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WO2003097023A1 - Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques - Google Patents

Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques Download PDF

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WO2003097023A1
WO2003097023A1 PCT/CN2002/000846 CN0200846W WO03097023A1 WO 2003097023 A1 WO2003097023 A1 WO 2003097023A1 CN 0200846 W CN0200846 W CN 0200846W WO 03097023 A1 WO03097023 A1 WO 03097023A1
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acid
ethyl
analgesic
piperidinecarboxylic
gaba
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PCT/CN2002/000846
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English (en)
French (fr)
Inventor
Lihe Guo
Jiahua Hu
Na Yang
Yinghua Ma
Jian Fei
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Shanghai Institutes For Biological Sciences, Cas
Shanghai Celstar Institute Of Biotechnology Co. Ltd.
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Application filed by Shanghai Institutes For Biological Sciences, Cas, Shanghai Celstar Institute Of Biotechnology Co. Ltd. filed Critical Shanghai Institutes For Biological Sciences, Cas
Priority to AU2002367951A priority Critical patent/AU2002367951A1/en
Publication of WO2003097023A1 publication Critical patent/WO2003097023A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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

Definitions

  • the invention relates to the field of biomedicine, and in particular to the application of a ⁇ -aminobutyric acid (GABA) transporter inhibitor in the preparation of analgesics.
  • GABA ⁇ -aminobutyric acid
  • Pain is a common condition that can be divided into mild, moderate and severe pain.
  • non-opiates are generally used for the treatment of mild pain
  • weak opioids are used for moderate pain
  • strong opioids are used for severe pain.
  • analgesics can be mainly divided into: (1) acting on peripheral pain receptors, which are weak analgesics; (2) acting on GABA receptors and enhancing the function of GABAergic nerves. Good sedative effect; (3) Inhibition of prostaglandin biosynthesis, mainly antipyretic and analgesics, such as aspirin; (4) Blocking of dopamine receptors in the brain, such as cranitonin; (5) Activation of opioid receptors, Such as morphine, pethidine.
  • opioids have the best analgesic effect, but their side effects are large (nausea, vomiting, constipation, drowsiness, dizziness, respiratory depression, etc.), and they are tolerant and addictive, so they should be used with caution. Because many diseases can cause pain, especially in the advanced stage of cancer, it can cause severe pain. Therefore, finding, designing and synthesizing high-efficiency, low-toxicity, intolerance and non-addiction analgesics have been pursued by drug research for a long time. aims.
  • GABA is the most important inhibitory neurotransmitter in the mammalian central nervous system.
  • the biological function of GABA transporters is to stop the transmission of neurosuppressive information by taking up GABA neurotransmitters in the synaptic cleft, and then to regulate the transmission of neural signals.
  • Strength and timeliness in order to achieve coordination and unity between complex neural network signals.
  • Compounds with specific inhibitory functions have been reported, mainly 3-piperidinecarboxylic acid and tetrahydronicotinic acid and many derivatives with these two compounds as the mother core.
  • GABA transporters such as high ⁇ -proline, tetrahydropyridyl isoxazol, pentaazaisoxazole and its derivatives, etc.
  • GABA transporters such as high ⁇ -proline, tetrahydropyridyl isoxazol, pentaazaisoxazole and its derivatives, etc.
  • GABA transporter inhibitors have been reported in the clinical treatment of epilepsy, and it is mentioned that tiagabine may be used for pain treatment, and this drug has small side effects and is safe for long-term use (Genton p., Et al., Epilepsia, 2001, 42 (Suppl.3): 42-45; Meldrum BS, et al., Epilepsia, 1999, 40 (Suppl.9): S2-S6).
  • Patent WO 9415618 (1994) also mentions that some abnormal conditions (such as epilepsy, myoclonus, chronic pain) are related to the overexpression or underexpression of GABA transporters.
  • the present invention finds a class of compounds that target the ⁇ -aminobutyric acid transporter as having good analgesic effects.
  • the present invention provides the use of a ⁇ -aminobutyric acid transporter inhibitor in the preparation of analgesic drugs.
  • the present invention finds that such compounds having an inhibitory function have a good effect on analgesia.
  • the mechanism of action of these compounds is to inhibit the function of the GABA transporter, increase the GABA concentration in the synaptic space, and eventually lead to the enhancement of the inhibitory GABAergic nerve function, thereby achieving analgesic effect. This can be confirmed by the following experiments.
  • ⁇ -aminobutyric acid transporter inhibitors include all compounds that reduce the function of ⁇ -aminobutyric acid transporter uptake (transport), such as the known compounds mentioned above, 3-piperidinecarboxylic acid, tetrahydronicotinic acid, and high ⁇ -proline , Tetrahydropyridyl isoxazol, pentahydroazaisoxazol, and their derivatives, etc. See FIG. 1 for a diagram of an exemplary compound structure (the above derivatives are not limited to these exemplary compounds). These compounds can be synthesized according to the methods reported in the aforementioned literatures or purchased from the market.
  • the hair One of the competitive inhibitors ethyl 3-piperidinecarboxylic acid (a derivative of 3-piperidinecarboxylic acid) and one non-competitive inhibitor, N- (diphenyliminoethanolyl) -tetrahydrogen, were selected.
  • Niacin NO-711, a derivative of tetrahydronicotinic acid
  • Heat-induced pain tail-flicking
  • formalin-induced inflammatory pain paw licking
  • acetic acid-induced visceral pain test were used to test mice for both 3-piperidinecarboxylic acid ethyl ester and NO-711 For the response, use saline as a control.
  • the analgesic application of ⁇ -aminobutyric acid transporter inhibitors can give effective doses of GABA transporter inhibitor drugs to patients with pain to achieve the purpose of treating pain.
  • These pains include painful diseases caused by various reasons such as thermal irritation, inflammation, internal organ damage, cancer, and the like.
  • Clinical administration can be by oral or injection. Oral medicines can be made into tablets, capsules, powders, solutions and other dosage forms according to conventional methods. The injection can be intramuscular, subcutaneous or intravenous.
  • ⁇ -aminobutyric acid transporter inhibitors in the treatment of pain depends on the nature and extent of the disease and the patient's treatment. Ultimately, it is up to the prescriber to decide how many doses to give to the patient. The clinically used dose is 0.1-2 mg per kilogram of body weight per day. GABA transporter inhibitor.
  • the drug may also include pharmacologically acceptable carriers, solvents, fillers, buffers and stabilizers, etc. substance.
  • pharmacologically acceptable is meant a non-toxic substance that does not affect the biological activity of a GABA transporter inhibitor. The choice of carrier and other substances depends on the different route of administration.
  • the invention discloses that the GABA transporter inhibitor has analgesic effect, and opens up a new application field for the GABA transporter inhibitor.
  • the inhibitor includes all compounds that inhibit the analgesic effect of the GABA transporter.
  • these compounds also have significant advantages: experiments have shown that they are small non-opioid molecules, are not tolerant, can avoid increasing doses, are not addictive, and can be avoided Subsequent withdrawal treatment after medication. Therefore, these compounds have clinical application value for the treatment of pain, and ⁇ -aminobutyric acid transporter inhibitors can be used to prepare analgesics.
  • Figure 1 illustrates compounds that inhibit GABA transporters.
  • 1-3-piperidinecarboxylic acid (piperidine-3 -carboxylic acid, nipecotic acid, C 6 H n N0 2 ), 2-tetrahydronicotinic acid (l, 2,5,6-tetrahydro-pyridine-3-carboxylic acid, guvacine, C 6 H 9 N0 2 ), 3 ⁇ 3-neoacetic acid ethyl ester (piperidine-3-carboxylic acid ethyl ester, ethyl nipecotate, C 8 H 15 N0 2 ), 4-n- (diphenylimine Ethyl alcohol) -tetrahydronicotinic acid (1- [2- [[((diphenyl) imino] oxy] ethyl] -3- (l, 2 5 5,6-te1xahydropyridin-l-yl) carboxylic acid, NO-711 , C 21 H 22
  • Figure 2 shows the analgesic effect of ethyl 3-piperidinecarboxylate on heat-induced pain.
  • Figure 3 shows the analgesic effect of NO-711 on heat-induced pain.
  • Figure 4 shows the analgesic effect of ethyl 3-piperidinecarboxylate and NO-711 on formalin-induced foot inflammation and pain.
  • the results show that ethyl 3-piperidinecarboxylate (60mg / kg) and NO-711 (10mg / kg) can have analgesic effects on inflammatory pain.
  • Figure 5 shows the analgesic effect of ethyl 3-piperidinecarboxylate on acetic acid-induced visceral pain.
  • ethyl 3-piperidinecarboxylic acid (30 mg / kg, 60 mg kg) has a good visceral analgesic effect and a high dose
  • Ethyl 3-piperidinecarboxylate has better analgesic effect than low-dose ethyl 3-piperidinecarboxylic acid (n-8-9, ** indicates p ⁇ 0.01, ethyl 3-piperidinecarboxylic acid is normal to normal saline, one- way ANOVA evaluation significance).
  • Figure 6 shows the analgesic effect of NO-711 on visceral pain induced by acetic acid.
  • NO-711 5mg / kg, 10mg / kg
  • High-dose NO-711 is lower than low-dose NO-711 has a good analgesic effect.
  • n 8-9, ** indicates p ⁇ 0.01, NO-711 vs. saline, one-way ANOVA evaluation significance).
  • Figure 7 shows that ethyl 3-piperidinecarboxylate (90 mg / kg) was not tolerated after 4 and 8 days of continuous injection (a). However, morphine (8mg / kg) showed significant tolerance after 4 and 8 days of continuous injection (b).
  • dl the first day
  • d4 the fourth day
  • d8 the eighth day
  • n 8 * means p ⁇ 0.05
  • ** means p ⁇ 0.01
  • the fourth day and the eighth day to the first day, one-way ANOVA evaluation significance
  • Ethyl 3-piperidinecarboxylate was purchased from ACROS, and NO-711 was purchased from Sigma.
  • the animals used in the experiment were C57 BL / 6J mice.
  • mice There are 8-10 mice in each group.
  • the tail flick experiment uses 51.0 ° C hot water to soak the tail.
  • the experimental operation is as follows: (1) Wrap the mouse with a soft cloth, the tail is exposed, (2) immerse the 3/4 length of the tail in hot water, and record that the tail is immersed in heat The time interval from water to tail flick, (3) mice were given ethyl 3-piperidinecarboxylic acid 30mg / kg, 60mg / kg, NO-711 10mg / kg or the same volume of normal saline by intraperitoneal injection, (4) After the drug injection, test the tail-flick delay time at 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes, respectively, and repeat steps (1) and (2).
  • % MPE (delay time after administration-delay time before administration) I (12-delay time before administration).
  • One-way ANOVA was used to evaluate significance.
  • the experimental operation is as follows: (1) Place the mouse alone, record the time when the mouse licks or bites the left paw, record every 5 minutes, record three time periods, (2) subcutaneously inject the mouse ⁇ 5% of formalin, immediately record the length of time that the mouse licked or bite the injection site, every 5 minutes, (3) After recording the second time interval, that is, intraperitoneal injection of 60 mg / kg ethyl 3-piperidinecarboxylate, 10mg / kg NO-71 1 Or the same volume of normal saline, (4) Then record the time of licking or biting the paw of the mouse, every 5 minutes until the termination of the formalin injection 55 minutes.
  • One-way ANOVA was used to evaluate significance. There were 8 mice in each group.
  • mice showed no significant difference in pain response in stage I (0-10 minutes) after formalin injection, while stage II (10-55 minutes) was ethyl 3-piperidinecarboxylate and NO-711.
  • stage II 10-55 minutes
  • NO-711 Ethyl 3-piperidinecarboxylate
  • the animals injected with ethyl 3-piperidinecarboxylate and NO-711 had a significantly lower response to formalin-induced inflammation and pain than the animals injected with saline, and the analgesic effect of NO-711 Ethyl 3-piperidinecarboxylic acid is good ((a) and (b) in Figure 4; * means p ⁇ 0.05, ** means p ⁇ 0.01, ⁇ means p ⁇ 0.01) o
  • the experimental procedure is as follows: 30 mg / kg ethyl 3-piperidinecarboxylate, 60 mg / kg ethyl 3-piperidinecarboxylic acid, 5 mg / kg NO-71K 10 mg / kg NO-711 or the same volume of physiological saline ( (Control group), immediately return to the mouse cage; (2) Remove the mouse after 5 minutes, inject 0.6% acetic acid ( ⁇ ⁇ / g) into the abdominal cavity of the mouse, and immediately return to the mouse cage; (3) 5 Minutes of mouse writhing began to be recorded after 15 minutes, and continued for 15 minutes. The significance was evaluated by one-way ANOVA, with 8-9 mice per group.
  • mice injected with ethyl 3piperidinecarboxylate or NO-711 were significantly lower than that in the control group, and it was smaller after pretreatment with high-dose ethyl 3-piperidinecarboxylic acid or NO-711.
  • the response to visceral pain in mice was weaker than that in mice pretreated with low-dose ethyl 3-piperidinecarboxylate or NO-711 (see Figures 5 and 6, ** indicates p ⁇ 0.01).
  • mice were injected subcutaneously with 90 mg / kg ethyl 3-piperidinecarboxylate or 8 mg / kg morphine once a day for 8 days, respectively, and ethyl 3-piperidinecarboxylic acid was tested on days 1, 4, and 8 respectively. And analgesic effects of morphine. Methods The tail-flick experiment was used, and the operation was the same as above.
  • mice were injected subcutaneously with 60 mg / kg ethyl 3-piperidinecarboxylate or 10 mg / kg NO-711 on the 1st, 3rd, and 5th days. Enter the selected medicine-feeding chamber, isolate it for 20 minutes, and inject the same volume of physiological saline on day 2, 4, and 6 and place it in the selected saline-feeding chamber, and also isolate it for 20 minutes.
  • Test mice (after dosing) preference for drug-feeding chambers and saline-feeding chambers, that is, place the mice in the middle chamber on day 7, and record the mice in the left and right sides within the prescribed time (18 minutes) Time spent in the cab. Calculate the percentage of mouse drug chamber dwell time relative to both.
  • One-way ANOVA was used to evaluate significance. There are 8-10 mice in each group. Control experiments (saline and morphine) were performed as above.
  • mice in the morphine group had a significant preference for morphine-administered compartments ( Figure 6; * indicates p ⁇ 0.05).
  • the liquid is sealed in ampoules, sterilized, made into products, and protected from light.
  • Dissolve NO-711 1.5g, 2.5g, 5g in 1 liter of water, mix and dispense into 3mg / 2ml / piece, 5mg / 2ml / piece, 10mg / 2ml / piece injection solution in ampoules. Medium sealed, sterilized, made into products, protected from light.
  • each tablet weighs about 0.3 grams, each tablet contains NO-711 20mg.

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Description

技术领域
本发明述及生物医药领域， 具体地讲是关于 γ-氨基丁酸 （GABA) 转运蛋白抑制剂在制备镇痛药物中的应用。
背景技术
疼痛是一种常见病症， 可分为轻度疼痛， 中度疼痛和重度疼痛。 目前， 对轻度疼痛的治疗一般使用非阿片类药物， 中度疼痛使用弱阿 片类药物， 重度疼痛使用强阿片类药物。 从作用机理上看， 镇痛药主 要可分为：（1)作用于外周痛觉感受器， 是弱镇痛药； （2)作用于 GABA 受体， 增强 GABA能神经的功能， 此类药兼有良好的镇定作用； （3 ) 抑制前列腺素的生物合成， 主要为解热镇痛药， 如阿司匹林； （4) 阻 断脑内多巴胺受体， 如颅通定； （5 )激活阿片受体， 如吗啡， 哌替啶。 在临床上阿片类药物具有最好的镇痛效果， 但是其副作用大 （恶心， 呕吐， 便秘， 嗜睡， 头暈， 呼吸抑制等）， 且具有耐受性， 成瘾性， 所以需慎用。 由于很多疾病都能引起疼痛， 尤其是在癌症晚期会引起 重度疼痛， 因此， 寻找、 设计和合成高效、 低毒、 不耐受、 不成瘾的 镇痛药物长期以来一直都是药物研究追求的目标。
GABA 是哺乳动物中枢神经系统中最重要的抑制性神经递质， GABA 转运蛋白的生物学功能是通过摄取神经突触间隙的 GABA神 经递质来终止其神经抑制信息传递， 进而达到调节神经信号传递的强 度和时效性， 以便实现复杂的神经网络系统信号之间的协调性和统一 性。 具有专一性抑制功能的化合物己有报道， 主要是 3-哌啶甲酸和四 氢烟酸及以这两种化合物为母核的很多衍生物。 除此以外还有很多化 合物是 GABA 转运蛋白的抑制剂，如高 β -脯氨酸、 四氢吡啶基异噁唑 醇、 五氢氮杂 基异噁唑醇及其衍生物等等， 有关这些化合物的合成 及作为抑制剂的研究参见文献 [Andersen K.E., et al.， J.Med.Chem.,2001, 44:2152-2163 ； Krogsgaard-Larsen P., et al., Current Pharmaceutical Design, 2000,6:1193-1209] 。 目前 GABA转运蛋白抑制剂已有报道在 临床上治疗癫痫， 也提及 tiagabine可能用于疼痛治疗， 并且这种药副 作用小， 长期使用也是安全的 ( Genton p., et al., Epilepsia, 2001， 42(Suppl.3): 42-45; Meldrum B.S., et al., Epilepsia, 1999, 40(Suppl.9):S2- S6)。 专利 WO 9415618 ( 1994年） 也曾提及一些不正常的情况 （如 癫痫， 肌阵挛， 慢性痛） 与 GABA转运蛋白的过高表达或过低表达相 关。 本发明则找到以 γ-氨基丁酸转运蛋白为靶标的一类化合物具有良 好的镇痛效果。
发明内容
为此， 本发明提供 γ-氨基丁酸转运蛋白抑制剂在制备镇痛药物中 的应用。
本发明找到上述这类具有抑制功能的化合物对镇痛有良好的效 果。 这类化合物的作用机理是抑制 GABA转运蛋白的功能， 使得突触 间隙 GABA浓度升高， 最终导致抑制性的 GABA能神经功能增强， 从而达到镇痛的效果。 通过以下实验可得到证实。 γ-氨基丁酸转运蛋 白抑制剂包括所有能降低 γ-氨基丁酸转运蛋白摄取 （转运） 功能的化 合物， 例如上述己知化合物 3-哌啶甲酸、 四氢烟酸、 高 β -脯氨酸、 四氢吡啶基异噁唑醇、 五氢氮杂 基异噁唑醇以及它们的衍生物等, 例举化合物结构图参见图 1 (上述衍生物并不限于这些例举化合物）。 这些化合物可按照前述文献上报道的方法合成或从市场上购买。 本发 明选取其中一种竞争性抑制剂 3-哌啶甲酸乙酯 （是 3-哌啶甲酸的衍生 物） 和一种非竞争性抑制剂 N- (二苯基亚胺基乙醇基） -四氢烟酸 (NO-711 , 是四氢烟酸的衍生物） 为例来测定它们的镇痛效果。 分别 采用热致痛 （甩尾） 实验、 福尔马林诱导的炎症疼痛 （舔爪） 实验和 乙酸诱导的内脏痛实验来测试小鼠对 3-哌啶甲酸乙酯和 NO-711 两种 化合物的反应， 以生理盐水作为对照。 结果表明， 给药的小鼠对疼痛 的反应显著降低， 说明 3-哌啶甲酸乙酯和 NO-711两种化合物具有良 好的镇痛效果。 用甩尾实验测试小鼠经过持续注射 3-哌啶甲酸乙酯 4 天和 8天后对急性热致痛的反应， 结果表明， 给药 4天和给药 8天小 鼠的甩尾反应与第一天无明显差异， 说明此化合物并不造成耐受。 用 条件型的地点偏好 （CPP) 模型测试小鼠对 3-哌啶甲酸乙酯和 NO-711 两种化合物的成瘾性， 结果表明， 小鼠对这两种化合物并不依赖。 上 述所有结果表明， 无论是竞争性的 GABA转运蛋白抑制剂还是非竞争 性的 GABA 转运蛋白抑制剂均具有镇痛作用， 并具有不耐受， 不成瘾 的优点。
γ-氨基丁酸转运蛋白抑制剂的镇痛应用， 可给予疼痛患者有效药 量的 GABA转运蛋白抑制剂药物达到治疗疼痛的目的。 这些疼痛包括 由各种原因例如热刺激、 炎症、 内脏受损、 癌症等引起的疼痛疾病。 临床使用给药方式可以是口服或注射。 口服药按常规可制成片剂、 胶 囊、 粉末、 溶液等剂型， 注射可以是肌肉注射、 皮下注射或静脉注射 等。
使用 γ-氨基丁酸转运蛋白抑制剂在治疗疼痛时， 药物的量取决于 疾病的性质和程度以及病人已接受治疗的情况。 最终由处方医生决定 给予病人多少剂量， 临床使用的剂量为每公斤体重每日可使用 0.1-2mg 的 GABA转运蛋白抑制剂。
在制备 γ-氨基丁酸转运蛋白抑制剂镇痛药物过程中， 药物除含有 GABA转运蛋白抑制剂外， 还可包括药理学上可被接受的载体、溶剂、 填充物、 缓冲剂和稳定剂等物质。 所谓 "药理学上可接受的"是指不 影响 GABA转运蛋白抑制剂生物活性的无毒物质。 载体和其它物质的 选择取决于不同的给药途径。
本发明揭示了 GABA转运蛋白抑制剂具有镇痛作用， 为 GABA 转运蛋白抑制剂开拓了一个新的应用领域。 该抑制剂包括所有能抑制 GABA 转运蛋白具有镇痛作用的化合物。 这类化合物除了具有良好的 镇痛作用以外， 还具有显著的优点： 实验证实， 它们是非阿片类的小 分子， 不具有耐受性， 可避免使用的剂量递增， 不具有成瘾性， 可避 免用药后的后继戒断治疗。 因此， 这类化合物对治疗疼痛具有临床应 用价值， γ-氨基丁酸转运蛋白抑制剂可用于制备镇痛药物。
附图说明
图 1 例举抑制 GABA 转运蛋白的化合物。 1一 3-哌啶甲酸 (piperidine-3 -carboxylic acid, nipecotic acid, C6HnN02), 2一四氢烟酸 (l,2,5,6-tetrahydro-pyridine-3-carboxylic acid, guvacine, C6H9N02)， 3― 3-呢捉甲酸乙酉旨 (piperidine-3-carboxylic acid ethyl ester, ethyl nipecotate, C8H15N02)， 4一 N- (二苯基亚胺基乙醇基） -四氢烟酸（1-[2- [[(diphenyl)imino]oxy]ethyl]-3-(l,255,6-te1xahydropyridin-l-yl)carboxylic acid, NO-711,C21H22N203)， 5—双 （三氟甲基苯基） 甲氧基乙基四氢 烟 酸 （ 1，2,5 ,6-tetrahydro- 1 - {2-[bis-[4-(trifluoromethyl)phenyl]methoxy] ethyl } -3-pyridinecarboxylic acid, CI-966, C23H21F6N03)， 6— N- (二苯基 -3- 丁烯基） 四氢烟酸（N-(4,4-diphenyl-3-butenyl)-l，2,5，6-tetrahydro-3- pyridinecarboxylic acid, DPB-Guvacine, C22H23N02), 7―二苯基甲氧乙 基) -3-呢淀甲酸 (l-[2-(diphenylmethoxy)ethyl]-3-piperidinecarboxylic acid, C21H25N03)， 8 —二苯 甲 叉基 乙氧基胺哌啶 甲 酸（1-[2- benzhydrylideneaminooxy-ethyl]- piperidine-3-carboxylic acid, C21H24N203)， 9一二苯乙烯氧基乙基哌啶甲酸（l-[2-(2,2-diphenyl- vinyloxy)-ethyl]- piperidine-3-carboxylic acid, C22H25N03)， 10―二苯 氨基乙氧基乙基哌啶甲酸（l-[2-(2-diphenylamino-ethoxy)-ethyl]- piperidine-3-carboxylic acid, C22H28N203)， 11一二苯丙氧基乙基哌啶甲 酸 ( 1 -[2-(3-diphenylpropoxy)ethyl]- piperidine-3-carboxylic acid, C23H29N03)， 12— 4,4-二对甲苯基 -3-丁烯基哌啶甲酸 (l-(4，4-di-o-tolyl- but-3-enyl)- piperidine-3-carboxylic acid, C24H29N02)， 13― 6-(3,3-二苯 丙基） 四氢烟酸 (6-(3,3-diphenylpropyl)guvacine, C21H23N02), 14—2- (3,3-二苯丙氧基）乙基哌啶甲酸（l-[2-(3，3-diphenyl-propoxy)-ethyl]- piperidine-3-carboxylic acid, C23H29N03), 15— 10,11-二氢-二苯氮杂葺 基） 乙氧基乙基哌啶甲酸（l-{2-[2-910,l l-dihydro-dibenzo-azepin-5-yl]- ethoxy} -ethyl)- piperidine-3-carboxylic acid, C24H30N2O3)， 16― 2-(9-对 甲氧基苯基）芴基乙氧基哌啶甲酸（l-{2-[9-(4-methoxyphenyl)-9H- fluoren-9-yloxy] -ethyl } - piperidine-3-carboxylic acid, SNAP 5294, C28H29N04)， 17—三对甲氧基苯基甲氧基乙基哌啶甲酸 (l-{2-[tris-(4- methox phenyl)-methoxy]ethyl } -3 - piperidine-carboxylic acid, (S)-SNAP 5114, C30H35NO6), 18—高 β -脯氨酸 (pyrrolidin-3-yl-acetic acid, Homo- β -proline, C6HuN02), 19一四氢吡啶基异噁唑醇 (4,5,6,7-tetrahydro- isoxazolo-[4,5-C]-pyridin-3-ol5 THPO, C6H8N202)， 20—五氢氮杂華基 异噁唑醇（4,5,6，7-tetrahydro-4H- isoxazolo-[4，5-C]-azepin-3-ol THAO, C7H10N2O2)， 21—四氢吡啶基硫代异噁唑醇（4，5，6，7-tetrahydro- isothiazolo-[4,5-C]-pyridin-3-ol, Thio-THPO, C6H8N2OS)， 22—五氢 -4- 胺基苯并异噁唑醇 ((R)(-)4-amino-3-hydroxy-4, 5， 6， 7-tetrahydro- 1 , 2- benzisoxazolo-[4, 5-C]-pyridin-3-ol, (R)-Exo-THPO, C7H10N2O2), 23 一五氢 -4-甲胺基苯并异噁唑醇（(R)-3-hydroxy-4-(l-methylamino)- 4,5,6, 7-tetrahydro- l,2-benzisoxazolo-[4,5-C]-pyridin-3-ol, (R)-N-Me-Exo- THPO, C8H12N202)， 24— 4,4-二苯基 -3-丁烯基四氢吡啶异噁唑醇 (5- (4,4-diphenyl-but-3-enyl)-4,5,6,7-tetrahydro-isoxazolo-[4,5-C]-pyridin-3-ol. DPB-THPO, C22H22N202)， 25—二苯基 -3-丁烯基五氢氮杂罩异噁唑醇 (5-(4,4-diphenyl-but-3-enyl)-5,6,7,8-tetrahydro-4H-isoxazolo-[4,5-C]- azepin-3-ol, DPB-THAO, C23H24N202)， 26— 3-氮杂芴基 -4-邻甲氧基苯 基 -fl比啶醇 (l-(3-carbazol-9-yl-prophl)-4-(2-methoxyphenyl)-piperidin-4-ol, 丽 C 05-2090, C27H30N2O2)。
图 2 显示 3-哌啶甲酸乙酯对热致痛的镇痛作用。 结果表明 3-哌 啶甲酸乙酯 G0mg/kg和 60mg/kg)能镇痛，并且是剂量依赖的 (n=8:10, **表示 p<0.01， 3-哌啶甲酸乙酯对生理盐水， one-way ANOVA评价显 著性)。
图 3 显示 NO-711 对热致痛的镇痛作用。 结果表明 NO-711 ( 10mg kg) 能镇痛， 其镇痛作用时间比 3-哌啶甲酸乙酯长 (n=8-10，** 表示 p<0.01, NO-711对生理盐水， one-way ANOVA评价显著性)。
图 4 显示 3-哌啶甲酸乙酯和 NO-711对福尔马林诱导的足部炎症 疼痛的镇痛作用。 结果表明 3-哌啶甲酸乙酯 (60mg/kg)和 NO- 711(10mg/kg)能对炎症痛起镇痛作用， NO-711 的镇痛作用时间长， 镇 痛效果比 3-哌啶甲酸乙酯好 （n=8，*表示 p<0.05， **表示 ρθ.01, 3-哌啶 甲酸乙酯和 NO-711对生理盐水； ††表示 p<0.01， NO-711对 3-哌啶甲 酸乙酯， one-way ANOVA评价显著性）。 图 5显示 3-哌啶甲酸乙酯对乙酸诱导的内脏痛的镇痛作用， 结果 表明， 3-哌啶甲酸乙酯 （30mg/kg， 60mg kg) 具有良好的内脏痛镇痛 效果， 高剂量的 3-哌啶甲酸乙酯比低剂量的 3-哌啶甲酸乙酯镇痛效果 好（n-8-9，**表示 p<0.01， 3-哌啶甲酸乙酯对生理盐水， one-way ANOVA 评价显著性）。
图 6显示 NO-711对乙酸诱导的内脏痛的镇痛作用， 结果表明， NO-711 ( 5mg/kg, 10mg/kg) 具有良好的内脏痛镇痛效果， 高剂量的 NO-711 比低剂量的 NO-711 镇痛效果好。 (n=8-9, **表示 p<0.01， NO-711对生理盐水， one-way ANOVA评价显著性）。
图 7 显示 3-哌啶甲酸乙酯 (90mg/kg)持续注射 4天和 8天后不具 有耐受性 （a)。 而吗啡 (8mg/kg) 持续注射 4天和 8天后具有显著的耐 受性 (b)。 dl—第一天， d4—第四天， d8—第八天 （n=8，*表示 p<0.05，** 表示 p<0.01, 第 4天和第 8天对第 1天， one-way ANOVA评价显著性）。
图 8 显示 3-哌啶甲酸乙酯 (60mg/kg)和 NO-711(10mg/kg)不具有 成瘾性，而吗啡 (8mg/kg)则具有显著的成瘾性 (n=8-10, *表示 p<0.05， 给 药后对给药前， one-way ANOVA评价显著性）。
具体实施方式
以下实施例所用药品的来源： 3-哌啶甲酸乙酯购自 ACROS 公司, NO-711购自 Sigma公司。 实验所用动物为 C57 BL/6J 小鼠。
实施例中的注射液配制及注射： 3-哌啶甲酸乙酯和 NO-711 两种 药物各别均匀溶解于生理盐水， 3-哌啶甲酸乙酸配成浓度分别为 1.5mg/ml, 3mg/ml, 4.5mg/ml和 6mg/ml的溶液， NO-711配成浓度分别 为 0.5mg/ml和 lmg/ml 的溶液， 腹腔注射用量为每克小鼠体重 20 μΐ 相应浓度的药物， 皮下注射用量为每克小鼠体重 10 μΐ 相应浓度的药 物。
实施例 1
3-哌啶甲酸乙酯和 NO-71 1对热致痛的镇痛效果测定
每组小鼠为 8-10 只。 甩尾实验采用 51.0°C热水浸尾， 实验操作 如下： （1 ) 将小鼠用软布包裹起来， 尾巴外露， （2 ) 将 3/4长度尾巴 浸入热水中， 记录从尾巴浸入热水到甩尾的时间间隔， （3 ) 小鼠通过 腹腔注射分别给药 3-哌啶甲酸乙酯 30mg/kg, 60mg/kg, NO-711 10mg/kg 或相同体积的生理盐水， （4)药物注射后分别在 5、 15、 30、 45、 60、 75、 90、 105、 120分钟时间点测试甩尾的延迟时间， 即重复步骤 （1 ) 和 （2)。 为避免尾组织损伤， 最长浸入热水时间为 12秒。 镇痛效果 通过如下公式计算： ％MPE= (给药后的延迟时间一给药前的延迟时 间） I ( 12—给药前的延迟时间）。 用 one-way ANOVA评价显著性。
测定结果 3-哌啶甲酸乙酯和 NO-711两种药物均具有对热致痛 的镇痛作用 （图 2， 图 3 ; **表示 p<0.01 ) , 不同剂量的 3-哌啶甲酸 乙酯产生不同的镇痛效果 （高剂量的镇痛效果较低剂量的好）， 3-哌啶 甲酸乙酯镇痛效果快， NO-711镇痛效果较 3-哌啶甲酸乙酯长。
实施例 2
' 3-哌啶甲酸乙酯和 NO-711 对福尔马林诱导的足部炎症疼痛的镇 痛效果测定
实验操作如下： （1 ) 将小鼠单只放置， 记录小鼠舔或咬左爪的时 间， 每 5 分钟间隔记录一次， 记录三个时间段， （2) 在小鼠左爪背部 的皮下注射 ΙΟμΙ 5%的福尔马林， 立即记录小鼠舔或咬注射部位的时 间长短， 每 5 分钟间隔记录一次， （3 ) 在记录完第二个时间间隔， 即 10 分钟后立即腹腔注射 60mg/kg 3-哌啶甲酸乙酯、 10mg/kg NO-71 1 或相同体积的生理盐水， （4) 接着记录小鼠舔爪或咬爪的时间， 每 5 分钟记录一次，直至福尔马林注射后 55分钟终止。 用 one-way ANOVA 评价显著性。 每组小鼠为 8只。
测定结果 三组小鼠在福尔马林注射后的阶段 I (0— 10分钟） 中痛觉反应无显著差异， 而阶段 II ( 10-55 分钟） 即 3-哌啶甲酸乙 酯、 NO-711或生理盐水注射后， 注射 3-哌啶甲酸乙酯和 NO-711的两 组动物比注射生理盐水的动物对福尔马林诱导的炎症疼痛反应明显降 低， 且 NO-711的镇痛效果较 3-哌啶甲酸乙酯好 （图 4中 (a)及 (b); * 表示 p<0.05, **表示 p<0.01 , 忖表示 p<0.01) o
实施例 3
3-哌啶甲酸乙酯和 NO-711 对乙酸诱导的内脏疼痛的镇痛效果测 疋
实验操作如下：给小鼠皮下注射 30mg/kg 3-哌啶甲酸乙酯、60mg/kg 3-哌啶甲酸乙酯、 5mg/kg NO-71K 10mg/kg NO-711 或相同体积的生 理盐水 （对照组）， 立即放回小鼠笼中； （2) 5分钟之后取出小鼠， 在 小鼠腹腔内注射 0.6%乙酸 （Ιθ μΐ/g), 立即放回小鼠笼中； （3) 5 分钟 之后开始记录小鼠扭体的次数，持续记录 15分钟，用 one-way ANOVA 评价显著性， 每组小鼠 8-9只。
测定结果 注射 3哌啶甲酸乙酯或 NO-711 的小鼠扭体次数比对 照组小鼠扭体次数明显减少，而且经高剂量 3-哌啶甲酸乙酯或 NO-711 预处理后的小鼠对内脏痛的反应比低剂量 3-哌啶甲酸乙酯或 NO-711 预处理的小鼠对内脏痛的反应要弱， （参见图 5 和图 6， **表示 p<0.01 )。 这些结果表明 3-哌啶甲酸乙酯和 NO-711对内脏痛均具有良 好的镇痛效果， 而且镇痛的效果是剂量依赖的。 实施例 4
3-哌啶甲酸乙酯和 NO-711的耐受性与成瘾性评价实验。
药品和动物来源同实施例 1。
a. 耐受性 分别给小鼠每天一次皮下注射 90mg/kg 3-哌啶甲酸乙 酯或 8mg/kg 吗啡,持续 8天， 在第 1， 4， 8天分别测试 3-哌啶甲酸乙 酯和吗啡的镇痛效果。 方法采用甩尾实验， 操作同上。
b. 成瘾性 本实验应用条件型的地点偏好 （CPP) 模型来测试 3- 哌啶甲酸乙酯和 NO-711 的成瘾性。 CPP模型由左右两个颜色， 粗糙 度和气味均不相同的小室及中间隔离的小室组成。 左右两边随机选定 一室给药， 另一室喂生理盐水。 实验操作如下： （1 ) 测试小鼠 （给药 前） 对左右两间小室的偏好， 即将小鼠放入中间小室， 记录小鼠在规 定时间 （18分钟） 内分别在左右两小室中停留的时间， （2) 进行条件 训练 （给药）， 即在第 1， 3, 5 天给小鼠皮下注射 60mg/kg 3-哌啶甲 酸乙酯或 10mg/kg NO-711,立即将小鼠放入选定的喂药小室， 将其隔 离于室内 20分钟， 在第 2， 4， 6天注射相同体积的生理盐水， 将其 放入选定喂生理盐水的小室， 同样隔离 20 分钟， （3 ) 测试小鼠 （给 药后） 对喂药小室和喂生理盐水小室的偏好， 即在第 7天将小鼠置于 中间小室内， 记录小鼠在规定时间 （18分钟） 内分别在左右两小室中 停留的时间。 计算小鼠喂药小室停留时间相对于其两者的百分率。 用 one-way ANOVA评价显著性。 每组小鼠为 8-10只。 对照实验 （生理 盐水和吗啡） 的操作同上。
实验结果：
a. 耐受性 持续注射 3-哌啶甲酸乙酯 4天和 8天， 3-哌啶甲酸 乙酯对小鼠的镇痛作用与第 1 天相比无显著差异， 表明持续给药并不 造成 3-哌啶甲酸乙酯镇痛药效的减弱， 即不具有耐受性。 而持续注射 吗啡 4天和 8天， 吗啡对小鼠的镇痛作用与第 1天相比有显著差异， 表明持续吗啡使用后， 吗啡的药效大大降低， 具有耐受性。 （图 5中 (a) 及 (b); *表示 p<0.05， **表示 p<0.01)。
b. 成瘾性 小鼠在训练后对给 3-哌啶甲酸乙酯和 NO-711 小室 的偏好与训练前相比并无显著变化， 与注射生理盐水的小鼠相似， 表 明 3-哌啶甲酸乙酯和 NO-711 两种药品对小鼠不造成依赖性， 也无厌 恶反应。 而吗啡组小鼠对给吗啡的小室具有显著的偏好 （图 6; *表 示 p<0.05)。
实施例 5 镇痛注射液的制备
将 3-哌啶甲酸乙酯 1.5克、 2.5克、 5克各别溶解于 1升水中， 混 合均匀后分装成 3mg/2ml/支、 5mg/2ml/支、 10mg/2ml/支浓度的注射 液于安瓿瓶中密封， 消毒杀菌， 制成产品， 避光保藏。
实施例 6 镇痛注射液的制备
将 NO-711 1.5克、 2.5克、 5克各别溶解于 1升水中， 混合均匀 后分装成 3mg/2ml/支、 5mg/2ml/支、 10mg/2ml/支浓度的注射液于安 瓿瓶中密封， 消毒杀菌， 制成产品， 避光保藏。
实施例 7 镇痛片剂的制备
按公知的制片技术， 取 NO-711 20克， 糊精 130克， 淀粉 100克， 羧甲基淀粉 50克， 一起放入粉碎机内充分混合 25-30分钟， 粉碎至约 80-120 目， 再加入硬脂酸镁 3克， 均匀混合， 经制片机制成 1000片 片剂， 每片重量约 0.3克， 每片含 NO-711 20mg。

Claims

1、 一种 γ-氨基丁酸转运蛋白抑制剂 (tiagabine 除外)在制备镇痛 药物中的应用。 '
2、 如权利要求 1 所述的应用， 其特征是包括 3-哌啶甲酸， 四氢 烟酸， 高 脯氨酸、 四氢吡啶基异噁唑醇、 五氢氮杂率基异噁唑醇 以及它们的衍生物（tiagabine 除外)为抑制剂在制备镇痛药物中的应 用。
3、 如权利要求 2 所述的应用， 其特征是包括但并不限于下列这 些化合物： 3-哌啶甲酸， 四氢烟酸， 3-哌啶甲酸乙酯， N- (二苯基亚 胺基乙醇基) -四氢烟酸， 双 （三氟甲基苯基） 甲氧基乙基四氢烟酸， N- (二苯基- 3-丁烯基） 四氢烟酸， （二苯基甲氧乙基) -3-哌啶甲酸， 二苯甲叉基乙氧基胺哌啶甲酸， 二苯乙烯氧基乙基哌啶甲酸， 二苯氨 基乙氧基乙基哌啶甲酸， 二苯丙氧基乙基哌啶甲酸， 4, 4-二对甲苯基 -3 -丁烯基哌啶甲酸， 6- (3， 3-二苯丙基） 四氢烟酸， 2- (3， 3-二苯丙 氧基）乙基哌啶甲酸， （10, 11-二氢-二苯氮杂 基） 乙氧基乙基哌啶 甲酸， 2- (9-对甲氧基苯基）芴基乙氧基哌啶甲酸， 三对甲氧基苯基甲 氧基乙基哌啶甲酸，高 β -脯氨酸，四氢吡啶基异噁唑醇，五氢氮杂 基 异噁唑醇， 四氢吡啶基硫代异噁唑醇， 五氢- 4-胺基苯并异噁唑醇， 五氢 -4-甲胺基苯并异噁唑醇， 4， 4-二苯基 -3-丁烯基四氢吡啶异噁唑 醇， 二苯基 -3-丁烯基五氢氮杂草异噁唑醇， 3-氮杂芴基 -4-邻甲氧基 苯基-吡啶醇， 为抑制剂在制备镇痛药物中的应用。
PCT/CN2002/000846 2002-05-21 2002-11-26 Utilisation du transmetteur de l'inhibiteur de l'acide $g(g)-aminobutyrique (gaba) dans la preparation d'analgesiques WO2003097023A1 (fr)

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