WO2020259447A1 - 金属络合物的新应用 - Google Patents

金属络合物的新应用 Download PDF

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WO2020259447A1
WO2020259447A1 PCT/CN2020/097507 CN2020097507W WO2020259447A1 WO 2020259447 A1 WO2020259447 A1 WO 2020259447A1 CN 2020097507 W CN2020097507 W CN 2020097507W WO 2020259447 A1 WO2020259447 A1 WO 2020259447A1
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pain
alkyl
group
vanadyl
hydroxyl
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PCT/CN2020/097507
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谢方
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湖南方升泰医药科技有限公司
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Priority to EP20832516.7A priority Critical patent/EP3988092A4/en
Priority to JP2021577521A priority patent/JP7349052B2/ja
Priority to US17/622,417 priority patent/US20220370472A1/en
Publication of WO2020259447A1 publication Critical patent/WO2020259447A1/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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/28—Compounds containing heavy metals
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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]

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  • the present invention relates to methods and pharmaceutical ingredients for the treatment of pain, in particular to the treatment of acute pain, chronic pain, inflammatory pain, cancer pain, and pain caused by cancer treatment, visceral pain, and neuropathic pain , Diabetic neuropathy (diabetic neuropathy), post-herpetic pain (post-herpetic pain), migraine, fibromyalgia (fibromyalgia), trigeminal neuralgia (trigeminal neuralgia).
  • Diabetic neuropathy diabetic neuropathy
  • post-herpetic pain post-herpetic pain
  • migraine fibromyalgia
  • trigeminal neuralgia trigeminal neuralgia
  • pain can be divided into acute pain and chronic pain. According to the location of the pain, it can be divided into visceral pain, joint pain, muscle pain, migraine, etc. Pain can also be classified from the perspective of mechanism, such as inflammatory pain and neuropathic pain. However, there are theories that the essence of neuropathic pain is nerve inflammation, and nerve pain and inflammatory pain are inseparable from each other.
  • the integrity of the human body is guaranteed by the coordinated operation of two major systems: the immune system and the nervous system.
  • the immune system When human tissues are damaged, these two systems not only work together to make people feel the damaged part, but also cooperate to prevent the damage from spreading further and quickly repair the damaged part.
  • This is the inflammatory process.
  • this process When this process is regulated by the immune system, it is humoral inflammation, and what is caused by the nervous system is called neurogenic inflammation.
  • the pain caused by inflammation begins with the activation of nerve endings, which are composed of sensorial neurons, also known as nociceptor neurons or nociceptors. These receptors transmit signals of tissue damage to the spinal cord and brain pain processing centers.
  • nociceptors After the pain is transmitted to the brain and central nervous system, nociceptors will perform its efferent function, release pain-promoting and pro-inflammatory molecules, stimulate inflammation and pain, and change the excitement of nociceptors Level (excitability) or peripheral sensitization (peripheral sensitization), causing changes in the perception of irritation at the site of inflammation, such as hyperalgesia (hyperalgesia) or allodynia (allodynia). The continuous excitement of peripheral nociceptors will cause synaptic changes in the spinal cord, which will cause central sensitization.
  • non-steroidal anti-inflammatory drugs represented by aspirin and ibuprofen
  • morphine drugs and anticonvulsants and antidepressants.
  • these existing drugs have great limitations.
  • the analgesic effect of non-steroidal anti-inflammatory drugs has a ceiling effect, that is, increasing the dose of the drug after reaching a certain limit can no longer reduce the pain; moreover, they can cause intestinal discomfort, and long-term use can also cause gastric ulcers.
  • morphine drugs are widely used, their side effects, such as constipation, decreased respiratory function, and addiction, make their dosage for patients strictly limited.
  • the existing drugs are far from meeting human requirements for pain control, especially for the treatment of chronic pain.
  • the development of new target drugs is particularly important, because the limitations of traditional analgesic drugs are probably caused by the limitations of the targets they act on. It is the direction of drug development to find analgesic drugs with small side effects and long-acting effects or drugs that cure pain.
  • the present invention provides an analgesic drug component, the chemical structure of the component is as shown in formula I, that is, composed of a transition metal ion (such as Zn 2+ , Co 2+ , Pt 2+ ) or oxygenated metal ion (such as VO (IV), MoO 2 (VI)) and alpha-hydroxypyrone or alpha-hydroxypyridone ligands form a metal complex, the metal complex is characterized by: two identical alpha-hydroxypyrone The ketone or alpha-hydroxypyridone ligand is complexed with a transition metal ion or oxygenated metal ion, wherein the transition metal ion or oxygenated metal ion and X 1 and X 2 form an unsaturated metal ion-containing five The membered ring, X 1 and X 2 are both heteroatoms.
  • VO(IV) means MoO 2 (VI) means
  • R 2 , R 3 or R 4 are H, hydroxyl, mercapto, C 1 -C 14 alkyl, hydroxyl C 1 -C 14 alkyl, C 1 -C 14 alkoxy, mercapto C 1 -C 14 alkane Group, C 1 -C 14 alkylthio, aryl or aryl C 1 -C 14 alkyl.
  • the ligand that forms the metal complex shown in formula I that is, alpha-hydroxypyrone or alpha-hydroxypyridone compounds, can be represented by formula II.
  • the common feature of these compounds is that the hydroxyl group (or mercapto group) is adjacent to a carbonyl group (or thiocarbonyl group).
  • X 1 O or S
  • X 2 O or S
  • Y O or NR 4
  • R 1 , R 2 , R 3 and R 4 are respectively H, hydroxyl, mercapto, hydroxyl C 1 -C 14 alkyl , C 1 -C 14 alkoxy, C 1 -C 14 alkyl, mercapto C 1 -C 14 alkyl, C 1 -C 14 alkylthio, aryl or aryl C 1 -C 14 alkyl.
  • the metal complex formed by the further optimized alpha-hydroxypyrone ligand or alpha-hydroxypyrone ligand and the aforementioned transition metal ion or oxygenated metal ion (as shown in formula I) can be represented by formula III :
  • M' VO(IV), Co 2+ , Zn 2+ , MoO 2 (IV) or Pt 2+ ;
  • a further preferred compound is an alpha-hydroxypyrone metal complex represented by formula IV:
  • M' VO(IV), Co 2+ , Zn 2+ , MoO 2 (IV) or Pt 2+ ;
  • the aforementioned ligands can be synthesized by conventional chemical synthesis techniques.
  • the compound can be prepared according to known methods reported in the literature [see SDKushch, ENIzakovich, OSRoshchunkina, VMNichvoloda, and MLKhidekel, Bull.Acad.Sci., Div.Chem.Sci.30, 681-682( 1981)].
  • the compound can be prepared according to a method reported in the known literature [see B.S. Parjon-Costa and E.J. Baran, Spectrochim. Acta Part A: Mol. and Biomol. Spectro. 113, 337-339 (2013)].
  • the compound can be prepared according to a method reported in the known literature [see S.J. Greaves and W.P. Griffith. Polyhedron, 7, 1973 (1988)].
  • the compound can be prepared according to the methods reported in the known literature (see SJLord, NAEpstein, RLPaddock, CVogels, TL Hennigar, MJ Zaworotko, NJTaylor, WRDriedzic, TL Broderick, and SAWestcott, Can.J. Chem. 77, 1249-1261 (1999)].
  • the compound can be prepared according to the methods reported in the known literature (see P. Caravan, L. Gelmini, N. Glover, FGHerring, H. Li, JHMcNeill, SJRettig, IASetyawati, E. Shuter, Y. Sun , ASTracey, VG Yuen; and C. Orvig, J. Am. Chem. Soc. 117, 12759-12770 (1995)].
  • the compound can be prepared according to the methods reported in the known literature (see KHThompson, BDLboiron, Y. Sun, KDDBellman, IA Setyawati, BOPatrick, V. Karunaratne, G. Rawji, J. Wheeler, K. Sutton, S. Bhanot, C. Cassidy, JHMcNeill, VGYuen, and C. Orvig, J. Biol. Inorg. Chem. 8, 66-74 (2003)]
  • Vanadyl Dikojic Acid (Bis(kojato)oxovanadium(IV),VO(ka) 2 ]
  • the compound can be prepared according to the methods reported in the known literature [see VGYuen, P. Caravan, L. Gelmini, N. Glover, JHMcNeill, IASetyawati, Y. Zbou, and C. Orvig, J. Inorg. Biochem .68, 109-116 (1997)].
  • the compound can be prepared according to the method reported in the known literature [see A.Katoh, M.Yamaguchi, K.Taguchi, R.Saito, Y.Adachi, Y.Yoshikawa, and H.Sakurai, Biomed.Res.Trace Elements 17,1-10 (2006) and references cited in the text].
  • the compound can be prepared according to the methods reported in the known literature [see C. Queiros, MJAmorim, A. Leite, M. Ferreira, P. Gameiro, B. de Castro, K. Biernacki, A. J. Burgess, and M. Range, Eur. J. Inorg. Chem. 1131-140 (2011)].
  • the above compounds can contain 1-20 crystal water or other solvent molecules, such as DMSO, ethanol, isopropanol, pyridine, etc.
  • the above-mentioned compounds can also be administered by other conventional methods, such as transdermal, rectal, intravenous, subcutaneous, sublingual, and intraperitoneal methods. Choosing a suitable ligand needs to consider the substituents on its skeleton and ring.
  • the so-called “fit” criterion is the solubility of the overall complex.
  • the complex is preferably electrically neutral as a whole, its water solubility is at least 0.1 mM, preferably at least 0.2 mM, and can be absorbed orally (preferably with good gastrointestinal absorption efficiency).
  • the ligand should have general to strong complexing ability (for example, the complex constant is 2 ⁇ log ⁇ 2 ⁇ 30, preferably between 5 and 22)
  • composition of pharmaceutical preparations is in conventional forms, such as capsules, tablets, coated tablets, solutions, suspensions, syrups, suppositories, etc., and auxiliary agents and excipients of conventional preparations can be used, such as viscosity modifiers, buffers Solutions, flavoring agents, suspending agents, stabilizers and other additives.
  • the pharmaceutical composition of the present invention may include the addition of other therapeutic agents, such as analgesic agents (such as aspirin, etc.). It can also be combined with other analgesic drugs for combined treatment.
  • analgesic agents such as aspirin, etc.
  • the metal complex is generally administered at a dose of 0.00001 to 1500 mg (calculated by metal atoms)/kg body weight per day.
  • the dosage is so wide because different mammals have different effective doses, and their effective doses are very different from mice.
  • the effective dose for humans can be 10 times, 20 times, 30 times, or even more times lower than that of mice. Effective dose (unit body weight).
  • Different routes of administration also affect the dosage.
  • the oral dose can be 10 times the injection dose.
  • the preferred dosage range is 0.01 to 300 mg (calculated as metal atoms)/kg per day.
  • the preferred dosage range is 0.00005 to 5 mg (calculated as metal atoms)/kg per day.
  • the unit dose of the drug is 0.001 mg to 1000 mg (calculated as metal atoms), preferably 0.1 mg to 300 mg (calculated as metal atoms).
  • Figure 1 is a graph showing the pain-inhibiting effects of vanadyl dimaltol (S1), vanadyl diethyl maltol (S2) and vanadyl dikoxate (S3).
  • the abscissa is time, and the ordinate is pain threshold; the analgesic used in the positive control group is aspirin.
  • Diethylmaltolato vanadyl (Bis(ethylmaltolato)oxovanadium(IV), VO(ema) 2 ] Source: Synthesized by literature method or purchased from Hubei Hongxin Ruiyu Fine Chemical Co., Ltd.
  • Vanadium dicoxylate (Bis(kojato)oxovanadium(IV), VO(ka) 2 ] Source: Synthesized by literature method.

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Abstract

一种式I结构的治疗疼痛的药物成分。该药物可以通过口服、经皮、直肠、静脉、皮下、舌下、腹腔等方式进入动物体，发挥其镇痛作用。药物的活性组分方便制备、容易鉴别鉴定，其化学结构与现有其他镇痛药物不同，是一种新型的、有效的镇痛化合物。

Description

金属络合物的新应用 技术领域
本发明涉及用于治疗疼痛的方法和药物成分，尤其是治疗急性疼痛(acute pain)、慢性疼痛(chronic pain)、炎性疼痛、癌性疼痛以及癌症治疗引发的疼痛、内脏痛、神经性疼痛、糖尿病神经病变带来的疼痛(diabetic neuropathy)、带状疱疹后神经痛(post-herpetic pain)、偏头痛、纤维肌痛(fibromyalgia)、三叉神经痛(trigeminal neuralgia)。
背景技术
疼痛是一种与组织损伤或潜在组织损伤相关的不愉快的主观感觉和情感体验。在临床上，疼痛往往是病人的主诉。许多疼痛因不能得到有效的治疗，使得患者的整体能力降低，行动受限，睡眠紊乱，生活质量下降。不仅如此，疼痛可以引发更为严重的后果，根据1999年的统计，每天就有两百万以上的人因为疼痛失去了行动能力[M.Williams,E.A.Kowaluk,and S.P.Arneric,J.Med.Chem.42,1481-1500(1999)]，比如，癌症、关节炎、偏头痛等引发的疼痛。
疼痛类型多种多样，按照病程长短疼痛可以分为急性疼痛和慢性疼痛，按照发生部位疼痛可以分为内脏痛、关节痛、肌肉痛、偏头痛等。疼痛也可以从机理的角度进行分类，比如炎性疼痛和神经性疼痛。但有理论认为，神经性疼痛的本质就是神经的炎症，神经疼痛与炎性疼痛有着不可脱离的干系。
人体的完整性是由两大***协调运行而保证的：免疫***和神经***。当人体组织受到损伤的时候，这两大***不仅通过协同运作让人对受到损伤的部分有所感知，还协同防止损伤进一步扩散，并且，对损伤部分进行快速修复，这就是炎症过程。当这个过程由免疫***主导调节时就是体液性炎症(humoral inflammation)，而由神经***引起的则叫做神经性炎症(neurogenic inflammation)。炎症引起的疼痛始于神经末梢的激活，神经末梢由感觉神经元(sensorial neurons)组成，又称为伤害感受神经元(nociceptor neurons)或伤害感受器(nociceptors)。这些感受器将组织损伤的信号传递给脊髓和大脑的疼痛处理中心。(US 2011/0206752 A1及其引述的文献)疼痛传递到大脑和中枢神经后伤害感受器又会施展它的传出功能，释放促痛、促炎的分子，激发炎症和疼痛，改变伤害感受器的兴奋水平(excitability)或者外周致敏(peripheral sensitization)，引起对炎症部位刺激知觉的变化， 比如痛觉过敏(hyperalgesia)或异常性疼痛(allodynia)。周边伤害感受器的持续性兴奋会导致脊髓的突触改变(synaptic changes)，从而引起中枢致敏的过程。
免疫***与疼痛之间亲密关系有实在的生物学证据：无论是生理条件下还是病理条件下，伤害感受器上会表达一系列免疫相关的受体，比如趋化因子(chemokine)受体和免疫球蛋白(Fc)受体，这些受体常常在免疫细胞上被发现。[T.Wang and C.Ma,Adv.Exp.Med.Biol.904,77-85(2016)]
对疼痛的传统治疗方法大致分为四类：以阿司匹林和布洛芬为代表的非甾体类抗炎药物(NSAIDs)，***类药物，另外还有抗惊厥和抗抑郁类药物。但这些现有药物均有着很大的局限性。比如，非甾体类抗炎药物的止痛作用有上限效应，即到了一定限度后增加药物剂量无法再减轻疼痛；而且，它们会引起肠道不适，长期服用还会引起胃溃疡。又如，***类药物虽然应用广泛，但其副作用，比如便秘、呼吸功能降低和成瘾性，让其用于病人的剂量受到严格的限制。
总之，现有药物远远不能满足人类对疼痛控制的要求，尤其对于慢性疼痛的治疗。新靶点药物的开发尤为重要，因为传统镇痛药物的局限性很可能是由于其所作用的靶点的局限性而造成的。寻找副作用小、长效的镇痛药物或者根治疼痛的药物是药物研发的方向。
发明内容
本发明提供一种镇痛药物成分，该成分的化学结构如式I所示，即由一种过渡金属离子(比如Zn 2+，Co 2+，Pt 2+)或氧合金属离子(比如VO(IV)，MoO 2(VI))与alpha-羟基吡喃酮或alpha-羟基吡啶酮类配体形成的金属络合物，该金属络合物的特点为：两个相同的alpha-羟基吡喃酮或alpha-羟基吡啶酮类配体与一个过渡金属离子或氧合金属离子络合，其中，过渡金属离子或氧合金属离子与X 1和X 2形成不饱和的、包含金属离子的五元环，X 1和X 2均为杂原子。VO(IV)表示
Figure PCTCN2020097507-appb-000001
MoO 2(VI)表示
Figure PCTCN2020097507-appb-000002
Figure PCTCN2020097507-appb-000003
其中，M'＝VO(IV)、Co 2+、Zn 2+、MoO 2(IV)或Pt 2+；X 1＝O或S；X 2＝O或S；Y＝O或NR 4，R 1、R 2、R 3或R 4为H、羟基、巯基、C 1-C 14烷基、羟基C 1-C 14烷基、C 1-C 14烷氧基、巯基C 1-C 14烷基、C 1-C 14烷硫基、芳基或芳基C 1-C 14烷基。
形成式I所示金属络合物的配体，即alpha-羟基吡喃酮或alpha-羟基吡啶酮类化合物，可以用式II表示。这些化合物的共同特点是：羟基(或巯基)与一个羰基(或硫代羰基)相邻。
Figure PCTCN2020097507-appb-000004
其中，X 1＝O或S；X 2＝O或S；Y＝O或NR 4，R 1、R 2、R 3和R 4分别为H、羟基、巯基、羟基C 1-C 14烷基、C 1-C 14烷氧基、C 1-C 14烷基、巯基C 1-C 14烷基、C 1-C 14烷硫基、芳基或芳基C 1-C 14烷基。
进一步优化的alpha-羟基吡喃酮类配体或alpha-羟基吡啶酮类配体与上述过渡金属离子或氧合金属离子所形成的金属络合物(如式I所示)可以用式III表示：
Figure PCTCN2020097507-appb-000005
其中，M'＝VO(IV)、Co 2+、Zn 2+、MoO 2(IV)或Pt 2+；Y＝O，R 1、R 2和R 3分别为羟基、巯基、羟基C 1-C 4烷基、C 1-C 4烷氧基、巯基C 1-C 4烷基、C 1-C 4烷基硫基、苯基或苯基C 1-C 4烷基；或Y＝NR 4，R 3＝H，R 1、R 2和R 4分别为羟基、巯基、羟基C 1-C 4烷基、C 1-C 4烷氧基、巯基C 1-C 4烷基、C 1-C 4烷基硫基、苯基或苯基C 1-C 4烷基。
进一步优选的化合物为式IV所示的alpha-羟基吡喃酮类金属络合物：
Figure PCTCN2020097507-appb-000006
其中，M'＝VO(IV)、Co 2+、Zn 2+、MoO 2(IV)或Pt 2+；R 1＝H、R 2＝Me；或R 1＝H、R 2＝-CH 2CH 3；或R 1＝-CH 2OH、R 2＝H。
上述配体可以通过常规化学合成技术进行合成。这些配体的金属络合物通常可以通过混合适当的金属盐(比如，ZnSO 4，K 2PtCl 4，VOSO 4，Co(NO 3) 2,(NH 4) 2Mo 2O 7，等等)与配体(比如，麦芽酚，乙基麦芽酚，曲酸，等等)进行一锅法合成而成，其中，麦芽酚的分子结构为R 1＝R 3＝H、R 2＝Me、X 1＝X 2＝Y＝O的式II；乙基麦芽酚的分子结构为R 1＝R 3＝H、R 2＝-CH 2CH 3、X 1＝X 2＝Y＝O的式II；曲酸的分子结构为R 2＝R 3＝H、R 1＝-CH 2OH、X 1＝X 2＝Y＝O的式II。
本发明特别优选如下化合物：
二麦芽酚铂[bis(maltolato)platinum]
Figure PCTCN2020097507-appb-000007
该化合物可以根据已知文献报道的方法制备而成[参见S.D.Kushch,E.N.Izakovich,O.S.Roshchunkina,V.M.Nichvoloda,and M.L.Khidekel,Bull.Acad.Sci.，Div.Chem.Sci.30，681-682(1981)]。
二麦芽酚锌[bis(maltolato)zinc]
Figure PCTCN2020097507-appb-000008
该化合物可以根据已知文献报道的方法制备而成[参见B.S.Parjon-Costa and E.J.Baran,Spectrochim.Acta Part A:Mol.and Biomol.Spectro.113,337-339(2013)]。
二麦芽酚二氧钼[Bis(maltolato)dioxomolybdenum(VI)]
Figure PCTCN2020097507-appb-000009
该化合物可以根据已知文献报道的方法制备而成[参见S.J.Greaves and W.P.Griffith.Polyhedron,7,1973(1988)]。
二(5-羟基-2-羟甲基-4-吡喃酮)二氧钼(VI)或二曲酸二氧钼
[Bis(5-hydroxy-2-hydroxymethyl-4-pyronato)dioxomolybdenum(VI),Bis(kojato)oxovanadium(IV),MoO 2(ka) 2]
Figure PCTCN2020097507-appb-000010
该化合物可以根据已知文献报道的方法制备而成[参见S.J.Lord,N.A.Epstein,R.L.Paddock,C.M.Vogels,T.L.Hennigar,M.J.Zaworotko,N.J.Taylor,W.R.Driedzic,T.L.Broderick,and S.A.Westcott,Can.J.Chem.77,1249-1261(1999)]。
二麦芽酚氧钒[Bis(maltolato)oxovanadium(IV),VO(ma) 2]
Figure PCTCN2020097507-appb-000011
该化合物可以根据已知文献报道的方法制备而成[参见P.Caravan,L.Gelmini,N. Glover,F.G.Herring,H.Li,J.H.McNeill,S.J.Rettig,I.A.Setyawati,E.Shuter,Y.Sun,A.S.Tracey,V.G.Yuen；and C.Orvig,J.Am.Chem.Soc.117,12759-12770(1995)]。
二乙基麦芽酚氧钒[Bis(ethylmaltolato)oxovanadium(IV),VO(ema) 2]
Figure PCTCN2020097507-appb-000012
该化合物可以根据已知文献报道的方法制备而成[参见K.H.Thompson,B.D.Liboiron,Y.Sun,K.D.D.Bellman,I.A.Setyawati,B.O.Patrick,V.Karunaratne,G.Rawji,J.Wheeler,K.Sutton,S.Bhanot,C.Cassidy,J.H.McNeill,V.G.Yuen,and C.Orvig,J.Biol.Inorg.Chem.8,66-74(2003)]
二曲酸氧钒[Bis(kojato)oxovanadium(IV),VO(ka) 2]
Figure PCTCN2020097507-appb-000013
该化合物可以根据已知文献报道的方法制备而成[参见V.G.Yuen,P.Caravan,L.Gelmini,N.Glover,J.H.McNeill,I.A.Setyawati,Y.Zbou,and C.Orvig,J.Inorg.Biochem.68,109-116(1997)]。
二(3-羟基-1-甲基-2-甲基-4-吡啶酮)氧钒(IV)
[Bis(3-hydroxy-1-methyl-2-methyl-4-pyridinonato)oxovanadium(IV),VO(mmp) 2]
Figure PCTCN2020097507-appb-000014
该化合物可以根据已知文献报道的方法制备而成[参见A.Katoh,M.Yamaguchi,K.Taguchi,R.Saito,Y.Adachi,Y.Yoshikawa,and H.Sakurai,Biomed.Res.Trace Elements 17,1-10(2006)以及文中引述的文献]。
二(3-羟基-2-甲基-4-吡啶酮)Co(II)[Bis(3-hydroxy-2-methyl-4-pyridinonato)Cobalt(II),Co(mpp) 2]
Figure PCTCN2020097507-appb-000015
该化合物可以根据已知文献报道的方法制备而成[参见C.Queiros,M.J.Amorim,A.Leite,M.Ferreira,P.Gameiro,B.de Castro,K.Biernacki,A.
Figure PCTCN2020097507-appb-000016
J.Burgess,and M.Rangel,Eur.J.Inorg.Chem.1131-140(2011)]。
以上化合物可以包含1-20个结晶水或其他溶剂分子，比如DMSO、乙醇、异丙醇、吡啶等。
然而，以上这些化合物虽然已知，但没有镇痛方面的研究报道。
上述化物物除了可以通过口服的方式给药，还可以通过其他常规方式，比如经皮、直肠、静脉、皮下、舌下、腹腔等方式。挑选合适的配体需从其骨架和环上的取代基考虑。
对于口服而言，所谓的“适合”标准则是整体络合物的溶解性。络合物最好在整体上呈电中性，其水溶性至少0.1mM，最好至少溶解0.2mM，可以口服吸收(最好有很好的肠胃吸收效率)。配体应具备一般到很强的络合能力(比如，络合常数在2≤logβ 2≤30，最好在5到22之间)
药物制剂的组成是常规的形式，比如，胶囊、片剂、包衣片剂、溶液、悬浮液、糖浆、栓剂等，可以使用常规制剂的辅助剂和赋形剂，比如，粘度调节剂、缓冲溶液、调味剂、悬浮剂、稳定剂以及其他添加剂。
本发明的药物组成可以包括加入其他治疗用试剂，比如，镇痛试剂(比如阿司匹林等)。还可以与其他镇痛药物相配合，进行联合用药治疗。
根据给药对象、身体状况以及给药途径的不同，金属络合物一般按照每天0.00001到1500mg(以金属原子计)/kg体重的剂量给药。首先，给药剂量如此宽泛因为不同哺乳动物的有效剂不同，而且它们与小鼠有效剂量差别很大，比如人体有效剂量可以10倍、20倍、30倍、甚至更多倍数地低于小鼠有效剂量(单位体重)。给药途径的不同也会影响剂量。比如，口服剂量可以10倍于注射剂量。对于小鼠而言，优选的剂量范围为每天0.01到300mg(以金属原子计)/kg。对于人而言，优选剂量范围为每天0.00005到5mg(以金属原子计)/kg。
药物单位剂量0.001mg到1000mg(以金属原子计)，优选0.1mg到300mg(以金属原子计)。
附图说明
附图1是二麦芽酚氧钒(S1)、二乙基麦芽酚氧钒(S2)和二曲酸氧钒(S3)抑制疼痛的效果图。其中，横坐标为时间，纵坐标为疼痛阈值；阳性对照组使用的镇痛药物是阿司匹林。
具体实施方式
药物镇痛活性实验
以下列举了三种钒化合物(二麦芽酚氧钒、二乙基麦芽酚氧钒、二曲酸氧钒)对于小鼠的镇痛实验。部分结果在附图1中显示，其中S1为二麦芽酚氧钒，S2为二乙基麦芽酚氧钒，S3为二曲酸氧钒，阳性组(即阳性对照组)为阿司匹林组。
注射完全弗氏佐剂(CFA)10μl于小鼠(♂昆明种小鼠，22-40g)的左后足，使其产生炎症。注射24小时后进行Von Frey测试以测定疼痛阈值，即在Dixon的Up-Down方法的指导下，用Von Frey纤维诱发小鼠机械性缩足，采集数据并计算其50％缩足阈值(即50％paw withdrawal threshold)，简称为缩足阈值或PWT，也就是疼痛阈值。后将小鼠分组，即生理盐水组，阳性对照组和药物组，分别腹腔注射0.4ml生理盐水、0.4ml浓度为20mg/ml的阿司匹林(乙酰水杨酸，或ASA)Tris-buffer溶液和被检测化合物与0.4ml纤维素溶液(1％)的混合液。然后，再用Von Frey测试监测疼痛阈值的变化。
实验1：二麦芽酚氧钒[Bis(maltolato)oxovanadium(IV),VO(ma) 2]的镇痛活性测试
二麦芽酚氧钒[Bis(maltolato)oxovanadium(IV),VO(ma) 2]来源：通过文献方法合成或从上海笛柏化学品技术有限公司购买。
腹腔注射给药剂量为9mg/kg(约0.03mmol/kg)后，7只小鼠均对该化合物有反应，痛阈普遍增高。
实验2：二乙基麦芽酚氧钒[Bis(ethylmaltolato)oxovanadium(IV),VO(ema) 2]的镇痛活性测试
二乙基麦芽酚氧钒[Bis(ethylmaltolato)oxovanadium(IV),VO(ema) 2]来源：通过文献方法合成或从湖北鸿鑫瑞宇精细化工有限公司购买。
腹腔注射给药剂量为10mg/kg(约0.03mmol/kg)后，7只小鼠均对该化合物有反应，痛阈普遍增高。
实验3：二曲酸氧钒[Bis(kojato)oxovanadium(IV),VO(ka) 2]的镇痛活性测试
二曲酸氧钒[Bis(kojato)oxovanadium(IV),VO(ka) 2]来源：通过文献方法合成。
腹腔注射给药剂量为11mg/kg(约0.03mmol/kg)后，7只小鼠均对该化合物有反应，痛阈普遍增高。
注射CFA的24小时后，小鼠的缩足阈值明显降低(附图1)，其表现为机械性痛觉超敏，表明炎性疼痛的形成。此时注射药物，即二麦芽酚氧钒(附图1中S1)，二乙基麦芽酚氧钒(附图1中S2)或二曲酸氧钒(附图1中S3)，炎性疼痛小鼠的缩足阈值则有很大的升高。在给药后30min，S1，S2或S3分别使炎性疼痛小鼠的缩足阈值从(0.072±0.0076)升高至(0.74±0.17)(P<0.01,n＝7)、(0.45±0.15)(P<0.01,n＝7)和(0.52±0.23)(P<0.01,n＝7)，展现出与阿司匹林相似或更强的阵痛作用。

Claims (4)

  1. 通式I的化合物在制备治疗疼痛的药物中的用途，
    Figure PCTCN2020097507-appb-100001
    其中，M'＝VO(IV)、Co 2+、Zn 2+、MoO 2(IV)或Pt 2+；X 1＝O或S；X 2＝O或S；Y＝O或NR 4，R 1、R 2、R 3或R 4为H、羟基、巯基、C 1-C 14烷基、羟基C 1-C 14烷基、C 1-C 14烷氧基、巯基C 1-C 14烷基、C 1-C 14烷硫基、芳基或芳基C 1-C 14烷基。
  2. 通式III的化合物在制备治疗疼痛的药物中的用途，
    Figure PCTCN2020097507-appb-100002
    Y＝O，R 1、R 2和R 3分别为羟基、巯基、羟基C 1-C 4烷基、C 1-C 4烷氧基、巯基C 1-C 4烷基、C 1-C 4烷基硫基、苯基或苯基C 1-C 4烷基；或Y＝NR 4，R 3＝H，R 1、R 2和R 4分别为羟基、巯基、羟基C 1-C 4烷基、C 1-C 4烷氧基、巯基C 1-C 4烷基、C 1-C 4烷基硫基、苯基或苯基C 1-C 4烷基。
  3. 通式IV的化合物在制备治疗疼痛的药物中的用途，
    Figure PCTCN2020097507-appb-100003
    其中，R 1＝H、R 2＝Me；或R 1＝H、R 2＝-CH 2CH 3；或R 1＝-CH 2OH、R 2＝H。
  4. 权利要求1至3任意项的用途，其中式I、式III或式IV的化合物选自如下化合物：
    二麦芽酚铂
    Figure PCTCN2020097507-appb-100004
    二麦芽酚锌
    Figure PCTCN2020097507-appb-100005
    二麦芽酚二氧钼
    Figure PCTCN2020097507-appb-100006
    二曲酸二氧钼(VI)
    Figure PCTCN2020097507-appb-100007
    二麦芽酚氧钒
    Figure PCTCN2020097507-appb-100008
    二乙基麦芽酚氧钒
    Figure PCTCN2020097507-appb-100009
    二曲酸氧钒
    Figure PCTCN2020097507-appb-100010
    二(3-羟基-1-甲基-4-吡啶酮)氧钒(IV)
    Figure PCTCN2020097507-appb-100011
    二(3-羟基-2-甲基-4-吡啶酮)Co(II)
    Figure PCTCN2020097507-appb-100012
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