Water-soluble derivatives of 3,5-diphenyl-diazole compounds

Patent metadata

Field	Value
Publication number	US-10308671-B2
Application number	US-201616062258-A
Country	US
Kind code	B2
Filing date	Dec 14, 2016
Priority date	Dec 14, 2015
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

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.

First claim

The invention claimed is:

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 CR 2 ;
wherein R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted with at least one halogen; and C 6-10 aryl, wherein the aryl ring is unsubstituted or substituted by C 1-4 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.

2. The compound of claim 1 , wherein Y is N and Z is —CH—.

3. 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.

4. 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.

5. The compound of claim 4 , wherein both R are sodium.

6. The compound of claim 1 , wherein Hal is bromine.

7. The compound of claim 1 , wherein Hal is chlorine.

8. 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.

9. 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.

10. 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.

11. 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.

12. The composition of claim 11 , wherein Y is N and Z is —CH—.

13. 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.

14. 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.

15. The composition of claim 14 , wherein both R are sodium.

16. The composition of claim 11 , wherein Hal is bromine.

17. The composition of claim 11 , wherein Hal is chlorine.

18. The composition of claim 11 , comprising a mixture of a compound having structure Ia and a compound having structure Ib.

Assignees

• Max Planck Gesellschaft
• Giese Armin
• Schmidt Felix
• Max Planck Ges Zur Forderung

Inventors

• Giese Armin
• Schmidt Felix
• Griesinger Christian
• Leonov Andrei
• Ryazanov Sergey

Classifications

• C07F9/11 Primary

  with hydroxyalkyl compounds without further substituents on alkyl · CPC title

• A61P25/28

  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 · CPC title

• C07F9/65517 Primary

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title