# US 10,308,671 B2 · Water-soluble derivatives of 3,5-diphenyl-diazole compounds > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,308,671 B2 - Document ID: US10308671B2 - Status: Granted - Kind: B2 - Application number: 16/062,258 - Filed: 2016-12-14 - Published: 2018-12-27 - Granted: 2019-06-04 - Earliest claimed: 2015-12-14 - Assignees: Max-Planck-Gesellschaft zur Forderung - Applicants: Max-Planck-Gesellschaft zur Förderung; Armin Giese; Felix Schmidt - Inventors: Armin Giese; Felix Schmidt; Christian Griesinger; Andrei Leonov; Sergey Ryazanov - Web page: https://patentgrep.com/patent/US10308671B2 ## CPC - C07F 9/11: with hydroxyalkyl compounds without further substituents on alkyl - A61P 25/16: Anti-Parkinson drugs - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention is concerned with derivatives of 3,5-diphenyl-diazole compounds, which are effective therapeutic agents for use in treating diseases linked to protein aggregation and/or neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob disease (CJD). The therapeutic effect is caused by the inhibition of the protein aggregation in the affected tissue, such as the brain. 3,5-Diphenyl-diazole derivatives have been shown to be effective in inhibiting aggregation of proteins but are also characterized by their poor solubility in aqueous solutions. The prodrugs of the invention are modified 3,5-diphenyl-diazole derivatives, which are characterized by their improved solubility in aqueous solutions, and by their increased bioavailability. ## Claims ### Claim 1 A compound defined by one of the following isomeric structures Ia and Ib wherein one of Y and Z is N, and the other one is CR2; wherein R2 is selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 alkyl substituted with at least one halogen; and C6-10 aryl, wherein the aryl ring is unsubstituted or substituted by C1-4 alkyl or halogen; wherein either X is and Hal is halogen selected from chlorine or bromine, or wherein X is and Hal is bromine; and wherein each R independently is hydrogen or a cation. ### Claim 2 (depends on 1) The compound of claim 1, wherein Y is N and Z is —CH—. ### Claim 3 (depends on 1) The compound of claim 1 which is wherein Hal is a halogen selected from chlorine or bromine, and wherein each R independently is selected from hydrogen, or a cation. ### Claim 4 (depends on 1) The compound of claim 1, wherein at least one R is a cation chosen from sodium, lithium, potassium, ammonium, or protonated forms of ethanolamine, choline, lysine, meglumine, piperazine, and tromethamine. ### Claim 5 (depends on 4) The compound of claim 4, wherein both R are sodium. ### Claim 6 (depends on 1) The compound of claim 1, wherein Hal is bromine. ### Claim 7 (depends on 1) The compound of claim 1, wherein Hal is chlorine. ### Claim 8 (depends on 1) A method of treating a disease associated with protein aggregation, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof wherein the disease is selected from the group consisting of Parkinson's disease, prion disease, Alzheimer's disease, multiple system atrophy, Diffuse Lewy body disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease's, spinocerebellar ataxias and other Poly-Q diseases, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, primary systemic amyloidosis (AL amyloidosis), reactive systemic amyloidosis (AA amyloidosis), type H diabetes, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, and Finnish hereditary systemic amyloidosis. ### Claim 9 (depends on 8) The method of claim 8, wherein the disease associated with protein aggregation is characterized by the presence of an aggregated form of at least one protein or a fragment or derivative thereof, wherein the protein is selected from the group consisting of prion protein, amyloid precursor protein (APP), alpha-synuclein, superoxide dismutase, tau, immunoglobulin, amyloid-A, transthyretin, beta 2-microglobulin, cystatin C, apolipoproteine A1, TDP-43, islet amyloid polypeptide, ANF, gelsolin, insulin, lysozyme, fibrinogen, huntingtin and ataxin and other proteins with a Poly-Q stretch. ### Claim 10 (depends on 8) The method of claim 8, wherein the prion disease is selected from the group consisting of sporadic and genetic Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease (vCJD), a human disorder caused by the infectious agent of bovine spongiform encephalopathy (BSE), Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, kuru, BSE of cattle, scrapie of sheep and goats, feline spongiform encephalopathy (FSE) of cats, transmissible mink encephalopathy (TME) of minks, exotic ungulate encephalopathy (EUE) of Nyala and Greater Kudu, and chronic wasting disease (CWD) of deer and elk. ### Claim 11 (depends on 1) A composition comprising one of the compounds of isomeric structures Ia and Ib of claim 1, or a mixture thereof and a pharmaceutically acceptable additive. ### Claim 12 (depends on 11) The composition of claim 11, wherein Y is N and Z is —CH—. ### Claim 13 (depends on 11) The composition of claim 11, wherein the compound is wherein Hal is a halogen selected from chlorine or bromine, and wherein each R independently is selected from hydrogen, or a cation. ### Claim 14 (depends on 11) The composition of claim 11, wherein at least one R is a cation selected from the group consisting of sodium, lithium, potassium, and ammonium, or protonated forms of ethanolamine, choline, lysine, meglumine, piperazine, and tromethamine. ### Claim 15 (depends on 14) The composition of claim 14, wherein both R are sodium. ### Claim 16 (depends on 11) The composition of claim 11, wherein Hal is bromine. ### Claim 17 (depends on 11) The composition of claim 11, wherein Hal is chlorine. ### Claim 18 (depends on 11) The composition of claim 11, comprising a mixture of a compound having structure Ia and a compound having structure Ib.