009097774A1 (zh)

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CN101496802B (zh) 2011-04-27

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