Method for treating neurological diseases using supramolecule polymer therapeutics

Patent metadata

Field	Value
Publication number	US-2024197682-A1
Application number	US-202318468657-A
Country	US
Kind code	A1
Filing date	Sep 15, 2023
Priority date	Sep 15, 2022
Publication date	Jun 20, 2024
Grant date	—

Abstract

A method of inhibiting propagation of protein misfolding associated with a neurological disease, is carried out by contacting an environment populated with a propagating amyloid conformation of a protein (prion) associated with a neurological disease with molecules which binds multiple adjacent sites of the protein assemblies and allowing the molecules to bind multiple cites of the protein assemblies; and thereby impeding propagation of the disease-associated conformation of the protein in the environment. Drug/prion complexes are formed and uses of the drugs in detection and treatment of neurodegenerative diseases are disclosed.

First claim

1 . A method of interrupting propagation of stacked proteins associated with a neurological disease, comprising:
contacting an environment populated with stacked proteins associated with a neurological disease with molecules which bind multiple sites of the stacked proteins; allowing the molecules to bind multiple sites of the stacked proteins; and thereby impeding propagation of the stacked proteins in the environment.

2 . The method of claim 1 wherein the molecules which binds multiple sites of the stacked proteins is characterized by:
(a) a planar core comprised of one or two rings which are optionally heterocycle;
(b) an accessible molecular conformation allowing three or more of the molecules to self-associate in a repeating, parallel-displaced stack along the stacked proteins;
(c) a configuration as shown in FIG. 3 , wherein a distance between an atom within adjacent planar cores is 3.3-3.5 Å;
(d) a configuration as shown in FIG. 4 , wherein a distance between equivalent atoms on two adjacent molecules is 4.8 Å,
(e) a configuration as shown in FIG. 5 , wherein an angle (θ) between a line defined by two equivalent atoms on adjacent molecules and a line perpendicular to planes of the planar core is 44°;
(f) a configuration as shown in FIG. 3 , wherein a minimal distance between any atom within the plane of the core and an equivalent atom within adjacent molecule bound to a stacked protein is 3.2-3.6 Å; and
(g) substituents forming non-covalent interactions with the stacked proteins which interactions are selected from the group consisting of hydrogen bonds, Van der Waals contacts, pi-pi interactions, and chalcogen bond.

3 . The method of claim 1 , wherein the stacked proteins are selected from the group consisting of tau, α-synuclein, and amyloid β.

4 . The method of claim 1 , wherein the contacting the environment populated with stacked proteins associated with a neurological disease comprises administering to an individual who has or is suspected to have the neurological disease an effective amount of the molecule.

5 . The method of claim 1 , wherein the neurological disease is selected from the group consisting of: Multiple Systems Atrophy, Parkinson's disease, and Alzheimer's disease.

6 . The method of claim 1 , wherein the impeding propagation of the stacked proteins in the environment treats the neurological disease.

7 . The method of claim 1 , wherein the molecule is a compound, or a salt or a hydrate or a solvate thereof, having a structure according to formula (I):

wherein
T is substituted or unsubstituted naphthyridinone or substituted or unsubstituted dihydronaphthyridinone;
X is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein X is monocyclic; and
Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted ethenyl.

8 . The method of claim 7 , wherein T is

wherein R a , R b , R c , and R d are independently selected from H, halogen, substituted or unsubstituted C 1-3 alkyl, C 2 -C 4 alkenyl, substituted or unsubstituted C 1-3 alkoxy, and when the connection between C* and C** is a single bond, R a and R b can be optionally joined with C* or with C** to form a substituted or unsubstituted cyclopropyl.

9 . The method of claim 7 , wherein T is

10 . The method of claim 7 , wherein T is

11 . The method of claim 7 , wherein X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted thienyl.

12 . The method of claim 7 , wherein X is 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 2-(trifluoromethyl)pyridin-5-yl, or 2-(1,1-difluoroethyl)pyridin-5-yl.

13 . The method of claim 7 , wherein Z is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted furan, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted oxazolyl.

14 . The method of claim 7 , wherein Z is 1-methylisoquinolin-6-yl, 2-(trifluoromethyl)pyrimidin-4-yl, 2-methylpyrimidin-4-yl, 1-methyl-6-isoquinolyl, 1-(2-hydroxyethyl)-6-isoquinolyl, 3-isoquinolyl, 6-quinolyl, 8-fluoro-3-quinolyl, 8-fluoro-7-quinolyl, 4-methyl-1,7a-diaza-2-indenyl, 1-thia-5-aza-2-indenyl, 1-(2-fluoroethyl)-1H-indazol-5-yl, 3-quinolyl, 2-cyclopropyl-2H-indazol-5-yl, 6-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-2-pyridyl, 1-benzofuran-2-yl, or phenyl.

15 . The method of claim 7 , having a structure according to formula (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX):

16 . The method of claim 7 , which is 7-{5-[6-(1,1-difluoroethyl)-3-pyridyl]-2-(1-methyl-6-isoquinolyl)-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-[1-(2-hydroxyethyl)-6-isoquinolyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-[1-(2-hydroxyethyl)-6-isoquinolyl]-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-[5-(p-fluorophenyl)-2-(3-isoquinolyl)-1,3-oxazol-4-yl]-1,7-diaza-8(7H)-naphthalenone, 7-[5-(p-fluorophenyl)-2-(6-quinolyl)-1,3-oxazol-4-yl]-1,7-diaza-8(7H)-naphthalenone, 7-{2-(8-fluoro-3-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-[5-(p-fluorophenyl)-2-(8-fluoro-7-quinolyl)-1,3-oxazol-4-yl]-1,7-diaza-8(7H)-naphthalenone, 7-{2-(4-methyl-1,7a-diaza-2-indenyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-(1-thia-5-aza-2-indenyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-[1-(2-fluoroethyl)-1H-indazol-5-yl]-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-(3-quinolyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-(2-cyclopropyl-2H-indazol-5-yl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-(6-fluoro-1,3-benzoxazol-2-yl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{5-[p-(trifluoromethyl)phenyl]-2-[2-(trifluoromethyl)-4-pyrimidinyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-{2-(5-fluoro-2-pyridyl)-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone, 7-[2-(1-benzofuran-2-yl)-5-(p-fluorophenyl)-1,3-oxazol-4-yl]-1,7-diaza-8(7H)-naphthalenone, or 7-{2-phenyl-5-[p-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}-1,7-diaza-8(7H)-naphthalenone.

17 . The method of claim 7 , wherein the compound is 7-(5-(4-(trifluoromethyl)phenyl)-2-(2-(trifluoromethyl)pyrimidin-4-yl)oxazol-4-yl)-1,7-naphthyridin-8(7H)-one.

18 . The method of claim 7 , wherein the compound is 7-(2-(1-methylisoquinolin-6-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-4-yl)-1,7-naphthyridin-8(7H)-one.

19 . The method of claim 1 , wherein the labeled molecule is a compo

Assignees

• Univ California

Inventors

• Prusiner Stanley B
• Paras Nick A
• Conrad Jay
• Sin Ny
• Raikar Sandeep
• Vander Wal Mark
• Grandjean Jean-Marc M
• Yamanoi Shigeo
• Inoue Masahiro
• Hirano Shimpei
• Honzumi Masatoshi
• Iwamoto Osamu
• Sasaki Koji
• Suzuki Yamato
• Tengeiji Atsushi
• Southworth Daniel R
• Hutt Darren
• Ayers Jacob I
• Olson Steven H
• Ly Cuong Quoc
• West John
• Merz Gregory E
• Viart Helene

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title