# US 10,370,345 B2 · Amyloid targeting agents and methods of using the same

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- Number: US 10,370,345 B2
- Document ID: US10370345B2
- Status: Granted
- Kind: B2
- Application number: 15/969,328
- Filed: 2018-05-02
- Published: 2018-11-15
- Granted: 2019-08-06
- Earliest claimed: 2014-03-19
- Assignees: The Regents of the University of California; Amydis Diagnostics, Inc.
- Applicants: The Regents of the University of California; Amydis, Inc.
- Inventors: Jerry Yang; Emmanuel A. Theodorakis; Stella Sarraf
- Web page: https://patentgrep.com/patent/US10370345B2

## CPC

- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- A61B 5/0075: {by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy (A61B5/0071 takes precedence)}
- 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
- C07C 255/42: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C 255/58: containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C 255/59: the carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C 311/35: of an unsaturated carbon skeleton containing rings
- C07D 211/06: having no double bonds between ring members or between ring members and non-ring members
- C07D 213/57: Nitriles
- C07D 213/85: in position 3
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 265/30: not condensed with other rings
- C07D 295/04: with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 333/22: Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 407/10: linked by a carbon chain containing aromatic rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07H 13/04: having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H 19/056: Triazole or tetrazole radicals
- A61B 5/4082: {Diagnosing or monitoring movement diseases, e.g. Parkinson, Huntington or Tourette}
- A61B 5/4088: {Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia}
- Y02E 10/549: Organic PV cells
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- Y02E: REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION

## Abstract

Provided herein is the design and synthesis of novel molecular rotor fluorophores useful for detection of amyloid or amyloid like proteins. The fluorophores are designed to exhibit enhanced fluorescence emission upon associating with amyloid or amyloid like proteins as compared to unbound compound. Also disclosed herein are methods for treating diseases associated with amyloid or amyloid like proteins.

## Claims

### Claim 1

A method for monitoring response to a treatment of a patient having a disease or condition characterized by amyloid deposit in a body part or a body area of the patient, comprising:
(i) forming a detectable complex in the body part or the body area following the treatment by contacting an effective amount of a compound of Formula Ic, or a salt or solvate thereof, or a pharmaceutical composition thereof, with the amyloid deposit; and
(ii) detecting the detectable complex, wherein a decrease of detectable complex as compared to before the treatment indicates that the patient is responsive to the treatment;
wherein the compound of Formula Ic has the structure:
wherein
EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R17;
each R17 is independently halogen, —OR18, —NR19R20, C1-C10 alkyl, or C1-C10 heteroalkyl;
each of R18, R19 and R20 is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, or cycloalkyl of no more than 10 carbon atoms, each of which except for hydrogen is optionally substituted with one or more R21;
each R21 is independently halogen, —OR22, —NR23R24, C1-C10 alkyl, C1-C10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each of R22, R23 and R24 is independently hydrogen or C1-C10 alkyl;
Ar is arylene of no more than 14 carbon atoms optionally substituted with one or more R1;
each R1 is independently halogen, —OR2, —NR3R4, C1-C10 alkyl, C1-C10 heteroalkyl,
each of R2, R3 and R4 is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl;
R84 is hydrogen or C1-C10 alkyl;
EWG is halogen, —CN, —NO2, or methyl;
WSG is:
wherein n is an integer from 2-50, and R81 is hydrogen, a C1-C10 alkyl, a C2-C10 alkenyl, or a C2-C10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C1-C10 alkyl, C1-C10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each R82 is independently hydrogen or C1-C10 alkyl;
X is C═O or SO2; and
Y is NH or S.

### Claim 2 (depends on 1)

The method of claim 1, in which the amyloid deposit comprises an amyloid or amyloid like protein, wherein the amyloid or amyloid like protein is Aβ peptide, prion peptide, alpha-synuclein, or superoxide dismutase.

### Claim 3 (depends on 2)

The method of claim 2, wherein the amyloid or amyloid like protein is beta amyloid (1-42) (Aβ(1-42)).

### Claim 4 (depends on 1)

The method of claim 1, wherein EDG is

### Claim 5 (depends on 1)

The method of claim 1, wherein EDG is

### Claim 6 (depends on 1)

The method of claim 1, wherein EWG is —CN.

### Claim 7 (depends on 1)

The method of claim 1, wherein R84 is hydrogen or methyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein WSG is:
wherein R81 is methyl or CH2—C≡CH,
wherein n is 2, 3, 4, 5, 6, 7, 8, 9, or 10;

### Claim 9 (depends on 1)

The method of claim 1, wherein WSG is
wherein n is an integer from 2-50 and R81 is C1-C10 alkyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein R81 is methyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein n is 3 or 6.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound of Formula Ic is:
wherein n is an integer from 2 to 10, and n′ is an integer from 2 to 10.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of Formula Ic is:

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound of Formula Ic is:

### Claim 15 (depends on 1)

The method of claim 1, wherein the disease or condition is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, or Down's syndrome.

### Claim 16 (depends on 1)

The method of claim 1, wherein the disease or condition is a prion disease or condition.

### Claim 17 (depends on 1)

The method of claim 1, wherein the disease or condition is Creutzfeldt-Jakob disease.

### Claim 18

A method for monitoring response to a treatment of a patient having a disease or condition characterized by amyloid deposit in a body part or a body area of the patient, comprising
(i) forming a detectable complex in the body part or the body area following the treatment by contacting an effective amount of a compound of the formula:
or a salt or solvate thereof, or a pharmaceutical composition thereof, with the amyloid deposit; and
(ii) detecting the detectable complex, wherein a decrease of detectable complex as compared to before the treatment indicates that the patient is responsive to the treatment.

### Claim 19

A method of detecting an amyloid or amyloid like protein comprising
(i) contacting a compound of Formula Ic, or a salt or solvate thereof, with a body part or a body area of a patient potentially comprising the amyloid or amyloid like protein;
(ii) forming a detectable complex of the amyloid or amyloid like protein; and
(iii) detecting the detectable complex such that the presence or absence of the detectable complex correlates with the presence or absence of the amyloid or amyloid like protein;
wherein the compound of Formula Ic has the structure:
wherein
EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R17;
wherein each R17 is independently halogen, —OR18, —NR19R20, C1-C10 alkyl, or C1-C10 heteroalkyl;
each of R18, R19 and R20 is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl, or cycloalkyl of no more than 10 carbon atoms, each of which except for hydrogen is optionally substituted with one or more R21;
each R21 is independently halogen, —OR22, —NR23R24, C1-C10 alkyl, C1-C10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each of R22, R23 and R24 is independently hydrogen or C1-C10 alkyl;
Ar is aryl of no more than 14 carbon atoms optionally substituted with one or more R1;
each R1 is independently halogen, —OR2, —NR3R4, C1-C10 alkyl, C1-C10 heteroalkyl,
each of R2, R3 and R4 is independently hydrogen, C1-C10 alkyl, C1-C10 heteroalkyl;
R84 is hydrogen or C1-C10 alkyl;
EWG is halogen, —CN, —NO2, or methyl;
WSG is:
wherein n is an integer from 2 to 50, and R81 is hydrogen, a C1-C10 alkyl, a C2-C10 alkenyl, or a C2-C10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C1-C10 alkyl, C1-C10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each R82 is independently hydrogen or C1-C10 alkyl;
X is C═O or SO2; and
Y is NH or S.

### Claim 20 (depends on 19)

The method of claim 19, wherein the patient suffers from or is at risk of having a disease or condition selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, Down's syndrome, and Creutzfeldt-Jakob disease.

### Claim 21

A method for monitoring response to a treatment of a patient having a disease or condition characterized by amyloid deposit in a body part or a body area of the patient, comprising
(i) forming a detectable complex in the body part or the body area following the treatment by contacting the amyloid deposit with an effective amount of a compound of the formula:
wherein n is an integer from 2 to 10; or a salt or solvate thereof, or a pharmaceutical composition thereof; and
(ii) detecting the detectable complex, wherein a decrease of detectable complex as compared to before the treatment indicates that the patient is responsive to the treatment.