Methods for Treating Pain with Vanadium Compounds

Abstract

The present invention provides an analgesic ingredient which is a +4- or +5-valent vanadium compound selected from inorganic vanadium compounds or organic vanadium compounds, the organic vanadium compound being selected from vanadium complexes or chelates, or the present invention provides use of the +4- or +5-valent vanadium compound in the manufacture of an analgesic drug.

Description

[Technical field]

[0001] The present invention relates to methods and pharmaceutical compositions for treating pain, particularly acute pain, chronic pain, inflammatory pain, cancer pain and pain due to cancer treatment, visceral pain, neuropathic pain, diabetic neuropathy, post-herpetic pain, migraine, fibromyalgia, and trigeminal neuralgia. [Background technology]

[0002] Pain is an unpleasant subjective sensation and emotional experience associated with tissue damage or potential tissue damage. Pain affects the normal life of individuals, families and communities. Statistics show that 37.3% of adults in developed countries and 41.1% of adults in developing countries suffer from chronic pain (Tsang, A., Von Korff, M., Lee, S., Alonso, J., Karam, E., Angermeyer, MC, 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 can lead to 1) limitations in behavior 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) perceptions of poor health and reduced quality of life (A and B). Pain affects approximately 50 million adults in the United States.Of these, 20 million people are so severely affected that they are unable to work or function 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 mechanism of pain generation is extremely complex and, although it can be demonstrated by electrophysiological methods, it is actually a subjective sensation. The intensity and characteristics of pain are related to internal and external factors, and even the same stimulus can be experienced differently depending on the environment, physical and psychological state.

[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 is associated with skeletal muscle spasms and activation of the sympathetic nervous system, is caused by certain diseases and disorders, has a biologically useful purpose, and is self-suppressed. When causing persistent injury, the peripheral and central nervous systems (which are the components of the pain transmission pathway) show great plasticity, during which pain signals are intensified and anaphylaxis also occurs. This is beneficial when plasticity favors defense against reflexes, but if the changes persist, it can cause chronic pain. On the other hand, chronic pain is considered a disease state. When it is related to disease or physical injury, pain can occur beyond the normal healing time. Chronic pain can arise from a psychological state, in which case there is no biological cause and no clear end point. Persistent pain associated with wounds or diseases (diabetes, arthritis or tumor growth) is caused by changes in the surrounding nerves, which may occur through damage to nerve fibers, leading to increased self-generation and altered transmission / neurotransmission properties. Indeed, the fact that systematic application of local anesthetics is useful in treating various neuralgias (e.g. postherpetic neuralgia) may reflect the action of these anesthetics on sodium channels that accumulate in damaged nerve fibers.

[0005] As knowledge and research on pain expanded, many analgesics emerged. These drugs can be classified into the following categories: 1) non-steroidal anti-inflammatory drugs, such as aspirin, ibuprofen, naproxen, ketoprofen, diclofenac, and COX-2 inhibitors (e.g., rofecoxib and valdecoxib); 2) opiate analgesics, such as morphine, oxycodone, buprenorphine, and fentanyl; 3) analgesics and antipyretics, such as acetaminophen; antidepressants, such as nortriptyline and desipramine; 4) anticonvulsants, such as carbamazepine and gabapentin; 5) antipsychotics, such as olanzapine and quetiapine; 6) serotonin receptor agonists, such as sumatriptan, ergotamine and lasmiditan; 7) calcitonin gene-related peptides (CGRP), such as erenumab and fremanezumab; 8) other analgesics, such as ziconotide.

[0006] Most nonsteroidal anti-inflammatory drugs and opioid analgesics are broad-spectrum analgesics, that is, drugs that can be used for various pain indications, and all other types of analgesics have obvious limitations. Meanwhile, for each individual analgesic drug, each drug has obvious deficiencies in one or more aspects, such as efficacy, drug resistance, and side effects. For example, nonsteroidal anti-inflammatory drugs are only effective for mild and moderate pain, and the most commonly used aspirin and ibuprofen both have serious side effects on the gastrointestinal tract. Opioid drugs have drug resistance problems and may cause side effects such as constipation, respiratory depression, and addiction. Therefore, it is necessary to find better analgesics.

[0007] Vanadium belongs to group VB of the periodic table and is an essential trace element for the human body. Vanadium can exist in nature in multiple valences, with its valence states in the body being +3, +4, and +5. +3 vanadium is present in the cells of a few lower marine organisms. 3+ It exists as an ion (Crans DC, Mahroof-Tahir M, Keramidas AD. Mol Cell Biochem, 1995, 153:17-24), but under physiological conditions in animals it exists primarily in the +4 and +5 valence forms.

[0008] The medicinal value of vanadium compounds has been discovered for many years. For example, studies have revealed that vanadium compounds have the activity of inhibiting protein tyrosine phosphatase 1B (PTB1B), inducing Hsp60-PPARγ protein interaction, eliminating insulin resistance in tissues, improving the level of adiponectin, and activating PPARα. Therefore, vanadium compounds have the ability to increase the energy metabolism level of cells and improve glucose / lipid metabolism, and are expected to be therapeutic agents for diabetes and anti-Alzheimer's disease (AD). Vanadium compounds also have antiproliferative activity and have potential applications in antitumor and anticancer. Research has also shown that vanadium compounds have antiparasitic, antibacterial and antiviral properties (1. Rehder, D. Perspectives for vanadium in health issues. Future Med. Chem. xxx; 2. References in US6,232,340 B; 3. Dong Yaqiong, Niu Xia, Xiao Ruyue, Zhang Yue, Xia Qing, Yang Xiaoda. Pharmacological effects and rational drugs of vanadium complexes. Design of Chinese science: Chemistry, 2017, 47(2), 162-171).

[0009] In their patents (CN102309507A and CN102309509A), Lei et al. proposed the use of a mixture of inorganic salts of small amounts of +5-valent vanadium and +3- and / or +4-valent vanadium for pain relief. However, the use of a highly acidic solution for the footbath caused significant side effects and very poor patient compliance.

[0010] In addition, while investigating the mechanism of action of spinal protein tyrosine phosphatases (PTPs) in inflammatory pain, Li et al. injected sodium orthovanadate, a type of phosphatase inhibitor, intrathecally in mice with pain induced by inflammation, and observed an analgesic effect, proposing a relationship between the activity of spinal protein tyrosine phosphatases and inflammatory pain. This study does not lead to research on vanadium compounds as an analgesic, but rather makes it seem unlikely that they will be used as an analgesic administered by any method other than intrathecal injection. Phosphatases are widely present in the human body, such as in blood, cell tissue, and bone, and when vanadium compounds are administered orally, by blood injection, subcutaneous injection, transdermal administration, etc., vanadium ions must bind to phosphatases in the "pathway" (e.g., in the blood) before reaching the spinal cord. In this case, two problems arise. a) Can vanadium ions be transported to the spinal cord and bind to phosphatases among them? b) After binding with so many phosphatases in the "pathway", the final physiological response is analgesia. For this reason, not only have there been no reports from Li et al.'s scientific research group on the analgesic use of vanadium compounds, but there have also been no reports from other scientific research groups on the analgesic use of vanadium compounds.

[0011] In clinical studies using vanadium metal-containing compounds to treat diseases such as diabetes, the therapeutic doses of such compounds have serious side effects, and ultimately fail to be medicinal. The inventors unexpectedly discovered that vanadium metal-containing compounds can effectively treat pain at lower doses, and that when the dose is increased to a certain level, the therapeutic level of pain reaches a plateau, and therefore pain can be treated at a certain dose of vanadium compounds and the side effects of vanadium compounds can be avoided. This led to the completion of the present invention. Summary of the Invention

[0012] The present invention provides a method for treating pain using a compound containing +4-valent vanadium or a compound containing +5-valent vanadium. Specifically, the present invention provides a method for administering a therapeutically effective amount of a compound containing +4-valent vanadium or a compound containing +5-valent vanadium to a patient suffering from pain, in which the amount of the compound containing +4-valent vanadium or the compound containing +5-valent vanadium used is 0.00001 mg / kg body weight to 300 mg / kg body weight, preferably 0.0001 mg / kg body weight to 50 mg / kg body weight, more preferably 0.001 mg / kg body weight to 5 mg / kg body weight per day in terms of vanadium mass.

[0013] The vanadium compound of the present invention may be an inorganic vanadium compound or an organic vanadium compound. According to the present inventors, a compound containing vanadium, whether it is an organic compound or an inorganic compound, and whether the valence of the vanadium contained therein is tetravalent or pentavalent, can produce an analgesic effect as long as it is absorbed by a mammal (or human body), and the difference in the valence or ligand affects the onset time, analgesic strength and duration. Under physiological conditions of the human body, vanadium mainly exists in the tetravalent or pentavalent form and mainly exists in the form of oxygen-containing vanadium, so that the active substance that exerts an analgesic effect in the body is V. IV O and V V Specifically, the vanadium compound of the present invention is a) a material containing +5 valent vanadium ("5 valent vanadium", "+5 valent vanadium", "V V ", "V 5+ ", "vanadium(V)", or "V(V)") forms chemical bonds with other atoms (or ions), i.e., ionic bonds and / or secondary covalent bonds, and b) +4-valent vanadium ("4-valent vanadium", "+4-valent vanadium", "V IV ", "V 4+", "vanadium(IV)", or "V(IV)" includes +4-valent vanadium compounds in which vanadium (IV) forms a secondary bond with another atom (or ion), i.e., an ionic bond and / or a covalent bond. Here, the secondary bond includes a dipole-dipole interaction, a London dispersion interaction, a hydrogen bond, and the like.

[0014] The vanadium(V) or vanadium(IV) compound preferably contains 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 is a vanadium compound containing two or more of these bonds. The vanadium compound is often present in the form of a complex, which is characterized as follows: a) the ligand may be an inorganic ligand or an organic ligand; b) the ligand may be a neutral molecule, a negatively charged ion, or a positively charged ion; c) the ligand may be monodentate (containing one donor) or polydentate (containing two or more donors, generally including O-, N-, S-, or C-donors); d) the complex may 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) compounds may be covalent compounds containing only covalent bonds (including coordinate bonds) or may be salt-based compounds containing only ionic bonds or both ionic and covalent bonds. The moieties containing vanadium(V) or vanadium(IV) may be present in the anion or cation of the salt. f) The vanadium(V) or vanadium(IV) compounds may exist in mononuclear or polynuclear polymeric forms, where "nucleus" refers to the center containing vanadium(V) or vanadium(IV). g) The vanadium(V) or vanadium(IV) compounds are often accompanied in the solid state by a crystalline solvent such as water, methanol, ethanol, isopropyl alcohol, pyridine, DMSO, etc.

[0015] In general, the coordination number (CN) of vanadium coordination compounds is 4 to 8, and the geometric shapes formed by the coordination are tetrahedron, square plane, trigonal bipyramid, square pyramid, octahedron, trigonal prism, pentagonal bipyramid, capped octahedron, capped trigonal prism, square antiprism, and dodecahedron. The coordination number and geometric shapes of vanadium compounds actually formed may deviate from the above induction.

[0016] The vanadium(V) or vanadium(IV) compounds may be in different forms in the solid state or in solution, and the structural features described herein may be contained or partially contained in the solid state or in solution.

[0017] More preferred vanadium compounds are vanadium(V) or vanadium(IV) compounds that contain a vanadium-oxygen bond, including, but not limited to, the following various compounds:

[0018] I. Oxides of vanadium(V), including but not limited to V2O5 and its hydrates (e.g., V2O5·H2O, V2O5·2H2O, V2O5·8H2O, etc.); Oxides of vanadium(IV), including but not limited to VO2, V2O4 and their hydrates.

[0019] II. Orthovanadic acid (H3VO4), metavanadic acid (HVO3), polyvanadic acid (e.g., H4V2O7, H4V4O 12 , H5V5O 15 , H6V 10 O 28 , H3V3O9, H4V4O 12vanadate(V) acids, including but not limited to, vanadium heteropolyacids (e.g., vanadium-phosphorus heteropolyacid, PPV, PVP, vanadium-arsenic heteropolyacid, etc.); vanadate(IV) acids, including but not limited to, H4VO4, H6VO5, H2VO3, polyacids (e.g., H2V2O5), heteropolyacids (e.g., vanadium-phosphorus heteropolyacid (e.g., H2[VO(P2O7)]), vanadium-arsenic heteropolyacid, vanadium-molybdenum heteropolyacid, etc.);

[0020] III. Salts formed by various vanadate anions with inorganic or organic cations Here, the vanadate(V) anion is the orthovanadate anion (i.e., VO4 3- and its protonated forms VO4H2-, VO4H 2- ), metavanadate radical (i.e., VO3 - ), polyvanadate radicals (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), heteropoly acid radicals (e.g., phosphorus-vanadium heteropoly acid radicals JPEG0007672493000001.jpg23170). The vanadate(IV) anion is, for example, VO4 4- (and its protonated form H n VO4 4-n , n = 1-3), VO5 6- (and its protonated form H n VO4 6-n , n = 1-5), VO3 2- (and its protonated form HVO3-), V2O5 2- (and its protonated form HV2O5 - ), V4O9 2-(and its protonated form HV4O9-), heteropolyacid radicals (e.g., VO(P2O7) 2- , MO3V3O 19 8- etc.). Here, the inorganic or organic cation is a quaternary ammonium ion, i.e., R1R2R3R4N + (R1, R2, R3, and R4 may be H or a lower alkane, or at least one pair of these may be linked (through an atom between them) to form a substituted or unsubstituted nitrogen-containing heterocycle, for example, R1R2R3R4N + is NH4 + or ammonium root, PyH + or pyridine hydrogen, N-alkylpyridine cation, etc.);Na + , K + , Li + , Rb + Alkaline metal cations such as Mg 2+ , Ca 2+ , B.E. 2+ , Sr 2+ , B.A. 2+ Ions such as; metal cations in IIIA, IVA, VA and VIA; e.g., Fe 2+ , Fe 3+ , Cu 2+ , Zn 2+ , Ti 2+ , Ti 3+ , Ti 4+ , Ni 2+ , Ni 3+ , Cr 2+ , Cr 3+ , Cr 6+ These include, but are not limited to, transition metal element cations such as: Specific examples of vanadium(V) salts include NH4VO3, Ca(VO3)2·4H2O, K2Ca(VO3)4·7H2O, Rb4Ca4(V2O7)3·17H2O, Na3VO4, KCaVO4·6H2O, Na4V2O7, and K3V5O. 14 , Ca3V 10 O 28 , BiVO4, FeVO4, etc. Specific examples of vanadium(IV) salts include, for example, MI 4VO4, M II 3VO5, M II 2VO4, M I 2VO3, M I 2V2O5, K2V3O7 2.66H2O, where M I is a metal ion with a valence of +1, and M II is a metal ion with a valence of +2.

[0021] IV. Oxygen-containing vanadium compounds in which vanadium is complexed with monodentate or polydentate ligands, including but not limited to the following: a) Oxygen-containing vanadium compounds formed by complexing vanadium with monodentate ligands The monomeric ligand is F - , Cl - , Br - , I - , NO, H2O, CN - , NO2 - , SCN - , N.C.S. - , NH3, N3 - , O.H. - , CO, HCO3 - , H2PO4 - , HSO4 - , HSO3 - , ClO4 - , NO3 - , SO3F - , H.C.O.O. - , mercaptohydrogen-based compounds (e.g., SH-), phosphate-based compounds (e.g., dipolyphosphate), and monodentate organic ligands containing O-, S-, or N-donors (organic monodentate O-, S-, or N-donor ligands), including, but not limited to, alcohols, phenols, amines, carboxylic acids, and organic phosphate compounds. Specifically, vanadium (V) compounds include, for example, 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, JPEG0007672493000002.jpg24170, where M is Li, Na, K, Rb, Cs; Hal=F, Cl, Br, I; and R, R1, R2=H, an alkane, an aromatic hydrocarbon, or other organic group. Specifically, vanadium (IV) compounds include, for example, VOSO4, 3VO2(2SO2), M I 2[VO(SO3)2], M II [VO(SO3)2], VOHal2, VO(HalO4)2 (e.g. VO(ClO4)2·5H2O), M I 2[VOHal4] or M I 3[VOHal5] {e.g. 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 metal ion with a valence of +1, and M II is a metal ion with a valence of +2. b) Oxygen-containing vanadium compounds formed by complexing vanadium with polydentate ligands The multidentate ligand is CO3 2- , O 2- , C2O4 2- , SO4 2- , SO3 2- , PO4 3- , HPO4 2- , inorganic ligands such as triphosphate, and multidentate organic ligands containing O-, N-, or S-donors. For example, glycols (e.g., ethylene glycol, sugar compounds, nucleoside compounds), glycerin, hydroxycarboxylic acids (e.g., α-hydroxycarboxylic acids such as lactic acid, citric acid, tartaric acid, etc.), salicylic acid compounds, diacids (e.g., oxalic acid, malonic acid, succinic acid, etc.), oximic acids (or hydroxamic acids), acids), HONHCOR, where R is an organic group; sulfur-containing ligand compounds (e.g., β-mercaptoethanol, dithiozotol, bis(2-mercaptoethyl)ether, tris(2-mercaptoethyl)amine, cysteine, glutathione, oxidized glutathione, disulfides, and related compounds or derivatives thereof); amino alcohols and related ligand compounds (e.g., ethanolamine, ethylenediamine, amino acids and derivatives thereof, 2-aminoethanethiol, diethanolamine and derivatives thereof, ethylene-N,N'-diacetic acid (EDDA) and analogs thereof, pyridine carboxylic acids, hydroxypyridines, amides, and dipeptide and polypeptide compounds. Specifically, vanadium(V) compounds include, for example, V2O3(SO4)2·2H2O, VOPO4·2H2O, M[VO2(SO4)], K2[VO2(C2O4)2], M3[VO2(C2O4)2]; JPEG0007672493000003.jpg23170 Glycol-based ligand complexes containing moieties; JPEG0007672493000004.jpg24170 amino alcohol ligand complexes containing the moiety, JPEG0007672493000005.jpg24170 Hydroxycarboxylic acid-based ligand complexes containing the moiety, JPEG0007672493000006.jpg23170 amino acid-based ligand complexes containing the moiety, JPEG0007672493000007.jpg26170 3-hydroxy-4H-pyran-4-one based ligand complexes containing the moiety, JPEG0007672493000008.jpg15170 Oxime acid ligand complexes containing moieties, JPEG0007672493000009.jpg23170 Diacid-based ligand complexes containing moieties, JPEG0007672493000010.jpg27170 sulfur-containing ligand complexes containing the moiety, JPEG0007672493000011.jpg32170 moiety, wherein V = V(V), M = Li, Na, K, Rb, Cs, R1, R2, R3, R4 or R5 is H or other group, and R is -(CH2) n It may be a - group (n=0 to 4), a -CR1R2- group, or other groups such as homoaromatic hydrocarbons and heterocycles. Specifically, vanadium(IV) compounds include, for example, V(SO4)2, VOSO4, M II 2[VO(SO4)3], M I 2[(VO)2(SO4)3], VO3(PO4)2, M II [VO(PO4)]2 {e.g., Ba[VO(PO4)]2·4H2O}; JPEG0007672493000012.jpg23170 Glycol-based ligand complexes containing moieties; JPEG0007672493000013.jpg27170 amino alcohol ligand complexes containing the moiety, JPEG0007672493000014.jpg25170 Hydroxycarboxylic acid-based ligand complexes containing the moiety, JPEG0007672493000015.jpg23170 amino acid-based ligand complexes containing the moiety, JPEG0007672493000016.jpg26170 3-hydroxy-4H-pyran-4-one based ligand complexes containing the moiety, JPEG0007672493000017.jpg17170 moiety-containing oxime acid-based ligand complexes; JPEG0007672493000018.jpg23170 Diacid-ligand complexes containing moieties, JPEG0007672493000019.jpg25170 sulfur-containing ligand complexes containing moieties; JPEG0007672493000020.jpg27170 is an α-pyridine carboxylic acid-based ligand complex containing the moiety, provided that M I is a metal ion with a valence of +1, and M II is a +2 valent metal ion, where V=V(IV), R1, R2, R3, R4 or R5 is H or another group, and R is -(CH2) n It may be a - group (n=0 to 4), a -CR1R2- group, or other groups such as homoaromatic hydrocarbons and heterocycles. Multidentate complexes are characterized by containing VO, VN, and / or VS bonds, and vanadium often forms five-, six-, etc. membered ring structures with the ligands.

[0022] V. Peroxo vanadates Compounds containing V(O2), such as: a) H2VO3(O2) - , HVO3(O2) 2- , VO2(O2)2 3- , HVO2(O2)2 2- , H2VO2(O2)2 - , HV(O2)3 2- Peroxovanadate anions such as H2VO3(O2)- JPEG0007672493000021.jpg22170, HVO2(O2)2 2- The structure of JPEG0007672493000022.jpg21170, HV(O2)3 2- The structure of JPEG0007672493000023.jpg22170) in combination with a cation as described in III to form a salt, and b) compounds containing V(O2) and complexed with a monodentate or polydentate ligand as described in IV. Specific compounds include KH2[VO2(O2)2]·H2O and (NH4)2H[VO2(O2)2]·H2O.

[0023] VI. Hydroxamido vanadates, i.e., compounds containing V(ONR1R2), where R1 and R2 are H or organic groups, and VO2(ONR1R2)2 - Hydroxamidovanadate anions, such as, but not limited to, the structure JPEG0007672493000024.jpg22170, which combines with a cation as described in III to form a salt. b) Compounds containing V(ONR1R2)2, complexed with a monodentate or polydentate ligand as described in IV, where R1, R2 are H or other groups. Vanadium compounds can exist in mononuclear, dinuclear and multinuclear forms. Vanadium compounds complexed with a single ligand have the general formula V a L b where V represents a vanadium nucleus (or vanadium center), L represents a ligand, and a and b represent numbers, and the stoichiometric ratio of vanadium to ligand may 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, where a or b is an integer or decimal number from 0 to 100. Vanadium compounds in which two or more ligands are complexed can be represented by the general formula V a L b ···L n-1 b(n-1) where b(n-1) is L n where a or b(n-1) is an integer or decimal number between 0 and 100. For example, when n=1 (i.e., one type of ligand), the general formula is V a L b and when n=2 (i.e., two types of ligands), the general formula is V a L b L 1 b1 (i.e., L and L 1 The number of ligands is b and b1, respectively. When n=3 (i.e., three types of ligands), the general formula is V a L b L 1 b1 L2 b2 (i.e., L, L 1 , L 2 (The number of these ligands is b, b1, and b2, respectively.) By analogy, the vanadium compound may also contain different numbers of solvent molecules, such as H2O, methanol, ethanol, isopropyl alcohol, pyridine, DMSO, etc., in the solid state.

[0024] Further preferred compounds include lithium orthovanadate, sodium orthovanadate, potassium orthovanadate, lithium polyvanadate, sodium polyvanadate, potassium polyvanadate, lithium metavanadate, sodium metavanadate, potassium metavanadate, and quaternary ammonium metavanadates (i.e., R1R2R3R4N + In VO3, R1, R2, R3, and R4 may be H, other groups, or lower alkanes, or at least one pair of these may be linked (by an atom between them) to form a substituted or unsubstituted nitrogen-containing heterocycle, for example, R1R2R3R4N + is NH4 + or ammonium root, PyH + or pyridine hydrogen, N-alkylpyridine cations. For example, ammonium metavanadate), vanadyl sulfate (VOSO4, or VOSO4·nH2O, n=1-20), vanadium oxide dichloride, and their compounds containing solvents for crystallization (e.g., water, methanol, ethanol, isopropanol, DMSO, pyridine, DMF, etc.).

[0025] Further preferred vanadium(V) or vanadium(IV) compounds include complexes formed by vanadium(V) or vanadium(IV) with the following ligand substances: a) hydroxycarboxylic acid compounds (including hydroxycarboxylic acids and hydroxycarboxylates), such as glycolic acid or glycolate, lactic acid or lactate, tartaric acid or tartrate, 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) monocarboxylic acid, dicarboxylic acid or polycarboxylic acid (mono-, di- or polycarboxylic acid, or carboxylate) compounds, such as formic acid or format, 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; bacates, succinates or succinates, phthalates or phthalates, etc.; c) mono-, di- or polyhydroxyl compounds, for example monoalcohols such as methanol, ethanol, isopropanol, geraniol, menthol, retinol, o-diol or m-diol containing compounds (e.g. ethylene glycol, 1,2-dihydroxypropane, 1,2-dihydroxypropane, 1,2-dihydroxycyclopentane, 1,2-dihydroxycyclohexane), glycerol, monosaccharides, disaccharides, 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) phenols, diphenols or polyphenols, for example phenol, catechol or pyrocatechol, polyhydroxy aromatic 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), GSMe (Me=methyl), GSSG, D-aspartic acid, β-alanyl-L-histidine (carnosine), collagen, serum proteins; amino acids (e.g. glycine, alanine, glutamic acid, etc.) and the Schiff bases they form with salicylaldehyde or pyridoxal; e) diamines and the Schiff bases they form, such as diamines such as ethylenediamine, propylenediamine or phenylenediamine and the Schiff bases they form with salicylaldehyde or pyridoxal; f) β-diketones, such as acetylacetone, dibenzoylmethane, benzoylacetone, furoyltrifluoroacetone, etc. and the Schiff bases they form with amine compounds; g) hydroxy hydroxypyrones and hydroxypyridinones, such as maltol (3-hydroxy-2-methyl-4-pyrone), kojic acid or 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, diphosphatidylglycerol and sphingomyelin; i) hydroxylamine compounds, such as N-hydroxylamine, N,N-dialkylhydroxylamine, 2-hydroxylamine, 3-hydroxylamine, etc.; j) urea or biguanides; k) compounds represented by the following formula I or II: JPEG0007672493000025.jpg22170 General formula I (X 1 and X 3 is O, S or NX 6 and preferably O or NX 6 and X2 is N or CX 7 and X 4 , X 5 , X 6 , and X 7 is an inert H (non-labile proton), or any substituted alkyl, aromatic, aralkyl, or alkaryl group, or X 4 From X 7 At least one pair of X is linked (by an atom), preferably 4 and X 5 or any substituted, saturated or unsaturated homocyclic (or carbocyclic) or heterocyclic ring formed by 1 is one NX 6 represents a group, and X 4 There is one X 8 H group, where X 5 is O or S, and X 1 Or X 8 One of the protons connected to X is active (preferably X 1 The proton connected to is active.) JPEG0007672493000026.jpg36170 General formula II Another class of preferred ligand compounds may be represented by the general formula II, where A and B are 5-, 6- or 7-membered rings containing 0, 1 or 2 heteroatoms (selected from O, S, N) on the ring, and X 4 , oxygen (oxo), sulfur (thio) or NX 4 is arbitrarily replaced by (X 4 is defined above). Ring A and ring B are preferably 1,2-phenylene, an oxazolin-2-yl group or a thiazolin-2-yl group as shown below. JPEG0007672493000027.jpg23170 (where X 4 is H or optionally substituted hydroxy C 1-4 is an alkyl group.

[0026] Preferred ligand compounds satisfying the general formulas I and II below include: Hydroxamates (general formulas III and IV) JPEG0007672493000028.jpg28170 General formula III JPEG0007672493000029.jpg39170 General formula IV α-Hydroxypyridinones (general formula V) JPEG0007672493000030.jpg34170 General formula V α-Hydroxypyrones (general formula VI) JPEG0007672493000031.jpg28170 General formula VI α-Amino acids (general formula VII) JPEG0007672493000032.jpg23170 General formula VII α-Hydroxycarboxylic acids (general formula VIII) JPEG0007672493000033.jpg28170 General formula VIII α-Hydroxycarbonyl compounds (general formulas IX and X) JPEG0007672493000034.jpg31170 General formula IX JPEG0007672493000035.jpg21170 General formula X Thiohydroxamates (general formulas XI and XII) JPEG0007672493000036.jpg18170 General formula XI JPEG0007672493000037.jpg17170 General formula XII 2-Oxazolin-2-yl-phenols and 2-thiazolin-2-yl-phenols (general formulas XIII and XIV) JPEG0007672493000038.jpg30170 General formula XIII JPEG0007672493000039.jpg32170 General formula XIV Here, R1 ~R 29 is H or any organic group, such as any hydroxy C 1-4 It is an alkane.

[0027] Further preferred ligands are: JPEG0007672493000040.jpg33170maltol JPEG0007672493000041.jpg29170 Ethylmaltol JPEG0007672493000042.jpg29170 Kojic acid JPEG0007672493000043.jpg34170 Citric aid JPEG0007672493000044.jpg22170 Glycolic acid JPEG0007672493000045.jpg18170 Lactic acid (L-, D- or mixture) JPEG0007672493000046.jpg35170 Tartaric acid (L-, D- or mixture)

[0028] The complexes of vanadium(V) and vanadium(IV) with the above-mentioned ligands can be synthesized by known methods (see US Pat. No. 5,620,967,4 / 1997, McNeill et al.). In particular, the present invention is directed to bis(maltolato)oxovanadium(IV) (BMOV), bis(ethylmaltolato)oxovanadium(IV) (BEOV), vanadyl kojate, vanadyl sulfate, sodium orthovanadate, potassium orthovanadate, sodium metavanadate, potassium metavanadate, and vanadium compounds prepared with citric acid, tartaric acid, lactic acid, glycolic acid, ethylene glycol, glycerin or triethanolamine (tri(2-hydroxyethyl)amine) in a molar ratio of 1:0.5 to 1:10, and the citrate complex K[VO2(C6H6O7)]·H2O.

[0029] The vanadium compounds of the present invention can be synthesized by conventional chemical synthesis techniques.

[0030] The vanadium compounds of the present invention may be used in combination with other analgesics, such as by forming a complex with the other analgesic, by mixing with the other analgesic, or by using the same analgesic either simultaneously or at intervals.

[0031] The compounds of the present invention can be prepared into pharmaceutical compositions in a variety of conventional dosage forms, such as tablets, injections, capsules, patches, inhalants and the like.

[0032] These pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories, or parenterally, for example as injections to be administered subcutaneously, intramuscularly or intravenously, or as patches, sprays or the like to be administered transdermally, or as inhalants to be administered via the nasal or oral mucosa.

[0033] Pharmaceutical compositions containing the compounds of the present invention can be prepared by conventional mixing, encapsulation, dissolving, granulation, emulsification, encapsulation, sugar-coated pilling, lyophilization, or other methods known in the art. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as carriers for tablets, coated tablets, sugar-coated pills, and hard gelatin capsules. Suitable carriers for preparing soft capsules include vegetable oils, waxes, and fatty oils. Suitable carriers for preparing solutions or syrups are water, polyhydric alcohols, sucrose, invert sugar, and glucose. Suitable carriers for injections are water, alcohols, polyhydric alcohols, glycerin, vegetable oils, phosphoric acid, and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fatty oils, and semisolid polyhydric alcohols.

[0034] The pharmaceutical preparation may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing osmotic pressure, buffers, coating agents, or antioxidants.

[0035] A therapeutically effective amount of a compound according to the invention is an amount effective to prevent, delay or ameliorate the symptoms of a disease or to prolong the life of the patient being treated. The therapeutically effective amount or dose of a compound according to the invention can vary over a wide range. This dose will be adjusted according to the individual needs in each particular situation, including the particular compound being administered, the route of administration, the situation being treated, and the patient being treated.

[0036] Metal complexes are generally administered at a dose of 0.00001-1500 mg (vanadium mass equivalent) / kg body weight per day depending on the recipient, physical condition, and route of administration. First, the wide range of dosages is due to the fact that the effective dosage varies depending on the mammal, and the effective dosage for mammals is significantly different from the effective dosage for mice. For example, the effective dosage for the human body may be 10 times, 20 times, 30 times, or even more times lower than the effective dosage (unit body weight) for mice. The difference in the route of administration also affects the dosage. For example, the oral dosage can be 10 times the injection dosage. In terms of vanadium mass equivalent, the dosage is preferably in the range of 0.00001 mg / kg-300 mg / kg per day, more preferably in the range of 0.0001 mg / kg-50 mg / kg per day, and more preferably in the range of 0.001 mg / kg-5 mg / kg per day.

[0037] The unit dose of the drug is 0.001 mg to 1000 mg (converted into metal atom), preferably 0.01 mg to 300 mg (converted into vanadium mass).

[0038] In general, when administered orally to an adult of about 70 kg, the appropriate daily dose (converted to vanadium mass) is about 0.0005 mg to about 500 mg, preferably about 0.005 mg to about 300 mg, more preferably about 0.05 mg to about 300 mg, and when administered by injection, the appropriate daily dose (converted to vanadium mass) is about 0.001 mg to about 10 mg, preferably about 0.01 mg to about 5 mg. Although there are indications that the upper limit may be exceeded, the daily dose can be administered in a single dose or in separate doses.

[0039] Vanadium(V) or vanadium(IV) forms polymers in an aqueous solution depending on the concentration or pH, which affects the analgesic effect. The present invention provides a composition containing, in addition to a vanadium(V) or vanadium(IV) compound, one or more of the following substances: a) hydroxycarboxylic acid compounds (including hydroxycarboxylic acids and hydroxycarboxylates), such as glycolic acid or glycolate, lactic acid or lactate, tartaric acid or tartrate, citric acid or citrate, α-hydroxyisobutyric acid or α-hydroxyisobutyrate, 2-ethyl-2-hydroxybutyrate, malic acid or malate, mandelic acid or mandelate, ascorbic acid or ascorbate; b) monocarboxylic acid, dicarboxylic acid or polycarboxylic acid (mono-, di- or polycarboxylic acid, or carboxylate) compounds, such as formic acid or format, 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. bacates, succinates or succinates, phthalates or phthalates, etc.; c) mono-, di-, or polyhydroxyl compounds, e.g., monoalcohols such as methanol, ethanol, isopropanol, geraniol, menthol, retinol, etc., o-diol- or m-diol-containing compounds (e.g., ethylene glycol, 1,2-dihydroxypropane, 1,2-dihydroxypropane, 1,2-dihydroxycyclopentane, 1,2-dihydroxycyclohexane), glycerol, monosaccharides, disaccharides, 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 acetylamino sugars (amino- or acetamino sugars). sugars; c) phenols, diphenols or polyphenols, such as phenol, catechol or pyrocatechol, polyhydroxy aromatic 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), GSMe (Me=methyl), GSSG, D-aspartic acid, β-alanyl-L-histidine (carnosine), collagen, serum proteins;Amino acids (e.g., glycine, alanine, glutamic acid, etc.) and the Schiff bases they form with salicylaldehyde or pyridoxal; e) diamines and the Schiff bases they form with salicylaldehyde or pyridoxal; f) β-diketones, such as acetylacetone, dibenzoylmethane, benzoylacetone, furoyltrifluoroacetone, etc., and the Schiff bases they form with amine compounds; g) hydroxypyrones and hydroxypyridinones, such as maltol or maltol (3-hydroxy-2-methylphenyl)-2-propanediol; -4-pyrone), kojic acid or kojic acid side (5-hydroxy-2-hydroxymethyl-4-pyrone), ethylmaltol or ethylmaltol (2-ethyl-3-hydroxy-4-pyrone); h) phospholipids including phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylinositol, phosphatidylglycerol or glycerophospholipid, diphosphatidylglycerol and sphingomyelin; i) hydroxylamine compounds, such as N-hydroxylamine, N,N-dialkylhydroxylamine, 2-hydroxylamine, 3-hydroxylamine, etc.; j) urea or biguanide compounds; k) compounds represented by the following formula I or II: JPEG0007672493000047.jpg23170 General formula I (X 1 and X 3 is O, S or NX 6 and preferably O or NX 6 and X 2 is N or CX 7 and X 4 , X 5 , X 6 , and X 7is an inert H (non-labile proton), or any substituted alkyl, aromatic, aralkyl, or alkaryl group, or X 4 From X 7 At least one pair of X is linked (by an atom), preferably 4 and X 5 or any substituted, saturated or unsaturated homocyclic (or carbocyclic) or heterocyclic ring formed by 1 is one NX 6 represents a group, and X 4 There is one X 8 H group, where X 5 is O or S, and X 1 Or X 8 One of the protons connected to X is active (preferably X 1 The proton connected to is active.) JPEG0007672493000048.jpg40170 General formula II Another class of preferred ligand compounds may be represented by the general formula II, where A and B are 5-, 6- or 7-membered rings containing 0, 1 or 2 heteroatoms (selected from O, S, N) on the ring, and X 4 , oxygen (oxo), sulfur (thio) or NX 4 is arbitrarily replaced by (X 4 is defined above). Ring A and ring B are preferably 1,2-phenylene, an oxazolin-2-yl group or a thiazolin-2-yl group as shown below. JPEG0007672493000049.jpg28170 (where X 4 is H or optionally substituted hydroxy C 1-4 is an alkyl group.

[0040] Preferred ligand compounds satisfying the general formulas I and II below include: Hydroxamates (general formulas III and IV) JPEG0007672493000050.jpg24170 General formula III JPEG0007672493000051.jpg44170 General formula IV α-Hydroxypyridinones (general formula V) JPEG0007672493000052.jpg38170 General formula V α-Hydroxypyrones (general formula VI) JPEG0007672493000053.jpg35170 General formula VI α-Amino acids (general formula VII) JPEG0007672493000054.jpg23170 General formula VII α-Hydroxycarboxylic acids (general formula VIII) JPEG0007672493000055.jpg29170 General formula VIII α-Hydroxycarbonyl compounds (general formulas IX and X) JPEG0007672493000056.jpg33170 General formula IX JPEG0007672493000057.jpg22170 General formula X Thiohydroxamates (general formulas XI and XII) JPEG0007672493000058.jpg17170 General formula XI JPEG0007672493000059.jpg20170 General Formula XII 2-Oxazolin-2-yl-phenols and 2-thiazolin-2-yl-phenols (general formulas XIII and XIV) JPEG0007672493000060.jpg32170 General formula XIII JPEG0007672493000061.jpg30170 General formula XIV Here, R 1 ~R 29 is H or any organic group, such as any hydroxy C 1-4 It is an alkane.

[0041] Further preferred ligands are: JPEG0007672493000062.jpg33170maltol JPEG0007672493000063.jpg33170 Ethylmaltol JPEG0007672493000064.jpg29170 Kojic acid JPEG0007672493000065.jpg38170 Citric aid JPEG0007672493000066.jpg22170 Glycolic acid JPEG0007672493000067.jpg22170 Lactic acid (L-, D- or mixture) JPEG0007672493000068.jpg38170 Tartaric acid (L-, D- or mixture)

[0042] In the composition, the weight ratio of the vanadium (V) compound to the above-mentioned substance, or the weight ratio of the vanadium (IV) compound to the above-mentioned substance, can be adjusted according to the actual situation to ensure that the vanadium (V) compound or the vanadium (IV) compound does not form a polymer in the aqueous solution of the composition in order to ensure its analgesic effect. In this case, the pH of the aqueous solution is also close to neutral, for example, pH 6 to 8. For example, the vanadium (V) compound or the vanadium (IV) compound is mixed with citric acid, tartaric acid, lactic acid, glycolic acid, ethylene glycol, glycerin or triethanolamine (tris(2-hydroxyethyl)amine) in a molar ratio of 1:0.1 to 1:1000 to prepare a composition. [Brief description of the drawings]

[0043] [Figure 1]This is a diagram showing the effect of sodium orthovanadate solution on the pain threshold of mice (dosage is calculated in vanadium atomic mass terms). Abscissa: time (unit: min or min), ordinate: pain threshold. Administration method: intraperitoneal injection. Abscissa: time (unit: min or min), ordinate: pain threshold (unit: g or gram). "▲": A1 solution, dose of about 0.97 mg / kg. "●": aspirin solution (or S solution), dose of about 250 mg / kg. "+": blank control. [Diagram 2] This is a diagram showing the effect of sodium orthovanadate solutions at various doses (calculated as vanadium atomic mass) on the pain threshold of mice. Abscissa: time (unit: min or minute), ordinate: pain threshold (unit: g or gram) Administration method: intraperitoneal injection "●": A1 solution, dose of about 0.97 mg / kg "■": A2 solution, dose of about 0.19 mg / kg "▲": A3 solution, dose of about 0.097 mg / kg "+": blank control [Diagram 3] FIG. 1 shows cis-bis(maltolato)methoxyoxovanadium(V) (dosage is calculated as vanadium atomic mass). Method of administration: intraperitoneal injection. Abscissa: time (unit: min or minute), ordinate: pain threshold (unit: g or gram). "▲": C solution, dose of about 0.97 mg / kg. "●": S ​​solution, dose of about 250 mg / kg. "+": blank control. [Figure 4] This is a diagram showing the effect of sodium metavanadate solution on the pain threshold of mice (doses are calculated in terms of vanadium atomic mass). Administration method: intraperitoneal injection. Abscissa: time (unit: min or minute), ordinate: pain threshold (unit: g or gram). "▲": D solution, dose of about 0.97 mg / kg. "●": S ​​solution, dose of about 250 mg / kg. "+": blank control. [Diagram 5] This is a diagram showing the effect of a sodium salt solution of orthovanadate / citric acid complex on the pain threshold of mice (dosage is calculated in terms of vanadium atomic mass). Administration method: intraperitoneal injection. Abscissa: time (unit: min or minute), ordinate: pain threshold (unit: g or gram). "▲": B solution, dose of about 0.97 mg / kg. "●": S ​​solution, dose of about 250 mg / kg. "+": blank control. [Figure 6]The effect of a sodium metavanadate / citric acid complex solution on the pain threshold of mice (dosage is calculated as vanadium atomic mass). Method of administration: intraperitoneal injection. Abscissa: time (unit: min or minute), ordinate: pain threshold (unit: g or gram). "▲": E solution, dose of about 0.97 mg / kg. "●": ASA solution, dose of about 250 mg / kg. "+": blank control. [Figure 7] The effect of a potassium salt solution of metavanadate / citric acid complex on the pain threshold of mice (the dose is calculated as vanadium atomic mass). Method of administration: intraperitoneal injection. Abscissa: time (unit: min or minute), ordinate: pain threshold (unit: g or gram). "▲": F solution, dose of about 0.97 mg / kg. "●": ASA solution, dose of about 250 mg / kg. "+": blank control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] In order to better understand the gist of the present invention, the use of the compounds of the present invention in the treatment of pain is described below with the results of animal experiments, which show that the compounds of the present invention have a fast onset of analgesia, a long duration of analgesia, and can provide rapid and long-lasting analgesic effect. The effect examples provide the activity data of the compounds of the present invention. It should be noted that the pharmacological examples of the present invention are used for the explanation of the present invention, not the limitation of the present invention. Simple modifications made to the present invention based on the gist of the present invention also fall within the scope of the present invention. Example 1: Construction of a mouse pain model

[0045] Mice (♂ Kunming mice, 22-40g) were injected with 10μl of complete Freund's adjuvant (CFA) into the left hind paw to induce inflammation. 24 hours after injection, the Von Frey test was performed to measure the pain threshold, i.e., mechanical paw withdrawal of the mice was induced using a Von Frey fiber according to the Up-Down method by Dixon, data were collected, and the 50% paw withdrawal threshold (i.e., 50% paw withdrawal threshold), called paw withdrawal threshold or PWT, was calculated as the pain threshold. Then, the mice were divided into saline group, positive control group, and drug group, and saline, aspirin (acetylsalicylic acid, or ASA) solution, and test compound solution were intraperitoneally injected, respectively. The changes in pain threshold were then monitored by the Von Frey test.

[0046] After modeling, the pain threshold of the mice decreased. Before modeling, the average pain threshold of the mice was about 2.5, and after modeling, mice with an average pain threshold of about 0.1 were selected. When aspirin, a known analgesic, was administered, the pain threshold regressed to a certain extent, proving the success of the modeling.

[0047] Mice were divided into three groups: a blank control group, an aspirin (ASA) group, and a drug group. In the blank control group, mice were administered the same amount of saline, deionized water, or deionized water containing 5% or less DMSO as in the drug group. In the ASA group, mice were administered the known analgesic drug ASA as a positive control for the test drug. In the drug groups, mice were administered the test drug, and after injection of the test compound solution, it was observed whether the pain threshold regressed, the duration of regression, and the width of regression, and from these, whether the test compound had an analgesic effect, and the duration and strength of the drug effect were estimated. Example 2 Preparation of positive control samples and test drug samples

[0048] 1. Preparation of positive control S solution: Aspirin (ASA) was dissolved in 0.1 M tris-HCl buffer and the pH was adjusted with sodium hydroxide solution to prepare a 0.11 M solution, with a final pH of about 7.4 to 7.6.

[0049] 2. Preparation of sodium orthovanadate solution (solution A) Sodium orthovanadate (Na3VO4): purchased from Sigma-Aldrich A0 solution: 184 mg of sodium orthovanadate was weighed out and dissolved in 6 ml of deionized water, and the pH was adjusted to 10 with hydrochloric acid. The solution was then heated until it became colorless, cooled to room temperature, and the pH was detected. If the pH changed, the above process was repeated until the pH was 10. The solution was supplemented with 8 ml of deionized water and stored at 4°C. This solution was called sodium orthovanadate stock solution. A1 solution: Dilute the above sodium orthovanadate stock solution with deionized water to obtain A0 solution with a concentration of 1.5 × 10 -3 An aqueous solution of sodium orthovanadate M was prepared. A2 solution: Dilute A0 solution with deionized water to a concentration of 3.0 × 10 -4 An aqueous solution of sodium orthovanadate M was prepared. A3 solution: Dilute A0 solution with deionized water to a concentration of 1.5 × 10 -4 An aqueous solution of sodium orthovanadate M was prepared. A4 solution: Dilute A0 solution with deionized water to a concentration of 3.0 × 10 -3 An aqueous solution of sodium orthovanadate M was prepared. A5 solution: Dilute A0 solution with deionized water to a concentration of 7.5 × 10 -4 An aqueous solution of sodium orthovanadate M was prepared. A6 solution: Dilute A0 solution with deionized water to a concentration of 7.5 × 10 -6 An aqueous solution of sodium orthovanadate M was prepared.

[0050] 3. Preparation of sodium orthovanadate / citric acid complex solution (solution B) Solution B: 14.8 mg of sodium orthovanadate was dissolved in 3.5 ml of water, to which 0.25 M citric acid solution was added dropwise until the pH of the solution reached about 7. A small amount of water was added until the total volume reached 4 ml, yielding a vanadium citrate complex solution with a concentration of 0.020 M (vanadium equivalent). This solution was then diluted to a concentration of 1.5 x 10-3 The solution was diluted to M to prepare a test solution.

[0051] 4. Preparation of cis-bis(maltolato)methoxyoxovanadium(V) solution (solution C) cis-Bis(maltolato)methoxyoxovanadium(V), VO(OCH3)(ma)2 Bis(maltolato)oxovanadium(IV) (VO(ma)2, 5 g, 16 mmol) was dissolved in 50 ml of methanol and stirred for 24 hours under air. The solution was frozen at -35°C overnight and the precipitated crystals were collected by filtration in a 65% yield (P. Caravan, L. Gelmini, N. Glover, FG Herring, H. Li, JH McNeill, SJ Rettig, IA Setyawati, E. Shuter, Y. Sun, AST Tracey, VG Yuen; and C. Orvig, J. Am. Chem. Soc. 1995, 117, 12759-12779). Solution C: 3.0 × 10 VO(OCH3)(ma)2 in a small amount (<5% of the total volume) of DMSO to aid dissolution. -3 M aqueous solution was prepared.

[0052] 5. Preparation of sodium metavanadate solution (or solution D) Sodium metavanadate (NaVO3): purchased from Sigma-Aldrich. Solution D: Sodium metavanadate 3.0 x 10 -3 M was prepared in aqueous solution.

[0053] 6. Preparation of sodium metavanadate / citric acid complex solution (solution E) Solution E: 1 ml of sodium metavanadate solution with a concentration of 0.26 M was added to 2 ml of citric acid solution with a concentration of 0.135 M. The concentration was 1.5 x 10 -3 The solution was diluted to 100 ml and used as the test solution.

[0054] 7. Preparation of potassium salt solution of metavanadate / citric acid complex (solution F) 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 citric acid solution (citric acid·H2O: 1.21 g, 6.0 mM, water: 5 ml) was added dropwise with stirring. The mixture was left to stand at 4°C (refrigerator) overnight. A pale powder was obtained by filtration and drying. The yield was 43% (ref: Inorg. Chem. 1989, 719-723). F solution: Take 13 mg of K[VO2(C6H6O7)]·H2O solid and dilute it to 1.5×10 with deionized water. -3 A solution of M was prepared and used as the test solution.

[0055] 8. Preparation of vanadyl sulfate solution (solution G) Vanadyl sulfate (VOSO4·5H2O): Purchased from Alfa Aesar. G1 solution: 1.5 x 10 concentration in deionized water -3 A vanadyl sulfate aqueous solution of M was prepared. G2 solution: 3.0 x 10 concentration in deionized water -3 A vanadyl sulfate aqueous solution of M was prepared. G3 solution: 7.5 x 10 concentration in deionized water -4 A vanadyl sulfate aqueous solution of M was prepared. G4 solution: 7.5 x 10 concentration in deionized water -6 A vanadyl sulfate aqueous solution of M was prepared.

[0056] 9. Preparation of bis(maltolato)oxovanadium(IV) solution (H solution) Bis(maltolato)oxovanadium(IV) [i.e., Bis(maltolato)oxovanadium(IV), VO(ma)2 or BMOV] origin: synthesized according to the literature method [see P. Caravan, L. Gelmini, N. Glover, FG Herring, H. Li, JH McNeill, SJ Rettig, IA Setyawati, E. Shuter, Y. Sun, AST Tracey, VG Yuen; and C. Orvig, J. Am. Chem. Soc. 117, 12759-12770 (1995)] or purchased from Shanghai Fibai Chemical Technology Co., Ltd. H1 solution: DMSO and deionized water at a concentration of 1.5 x 10 -3 A solution of M bis(maltolato)oxovanadium(IV) was prepared, in which the DMSO content was less than 5%. H2 solution: DMSO and deionized water at a concentration of 3.0 x 10 -3 A solution of M bis(maltolato)oxovanadium(IV) was prepared, in which the DMSO content was less than 5%. H3 solution: DMSO and deionized water at a concentration of 6.0 x 10 -3 A solution of M bis(maltolato)oxovanadium(IV) was prepared, in which the DMSO content was less than 5%.

[0057] 10. Preparation of bis(ethylmaltolato)oxovanadium(IV) solution (I solution) Bis(ethylmaltolato)oxovanadium(IV) [i.e., Bis(ethylmaltolato)oxovanadium(IV), VO(ema)2 or BEOV] origin: synthesized according to literature methods [see KH Thompson, BD Liboiron, Y. Sun, KD D Bellman, IA Setyawati, BO Patrick, V. Karunaratne, G. Rawji, J. Wheeler, K. Sutton, S. Bhanot, C. Cassidy, JH McNeill, VG Yuen, and C. Orvig, J. Biol. Inorg. Chem. 8, 66-74 (2003)] or purchased from Hubei Hongqin Ruiyu Precision Chemical Co., Ltd. Solution I: DMSO and deionized water at a concentration of 1.5 × 10 -3 A solution of M bis(ethylmaltolato)oxovanadium(IV) was prepared, in which the DMSO content was less than 5%.

[0058] 11. Preparation of bis(kojato)oxovanadium(IV) solution (J solution) Bis(kojato)oxovanadium(IV) [i.e., Bis(kojato)oxovanadium(IV) or VO(ka)] origin: Synthesized according to the 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)]. J solution: DMSO and deionized water at a concentration of 1.5 × 10 -3 A solution of M bis(kojato)oxovanadium(IV) was prepared, in which the DMSO content was 5% or less.

[0059] 12. Preparation of vanadyl acetylacetonate(IV) solution (K solution) Vanadyl acetylacetonate (IV) [Vanadyl acetylacetonate, bis(acetylacetonato)oxovanadium(IV) or VO(acac)2]: purchased from Shanghai Qiming Biotechnology Co., Ltd. K solution: DMSO and deionized water at a concentration of 1.5 x 10 -3 A vanadyl acetylacetonate (IV) solution of M was prepared, in which the DMSO content was 5% or less.

[0060] 13. Preparation of vanadyl oxalate solution (L solution) Vanadyl oxalate: purchased from Shanghai Gongtai Pharmaceutical Technology Co., Ltd. L solution: DMSO and deionized water at a concentration of 1.5 x 10 -3 A vanadyl oxalate solution of M was prepared, in which the DMSO content was 5% or less.

[0061] 14. Preparation of bis(picolinato)oxovanadium(IV) solution (M solution) Bis(picolinato)oxovanadium(IV) [i.e., bis(picolinato)oxovanadium(IV), VO(pic)2 or BPOV]: purchased from Shanghai Qiming Biotechnology Co., Ltd. M solution: DMSO and deionized water at a concentration of 1.5 x 10 -3 A solution of M bis(picolinato)oxovanadium(IV) was prepared, in which the DMSO content was 5% or less.

[0062] 15. Preparation of sodium salt solution of orthovanadic acid / ethylene glycol complex (N solution) N solution: 2ml of A4 solution (concentration: 3.0×10 -3 M in an ethylene glycol solution (1.8 x 10 -2 M) was added, followed by deionized water until the total volume was 4 ml.

[0063] 16. Preparation of sodium salt solution of orthovanadate / propylene glycol complex (O solution) O solution: 2ml of A4 solution (concentration: 3.0×10 -3 M) in 1,2-propylene glycol aqueous solution (1.8 × 10 -2 M) was added, followed by deionized water until the total volume was 4 ml.

[0064] 17. Preparation of sodium salt solution of orthovanadate / glycerin complex (solution P) P solution: 2ml of A4 solution (concentration: 3.0×10 -3 M) in 1,2-propylene glycol aqueous solution (1.8 × 10 -2 M) was added, followed by deionized water until the total volume was 4 ml.

[0065] 18. Preparation of sodium orthovanadate / lactate complex solution (Q solution) A 0.25M lactic acid solution was added dropwise to 1 ml of a 0.025M sodium orthovanadate solution until the pH of the solution reached about 7. -3 The solution was replenished with deionized water until it reached M (converted into vanadium), and this was used as the test solution.

[0066] 19. Preparation of sodium orthovanadate / glycolate complex solution (R solution) A 0.25M glycolic acid solution was added dropwise to 1 ml of a 0.025M sodium orthovanadate solution until the pH of the solution reached about 7. -3 M (converted into vanadium) was added with deionized water to prepare a test solution. Example 3 Pain relief experiment of sodium orthovanadate solution

[0067] A1 was intraperitoneally injected according to a dose standard of 0.97 mg / kg (converted into vanadium atomic mass), and the collected data were compared with the ASA group and blank group (Figure 1). JPEG0007672493000069.jpg38170 Explanation of experimental results: The A1 solution began to affect the pain threshold of mice 30 - 45 min after intraperitoneal injection, increasing the pain threshold. Moreover, the pain threshold of the mice did not return to the baseline value even 90 min after injection. The S solution began to increase the pain threshold 15 - 30 min after injection, but the pain threshold returned to the baseline value around 60 min. During most of the time after the A1 solution began to increase the pain threshold, the threshold of the mice in the A1 group was higher than that of the mice in the S group after the pain threshold was increased by the S solution. Example 4 Analgesic experiment at each concentration of sodium orthovanadate solution

[0068] According to the dosage standards of about 0.19 mg / kg and about 0.097 mg / kg (in terms of vanadium atomic mass conversion), A2 and A3 were intraperitoneally injected into two groups of mice respectively, and the collected data were compared with those of the A1 and blank groups (Figure 2). JPEG0007672493000070.jpg49170 Explanation of experimental results: A1, A2, and A3 all began to increase the pain threshold of mice 30 - 45 min after injection, and the pain thresholds of the mice did not all return to the baseline value 90 min after injection. However, with the decrease in the administration concentration, the increase amplitude of the pain threshold decreased, that is, A3 < A2 < A1. Summarizing Examples 3 and 4, the sodium orthovanadate solution has an analgesic effect. Not only can a similar or better analgesic intensity than that of ASA be obtained at a concentration much lower than that of ASA, but also the duration is clearly longer than that of the latter. In addition, the tendency that the drug effect decreases with the decrease in the sodium orthovanadate concentration, that is, A3 < A2 < A1, was also shown in the examples. Example 5 Analgesic experiment of cis-bis(maltato)methoxoxovanadium(V) solution

[0069] According to the dosage standard of about 1.9 mg / kg (in terms of vanadium atomic mass conversion), the C solution was intraperitoneally injected, and the collected data were compared with those of the ASA and blank groups (Figure 3). JPEG0007672493000071.jpg38170Explanation of experimental results: C solution began to affect the pain threshold of the mice 15-30 min after intraperitoneal injection, increasing the pain threshold, and the pain threshold of the mice returned to the baseline value 90 min after injection. S solution began to increase the pain threshold 15-30 min after injection, but the pain threshold returned to the baseline value around 60 min. For most of the time after C solution began to affect the pain threshold, the threshold of the mice in group C was equivalent to that of the mice in group S after the pain threshold was increased by S solution. Thus, cis-bis(maltolato)methoxyoxovanadium(V) solution has an analgesic effect, not only with a similar analgesic strength to the ASA solution at a much lower concentration, but also with a significantly longer duration of action (approximately 60 min) than the latter (<45 min). Example 6 Analgesic experiment of sodium metavanadate solution

[0070] D solution was injected intraperitoneally according to a dose scale of about 1.9 mg / kg, and the collected data were compared with the ASA and blank groups (Figure 4). JPEG0007672493000072.jpg33170Explanation of experimental results: D solution began to affect the pain threshold of the mice 0-15 min after injection, increasing the pain threshold, and the pain threshold of the mice returned to the baseline value at about 90 min after injection. S solution began to increase the pain threshold 15-30 min after injection, but the pain threshold returned to the baseline value around 60 min. For most of the time after D solution began to affect the pain threshold, the threshold of group D mice was better or equal to the threshold of group S mice after the pain threshold was increased by S solution. Thus, sodium metavanadate solution has an analgesic effect, which not only provides similar analgesic strength to the ASA solution at a much lower concentration, but also lasts longer (>60 min) than the latter (<45 min). Example 7 Pain relief experiment of sodium salt solution of orthovanadate / citric acid complex

[0071] B1 solution was injected according to a dose standard of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data was compared with the ASA and blank groups (Figure 5). JPEG0007672493000073.jpg39170Explanation of experimental results: Solution B began to affect the pain threshold of the mice 15-30 minutes after intraperitoneal injection, increasing the pain threshold, and the pain threshold of the mice did not return to the baseline value even 90 minutes after injection. Solution S began to increase the pain threshold 15-30 minutes after injection, but the pain threshold returned to the baseline value around 60 minutes. For most of the time after solution B began to increase the pain threshold, the threshold of the mice in group B was higher than that of the mice in group S, whose pain threshold was increased by solution S. Thus, the sodium salt solution of orthovanadate / citric acid complex has an analgesic effect, which not only provides similar analgesic strength to the ASA solution at a much lower concentration, but also lasts longer (>60 min) than the ASA solution (<45 min). Example 8 Analgesic experiment of sodium salt solution of metavanadate / citric acid complex

[0072] E solution was injected according to a dose basis of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data was compared with the ASA and blank groups (Figure 6). JPEG0007672493000074.jpg37170Explanation of experimental results: E solution began to affect the pain threshold of the mice 15-30 min after intraperitoneal injection, increasing the pain threshold, and the pain threshold of the mice did not return to the baseline value even 90 min after injection. S solution began to increase the pain threshold 15-30 min after injection, but the pain threshold returned to the baseline value around 60 min. For most of the time after E solution began to increase the pain threshold, the threshold of the mice in the E group was higher than that of the mice in the S group after the pain threshold was increased by S solution. Thus, the sodium salt solution of metavanadate / citric acid complex has an analgesic effect, which not only provides similar analgesic strength to the ASA solution at a much lower concentration, but also lasts longer (>60 min) than the ASA solution (<45 min). Example 9 Analgesic experiment of potassium salt solution of metavanadate / citric acid complex

[0073] F solution was injected according to a standard of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data was compared with the ASA and blank groups (Figure 7). JPEG0007672493000075.jpg38170Explanation of experimental results: F solution began to affect the pain threshold of the mice 15-30 min after intraperitoneal injection, increasing the pain threshold, and the pain threshold of the mice did not return to the baseline value even 90 min after injection. S solution began to increase the pain threshold 15-30 min after injection, but the pain threshold returned to the baseline value around 60 min. For most of the time after F solution began to increase the pain threshold, the threshold of the mice in the F group was higher than that of the mice in the S group after the pain threshold was increased by S solution. Thus, the potassium salt solution of metavanadate / citric acid complex has an analgesic effect, which not only gives similar analgesic strength to the ASA solution at a much lower concentration, but also lasts longer (>60 min) than the ASA solution (<45 min). Explanation: Environmental factors, different mice, and different tests all have a certain effect on the absolute values ​​of analgesic strength and analgesic duration, but compared to the aspirin control group, groups A, B, C, D, E, and F all showed a stable trend. a) The effective concentration (the concentration that produces an analgesic effect) is much lower than aspirin. b) The analgesic strength is equal to or greater than aspirin. b) The effective duration is longer than aspirin. Example 10: Analgesic experiment using vanadyl sulfate

[0074] G1 solution was injected via tail vein according to a standard of approximately 0.49 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with ASA and blank groups. JPEG0007672493000076.jpg44170Example 11 Pain relieving experiment with (maltolato)oxovanadium

[0075] H1 solution was intraperitoneally injected according to a standard value of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000077.jpg28170Example 11 Pain relieving experiment with (ethylmaltolato)oxovanadium

[0076] I solution was injected intraperitoneally according to a standard of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000078.jpg39170Example 12 Pain relief experiment using vanadyl kojic acid

[0077] J solution was injected intraperitoneally according to a standard of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000079.jpg38170Example 13 Analgesic experiment using vanadyl acetylacetonate (IV)

[0078] K solution was injected intraperitoneally according to a standard of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000080.jpg38170Example 14 Analgesic experiment using vanadyl oxalate

[0079] L solution was intraperitoneally injected according to a standard of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000081.jpg39170Example 15 Pain relief experiment with bis(picolinato)oxovanadium(IV)

[0080] M solution was injected intraperitoneally according to a standard of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000082.jpg39170Example 16 Pain relief experiment of sodium salt solution of orthovanadate / ethylene glycol complex

[0081] N solution was injected intraperitoneally according to a standard of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000083.jpg39170 Example 17 Pain relief experiment of sodium salt solution of orthovanadate / propylene glycol complex

[0082] O solution was injected intraperitoneally according to a standard of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000084.jpg39170Example 18 Pain relief experiment using sodium salt solution of orthovanadate / glycerin complex

[0083] P solution was injected intraperitoneally according to a standard of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000085.jpg39170Example 19 Pain relief experiment using sodium salt solution of orthovanadate / lactate complex

[0084] The Q solution was injected intraperitoneally according to a standard of about 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000086.jpg39170Example 20 Pain relief experiment using sodium salt solution of orthovanadate / glycolic acid complex

[0085] R solution was injected intraperitoneally according to a standard of approximately 0.97 mg / kg (calculated as vanadium atomic mass), and the collected data were compared with the ASA and blank groups. JPEG0007672493000087.jpg39170Example 21 Experiment on effective concentration and plateau period of vanadium compounds

[0086] Since various vanadium (IV) or vanadium (V) compounds, such as complexes of vanadium containing inorganic salts and organic ligands, all have analgesic effects, it can be determined that the possibility of drug ligands being involved in pain suppression is very low, and their role is only to act as carriers of vanadium elements. Vanadium-based compounds dissociate before entering the body and reaching the analgesic target (there may be multiple targets), i.e., vanadium elements dissociate from the original ligands, and instead, the ingested vanadium elements act on the next analgesic reaction after recomplexing with natural ligands contained in the body (e.g., blood), especially inorganic ligands such as chloride ions, phosphate ions, or hydrogen phosphate ions, and organic ligands containing O-, N-, and S-donors. In addition, tetravalent or pentavalent vanadium compounds rapidly generate a new equilibrium through oxidation-reduction reactions under physiological conditions. Based on this idea, by tail vein injection of inorganic salts of vanadium (VOSO4 and Na3VO4), vanadium elements can not only be directly taken into the blood, but also rapidly bind with natural ligands in the body to form an effective form required for analgesia. Compared with vanadium compounds containing organic ligands (especially tightly bound organovanadium complexes), VOSO4 and Na3VO4 represent "bare" donors of the vanadium element (herein referred to as "bare vanadium"); the former represents a donor of VO 2+ The latter provides tetravalent vanadium such as VO4 3- , HVO4 2- , H2VO4 - , or VO 3+ This provides a pentavalent vanadium such as, thereby eliminating the step of dissociating it from its own ligands and avoiding the risk of it being excreted from the body due to not being complexed with the natural ligand.

[0087] The relationship between "bare vanadium" and the actual active analgesic substance is the strongest. By administering different amounts of the "bare vanadium" donors VOSO4 or Na3VO4, the inventors found the minimum blood concentrations at which tetravalent and pentavalent vanadium were effective in mice. First, the minimum effective dose, i.e., approximately 1.0 × 10 -3The vanadium concentrations in the blood of these mice were calculated as follows:

[0088] The average blood volume of a mouse is 2 ml / 30 g, and the blood volume is 1.0 × 10 -3 The blood concentration after intravenous injection of 1.0 mg / kg of -6 mg / g × 30g) / (51 × 2) = 2.9 × 10 -7 M (or 0.29 μM).

[0089] Therefore, the minimum blood concentration at which vanadium compounds exerted an analgesic effect on mice was approximately 0.29 μM. When converted to a dosage ratio of 1:9.3 between humans and experimental animals, the minimum blood concentration at which vanadium compounds exerted an analgesic effect on the human body was 0.031 μM.

[0090] The inventors have also found that with increasing doses of vanadium, the intensity and duration of analgesia also increase, but when the blood concentration of vanadium reaches a certain level, the analgesic effect plateaus, i.e., the intensity of analgesia no longer increases, or even decreases, and / or the duration of analgesia no longer extends (or becomes irregular).

[0091] When VOS4 or Na3VO4 solution was injected into the tail vein, the dose required to reach the plateau phase was 0.49mg / kg or more (see "Plateau Phase Experimental Data Sheet"), which corresponds to a blood concentration of 140μM. When the dosage ratio of humans and experimental animals was converted to 1:9.3, it was found that the analgesic plateau phase appeared when the vanadium concentration reached 15μM in humans.

[0092] The minimum effective dose for other vanadium compounds is expected to be related to the dose at which the plateau phase is reached and the tightness of vanadium / ligand complexation; in the case of BMOV, the dose at which the plateau phase is reached was approximately 0.97 mg / kg or more.

[0093] JPEG0007672493000088.jpg103170

[0094] JPEG0007672493000089.jpg49170

Claims

1. A medicament for treating pain comprising a +4-valent vanadium compound or a +5-valent vanadium compound containing a vanadium-oxygen bond, the amount of the tetravalent vanadium compound or the pentavalent vanadium compound used is 0.00001 mg / kg body weight to 5 mg / kg body weight in terms of vanadium mass; The tetravalent vanadium compound is VCl ４ , VOCl ２ , VOSO ４ , (V.O.) ３ (P.O. ４ ) ２ , VOHPO ４ , and VO(H ２ P.O. ４ ) ２ is selected from the group consisting of The pentavalent vanadium compound is an alkali metal, alkaline earth metal or transition metal salt of orthovanadic acid or metavanadic acid, The compound is administered subcutaneously, intramuscularly or intravenously. Medicine.

2. 2. The pharmaceutical composition according to claim 1, wherein the pentavalent vanadium compound is sodium orthovanadate or potassium orthovanadate.

3. 2. The pharmaceutical composition according to claim 1, wherein the pentavalent vanadium compound is sodium metavanadate or potassium metavanadate.

4. 2. The medicament of claim 1, wherein the compound is selected from the group consisting of lithium orthovanadate, sodium orthovanadate, potassium orthovanadate, lithium metavanadate, sodium metavanadate, potassium metavanadate, vanadyl sulfate, vanadium dichloride, and compounds thereof including crystallizing solvents.

5. A pharmaceutical for treating pain, comprising a +4-valent vanadium compound or a +5-valent vanadium compound containing a vanadium-oxygen bond, the amount of the tetravalent vanadium compound or the pentavalent vanadium compound used is 0.00001 mg / kg body weight to 5 mg / kg body weight in terms of vanadium mass; the compound is selected from the group consisting of vanadyl sulfate, sodium orthovanadate, potassium orthovanadate, sodium metavanadate, potassium metavanadate, and vanadium compounds prepared therefrom with citric acid, tartaric acid, lactic acid, glycolic acid, ethylene glycol, glycerin, or triethanolamine [tris(2-hydroxyethyl)amine] in a molar ratio of 1:0.5 to 1:1000; The compound is administered subcutaneously, intramuscularly or intravenously.

6. The method according to any one of claims 1 to 5, wherein the compound is administered intravenously.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is in the form of an injection.

Images