# US 2024/0201205 A1 · Method for detecting neurological diseases using supramolecule polymer therapeutics

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- Number: US 2024/0201205 A1
- Document ID: US20240201205A1
- Status: Published application
- Kind: A1
- Application number: 18/468,639
- Filed: 2023-09-15
- Published: 2024-06-20
- Earliest claimed: 2022-09-15
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Stanley B. Prusiner; Nick A. Paras; Jay Conrad; Ny Sin; Sandeep Raikar; Mark Vander Wal; Jean-Marc M. Grandjean; Shigeo Yamanoi; Masahiro Inoue; Shimpei Hirano; Masatoshi Honzumi; Osamu Iwamoto; Koji Sasaki; Yamato Suzuki; Atsushi Tengeiji; Daniel R. Southworth; Darren Hutt; Jacob I. Ayers; Steven H. Olson; Cuong Quoc Ly; John West; Gregory E. Merz; Helene Viart
- Web page: https://patentgrep.com/patent/US20240201205A1

## CPC

- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/4245: Oxadiazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/497: containing further heterocyclic rings
- A61K 31/499: Spiro-condensed pyrazines or piperazines
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- 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
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 495/04: Ortho-condensed systems
- C07D 519/00: 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
- G01N 33/58: involving labelled substances (G01N33/53 takes precedence)
- G01N 2800/2821: Alzheimer
- G01N 2800/2835: Movement disorders, e.g. Parkinson, Huntington, Tourette
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A method for detecting a neurological disease the method comprising isolating brain tissue from its natural environment, contacting the brain tissue with a labeled molecule which binds to multiple sites of stacked proteins associated with neurodegenerative disease, determining the binding of the labeled molecule; and thereby determining a neurodegenerative disease associated with the brain tissue.

## Claims

### Claim 1

A method of detecting a neurological disease, comprising:
contacting the brain tissue with a labeled molecule which binds multiple sites of stacked proteins associated with a neurological disease;
determining binding of the labeled molecule; and
thereby determining a neurological disease associated with the brain tissue.

### Claim 2 (depends on 1)

The method of claim 1, wherein the determining comprises performing positron emission tomography, imaging mass spectrometry, or magnetic resonance imaging.

### Claim 3 (depends on 1)

The method of claim 1, wherein a binding portion of the labeled molecule 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. 4, 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 to hydrogen bonds, Van der Waals contacts, pi-pi interactions, and chalcogen bonds.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The method of claim 1, wherein the labeled molecule contains one or more of [2H], [3H], [11C], [18F], or [13N].

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The method of claim 1, wherein the labeled 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.

### Claim 8 (depends on 7)

The method of claim 7, wherein T is
wherein Ra, Rb, Rc, and Rd are independently selected from H, halogen, substituted or unsubstituted C1-3 alkyl, C2-C4 alkenyl, substituted or unsubstituted C1-3 alkoxy, and when the connection between C* and C** is a single bond, Ra and Rb can be optionally joined with C* or with C** to form a substituted or unsubstituted cyclopropyl.

### Claim 9 (depends on 7)

The method of claim 7, wherein T is

### Claim 10 (depends on 7)

The method of claim 7, wherein T is

### Claim 11 (depends on 7)

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.

### Claim 12 (depends on 7)

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.

### Claim 13 (depends on 7)

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.

### Claim 14 (depends on 7)

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.

### Claim 15 (depends on 7)

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

### Claim 16 (depends on 7)

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-fluoro ethyl)-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-(trifluoro methyl)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.

### Claim 17 (depends on 7)

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

### Claim 18 (depends on 7)

The method of claim 7, wherein the compound is N-methyl {1-[5-(3,4-difluorophenyl)-2-(4,6-dimethyl-2-pyridyl)-1,3-oxazol-4-yl]-5-fluoro-2-oxo-1,2-dihydro-4-pyrimidinyl}amine.

### Claim 19 (depends on 1)

The method of claim 1, wherein the labeled molecule is a compound of formula (XVI):
wherein:
R1, R5, and R6 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, —CH2R20, —CHMeR20, —CH(OH)R20, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, alkenyl, alkynyl, acyl, nitro, halo, amino, substituted amine, ether, thioether, and H;
Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
A is selected from N, CH, C(halo);
X is selected from O and N—R2,
R2 and R20 are each independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, alkenyl, alkynyl, acyl, and H; and
Ring B is a 5-membered heteroaryl ring.

### Claim 20 (depends on 1)

The method of claim 1, wherein the molecule has a structure as shown in one of the structures of FIG. 6.