WO2007142626A1 - Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate - Google Patents

Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate Download PDF

Info

Publication number
WO2007142626A1
WO2007142626A1 PCT/US2006/021529 US2006021529W WO2007142626A1 WO 2007142626 A1 WO2007142626 A1 WO 2007142626A1 US 2006021529 W US2006021529 W US 2006021529W WO 2007142626 A1 WO2007142626 A1 WO 2007142626A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
alkyldiyl
heteroalkyldiyl
taken together
compound
Prior art date
Application number
PCT/US2006/021529
Other languages
English (en)
Inventor
Melissa L. P. Price
Robert J. Ternansky
Andrew P. Mazar
Original Assignee
Attenuon, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Attenuon, Llc filed Critical Attenuon, Llc
Priority to PCT/US2006/021529 priority Critical patent/WO2007142626A1/fr
Publication of WO2007142626A1 publication Critical patent/WO2007142626A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates generally to methods for increasing the bioavailability of thiomolybdate and thiotungstate compounds by the combined adminstration of (1) a thiomolybdate or thiotungstate compound, and (2) a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • the invention also relates to pharmaceutical compositions comprising (1) a thiomolybdate or thiotungstate compound, and (2) a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid; and (3) a pharmaceutically acceptable vehicle.
  • the methods and compositions of the invention can be used to improve the treatment of diseases associated with aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity, inflammatory disorders, and fibrotic diseases.
  • angiogenesis i.e., aberrant vascularization
  • diseases e.g., ocular neo vascular disease, macular degeneration, rheumatoid arthritis, etc.
  • angiogenesis inhibition has been directly correlated with adipose tissue loss and weight loss in animal models, which suggests anti-angiogenic therapy may be useful in prevention of obesity (Rupnick et al, 2002, Proc. Natl. Acad. Sci. 99:10730-10735).
  • angiogenesis requires copper, as has been shown by numerous studies (Parke et al, 1988, Am. J. Pathol. 137:173-178; Raju et al, 1982, Natl. Cancer Inst.
  • PCT/US99/20374 have shown that the copper chelators, (e.g., tetrathiomolybdate) may be effective in treating diseases (e.g., solid tumor growth), which require angiogenesis.
  • Tetrathiotungstate compounds are another class of copper chelators (see PCT International Application No. WO 2004/110364).
  • copper may also have a direct role in tumor cell growth and survival. High copper levels exist in both the plasma and in tumor tissue from patients with many different solid cancers
  • tetrathiomolybdate has been shown to down-regulate the expression of NF- ⁇ B as well as inhibit its translocation to the nucleus in the inflammatory breast cancer cell line SUM 149 (Pan et al, 2002, Cancer Res. 62: 4854-4859).
  • the NF- ⁇ B system may be involved in mediating tumor cell survival and thus its down-regulation in tumor cells by tetrathiomolybdate suggests a direct effect of copper chelation on tumor survival.
  • Thiomolybdates are acid labile drugs and degrade under acidic conditions, such as those found in the stomach, to release H 2 S gas (Weber et ah, 1979, Br J Nutr. 41:403-5). In clinical trials of bis(choline) tetrathiomolybdate, it was observed that the plasma levels of the drug were highly variable and that patients complained of sulfur burps. Thiotungstates are also to some degree acid labile.
  • the present invention satisfies these and other needs by providing methods of increasing the bioavailability of a thiomolybdate or thiotungstate compound in a patient and/or reducing side effects of the thiomolybdate or thiotungstate compound comprising the steps of (a) administering to the patient an effective amount of a thiomolybdate or thiotungstate compound; and (b) administering to the patient an effective amount of a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • the invention also provides methods of increasing the bioavailability of a thiomolybdate or thiotungstate compound in a patient and/or reducing side effects of the thiomolybdate or thiotungstate compound comprising the steps of (a) having the patient intake a high protein meal; and (b) subsequently administering to the patient an effective amount of a thiomolybdate or thiotungstate compound.
  • the side effects that can be thereby reduced include but are not limited to sulfur burps, nausea and diarrhea.
  • the thiomolybdate or thiotungstate compound is a compound of structural formula (I):
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl; [0012] R 4 and R 8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, substituted cycloheteroalkyl,
  • R 5 and R 6 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl, substituted heteroalkyldiyl or form an aromatic or heteraromatic ring;
  • R 1 and R 2 taken together, R 2 and R 3 taken together, and
  • R 2 and R 4 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; [0016] optionally, R 5 and R 6 taken together, R 6 and R 7 taken together, and
  • R 6 and R 8 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; [0017] optionally, R 3 and R 7 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl; and
  • Y “2 is (MoS 4 )- 2 , (Mo 2 S 12 ) “2 , (Mo 2 S 9 ) “2 , (Mo 2 S 7 ) “2 , (Mo 2 S 8 ) “2 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are identical then each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R is not hydrogen, methyl, ethyl or n-propyl.
  • Y “2 is (WS 4 ) "2 and all of R 1 , R 2 , R 3 , R 4 , R 5 ,
  • R 6 , R 7 and R 8 are not hydrogen.
  • Y “2 is (WS 4 ) "2 and all of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are not alkyl.
  • the thiomolybdate compound is bis(choline) tetrathiomolybdate, the ammonium salt of tetrathiomolybdate, or tetrapropylammoniumtetrathiomolybdate.
  • the proton pump inhibitor is selected from the group consisting of esomeprazole, lansoprazole, leminoprazole, omeprazole, pantoprazole, and rabeprazole, alkaline salts of any of the foregoing, and mixtures of any two or more of the foregoing.
  • the H 2 receptor antagonist is burimamide, cimetidine, ebrotidine, famotidine, metiamide, nizatidine, oxmetidine, ranitidine, roxatidine, or tiotidine.
  • the antacid is selected from the group consisting of alumina, aluminum carbonate, basic, aluminum hydroxide, calcium carbonate, magaldrate, magnesia, magnesium alginate, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, simethicone, sodium bicarbonate, and mixtures of any two or more of the foregoing.
  • the preferred antacids are generally carbonate or hydroxide salts of aluminum, calcium or magnesium, including, for example, aluminum hydroxide, calcium carbonate, calcium hydroxide, magnesium hydroxide, and magnesium carbonate.
  • the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered orally.
  • the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered prior to the administering of the thiomolybdate or thiotungstate compound. In other embodiments, the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered concurrently with the administering of the thiomolybdate or thiotungstate compound. In yet other embodiments, the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered subsequent to the administering of the thiomolybdate or thiotungstate compound.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered up to 5 minutes apart, up to 10 minutes apart, up to 15 minutes apart, or up to 30 minute apart, or up to 1 hour apart.
  • the patient is a human and has a disease characterized by aberrant vascularization, such as cancer.
  • cancers include, but are not limited to, breast cancer, renal cancer, brain cancer, colon cancer, prostrate cancer, chondrosarcoma or angiosarcoma.
  • the invention also relates to methods of treating or preventing a disease or condition characterized by aberrant vascularization in a patient comprising the steps of (a) administering to the patient an effective amount of a thiomolybdate or thiotungstate compound; and (b) administering to the patient an effective amount of a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • the disease or condition is cancer, arthritis, diabetes, arteriosclerosis, arteriovenous malformations, corneal graft neovascularization, delayed wound healing, diabetic retinopathy, age related macular degeneration, granulations, burns, hemophilic joints, rheumatoid arthritis, hypertrophic scars, neovascular glaucoma, nonunion fractures, Osier Weber Syndrome, psoriasis, granuloma, retrolental fibroplasia, pterygium, scleroderma, trachoma, vascular adhesions, ocular neovascularization, parasitic diseases, hypertrophy following surgery, inhibition of hair growth, macular degeneration or osteoarthritis.
  • the invention also relates to methods of treating or preventing an inflammatory or fibrotic disease or condition in a patient comprising the steps of (a) administering to the patient an effective amount of a thiomolybdate or thiotungstate compound; and (b) administering to the patient an effective amount of a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid, hi certain embodiments, the inflammatory or fibrotic disease or condition is a pulmonary disease, liver disease, kidney disease, scleroderma, cystic fibrosis, pancreatic fibrosis, keloid, secondary fibrosis in the gastrointestinal tract, hypertrophic burn scars, myocardial fibrosis, retinal detachment inflammation, fibrosis resulting after surgery, graft versus host rejection, or host versus graft rejection.
  • the invention also relates to pharmaceutical compositions comprising
  • the invention also relates to a kit comprising a first container containing a thiomolybdate or thiotungstate compound; and a second container containing a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • FIG. 1 illustrates the pharmacokinetics of a single dose (150mg) of bis(choline) tetrathiomolybdate (ATN-224) in humans with and without pretreatment with the proton pump inhibitor, lansoprazole.
  • the present invention is directed to methods of increasing the bioavailability and/or reducing the side effect(s) of thiomolybdate or thiotungstate compounds by administering one or more of a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • Applicants have demonstrated, by way of example, that pretreatment with a proton pump inhibitor in patients receiving tetrathiomolybdate increased plasma levels of tetrathiomolybdate and decreased side effects, such as sulfur burps.
  • approaches to prevent degradation and improve bioavailability include the use of proton pump inhibitors, H 2 receptor antagonists or active metabolites thereof, antacids, and administering a thiomolybdate or thiotungstate compound after a protein rich meal. It is understood that the methods and compositions of the invention may employ more than one of these approaches.
  • the present invention is also directed to pharmaceutical compositions comprising (a) a thiomolybdate or thiotungstate compound; (b) a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid, and (c) a pharmaceutically acceptable vehicle. [0033] It is believed that the methods and compositions of the invention improve the bioavailability of a thiomolybdate or thiotungstate compound thereby improving its efficacy in treating and preventing diseases associated with angiogenesis.
  • Thiomolybdate or thiotungstate compounds include, but are not limited to, compounds encompassed by structural formula (I) disclosed herein and includes any specific compounds within that generic formula whose structure is disclosed herein.
  • the compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds disclosed herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • the chemical structures depicted herein encompass all possible enantiomers (i.e., R or S; L or D) and stereoisomers (e.g., cis or tram) of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, including equimolar mixtures of enantiomers, i.e., racemates.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N,
  • Alkyl by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan- 1 -yl, prop- 1 -en- 1 -yl, prop- 1 -en-2-yl, prop-2-en- 1 -yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan- 2-yl, cyclobutan-1-yl, but-1-en-l-yl, but- 1 -en-2-yl, 2-methyl-prop-l-en-yl, but-2
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon- carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.
  • an alkyl group comprises from 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms, most preferably, from 1 to 6 carbon atoms.
  • Alkanyl by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan- 1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (t- butyl), cyclobutan-1-yl, etc.; and the like.
  • alkenyl by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop- 1 -en- 1 -yl, prop- 1 -en-2-yl, prop-2-en- 1 -yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl, cycloprop-2-en-l-yl; butenyls such as but-1-en-l-yl, but- 1 -en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut- l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • Alkynyl by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-1-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like.
  • Alkyldiyl by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • the two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms.
  • Typical alkyldiyl groups include, but are not limited to methandiyl; ethyldiyls such as ethan-l,l-diyl, ethan-l,2-diyl, ethen-l,l-diyl, ethen-l,2-diyl; propyldiyls such as propan-l,l-diyl, propan-l,2-diyl, propan-2,2-diyl, propan-l,3-diyl, cyclopropan-l,l-diyl, cyclopropan-l,2-diyl, prop- l-en-l,l-diyl, prop-l-en-l,2-diyl, prop-2-en-l,2-diyl, prop-l-en-l,3-diyl, cycloprop- l-en-l,2-diyl, prop-2-en-l,
  • alkanyldiyl alkenyldiyl and/or alkynyldiyl
  • the alkyldiyl group is (C 1 -C 2O ) alkyldiyl, more preferably, (C 1 -C 1O ) alkyldiyl, most preferably, (C 1 -C 6 ) alkyldiyl.
  • Alkyleno by itself or as part of another substituent, refers to a straight-chain alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne.
  • Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, prop[l]eno, propa[l,2]dieno, prop[l]yno, etc.; butylenos such as butano, but[l]eno, but[2]eno, buta[l,3]dieno, but[l]yno, but[2]yno, but[l,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used.
  • the alkyleno group is (C 1 -C 2O ) alkyleno, more preferably, (C 1 -C 1O ) alkyleno, most preferably, (C 1 -C 6 ) alkyleno.
  • Preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
  • R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
  • Acylamino by itself or as part of another substituent, refers to a radical — NR 31 C(O)R 32 , where R 31 and R 32 are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein.
  • Representative examples include, but are not limited to, formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl- carbonylamino, benzoylamino, benzylcarbonylamino and the like.
  • R 33 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.
  • Alkoxycarbonyl by itself or as part of another substituent, refers to a radical — C(O)OR 34 where R 34 represents an alkyl or cycloalkyl group as defined herein.
  • Aryl by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s- indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rabicene, triphenylene, trinaphthalene and the like.
  • an aryl group comprises from 6 to 20 carbon atoms, more preferably from 6 to 12 carbon atoms.
  • ArylalkyP' by itselfor as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2- phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used.
  • an arylalkyl group is (C 6 -C 30 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 10 ) and the aryl moiety is (C 6 -C 2O ), more preferably, an arylalkyl group is (C 6 -C 20 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 8 ) and the aryl moiety is (C 6 -C 12 ).
  • Cycloalkyl by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used.
  • Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
  • the cycloalkyl group is (C 3 -C 10 ) cycloalkyl, more preferably (C 3 -C 7 ) cycloalkyl.
  • Cycloheteroalkyl by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
  • Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like. [0050] "Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkanyl,
  • Heteroalkyldiyl and Heteroalkyleno by themselves or as part of another substituent, refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic groups.
  • Heteroaryl by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyr
  • the heteroaryl group is from 5-20 membered heteroaryl, more preferably from 5-10 membered heteroaryl.
  • Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Heteroarylalkyl by itself or as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group.
  • heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12 membered heteroaryl.
  • Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system.
  • parent aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
  • Parent Heteroaromatic Ring System by itself or as part of another substituent, refers to a parent aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc.
  • fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
  • Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thi
  • Substituted refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s).
  • Thiomolybdate compounds include compounds comprising a molybdenum atom bonded to at least one sulfur atom.
  • Thiotungstate compounds include compounds comprising a tungstate atom bonded to at least one sulfur atom
  • Representative thiomolybdate compounds useful in the present invention include, but are not limited to, those disclosed in U.S. Patent Application Publication No. U.S. 2004/0259945, incorporated by reference herein in its entirety.
  • thiomolybdate compounds include, but are not limited to, dithiomolybdate, dodecathiodimolybdate, iron octathiodimolybdate, monothiomolybdate, tetrathiomolybdate, and trithiomolybdate.
  • thiotungstate compounds include, but are not limited to, tetrathiotungstate; tetrathimolybdate, bis(ammonium); tetrathimolybdate, bis(triethylphenyl ammonium); tetrathimolybdate, bis(benzyltrimethylammonium); tetrathimolybdate, bis(acetylcholine); tetrathimolybdate, bis(choline); tetrathimolybdate, bis(l-ethyl-3 -methyl- IH- imidazolium); tetrathimolybdate, bis(l-4-dimethylpyridinium); tetrathimolybdate, bis(acetyl- ⁇ -methylcholine); tetrathimolybdate, bis(l -4-dimethylpyridinium); tetrathimolybdate, bis(2-hydroxyimino- 1 -methyl-pyridinium); tetrathimol
  • the thiomolybdate compound is tetrathiomolybdate.
  • Tetrathiomolybdate is a compound made up of a molybdenum atom surrounded by four sulf ⁇ do groups.
  • the thiomolybdate compound also comprises at least a first iron atom and/or at least a first oxygen atom.
  • thiomolybdate compounds or complexes are those comprising one, two or three molybdenum atom(s), e.g., one molybdenum atom and one iron atom, two molybdenum atoms and one iron atom, and one molybdenum atom and two iron atoms.
  • molybdenum atom(s) e.g., one molybdenum atom and one iron atom, two molybdenum atoms and one iron atom, and one molybdenum atom and two iron atoms.
  • Cat is a cation that makes the complex water soluble, for example NH 4 +
  • L is a ligand such as Cl " or R-Ph-S, where R is a functional group that makes the complex water soluble, such as a sulfonate, and Ph is a phenyl group.
  • Examples of other thiomolybdate compounds that can be used in the present invention include, but are not limited to, nonathiomolybdate ([M0S 9 ] "2 ), hexathiodimolybdate ([Mo 2 S 6 ] '2 ), heptathiodimolybdate ([Mo 2 S 7 ] "2 ), octathiodimolybdate ([Mo 2 S 8 ] "2 ), nonathiodimolybdate ([Mo 2 Sp] '2 ), decathiodimolybdate ([Mo 2 S 12 ] "2 ), undecathiodimolybdate ([Mo 2 S 11 ] "2 ), dodecathiodimolybdate ([Mo 2 S 12 ] ⁇ 2 ), the ammonium salt of dodecathiodimolybdate ((NH 4 ) 2 [Mo 2 (S 2 ) 6
  • the thiomolybdate compound is the ammonium salt of tetrathiomolybdate or an alkylammonium thiomolybdate as disclosed in U.S. Patent Application Publication No. 2004/0259945, incorporated by reference herein in its entirety.
  • a preferred example of an alkylammonium thiomolybdate is tetrapropylammonium tetrathiomolybdate (TP-TM).
  • tetrathiotungstate compounds may also be used in the invention, wherein tungsten is employed in place of molybdenum.
  • the thiotungstate compound is the ammonium salt of tetrathiotungstate as disclosed in International Publication No. WO 2004/110364.
  • the thiomolybdate is a tetrathiomolybdate derivative disclosed in U.S. Patent Application Publication No. U.S. 2004/0019087, or the thiotungstate is a thiotungstate derivative disclosed in International Publication No. WO 2004/110364, each of which is incorporated by reference herein in its entirety, e.g., a compound of structural formula (I): R 2 - ?N +1 -R 4 Y "2 R 6 - TN + -R 8
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl;
  • R 4 and R 8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl or are absent when N is part of an aromatic ring;
  • R 1 and R 2 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl, substituted heteroalkyldiyl or form an aromatic or heteraromatic ring;
  • R 5 and R 6 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl, substituted heteroalkyldiyl or form an aromatic or heteraromatic ring; [0070] optionally, R 1 and R 2 taken together, R 2 and R 3 taken together, and
  • R 2 and R 4 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
  • R 6 and R 8 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
  • R 3 and R 7 taken together are alkyldiyl, substituted alkyldiyl, heteroalkyldiyl or substituted heteroalkyldiyl;
  • y 2 is (MoS 4 )- 2 , (Mo 2 S 12 ) *, (Mo 2 S 9 ) ⁇ 2 , (Mo 2 S 7 ) '2 , (Mo 2 S 8 ) ⁇ 2 ,
  • Y “2 is (WS 4 )- 2 , (W 2 S 12 ) - 2 , (W 2 S 9 ) “2 , (W 2 S 7 ) "2 , (W 2 S 8 ) "2 , (W 2 S 11 ) "2 ,
  • Y -2 is (WS 4 ) "2 and all of R 1 , R 2 , R 3 , R 4 , R 5 ,
  • R 6 , R 7 and R 8 are not hydrogen.
  • Y “2 is (WS 4 ) "2 and all of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are not alkyl.
  • Y "2 is (MoS 4 ) "2 or (WS 4 ) "2 .
  • R 6 , R 7 and R 8 are not alkyl.
  • Y “2 is (MoS 4 ) "2 or (WS 4 ) "2 .
  • at least one of R 1 , R 2 , R 3 and R 4 is not alkyl.
  • R 1 , R 2 and R 4 are hydrogen, alkanyl or substituted alkanyl.
  • R 1 , R 2 and R 4 are hydrogen, methyl or ethyl.
  • R 1 and R 2 are alkanyl.
  • R 1 and R 2 are methyl or ethyl.
  • R 1 is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl or substituted cycloalkyl.
  • R 1 and R 2 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno. More preferably, R 1 and R 2 taken together are alkyleno or heteroalkyleno.
  • R 1 and R 2 taken together, R 2 and R 3 taken together and R 2 and R 4 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
  • R 1 and R 2 taken together, R 2 and R 3 taken together and R 2 and R 4 taken together are alkyleno.
  • R 1 (R 2 )(R 3 )( R 4 )N has the structure:
  • R 3 and R 7 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
  • R and R 7 taken together are alkyleno or heteroalkyleno.
  • R 1 , R 2 and R 4 are hydrogen, alkanyl or substituted alkanyl and R 3 is alkyl, substituted alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or R 3 and R 7 taken together are alkyleno, substituted alkyleno, heteroalkyleno or substituted heteroalkyleno.
  • R 1 , R 2 and R 4 are methyl or ethyl and R 3 is alkyl, substituted alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or R 3 and R 7 taken together are alkyleno or heteroalkyleno.
  • R 1 , R 2 and R 4 are methyl or ethyl and R 3 is alkyl, substituted alkyl, alkenyl, aryl, arylalkyl or cycloalkyl.
  • R 1 CR 2 XR 3 X R 4 )N is
  • R 1 (R 2 )(R 3 )( R 4 )N is
  • R 1 CR 2 XR 3 X R 4 )N is
  • R 1 , R 2 and R 4 are methyl or ethyl and R 3 and R 7 taken together are alkyleno or heteroalkyleno.
  • R 1 (R 2 )(R 3 )( R 4 )N has the structure:
  • R 1 , R 2 and R 4 are hydrogen and R 3 is substituted alkyl, cycloalkyl or substituted heteroaryl or R 3 and R 7 taken together are alkyleno.
  • R 1 and R 2 are alkanyl and R 3 and R 4 are alkyl, substituted alkyl, aryl, arylalkyl or alkyleno.
  • R 1 and R 2 are methyl or ethyl and R 3 and R 4 are alkyl, substituted alkyl, aryl, arylalkyl or alkyleno.
  • R 1 (R 2 )(R 3 )( R 4 )N are
  • R 9 is a straight chain alkanyl group which has at least eight carbon atoms and not more than eighteen carbon atoms.
  • R 1 , R 2 and R 4 are hydrogen and R 3 is substituted alkyl, substituted heteroaryl, cycloalkyl or alkyleno.
  • R 1 CR 2 XR 3 X R 4 )N has the structure:
  • R 1 and R 2 taken together are alkyleno, substituted alkyleno, heteroalkyleno, substituted heteroalkyleno or form an aromatic or heteroaromatic ring
  • R 3 is alkyl or substituted alkyl
  • R 4 is hydrogen or is absent.
  • R 1 (R 2 )(R 3 )N or R 1 (R 2 )(R 3 )( R 4 )N has the structure:
  • the thiomolybdate compound is bis(choline)tetrathiomolybdate.
  • the thiotungstate compound is bisCcholine)tetrathiotungstate, ammonium tetrathiotungstate, tetrapropylammonium tetrathiotungstate, bis(acetylcholine)tetrathiotungstate, or bis(triethylmethyl ammonium) tetrathiotungstate.
  • WO 2004/110364 each of which is incorporated by reference herein in its entirety.
  • the compounds may be obtained via conventional synthetic methods illustrated in Schemes 1 and 2.
  • Starting materials useful for preparing compounds of the invention and intermediates thereof are commercially available or can be prepared by well-known synthetic methods.
  • ammonium thiomolybdate may be purchased from well-known chemical suppliers (e.g., Aldrich Chemical Company, Milwaukee, Wis.).
  • Substituted ammonium salts e.g., ammonium hydroxide and ammonium halides
  • Preferred thiomolybdate or thiotungstate compounds can be assayed for activity in assays described in U.S. Patent Application Publication No. 2004/0019087, incorporated by reference herein in its entirety.
  • the bioavailability of a thiotungstate or thiomolybdate compound can be measured by methods known to one of skill in the art, e.g., by measuring the amount of molybdenum ion present in plasma.
  • the reduction of a side effect can be measured by methods known to one of skill in the art, i.e., methods practiced by a physician.
  • a thiomolybdate or thiotungstate compound is administered in combination with a proton pump inhibitor.
  • Proton pump inhibitors are compounds that inhibit or suppress gastric acid secretion by inhibition of the H + -K + ATPase enzyme system at the secretory surface of gastric parietal cells. This includes in particular active compounds having a 2-[(2- pyridinyl)methylsulphinyl]-lH-benzimidazole skeleton or a related skeleton, where these skeletons may be substituted in various forms.
  • Exemplary proton pump inhibitors are those described in the following patent applications and patents: U.S. Pat. Nos. 4,045,563, 4,255,431, 4,359,465. 4,472,409, 4,508,905, 4,628,098,
  • EP-A-O 005 129 EP-A-O 124 495, EP-A-O 166 287, EP-A 0 174 726, EP-A 0 184 322, EP-A 0 254 588, EP-A-O 261 478, EP-A-O 268 956, EP-A-O 295 603, EP-A-O 434 999, EP-A-O 519 365, and DE-A-3531487, GB 2,163,747, JP-A- 59181277, and WO 95/23149, each of which is incorporated by reference herein in its entirety.
  • Proton pump inhibitors include, but are not limited to, the compounds
  • Active metabolites of proton pump inhibitors suitable for use according to the invention include, but are not limited to, hydroxy-omeprazole, hydroxy-lansoprazole, the carboxylic acid derivative of omeprazole, and desmethyl-pantoprazole.
  • Omeprazole, lansoprazole, pantoprazole, and rabeprazole may be prepared by syntheses known to those of ordinary skill in the art, particularly from U.S. Pat. Nos. 4,544,750, 4,620,008, 4,620,008, 4,758,579, 5,045,552, 5,374,730, 5,386,032, 5,470,983, 5,502,195, and 5,877,192, each of which is expressly incorporated by reference herein.
  • the proton pump inhibitors are present as such or in the form of their salts with bases.
  • salts with bases which may be mentioned are sodium, potassium, magnesium or calcium salts.
  • the proton pump inhibitors or their salts are isolated in crystalline form, the crystals may contain variable amounts of solvent.
  • the proton pump inhibitors also includes all solvates, in particular all hydrates, of the proton pump inhibitors and their salts.
  • Particularly preferred proton pump inhibitors include benzimidazole compounds, for example, omeprazole (PRILOSEC ® , Proctor & Gamble, Cincinnati, Ohio), lansoprazole (PREV ACID ® , TAP Pharmaceutical Products Inc., Lake Forest, Illinois), rabeprazole (ACIPHEX ® , Eisai Co., Ltd., Tokyo, Japan), pantoprazole (PROTONIX ® , Wyeth Pharmaceuticals Inc., Philadelphia, Pennsylvania) and esomeprazole (NEXIUM ® , AstraZeneca Pharmaceuticals LP, Wilmington, Delaware). 5.3.2 Hi receptor antagonists and active metabolites thereof
  • a thiomolybdate or thiotungstate compound is administered in combination with a H 2 receptor antagonist or active metabolite thereof (active in inhibiting gastric acid secretion).
  • H 2 receptor antagonists competitively inhibit the interaction of histamine with H 2 receptors. They are highly selective and have little or no effect on H 1 receptors. Although H 2 receptors are present in numerous tissues, including vascular and bronchial smooth muscle, H 2 receptor antagonists interfere remarkably little with physiological functions other than gastric acid secretion.
  • H 2 receptor antagonists include, but are not limited to, nizatidine (AXID ® , Reliant Pharmaceuticals, Liberty Corner, New Jersey), ranitidine (ZANTAC ® , GlaxoSmithKline, Philadelphia, Pennsylvania), famotidine (PEPCID AC ® , Johnson & Johnson - Merck Consumer Pharmaceuticals Co., Fort Washington, Pennsylvania), and cimetidine (TAGAMET ® , GlaxoSmithKline, Philadelphia, Pennsylvania). See Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, pp. 901-915 (1996). Active metabolites of H 2 receptor antagonists can also be used and include, but are not limited to, N2-monodesmethylnizatidine. 5.3.3 Antacids
  • a thiomolybdate or thiotungstate compound is administered in combination with an antacid.
  • antacids for use in this aspect of the invention include any antacid known in the art.
  • Antacids may include one or more of the following: alumina, aluminum carbonate, basic, aluminum hydroxide, calcium carbonate, magaldrate, magnesia, magnesium alginate, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, simethicone, and sodium bicarbonate.
  • Preferred antacids are generally carbonate or hydroxide salts of calcium, magnesium or aluminum, including, for example, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, calcium carbonate and calcium hydroxide.
  • Antacids may comprise, by way of example, any of the following combinations or compounds: alumina, calcium carbonate, and sodium bicarbonate; alumina and magnesia; alumina, magnesia, calcium carbonate, and simethicone; alumina, magnesia, and magnesium carbonate; alumina, magnesia, magnesium carbonate, and simethicone; alumina, magnesia, and simethicone; alumina, magnesium alginate, and magnesium carbonate; alumina and magnesium carbonate; alumina, magnesium carbonate, and simethicone; alumina, magnesium carbonate, and sodium bicarbonate; alumina and magnesium trisilicate; alumina, magnesium trisilicate, and sodium bicarbonate; alumina and simethicone; alumina and sodium bicarbonate; aluminum carbonate, basic ; aluminum carbonate, basic, and simethicone; aluminum hydroxide; calcium carbonate; calcium carbonate and magnesia; calcium carbonate, and sime
  • Antacids readily neutralize acids in the gastrointestinal (GI) tract and are commonly available in or as antacid tablets.
  • Some typical consumer antacid products are: ALKA-SELTZER ® (Bayer HealthCare LLC, Morristown, New Jersey), which contains citric acid and sodium bicarbonate; CHOOZ ® (Heritage Consumer Products Co., Brookfiled, Connecticut), which contains calcium carbonate; DI-GEL , which contains magnesium hydroxide, simethicone and calcium carbonate; PHILLIPS' ® Milk of Magnesia (Bayer HealthCare LLC, Morristown, New Jersey), which contains magnesium hydroxide; MYLANTA ® (Johnson & Johnson - Merck Consumer Pharmaceuticals Co., Fort Washington, Pennsylvania), which contains simethicone, aluminum hydroxide and magnesium hydroxide; ROLAIDS ® (Pfizer Consumer Healthcare, Morris Plains, New Jersey), which contains calcium carbonate and magnesium hydroxide; and TUMS (GlaxoSmithKline, Philadelphia, Pennsylvania), which
  • a thiomolybdate or thiotungstate compound is administered after the patient takes a high protein meal.
  • the patient may take a high protein meal within 5 minutes, 10 minutes, 15 minutes, 30 minutes or up to one hour before administration of the thiomolybdate or thiotungstate compound.
  • a high protein meal comprises at least one high protein food, for example, meat or peanut butter, in a portion size of preferably 1 to 20 oz, more preferably 2-10 oz or 3-8 oz, or at least 2 oz or at least 4 oz.
  • thiomolybdate or thiotungstate compounds and/or pharmaceutical compositions thereof are useful for the treatment or prevention of various diseases characterized by aberrant vascularization, copper metabolism disorders, neurodegenerative disorders and obesity.
  • Thiomolybdate or thiotungstate compounds and/or pharmaceutical compositions thereof are useful for the treatment of any inflammatory and/or fibrotic disease, which includes response to injury.
  • thiomolybdate or thiotungstate compounds and/or pharmaceutical compositions thereof may be administered or applied singly, or in combination with other agents, such as proton pump inhibitors, H 2 -receptor antagonists or active metabolites thereof, and/or antacids.
  • the compounds and/or pharmaceutical compositions of the invention may also be administered or applied singly, in combination with other pharmaceutically active agents ⁇ e.g., other anti-cancer agents, other anti-angiogenic agents, other chelators such as zinc, penicillamine, etc. and other anti-obesity agents), including other thiomolybdate or thiotungstate compounds.
  • the current invention provides methods of treatment and prophylaxis by administration to a patient of a therapeutically effective amount of a thiomolybdate or thiotungstate compound, optionally with a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • the patient, or subject may be an animal, more preferably, is a mammal, such as a human, primate, non-human animal, dog, cat, horse, cow, mouse, rat, etc., and most preferably is a human.
  • treating or treatment refers to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating or treatment refers to ameliorating at least one physical parameter, which may not be discernible by the patient.
  • treating or treatment refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • Therapeutically effective amount means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • an "effective amount" of a thiomolybdate or thiotungstate compound is administered, packaged, or placed in combination with an "effective amount" of a second substance selected from among the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • an “effective amount” of the thiomolybdate or thiotungstate compound refers to an amount which is therapeutically effective in combination with the second substance; thus, for example, such an amount may be suboptimal (too low to achieve efficacy) when not in combination with the second substance, or alternatively, may be therapeutically effective on its own.
  • An “effective amount” of the second substance refers to that amount effective to increase bioavailability of the thiomolybdate or thiotungstate compound.
  • Combined administration means that the individual components can be administered simultaneously (in the form of a combination medicament), more or less simultaneously (from separate pack units) or in succession (one directly after the other directly or else alternatively within a relatively large time span).
  • the administration of each substance can be concurrent/simultaneous or in any order.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered simultaneously.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered to a subject in a sequence and within a time interval such that the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid can act together with the thiomolybdate or thiotungstate compound to reduce the side effects and/or prevent degradation of the thiomolybdate or thiotungstate compound.
  • each e.g., thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid
  • the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered prior to administration of the thiomolybdate or thiotungstate compound.
  • Each can be administered separately and in any appropriate form .
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered by oral administration.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered to a subject within a time frame that allows for both the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid to both be active at the same time.
  • the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered before the thiomolybdate or thiotungsate compound is administered.
  • the thiomolybdate or thiotungstate compound is administered to a subject at reasonably the same time as the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • the two administrations are performed within a time frame of less than one minute to about five minutes, about five minutes to about 10 minutes, about 10 minutes to 30 minutes, about 30 minutes up to about sixty minutes from each other.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered at or within 1, 2, 4, 8, 12, or 24 hours apart.
  • the thiomolybdate or thiotungstate compound is administered prior to the administration of the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid. In alternate specific embodiment, the thiomolybdate or thiotungstate compound is administered subsequent to the administration of the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • the thiomolybdate or thiotungstate compound and the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid can be administered simultaneously.
  • the thiomolybdate or thiotungstate compound and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered as a single pharmaceutical composition.
  • a pharmaceutical composition of the invention is administered once a day, twice a day, or three times a day.
  • the pharmaceutical composition is administered once a week, twice a week, once every two weeks, once a month, once every six weeks, once every two months, twice a year or once per year. It will also be appreciated that the effective dosage of the thiomolybdate or thiotungstate compound used for treatment may increase or decrease over the course of a particular treatment.
  • thiomolybdate or thiotungstate compounds and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid are administered orally.
  • Various delivery systems are known (e.g., formulation as a tablet, liquid suspension, encapsulation in liposomes, microparticles, microcapsules, capsules, etc.), that can be used to administer a compound and/or pharmaceutical composition of the invention.
  • the thiomolybdate or thiotungstate compounds can be delivered in a vesicle, in particular a liposome (See, Langer, 1990, Science, 249:1527-1533; Treat et al., in "Liposomes in the Therapy of Infectious Disease and Cancer," Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); see generally “Liposomes in the Therapy of Infectious Disease and Cancer,” Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989)).
  • the thiomolybdate or thiotungstate compounds can be delivered via sustained release systems, preferably oral sustained release systems.
  • a pump may be used (See, Langer, supra; Sefton, 1987, CRC Crit RefBiomed Eng. 14:201; Saudek et al, 1989, N. Engl. J. Med. 321:574).
  • polymeric materials can be used (see “Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); “Controlled Drug Bioavailability,” Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, 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. Neurosurg. 71 : 105).
  • polymeric materials are used for oral sustained release delivery.
  • Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred, hydroxypropyl methylcellulose).
  • Other preferred cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9). Factors affecting drug release are well known to the skilled artisan and have been described in the art (Bamba et al, Int. J. Pharm., 1979, 2, 307).
  • osmotic delivery systems are used for oral sustained release administration (Verma et al, Drug Dev. Ind. Pharm., 2000, 26:695-708).
  • OROSTM osmotic devices are used for oral sustained release delivery devices (Theeuwes et al, U.S. Pat. No. 3,845,770; Theeuwes et al, U.S. Pat. No. 3,916,899).
  • the present invention is directed to pharmaceutical compositions containing (1) a thiomolybdate or thiotungstate compound; (2) a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof,, or antacid; and (3) a pharmaceutically acceptable vehicle so as to provide a form for proper administration to a patient.
  • a vehicle when used in this context refers to a diluent, adjuvant, excipient, or carrier.
  • the compounds and pharmaceutically acceptable vehicles are preferably sterile. Water, saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present pharmaceutical compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • compositions comprising a compound of the invention may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more pharmaceutically acceptable vehicles, such as physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds of the invention into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the pharmaceutically acceptable vehicle is a capsule (see e.g., Grosswald et ah, U.S. Pat. No. 5,698,155).
  • suitable pharmaceutical vehicles have been described in the art (see Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy and Science, 20.sup.th Edition, 2000).
  • compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered pharmaceutical compositions may contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry coloring agents and preserving agents, to provide a pharmaceutically palatable preparation.
  • the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds of the invention.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time delay material such as glycerol monostearate or glycerol stearate may also be used.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.
  • suitable carriers, excipients or diluents include water, saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM) etc.
  • alkyleneglycols e.g., propylene glycol
  • polyalkylene glycols e.g., polyethylene glycol
  • slightly acidic buffers between pH 4 and pH 6 e.g., acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM
  • flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines and the like may be added.
  • a thiomolybdate or thiotungstate compound of the invention may be included in any of the above-described formulations as the free acid, a pharmaceutically acceptable salt, a solvate or a hydrate.
  • Pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- dis
  • compositions which substantially retain the activity of free acids, may be prepared by reaction with bases and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid form.
  • the proton pump inhibitor may be optionally mixed with alkaline compounds and further mixed with suitable ingredients as set forth above and then formulated into the substrate.
  • suitable ingredients include fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives.
  • the alkaline compound may be selected from substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminum, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as Al 2 O 3 OMgO CO 2 12H 2 O, (Mg 6 Al 2 (OH) 16 CO 3 4H 2 O), MgO' Al 2 O 3 2SiO 2 .nH 2 O or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances. 5.6 Doses
  • a thiomolybdate or thiotungstate compound, or pharmaceutical compositions thereof will generally be used in an amount effective to achieve the intended purpose.
  • the thiomolybdate or thiotungstate compounds for example, those of structural Formula (I), and/or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount.
  • a thiomolybdate or thiotungstate compound that will be effective in the treatment of a particular disorder or condition disclosed 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 may optionally be employed to help identify optimal dosage ranges. The amount of a compound of the invention administered will, of course, be dependent on, among other factors, the subject being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the dosage may be delivered in a pharmaceutical composition by a single administration, by multiple applications or controlled release.
  • the compounds of the invention are delivered by oral sustained release administration.
  • the compounds of the invention are administered twice per day (more preferably, once per day). Dosing may be repeated intermittently, may be provided alone or in combination with other drugs and may continue as long as required for effective treatment of the disease state or disorder.
  • Suitable dosage ranges for oral administration depend on the potency of the drug, but are generally between about 0.01 mg to about 200 mg of a compound of the invention per kilogram body weight. Dosage ranges may be readily determined by methods known to the artisan of ordinary skill.
  • effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well-known in the art.
  • Exemplary dosage ranges include about 0. 1 mg/kg to about 1 mg/kg, 0.05 mg/kg to about 50 mg/kg, and about 1 mg/kg to about 100 mg/kg.
  • Exemplary dosages include 5, 10, 25, 50 or 75 mg/kg given every day once daily.
  • the dosage administered is not based on body weight, but is an absolute amount, for example, in the range of 1 to 1000 mg per dose.
  • the dosage is 10 to 750 mg per dose, e.g., 20 mg, 100 mg, or 600 mg per dose.
  • the dose is administered from one to several (e.g., 2, 3, 4, or 7) times a week.
  • the dosage is 210, 240, 270, 300, or 330 mg given once daily.
  • a therapeutically effective dose of a thiomolybdate or thiotungstate compound will provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of compounds of the invention may be determined using standard pharmaceutical procedures and may be readily ascertained by the skilled artisan.
  • the dose ratio between toxic and therapeutic effect is the therapeutic index.
  • a compound of the invention will preferably exhibit particularly high therapeutic indices in treating disease and disorders.
  • the dosage of a compound of the inventions described herein will preferably be within a range of circulating concentrations that include an effective dose with little or no toxicity.
  • Suitable daily dosage ranges of proton pump inhibitors can be readily determined by those skilled in the art.
  • the total daily dosage of a proton pump inhibitor for the conditions described herein, such as lansoprazole, pantoprazole, rabeprezole, omeprazole, or active metabolites thereof is from about 1 mg to about 200 mg, preferably from about 5 mg to about 150 mg, and more preferably from about 10 mg to about 100 mg.
  • the proton pump inhibitor is usually administered in a dose of from 5 to 100, advantageously from 10 to 60, in particular from 20 to 40 mg, administered once or, if required, twice a day.
  • omeprazole is typically administered in a 20 mg dose/day, 40 mg dose/day, 60 mg dose/day and up to 120 mg/day.
  • the amount of proton pump inhibitor which is included in the dosage form is an amount which is considered to be therapeutically effective, in accordance with the dosages set forth above to reduce the side effects associated with administration of a thiomolybdate or thiotungstate compound and/or prevent its degradation.
  • the dose of proton pump inhibitor is sub-therapeutic.
  • the dosage form may contain from about 0.1 mg/day to about 120 mg/day omeprazole.
  • Lansoprazole is typically administered about 15-30 mg/day, rabeprazole is typically administered 20 mg/day and pantoprazole is typically administered 40 mg/day.
  • a subtherapeutic amount refers to an amount of a compound that by itself has no effect but, when used in combination with another compound, results in an desired effect, such as improved bioavailability.
  • Suitable daily dosage ranges of H 2 receptor antagonists can be readily determined by those skilled in the art. For example, see the Physician's Desk Reference ® , Medical Economics Co., Inc., 52nd Edition (1999) for suitable dosages presently used for known H 2 receptor antagonists.
  • ranitidine may be administered using an oral daily dose range from about 1 mg to about 800 mg, preferably from about 100 mg to about 600 mg, and more preferably from about 250 mg to about 500 mg.
  • the oral daily dose range may be from about 1 mg to about 240 mg, preferably from about 400 mg to about 1600 mg, more preferably from about 600 mg to about 100 mg.
  • the oral daily dose range may be from about 1 mg to about 200 mg, preferably from about 10 mg to about 80 mg, more preferably from about 15 mg to about 50 mg.
  • the oral daily dose range may be from about 1 mg to about 600 mg, preferably from about 50 mg to about 500 mg, more preferably from about 250 mg to about 350 mg.
  • Suitable daily dosage ranges of antacids can be readily determined by those skilled in the art. Commercially available antacids can be used according to the manufacturer's instructions.
  • a thiomolybdate or thiotungstate compound e.g., a compound of structural formula (I) and/or a pharmaceutical composition thereof, is used to treat or prevent a disease characterized by aberrant vascularization by administration to a patient, preferably a human, suffering from a disease characterized by aberrant vascularization or in danger or developing a disease characterized by aberrant vascularization.
  • Aberrant vascularization includes abnormal neovascularization such as the formation of new blood vessels, larger blood vessels, more branched blood vessels and any other mechanism, which leads to an increased blood carrying capacity to a diseased tissue or site.
  • Thiomolybdate or thiotungstate compounds and pharmaceutical compositions of the invention treat aberrant vascularization.
  • Diseases characterized by aberrant vascularization include, but are not limited to, cancer (e.g. , any vascularized tumor, preferably, a solid tumor, including but not limited to, carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, bilary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostrate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, neuroblastomas, sarcomas (e.g., angiosarcomas, chondrosarcomas)), arthritis, diabetes, arteriosclerosis, arteriovenous, malformations, corneal graft neovascularization, delayed wound healing, diabetic retinopathy, age related macular degeneration, granulations, burns, hemophilic joints,
  • cancer
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) and/or a pharmaceutical composition thereof may be administered to a patient, preferably a human, suffering from a disease associated with copper metabolism disorders (e.g., Wilson's disease) to treat such a disease.
  • a disease associated with copper metabolism disorders e.g., Wilson's disease
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I), and/or a pharmaceutical composition thereof may be administered to a patient, preferably a human, to treat obesity.
  • the thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I)
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) and/or a pharmaceutical composition thereof may be administered to a patient, preferably a human, suffering from a neurodegenerative disorder, to treat the neurodegenerative disorder.
  • Elevated levels of copper have been reported in the art to mediate the pathobiology of various neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion disease (Llanos et al, DNA Cell Biol.
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) and/or a pharmaceutical composition thereof may be administered to a patient, preferably a human, to treat diseases characterized by dysregulated activity of the NF- ⁇ B or dysregulated inflammation of inflammatory response, i.e., any inflammatory disorder or f ⁇ brotic disease, which includes response to injury.
  • the inflammatory disorder or fibrotic disease is a result of the activation or over-activation of transforming growth factor beta (TGF- ⁇ ).
  • Exemplary fibrotic diseases that may be treated by a method of the present invention include, but are not limited to, pulmonary disease including pulmonary fibrosis and acute respiratory distress syndrome, liver disease including liver cirrhosis and hepatitis C, kidney disease including renal interstitial fibrosis, scleroderma, cystic fibrosis, pancreatic fibrosis, keloid, secondary fibrosis in the gastrointestinal tract, hypertrophic burn scars, myocardial fibrosis, Alzheimer's disease, retinal detachment inflammation and/or fibrosis resulting after surgery, and graft versus host and host versus graft rejections.
  • pulmonary disease including pulmonary fibrosis and acute respiratory distress syndrome
  • liver disease including liver cirrhosis and hepatitis C
  • kidney disease including renal interstitial fibrosis, scleroderma, cystic fibrosis, pancreatic fibrosis, keloid, secondary fibrosis in the gastrointestinal tract
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) and/or pharmaceutical compositions thereof are administered to a patient, preferably a human, as a preventative measure against various diseases or disorders characterized by aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity, NF- ⁇ B dysregulation, inflammatory and/or fibrotic disease.
  • compounds of structural Formula (I) and/or pharmaceutical compositions thereof may be used for the prevention of one disease or disorder and concurrently treating another (e.g., preventing Wilson's disease or Alzheimer's while treating cancer).
  • thiomolybdate and thiotungstate compounds in treating or preventing various diseases or disorders characterized by aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity, NF- ⁇ B dysregulation, or inflammatory and/or fibrotic disease may be determined by methods described in the art and herein. Accordingly, it is well with the capability of those of skill in the art to assay and use thiomolybdate and thiotungstate compounds to treat or prevent aberrant vascularization, copper metabolism disorders, neurodegenerative disorders, obesity , NF- ⁇ B dysregulation, or inflammatory and/or fibrotic disease.
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) in combination with a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid can also be used in combination therapy with at least one other therapeutic agent.
  • the invention is directed to methods comprising (a) administering of an effective amount of athiomolybdate or thfotungstate compound, (b) administering of an effective amount of a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid, and (c) administering an effective amount (effective alone or in combination with (a) and (b)) of at least one other therapeutic agent.
  • the thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) and the therapeutic agent can act additively or, moie preferably, synetgisticaUy.
  • a thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I), and/or the proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered concurrently with the administration of another therapeutic agent for the same disease or disorder being treated or prevented, which may be part of the same pharmaceutical composition or a different pharmaceutical composition.
  • a thiomolybdate or thiotungstate compound and/or proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid is administered prior or subsequent to administration of another therapeutic agent.
  • the thiomolybdate or thiotungstate compound e.g, a compound of structural formula (I) and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid can be used in combination therapy with other chemotherapeutic agents ⁇ e.g., alkylating agents (e.g., nitrogen mustards (e.g., cyclophosphamide, ifosfatnide, mechlorethamine, melphalen, chlorambucil, hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas, triazines) antimetabolites (e.g., folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, cytosine arabinoside, etc.), purine analogs (e.g., mercaptopur
  • alkylating agents e.g.
  • the current invention provides therapeutic kits comprising in one or separate containers: (1) a thiomolybdate or thiotungstate compound, (2) a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid, and (3) optionally a therapeutic agent other than a thiomolybdate compound or thiotungstate compound, respectively.
  • the present invention also provides therapeutic kits comprising in a container a pharmaceutical composition of the invention.
  • the other therapeutic can be selected from, e.g., chemotherapeutic agents, natural products, hormones or antagonists, anti-angiogenesis agents or inhibitors, apoptosis-inducing agents or chelators, etc., as described above.
  • Therapeutic kits may have a single container which contains the pharmaceutical composition of the invention with or without other components (e.g., other compounds or pharmaceutical compositions of these other compounds) or may have distinct container for each component, e.g., (1) thiomolybdate or thiotungstate compound and (2) a proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid.
  • Therapeutic kits of the invention may include a thiomolybdate or thiotungstate compound, and proton pump inhibitor, H 2 receptor antagonist or active metabolite thereof, or antacid packaged in separate containers or in the same container for use in combination with the co-administration of a second compound (contained in the same or a separate container) (preferably, a chemotherapeutic agent, a natural product, a hormone or antagonist, a anti- angiogenesis agent or inhibitor, a apoptosis-inducing agent or a chelator) or a pharmaceutical composition thereof.
  • the components of the kit may be pre-mixed or each component may be in a separate distinct container prior to administration to a patient.
  • the components of the kit may be provided in one or more liquid solutions, preferably, an aqueous solution, more preferably, a sterile aqueous solution.
  • the components of the kit may also be provided as solids, which may be converted into liquids by addition of suitable solvents, which are preferably provided in another distinct container.
  • the container of a therapeutic kit may be a vial, test tube, flask, bottle, syringe, or any other means of enclosing a solid or liquid.
  • the kit will contain a second vial or other container, which allows for separate dosing.
  • the kit may also contain another container for a pharmaceutically acceptable liquid.
  • a therapeutic kit will contain apparatus (e.g., one or more needles, syringes, eye droppers, pipette, etc.), which enables administration of the components of the kit.
  • apparatus e.g., one or more needles, syringes, eye droppers, pipette, etc.
  • the invention is further defined by reference to the following example, which describe in detail, pretreatment with a proton pump inhibitor and methods for measuring the pharmacokinetics of bis(choline)tetrathiomolybdate (ATN-224). It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne généralement des procédés pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate par l'administration conjuguée (1) d'un composé de thiomolybdate ou thiotungstate, et (2) d'un inhibiteur de la pompe à protons, d'un antagoniste du récepteur H2 ou l'un de ses métabolites actifs, ou d'un antiacide. L'invention concerne également des compositions pharmaceutiques comprenant (1) un composé de thiomolybdate ou thiotungstate, et (2) un inhibiteur de la pompe à protons, un antagoniste du récepteur H2 ou l'un de ses métabolites actifs, ou un antiacide. Les procédés et compositions de l'invention peuvent être utilisés pour améliorer le traitement de maladies associées à une vascularisation aberrante, des troubles du métabolisme du cuivre, des troubles neurodégénératifs, l'obésité, des troubles inflammatoires et des maladies de type fibrose.
PCT/US2006/021529 2006-06-02 2006-06-02 Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate WO2007142626A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2006/021529 WO2007142626A1 (fr) 2006-06-02 2006-06-02 Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2006/021529 WO2007142626A1 (fr) 2006-06-02 2006-06-02 Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate

Publications (1)

Publication Number Publication Date
WO2007142626A1 true WO2007142626A1 (fr) 2007-12-13

Family

ID=38801748

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/021529 WO2007142626A1 (fr) 2006-06-02 2006-06-02 Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate

Country Status (1)

Country Link
WO (1) WO2007142626A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130131101A1 (en) * 2008-01-16 2013-05-23 Ulrich Schraermeyer Tetrahydropyridoethers for treatment of amd
CN111084786A (zh) * 2020-01-09 2020-05-01 上海市同济医院 四硫代钼酸铵在制备治疗肾间质纤维化的药物中的应用
WO2022165339A1 (fr) * 2021-01-31 2022-08-04 Alexion Pharmaceuticals, Inc. Nouvelle formulation pour le traitement de maladies ou de troubles associés au métabolisme du cuivre

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CIGLENECKI I. ET AL.: "Voltammetric Behavior of MoS4-2 and SbS4-3 as possible components of 'dissolved sulfide' in oxic natural waters", ELECTROANALYSIS, vol. 15, no. 2, 2003, pages 145 - 150, XP008070072 *
DATABASE HCAPLUS [online] SHARMA ET AL.: "Synthetic and Antibacterial studies of some binuclear compounds of tungsten", XP003001339, Database accession no. (127:116652) *
JOURNAL OF THE INSTITUTION OF CHEMISTS (INDIA), vol. 69, no. 1, 1997, pages 16 - 17 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130131101A1 (en) * 2008-01-16 2013-05-23 Ulrich Schraermeyer Tetrahydropyridoethers for treatment of amd
US9314453B2 (en) * 2008-01-16 2016-04-19 Katairo Gmbh Tetrahydropyridoethers for treatment of AMD
CN111084786A (zh) * 2020-01-09 2020-05-01 上海市同济医院 四硫代钼酸铵在制备治疗肾间质纤维化的药物中的应用
WO2022165339A1 (fr) * 2021-01-31 2022-08-04 Alexion Pharmaceuticals, Inc. Nouvelle formulation pour le traitement de maladies ou de troubles associés au métabolisme du cuivre

Similar Documents

Publication Publication Date Title
AU2018214064B2 (en) Compositions of compounds and uses thereof
AU2006279589B2 (en) Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereof
DK1556029T3 (en) THIOMOLYBDAL SALTS AND APPLICATIONS THEREOF
EP1729784A1 (fr) Formulations de composés de thiomolybdate ou de thiotungstate et leurs utilisations
EP3135672B1 (fr) Compositions et méthodes pour traiter les troubles liés à la consommation d'alcool, la douleur et d' autres maladies
EP2064192A2 (fr) Composés et procédés d'inhibition de l'interaction de protéines bcl avec des partenaires de liaison
WO2007022121A2 (fr) Composes o-nitro, compositions pharmaceutiques correspondantes, et leurs utilisations
JP2014051517A (ja) デフェラシロックス（ｉｃｌ６７０ａ）の多形形態
WO2007142626A1 (fr) Procédés et compositions pour augmenter la biodisponibilité de composés de thiomolybdate et thiotungstate
JP2022522395A (ja) 選択的エストロゲン受容体分解剤の新規な塩
EP1633310A2 (fr) Analogues de thiotungstate et leurs utilisations
US20040019043A1 (en) Thiomolybdate analogues and uses thereof
JP5102849B2 (ja) Ｎ−ヒドロキシ−４−｛５−［４−（５−イソプロピル−２−メチル−１，３−チアゾール−４−イル）フェノキシ］ペントキシ｝ベンズアミジン２エタンスルホン酸塩、その製造方法およびそれを含む薬学組成物
WO2023280090A1 (fr) Composition pharmaceutique, son procédé de préparation et son application

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06772004

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING LOSS OF RIGHTS PURSUANT TO RULE112(1) EPC DATED 16.03.2009.

122 Ep: pct application non-entry in european phase

Ref document number: 06772004

Country of ref document: EP

Kind code of ref document: A1