Method of using vanadium compounds for the treatment of pain

Abstract

The present invention provides an analgesic pharmaceutical ingredient, which is a +4 or +5 valent vanadium compound, including inorganic vanadium compounds and organic vanadium compounds (including vanadium complexes or chelates). The present invention also provides the use of the above-mentioned compounds in the preparation of an analgesic pharmaceutical.

Description

TECHNICAL FIELD

[0001] The present application relates to methods and pharmaceutical compositions for the treatment of pain, in particular acute pain, chronic pain, inflammatory pain, cancer pain and pain induced by cancer therapy, visceral pain, neuropathic pain, pain due to diabetic neuropathy, post-herpetic pain, migraine, fibromyalgia, trigeminal neuralgia. BACKGROUND

[0002] Pain is an unpleasant subjective feeling and emotional experience associated with tissue damage or potential tissue damage. Pain affects the normal life of individuals, families, and communities. According to statistics, 37.3% and 41.1% of adults in developed and developing countries, respectively, suffer from chronic pain. (Tsang, A., Von Korff, M., Lee, S., Alonso, J., Karam, E., Angermeyer, M.C., et al. (2008). Common chronic pain conditions in developed and developing countries: Gender and age differences and comorbidity with depression-anxiety disorders? Journal of Pain, 9(10), 883-891.) Chronic pain is associated with 1) limited mobility and daily activities (A. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and wellbeing. A World Health Organization study in primary care. JAMA 1998;280:147-51. B. Smith BH, Elliott AM, Chambers WA, Smith WC, Hannaford PC, Penny K. The impact of chronic pain in the community. Fam Pract 2001;18:292-9.), 2) opioid addiction (Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: National Academies Press; 2011.), 3) anxiety and depression (A.), and 4) poor self-perceived health status and decreased quality of life (A and B). In the United States, approximately 50 million adults are affected by pain. Of these, 20 million are severely affected, unable to work or live normally most of the time (even every day).(Schappert SM, Burt CW. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 2001-02. Vital Health Stat 13 2006; 13: 1-66.).

[0003] The mechanisms of pain generation are extremely complex and, although they can be supported by electrophysiological methods, they are actually subjective. The intensity and characteristics of pain are related to both internal and external causes, and the same stimulus can give different experiences in different environments, different bodies and psychological states.

[0004] The nervous system recognizes and interprets various thermal and mechanical stimuli, as well as environmental and endogenous chemical stimuli. Clinically, acute and chronic pain are very different. Acute pain, which is associated with skeletal muscle spasm and sympathetic nervous system activation, is caused by a specific disease or injury, has a useful biological purpose, and is self-limiting. When a persistent injury is present, both the peripheral and central nervous systems (i.e. components of the pain transmission pathway) show great plasticity, and in this case, the pain signal is amplified and hyperalgesia develops. When plasticity is beneficial for defensive reflexes, this can be advantageous, but when the changes persist, it can lead to chronic pain. In contrast, chronic pain can be considered a disease state. If associated with a disease or body injury, pain can exceed the normal healing time. Chronic pain can result from a psychological state, has no biological purpose, and has no apparent endpoint. Persistent pain associated with trauma or disease (diabetes, arthritis or tumor growth) can be due to changes in peripheral nerves that can occur through damage to the nerve fibers, leading to increased spontaneous firing or changes in conduction / neurotransmitter properties. In fact, the practicality of the use of local anesthetics in the treatment of different neuropathic pains (e.g. post-herpetic neuralgia) can reflect their action on sodium channels accumulated in damaged nerve fibers.

[0005] With the continuous understanding and research of pain, a number of analgesic drugs have emerged. These drugs can be divided into the following categories: 1) non-steroidal anti-inflammatory drugs (non-steroidal anti-inflammatory drugs): such as aspirin, ibuprofen, naproxen, ketoprofen, diclofenac, and so on, and COX-2 inhibitors (such as rofecoxib and valdecoxib, etc.); 2) opiate analgesics: such as morphine, oxycodone, buprenorphine and fentanyl, etc.; 3) analgesics and antipyretics: such as acetaminophen, etc.; antidepressants: such as nortriptyline and desipramine, etc.; 4) anticonvulsants: such as carbamazepine and gabapentin, etc.; 5) antipsychotics: such as olanzapine and quetiapine, etc.; 6) serotonin receptor agonists: such as sumatriptan, ergotamine and lasmiditan, etc.; 7) CGRP (Calcitonin Gene-Related Peptide) inhibitors: such as erenumab and fremanezumab, etc.; 8) other types of analgesics: such as ziconotide, etc.

[0006] Most non-steroidal anti-inflammatory drugs and opiate analgesics are broad-spectrum analgesics, i.e. drugs that can be used for a variety of pain indications, and other categories of analgesic drugs have obvious limitations. As for individual analgesic drugs, each drug has obvious defects in one or more aspects of efficacy, drug resistance, side effects, etc. For example, non-steroidal anti-inflammatory drugs are only effective for mild and moderate pain; the most commonly used aspirin and ibuprofen have serious side effects on the gastrointestinal tract; opioid drugs have the problem of drug resistance, and may cause constipation, respiratory depression, addiction and other side effects. Therefore, it is necessary to find better analgesic drugs.

[0007] Vanadium belongs to VB group in the periodic table and is an essential trace element for human body. Vanadium can exist in various valence states in nature, while in the organism, it exists in +3, +4 and +5 valence states. +3 valence vanadium can exist in the form of V 3+ Vanadium ions exist in the cells of a few lower marine organisms (Crans DC, Mahroof-Tahir M, Keramidas AD. Mol Cell Biochem, 1995, 153: 17-24), while in animals, vanadium mainly exists in the form of +4 and +5 valence under physiological conditions.

[0008] For many years, the medicinal value of vanadium compounds has been continuously explored. For example, it has been found that vanadium compounds have the activity of inhibiting protein tyrosine phosphatase 1B (PTB1B); and can induce Hsp60-PPARγ protein interaction, eliminate tissue insulin resistance; at the same time, up-regulate the level of adiponectin and activate PPARα. Therefore, vanadium compounds have the ability to improve the level of cell energy metabolism and improve sugar / lipid metabolism, and are expected to become drugs for treating diabetes and Alzheimer's disease (AD). Vanadium compounds also have anti-proliferative activity and have potential use in anti-tumor and anti-cancer. In addition, it has been found that vanadium compounds have the effects of anti-parasite, anti-bacterial and anti-virus. (1. Rehder, D. Perspectives for vanadium in health issues. Future Med. Chem. xxx; 2. US6,232,340B cited literature; 3. Dong Yajiong, Niu Xia, Xiao Ruyu, Zhang Yue, Xia Qing, Yang Xiaoda Pharmacological effects and rational drug design of vanadium complexes. Chinese Science: Chemistry, 2017, 47(2), 162-171)

[0009] Lei proposed the analgesic use of a mixture of a small amount of +5 valence vanadium and inorganic salts of +3 and / or +4 valence vanadium in patents (CN102309507A and CN102309509A), but in which a very strong acidic solution is used for foot soaking, and the side effects are large, and the compliance of patients is very poor.

[0010] In addition, in the study of the mechanism of action of spinal cord protein tyrosine phosphatases (PTPs) in inflammatory pain, Li et al. intrathecally injected sodium orthovanadate, a phosphatase inhibitor, into mice with induced inflammatory pain and found analgesic effect, thus proposing the relationship between the activity of spinal cord protein tyrosine phosphatases and inflammatory pain. This study not only did not stimulate the research of vanadium compounds in analgesic drugs, but also led people to believe that vanadium compounds are difficult to become analgesic drugs for administration other than intrathecal injection. Phosphatases exist widely in the human body, such as blood, cell tissue, and bone. If vanadium compounds are administered by oral administration, blood injection, subcutaneous injection, transdermal administration, etc., before reaching the spinal cord, vanadium ions need to bind to phosphatases in the "pathway" (such as in the blood). Thus, two problems arise: a) Can vanadium ions be transported to the spinal cord and bind to phosphatases therein? b) Can the final physiological response still be analgesia after binding to so many phosphatases in the "pathway"? For this reason, not only did Li's research team not report follow-up studies on the analgesic use of vanadium compounds, but also no other research team has reported analgesic studies on vanadium compounds.

[0011] In clinical studies of the treatment of diseases such as diabetes using compounds containing metallic vanadium, the therapeutic dose of such compounds causes serious side effects, and ultimately cannot be made into a drug. The present inventors have unexpectedly found that a compound containing metallic vanadium can effectively treat pain at a small dose, and when the dose is increased to a certain level, the level of pain treatment reaches a plateau, so that a vanadium compound at a certain dose can both treat pain and avoid the side effects of vanadium-containing compounds. Therefore, the present application is completed. SUMMARY

[0012] The present application provides a method for treating pain using a compound containing tetravalent vanadium or a compound containing pentavalent vanadium. Specifically, the present application provides a method for treating pain in a patient suffering from a pain condition by administering to the patient a compound containing tetravalent vanadium or a compound containing pentavalent vanadium in a therapeutically effective amount, wherein the compound containing tetravalent vanadium or the compound containing pentavalent vanadium is administered in an amount of 0.00001 mg / kg body weight to 300 mg / kg body weight of vanadium per day, preferably 0.0001 mg / kg body weight to 50 mg / kg body weight, and more preferably 0.001 mg / kg body weight to 5 mg / kg body weight.

[0013] The vanadium compound of the present application can be an inorganic vanadium compound and an organic vanadium compound. The inventors have found that a vanadium-containing compound, whether an organic compound or an inorganic compound, and whether the vanadium contained therein is in a tetravalent or pentavalent state, can produce an analgesic effect if it is absorbed by a mammal (or a human body), and the difference in valence or ligand can affect the onset time, analgesic intensity and duration. Under the physiological conditions of the human body, vanadium mainly exists in the form of tetravalent or pentavalent vanadium, and mainly exists in the form of oxygen-containing vanadium. Therefore, in the body, the active substance that produces an analgesic effect should be a substance containing V IV O and V V O. Specifically, the vanadium compound of the present application includes: a) a pentavalent vanadium compound, i.e. pentavalent vanadium [which can also be indicated as "pentavalent vanadium", "+5 valent vanadium", "V V ", "V 5+ ", "vanadium (V)" or "V(V)"] that is formed by forming a chemical bond, i.e. an ionic bond and / or a covalent bond and a secondary bond, with other atoms (or ions); and b) a tetravalent vanadium compound, i.e. tetravalent vanadium [which can also be indicated as "tetravalent vanadium", "+4 valent vanadium", "V IV ", "V 4+ ", "vanadium (IV)" or "V(IV)"] that is formed by forming a chemical bond, i.e. an ionic bond and / or a covalent bond and a secondary bond, with other atoms (or ions). The secondary bond includes dipole-dipole interaction, London dispersion interaction and hydrogen bonding, etc.

[0014] Preferably, the vanadium (V) or vanadium (IV) compound is a vanadium compound containing a vanadium-oxygen bond, a vanadium-halogen bond, a vanadium-nitrogen bond, a vanadium-phosphorus bond, a vanadium-sulfur bond, or a vanadium-carbon bond, or a vanadium compound containing two or more of the above bonds. The vanadium compound often exists in the form of a complex, which is characterized by: a) the ligand can be an inorganic ligand or an organic ligand; b) the ligand can be a neutral molecule, a negatively charged ion, or a positively charged ion; c) the ligand can be a monodentate ligand (containing one donor) or a polydentate ligand (containing two or more donors, usually O-, N-, S-, or C- donors); d) the complex can contain only one monodentate ligand, two or more monodentate ligands, one polydentate ligand, two or more polydentate ligands, or both monodentate and polydentate ligands; e) the vanadium (V) or vanadium (IV) compound can be a covalent compound containing only covalent bonds (including coordination bonds), or a salt compound containing only ionic bonds or both ionic and covalent bonds; the vanadium (V) or vanadium (IV) moiety can be present in the anion or the cation of the salt; f) the vanadium (V) or vanadium (IV) compound can exist in a mononuclear form or a polynuclear polymeric form, wherein the "nucleus" refers to the vanadium (V) or vanadium (IV) center; g) the vanadium (V) or vanadium (IV) compound often contains a crystallization solvent in the solid state, such as water, methanol, ethanol, isopropanol, pyridine, DMSO, etc.

[0015] Generally, the coordination number (CN) of the vanadium coordination compound is between 4 and 8, and the geometry formed by coordination is: tetrahedron, square plane, trigonal bipyramid, square pyramid, octahedron, trigonal prism, pentagonal bipyramid, capped octahedron, capped trigonal prism, square antiprism, dodecahedron. The actual vanadium compound formed can deviate from the above generalization in terms of coordination number or geometry.

[0016] The vanadium (V) or vanadium (IV) compound can exhibit different forms in the solid state or in solution, and the structural features described in this patent are contained or partially contained in the solid state or in the solution state.

[0017] More preferably, the vanadium compound is a vanadium (V) or vanadium (IV) compound containing a vanadium-oxygen bond, including but not limited to the following types of compounds:

[0018] I. Oxides of vanadium (V), including but not limited to V2O5and its hydrates (e.g., V2O5-H2O, V2O5-2H2O, V2O5-8H2O, etc.); oxides of vanadium (IV), including but not limited to VO2, V2O4and its hydrates.

[0019] II. Vanadates of vanadium (V), including but not limited to orthovanadate (H3VO4), metavanadate (HVO3), polyvanadates (e.g., H4V2O7, H4V4O 12 15 H5V5O 10 28 H6V 12 O 3- , H3V3O9, H4V4O - , etc.), heteropolyacids of vanadium (e.g., vanadophosphoric acid, PPV, PVP, vanadoarsenic acid, etc.), etc.; vanadates of vanadium (IV), including but not limited to H4VO4, H6VO5, H2VO3, polyacids (e.g., H2V2O5), heteropolyacids (e.g., vanadophosphoric acid, such as H2[VO(P2O7)]; vanadoarsenic acid, vanadomolybdic acid, etc.), etc.

[0020] III. Salts of various vanadate anions with inorganic or organic cations

[0021] wherein the vanadium (V) anions include but are not limited to: orthovanadate (i.e., VO4 3- , and its protonated forms VO4H2 - , VO4H 2- ), metavanadate (i.e., VO3 - ), polyvanadates (e.g., V2O7 4+ , V4O 12 4- , V5O 15 5- , V 10 O 28 6- , V3O9 3- , V4O 12 4- , etc., and their protonated forms), heteropolyanions (e.g., phosphovanadate vanadium (IV) anions, such as VO4 4- ( and its protonated forms H n VO4 4-n , n = 1-3), VO5 6- ( and its protonated forms H n VO4 6-n , n = 1-5), VO3 2- ( and its protonated forms HVO3 - ), V2O5 2- ( and its protonated forms HV2O5- ), V4O9 2- (its protonated form HV4O9 - ), heteropolyanions (such as VO(P2O7) 2- , Mo3V3O 19 8- , etc.);

[0022] where the inorganic or organic cation includes, but is not limited to, quaternary ammonium ions, i.e., R1R2R3R4N + (R1, R2, R3, and R4may be H, or lower alkyl, or a substituted or unsubstituted nitrogen-containing heterocycle formed by at least one pair of the R1, R2, R3, and R4being linked (through intervening atoms), such as R1R2R3R4N + may represent NH4 + or ammonium, PyH + or pyridinium, N-alkylpyridinium cation, etc.); alkali metal cations, such as Na + , K + , Li + , Rb + , etc.; alkaline earth metal cations, such as Mg 2+ , Ca 2+ , Be 2+ , Sr 2+ , Ba 2+ , etc.; cations of metals in Groups IIIA, TVA, VA, and VIA; transition metal cations, such as Fe 2+ , Fe 3+ , Cu 2+ , Zn 2+ , Ti 2+ , Ti 3+ , Ti 4+ , Ni 2+ , Ni 3+ , Cr 2+ , Cr 3+ , and Cr 6+ .

[0023] Vanadium (V) salts include, for example, NH4VO3, Ca(VO3)2-4H2O, K2Ca(VO3)4-7H2O, Rb4Ca4(V2O7)3-17H2O, Na3VO4, KCaVO4-6H2O, Na4V2O7, K3V5O 14 , Ca3V 10 O 28 , BiVO4, FeVO4, etc.; Vanadium (IV) salts include, for example, M I 4VO4, M II 3VO5, M II 2VO4, M I2VO3, M I 2V2O5, K2V3O7.2.66H2O, wherein M I is a +1 valent metal ion, M II is a +2 valent metal ion.

[0024] IV. Oxygen-containing vanadium compounds formed by complexation of vanadium with monodentate or polydentate ligands, including but not limited to the following:

[0025] a) Oxygen-containing vanadium compounds formed by complexation of vanadium with monodentate ligands

[0026] Monodentate ligands include but are not limited to: F - , Cl - , Br - , I - , NO, H2O, CN - , NO2 - , SCN - , NCS - , NH3.N3 - , OH - , CO, HCO3 - , H2PO4 - , HSO4 - , HSO3 - , ClO4 - , NO3 - , SO3F - , HCOO - , thiol compounds (e.g., SH - ), phosphonic compounds (e.g., diphosphonic acid), and O-, S-, or N-donor monodentate organic ligands, including but not limited to alcohols, phenols, amines, carboxylic acids, and organophosphonic compounds.

[0027] Specifically, vanadium (V) compounds such as VOF3, VOCl3, VOBr3, VO(ClO4)3, VO(NO3)3, VOCl2(N3), VOHal2(OR), VOHal(OR)2, VO(OR)3, M3[VO2F4], M2[VO2F3], M[VO2Cl2], M[VOF4], M2[VOF5], M2[VOCl5], [PyH][VOCl4], M3VO4, M3VO3S, M3VO2S2, M3VOS3, M4[O3VSVO3], VO(OOCR)3, VO(NR1R2)3, where M is Li, Na, K, Rb, Cs; Hal = F, Cl, Br, I; R, R1, R2= H, alkane, aromatic, or other organic group.

[0028] Specifically, vanadium (IV) compounds such as VOSO4, 3VO2(2SO2), M I 2[VO(SO3)2], M II [VO(SO3)2], VOHal2, VO(HalO4)2(such as VO(ClO4)2-5H2O), M I 2[VOHal4] or M I 3[VOHal5] {such as K2[VOHal4(H2O)], Cs3[VOCl5]}, M I 3[VO(CN)5], M I 2[VO(NCS)4], Na(VO)2(OH)5, where Hal = F, Cl, Br, I, M I is a +1 valent metal ion, M II is a +2 valent metal ion.

[0029] b) oxygen-containing vanadium compounds formed by complexation of vanadium with multidentate ligands

[0030] Multidentate ligands include, but are not limited to: CO3 2- , O 2- , C2O4 2- , SO4 2- , SO3 2- , PO4 3- , HPO4 2- , triphosphate, and other inorganic ligands, and multidentate organic ligands containing O-, N-, or S- donors.

[0031] Such as diols (such as ethylene glycol, sugar compounds, nucleoside compounds), glycerol, hydroxycarboxylic acids (such as lactic acid, citric acid, tartaric acid, and other alpha-hydroxycarboxylic acids), salicylic acid compounds, diacids (such as oxalic acid, malonic acid, succinic acid, and others), hydroxamic acids (HONHCOR, R is an organic group), sulfur-containing ligand compounds (such as beta-mercaptoethanol, dithiothreitol, bis(2-mercaptoethyl)ether, tris(2-mercaptoethyl)amine, cysteine, glutathione, oxidized glutathione, disulfides, and related compounds or derivatives thereof, and others), amino alcohols and related ligand compounds (such as ethanolamine, ethylenediamine, amino acids and derivatives thereof, 2-aminoethanethiol, diethanolamine and derivatives thereof, ethylene-N,N'-diacetic acid (EDDA) and analogs thereof, pyridinecarboxylic acids, hydroxypyridines, amides, and others), dipeptides and polypeptide compounds.

[0032] Specifically, vanadium (V) compounds such as V2O3(SO4)2.2H2O, VOPO4.2H2O, M[VO2(SO4)], K2[VO2(C2O4)2], M3[VO2(C2O4)2]; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing n wherein V = V(V), M = Li, Na, K, Rb, Cs; R1, R2, R3, R4or R5are H or other groups, R can be -(CH2)n- group, n = 0-4, -CR1R2- or other groups such as homocyclic aromatic hydrocarbons, heterocycles, etc. n wherein V = V(V), M = Li, Na, K, Rb, Cs; R1, R2, R3, R4or R5are H or other groups, R can be -(CH2)n- group, n = 0-4, -CR1R2- or other groups such as homocyclic aromatic hydrocarbons, heterocycles, etc.

[0033] Specifically, vanadium (IV) compounds such as V(SO4)2, VOSO4, M II 2[VO(SO4)3] or M I 2[(VO)2(SO4) 3 ], (VO)3(PO4)2, M II [VO(PO4)]2{e.g., Ba[VO(PO4)]2.4H2O}; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing a diol ligand complex; containing wherein M I is a +1 valence metal ion, M IIIt is a +2 valence metal ion; V = V(IV) in the structural formula; R1, R2, R3, R4 or R5 are H or other groups, and R can be -(CH2). n -Groups, n=0-4, -CR1R2- or other groups, such as allotropic aromatic hydrocarbons, heterocycles, etc.

[0034] The structural characteristics of multidentate complexes are the presence of VO, VN, and / or VS bonds; vanadium often forms cyclic structures with ligands, such as five-membered rings and six-membered rings.

[0035] V. Peroxovanadates, i.e. compounds containing V (O2), including but not limited to a) H2VO3 (O2). - HVO3(O2) 2- VO2(O2)2 3- HVO2(O2)2 2- H2VO2(O2)2 - HV(O2)3 2- Pervanadate anions (e.g., H₂VO₃(O₂)) - The structure is HVO2(O2)2 2- The structure is HV(O2)3 2- The structure is (a) A compound that combines with the cations described in III to form a salt; (b) A compound containing V(O2) and complexed with the monodentate or polydentate ligands described in IV.

[0036] Specific compounds include KH2[VO2(O2)2]·H2O, (NH4)2H[VO2(O2)2]·H2O, etc.

[0037] VI. Hydroxamido vanadates, i.e., containing V(ONR1R2), where R1 and R2 are H or organic groups, including but not limited to hydroxylamine vanadate anions, such as VO2(ONR1R2)2. - Its structure is a) A compound containing V(ONR1R2)2 and complexed with monodentate or polydentate ligands as described in IV. Wherein, R1 and R2 are H or other groups.

[0038] Vanadium compounds can exist in mononuclear, dinuclear, and multinuclear forms; vanadium compounds formed by complexation with a single ligand can be expressed using V... a L bwherein V represents a vanadium core (or vanadium center), L represents a ligand, a, b represent the number, the stoichiometric ratio of vanadium to ligand can be 1 / 1, 1 / 2, 1 / 3, 2 / 3, 2 / 5, 3 / 2, 3 / 5, etc. and can be represented by the general formula a / b, wherein a or b = an integer or decimal number between 0 and 100; vanadium compounds formed by complexation of two or more ligands can be represented by the general formula V a L b ...L n-1 b (n-1) wherein b(n-1) is the number of L n and a or b(n-1) = an integer or decimal number between 0 and 100. For example, when n = 1 (i.e. one ligand), the general formula is V a L b ; when n = 2 (i.e. two ligands), the general formula is V a L b L 1 b1 (i.e. containing two ligands: L and L 1 ; their numbers are b and b1, respectively); when n = 3 (i.e. three ligands), the general formula is V a L b L 1 b1 L 2 b2 (i.e. containing three ligands: L, L 1 , L 2 ; their numbers are b, b1 and b2, respectively), and so on. In addition, vanadium compounds in the solid state can contain solvent molecules in varying amounts, such as H2O, methanol, ethanol, isopropanol, pyridine, DMSO, etc.

[0039] Further preferred compounds: lithium orthovanadate, sodium orthovanadate, potassium orthovanadate, lithium polyvanadate, sodium polyvanadate, potassium polyvanadate, lithium metavanadate, sodium metavanadate, potassium metavanadate, quaternary ammonium salt of metavanadic acid (i.e. R1R2R3R4N + VO3, R1, R2, R3 and R4 can be H, or other groups, lower alkanes, and can also be substituted or unsubstituted nitrogen-containing heterocycles in which at least one pair is connected (through intervening atoms), such as R1R2R3R4N + can represent NH4 + or ammonium, PyH + or pyridine hydrogen, N-alkyl pyridinium cation, etc.; such as ammonium metavanadate), vanadyl sulfate (VOSO4, or VOSO4-nH2O, n = 1-20), vanadyl dichloride, and compounds thereof containing crystallization solvents (such as water, methanol, ethanol, isopropanol, DMSO, pyridine, DMF, etc.);

[0040] Further preferred vanadium (V) or vanadium (IV) compounds include complexes of vanadium (V) or vanadium (IV) with the following ligand species: a) hydroxy carboxylic acid (including hydroxy carboxylic acids and hydroxy carboxylates) compounds such as glycolic acid or glycolate, lactic acid or lactate, tartaric acid or tartarate, citric acid or citrate, α-hydroxyisobutyric acid or α-hydroxyisobutyrate, 2-ethyl-2-hydroxybutyric acid or 2-ethyl-2-hydroxybutyrate, malic acid or malate, mandelic acid or mandelate, ascorbic acid or ascorbate; b) mono-, di- or poly-carboxylic acids or carboxylates compounds such as formic acid or formate, acetic acid or acetate, stearic acid or stearate, oxalic acid or oxalate, malonic acid or malonate, alkyl- or aryl-malonic acid or malonate, sebacic acid or sebacate, succinic acid or succinate, phthalic acid or phthalate, etc.; c) mono-, di- or poly-hydroxy compounds such as monool alcohols such as methanol, ethanol, isopropanol, geraniol, menthol, retinol, etc., compounds containing vicinal diols or meta-diol compounds (such as ethylene glycol, 1,2-dihydroxypropane, 1,3-dihydroxypropane, 1,2-dihydroxycyclopentane, 1,2-dihydroxycyclohexane), glycerol, mono-, di- or polysaccharides and their derivatives such as ribose, ADP, ATP, D-glucose, D-fructose, D-turanose, D-gluconic acid or D-gluconate, L-threonic acid or L-threonate, and amino- or acetamino sugars; d) amino acids such as alanine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, valine, cysteine, cystine, tyrosine, tryptophan, arginine, asparagine, glutamine,c) phenol, di- or polyphenol, such as phenol, catechol or pyrocatechol, polyhydroxyaromatic compounds, d) amino acids, dipeptides, polypeptides, proteins and their derivatives (e.g. Schiff bases), such as cysteine, glutathione (GSH, gamma-L-glutamyl-L-cysteinyl-glycine) and GSMe (Me = methyl) and GSSG, D-aspartic acid, beta-alanyl-L-histidine (carnosine), collagen, serum proteins; amino acids (e.g. glycine, alanine, glutamica acid, etc.) and their Schiff bases with salicylaldehyde or pyridoxal; e) diamines and their Schiff bases, such as ethylenediamine, propylenediamine or phenylenediamine and their Schiff bases with salicylaldehyde or pyridoxal; f) beta-diketones, such as acetylacetone, dibenzoylmethane, benzoylacetone, furoyltrifluoroacetone, etc., and their Schiff bases with amines; g) hydroxypyrones and hydroxypyridinones, such as maltol (3-hydroxy-2-methyl-4-pyrone), kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone), ethylmaltol (2-ethyl-3-hydroxy-4-pyrone); h) phospholipids, including phosphatidylcholine (lecithin), phosphatidylethanolamine (cephaline), phosphatidylserine, phosphatidylinositol, phosphatidylglycerol or glycerophospholipids, diphosphatidylglycerol and sphingomyelin, etc.; i) hydroxylamines, such as N-hydroxylamine, N,N-dialkylhydroxylamine, 2-hydroxylamine, 3-hydroxylamine, etc.; j) urea or biguanides; k) compounds comprising formula I:

[0041]

[0042] X 1 and X 3 is O, S or NX 6 , preferably O or NX 6;

[0043] X 2 Is it N or CX? 7 ;

[0044] X 4 X 5 X 6 and X 7 It is an inactive H (non-labile protons) or an substituted alkyl, aromatic, aralkyl, or alkaryl group or X. 4 To X 7 At least one pair is connected (through the intervention of atoms), preferably X. 4 With X 5 The resulting substituted, saturated, or unsaturated allotropic rings (or carbocyclic rings) or heterocycles, or X 1 Represents an NX 6 Group, X 4 It can represent an X 8 H group, in which X 5 It is O or S; and X 1 or X 8 One of the attached protons is active (preferably: with X). 1 (The connected protons are active).

[0045] Or compounds of formula II:

[0046]

[0047] Another class of preferred ligand compounds can be represented by general formula II. Here, A and B are five-, six-, or seven-membered rings containing 0, 1, or 2 heteroatoms (selected from O, S, and N), and are composed of X. 4 Oxygen (oxo), sulfur (thio) or NX 4 Arbitrary substitution (X) 4 (As defined above). Rings A and B are preferably 1,2-phenylene, oxazolin-2-yl, or thiazolin-2-yl, as shown below:

[0048]

[0049] Among them, X 4 It is H or a randomly substituted hydroxyl group C. 1-4 alkyl.

[0050] Preferred ligand compounds conforming to general formulas I and II include:

[0051] Hydroxamates (general formulas III and IV:

[0052]

[0053] α-hydroxypyridinones (general formula V):

[0054]

[0055] α-hydroxypyrones (formula VI):

[0056]

[0057] α-Amino acids (General Formula VII)

[0058]

[0059] α-Hydroxycarboxylic acid (formula VIII)

[0060]

[0061] α-Hydroxycarbonyl compounds (general formulas IX and X)

[0062]

[0063] Thiohydroxamates (general formulas XI and XII)

[0064]

[0065] 2-Oxazolin-2-yl-phenols and 2-thiazolin-2-yl-phenols (general formulas XIII and XIV)

[0066]

[0067] Among them, R 1 -R 29 It is H or any organic group, such as any hydroxyl group C. 1-4 Alkanes.

[0068] Further optimization of ligands is:

[0069]

[0070] Maltol

[0071]

[0072] Ethyl maltol

[0073]

[0074] Kojic acid

[0075] Citric aid

[0076]

[0077] Glycolic acid

[0078]

[0079] Lactic acid (L-, D- or racemic)

[0080]

[0081] Tartaric acid (L-, D- or mixed)

[0082]

[0083] Complexes of vanadium (V) and vanadium (IV) with the above ligands can be synthesized by known methods (see USP 5,620,967, 4 / 1997, McNeill et al.). The present application particularly prefers the following compounds: vanadyl methyl maltol (BMOV), vanadyl ethyl maltol (BE0V), vanadyl kojate, vanadyl sulfate, sodium orthovanadate, potassium orthovanadate, sodium metavanadate, potassium metavanadate, and vanadium compounds prepared in a molar ratio of 1:0.5 to 1:1000 with citric acid, tartaric acid, lactic acid, glycolic acid, ethylene glycol, glycerol or triethanolamine (tris(2-hydroxyethyl)amine), and the citric acid complex K[VO2(C6H6O7)]-H2O.

[0084] The vanadium compounds of the present application can be synthesized by conventional chemical synthesis techniques.

[0085] The vanadium compounds of the present application can be used in combination with other analgesic drugs, such as forming a complex with other analgesic drugs, mixing with other analgesic drugs, or using simultaneously or at intervals with other analgesic drugs.

[0086] The compounds of the present application can be prepared into various conventional dosage forms of pharmaceutical compositions. For example, tablets, injection solutions, capsules, patches, inhalants, etc.

[0087] These pharmaceutical compositions can be orally administered, for example, as tablets, coated tablets, sugar-coated tablets, hard or soft gel capsules, solutions, emulsions or suspensions; rectally, for example, as suppositories; or parenterally, for example, as injections through subcutaneous, intramuscular or intravenous administration, or transdermally, for example, as patches, sprays or the like, or nasally or buccally as inhalants or the like.

[0088] Pharmaceutical compositions comprising the compounds of the present application can be manufactured by means known in the art, e.g., by means of conventional mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, sugar coating or lyophilizing processes. These pharmaceutical preparations can be formulated with a therapeutically inert, inorganic or organic carrier, such as lactose, corn starch or derivatives thereof, talc, stearic acids or its salts. Suitable carriers for tablets, coated tablets, sugar-coated tablets and hard gelatin capsules are lactose, corn starch or derivatives thereof, talc, stearic acids or its salts. Suitable carriers for soft gelatin capsules are vegetable oils, waxes and fatty oils. Suitable carriers for solutions or syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injections are water, alcohols, polyols, glycerol, vegetable oils, phosphoric acids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fatty oils and semisolid polyols.

[0089] The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying osmotic pressure, buffers, coating agents or antioxidants.

[0090] A therapeutically effective amount of a compound according to the present application means an amount sufficient to prevent, slow or ameliorate the symptoms of a disease or to prolong the life of a patient being treated. A therapeutically effective amount or dose of a compound according to the present application can vary widely depending on the particular compound employed, the route of administration, the condition being treated, and the patient being treated.

[0091] The metal complex is generally administered at a dose of 0.00001 to 1500 mg (in terms of vanadium mass) per kg of body weight per day, depending on the subject, the physical condition, and the route of administration. The dose is first so wide because the effective dose differs among different mammals, and they differ greatly from the effective dose in mice, for example, the effective dose in humans can be 10 times, 20 times, 30 times, or even more times lower than that in mice (per unit body weight). The route of administration also affects the dose. For example, the oral dose can be 10 times that of injection. The dose range, in terms of vanadium mass, is preferably 0.00001 mg / kg of body weight per day to 300 mg / kg of body weight per day, more preferably 0.0001 mg / kg of body weight per day to 50 mg / kg of body weight per day, and even more preferably 0.001 mg / kg of body weight per day to 5 mg / kg of body weight per day.

[0092] The pharmaceutical unit dose is 0.001 mg to 1000 mg (as metal atoms), preferably 0.01 mg to 300 mg (as mass of vanadium).

[0093] Generally, for oral administration to an adult human of about 70 Kg, a dosage of about 0.0005 mg to about 500 mg, preferably about 0.005 mg to about 300 mg, and more preferably about 0.05 mg to about 300 mg, as mass of vanadium, per day should be appropriate; for injectable administration, a dosage of about 0.001 mg to about 10 mg, preferably about 0.01 mg to about 5 mg, as mass of vanadium, per day should be appropriate. It is possible that the upper limit can be exceeded, although there are indications that this is not desirable. The daily dose can be given in one or more separate doses.

[0094] Vanadium (V) or vanadium (IV) forms polymers in aqueous solution with changes in concentration and pH, which can affect the analgesic effect. The present invention provides a composition which, in addition to containing a vanadium (V) or vanadium (IV) compound, also contains one or more of the following:

[0095] a) hydroxy carboxylic acids (including hydroxy carboxylic acids and hydroxy carboxylates) compounds such as glycolic acid or glycolate, lactic acid or lactate, tartaric acid or tartarate, citric acid or citrate, a-hydroxyisobutyric acid or a-hydroxyisobutyrate, 2-ethyl-2-hydroxybutyric acid or 2-ethyl-2-hydroxybutyrate, malic acid or malate, mandelic acid or mandelate, ascorbic acid or ascorbate; b) mono-, di- or poly-carboxylic acids or carboxylates compounds such as formic acid or formate, acetic acid or acetate, stearic acid or stearate, oxalic acid or oxalate, malonic acid or malonate, alkyl- or aryl-malonic acid or malonate, sebacic acid or sebacate, succinic acid or succinate, phthalic acid or phthalate, etc.; c) mono-, di- or poly-hydroxy compounds such as monool of methanol, ethanol, isopropanol, geraniol, menthol, retinol, etc., compounds containing vicinal diols or meta-diol (such as ethylene glycol, 1,2-dihydroxypropane, 1,3-dihydroxypropane, 1,2-dihydroxycyclopentane, 1,2-dihydroxycyclohexane), glycerol, mono-, di- or polysaccharides and their derivatives such as ribose, ADP, ATP, D-glucose, D-fructose, D-turanose, D-gluconic acid or D-gluconate, L-threonic acid or L-threonate, and amino- or acetamino sugars;c) phenol, diphenol or polyphenol, such as phenol, catechol or pyrocatechol, polyhydroxyaromatic compounds, d) amino acid, dipeptide, polypeptide, protein and their derivatives (such as Schiff base), such as cysteine, glutathione (GSH, gamma-L-glutamyl-L-cysteinyl-glycine) and GSMe (Me = methyl) and GSSG, etc., D-aspartic acid, β-alanyl-L-histidine (carnosine), collagen, serum proteins; Schiff base of amino acid (such as glycine, alanine, glutamic acid, etc.) with salicylaldehyde or pyridoxal; e) diamine and Schiff base formed therefrom, such as ethylenediamine, propylenediamine or phenylenediamine, etc., and Schiff base formed therefrom with salicylaldehyde or pyridoxal; f) β-diketone, such as acetylacetone, dibenzoylmethane, benzoylacetone, furoyltrifluoroacetone, etc., and Schiff base formed therefrom with amine compound; g) hydroxypyrones and hydroxypyridinones, such as maltol (3-hydroxy-2-methyl-4-pyrone), kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone), ethylmaltol (2-ethyl-3-hydroxy-4-pyrone); h) phospholipids, including phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylinositol, phosphatidylglycerol or glycerophospholipid, bisphosphatidylglycerol and sphingomyelin, etc.; i) hydroxylamine compound, such as N- or N,N-alkylhydroxylamine, 2-hydroxylamine, 3-hydroxylamine, etc.; j) urea or biguanides; k) compound contained in formula I below:

[0096]

[0097] X 1 and X 3 is O, S or NX 6 , preferably O or NX 6 ;

[0098] X 2 Is it N or CX? 7 ;

[0099] X 4 X 5 X 6 and X 7 It is an inactive H (non-labile protons) or an substituted alkyl, aromatic, aralkyl, or alkaryl group or X. 4 To X 7 At least one pair is connected (through the intervention of atoms), preferably X. 4 With X 5 The resulting substituted, saturated, or unsaturated allotropic rings (or carbocyclic rings) or heterocycles, or X 1 Represents an NX 6 Group, X 4 It can represent an X 8 H group, in which X 5 It is O or S; and X 1 or X 8 One of the attached protons is active (preferably: with X). 1 (The connected protons are active).

[0100] Or compounds of formula II:

[0101]

[0102] Another class of preferred ligand compounds can be represented by general formula II. Here, A and B are five-, six-, or seven-membered rings containing 0, 1, or 2 heteroatoms (selected from O, S, and N), and are composed of X. 4 Oxygen (oxo), sulfur (thio) or NX 4 Arbitrary substitution (X) 4 (As defined above). Rings A and B are preferably 1,2-phenylene, oxazolin-2-yl, or thiazolin-2-yl, as shown below:

[0103]

[0104] Among them, X 4 It is H or a randomly substituted hydroxyl group C. 1-4 alkyl.

[0105] Preferred ligand compounds conforming to general formulas I and II include:

[0106] Hydroxamates (general formulas III and IV:

[0107]

[0108] α-hydroxypyridinones (general formula V):

[0109]

[0110] α-hydroxypyrones (formula VI):

[0111]

[0112] α-Amino acids (General Formula VII)

[0113]

[0114] α-Hydroxycarboxylic acid (formula VIII)

[0115]

[0116] α-Hydroxycarbonyl compounds (general formulas IX and X)

[0117]

[0118] Thiohydroxamates (general formulas XI and XII)

[0119]

[0120]

[0121] 2-Oxazolin-2-yl-phenols and 2-thiazolin-2-yl-phenols (general formulas XIII and XIV)

[0122]

[0123] Among them, R 1 -R 29 It is H or any organic group, such as any hydroxyl group C. 1-4 Alkanes.

[0124] Further optimization of ligands is:

[0125]

[0126] Maltol

[0127]

[0128] ethyl maltol

[0129]

[0130] kojic acid

[0131] citric aid

[0132]

[0133] glycolic acid

[0134]

[0135] lactic acid (L-, D- or racemic)

[0136]

[0137] tartaric acid (L-, D- or mixed)

[0138]

[0139] The weight ratio of vanadium (V) compound to the above-mentioned substance, or the weight ratio of vanadium (IV) compound to the above-mentioned substance in the composition can be adjusted according to the actual situation, as long as the vanadium (V) compound or vanadium (IV) compound does not form a polymer in the aqueous solution of the composition to ensure its analgesic effect. In this case, the pH value of the above-mentioned aqueous solution should also be close to neutral, for example, the pH value is 6 to 8. For example, vanadium (V) compound or vanadium (IV) compound is mixed with citric acid, tartaric acid, lactic acid, glycolic acid, ethylene glycol, glycerol or triethanolamine (tris (2-hydroxyethyl) amine) to prepare the composition according to the molar ratio of 1:0.1 to 1:1000. BRIEF DESCRIPTION OF DRAWINGS

[0140] Figure 1 Figure. Effect of sodium orthovanadate solution on the pain threshold of mice (dose in terms of vanadium atomic mass).

[0141] Horizontal coordinate: time (unit: min or minute); vertical coordinate: pain threshold value;

[0142] Dosing method: intraperitoneal injection;

[0143] Horizontal coordinate: time (unit: min or minute); vertical coordinate: pain threshold value (unit: g or gram);

[0144] "▲": A1 solution, dose about 0.97 mg / kg;

[0145] "■": A2 solution, dose about 0.19 mg / kg;

[0146] "+": Blank control.

[0147] Figure 2 : Effect of sodium orthovanadate solution on pain threshold of mice (dose in terms of vanadium atomic mass) graph.

[0148] Horizontal axis: Time (unit: min or minute); Vertical axis: Pain threshold (unit: g or gram);

[0149] Dosing method: Intraperitoneal injection

[0150] "▲": A1 solution, dose about 0.97 mg / kg;

[0151] "■": A2 solution, dose about 0.19 mg / kg;

[0152] "▲": A3 solution, dose about 0.097 mg / kg;

[0153] "+": Blank control.

[0154] Figure 3 : Dimethylglyoxime methoxyoxovanadium (dose in terms of vanadium atomic mass) graph.

[0155] Dosing method: Intraperitoneal injection

[0156] Horizontal axis: Time (unit: min or minute); Vertical axis: Pain threshold (unit: g or gram);

[0157] "▲": C solution, dose about 0.97 mg / kg;

[0158] "■": S solution, dose about 250 mg / kg

[0159] "+": Blank control.

[0160] Figure 4 : Effect of sodium metavanadate solution on pain threshold of mice (dose in terms of vanadium atomic mass) graph.

[0161] Dosing method: Intraperitoneal injection

[0162] Horizontal axis: Time (unit: min or minute); Vertical axis: Pain threshold (unit: g or gram);

[0163] "▲": D solution, dose about 0.97 mg / kg;

[0164] "■": S solution, dose about 250 mg / kg

[0165] " + ": Control.

[0166] Figure 5 : Effect of sodium salt solution of metavanadate / citrate complex on pain threshold of mice (dose in terms of vanadium atomic mass)

[0167] Method of administration: intraperitoneal injection

[0168] Horizontal axis: time (unit: min or minute); vertical axis: pain threshold (unit: g or gram);

[0169] "▲": B solution, dose about 0.97 mg / kg;

[0170] "■": S solution, dose about 250 mg / kg

[0171] " + ": Control.

[0172] Figure 6 : Effect of sodium salt solution of metavanadate / citrate complex on pain threshold of mice (dose in terms of vanadium atomic mass)

[0173] Method of administration: intraperitoneal injection

[0174] Horizontal axis: time (unit: min or minute); vertical axis: pain threshold (unit: g or gram);

[0175] "▲": E solution, dose about 0.97 mg / kg;

[0176] "■": ASA solution, dose about 250 mg / kg

[0177] " + ": Control.

[0178] Figure 7 : Effect of potassium salt solution of metavanadate / citrate complex on pain threshold of mice (dose in terms of vanadium atomic mass)

[0179] Method of administration: intraperitoneal injection

[0180] Horizontal axis: time (unit: min or minute); vertical axis: pain threshold (unit: g or gram);

[0181] "▲": F solution, dose about 0.97 mg / kg;

[0182] "■": ASA solution, dose about 250 mg / kg

[0183] " + ": Control. DETAILED DESCRIPTION

[0184] In order to better understand the essence of the present application, the following animal experiment results of the compounds of the present application are used to illustrate the use of the compounds for treating pain, from which it can be seen that the compounds of the present application have a fast onset and long duration of analgesic effect, thus achieving a fast and long-acting analgesic effect. The effect examples give the activity data of the compounds of the present application. It must be emphasized that the pharmaceutical effect examples of the present application are used to illustrate the present application and are not a limitation of the present application. Simple improvements of the present application according to the essence of the present application all fall within the protection scope of the present application.

[0185] Example 1 Construction of a mouse pain model

[0186] Inflamed was induced in mice (♂ Kunming mice, 22-40 g) by injecting 10 μl of complete Freund's adjuvant (CFA) into the left hind paw. Von Frey test was performed 24 hours after injection to determine the pain threshold, i.e. under the guidance of Dixon's Up-Down method, Von Frey fiber was used to induce mice to withdraw their paws mechanically, data was collected and the 50% paw withdrawal threshold (i.e. 50% paw withdrawal threshold) was calculated, which is also referred to as paw withdrawal threshold or PWT, i.e. pain threshold. Then the mice were divided into groups, i.e. normal saline group, positive control group and drug group, and were injected intraperitoneally with normal saline, aspirin (acetylsalicylic acid, or ASA) solution and the tested compound solution, respectively. Then, the change of pain threshold was monitored by Von Frey test.

[0187] The pain threshold of the mice decreased after modeling, and the threshold of the mice before modeling was about 2.5 on average, and the pain threshold of the mice selected after modeling was about 0.1 on average. After using aspirin, a known analgesic drug, the pain threshold increased, which proved that the modeling was successful.

[0188] The mice were divided into three groups: blank control group, aspirin (ASA) group and drug group. In the blank control group, the mice were given normal saline, deionized water or deionized water containing ≤5% DMSO in an amount equal to that of the drug group; in the ASA group, the mice were given a known analgesic drug ASA as a positive control of the tested drug; in the drug group, the mice were given the tested drug respectively, and whether the pain threshold increased after injection of the tested compound solution, the duration of the increase and the amplitude of the increase were observed, so as to estimate whether the tested compound had an analgesic effect, the duration and strength of the effect.

[0189] Example 2 Preparation of positive control samples and tested drug samples

[0190] 1. Preparation of positive control

[0191] S solution: aspirin (ASA) was prepared into a solution with a concentration of 0.11 M using 0.1 M tris-HCl buffer as the solvent and adjusting the pH value with sodium hydroxide solution, and the final pH value was about 7.4-7.6.

[0192] 2. Preparation of sodium orthovanadate solution (A solution)

[0193] Sodium orthovanadate (Na3VO4): purchased from Sigma-Aldrich.

[0194] A0 solution: Weigh 184 mg of sodium orthovanadate, dissolve in 6 ml of deionized water, adjust the pH to 10 with hydrochloric acid, heat to colorless, cool to room temperature, test the pH, if the pH changes, repeat the above process until the pH is about 10. Add deionized water to 8 ml, and store at 4°C, this solution is called sodium orthovanadate stock solution.

[0195] A1 solution: Dilute the above-mentioned sodium orthovanadate stock solution, i.e. A0 solution, with deionized water to prepare a solution with a concentration of 1.5 x 10 -3 M of sodium orthovanadate aqueous solution;

[0196] A2 solution: Dilute A0 solution with deionized water to prepare a solution with a concentration of 3.0 x 10 -4 M of sodium orthovanadate aqueous solution;

[0197] A3 solution: Dilute A0 solution with deionized water to prepare a solution with a concentration of 1.5 x 10 -4 M of sodium orthovanadate aqueous solution;

[0198] A4 solution: Dilute A0 solution with deionized water to prepare a solution with a concentration of 3.0 x 10 -3 M of sodium orthovanadate aqueous solution;

[0199] A5 solution: Dilute A0 solution with deionized water to prepare a solution with a concentration of 7.5 x 10 -4 M of sodium orthovanadate aqueous solution;

[0200] A6 solution: Dilute A0 solution with deionized water to prepare a solution with a concentration of 7.5 x 10 -6 M of sodium orthovanadate aqueous solution;

[0201] 3. Preparation of sodium salt solution of orthovanadate / citrate complex (B solution)

[0202] B solution: 14.8 mg of sodium orthovanadate is dissolved in 3.5 ml of water, and 0.25 M citric acid solution is added dropwise until the solution pH is about 7. Add a small amount of water to a total volume of 4 ml to obtain a solution of vanadium citrate complex with a concentration of 0.020 M (calculated as vanadium). Further dilute the solution to a concentration of 1.5 x 10 -3 M as the test solution.

[0203] 4. Preparation of dimethylol methoxy oxovanadium solution (C solution)

[0204] cis-Bis(maltolato)methoxyoxovanadium (V), VO(OCH3)(ma)2: Bis(maltolato)oxovanadium (VO(ma)2, 5 g, 16 mmol) was dissolved in 50 ml of methanol and stirred under air for 24 h, the solution was frozen overnight at -35 °C, the crystals that separated were collected by filtration, yield 65%. (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. 1995, 117, 12759-12779)

[0205] C solution: VO(OCH3)(ma)2was formulated into 3.0 x 10 -3 M aqueous solution.

[0206] 5. Preparation of sodium metavanadate solution (or D solution)

[0207] Sodium metavanadate (NaVO3): purchased from Sigma-Aldrich.

[0208] D solution: Sodium metavanadate was formulated into 3.0 x 10 -3 M aqueous solution.

[0209] 6. Preparation of sodium salt of metavanadate / citrate complex solution (E solution)

[0210] E solution: To 1 ml of sodium metavanadate solution at a concentration of 0.26 M, 2 ml of citric acid solution at a concentration of 0.135 M was added. Diluted to a concentration of 1.5 x 10 -3 M as the test solution.

[0211] 7. Preparation of potassium salt of metavanadate / citrate complex solution (F solution)

[0212] Preparation of potassium dioxo(citrato)vanadate (V), i.e. potassium dioxo(citrato)vanadate(V) hydrate {K[VO2(C6H6O7)]-H2O}: V2O5(0.50 g, 2.75 mM) was suspended in an aqueous solution of KOH (0.31 g, 5.5 mM), cooled in an ice bath and a solution of citric acid (citric acid-H2O: 1.21 g, 6.0 mM; water: 5 ml) was added dropwise under stirring. The mixture was left to stand overnight at 4°C (fridge). It was filtered and dried to obtain a pale yellow powder. Yield 43%. (ref: Inorg. Chem. 1989, 719-723)

[0213] F solution: 13 mg of K[VO2(C6H6O7)]-H2O solid was dissolved in 1.5 x 10 -3 M solution, as the solution under test.

[0214] 8. Preparation of vanadyl sulfate solution (G solution)

[0215] Vanadyl sulfate (VOSO4-5H2O): purchased from Alfa Aesar.

[0216] Gl solution: 1.5 x 10 -3 Vanadyl sulfate aqueous solution of M;

[0217] G2 solution: 3.0 x 10 -3 Vanadyl sulfate aqueous solution of M;

[0218] G3 solution: 7.5 x 10 -4 Vanadyl sulfate aqueous solution of M.

[0219] G4 solution: 7.5 x 10 -6 Vanadyl sulfate aqueous solution of M.

[0220] 9. Preparation of vanadyl dimethylglycinate solution (H solution)

[0221] Bis(maltolato)oxovanadium (IV), VO(ma)2or BMOV Source: synthesized by literature method [see 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)] or purchased from Shanghai Dibai Chemical Technology Co., Ltd.

[0222] H1 solution: prepared with DMSO and deionized water to a concentration of 1.5 x 10 -3 Bis(maltolato)oxovanadium solution of M, wherein the DMSO content is < 5%;

[0223] H2 solution: prepared with DMSO and deionized water to a concentration of 3.0 x 10 -3 Bis(maltolato)oxovanadium solution of M, wherein the DMSO content is < 5%:

[0224] H2 solution: prepared with DMSO and deionized water to a concentration of 6.0 x 10 -3 Bis(maltolato)oxovanadium solution of M, wherein the DMSO content is < 5%.

[0225] 10. Preparation of Bis(ethylmaltolato)oxovanadium solution (I solution)

[0226] Bis(ethylmaltolato)oxovanadium (IV), VO(ema)2or BEOV Source: synthesized by literature method [see 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)] or purchased from Hubei Hongxinruiyu Fine Chemical Co., Ltd.

[0227] I solution: prepared with DMSO and deionized water to a concentration of 1.5 x 10 -3 Bis(ethylmaltolato)oxovanadium solution of M, wherein the DMSO content is < 5%.

[0228] 11. Preparation of Bis(kojato)oxovanadium solution (J solution)

[0229] Bis(kojato)oxovanadium [i.e. Bis(kojato)oxovanadium(IV) or VO(ka)2]: Synthesized by literature method see 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)].

[0230] J solution: Prepared in DMSO and deionized water to a concentration of 1.5 x 10 -3 Bis(kojato)oxovanadium solution of M, wherein the DMSO content is < 5%.

[0231] 12. Preparation of Vanadyl acetylacetonate solution (K solution)

[0232] Vanadyl acetylacetonate [i.e. Bis(acetylacetonato)oxovanadium(IV) or VO(acac)2]: Purchased from Shanghai Qiming Biotech Co., Ltd.

[0233] K solution: Prepared in DMSO and deionized water to a concentration of 1.5 x 10 -3 Vanadyl acetylacetonate solution of M, wherein the DMSO content is < 5%.

[0234] 13. Preparation of Vanadyl oxalate solution (L solution)

[0235] Vanadyl oxalate [i.e. vanadyl oxalate]: Purchased from Shanghai Run Tai Pharmaceutical Technology Co., Ltd.

[0236] L solution: Prepared in DMSO and deionized water to a concentration of 1.5 x 10 -3 Vanadyl oxalate solution of M, wherein the DMSO content is < 5%.

[0237] 14. Preparation of Bis(picolinato)oxovanadium solution (M solution)

[0238] Bis(picolinato)oxovanadium [i.e. Bis(picolinato)oxovanadium(IV), VO(pic)2 or BPOV]: Purchased from Shanghai Qiming Biotech Co., Ltd.

[0239] M solution: Prepared in DMSO and deionized water to a concentration of 1.5 x 10 -3 Bis(picolinato)oxovanadium solution of M, wherein the DMSO content is < 5%.

[0240] 15. Preparation of a sodium salt solution of a vanadate / ethylene glycol complex (N solution)

[0241] N solution: To 2 ml of A4 solution (concentration: 3.0 x 10 -3 M), add 1 ml of an aqueous ethylene glycol solution (1.8 x 10 -2 M), and then add ion-free water to a total volume of 4 ml.

[0242] 16. Preparation of a sodium salt solution of a vanadate / propylene glycol complex (O solution)

[0243] O solution: To 2 ml of A4 solution (concentration: 3.0 x 10 -3 M), add 1 ml of an aqueous 1,2-propylene glycol solution (1.8 x 10 - 2 M), and then add ion-free water to a total volume of 4 ml.

[0244] 17. Preparation of a sodium salt solution of a vanadate / glycerol complex (P solution)

[0245] P solution: To 2 ml of A4 solution (concentration: 3.0 x 10 -3 M), add 1 ml of an aqueous 1,2-propylene glycol solution (1.8 x 10 - 2 M), and then add ion-free water to a total volume of 4 ml.

[0246] 18. Preparation of a sodium salt solution of a vanadate / lactic acid complex (Q solution)

[0247] To 1 ml of a 0.025 M sodium vanadate solution, add a 0.25 M lactic acid solution dropwise until the solution has a pH of about 7. Add ion-free water to a concentration of 1.5 x 10 -3 M (calculated as vanadium) as a test solution.

[0248] 19. Preparation of a sodium salt solution of a vanadate / glycolic acid complex (R solution)

[0249] To 1 ml of a 0.025 M sodium vanadate solution, add a 0.25 M glycolic acid solution dropwise until the solution has a pH of about 7. Add ion-free water to a concentration of 1.5 x 10 -3 M (calculated as vanadium) as a test solution.

[0250] Example 3 Analgesic experiment with a sodium vanadate solution

[0251] A1 was injected intraperitoneally according to a dose standard of 0.97 mg / kg (calculated as vanadium atomic mass), and the data collected were compared with those of the ASA group and the blank group Figure 1 ).

[0252] Test solution Onset time (min) Duration (min) A1 Between 30 and 45 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0253] The results of the experiment are described as follows: the A1 solution began to affect the pain threshold of the mice between 30-45 minutes after the intraperitoneal injection, and the pain threshold of the mice was elevated and remained above the baseline value 90 minutes after the injection; the S solution began to elevate the pain threshold between 15-30 minutes after the injection, but returned to the baseline value around 60 minutes. During the period when the pain threshold of the A1 solution was elevated, the pain threshold of the A1 group was higher than that of the S group.

[0254] Example 4: Analgesic experiment of sodium orthovanadate solution at different concentrations

[0255] According to the dosage standard of about 0.19 mg / kg and about 0.097 mg / kg (based on the atomic mass of vanadium), two groups of rats were injected intraperitoneally with A2 and A3, respectively, and the collected data were compared with those of the A1 and blank groups. Figure 2

[0256] Test solution Onset time (min) Duration (min) A1 Between 30 and 45 days after injection ＞60 A2 Between 30 and 45 days after injection ＞60 A3 Between 30 and 45 days after injection ＞60 blank invalid none

[0257] The results of the experiment are described as follows: the A1, A2 and A3 solutions all began to elevate the pain threshold of the mice between 30-45 minutes after the injection, and the pain threshold of the mice remained above the baseline value 90 minutes after the injection. However, as the concentration of the drug decreased, the amplitude of the elevated pain threshold decreased, i.e., A3

[0258] From Examples 3 and 4, it can be concluded that the sodium orthovanadate solution has an analgesic effect, and not only can it achieve an analgesic intensity similar to or better than that of ASA at a much lower concentration, but also has a significantly longer duration than ASA. In addition, the examples also show that as the concentration of sodium orthovanadate decreases, the drug effect decreases, i.e., A3

[0259] Example 5: Analgesic experiment of dimethylglycol methoxyoxovanadium solution

[0260] According to the dosage standard of about 1.9 mg / kg (based on the atomic mass of vanadium), the C solution was injected intraperitoneally, and the collected data were compared with those of the ASA and blank groups. Figure 3

[0261] Test solution Onset time (min) Duration (min) C Between 15 and 30 days after injection Approximately 60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0262] ​​The results of the experiment show that the C solution begins to affect the pain threshold of the mice between 15 and 30 minutes after intraperitoneal injection, increasing the pain threshold, and that the pain threshold of the mice returns to the baseline value only after 90 minutes from the injection; the S solution begins to increase the pain threshold between 15 and 30 minutes after the injection, but returns to the baseline value after about 60 minutes. For most of the time after the C solution begins to affect the pain threshold, the threshold of the mice of the C group is comparable to the threshold of the mice of the S group, whose pain threshold is increased by the S solution.

[0263] Therefore, the dimethylglyoxime methoxyoxovanadium solution has analgesic action. It achieves an analgesic intensity similar to that of the ASA solution, but at a much lower concentration, and has a duration (about 60 minutes) that is significantly longer than that of the latter (less than 45 minutes).

[0264] Example 6 Analgesic experiment with sodium metavanadate solution

[0265] The data collected after intraperitoneal injection of the D solution at a dose of about 1.9 mg / kg were compared with those of the ASA and blank groups. Figure 4 ).

[0266]

[0267]

[0268] The results of the experiment show that the D solution begins to affect the pain threshold of the mice between 0 and 15 minutes after intraperitoneal injection, increasing the pain threshold, and that the pain threshold of the mice returns to the baseline value only after 90 minutes from the injection; the S solution begins to increase the pain threshold between 15 and 30 minutes after the injection, but returns to the baseline value after about 60 minutes. For most of the time after the D solution begins to affect the pain threshold, the threshold of the mice of the D group is better than or comparable to the threshold of the mice of the S group, whose pain threshold is increased by the S solution.

[0269] Therefore, the sodium metavanadate solution has analgesic action. It achieves an analgesic intensity similar to that of the ASA solution, but at a much lower concentration, and has a duration (> 60 minutes) that is significantly longer than that of the latter (< 45 minutes).

[0270] Example 7 Analgesic experiment with sodium salt of the sodium vanadate / citric acid complex solution

[0271] The data collected after injection of the B1 solution at a dose of about 0.97 mg / kg (in terms of vanadium atomic mass) were compared with those of the ASA and blank groups. Figure 5 ).

[0272] Test solution Onset time (min) Duration (min) B Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0273] The results of the experiment are described as follows: the B solution began to affect the pain threshold of the mice between 15 and 30 minutes after intraperitoneal injection, causing the pain threshold to increase, and the pain threshold of the mice did not return to the baseline value until 90 minutes after injection; the S solution began to increase the pain threshold between 15 and 30 minutes after injection, but returned to the baseline value at about 60 minutes. During most of the time after the B solution began to increase the pain threshold, the threshold of the mice in the B group was higher than the threshold of the mice in the S group after the pain threshold was increased by the S solution.

[0274] Therefore, the sodium salt solution of the metavanadate / citrate complex has analgesic effect. It can achieve similar analgesic intensity to the ASA solution at a much lower concentration, and the duration (> 60 min) is also significantly longer than that of the latter (< 45 min).

[0275] Example 8 Analgesic experiment of sodium salt solution of metavanadate / citrate complex

[0276] The E solution was injected according to the standard of about 0.97 mg / kg (based on the atomic mass of vanadium), and the collected data were compared with the ASA and blank groups. Figure 6 ).

[0277] Test solution Onset time (min) Duration (min) E Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0278] The results of the experiment are described as follows: the E solution began to affect the pain threshold of the mice between 15 and 30 minutes after intraperitoneal injection, causing the pain threshold to increase, and the pain threshold of the mice did not return to the baseline value until 90 minutes after injection; the S solution began to increase the pain threshold between 15 and 30 minutes after injection, but returned to the baseline value at about 60 minutes. During most of the time after the B solution began to increase the pain threshold, the threshold of the mice in the B group was higher than the threshold of the mice in the S group after the pain threshold was increased by the S solution.

[0279] Therefore, the sodium salt solution of the metavanadate / citrate complex has analgesic effect. It can achieve similar analgesic intensity to the ASA solution at a much lower concentration, and the duration (> 60 min) is also significantly longer than that of the latter (< 45 min).

[0280] Example 9 Analgesic experiment of potassium salt solution of metavanadate / citrate complex

[0281] The F solution was injected according to the standard of about 0.97 mg / kg (based on the atomic mass of vanadium), and the collected data were compared with the ASA and blank groups. Figure 7 ).

[0282] Test solution Onset time (min) Duration (min) F Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0283] Results: The F solution started to affect the pain threshold of the mice between 15 and 30 minutes after the intraperitoneal injection, increasing the pain threshold, and the pain threshold of the mice did not return to the baseline value until 90 minutes after the injection. The S solution started to increase the pain threshold between 15 and 30 minutes after the injection, but returned to the baseline value around 60 minutes. During most of the time in which the F solution started to increase the pain threshold, the threshold of the mice of the F group was higher than the threshold of the mice of the S group, in which the pain threshold was increased by the S solution.

[0284] Therefore, the potassium salt solution of the vanadate / citrate complex has an analgesic effect. It not only reaches an analgesic intensity similar to that of the ASA solution at a much lower concentration than the latter, but also has a duration (> 60 minutes) much longer than that of the latter (< 45 minutes).

[0285] Explanation: Environmental factors, differences between mice, and differences in the test can have some influence on the absolute values of the analgesic intensity and duration, but, relative to the ASA control group, the A, B, C, D, E, and F groups show a stable trend: a) the effective concentration (i.e., the concentration at which the analgesic effect is produced) is much lower than that of ASA; b) the analgesic intensity is similar to or higher than that of ASA; and b) the effective time is longer than that of ASA.

[0286] Example 10: Analgesic experiment with vanadyl sulfate

[0287] The G1 solution was injected intravenously according to a standard of about 0.49 mg / kg (in terms of the atomic mass of vanadium), and the data collected were compared with those of the ASA and blank groups.

[0288] Test solution Onset time (min) Duration (min) G1 Between 0-15 days after injection ＞60 S Between 0-15 days after injection ＜45 blank invalid none

[0289] Example 11: Analgesic experiment with vanadyl maltol

[0290] The H1 solution was injected intraperitoneally according to a standard of about 0.97 mg / kg (in terms of the atomic mass of vanadium), and the data collected were compared with those of the ASA and blank groups.

[0291] Test solution Onset time (min) Duration (min) H1 Between 0-15 days after injection ＞60 S Between 0-15 days after injection ＜45 blank invalid none

[0292] Example 11: Analgesic experiment with vanadyl maltol

[0293] The I solution was injected intraperitoneally according to a standard of about 0.97 mg / kg (in terms of the atomic mass of vanadium), and the data collected were compared with those of the ASA and blank groups.

[0294] Test solution Onset time (min) Duration (min) I Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0295] Example 12: Analgesic experiment with vanadyl kojic acid

[0296] The data collected were compared with the ASA and blank groups after intraperitoneal injection of J solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0297] Test solution Onset time (min) Duration (min) J Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0298] Example 13: Analgesic experiment of vanadyl acetylacetonate

[0299] The data collected were compared with the ASA and blank groups after intraperitoneal injection of K solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0300] Test solution Onset time (min) Duration (min) K Between 15 and 30 days after injection ＞60 S Between 0-15 days after injection ＜45 blank invalid none

[0301] Example 14: Analgesic experiment of vanadyl oxalate

[0302] The data collected were compared with the ASA and blank groups after intraperitoneal injection of L solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0303] Test solution Onset time (min) Duration (min) L Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0304] Example 15: Analgesic experiment of vanadyl picolinate

[0305] The data collected were compared with the ASA and blank groups after intraperitoneal injection of M solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0306] Test solution Onset time (min) Duration (min) M Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0307] Example 16: Analgesic experiment of sodium salt solution of orthovanadate / ethylene glycol complex

[0308] The data collected were compared with the ASA and blank groups after intraperitoneal injection of N solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0309] Test solution Onset time (min) Duration (min) N Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0310] Example 17: Analgesic experiment of sodium salt solution of orthovanadate / propanediol complex

[0311] The data collected were compared with the ASA and blank groups after intraperitoneal injection of O solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0312] Test solution Onset time (min) Duration (min) 0 Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0313] Example 18: Analgesic experiment of sodium salt solution of orthovanadate / glycerol complex

[0314] The data collected were compared with the ASA and blank groups after intraperitoneal injection of the P solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0315] Test solution Onset time (min) Duration (min) P Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0316] Example 19: Analgesic experiment of sodium salt solution of orthovanadate / lactate complex

[0317] The data collected were compared with the ASA and blank groups after intraperitoneal injection of the Q solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0318] Test solution Onset time (min) Duration (min) Q Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0319] Example 20: Analgesic experiment of sodium salt solution of orthovanadate / glycolate complex

[0320] The data collected were compared with the ASA and blank groups after intraperitoneal injection of the R solution according to the standard of about 0.97 mg / kg (in terms of vanadium atomic mass).

[0321] Test solution Onset time (min) Duration (min) R Between 15 and 30 days after injection ＞60 S Between 15 and 30 days after injection ＜45 blank invalid none

[0322] Example 21: Onset concentration and plateau experiment of vanadium compounds:

[0323] Since various vanadium (IV) or vanadium (V) compounds have analgesic effects, such as inorganic salts and vanadium complexes containing organic ligands, it can be judged that the possibility of drug ligands participating in the inhibition of pain is very low, and their role is only to act as carriers of vanadium elements: vanadium compounds are dissociated before entering the body and reaching the analgesic target (possibly more than one), that is, the vanadium element is dissociated from the original ligand, and instead of the ingested vanadium element, it is re-complexed with natural ligands in the body (such as blood), especially inorganic ligands such as chloride, phosphate or hydrogen phosphate ions and organic ligands containing O-, N-, S- donors, and then the next step of analgesic response. In addition, tetravalent vanadium or pentavalent vanadium compounds will quickly produce a new balance through redox reactions under physiological conditions. Based on this consideration, intravenous injection of inorganic salts of vanadium (VOSO4 and Na3VO4) not only allows the vanadium element to directly enter the blood, but also allows it to quickly bind to natural ligands in the body to form the effective form required for analgesia. Compared with vanadium compounds containing organic ligands (especially tightly bound organic vanadium complexes), VOSO4 and Na3VO4 are equivalent to donors of "naked" vanadium elements (hereinafter referred to as "naked vanadium", the former provides tetravalent vanadium, such as VO 2+ , and the latter provides pentavalent vanadium, such as VO4 3- , HVO4 2- , H2VO4 - , or VO 3+), omitting the step of dissociating from its own ligand, and avoiding the risk of being expelled from the body because of not being complexed with the natural ligand.

[0324] The "naked vanadium" is most closely related to the actual active analgesic substance. By administering different dosages of the "naked vanadium" donors VOSO4 or Na3VO4, the inventors found the minimum blood concentration of tetravalent and pentavalent vanadium to take effect on mice. First, the minimum dosage to take effect was found, i.e. about 1.0 x 10 -3 mg / kg (see "Table of effective concentration data"). The blood vanadium concentration of mice was calculated therefrom, the calculation method being as follows:

[0325] Taking the average blood volume of mice as 2 ml / 30 g, the blood concentration after tail vein injection of 1.0 x 10 -3 mg / kg dosage was (1.0 x 10 -6 mg / g x 30 g) / (51 x 2) = 2.9 x 10 -7 M (or 0.29 μM).

[0326] Therefore, the minimum blood concentration of vanadium compounds to produce analgesic effect on mice is about 0.29 μM. If the conversion relationship of 1:9.3 of human and experimental animal drug dosage can be obtained: the minimum blood concentration of vanadium compounds to produce analgesic effect on human body is 0.031 μM.

[0327] The inventors also found that as the dosage of vanadium increases, the analgesic intensity and analgesic duration also increase. But when the blood concentration of vanadium reaches a certain value, the analgesic effect reaches a plateau, i.e. the analgesic intensity no longer increases or even decreases and / or the analgesic duration no longer extends (or has no regularity).

[0328] Tail vein injection of VOSO4 or Na3VO4 solution, the dosage to reach the plateau is ≥0.49 mg / kg (see "Table of plateau experiment data"), and the blood concentration is 140 μM. If the conversion relationship of 1:9.3 of human and experimental animal drug dosage can be obtained: when the vanadium concentration reaches 15 μM in the human body, the analgesic plateau appears.

[0329] It can be predicted that the minimum effective dosage of other vanadium compounds and the dosage to reach the plateau are related to the tightness of the complex between vanadium / ligand. For example, the dosage of BMOV to reach the plateau is about ≥0.97 mg / kg.

[0330] Table of plateau experiment data:

[0331]

[0332] Table of effective concentration data

[0333]

Claims

1. Use of a pentavalent vanadium compound having a vanadium-oxygen bond for the manufacture of a medicament for the treatment of pain, wherein the pentavalent vanadium compound is used in an amount of 0.0001 mg / kg body weight to 5 mg / kg body weight based on the mass of vanadium, the medicament is in the form of an injection solution, and the pentavalent vanadium compound is a compound of pentavalent vanadium with a polycarboxylic acid or an organic ligand.

2. The use according to claim 1, wherein the ligand is selected from the group consisting of maltol, ethyl maltol, kojic acid, citric acid, glycolic acid, lactic acid, tartaric acid.

3. The use according to claim 1, wherein the compound is formed of pentavalent vanadium with citric acid.

4. The use according to claim 1, wherein the compound formed with an organic ligand is dimaltol methoxyoxovanadium.

5. The use according to any one of claims 1 to 4, wherein the compound is administered by intravenous injection or subcutaneous injection.

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