TW200538107A - Thiotungstate analogues and uses thereof - Google Patents

Abstract

The current invention provides novel thiotungstate derivatives, methods of making novel thiotungstate derivatives, pharmaceutical compositions of novel thiotungstate derivatives, methods of using novel thiotungstate derivatives to treat diseases associated with aberrant vascularization, copper metabolism disorders and obesity and methods of using pharmaceutical compositions of thiotungstate derivatives to treat diseases associated with aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity or NF-κB dysregulation.

Description

200538107 玖 发明, Description of the invention [Technical field to which the invention belongs] 1. Field The present invention generally relates to tetrathiotungstate derivatives, methods for making novel thiotetratungstate derivatives, novel tetrathiotungstates Derivative medicinal composition, medicinal composition using novel tetrathiotungstate derivative and tetrathiotungstate derivative to treat or prevent diseases related to abnormal angiogenesis, disorders of copper metabolism, neurodegenerative disorders and obesity Disease method. [Prior art] 2. Background Most forms of cancer are derived from solid tumors (Shockley et al., Ann. NY Acad. Sci. 199 1,617: 367-382, which has been clinically proven to be resistant to treatments such as monoclonal antibodies And the use of immunotoxins. Antiangiogenic therapies for the treatment of cancer have evolved from the recognition that solid tumors need to maintain growing angiogenesis (ie, neovascularization) (Folkman, Ann. Surg. 19 7 2 175: 409-416; Folkman,

Mol. Med. 1 995, 1 (2): 120-122; Folkman, Breast Res. Treat · 1 995, 3 6 (2): 1 09- 1 1 8; Hanahan et al., Cell 1 996, 8 6 ( 3): 3 5 3 -3 64). Animal models have demonstrated the efficacy of antiangiogenic therapy (Millauer et al. Cancer Res. 1996, 56 • 1 6 1 5-1 620; Borgstrom et al., Prostrate 1998, 35: 1-10; Ben Jiemin et al., J Clin. Invest. 1999, 103: 159-165;

Merajver et al., Proceedings of Special AACR Conference 200538107 (2) on Angiogenesis and Cancer 1998, Abstract # Β · 11, January 22-24). In the absence of angiogenesis, the cell layer within a solid tumor is undernourished. Further, angiogenesis (ie, abnormal angiogenesis) has been implicated in many other diseases (eg, neovascular diseases of the eye, speckle degeneration, rheumatoid arthritis, etc.). Recently, angiogenesis-inhibiting effects in animal models have been directly related to adipose tissue loss and weight loss. 'The spectrum of antiangiogenic therapy can be used to prevent obesity (Rupnick et al., Proc. Natl. Acad. Sci. 2002, 99: 1 073 0- 1 073 5). In contrast, normal tissues do not require angiogenesis except under specific circumstances (eg, wound repair, uterine lining hyperplasia during the menstrual cycle, etc.). Therefore, the need for angiogenesis is a significant difference between tumor cells and normal tissues. Importantly, when compared to normal cells, tumor cells are more dependent on angiogenesis than the differences in cell replication and cell death, and between normal tissues and tumor tissues are often developed in cancer treatment. Angiogenesis requires copper, which has been shown by many studies (Parke et al., Am. J. Pathol, 1 9 8 8, 1 37: 1 73-1 78; Rajuet et al.,

Natl. Cancer Inst. 1 982, 69: 1 1 83-1 1 8 8; Zichee et al., Natl. Cancer Inst. 1 982, 69 · 475-482; Gullino,

Anti cancer Res. 1986, 6 (2): 153-158) ° In this technique attempts have been reported to prevent angiogenesis and therefore tumor growth in animal models by reducing the amount of copper in vivo (Brem et al., Neurosurgery 1 990, 26: 3 9 1-3 96; Brem et al., Am. J. Pathol. 1 990, 1 3 7 (5): 1121-1142; Yoshida et al., Neurosurgery 1995 200538107 (3) 3 7 (2) : 2 8 7 -2 9 5). These methods combine both copper clamps and low-copper food. Recently, Brewer et al. 'International Application No. PCT / US 99/203 74 have shown that copper clamps (eg, tetrathiomolybdate) are effective in treating diseases (eg, solid tumor growth) that require angiogenesis and are also effective of. In addition to inducing angiogenesis, copper can also play a direct role in tumor cell growth and survival. High copper content is found in blood violet and tumor tissue from patients with many different solid cancers (Chakravarty et al., J. Cancer Res. Clin. Oncol. 1 984, 108: 312-315). Recently, tetrathiomolybdate has been shown to down-regulate the expression of NF-/ c B and inhibit its metastasis to the nucleus in the inflammatory breast cancer cell line S UM 1 4 9 (pan et al. Cancer Res. 2002, 62 : 4854-4859). The NF- / cB system can be involved in the survival of vectored tumor cells and is thus down-regulated in the tumor cells by tetrathiomolybdic acid, demonstrating the direct impact of copper clamp cooperation on tumor survival. Therefore, novel compounds such as tetrathiotungstate compounds, which are copper clamps, are needed to fully explore the possibilities of copper clamps in the treatment and / or prevention of angiogenesis and tumor cell viability. These novel tetrathiotungstate compounds are effective in treating various angiogenesis-related diseases such as cancer and obesity together with copper metabolic disorders and neurodegenerative disorders. Obesity is caused by disease pathways such as NF- / cB pathway dysregulation, such as inflammation. Sexually transmitted diseases. [Summary of the invention] 3. Describe the present invention by providing a novel tetrathiotungstate derivative, manufacturing novel-7-200538107 (4) a method of a tetrathiotungstate derivative, a novel tetrathiotungstate Derivative pharmaceutical composition, method using novel thiotungstate derivative for treating diseases related to abnormal blood vessel formation, copper metabolism disorder and obesity, and pharmaceutical composition using tetrathiotungstate derivative for treating and abnormality Methods for angiogenesis-related diseases, copper metabolism disorders, neurodegeneration disorders, obesity, and NF- / B disorder (dysregulation) meet this and other needs. In a first aspect, the present invention provides a transformation of the structural formula (I)

Compound: R1 R2-N: +-R4 R3

Or a solvate, hydrate or N-oxide thereof, wherein:

R1, R2, R3, R5, R6 and R7 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, cycloalkyl, Substituted cycloalkyl, cycloheteroalkyl, substituted cyclohetero

Alkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; R4 and R8 are independently hydrogen, alkyl, Substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, hetero Aryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl or substituted heteroalkyl or when N is an aromatic ring moiety, does not exist; optionally, R] and R2 — together, are alkanediyl, substituted alkanediyl, heteroalkanediyl, or substituted heteroalkanediyl; optionally, R5 and R6 — are alkanediyl, substituted alkanediyl , -8- 200538107 (5) heteroalkanediyl or substituted heteroalkanediyl; optionally, R1 and R2 together, R2 and R3 together, and R2 and r4 together are alkanediyl, substituted alkandi Group, heteroalkyldiyl or substituted heteroalkyldiyl; optionally, R5 and R6 together, R6 and R7 together, and R6 and r8 together are alkyldiyl, substituted alkyldiyl, heteroalkyldi Base or substituted Diyl; optionally, R3 and R7 together are alkanediyl, substituted alkanediyl, heteroalkanediyl or substituted heteroalkanediyl, and Y-2 is (WS4) _2, (M2S12) _ 2, (W2S9)-2, (W2S7)-2, (W2S8) -2, (W2S]]) -2, (W2S6)-2 or (W2S13)-2. In a second aspect, the present invention provides a pharmaceutical composition of a compound of the present invention. Such pharmaceutical compositions typically include one or more compounds of the invention, their hydrates or solvates, and pharmaceutically acceptable diluents, carriers, excipients, and adjuvants. The choice of diluent, carrier, excipient and adjuvant will depend on other factors and the desired mode of administration. In a third aspect, the present invention provides a method for treating or preventing a disease or disorder characterized by abnormal angiogenesis, copper metabolism disorders, neurodegeneration disorders, obesity, or N F — / c B disorders. Such methods typically include administering a therapeutically effective amount of a compound of the invention and / or a pharmaceutical composition to a patient in need of such treatment or prevention. In a fourth aspect, the present invention provides a method for treating or preventing a patient in need of such treatment or prevention with abnormal angiogenesis, copper metabolism disorders, nerves-9-200538107 (6) degenerative disorders, obesity or NF- / c B disorders A pharmaceutical composition characterized by a disease or disorder. 4. Brief Description of the Schematic Figure 1 illustrates the inhibition of angiogenesis by ammonium tetrathiotungstate in a Matri gel® plug assay. 5.1 Definitions "Compound" means a compound encompassed by the structural formula (1) disclosed herein and includes any specific compound within the general formula of the structure disclosed herein. Compounds can be defined by any chemical structure and / or chemical name. When the chemical structure and the chemical name conflict, the chemical structure is the determining factor of the nature of the compound. Compounds may contain one or more palm centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (ie, geometric isomers), mirror isomers, or non-mirror Thing. Accordingly, the chemical structures described herein include all possible mirror isomers and stereoisomers of the illustrated compounds, including stereoisomeric pure forms (eg, pure geometry, pure mirror isomer, or pure non-mirror isomer) and Mirror isomers and stereoisomeric mixtures. Enantiomers and stereoisomeric mixtures can be resolved into their constituent enantiomers or stereoisomers using separation techniques or palm synthesis techniques known to those skilled in the art. The compounds may also exist in several tautomeric forms including enol, keto, and mixtures thereof. Accordingly, the chemical structures described herein include all possible tautomeric forms of the illustrated compounds. The present invention also includes isotopically-labeled compounds in which one or more of the atoms -10-200538107 (7) have an atomic mass different from the atomic mass or mass number conventionally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include (

But not limited to) 2 Η, 3 Η, 13 C, 14 C, 15 N, 18 Ο,] 7 0 and 3 5 S. The compounds may be in unsolvated forms and solvated shapes, including hydrated forms and present as N-oxides. Generally, hydrated, solvated forms, and N-oxides are within the scope of this invention. Certain compounds may exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the intended use herein. Further, it should be understood that when the structure of the compound portion is explained, the 'brackets indicate the point at which the partial structure is connected to the rest of the molecule. The "alkyl" itself or the portion as another substituent refers to the A saturated or unsaturated branched, linear, or cyclic monovalent hydrocarbon group obtained by removing a hydrogen atom from a single carbon atom of an alkene, alkene, or alkyne. Typical alkyls include (but are not limited to) methyl; ethyls such as ethyl, vinyl, and ethynyl; propyls such as propane-1, propane-2-yl, cyclopropane-1, propane One 1-flammable 1-based, propane 1-diluted 2-based, propan-2-propane-1-yl (allyl), cyclopropan-1, propene-1, propane-2 Alkenyl-one, propane-1, acetylene-1, propyl, 2-propynyl-1, etc., butyls such as butanyl-1, butan-2-yl, 2-methyl-1 Propanyl 1-yl, 2-methyl-propanyl 2-yl, cyclobutanyl 1-yl, dibutyl-1 1-methyl-1, dibutyl-1, 2-methyl, 2-methyl-propyl- 1—Small one, one, one, one, one, one, one, one, one, one, two, one, two, one, two, one, one, three, one, one, three, one, one, one, one, three, one, two, one 2-base, cyclobutadiene, one-ene-1, one-base, cyclobutane-1, one-flame—3-base, cyclobutane-1, 153—di-burn, one; I-base, butadiene—one-alkyne—1 • 11-200538107 (8) mono-, butan-1-alkyn-3-yl, butan-3-yn-1-yl, etc., and the like. The term "alkyl" is expressly intended to include such radicals having any degree or level of saturation, that is, radicals having a carbon-carbon single bond, radicals having one or more carbon-carbon double bonds, having one or Multiple carbon-carbon reference bonds and bases with a mixture of carbon-carbon single 'double and reference bonds. Where a particular level of saturation is intended, the terms "alkylalkenyl" and "alkynyl" are used. Preferably, the alkyl group contains from 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms, and most preferably, from 1 to 6 carbon atoms. "Alkanyl" itself or as part of other substituents refers to a saturated branched, straight or cycloalkyl group obtained by removing a hydrogen atom from a single carbon atom of the parent alkane. Typical alkyl groups include, but are not limited to, methyl groups; ethyl groups; propyl groups such as propane-1-yl, propane-2-yl (isopropyl), cyclopropyl-1-yl, etc., butyl Classes such as butanyl: [-based, butan-2-yl (secondary monobutyl), 2-methyl-propanyl-1 (isobutyl), 2-methyl-propanyl 2-yl (three Grade one butyl), Cyclobutene :! One base, etc., and similar. "Dilute radical" itself or as part of other substituents refers to an unsaturated branched, straight chain having at least one carbon to carbon double bond obtained by removing a hydrogen atom from a single carbon atom of the parent group. Chain or cycloalkyl. Basic double bonds (and so on) can be in cis or trans configuration. Typical alkenyls include (but are not limited to) vinyl; propenyls such as allyl-1, allyl-1, allyl-1, allyl-2, allyl-2, allyl-1, allyl (allyl) Acryl), allyl 2-ene-2, allyl, cyclopropyl-1, allene-1, allyl; cyclopropan-2-ene-1] -yl; butene-12- 200538107 (9) bases such as butyl-1 Mono-ene-1 mono-, but-1--1-ene-2-yl, 2-methyl-propane-1 mono-ene-1 1-yl, butadi-2-ene-1-yl, butadi-2-ene-1 1 Base, but-2-ene-2, base-1, butane-1,3-diene ~ 1-one base, butane-1,3-diene-2 2-base, cyclobutane] oneene-1 base, ring Ding-1 is a 3-base, cyclic Ding-1, 3-2 is a 1-base, and so on; and the like. "• alkynyl" itself or as part of another substituent refers to an unsaturated branched chain having at least one carbon-carbon parameter by removing a hydrogen atom from a single carbon atom of the parent alkyne , Linear or cycloalkyl. Typical alkynyls include (but are not limited to) ethynyl; propynyls such as propionyl- 1-alkynyl 1-yl, prop-2-yl- 1-ynyl and the like; butynyls such as butanyl- 1-alkynyl One-one-one, butan-l-alkyn-3-yl, butan-l-alkyn-1-yl, etc., and the like. "Alkandiyl" itself or as part of other substituents means by removing one hydrogen atom from two different carbon atoms of the parent alkane, olefin or alkyne, or by removing from the parent alkane, A saturated or unsaturated branched, straight or cyclic divalent hydrocarbon group obtained by removing two hydrogen atoms from a single carbon atom of an alkene or alkyne. The valences of the two monovalent or divalent centers may be the same. Or different atoms form a bond. Typical alkylenediyls include (but are not limited to) methylenediyl; ethylenediyls such as ethylene-1,1,2-diyl, ethylene-1,2-diyl, ethylenyl-ι, ι One-diyl, ethylene-1,2-diyl; propanediyls such as propa-151-diyl, propa-u-diyl, propa-2,2-diyl, propa-1,3-diyl, Cyclopropene-1,2-diyl, Cyclopropene-1,2-diyl, Propylene-1 Propylene-1,2-diyl, Propyl-1 Propylene-1,2-diyl, Propyl-2-ene-152 -Diyl, propane], one burning one], 3 200538107 (10) —diyl, cyclopropane — one one, I, 2 — diyl, cyclopropane — 2-dilute one, 2 — —yl, cyclopropane —2 —ene-I, 1-diyl, propane-1__ Alkyne-U-one-based, etc .; Butane-based groups such as butane-, 1-one-based, butane-based, 2-one-based, butane-based, butane-based, butane-based, butane-based, butane-based 252-mono-, 2-methyl-propan-l, 1-diyl, 2-methyl-propan-l, 2-diyl, cyclobutan-i, 1-diyl; cyclobutan-1,2- Diyl, cyclobutane-diyl, butane-1 monoene-1,1-diyl, butane-1 monoene-1, 1,2-diyl, butane-1 monoene-1, 3-diyl, butyl — 1 one, 1,4-diyl, 2-methyl-propane-1, one-flammable 1,1-diyl, 2-methylene-propane-1, 1,1-diyl, butane-1,3 — One suspicion—1,1—diyl, butan-1,3-diene-1—diyl, butan1,3—monoene-1,3—diyl, butane1,3—diene-1 , 4-diyl, cyclobutane-1, 1-ene-1, 2-diyl, cyclobutane-1, 1-ene-1, 3-diyl, cyclobutane-2-ene-1, 2-diyl, cyclobutane Mono-1,3-diene-1,2-diyl, cyclobutane-1,3-diene-1,3-diyl, but-1-acetylene-1,3-diyl, butadiene-1 One 1,4 —two base , Butane-1,3-diyne-1,4-diyl, etc. 'and the like. In cases where a certain level of saturation is intended, the nomenclature alkanediyl, alkenyldiyl and / or alkynyldiyl are used Preferably, the alkanediyl group is (C! -C2G) alkanediyl group, more preferably, (C, -C].) Alkanediyl group, most preferably, (C] -C6) alkanediyl group, preferably saturated. Non-cycloalkanediyl, where the center of the group is at the terminal carbon, for example, methyldiyl (methano); ethylene-1,2-diyl (ethano); propan-l53-diyl ( Propyl (prOpan)); butyl-1,4-diyl (butano); and similar (also known as alkyleno, defined below). ”院 院 基 （a I ky 1 e η 〇）” itself or as a suitable part of ^ ^ body meaning 忭 other substituents -14-200538107 (11), which means that there are two A straight-chain alkanediyl group at the center of a terminal monovalent group obtained by removing one hydrogen atom from each of two terminal carbon atoms of an alkane, olefin, or alkyne. Typical alkylene groups include (but are not limited to) methylene groups; ethylidene groups such as ethylidene, vinylidene, and ethyleneethynyl; propylidene groups such as vinylidene, vinylidene [1] alkenyl, Propylene [1,2] dienyl, propylene [1] alkynyl, etc .; Butyls such as butylene [1], butylene [1] alkenyl, butylene [2] alkenyl, butylene [1, 3] dienyl, butylene [丨] alkynyl, butylene [2] alkynyl, butylene [1,3] dialkynyl, and the like, and the like. Where a particular level of saturation is intended, the nomenclature alkano, alkeno and / or alkyno are used. Preferably, the alkylene group is (C) -C2G) alkylene group, more preferably, (C! -C1G) alkylene group, most preferably, (C! -C6) alkylene group. More preferred are straight-chain saturated alkylenes such as methano, ethano, propano, butano, and the like. "Amidinyl" itself or as part of other substituents refers to the group -C (〇) R3 (), where R3G is hydrogen, scholyl, cyclosynyl, cycloheteroalkyl, aryl, as defined herein Group, aralkyl, heteroalkyl, heteroaryl, heteroaralkyl. Representative examples include (but are not limited to) formamyl, ethylamyl, cyclohexylcarbonyl, cyclohexylcarbonyl, benzamidine And benzoylcarbonyl and the like. "Amido" itself or as part of other substituents refers to the group -NR31C (0) R32, where R31 and R32 are each independently hydrogen, alkyl as defined herein , Cycloalkyl, cycloheteroalkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroaralkyl. Representative examples include (but are not limited to) formamido, acetamido , Cyclohexylcarbonylamino, cyclohexylmethylmonocarbonyl-15-200538107 (12) group, benzylamino, benzylamine and the like. "Alkoxy" itself or as other substituents The part refers to the radical OR33, where R33 represents an alkyl or cycloalkyl group as defined herein. Representative examples include (but are not limited to) methoxy, ethoxy , Propoxy, butoxy, cyclohexyloxy and alikes. '' Alkoxycarbonyl group "by itself or as part of another substituent, refers to a group C (Ο) OR33, wherein R33 is as defined above. "Aryl" itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group obtained by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. Typical aryl groups include, but are not limited to, those obtained from stilbene, anthracene, stilbene, stilbene, anthracene, molybdenum, benzene, cave, calyx, manganese, manganese, Liushen, Liufen, hexalene As , Fei, Qian, Bu, 蒎, 苒, 苒, 箓, Bitriphenyl, Bi Er Tu and similar. Preferably, the aryl group contains from 6 to 20 carbon atoms', more preferably from 6 to 12 carbon atoms. "Aralkyl" itself or as part of another substituent refers to a non-cycloalkyl 'hydrogen atom bonded to a carbon atom, typically a terminal or sp3 carbon atom, replaced by an aryl group. Typical aryl Alkyl groups include (but are not limited to) benzyl, 2-phenylethylene-1, 2-phenylethylene-1, 1-methyl, 2-methyl-1, 1-yl, 2-methyl-1, 1-yl Mono-, t-benzyl, 2-t-acetophen-1-yl and the like. In the case where a specific alkyl moiety is intended, the nomenclature aralkyl, arkenyl and / or aralkynyl is used. Preferably, the square group is (C6-C3 0) aralkyl, for example, the alkyl, ene-16-200538107 (13) group or alkynyl part of aralkyl is (C! —C1G) and aryl part Is (c6-C2G), more preferably the aralkyl is (C6-C2Q) aralkyl, for example, the alkyl, alkenyl or alkynyl molecule of aralkyl is (G-C8) and the aryl moiety is ( c6 — c12) 〇 "Cycloalkyl" itself or as part of other substituents refers to saturated or unsaturated cycloalkyl. In cases where a certain level of saturation is intended, nomenclature is used '' Cycloalkyl 'or' 'cycloalkenyl'. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Preferably, the cycloalkyl group is (C3-C1G) cycloalkyl, and more preferably, (c3-c7) cycloalkyl. "Cycloheteroalkyl" itself or as part of another substituent refers to a saturated or unsaturated cycloalkyl 'in which one or more of the carbon atoms (and any related hydrogen atoms) are independently substituted by the same or different Atom replacement. Typical heteroatoms replacing carbon atoms (etc.) include, but are not limited to, N, P, 0, S, Si, and the like. In cases where a certain level of saturation is intended, the nomenclature is used, 'cycloheteroalkylπ or πcycloheteroalkenyl. "Typical cycloheteroalkyls include (but are not limited to) derived from epoxides, nitrogen heterocycles Propylenes, thiapropanes, imidazolidine, morpholine, piperidine, piperidine, pyrazolidine, pyrrolidine, quinucleine, and similar groups. "Heteroalkyl, heteroalkyl, heteroalkenyl ``, Heteroalkyl, heteroalkanediyl, and alkylene '', or part of other substituents, refers to alkyl, alkyl, alkenyl, alkynyl, alkyldiyl, and alkylene respectively, one of which Multiple carbon atoms (and any related hydrogen atoms) are independently replaced by the same or different heteroatomic groups. Typical heteroatom groups that can be included in these groups include (but not limited to -17-200538107 (14) made by) —ο—, —s, —, —s-s, — o-s-,, NR35R36, = N — N =,-N = N-, -N = N — NR37R38 —, ~ PR39-,-P (0) 2 —,-POR39-,-O-P (0), -SO-, -S. 2—, — SnR41R42 — and the like, wherein Rh, R3 6, R3 7, R3 8, R3 9, R40, R4 1 and R42 are independently hydrogen, alkyl

, Substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl , Heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroaryl, or substituted heteroaralkyl.

"Heteroaryl" itself or as part of another substituent refers to a monovalent heteroaryl group obtained by removing a hydrogen atom from a single atom of the parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, those derived from acridine, arsenidene, carbazole, 0-carboline, fluorene, lateene, perylene, furan, imidazole, indole, indole, indole Indole, indole, isobenzofuran, isoprene, isopropene, isoindole, isoquinoline, isothiazole, isoxazole, pyrimidine, oxadiazole, oxazole, pyrimidine , Pyridin, phenanthroline, phenanthrene, cultivator, pteridine, purine, piperan, pyridine, pyrazole, dagen, pyridine, pyrimidine, pyrrole, pyrrohzine, D quinazoline 'pyrene , Quinucloline, quinucloprid, tetrazole, thiadiazepine, thiodiazepine, thiophene, triazole, gluten, and similar groups. Preferably, the heterosquaryl group is a 5- to 20-membered heteroaryl group, more preferably from 5 to 10-membered heteroaryl group. Preferred heterosquaryl groups are the same as those obtained from thiophene, pyrrole, benzothiophene, benzofuran, indone, stilbidine, phosphine, imidazole, oxazole, and pyrenyl. '' Heteroaryl group '' itself or as part of other substituents refers to an acyclic group 'a hydrogen atom bonded to a carbon atom, typically terminated or -18-200538107 (15) sp3 carbon atom' Replaced by a heteroaryl group. In the case where a specific alkyl moiety is intended, the nomenclature heteroaralkyl, heteroarylalkenyl, and / or heteroarylquickyl is used. In the preferred embodiment, 'heterofang: A heteroaryl group having 6 to 30 members, for example, the alkyl, alkenyl, or alkynyl part of a heteroaralkyl group is 1 to 10 members and the heteroaryl part is 5 to 20 members heteroaryl ' More preferably, a 6- to 20-membered heteroaralkyl group is, for example, an alkyl, alkenyl or alkynyl portion of a heteroaralkyl group is 8 to 8 members and a heteroaryl portion is 5 to 12 membered heteroaryl groups. The "parent aromatic ring system" itself or as part of other substituents refers to an unsaturated or polycyclic ring system having a conjugated 7Γ electronic system. Explicitly included in the definition of "parent aromatic ring system" is a fused ring system in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, manganese, hydrogen indene, Indene, osmium, etc. Typical mother aromatic ring systems include (but are not limited to) stilbene anthracene, stilbene, stilbene phenanthrene, anthracene, hydrazine, benzene, cave, caustic, anthracene, manganese, Liushen, Liufen, Liuion, as 1-indene, s-indene, indene, indene, tea, yashen, bafen, octadecane, azalea, penta-2,4-diene, wushen, maoya, wufen, chicory, radon, phenanthrene , Qian, Bu, 蒎, 苒, 茶, tea, bitriphenyl, bisandu and the like. "Parent heteroaromatic ring system" itself or as part of another substituent means a parent aromatic ring system in which one or more carbon atoms (and any related hydrogen atoms) are each independently the same or different heteroatom Base replacement. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, and the like. Explicitly included in the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, arsenic misprints, Benzodioxane, benzofuran, fluorene, pinene, indole-19-200538107 (16), indolin, gluten, etc. Typical parent heteroaromatic ring systems include, but are not limited to, arsenidene, carbazole, / 5-carboline, fluorene, pinene, oxoline, furan, imidazole, indazole, indole, indolinoline , Indigo, isobenzofran 'isopinene, isoindole, isoindole, isoD quinoline, isothiazole, isoxazoline, oxidazole, oxazole, pyrimidine, pyrene Pyridine, morpholine, cocoon, cocoon, purine, purine, piperan, pyridine, pyrazole, dacoline, pyridine, pyrimidine, pyrrole, pyrrozine, quinazoline, D | Porphyrin, tetrazole, thiadiazole, thiazole, thiophene, triazole, gutton, and the like. "'Pharmaceutical composition'" means at least one compound of the present invention and a compound with which the compound is administered to a patient's pharmaceutically acceptable excipient. "Pharmaceutically acceptable salt" means a salt of a compound of the present invention which has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanyl propionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, cis-butyl Adipic acid, trans-butenedioic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzyl) benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1 5 2 -ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, Benzoic acid, 4-Chlorobenzenesulfonic acid, 2-Tetrasulfonic acid, 4-Toluenesulfonic acid, Camphorsulfonic acid, 4-methyldisulfonic acid Cyclo [2.2.2] -octan-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfate, gluconic acid, amidine Acids, hydroxy acids, salicylic acid, stearic acid, adipic acid, and the like; or (2) when an acidic proton is present in the parent compound, and Metal ions, for example, alkali metal ions, alkaline earth ion-20-200538107 (17) ions, or aluminum ions; or coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methyl reduced glucosamine and the like The salt formed. "Pharmaceutically acceptable vehicle" means a diluent, adjuvant, excipient, or carrier with which a compound of the invention can be administered. "Patient" includes humans. The terms "human" and " "Patient" is used interchangeably herein. "Prevention" means reducing the risk of acquiring a disease or disorder (that is, developing at least one disease in a patient who is exposed to or susceptible to the disease but has not experienced or shows symptoms of the disease). Clinical symptoms do not develop). "Prodrugs" refer to derivatives of drug molecules that need to be transformed in the body to release the active drug. Prodrugs are often, although not necessarily, pharmacologically inactive until converted into the parent drug. Drugs can be converted into, for example, sulfonate, ester or carbonate prodrugs, which can be hydrolyzed in vivo to provide hydroxyl compounds. Amine-containing drugs can be converted into, for example, Carbamate, amidine, enamine, imine, N-phosphinofluorenyl, N-phosphonium phosphonium, or N-sulfenylphosphonium prodrug, which can be hydrolyzed in vivo to provide amine compounds. Carboxylic acid Acid drugs can be converted into esters (including silyl esters and thioesters), amidines, or amidine prodrugs, which can be hydrolyzed in vivo to provide carboxylic acid compounds. Drugs with functional groups different from those listed above are familiar It is known to those skilled in the art. "Anterior part" refers to the form of a protecting group that converts a drug into a prodrug when used to mask functional groups in the drug molecule. Typically, the anterior part is through enzymes in the living body. Or non-enzymatically cleaved bonds (etc.) will be attached to the drug-21-200538107 (18)

"Protecting group" refers to the classification of atoms (g r ο ι ι π n), which, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry" (Weiss' 2nd Edition '1 9 9 1) and Harris ο et al.', Essentials of Synthetic Organic Methods " , 1-8 books (John Weiss and son, 97j-1996). Representative amine protecting groups include (but are not limited to) formamyl, acetamyl, trifluoroacetamyl, benzyl Group, benzyloxycarbonyl, tertiary monobutoxycarbonyl ("Boc ,,), trimethylsilyl (" TMS ,,), 2-trimethylsilyl monoethanesulfonyl ("SeS "), Trityl and substituted trityl, allyloxycarbonyl, 9-manganylmethoxycarbonyl (" FMOC"), nitrotriazoxycarbonyl ("NV〇c ") and similar Representative examples of aryl-protecting groups include, but are not limited to, those in which the hydroxyl group is acidified or alkylated, such as benzyl, and trityl ethers and alkyl ethers, and tetrahydroanyl ethers. , Trialkylsilyl ether and allyl ether.

"Substituted" means that one or more hydrogen atoms are independently replaced by the same or different substituents (etc.). Typical substituents include (but are not limited to) -M, -R6〇, _ 〇_ -NR R, = NR6 °, -CF3, -CN, -0CN, -SCN, ~ NO, -N〇2, = n2, — n3, one s (〇) 2〇_, one s (〇),-S (O) 2R6〇, one 〇s (〇2) 〇_, one 〇s (〇) 2r6〇, ~ p (〇) (O) 2?-P (0) (OR6.) (〇-),-OP (〇) (OR6.) (OR6), a C (0) R6. , A c (s) r6〇,-c (0) OR6. , ~ C (0) NRwR6], —c (〇) 〇_, —

0, one 〇R 6 0

-SR 6 0

S

OR 6 0, —NR62C (〇) nr6〇r6], —nr62c (s) nr6〇r6-22- 200538107 (19) —NR62C (NR63) nr60r61 and one c (nr62) nr60r6], of which

M is independently halogen; R6G, R61, R62, and r63 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl 'ring Heteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R6Q and R61 together with the nitrogen atom to which they are bonded form a cycloheteroalkane Or substituted cycloheteroalkyl rings; and R64 and R65 are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted Cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R04 and R65 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted ring Heteroalkyl ring. Preferred 'substituents include -M, -R6〇, = 〇,-〇R60, -SR60, -S-, = S,-NR6〇R6], =: N R6 0 j -CF 3, -CN , One OCN, one SCN, one NO, ~ N 0 2

, = N2 5-N3, — S (O) 2R60, -〇S (〇2) 〇 ', ~ 〇S (0) 2R60,-P (O) (0_) 2,-P (〇) (OR60) (O ')

, -OP (O) (OR60) (OR6)), -C (0) R60, -C (S) R60, -C (O) OR60 ,, -C (〇) NR60R61, -C (0) 0- ,--Nr62c (〇) NR 60r6 1, more preferably -M, -.R60, = = 0, -OR60, -SR60, -NR60 R61, -cf3 1 -CN, -NO 1,-s (〇) 2R60 ,--P (〇) (OR 60) (〇_) -OP (〇) (OR60) (OR61), -C (〇) R60,--c (〇) OR60,-c (0) NR 60R61 , One c (〇) 0 ", best, one M, —-R60 ,: = 0, — OR60, SR60, — -NR (i0R6 1,-CF3, one -CN y — N02 ,. -S (0 ) 2R60, -OP (〇) (OR60) (OR 61)? A c (0) R60 5 • 23- 200538107 (20) —C (O) OR60, a C (〇) 〇—, where R60, R6] And R62 are as defined above. "Treatment" of any disease or disorder refers, in a specific embodiment, to ameliorating the disease or disorder (ie, braking or reducing the development of the disease or at least one clinical symptom). In another embodiment, "treatment" refers to the improvement of at least one physical parameter, which can be achieved without the patient Others. However, in another embodiment, "treatment" refers to the inhibition of a disease or disorder physically (eg, stabilization of discernible symptoms), physiologically (eg, stabilization of physical parameters), or both. In another embodiment, "treatment" refers to delaying the onset of a disease or disorder. "Therapeutically effective amount" means an amount of a compound that is sufficient to effectively treat the disease when administered to a patient to treat the disease. "Effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the patient to be treated. Reference is now made in detail to the preferred embodiments of the invention. The invention will be described in conjunction with the preferred embodiments It should be understood that the present invention is not intended to be limited to the preferred embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents that may equally be included within the spirit and scope of the invention as defined by the scope of the patent application. 5 · 2 compounds of structural formula (I) In the first embodiment, the compounds of the present invention include compounds of structural formula (I):

200538107 (21) or a solvate or hydrate thereof or N monoxide, wherein: R], R2, R3, R5, R6, and R7 are independently hydrogen, alkyl, substituted alkyl, aryl, or Substituted aryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl , Heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; R4 and R8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl , Aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroaryl Group, substituted heteroaralkyl, heteroalkyl or substituted heteroalkyl or does not exist when N is an aromatic ring moiety; optionally, R] and R2 are alkanediyl, substituted Alkanediyl, heteroalkanediyl or substituted heteroalkanediyl; optionally 'R5 and R6 together are alkanediyl, substituted alkanediyl, heteroalkanediyl or substituted heteroalkanediyl ; Arbitrary R1 and R2 together, R2 and R3 together, and R2 and R4 together are alkanediyl, substituted alkanediyl, heteroalkanediyl, or substituted heteroalkanediyl; optionally, R5 and R6 — R6 and R7—and R6 and R8—are alkanediyl, substituted alkanediyl, heteroalkanediyl, or substituted heteroalkanediyl; optionally, R3 and R7 are alkanediyl , Substituted alkanediyl, heteroalkanediyl, or substituted heteroalkanediyl, and W2S9) Y-2 is (ws4) _2, (W2S) 2) '2 5 (-25- 200538107 (22 ) W2S7)-2, (W2S8)-2, (W2S1 1) 2 '(W2 6 (W 2 S 1 3) 2. 1 In some specific embodiments, ya is (WS4) _2 and all ^ L R2 , R3, R4, R5, R6, R7 and R8 are not chlorine.

In the example, Y is (W S 4) — 2 and all R1, R2, R3, R, R7 and R8 are not alkyl.

In another specific embodiment, 'R1 R5 is ++ 屮 4: = R6- 屮 -R8 R3 R7. Preferably Y is (ws4) _2. In some embodiments, at least one of R1, r2, and R4 is not an alkyl group. In other specific embodiments, R1, r2, and r4 are a hydrogen 'group or a substituted alkyl group. Preferably, Ri, r2 and r4 are hydrogen, methyl or ethyl.

In other specific embodiments, R1 and R2 are alkyl. Preferably, R1 and R2 are methyl or ethyl. In other specific embodiments, R 1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl, substituted aralkyl, cycloalkane Or substituted cycloalkyl. Preferably, R1 and R2 are taken together as an alkylene (a) ky] eno), a substituted alkylene, a heteroalkylene or a substituted heteroalkylene. More preferably, R1 and R2 are taken together as an alkylene group or a heteroalkylene group. In other specific embodiments, R1 and R2 together, and R2 and R3 together with R2 and R4 are alkylene, substituted alkylene, heteroalkylene or -26-200538107 (23) substituted Heteroalkylene. Preferably, R1 and R2 together are R2 and R3 together and R2 and R4 together are alkylene. Preferably, R1 (R2) (R3) (r4) N has a structure:

In other embodiments, R3 and R7 are taken together as alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene. Preferably, R3 and R7 together are alkylene or heteroalkylene.

In other specific embodiments, R1, R2, and R4 are hydrogen, alkyl, or substituted alkyl, and R3 is alkyl, substituted alkyl, alkenyl, aryl, aromatic alkyl, cycloalkyl, or R3 Together with R7, it is an alkylene group, a substituted alkylene group, a heteroalkylene group, or a substituted heteroalkylene group. Preferably, R1, R2 and R4 are methyl or ethyl and R3 is alkyl. Substituted alkyl, alkenyl, aryl, aromatic alkyl, cycloalkyl or R3 and R7 together are alkylene. Or heteroalkylene. Preferably, R], R2, and R4 are methyl or ethyl and R3 is alkyl, and is substituted by an alkyl, alkenyl, aryl, aralkyl, or cycloalkyl group. In other specific embodiments, R1 (R2) (R3) (R4) N is • 27- 200538107 (24)

Or— In other specific embodiments, R1 (R2) (R3) (R4) Ν is —N + ~

I ο In other specific embodiments, R1 (R2) (R3) (R4) Ν is

18

In other specific embodiments, R], R2 and R4 are methyl or ethyl and R3 and R7 together are an alkylene or heteroalkylene. Preferably, R1 (R2) (R3) (R4) N has a structure: -28- 200538107 (25)

One 1 or

In other specific embodiments, R1, R2, and R4 are hydrogen and R3 is a substituted alkyl, cycloalkyl, or substituted heteroaryl, or R3 and R7 together are an alkylene. In other specific embodiments, R1 and R2 are alkyl and R3 and R4 are, alkyl, substituted alkyl, aryl, aralkyl, or alkylene. Preferably, R1 and R2 are methyl or ethyl and R3 and R4 are alkyl, aryl, aralkyl or alkylene. In other specific embodiments, R1 (R2) (R3) (R4) N is -29- 200538107 (26)

HO

$

NH2

A mixture of straight-chain alkyl groups. In other embodiments, R1, R2, and R4 are hydrogen and R3 is a substituted alkyl, substituted heteroaryl, cycloalkyl, or alkylene. Preferably, R1 (R2) (R3) (R4) N has a structure:

NH3 + ho, ^ \ ^ 〇h ΌΗ

In other specific embodiments, 'R1 and R2 together are an alkylene group, a substituted alkylene group, a heteroalkylene group, or a substituted heteroalkylene group, r3 is an alkyl group or a substituted alkyl group, and R4 is hydrogen. Or does not exist. Preferably, R1 (R2) (R3) (R4) N has a structure:

5.3. Synthesis of compounds The chelating compounds described herein can be obtained by the method shown in Schemes and 2 exemplified conventional methods. -30- 200538107 (27) Synthesis method. The starting materials useful in the preparation of the compounds and intermediates described herein are commercially available or can be prepared by well-known synthetic methods. Substituted ammonium salts (eg, ammonium hydroxide and ammonium halides) can be purchased from commercial sources or can be synthesized using well-known synthetic methods (Harrison et al., "The Essentials of Synthetic Organic Methods", vol. And son, 1 97 1 — 1 996); ”Beilstein's Handbook of Organic Chemistry”, Germany

Beilstein Organic Chemistry Association in Frankfurt; Feiser et al., "Reagents for Organic Synthesis", vols. 1-17, Weiss Interscience; Trost et al., "Inclusive Organic Synthesis", Pergamon Press, 1991; `` Theilheimer Organics Synthetic Methods in Chemistry ", Vol. 1-4, Karger, 1991; March," Advanced Organic Chemistry ", Weiss

Interscience, 1991; Larock, "The All-Inclusive Organic Transformation", VCH Press, 1989; Paquetie, "Encyclopedia of Reagents for Organic Synthesis," "John Weiss & Son, 195. Used to synthesize this article Other methods of the described compounds and / or starting materials are described in the art or will be readily apparent to those skilled in the art. Therefore, the methods mentioned in Schemes 1 and 2 herein are illustrative and not Inclusive. • 31-200538107 (28) Process R2- N +-R4 〇Η · + Division 3) 2wS4 R3 Shuijin 1r2- N 丨 + -R4j WS4 / 2

As shown above, in Scheme 1, the addition of quaternary ammonium hydroxide to the thiotungstate in the presence of water causes cation exchange (driving equilibrium to the product by removal of volatile ammonia) to provide the desired thiotungstic acid Salt derivatives. R ^ N + -R4 X + (NH3) 2WS4 R3 Process 2 Acetonitrile R2-N + -r4) WS, Heart, 2

As shown above, in Scheme 2, the addition of a quaternary ammonium halide to the thiotungstate in the presence of acetocyanine results in cation exchange (driving the equilibrium to the product by the formation of ammonium halide) to provide the desired thiotungstate derivative . It should be noted that thiotungstate derivatives in which the ammonium counter ion is different can be prepared from compound 3 by treatment with one equivalent of different ammonium counterions. This type of reaction is expected to produce a statistical mixture of products. Further, those skilled in the art will recognize that conventional methods involving the treatment of tungstate with ammonium and hydrogen sulfide can be used to synthesize many of the compounds described herein. 5.4 Assays Those skilled in the art should be aware that in vitro and in vivo assays used to measure the activity of the compounds described herein may be illustrative and not all-inclusive. -32- 200538107 (29) 5.4.1 Assay of endothelial cell transfer For endothelial cell transfer, add 200 // L collagen solution per type of transfer well to coat with type I collagen (50 g / ml), and then 37 ° C Incubate overnight. The transfer wells are assembled on a 24-well dish and a chemical attractant (eg, FGF-2) is added to the lower chamber at a total volume of 0.8 ml of culture medium. Endothelial cells such as human umbilical vein endothelial cells (" HUVEC "), which have been isolated from monolayer cultures using trypsin, are diluted in blood-free medium to a final concentration of about 106 cells / ml and 0.2 ml of this cell Suspension was added to the upper chamber of each filter. Inhibitors were added to both the upper and lower chambers, and allowed to transfer for 5 hours at 37t in humid ambient gas. Remove the filter from the dish stained with DiffQuik®. Borrow Cells and separation membranes that were not transferred were removed from the upper chamber with a cotton swab, installed on a slide rail, and counted under a high force field (400x) to determine the number of transferred cells. 5.4.2 Anti-invasive activity organisms assay

Test compounds and / or compositions for resistance to invasion. The ability of cells such as endothelial cells or tumor cells (eg, PC-3 human prostatic cancer) to invade through the reconstructed basement membrane (Matrigel®) in an assay is known as the Matrigel® Invasion Assay (Kleinman et al. ' Biochemistry 1986, 25: 312-318; Parish et al., Int J. Cancer 1992, 52: 378-383). Matrigel® is a reconstructed basement membrane containing type IV collagen, laminin, heparan sulfate polysaccharide proteins such as basement proteoglycan (perl ecan), which binds to -33- 200538107 (30) and area BFGF, vitronectin, and transforming growth factor-1 (known as plasminogen activator inhibitor type I (PAI-1)), TGF cold, urokinase-type plasminogen activation Agent (u PA), tissue plasminogen activator (t PA), and serine protease preparation (serPin) (Chambers et al., 311 (: · Res. 1995, 55: 1578 — 1585). The results obtained in this assay for compounds that target extracellular receptors or enzymes are typically predictions of the efficacy of these compounds in vivo (Rabbani et al., 1995 'Int. J. Cancer 63: 840-845) ° These assays are used Filter tissue culture inserts. Invading cells are defined as cells that can traverse the upper orientation of Matrigel® and polycarbonate membranes and adhere to the bottom of the membranes. A membrane containing a polycarbonate membrane (8.0 micron pore size) ( Costar) Coated with iviatrigel® (collaborative research), which has been diluted in sterilized PBS to a final concentration of 75 μg / ml (60 μl of diluted Matrigel® per insert) and placed on a 24-well plate The membrane was dried overnight in a biosafety box, and then rehydrated on the shaker table by adding DMEM containing 100 microliters of antibiotics for 1 hour. DMEM was removed from each insert by pipetting and 0.8 Ml of DMEM / 1 0% FBS / antibiotic power □ to 24 — in each well of a dish to surround the outer side of the filter ("lower chamber"). Fresh DMEM / antibiotic (100 μl), human Glu-fibrin Lysogen (5 μg / ml), and any compounds to be tested are added to the upper end, on the inner side of the filter ("upper chamber"). The cells to be tested are trypsinized and resuspended In DEME / antibiotics, then add to the upper chamber of the filter at a final concentration of 200538107 (31) 8 00,000 cells / ml. The final volume of the upper chamber is adjusted to 200 μl. The mounted dish is then placed in a humidity of 5% C02 Incubate for 72 hours under ambient gas. After incubation Fixing the cells and using DiffQuik® (Giernsa stain) and the upper chamber then stained cotton rod to remove any cell scraping Matrigel® invasion and not passing through the membrane. The membranes separated from the filter using X-acto sheets were mounted on the slides using Permount (R) and cover-slide rails, and then counted under a high power (40 Ox) field. The 5-10 field counts were used to determine the mean radon of the invaded cells and plot it as a function of the inhibitory concentration. 5.4.3 Tube-forming assays for anti-angiogenic activity Compounds can be tested for anti-angiogenic activity in one of two different in vitro assay systems. Endothelial cells, for example, human umbilical vein endothelial cells (" HUVEC ") or human microvascular endothelial cells (" HMVEC"), which can be prepared or commercially obtained at a concentration of 2 X 105 cells / ml with fibrin Original (5 mg / ml in phosphate buffered saline ("PBS")) was mixed in a 1: 1 (v / v) ratio. Thrombin (5 units / ml final concentration) was added and the mixture was immediately transferred Go to 24-well plates (0.5 ml per well). Allow formation of fibrin gel, then add VEGF and bFGF to the wells (each at 5 ng / ml final concentration) along with the test compound. The Wait for the cells to be cultured at 5% C02 for 4 days at 37 ° C. During the calculation, the cells in each well are classified as round, extended without branches, extended with one branch, or extended with 2 or more Results are expressed as the average of 5 -35- 200538107 (32) compounds at each concentration in different wells. Typically, cells remain round or form undifferentiated tubes in the presence of angiogenesis inhibitors (eg, 〇 or 1 branch). This test is recognized in this art as a prediction of the efficacy of angiogenesis (or anti-angiogenesis) in vivo (Min et al. Cancer Res. 1 996, 5 6: 242 8 — 243 3). In alternative tests, when When endothelial cells were cultured on Matrigel (R), endothelial cell tube formation was observed (Schnaper et al., J. Cell. Physiol. 1 9 9 5, 165: 107-118). Endothelial cells (1 x 104 cells / well) ) Transfer on Matrigel®-coated 24-well dish and quantify tube formation after 48 hours. Inhibitors are tested by simultaneous addition of endothelial cells or at different time points thereafter. Tube formation can also be achieved by adding Angiogenesis growth factors such as bFGF or VEGF, differentiation stimulants (eg, PMA), or combinations thereof are stimulated. This assay builds a model of angiogenesis by providing endothelial cells with a specific type of basement membrane, the stroma layer, which metastasizes And differentiated endothelial cells are expected to be encountered first. In addition, the matrix components found in Matrigel® (and in situ basement membranes), or their proteolytic products, are responsible for endothelial cell tube formation. For stimulation, it makes this model complementary to the aforementioned fibrin gel angiogenesis model (Blood et al., 8 丨 〇 (: 1 ^ 111 · Biophys · Acta 1 990, 1 03 2: 8 9 — 1 1 8; Odedra Wait,

Pharmac. Ther. 1991, 49: 111-124). These compounds inhibit endothelial cell tube formation in both assays, suggesting that the compounds will also have anti-angiogenic activity. -36- 200538107 (33) 5.4.4 Assay for inhibition of proliferation The ability of a compound to inhibit the proliferation of endothelial cells can be determined in a 9 6 -well manner. Type I collagen (gelatin) is used to coat dish wells (0.1-1 mg / ml in PBS, 0.1 ml per well, 30 minutes at room temperature) ° After dish washing (3x w / PBS) Each well is plated with 3 -6,000 cells and allowed to adhere in endothelial growth medium (EGM; Clonetics) or M199 medium containing 0.1-2% FBS for 4 hours (37 ° C / 5% CO2). At the end of the 4-hour period, medium and any non-adherent cells and fresh medium containing bFGF (1-10 ng / ml) or VEGF (1-10 ng / ml) were added to each well. Compounds to be tested Finally add and allow dish culture (37 ° C / 5% C02) for 24 to 48 hours. MTS (Promega) was added to each well and allowed to grow from 1 to 4 hours. The absorbance at 490 nm, which is proportional to the number of cells, was then measured to determine the difference in proliferation between the control wells and the wells containing the test compound. Similar assay systems can be set up using cultured adherent tumor cells. However, collagen may be omitted in this way. Tumor cells (eg, 3,000-10,000 / well) are plated and adhered overnight. Bloodless maggot medium was then added to the wells and the cells were synchronized for 24 hours. Medium containing 10% FBS was then added to each well to stimulate proliferation. The compounds to be tested are contained in some wells. After 24 hours, MTS was added to the dish and development and reading assays were performed as described above. Similar methodologies can also be used to assess the effect of compounds of the invention on the proliferation of tumor cells including other cell types than VEGF and bFGF, which are not used to stimulate cell growth. If there is evidence of anti-proliferative effects, the induction of apoptosis can be measured using Tumor-37-200538107 (34) TACS (Genzyme). 5.4.5 Assay for cytotoxicity The cytotoxic effect of the compounds described herein can be measured on a variety of cell types including tumor cells, endothelial cells, fibroblasts, and macrophages. A typical assay includes cells with a density of 5-10 000 cells per well in a 96-well dish. Compounds were then added at various concentrations and the cells were allowed to grow for 24 hours. The cells were washed 3X with culture medium. For the cytotoxicity assay (measurement of cytolysis), the procedure used in the Promega 96-Well Cytotoxicity Kit 5.4.6 corneal angiogenesis model is basically the same as that described by Volpert et al., J. Clin. Invest. 1996, 98: 671- 679. In brief, paralyzed female Fischer rats (120-140 g) and a sphere (5 μl) composed of Hydron®, bFGF (150 0 χ Μ) and the compound to be tested were implanted 1 · 0-1 from the edge In a tiny incision made in a 5 mm cornea. Neovascularization was assessed 5 and 7 days after implantation. On day 7, the animals are paralyzed and the blood vessels are perfused and stained with a dye such as colloidal carbon. The animals were then euthanized, the cornea fixed with formalin, and the cornea flattened and photographed to assess the extent of new blood vessel formation. New blood vessels can be quantified by imaging the total blood vessel area or length or simply by calculating blood vessels. 5.4.7 Matrigel® plug Assay -38- 200538107 (35)

This assay was performed essentially as described by Passaniti et al., Lab. Invest. 1992, 67: 519-528. Frozen Matrigel® (eg, 500 μl) (Collaborative Biomedical Products, 86 (^ 〇1 ^, 1 ^ 八) and heparin (eg, 50 μg / ml),? 0? -2 (eg, 400 Ng / ml) and the compound to be tested. In some assays, bFGF can be replaced by tumor cells as a stimulus for angiogenesis. The Matrige 1 ® mixture is injected subcutaneously near the middle of the abdomen to the 4-8 week-old athymus (Athymic) In nude mice, preferably 3 injections per mouse. The injected Matrigel® forms a tangible solid gel. The injection site is selected so that each animal receives a positive control plug (eg, FGF-2 + heparin) , Negative control plugs (e.g., buffer + heparin) and plugs including compounds to be tested for their effect on angiogenesis (e.g., FGF-2 + heparin + compound). All treatments are preferably performed in groups of three. Animals About 7 days after injection or another pair to observe angiogenesis may be the best time to sacrifice with cervical dislocation. Isolate the mouse skin along the middle of the abdomen and immediately recover and scan the Matrige 1 ® suppository at high resolution. The plugs were dispersed in water and incubated overnight at 37 ° C. The hemoglobin (Hb) content was determined using Drabkin's solution (eg, from Sigma) according to the manufacturer's instructions. The amount of Hb in the plug is an indirect measure of angiogenesis, When the amount of blood in its anti-indene sample. In addition, or the animal may inject ml of a buffer (preferably PBS) containing a high molecular weight glucan bound to the fluorophore before sacrificing it. The amount of light in the plugs dispersed by fluorescence measurement is determined as a measure of angiogenesis in the plugs. MAb anti-CD3 1 (CD31 is a platelet-endothelial cell adhesion molecule or "PECAM") staining can also be used to determine the Neovascularization and -39- 200538107 (36) microvessel density. 5.4.8 Chicken embryo chorioallantoic membrane (CA M) angiogenesis assay This assay is basically performed as described by Nguyen et al. Microvascular Res. 1994, 47: 31-40. Nets containing either angiogenic factor (bFGF) or tumor cells + inhibitors were placed on the CAM of 8-day-old chicken embryos and the CAM was observed for 3-9 days after sample implantation. Angiogenesis By determination Percent quantification of the squares in the network containing blood vessels. 5.4.9 In vivo assessment of angiogenesis inhibitory and antitumor effects using Matrigel® suppository assay with tumor cells. In this assay, tumor cells, for example, 1- 5 X 1 06 cells of 3 LL Lewis lung cancer or mouse prostate cell line M at L y Lu, mixed with Matrige 1 ® and injected into the rat's lumbar fossa followed by the procedure described in section 4.4.7. The mass of tumor cells in these plugs and the effective angiogenic response can be observed after about 5 to 7 days. The antitumor and antiangiogenic effects of the compounds in the actual tumor environment can be assessed by including them in the plug. Measurements of tumor weight, Hb content, or fluorescence content (injection of dextran-fluorescence conjugate before sacrifice) were then performed. To measure Hb or fluorescence, the plugs are first homogenized with a tissue homogenizer. 5.4.10 Xenograft model of subcutaneous tumor growth -40- 200538107 (37)

Nude mice were subcutaneously inoculated with MDA-MB-231 cells (human breast cancer) and Matrigel® (0.2 ml of 1 X 106 cells) in the right lumbar fossa of the animals. These tumors proceed to 200 mm3 and then begin treatment with the test compound. Tumor volume was obtained every other day and the animals were sacrificed after 2 weeks of treatment. The tumor was removed, weighed, and embedded in paraffin. Histological sections of the tumor were analyzed with Η and E, anti-CD31, Ki67, TUNEL, and CD68 staining. Other human tumor cell lines including, but not limited to, PC-3, CWR22R, SK-0V-3, A27 80, A549, HCT116, HT2 9 can also be used in a similar manner to test the antitumor activity of the compounds described herein. 5.4.1 1 Metastatic xenograft model compounds can also use experimental transfer models to test the inhibitory effect of metastasis at an later stage (Cr 0w 1 ey et al., Pr 0c. Na 1 11. A cad. S c i. United States 1 9 9 3, 90 5 0 2 1-5 02 5). Late metastases include the steps of tumor cell adhesion and extravasation, local invasion, seeding, proliferation, and angiogenesis. To record genes, preferably green fluorescent protein (GFP) genes, transfected human prostate cancer cells (PC-3), but the alternative method is to encode the enzyme chloramphenicol acetamyl-transferase (C FT) gene, luciferin or LacZ, was inoculated into nude mice. This method allows one of these markers (fluorescent detection of GFP or histochemical (h i s t o c h e mi c a 1) colorimetric detection of enzyme activity) to track the availability of these cells. Cells were injected (preferably, i.v.) and metastases were identified after about 14 days, especially the lungs and also in the lymph nodes, femur, and brain. This mimics the organs that naturally metastasize in human prostate cancer. -41 · 200538107 (38) Official orientation. For example, GFP-expressing PC-3 cells (1 x 106 cells per mouse) were injected i.v. into nude mice (ηιι / ηιι) intravenously. Animals were treated with q.d. IP given 100 micrograms / animal / day of test composition. Visual inspection Single metastatic cells and diseased cells were quantified by fluorescence microscopy or light microscopy histological chemistry or by honing tissues and detectable labels in quantitative colorimetric assays. 5.4.12 Spontaneous metastatic murine syngeneic breast cancer system (Xing et al., Int. J. Cancer 1 996, 67: 42 3-429) inhibited by HPRG and functional derivatives in vivo using Mat Bill mouse breast cancer cells . Tumor cells, such as about 106, were suspended in 0.1 ml of PBS and inoculated into the fat pads of female Fisher mouse breasts. At the time of vaccination, a 14-day Alza osmotic mini pump was implanted intraperitoneally to separate the phenol test compound. The compound is dissolved in P B S (for example, 200 μM stock solution), sterilized, and placed in a mini pump to achieve a release rate of about 4 mg / kg / day. Animals in the control group received vehicle (PBS) or vehicle control peptide by mini pump alone. The animals were sacrificed in about i 4 days. Other models of experimental transfer can also be used to evaluate compounds described herein. These models will utilize the above-mentioned human tumor cell lines injected via the posterior vein of nude mice. Typically, these mice were sacrificed and evaluated for the presence of metastases in their lungs 28 days after tumor cell inoculation. 5.4.133LL Lewis lung cancer: initial tumor growth This tumor strain was spontaneous in the lung cancer of C57BL / 6 mice in 951200538107 (39)

Produced (Cancer Res. 1955 '75: 39. See also, Malave et al., J. Nat'I. Cane. Inst. 1979, 62: 83-88). It reproduces by subcutaneous inoculation in a channel in C57BL / 6 mice and is tested in semiallogeneic C57BL / 6 X DBA / 2 F! Mice or allogeneic C3H mice. Typically six animals per group are used for subcutaneous implants, or ten are used for intramuscular implants. Tumors can be inoculated subcutaneously with 2-4 mm fragments or approximately 0.5-2 X 10 6-cell suspension cells (i η oc u 1 um) intramuscularly or subcutaneously. Treatment begins 24 hours after implantation or until a tumor of a specified size (usually about 400 mg) may be palpated. Test compounds were administered daily at 11 p.m.

The animals were then weighed, palpated, and measured for tumor size. In the untreated control group, the typical tumor weight on the 12th day after intramuscular vaccination is 500-2500 mg. The typical average survival time is ι8 to 28 days. Compounds in the positive control group, for example, cyclophosphamide, are used 20 mg / kg / injection per day on 11 days. Computerized results include average animal weight, tumor size, tumor weight, and survival time. To demonstrate therapeutic activity, the test composition should be tested in two multiple dose assays. 5.4.14 3LL Lewis lung cancer: a model of staged growth and spontaneous metastasis This model has been used by many investigators (see, eg, Gorelik et al. '1 98 0, J. Nat, l. Cane. I nst. 65: 1 2 5 7 — 1 2 64, Gorelik et al., Rec. Results Cane. Res. 1 98 0? 75: 20 — 28, Isakov et al., Invasion Metas. 1982, 2: 12 — 32; Talmadge et al., J. N at, 1 · C an c. I ns t. 1 9 8 2, 6 9: 9 7 5 — -43- 200538107 (40) 98 0; Hilgard et al., Br. J. Cancer 1 9 7 7, 3 J: 78 — 86). The test mice were male C57BL / 6 mice, 2-3 months old. Implanted subcutaneously, intramuscularly, or in the palm of the foot, this tumor produces metastases, preferably in the lungs. With some tumor strains, the initial tumor exhibits an anti-metastatic effect and must be removed before metastasis is investigated (see also O'Reilly et al., U.S. Patent No. 5,63 9,72 5). Single cell suspensions were prepared from solid tumors by treating minced tumor tissue with a 0.3% trypsin solution. Cells were washed 3 times with PBS (pH 7.4) and suspended in PBS. The viability rate of the 3LL cells thus prepared is usually about 95 to 99% (excluded by cone blue dye). Viable tumor cells (3 X 104-5 X 106) suspended in 0.05 ml of PBS were injected subcutaneously into the dorsal region or hindfoot of C5 7BL / 6 mice. Visible tumors appeared 3 to 4 days after the dorsal subcutaneous injection of 106 cells. The date on which the tumor appeared was recorded and the diameter of the resulting tumor was measured with a caliper every two days. Treatment was given as one or two doses of the compound every week. In another specific embodiment, the compound is delivered as an osmotic minipump. In experiments involving tumor resection of dorsal tumors, when the tumor size reached approximately 1500 mm3, the mice were randomly divided into two groups: (1) complete removal of the initial tumor; or (2) sham surgery and tumor original Reserved. Although tumors from 500-3000 m m3 inhibit metastatic growth ', 1500 mm3 is an initial tumor that can be safely resected and has high survival without the largest size of local regrowth. After 21 days, all rats were sacrificed and necropsied. -44- 200538107 (41) Remove and weigh the lungs. The lungs were fixed in Boo'n's solution and the number of visible metastases was recorded. A binocular stereo equipped with a micrometer with eyepiece was also used to measure the diameter of the transfer at 8X magnification. From the recorded diameters, it is possible to calculate each transfer volume. To determine the total volume of each lung metastasis' the average number of visible metastases multiplied by the average volume of metastases. To further measure metastatic growth, it is possible to measure 125 IdUrd incorporated in lung cells (Thakur et al., J. Lab. Clin. Med. 1 977, 89: 217-228). Ten days after the tumor was removed, 25 // g of fluorodeoxyuridine was inoculated into the peritoneum with the tumor (and, if used, the tumor was removed from the rat). After 30 minutes, rats were given 125 IdUrd (iododeoxyuridine) of 1 // Ci. After one day, the lungs and spleen were removed and weighed and the degree of 125IdUrd binding was measured using an r counter. In mice with foot tumors, when the tumor diameter reached about 8 to 10 mm, the mice were randomly divided into two groups: (1) the ligature above the knee joints were truncated after ligation; or (2) untreated Mice were used as non-cut off control groups with tumors. (Excision of tumor-free feet in tumor-bearing mice has no known effect of subsequent metastasis, excluding possible effects of anesthesia, stress, or surgery). Rats were killed on days 10-4 after truncation. Assess transfer as described above. 5.5 Therapeutic use The compound of structural formula (I) and / or its pharmaceutical composition is administered to a patient, preferably a human, with a disease characterized by abnormal angiogenesis. Abnormality-45- 200538107 (42), or a major disease in the blood group can be compared with the disease, the blood guide drug to the tube-induced group new medicine, such as its regulations and the formation of organic substances and other blood. what. New appointments Chang and Rong are being formed into blood. The sphincter tube is added to the blood to increase the shape of the branch of the tube. The blood is placed to treat and / or prevent abnormal blood vessel formation. Preferably, diseases characterized by abnormal angiogenesis include (but are not limited to) cancer (eg, any angiogenic tumor, preferably, solid tumors, including but not limited to lung, breast, ovary, stomach, pancreas, Laryngeal, esophagus, 睪, liver, subauricular gland, bilary ary, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinoma, adenocarcinoma , Small cell carcinoma, melanoma, glioma, neuroblastoma, cancer of sarcoma (eg, angiosarcoma, chondrosarcoma), arthritis, diabetes, arteriosclerosis, arterial and venous, malformation, corneal transplantation Angiogenesis, delayed wound healing, diabetic retinopathy, age-related speckle degeneration, arachnoids, burns, hemophilic arthropathy, rheumatoid arthritis, hypertrophic scars, neovascular glaucoma, broken joints , Osler Weber syndrome, psoriasis, granulomas, post-crystal fibrous tissue hyperplasia, pterygium, scleroderma, trachoma, vascular adhesion, new blood in the eyes Angiogenesis, parasitic disease, postoperative hypertrophy, inhibitory effects of si growth, speckle degeneration (both wet and dry), rheumatoid arthritis and osteoarthritis. It is preferable to treat and / or prevent diseases characterized by abnormal blood vessel formation by administering a compound of the formula (I) and / or a pharmaceutical composition thereof, including cancer, speckle degeneration, and rheumatoid arthritis. Further, the compound of structural formula (I) and / or its pharmaceutical composition can be administered to patients, preferably humans, with diseases related to copper metabolism disorders (eg, Wilson 200538107 (43) 's disease) for treatment And / or prevent the disease.

Still further, the compound of formula (I) and / or its pharmaceutical composition can be administered to a patient, preferably a human, to treat and / or prevent obesity. Compounds of formula (I) can also be used to reduce the levels of inflammatory cytokines (eg, TNF-a, TNF- / 3, IL-8, etc.) and plasminogen activator inhibitors, which may be related to angiogenesis Associated with obesity (Loskutoff et al., Ann. N. A. Acad. Sci., 2000, 902: 2 7 2 -28 1; Pan et al., Cancer Res., 2002, 62: 4854-48 59; Hanada et al. , Cytokine Growth Factor Rev. 2002, 13: 13-421; Chen et al., Science 2002, 296: 634-5; Miyake et al., J. N europathol. Exp. Neurol. 59: 18-28; Koch et al., Science 19 92, 258: 1798-801; Osawa et al., Infect. I mmu n. 2002, 70: 6294-6301; Bajou et al., Nat. Meu. 1 998, 4: 923-8) °

Still further, the compound of formula (I) and / or its pharmaceutical composition can be administered to a patient, preferably a human, with a neurodegenerative disorder to treat and / or prevent the neurodegenerative disorder. Increased copper content has been reported in the art in a variety of media including pathologies of neurodegenerative disorders including Alzheimer's disease, amyotrophic primary spinal cord sclerosis (ALS), and mad cow disease (Llanos et al, DNA Cell B i ο 1 · 2 0 0 2, 2 1: 2 5 9-2 7 0; Carri et al., Funct. Neurol 2001, 16: 16: 181-188; Perry et al., CNS

Drugs 2002, 16: 3 3 9-3 52; Kowa] ik-Jankowska et al., Environ Health Perspect, 2002, 5: 869-870; Maynard et al., J. Biol. Chem., 2002, 277, 44670-44676 Gnjec -47-200538107 (44) yV 'Front Biosci. 2 002' 1 6 — 23, Strausak et al.,

Brain Res. Bull. 200 1 ^ 55: 1 7 5-1 8 5; Brown ^ Brain Res. Bull. 2 00 1, 5 5: 1 6 5 — 1 7 3; Brown, Biochem. Soc. Trans 2002, 3 0: 742-745). Still further, according to the present invention, the compound of formula (I) and / or its pharmaceutical composition can be administered to a patient, preferably a human being, and is characterized by the treatment of inflammatory disorders characterized by NF- / cB disordered activity or inflammatory response Disease. Further, in certain embodiments, the compound and / or its pharmaceutical composition is administered to a patient, preferably, human, as a kind of anti-allergic anti-angiogenesis, copper metabolism disorders, neurodegeneration disorders, obesity Or NF-/ c B disorder is a prophylactic measure of a disease or disorder. Therefore, the compound of structural formula (I) and / or its pharmaceutical composition can be used to prevent one disease or disorder while simultaneously treating another disease or disorder (for example, preventing Wilson's disease or Alzheimer's disease while treating cancer ). 5.6 Therapeutic / Prophylactic Administration The compound of formula (I) and / or its pharmaceutical composition can be advantageously used in human medicine. As described in section 4.5 above, the compound of structural formula (I) and / or its pharmaceutical composition can be used to treat or prevent abnormal blood vessel formation, copper metabolism disorders, neurodegenerative disorders, obesity or NF- / c B disorders. Characterized by various diseases or disorders. When used for the treatment and / or prevention of the aforementioned diseases or disorders, the compound of the formula (0) and / or its pharmaceutical composition can be administered or administered alone or in combination with other agents. The compound of the formula (I) and / Or its pharmaceutical group 200538107 (45) products can also be used alone or with other pharmaceutically active agents (for example, other anticancer agents, other antiangiogenic agents, other clamp agents such as zinc, penicillamine, etc.), and other anti-obesity agents ), Including other compounds of structural formula (I) and / or pharmaceutical composition combinations for administration or administration. Provided herein is the administration of a therapeutically effective amount of compounds of structural formula (I) and / or pharmaceutical compositions thereof. The method of treatment and prevention to the patient. The patient may be an animal, more preferably, a mammal, and best, a human. The compound of the formula (I) and / or its pharmaceutical composition is preferably administered orally. Structure The compound of formula (I) and / or its pharmaceutical composition can also be administered by any other convenient route, for example, by infusion or rapid infusion, by absorption through the epithelium or mucosal lining (eg, oral mucosa, rectum Intestinal mucosa, etc.). Administration can be systemic or local. Various delivery systems that can be used to administer the compound of formula (I) and / or its pharmaceutical composition are known, (eg, encapsulated in lipids Body, microparticles, microcapsules, capsules, etc.). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, nasal Intra-, intra-brain, intra-vaginal, transdermal, rectal, by inhalation or locally, especially ear, nose, eyes or skin. The preferred modalities for administration are left to the practitioner's careful consideration and will be partially considered Depending on the location of the medical condition. In most cases, administration releases the compound of structural formula (I) and / or its pharmaceutical composition into the bloodstream. In specific embodiments, one or more structures It is reasonable to administer the compound of formula (I) and / or its pharmaceutical composition to the area in need of treatment. This can (for example and without limitation) be achieved by local perfusion during surgery -49- 200538107 (46) , Topical application, for example, after surgery The wounds are bound together, by injection, via a catheter, via a suppository, or via an implant that is a porous, non-porous, or gel-like material, including a membrane, such as a sialastic (a silicone rubber) membrane or fiber Achieved. In a specific embodiment, administration may be by direct injection at the site (or anterior site) of abnormal blood vessel formation (eg, cancer or arthritis). In some embodiments, one or more structural formulas It is desirable that the compound of (I) and / or its pharmaceutical composition is introduced into the central nervous system by any appropriate route, including intraventricular, intraspinal and epidural injections. Intraventricular injections can be made through the ventricles Catheters, for example, are connected to a reservoir, such as an Ommaya reservoir, to help. The compound of formula (I) and / or its pharmaceutical composition can also be administered directly to the lungs by inhalation. For administration by inhalation, the compound of formula (I) and / or its pharmaceutical composition can be conveniently delivered to the lungs through many different devices. For example, a metered dose inhaler (" MDI "), which utilizes a suitable low-boiling point propellant, (eg, dichlorodifluoromethane, trichlorofluoromethane 'dichlorotetrafluoroethane, carbon dioxide or any other suitable gas) Can be used to deliver the compound of formula (I) and / or its pharmaceutical composition directly to the lungs. Alternatively, a " DPI " device can be used to deliver the compound of formula (I) and / Or its pharmaceutical composition is administered to the lung. DPI devices typically use a mechanism such as the rupture of a gas to create a dry powder cloud inside the container that can then be inhaled by the patient. DPI devices are also known in the art. A popular variation is the multi-dose DPI (" MDDP1 ") system, which allows 200538107 (47) to deliver more than one therapeutic dose. For example, gelatin capsules and cartridges used in inhalers or insufflators It can be formulated as a powder mixture comprising a compound of formula (I) and a powder base suitable for these systems, such as lactose or source powder. It can be used to deliver the compound of formula (I) and / or its pharmaceutical composition to another lung One type of device is a liquid spray device, for example, supplied by Aradigm, Hayward 'CA. The liquid spray system uses extremely small nozzle holes to atomize the liquid drug formulation, which can then be directly sucked into the lungs. In a specific embodiment, a nebulizer is used to deliver a compound of formula (1) and / or a pharmaceutical composition thereof to the lung. The nebulizer is produced from a liquid drug by using, for example, ultrasonic energy to form fine particles that can be easily inhaled Aerosols (see, for example, Verschoyle et al., British Cancer Stage, 1 999, 80, Suppl, 2, 96). Examples of nebulizers include medicaments provided by Sheffield (See, Armer et al., U.S. Patent No. 5,954,047; van der Linder et al., U.S. Patent No. 5,950,619; van der Linder et al., U.S. Patent No. 5,970,974) and 8816116 Lung Therapy, 0; 1111111) 115 ， 〇1 ^. In another embodiment, an electrohydrodynamic ("EHD") aerosol device is used to directly apply the compound of structural formula (I) and / or its pharmaceutical composition For delivery to the lungs. EHD aerosol devices use electrical energy to atomize liquid drug solutions or suspensions (see, eg, No akes et al., U.S. Patent No. 4,765,59 3). When the compound of formula (1) and / or its pharmaceutical 200538107 (48) composition is delivered to the lung by an EHD aerosol device, the electrochemical properties of the formulation can be important parameters for optimization and the optimization is familiar The artist performs routinely. The E H D aerosol device can deliver compounds to the lungs more efficiently than other lung delivery technologies. In some embodiments, the compound of structural formula (I) and / or its pharmaceutical composition is delivered in vesicles, especially liposomes (see Langer,

1 990, Science 249: 1 5 2 7-1 5 3 3; Treat et al., "Liposomes in the Treatment of Infectious Diseases and Cancer", Lopez — Berestein and Fidler (eds.), Liss, New York, 3 5 3-3 6 5 (1 98 9) • See generally "Lipid plastids in the treatment of infectious diseases and cancers", Lopez-Berestein and Fidler (eds.), 1 ^ 85, New York, 卩 卩 .353- 365 (1989)).

In other embodiments, the compound of formula (I) and / or its pharmaceutical composition can be delivered via a sustained release system, preferably an oral sustained release system. In a specific embodiment, a pump can be used (see, Langer, supra, Sefton, 198 7, CRC Crit. Ref. Biomed Eng. 14: 201; Saudek et al., 1989, N. Engl. J Med. 321: 574 ) °

However, in other embodiments, polymeric materials may be used (see "Medical Applications for Controlled Release", Langer and Wise (eds.), CRC Pre · 'Boca Raton, Florida (1974)); π-controlled drug bioavailability' ', Drug Product Devices and Efficacy, S m ο 1 e η and B a 11 (eds.)' Weiss' New York (1984), Langer et al., 193 3, J

Macromol · Sci. Rev. Macromol Chem. 23 ·· 61; See also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol · 25: 351; Howard et al., 1989, J.

Neur〇Surg · 7]: 105). In other embodiments, poly-52-200538107 (49) composite material can be used as an oral sustained release delivery. Preferred polymers include sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose (most preferably, hydroxypropyl methyl cellulose). Other preferred cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. &Amp; Prod. Mfr., 1 984, 5 (3) 1-9). Factors that affect drug release are known to those skilled in the art and have been described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307). In other embodiments, casing preparations can be used in Oral sustained release administration. Preferred coating materials include polymers with pH-dependent solubility (ie, pH-controlled release), slow or pH-dependent polymers with swelling, dissolution, or erosion (ie, time-controlled release), Enzyme-degraded polymers (that is, enzyme-controlled release) and polymers that form strong vitamins that are destroyed by increased stress (that is, pressure-controlled release). In other embodiments, an osmotic delivery system is used for oral sustained release administration (Verma et al., Drug Dev. Ind. Pharm., 2000 ' 26: 6 9 5-7 0 8). In still other embodiments, the ORSTM osmotic device is used for an oral sustained release delivery device (Theeuwes et al., U.S. Patent No. 3,84 5,7 70; Theeuwes et al., U.S. Patent No. 3,9 1 6,899 No.) In other embodiments, the control-release system may be placed near the target of the compound and / or pharmaceutical composition of the present invention, so only a portion of the system dose is required (see, for example, Good son, above ' "Medical Applications of Controlled-Release" Volume 2, pages 1 15-138 (1 984). 200538107 (50) can also be used to discuss other control-release systems in Langer, 1990, Science 249: 1527-1533. 5.7 Pharmaceutical composition This pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of formula (I), preferably in a purified form, together with an appropriate amount of a pharmaceutically acceptable vehicle, so as to provide proper administration to Patient form. When administered to a patient, the compound of formula (I) and a pharmaceutically acceptable vehicle are preferably sterilized. When the compound of formula (I) is administered intravenously, water is preferred Vehicle fluid. Brine and dextrose and glycerol aqueous solutions are (in particular) liquid vehicles for injectable liquids. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dry skim milk, glycerin, propylene, glycol, water, ethanol, and the like. This pharmaceutical composition, if necessary, It may also contain smaller amounts of wetting or emulsifying agents, or P Η buffering agents. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Pharmaceutical compositions containing compounds of formula (I) Mixing, dissolving, granulating, sugar-coated medicine manufacturing, grinding, emulsification, encapsulation, retention or freeze-drying methods are conventionally known. Pharmaceutical compositions may use one or more physiologically acceptable carriers and diluents in a conventional manner. Formulation of excipients or auxiliaries, which helps to process compounds of structural formula (I) into pharmaceutical preparations. The proper formulation depends on the chosen route of administration. The substance can be used as a solution, suspension, latex, lozenge 'medicine-54- 200538107 (51) Nine, granules, capsules, capsules containing liquids, powders, sustained-release preparations, suppositories, emulsions, aerosols, sprays, suspensions Liquid form or any other suitable form for use. In a specific embodiment, the pharmaceutically acceptable vehicle is a capsule (see, eg, Grosswald et al., U.S. Patent No. 5,698,155). Others of a suitable medical vehicle Examples have been described in the art (see Remington: Science and Practice in Pharmacy, Philadelphia College of Pharmacy and Science, 20th Edition, 2000). For topical administration, the compound of formula (I) can be formulated as a solution, gel, ointment, cream, suspension, etc., as known in the art. Systemic formulations include those designed for administration by injection, for example, subcutaneously, intravenously, intramuscularly, intrathecally or intraperitoneally, and those designed for transdermal, transmucosal, oral or Lung donors. Systemic S-week formulations can be manufactured in combination with an active agent that further improves mucosa of the airway mucus by reducing or reducing mucus viscosity. These active agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetamylcysteine, homocysteine, and phospholipids. In some specific embodiments, the compound of formula (I) is formulated into a pharmaceutical composition suitable for intravenous administration to humans according to the routine steps. Typically, the compound of formula (I) for intravenous administration is a solution in a sterilized isotonic water buffer. For injection, the compound of structural formula (I) can be formulated as an aqueous solution, preferably a physiologically compatible buffer such as R i n g e r 's solution, or a physiological saline buffer. The solution may contain formulation agents such as suspending, stabilizing and / or dispersing agents. When needed, such pharmaceutical compositions may also include a solubilizing agent. The pharmaceutical composition for intravenous administration may be arbitrary -55- 200538107 (52) A local anesthetic such as Hgnocaine is intentionally included to reduce pain at the injection site. Usually, the ingredients are supplied separately or in a unit dosage form, for example, freeze-dried powder or anhydrous concentrate, such as in a hermetically sealed container such as ampoules or sachettes indicating an active amount. When the compound of formula (I) is administered by infusion, it may be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound of formula (I) is administered by injection, an ampoule of sterile water or saline for injection can be provided so that the ingredients can be mixed before administration. For transmucosal administration, penetrants are used in the formulation to properly penetrate the barrier. Such penetrants are generally known in the art. Pharmaceutical compositions for oral delivery can be in the form of, for example, lozenges, dragees, water or oil suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Pharmaceutical compositions for oral administration may contain one or more of any agents, for example, sweeteners such as sugar, aspartic acid derivatives, or saccharin; flavoring agents such as mint, wintergreen, or cherry colorants and preservatives to provide A pharmaceutical delicious preparation. Moreover, in the case of tablets or medicinal forms, these pharmaceutical compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged time-release effect. A selectively permeable membrane surrounding a osmotically active driving compound is also suitable for oral administration of a compound of formula (I). In these later platforms, the liquid from the environment surrounding the capsule is absorbed by the driving compound, which expands and moves the reagent or reagent composition through the well. These delivery platforms can provide a substantially zero-order delivery profile as opposed to a spiked distribution of immediate release formulations. It can also be used at -56- 200538107 (53) delayed substances such as glyceryl monostearate or glyceryl stearate. Oral compositions may include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These vehicles are preferably of pharmaceutical grade. For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkanediols (e.g., propylene glycol), polyalkylene glycols (e.g., polymer Glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (eg, acetate, citrate, ascorbate between about 5.0 mM to about 50.0 mM), and others. Additionally, flavoring agents, preservatives, colorants, bile salts, acylcamitines, and the like may be added. For buccal administration, these pharmaceutical compositions may take the form of lozenges, dragees, and the like formulated in a conventional manner. Liquid pharmaceutical formulations suitable for use in sprayers and liquid spray devices and EHD aerosol devices will typically include a compound of formula (I) and a pharmaceutically acceptable vehicle. Preferably, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or perfluorocarbon. Optionally, additional materials can be added to modify the aerosol properties of a solution or suspension of a compound of the invention. Preferably, the substance is a liquid such as an alcohol, glycol, polyglycol or fatty acid. Other methods of formulating a liquid pharmaceutical solution or suspension suitable for use in an aerosol device are known to those skilled in the art (see 'for example, Biesalski, US Patent No. 5,112,598; Biesalski, US Patent No. 5,5 5 6, 6 1 No. 1).

Compounds of structural formula () can also be formulated into rectal or vaginal pharmaceutical compositions such as suppositories or retention enema containing, for example, the conventional suppository 1J-57-200538107 (54) matrix such as cocoa butter or other glycerolipids. In addition to the aforementioned formulations, the compounds of formula (I) can also be formulated into depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of formula (I) can be formulated with a suitable polymeric or hydrophobic material (e.g., an emulsion in an acceptable oil) or an ion exchange resin 'or a sparingly soluble derivative, such as a sparingly soluble salt. When the compound of formula (I) is acidic, it may be included in any of the above formulations in the form of a free acid, a pharmaceutically acceptable salt, solvate or hydrate. A pharmaceutically acceptable salt substantially retains the activity of the free acid ' can be prepared by reaction with a base and is more soluble in water and other protic solvents than the corresponding free acid form. 5.8 Therapeutic dose The compound of formula (I), and / or the pharmaceutical composition, will usually be used in an effective amount to achieve the intended purpose. For use in the treatment or prevention of diseases or disorders characterized by abnormal angiogenesis, copper metabolism disorders, neurodegeneration disorders, and obesity, the compound of formula (I) and / or its pharmaceutical composition is administered or supplied in a therapeutically effective amount. The amount of a compound of formula (I) effective to treat a particular disorder or condition described herein will depend on the nature of the disorder or condition and can be determined by standard clinical techniques known in the art, as previously described. In addition, in vitro or in vivo assays can optionally be used to help confirm the optimal dose range. • 58- 200538107 (55) The structural formula (0) of the compound to be administered will of course depend on other factors, the individual to be treated, the weight of the individual, the severity of the pain, the method of administration and the prescription of the prescribing physician. 'Dose can be delivered by a single administration, by multiple administrations or controlled release pharmaceutical compositions. In a specific embodiment, the compound of formula (I) is delivered by oral sustained release administration. Preferably, In this specific embodiment, the compound of formula (I) is administered twice daily (better, once a day). The dosage may be repeated intermittently, may be provided alone or in combination with other drugs and as long as the disease state or disorder is effective The treatment requires an appropriate dosage range that can be continuously provided. Oral administration depends on efficacy, but is usually between about 0.001 mg to about 200 mg per kilogram of body weight of a compound of formula (I). The dosage range can be easily understood by the It is determined by methods known to those skilled in the art. The appropriate dose range for intravenous (iv) administration is about 0.01 mg to about 100 mg per kg of body weight. The appropriate dose range for intranasal administration It is usually about 0.01 mg / kg body weight to about 1 mg / kg body weight. Suppositories usually contain about 0.01 mg to about 50 mg of a compound of formula (I) per kg body weight and are contained at about 0.5% to about 10 weight % Active ingredient. Recommended dosage for intranasal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracondylar administration is in the range of about 0.001 mg to about 200 mg per kg of body weight. Effective doses can be obtained from Dose-response curves are extrapolated from in vitro or animal model test systems. These animal models and systems are known in the art. -59- 200538107 (56) Compounds of formula (I) are preferably used in Tests for therapeutic or prophylactic activity previously in vitro and in vivo in humans. For example, in vitro assays can be used to determine the administration of a particular compound of formula (I) or a combination of compounds of formula (I) for the treatment or prevention of abnormalities. Are diseases or disorders characterized by angiogenesis, copper metabolism disorders, neurodegenerative disorders, and obesity better. The use of animal model systems can also prove that compounds of formula (I) are effective and safe Preferably, a therapeutically effective dose of a compound of formula (I) described herein will provide a therapeutic benefit without causing substantial toxicity. Toxicity of a compound of formula (I) can be determined using standard pharmaceutical procedures and can be familiarized with Those skilled in the art can easily determine. The dose ratio between toxic and therapeutic effects is the therapeutic index. The compound of formula (I) preferably shows a very high therapeutic index in the treatment of diseases and disorders. The structural formula described herein ( I) The dosage of the compound will preferably be within a range of circulating concentrations that include an effective dose with little or even no toxicity. 5.9 Combination Therapy In certain embodiments of the invention, the compound of formula (I) and / or The pharmaceutical composition can be used in combination with at least one other therapeutic agent or in combination with radiation therapy. The compound of structural formula (I) and / or its pharmaceutical composition and another therapeutic agent can act additively or, more preferably, synergistically. In some embodiments, the compound of structural formula (I) and / or its pharmaceutical composition is administered simultaneously with the administration of another therapeutic agent, which may be part of a pharmaceutical composition such as a compound of structural formula (I) Or a different pharmaceutical composition. -60- 200538107 (57) In other specific embodiments, the pharmaceutical composition of structural formula (I) is administered before or after the administration of another therapeutic agent. In some embodiments, the compound of formula (I) and / or its pharmaceutical composition can be used with other chemotherapeutic agents (for example, alkylating agents (for example, nitrogen mustard (for example, cyclophosphamide, isocycline Ifosfamide, mechlorethamine, melphalen, chlorambucil, hexamethamine

hexamethy lmelamine), thiotepa 'acid esters (for example, busulfan), nitroso excrement, triads), antimetabolites (for example, folate homologues, pyrimidine homologues (For example, fluorouracil, fluorouridine, cytosine arabinoside, etc.), purine homologues (for example, mercaptopurine, thi gunaine), pentostatin ( ρ e η ΐ 〇stati η) and so on

), Natural products (for example, vinblastine, vincristine, etoposide, tertiposide, dactinomycin, daunorubicin, doxurubicin, bleomycin , Mitomycin, mitomycin C, L-asparagine, interferon alpha), platinum coordination complexes (eg, cis-platin, carbo pi atin, etc.) , Mitoxanthinone (mit ο X antr ο ne), menstrual excretion, procarbazine, hormones and antagonists (for example, prednisone, hydroxyprogesterone hexanoate, medroxyprogesterone ) Acetate, megestrol acetate, diethylstilbestrol, diethylstilbestrol, tamoxifen, tapropionate propionate, fluoxymesterone, flutamide ( flutamide), leuprolide (-61-200538107 (58) 1 eupr ο 1 ide, etc.), antiangiogenic agents or inhibitors (for example, angiostatin, retinoic acid and paclitaxel), estrogen Cholesterol derivatives, thiazolopyrimidine derivatives, etc.), apoptosis-induced (For example, antisense nucleotides that block oncogenic genes that inhibit apoptosis, tumor suppressors, TRAIL, TRAIL polypeptides, Fas-related factor I, interleukin-1 A-converting enzymes, phosphotyrosine inhibitors, RXR-like optochrome receptor activators, nordone derivatives, etc.), clamps (penicillamine, zinc, trientine, etc.) and other anti-obesity agents in combination. 5. 10 Therapeutic Kits Also provided herein are therapeutic kits comprising a compound of structural formula (I) and / or a pharmaceutical composition thereof. The therapeutic kits may also include other compounds (e.g., chemotherapeutic agents, natural products, hormones or antagonists, anti-angiogenic agents or inhibitors, apoptosis-inducing agents or clamp agents) and / or their pharmaceutical compositions . Therapeutic kits may have a single container containing a compound of structural formula (I) and / or its pharmaceutical composition with or without other ingredients (eg, other compounds and / or its pharmaceutical composition) or may have one for each ingredient Different containers. Preferably, the therapeutic kit includes a co-administered second compound (preferably, a chemotherapeutic agent, natural product, hormone or antagonist, anti-angiogenic agent or inhibitor, apoptosis-inducing agent or clamp Mixture) or a pharmaceutical composition of the compound of structural formula (I) and / or a pharmaceutical composition thereof in a package. The components of the kit may be pre-complexed before administration to the patient or each component may be in a separate container. -62- 200538107 (59) The components of the kit can be provided in one or more liquid solutions, preferably, aqueous solutions, more preferably, sterilized aqueous solutions. The components of the kit can also be provided in solid form, which can be converted into a liquid by adding a suitable solvent, which is preferably provided in a different container. The container of the treatment kit may be an ampoule, test tube, flask, bottle, syringe or any other device surrounding a solid or liquid. Usually, when there is more than one ingredient, the kit will contain a second ampoule or other container, which allows separate doses. The kit may also contain another container for a pharmaceutically acceptable liquid. Preferably, the treatment kit will include devices (eg, one or more needles, syringes, eyedroppers, pipettes, etc.) that can administer the components of the kit [Embodiment] 6. Examples The present invention is further referenced The following example definitions describe in detail the preparation of compounds of the invention and methods for testing biological activity. Obviously, those skilled in the art will be able to implement many modifications to both the materials and methods without departing from the scope of the present invention. 6.1 Example 1: General procedure for the synthesis of tetrathiotungstate derivatives Tetraammonium hydroxide (2 equivalents) is an aqueous solution of commercially available products, added to ammonium tetrathiotungstate (1 equivalent) and deionized water is added Until all solid matter is dissolved. The solution was placed on a rotary evaporator under vacuum (approximately 5-10-2005-200538107 (60) Torr) in a 20 ° C water bath for one hour and if necessary changed the water to maintain a fixed volume. The reaction mixture was then evaporated to dryness and the resulting yellow solid was recrystallized from deionized water and isopropanol. The solid was collected by filtration, washed with isopropanol and diethyl ether, and then dried in a vacuum dryer under high vacuum in the presence of P205 for 24 hours. 6.2 Example 2: General Procedure for Synthesis of Tetrathiotungstate Derivatives Tetraammonium halide (2 equivalents), as a solid, added to ammonium tetrathiotungstate (1 equivalent) The resulting mixture was neutralized with a suspension in otic tetrathiotungstate (5 ml) and stirred under nitrogen at room temperature for 18 hours. If a precipitate is produced in this step, the solid is collected by filtration, washed with isopropanol and diethyl ether and recrystallized from deionized water and isopropanol. The yellow crystals were collected by filtration, washed with isopropanol and diethyl ether and dried in a vacuum drier under local vacuum in the presence of P205 for 24 hours. If the solution remained clear, the solvent was removed in vacuo, the residue was dissolved in dichloromethane, washed three times with water, once with brine, dried (Na2SO4), and concentrated the solution. The resulting oil or solid was dried in a vacuum dryer under high vacuum in the presence of P205 for 24 hours. 6.3 Example 3: General procedure for the synthesis of tetrathiotungstate derivatives Tetraammonium halide (2 equivalents) as a solution in deionized water (10 ml per millimolar tetrathiotungstate) The neutralized mixture was added to a suspension of ammonium tetrathiotungstate (1 equivalent) in anhydrous acetocyanine (20 ml per millimolar tetrathiotungstate) and stirred at room temperature for 18 hours. If this -64-200538107 (61) step produces a precipitate, the solid is collected by filtration, washed with water, isopropanol and diethyl ether, and then dried in a vacuum dryer under high vacuum in the presence of P205 for 24 hours . If the solution remains clear, the reaction mixture is filtered first and the filtrate is concentrated in vacuo. The obtained solid was recrystallized from deionized water and isopropanol, and the yellow crystals were collected by filtration, washed with isopropanol and diethyl ether, and then dried in a vacuum dryer under high vacuum in the presence of P205 for 24 hours. 6.4 Example 4: Tetrathiotungstate, bis (cholin) This compound was prepared in accordance with the procedure of Example 1 from ammonium tetrathiotungstate (158 mg, 0.454 mmol) and 50 weight of choline hydroxide % Aqueous solution (222 mg, 0.916 mmol), which provided 151 mg (64%) of the title compound as bright yellow crystals: IR (KBr, cm — 1) 3402, 4 5 9;] H NMR (300 MHz, DMSO -d6) 55.21 (t,

J = 4.8Hz, 2H), 3.88—3.81 (m, 4H), 3.46-3.43 (m, 4H) '3.14 (s, 18H); 13 CNMR (7 5 MHz, DMS O-d6) (5 6 6.8 (2 C), 55.2 (2C), 53.1 (6C); ES MS m / z (cholin) +1 04.3; UV (H2〇) 3 93.5 nm (ε = 1 673 0). Analysis and calculation of C10H28N2O2S4W 値C, 23.08; osmium, 5.42; N, 5.38; S, 24.65. 値: C, 23.17; osmium, 5.28; N, 5.43; S, 24.87. 6.5 Example 5: Tetrathiotungstic acid Salt, bis (triethylmethylammonium) This compound was prepared according to the procedure of Example 1 from ammonium tetrathiotungstate (-65-200538107 (62) 164 mg, 0.471 mmol) and triethylmethyl hydroxide A 20% by weight aqueous solution of ammonium (627 mg, 0.941 mmol) was prepared, which provided 147 mg (61%) of the title compound as bright yellow crystals: IR (KBr, cm-1) 460;] H NMR (300 MHz, DMSO -d6) 53.29 (q, J = 6.9Hz, 12H), 2.91 (s, 6H), 1.21 (t, J = 6.9Hz, 18H); 13CNMR (75MHz, DMSO-d6) 555.〇 (6C), 46.0 (2C), 7.5 (6C); ES MS m / z (triethylmethylammonium)

+ 116.4; UV (H2〇) 3 93.5nm (ε = 16 7 3 0). Analysis and calculation of U36N2S4W 値: C, 3 0.8 8; Η, 6.66 ·, N, 5.14; S, 23.55.値 ·· C, 3 0.8 7; Η, 6.33; N, 5.18; S, 23.7 7 were found. 6.6 Example 6: Tetrathiotungstate, bis (triethylphenylsulfonate)

This compound was prepared according to the procedure of Example I from a thiothiocranic acid table (155 mg, 0.444 mmol) and a 10% by weight aqueous solution of triethylphenylsulfonate (1.74 g, 0.889 mmol) It provided 198 mg (69%) of the title compound as bright yellow crystals: I r (κ B r, cm '1) 4 5 5;] H NMR (300 MHz, DMSO-d6) δ 7 92 (d, J = 8.4Hz, 4H), 7.71 — 7.57 (ni, 6H), 3 91 (q, J = 7.1Hz, 12H), 1.06 (t, J = 7.1Hz, 18H); 3c NMR (75MHz, DMSO- d6) (5 141.7 (2C) J 1 3〇-4 (4C),

130.0 (2C), 122.6 (4C), 55.3 (6C), 7.8 (6C); ES MS m / z (triethylphenylammonium) +178.4; UV (H2〇) 393 · 5ιιηι (e = 1 5 600 ). Analysis and calculation of C24H4〇N2 02 S4W 値: c, 43.1 1; Η, 6.03; N, 4.19; S, 19.18. Found 値 · C, 42.99; H-66-200538107 (63), 5.73; N, 4.25; S, 19.31. 6.7 Example 7: Tetrathiotungstate, bis (I, 4-dimethylpyridine) This compound was prepared from ammonium tetrathiotungstate (163 mg '0.46 7 mmol) according to the procedure of Example 2. And 1,4 dimethylpyridine iodide (221 mg, 0.940 mmol), which provided the title compound of 143 mg (58%) of bright yellow crystals: IR (KBr, 1) 45 8;

1H NMR (300MHz, DMSO-d6) 5 8.88 (d, J = 6.4Hz, 4H), 7.96 (d, J = 6.4Hz, 4H), 4.32 (s, 6H), 2.60 (s, 6H); 13C NMR (75MHz, DMSO-d6) 5 158.1 (2C), 144.8 (4C), 128.0 (4C), 47.1 (2C), 21.4 (2C); ES MS m / z (1,4-dimethyldimethylpyridine ) +108.3; UV () 3 93.5nm (ε = 1 603 0). C〗 4H2GN202 S4W analysis and calculation 値: C, 3 1. 8 2; Η, 3 · 8 1; N, 5 · 3 0; S, 2 4 · 2 7. Found 値:

3] · 67; Η, 3.77; N, 5.32; S, 24.13. 6.8 Example 8: Tetrathiotungstate, bis (1,1-dimethylpyrrole) This compound was prepared from ammonium tetrathiotungstate (300 mg, 0.861 mmol) and 1, according to the procedure of Example 3. Prepared from 1-dimethylpyrrole iodide (400 mg, 1.76 mmol), which provided 223 mg (51%) of the title compound as bright yellow crystals: IR (KBr, cm-1) 4 5 5; NMR ( 300 MHz ^ DMSO-d6) < 53.53— 3.47 (m, 8H), 3.13 (s, 12H), 2 ·] 4-2 · 08 (m, 8H); 3C NMR (-67- 200538107 ( 64) 75MHz'DMSO-d6) ^ 648 (4.), 51〇 (4C), 215 (4C) · 'SMS m / z (i, i-dimethylpyrrolidine) + 1003; uv (H20) 393.5nm (ε is called 695). Analysis and calculation of Ci2h28N2S4W4: C ’28 · 12; Η’ 5.51; n, 5.47; S, 25.03. It was found that 値: C '27 · 90; Η' 5.47; N, 556; s, 25.01. 6.9 Example 9: Tetrathiotungstate, bis (trimethylphenylammonium) This compound was prepared from ammonium tetrathiotungstate (167 mg '0.479 mmol) and phenyltrimethyl according to the procedure of Example 2. Ammonium chloride (166 mg '0.968 mmol) was prepared, which provided 139 mg (50%) of the title compound as bright yellow crystals: IR (KBr, cm-1) 459;] H NMR (300 MHz, DMSO- d6) 5 7 · 9 9 (d, J = 8 · 2 Hz, 4H), 7.68 —7.55 (m, 6H), 3.64 (s, 18H); 13C NMR (7 5 MHz

, DMSO— d6) 5 147.3 (2C), 130.1 (4C), 130.0 (2C), 120.5 (4C) 5 56.4 (6C); ESMSm / z (trimethylphenylene) + 1 3 6 · 2; UV (Η 2 〇) 3 9 4 · 0 nm (ε = 15 6 3 0) Analytical calculation of C18H28N2S4W 値: C, 3 6.99; Η, 4.83; N, 4.79; S, 21.94. Found 値:. C, 36.88; H, 4.72; N, 4.90; S, 21.92. 6. · 10 Example I 0: Tetrathiotungstate, bis (ethinocholine) This compound was prepared from ammonium tetrathiotungstate (17 mg, 0.491 mmol) and acetamidine according to the procedure of Example 2. Prepared from Choline Chloride (179 mg, 0.987 mmol), which provides 163 mg (55%) of Bright Yellow-68- 200538107 (65) Crystalline title compound: IR (KBr, cm — 1) 1 749,1 74 2,473, 4 5 6; 1HNMR (300MHz, DMS〇-d6) (5 4.47-4.41 (m, 4H), 3.72-3.69 (m, 4H), 3.16 (s, 18H), 2.07

(s, 6H);] 3C NMR (75MHz, DMSO-d6) 169.9 (2C), 63.8 (2C) »57.9 (2C), 53.0 (6C), 20.7 (2C); £ 8 1 ^ 3 111/2 (Ethylcholine) +146.4; 1 ^ (: «20) 393.511111 (ε = 1 5400). C] Analysis and calculation of 4H32N204 S4W 値: C, 27 · 82; Η, 5.34; N, 4.63; S, 21.22. Found 値: C, 27.62; Η, 5.12; N, 4.68; S, 20.71. 6.11 Example 11: Tetrathiotungstate, bis [alkyldimethyl (benzyl) ammonium] This compound was prepared from ® Ammonium thiotungstate (320 mg, 0.920 mmol) and Prepared from albacid (664 mg '1.84 mmol), which provides 65 1 mg (74%) of a thick red oil standard

The title compound: IR (thin film's cm)] 466;] H NMR (300MHz, DMSO — d6): 5 7.59—7.48 (m 5 10H) '4.56 (s'4H), 3.31-3.23 (m, 4 H) , 2.97 (s, 1 2 H), 1.84-1.72 (m, 4H), 1.32-1.22 (m'40H), 0.88-0.82 (m, 6H); ES MS m / z [undecyl-methyl ( Benzyl) table] + 304.7 '[tetradecyldimethyl (phenylmethyl) ammonium] + 332.7; UV (DMSO) 3 99.0 nm (ε 〇400) 0 6. 1 2 Example 1 2: Tetrasulfide Tungstate, cycloheptyl dicholin-69- 200538107 (66) This compound was prepared from ammonium tetrathiotungstate (299 mg, 0.860 mmol) and cycloheptyl dicholin Prepared with iodide (516 mg, 0.860 mmol), which provides; 115 mg (20%) of the title compound as bright yellow crystals: I r (KB r, cm — 1) 1 7 3 3, 1 7 1 9 , 455; NMR (300 MHz, DMSO — d6) (5 4.48—4.42 (m? 4H) ^ 3.73— 3.69 (mj 4H), 3.17 (s, 18H), 2.35 (t

, J = 7.4Hz, 4H), 1.59— 1.48 (m, 4H), 1.32-1.26 (

m, 4H); 13C NMR (75MHz, DMSO-d6) 5 1 72.3 (2C) 5 63.7 (2C) ^ 57.7 (2C), 52.8 (6C), 33.2 (2C), 28.0 (2C), 23.9 (2C) ; UV (H20) 394.Onm (ε = 15570). 6 · 1 3 Example 13: Tetrathiotungstate, pentane-1,5-bis (trimethylammonium) This compound was prepared from ammonium tetrathiotungstate (140 mg, 0.402 mmol) according to the procedure of Example 3. Mol) and N, N-pentamethylenebis (trimethylammonium iodide) (195 mg, 0.442 mmol), which provides 109 mg (54%) of the title compound as a bright yellow powder: IR ( KBr, cm ~ 1) 4 5 6; 1H NMR (300 MHz 5 D2〇) 53.34— 3.26 (m, 4H), 3.07 (s, 18H), 1.89-1.77 (m, 4H) »1.45 — 1.34 (m, 2H); UV (H20) 3 9 4 · 0 nm (ε = l 5 9 5 0) 〇

Analysis and calculation of ChH28N2S4W 値: c ’26 · 40; H, 5.64; N, 5 · 60; S, 2 5.63. It was found that: C, 2 6.60; H, 5.26; N, 5.75; S, 24.64. -70- 200538107 (67) Example 1 4: Tetrathiotungstate, butane ~ 1,4-bis () This compound was prepared according to the procedure of Example 3 from 200 mg of tetrathio, 0.574 mmol) and N , N-Tetramethylenebisammonium iodide) (271 mg, 0.632 mmol) and mg (66%) of the title compound as a bright yellow powder: ir (-456;) H NMR (300 MHz, D20) 53.45-3 4H), 3.11 (s, 18H), 1.92 — 1.82 (m, 4H H2〇) 3 94.0nm (ε = 1 5990) 〇C10H26N2S4W points: C, 24 · 69; Η, 5.39 N, 5.76; S, 26.37%, 24.77; Hf, 5.35; N, 5.85; S, 25.80. 6 · 1 5 Example 15: Tetrathiotungstate, propane-1,3-ammonium) This compound was prepared from tetrathio 201 mg, 0.578 mmol in accordance with the procedure of Example 3) and Ν, Ν- 三亚Methylbisammonium iodide) (263 mg, 0.635 mmol), S mg (70%) of the title compound as a bright yellow powder: IR (-1) 45 6; UV (Η 2〇) 3 9 3.5 nm ( ε = 16 Analysis and calculation of C9H24N2S4W 値 ·· C, 22.8 8; Η, 5 5.93; S, 27.15. Found 値: C, 22 · 94; Η, 5.01:; S, 26.79 ° trimethylammonium tungstate ( (Trimethyl provides 1 8 5 KB r, cm

• 35 (m,; UV (analytical calculations): C bis (trimethylammonium tungstate ((trimethyl: Provides 192 K B r, cm 190)). • 1 2; N, N, 6.01

-71-200538107 (68) 6.16 Example 15. Tetrathio ballastate, ethylenebis (dimethylaniline) This compound was prepared from ammonium tetrathiotungstate (200 mg, 0.5 7 3 mmol) and ethylene bis (trimethylammonium iodide) (249 mg, 0.623 mmol) and the title compound providing 171 mg (65%) of a bright yellow powder: IR (KBr, cm-1) 4 5 9; UV (H2〇) 3 93.5 nm (a = 15 72 0). Analysis and calculation of C8H22N2S4W: C, 20.96; H, 4.84; N, 6.11; S, 27.98. Found 値: C, 20.88; H, 4.71; N, 6.21; S, 27.39. 6.17 Example 17: Tetrathiotungstate, bis (N-benzyl-2-phenethylammonium) This compound was prepared from ammonium tetrathiotungstate (295 g, 0.848 mmol) according to the procedure of Example 3. ) And N-benzyl-2-phenylethyl galanyl chloride (422 mg, 1.70 mmol), but prepared by adding 6 ml of deionized water and providing 317 mg (51%) of an orange solid The title compound: IR (KBr, cm-1)) 4 5 5;] H NMR (300 MHz, DMSO— d6) 5 8.83 (br s, 4H), 7.57— 7.52 (m, 4H), 7.48-7.40 (m, 6H), 7.36-7.23 (m, 10H) »4.22

(s, 4 H), 3.21-3.15 (m, 4H), 3.03-2.95 (m, 4H);] 3C NMR (75MHz, DMSO-d6) (5 1 3 7.4 (2 C),

132.5 (2C), 1 30.0 (4C), 128,9 (2C) ,: 128.72 (8C), 128.68 (4C) ,: 126.8 (2C), 50.6 (2C), 48.1 (2C), 31.8 (2C); ESMSm / z [N —phenylmethyl-2 —phenethyl-72- 200538107 (69) ammonium] +212.4; UV (DMSO) 399.5 ηη (ε = 162 7 0). 6. 18 Example 1 8: Tetrathiotungstate, bis (1 ethyl- 3 -methyl 1 1 Η — microphone file)

This compound was prepared according to the procedure of Example 3 from tetrathiotungstate, bisammonium (0.400 g, 1.15 mmol) and 1-ethyl-3-methyl-1,1,4-methyl chloride (0.354 g, 2.41 mmol). Moore) Preparation of the title compound (0.217 g, 35%) yielding a yellow solid: IR (KB particles, cm-1) 3 43 8, 3 06 8, 1 5 69, 1 5 60, 1169, 4 5 0;! Η NMR (300MHz, DMSO-d6) (59.22 (s, 1 H), 7.78 (s, 1H), 7.70 (s, 1 H), 4.21 (q, 2H, J = 7.3Hz), 3.3 1 (s, 3H), 1.42 (t, 3H, J = 7.3Hz); 13C NMR (75MHz »

DMSO- d 6) (5 1 3 6 · 4, 1 2 3 · 4, 1 2 1 · 8, 4 4.0, 3 5 · 6 ·, 1 5 · 1; MS m / z (C6HmN2) +111.3; UV (H2〇) 3 94nm (ε = 15,891); Analytical calculation of C12H22N4WS44: c, 26.97; H, 4.15; N, 10.48; S, 24.0. Found 値: C, 26 · 91; Η, 3.92 , N, 10.55; S, 23.67〇6.1 9 Example 19: Tetrathiotungstate, bis (benzyltrimethylammonium)

This compound was prepared from tetrathiotungstate, bis (ammonium) (0.200 g, 0.574 mmol) and benzyltrimethylammonium hydroxide (0.4 8 g of a 40% aqueous solution) according to the procedure of Example 1. , 1.5 mmol) to prepare the title compound (0.246 g '70%) produced as a bright yellow solid: IR-73- 200538107 (70) (KBr, granules, cm-1) 3446, 2999, 1456 , 4 5 8; NMR (300MHz, DMSO-d6) 57.53-7.55 (m, 10H) ^ 4.56 (s, 4H), 3.05 (s, 18H); 13C NMR (75MHz, DMSO-d6) (5 132.7, 130.2 , 128.8, 128.3, 67.7, 51.7 (t); MS m / z (CioH16N) + 150.3; UV (H2〇) 394nm (ε = 1, 5,02 7). Analysis and calculation of C2GH32N2WS4: C, 39.21; H, 5.27; N, 4.57; S, 20.94. Thallium was found: C, 39.28, H, 4.88, N, 4.65; S, 20.89. 6.20 Example 20: Tetrathiotungstate, bis (2-hydroxyimine methyl) (1-1-methyl-pyridine) This compound was prepared according to the procedure of Example 3 from tetrathiotungstate, bis (ammonium) (0.20 g, 0.57 4 mmol) and 2 — Preparation of Pyridinal methyl chloride (0.198 g, 1.15 mmol) The title compound yielding a bright yellow solid (0.198 g, 59%): IR (KBr particles, cm—]) 3077, 1508, 1005, 4 5 5;] H NMR (300 MHz, DMSO— d6) (5 9.04 (d, 1H, J = 5.9Hz), 8.68 (s, 1H), 8.55 (app t, 1 H), 8.37 (d, 1H, J = 8.0 Hz), 8.07 (app t, 1 H), 4.39 (s, 3H); 13C NMR (75MHz, DMSO-d6) δ

147.3, 146.7, 144.8 '141.7, 127.1' 124.7 '46.1; MS m / z (C7H9N20) + 1 3 7.2; UV (H20) 3 94nm (ε = 1 5 3 8 0). Analysis and calculation of C14Hi8N402WS4 値: C, 28.67; Η, 3.09; N, 9.5 5; S, 2 1 · 87. Found 値 ·· C, 2 8 · 5 1, H, 2 · 8 7, N, 9.63; S, 21.55 ° -74- 200538107 (71) 6.21 Example 21: Tetrathiotungstate, bis (ethylamido) Monolithic-methylcholine) This compound was prepared from tetrathiotungstate, bis (ammonium) (0.200 g, 0.574 mmol) and acetamyl-p-methylcholin chloride ( 0.25 g, 1.20 mmol) was prepared to give the title compound as a bright yellow solid (0.115 g, 32%): IR (KBr particles, cm-1) 3 4 5 2, 3 008, 1 73 5,1 252,454; NMR (300 MHz, DM S 0-d6) 5 5.27 (m, lH), 3.58-3.74 (m, 2H), 3.13 (s, 9H), 2.06 (s, 3H), 1.24 (d, 3H, J = 6.3Hz); 13CNMR (75MHz, DMSO-d6) < 5169.5, 67.6, 65.2, 53.2, 21.1, 18.5; MS m / z (C8H18N〇2) +160.3; UV (H20) 3 94nm (ε = 5 83 i). C] Analysis and calculation of 6H36N2 04S4 \ V 値: C, 30 · 38;;, 5.74; N, 4.43; S, 20.28. Found 値: C, 30.10, Η, 5.62, N, 4.47; S, 20.47. 6.22 Example 2 2: Tetrathiotungstate, (succinylcholine) This compound was prepared from tetrathiotungstate 'bis (ammonium) (0.400 g, 1.1 5 mmol) and succinylcholine chloride dihydrate (.456 g, 1.15 mmol) to produce the title compound (0.414 g, 60%) as a bright yellow solid: grains, cm-1) 3 005, 1 7 3 2, 1 208, 1150, 4 5 5;] H NMR (300 MHz 'DMSO-d6) (54.47 (m, 4H), 3.68-3.72 (m, 4H), 3.30 (d, 18H , J = 4.2Hz), 2.66 (m, 4H); 13C NMR (-75- 200538107 (72) 75MHz, DMSO-d6) 5 1713, 58.〇, 52.9, 28.4; UV (H20) 3 94nm (ε = 15513). Analytical calculation of Ci4H300N2O4S4W 値: C, 27.91; Η, 5.02; N, 4.65; S, 21.29. Found 値: C, 27.84, Η, 4.80, N, 4 66; s, 21.06. 6.23 Example 2 3: Tetrathiotungstate, (Ethyl-1,2-b-bisammonium)

This compound was prepared according to the procedure of Example 3 from tetrathiotungstate, bis (ammonium) (0.300 g, 0.862 mmol), ammonium chloride (0.092 g, 1.72 mmol), and ethylenediamine (57.6 μl, 0.862 mmol) to prepare the title compound as a bright yellow solid (0.257 g, 80%). IR (KBr particles, cm-1) 3002, 1435, 1025, 451;] H NMR (

3 0 0 MHZ, DMSO--d6) 6 7.89 (bs, 6ii), 3.09 (s, 4H); 13C NMR (75MHz, DMSO-d6) (5 3 6.8; UV (H2〇) 394nm (ε = 13291). Analysis and calculation of C2H1 () N2S4W 値: C,

6.42; H, 2.69; N, 7.49; S, 34.27. It was found that ，: C, 6.58, Η, 2.43, N, 7.49; S, 32.98. 6.24 Example 24: Moisture stability of tetrathiotungstate The salt of tetrathiotungstate is placed in an acrylic chamber at room temperature and 95% relative humidity for two weeks. Analyze the purity of these samples according to previously reported methods, except for monitoring the absorbance at 493 nm and the molar absorption coefficient of 〖5710 Μ] cm 1 (McDonald et al., Inorg. Chim. Acta 1983 '72' 205- 210) . The results are reported in Table 1 below. -76- 200538107 (73) Table 1 Name% Decomposition Tetrathiotungstate, Bis (triethylphenylammonium) -0.12 Tetrathiotungstate, Bis (ammonium) -0.46 Tetrathiotungstate, Bis (trimethylphenylammonium) -0.46 Tetrathiotungstate, bis (benzyltrimethylammonium) 0.4 1 Tetrathiotungstate, bis (acetylcholine) 2.4 Tetrathiotungstic acid Salt, bis (cholin) 3.0 tetrathiotungstate, bis (1-ethyl-3-methyl-1H-imidose) 1.3 .tetrathiotungstate, bis (1,4-dimethylformate) Pyridinium) 2.0 Tetrathiotungstate, Bis (Ethyl- / 3-methylcholin) 4.2 Tetrathiotungstate, Bis (1, Dimethylpyrrole) 0.04 Acid salt, bis (2-hydroxyimidemethyl-bumethyl-zero ratio) 5.6 Tetrathiotungstate, pentane-1,5-bis (trimethylammonium) 19.8 * Tetrathiotungstate, Ethylenebis (trimethylammonium) 8.6 * Tetrathiotungstate, propane-1,3-bis (trimethylammonium) 23.8 * Tetrathiotungstate, butane-1,4-bis ( Trimethylammonium) 5.7 * tetrathiotungstate, (succinylcholine) 23.3 * tetrathiotungstate, cycloheptanate Dicholine 18.4 * Tetrathiomolybdate, bis (ammonium) 56 1 ± 5 Tetrathiomolybdate, bis (cholin) 36 J ± 2 Partially dissolved

77 Average of 2 data points -77- 200538107 (74) 6.2 5 Example 2 5: Copper-binding capacity of tetrathiotungstate according to tetrathiotungstate inhibits cysteine autooxidation (aut ο ο ο X idati ο η) ability to determine the copper-binding ability of the tetrathiotungstates is reported in Table 2 below. Table 2

Inhibition of cysteine autooxidation (100 // M Cys, 100βM coumarin-3 monocarboxylic acid, 100 // M CuS04) ^ ___, Guangbu · 〆 ^ factory-·-^ V w if / jqv IHJ || /,-Inhibitor inhibitor% inhibits trientin 50 μ M 3 9.7 1% tetrathiotungstate, bis (ammonium) 50 // M 9 5.94% tungsten tetrathio Acid salt, bis (trimethylphenylammonium) 50 β M 9 1.32% tetrathiotungstate, bis (dimethylphenylammonium) 50 β u 9 1.53% tetrathiotungstate, bis (benzene Methyltrimethylammonium) 50 Μ 9 4.6 2% Tetrathiotungstate, bis (acetylcholine) 50 # Μ 9 0.3 6% Tetrathiotungstate, bis (cholin) 50 μ Μ 92.54 % Tetrathiotungstate 5 Bis (1-ethyl-3 -methyl-1 Η-Mi file) 50 // Μ 9 1.16% Tetrathiotungstate, bis (1,4-dimethylpyridine) Ingot) 50 // Μ 8 9.9 8% tetrathiotungstate, bis (7 ″ fluorenyl- / 3-methylcholin) 5 0 // Μ 9 0.40% tetrathiotungstate, bis (1 , 4 -dimethylpyridine) 50 β Μ 8 9.66% " ---------- more than one ------- tetrathiotungstate 5 bis (2-hydroxyimine methyl · 1-methyl-¾ ingot 50 // Μ 9 1.15% tetrathiotungstate. Pentane-1 · 5-bis (dimethylammonium) 50 0 from Μ 9 0.69% -78- 200538107 (75) tetrathiotungstate, bis (Cholin) 50 μ Μ 9 1.99% Tetrathiotungstate, bis (ammonium) 50 β Μ 9 4.24% Tetrathiotungstate, Ethylene ion (dimethyl coin) 50 μ U 8 9.60% Tetrathiotungstate, propidium-1,3-bis (dimethyl money) 50 β Μ 9 2.95% Tetrathiotungstate, butane-1 5 4 -bis (trimethyl money) 50 β Μ 9 1.75% Trientin \ 0 β Μ 4.27% Tetrathiomolybdate, bis (ammonium) \ 0 β Μ 8 7.71% Tetrathiotungstate, ethylenebis (trimethylammonium) \ 0 β Μ 8 4.66% tetrathiotungstate, propane-1,3-bis (trimethylammonium) 10 β Μ 8 5.5 3% tetrathiotungstate, butane-1 5 4 -bis (trimethyl Ammonium) \ 0 β Μ 8 7.3 2% Trientin \ 0 μ Μ 17.72% Tetrathiomolybdate, bis (ammonium) \ 0 μ Μ 7 6.69% Tetrathiotungstate, bis (succinyl gallate) 1) 10 μM 8 1.38% tetrathiotungstate, cycloheptyldicholin \ 0 β Μ 7 7.83% Trientin 1 β Μ 0.00% tetrathiomolybdate, double Ammonium) 1 β Μ 6 8.4 8% tetrathiotungstate salts, bis (succinimidyl acyl choline) 1 β Μ 6 6.06% tetrathiotungstate salts, cycloheptyl two choline 1 β Μ 6 7.74%

6.25 Example 2 5: Inhibition of angiogenesis by tetrathiotungstic acid in the Matrige 1 ® p 1 ug assay. Tungsten tetrathiolate was tested in the matrigel® plug assay as described in Section 5.4.7 above. Acid ammonium. Two sets of positive control groups were used, with positive control 1 measured five days after implantation at the beginning of treatment, and implantation • 79- 200538107 (76) negative control group 2 measured five days after the end of treatment. Two negative control groups were used, with negative control 1 measured five days after implantation at the beginning of treatment, and negative control group 2 measured five days after implantation at the end of treatment. It can be seen from Figure 1 that treatment with ammonium tetrathiotungstate produced about 34% inhibition using this assay. Finally, it should be noted that there are alternative methods of implementing the invention. Therefore, the specific examples of the present invention are considered to be illustrative and not restrictive, and the present invention is not limited to those given here in detail, but may be amended within the scope and equivalents of the appended patent application scope. All publications and patents cited herein are incorporated by reference. [Schematic description] Figure 1 illustrates the inhibition of angiogenesis by ammonium tetrathiotungstate in the Matrigel® plug assay.

-80-

Claims (1)

200538107 (1) The scope of patent application 1. A compound of structural formula (I): R1 R5 R2-N + -R4 γ-2 R6 ^ N | + ^ r8 (I) or its solvate, hydrate or N -Oxides, wherein: R1, R2, R3, R5, R6 and R7 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aromatic compound , Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, hetero Alkyl or substituted heteroalkyl; R4 and R8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl'aralkyl, substituted aralkyl, cycloalkyl , Substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or Substituted heteroalkyl or absent when N is an aromatic ring moiety; optionally, R1 and R2 are taken together as alkanediyl, substituted alkanediyl, heteroalkanediyl, or substituted heteroalkanedi Base; arbitrarily, R 5 and R6 together are alkanediyl, substituted alkanediyl, heteroalkanediyl or substituted heteroalkanediyl; optionally, R1 and R2 together, R2 and R3 together and R2 and R4 together are alkane Diyl, substituted alkanediyl, heteroalkanediyl or substituted heteroalkanediyl; optionally 'R5 and R6 together, R6 and R7 together and r6 and r8 together are alkanediyl, substituted alkanediyl Group, heteroalkanediyl or substituted heteroalkane-81-200538107 (2) Optionally, R3 and R1 2 3 together are alkanediyl, substituted alkanediyl, heteroalkanediyl or substituted heterocycle Alkyl diyl; and Y _ 2 is (WS 4)-2 '(Μ 2 S) 2)-2, (w 2 S.9) _ 2, (W2S7) ~ 2, (W2S8)-2, (W2S丨 1)-2, (W2S6) " or (W2s13)-2. 2. The compound according to item 1 of the scope of patent application, wherein Y is (WS4) _2. For example, the scope of application of the Ira patent item 1 where R4 R5 -N 丨 + -R4 1 · As for the compound of the scope of patent application item 1, where r], R2 and R6 are hydrogen, alkyl or substituted courtyard. 2. The compound according to item 1 of the scope of patent application, wherein R1, R2 and R6 are hydrogen, methyl or ethyl. 3. The compound according to item 1 of the scope of patent application, wherein R1 and R2 are alkyl groups. 10. The compound according to item 1 of the scope of patent application, wherein R1 and R2 4 · The compound according to item 1 of the scope of patent application, wherein at least one of R], R2, R3 and R6 is not an alkyl group. 5 6 · If the scope of patent application is the first! The compound of the above item, wherein at least one of R2, R, R, R, and R'rIprS is not a radical. 6 · If the compound in the scope of the patent application item 3, where Y is ((WS 4) _ 2. 200538107 (3) is a methyl or ethyl group. 1 1 If the compound in the scope of the patent application item 1, where R1 is Alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl'aralkyl, substituted aralkyl, cycloalkyl, or substituted cycloalkyl. 12 · As for the compound in the scope of patent application, in which R1 and R2 together are alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene. 13. · In the scope of patent application, the first item Compounds in which R1 and R2 are alkylene or heteroalkylene together. 14. The compound in the scope of patent application No. 1 in which R1 and R2 are together, R2 and R3 together and R2 and R4 together are alkylene. Group, substituted alkylene 'heteroalkylene or substituted heteroalkylene. 1 5. The compound according to item 1 of the patent application, wherein R1 and R2 are together, R2 and R3 are together with R2 and R4 —It is an alkylene group. 16. The compound according to item 1 of the scope of patent application, wherein R1 (R2) (R3) (R4) N has the structure shown below: 17. The compound according to item 1 of the scope of patent application, wherein R3 and R7 together are an alkylene, a substituted alkylene, a heteroalkylene or a substituted heteroalkylene. 18. The compound as claimed in item 1 of the patent application, wherein R3 and R7 are both alkylene or heteroalkylene. -83- 200538107 (4) 19. The compound according to the scope of the application for patent, wherein r1, ^ and R4 are hydrogen, alkyl or substituted alkyl, and R3 is alkyl, substituted k group, olefin Aryl, aryl, aralkyl, cycloalkyl, or ... and R7 ~ are alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene 0. 0. Such as Shen The first scope of the compound, wherein R1, r2 and R4 are methyl or ethyl and R3 is alkyl, substituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl or R3 and R7 — Starting from alkyl or heteroalkyl. 2 1 · The compound according to item 1 of the scope of patent application, wherein R1, R2 and r4 are methyl or ethyl and R3 is alkyl, substituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl . 22. The compound according to item 1 of the scope of patent application, wherein R1 (R2 -84- 200538107 (5) 24. For the compound in the scope of patent application item 1, wherein R1 (R1) (R3) (R4) N has the structure shown below: 25. For the compound in the scope of application for item 1, wherein R1 (R1) (R3) (R4) N has the structure shown below: 2 6. The compound according to item 1 of the scope of patent application, wherein R1, R1 and R4 are methyl or ethyl, and R3 and R7 together start as an alkylene or heteroalkylene. 27. The compound according to item 1 of the scope of patent application, wherein R1 (R2) (R3) (R4) N has the structure shown below: -85- 1 8. If the compound in the scope of application for patent No. 1 has R1, R1 and 200538107 (6) R4 is hydrogen and R3 is substituted alkyl, cycloalkyl or substituted heteroaryl or R3 and R7 —From the alkylene group. 29. The compound according to item 1 of the scope of patent application, wherein R1 and R2 are alkyl groups and R3 and R4 are hydrogen, alkyl, substituted alkyl, aryl, aralkyl or alkylene. 3 0 · The compound according to item 1 in the scope of patent application, wherein r 1 and R 2 are methyl or ethyl and R 3 and R 4 are hydrogen, alkyl, substituted fluorenyl, aryl, aralkyl, or alkylene . 3 1 · As for the compound in scope 1 of the patent application, wherein R1 (R2) (R3) (R4) N has the structure shown below: Where R9 is a mixture of linear alkyl groups having at least eight carbon atoms and no more than eighteen carbon atoms. 3 2 · If the scope of patent application is the first! A compound of the formula wherein r1, R2 and R4 are hydrogen and R3 is a substituted alkyl group, a substituted heteroaryl group, a cycloalkyl group or an alkylene group. 3 3. The compound according to item 1 of the scope of patent application, wherein R] (R2) (R) (R) N has the structure shown below: -86- 200538107 (7) 3 4. If the compound in the first item of the scope of patent application, r 1 and r 2 together are alkylene, substituted alkylene, heteroalkylene or substituted heteroalkylene, and R3 is alkyl or The substituted alkyl and R4 are hydrogen or absent. 3 5. The compound according to item 1 of the scope of patent application, wherein R1 (R2 (R3) (R4) N has the structure shown below: 3 6. A pharmaceutical composition comprising a compound as described in the first patent application scope and a pharmaceutically acceptable diluent, excipient or adjuvant. 37. A medicinal composition for treating or preventing cancer, which comprises a therapeutically effective amount of a compound such as the item 1 in the scope of patent application. 38. The pharmaceutical composition according to item 37 of the patent application scope, further comprising a therapeutically effective amount of one or more other anticancer agents. 39. The pharmaceutical composition according to item 37 of the patent application, further comprising a therapeutically effective amount of zinc. 40. The pharmaceutical composition of claim 37, wherein the cancer is breast cancer, kidney cancer, brain cancer, colon cancer, prostate cancer, chondrosarcoma or angiosarcoma. 41. A pharmaceutical composition for treating or preventing wet spot degeneration or rheumatoid arthritis, which comprises a therapeutically effective amount of a compound such as the one in the scope of the patent application]. -87- 200538107 (8) 4 2-A pharmaceutical composition for treating or preventing abnormal blood vessel formation, which contains a therapeutically effective amount of a compound such as the item 1 in the scope of patent application. 4 3. —A pharmaceutical composition for treating or preventing copper overdose, which contains a therapeutically effective amount of a compound such as the one in the scope of patent application. 4 4. A pharmaceutical composition for treating or preventing obesity, which contains a therapeutically effective amount of a compound such as the one in the scope of patent application. 45. The pharmaceutical composition of claim 44 which further comprises a therapeutically effective amount of one or more other anti-obesity agents. 46.-A pharmaceutical composition for treating or preventing a neurodegenerative disease, which comprises a therapeutically effective amount of a compound such as the item 1 in the scope of patent application. 47. The pharmaceutical composition of claim 46, wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic primary spinal cord sclerosis, or mad cow disease. • 88-