# US 9,006,283 B2 · Methods of modifying amyloid β oligomers using non-peptidic compounds

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- Number: US 9,006,283 B2
- Document ID: US9006283B2
- Status: Granted
- Kind: B2
- Application number: 11/777,264
- Filed: 2007-07-12
- Published: 2009-01-15
- Granted: 2015-04-14
- Earliest claimed: 2007-07-12
- Assignees: Acumen Pharmaceuticals, Inc.
- Applicants: Grant A. Krafft; Todd Pray; William F. Goure
- Inventors: Grant A. Krafft; Todd Pray; William F. Goure
- Web page: https://patentgrep.com/patent/US9006283B2

## CPC

- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/02: Suppositories; Bougies; Bases therefor; {Ovules}(apparatus for making A61J3/08; devices for introducing into the body A61M31/00)
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/381: having five-membered rings
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/415: 1,2-Diazoles
- A61P 25/00: Drugs for disorders of the nervous system
- C12N 5/0619: {Neurons}
- C12N 2501/999: Small molecules not provided for elsewhere
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Disclosed are methods of inhibiting, regulating, and/or modulating the formation of soluble, globular, non-fibrillar, neurotoxic amyloid β1-42 oligomers from amyloid β1-42 monomers. Also disclosed are methods of treating a patient suffering from diseases associated with the formation of soluble, globular, non-fibrillar, neurotoxic amyloid β1-42 oligomers.

## Claims

### Claim 1

A method for antagonizing neurotoxic ADDL formation from monomeric Aβ1-42 by contacting monomeric Aβ1-42 with an effective amount of a compound selected from the group consisting of
N-(2-Methoxy-phenyl)-2-oxo-2-{N′-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-prop-(Z)-ylidene]-hydrazino}-acetamide,
2-{[1-(2-Hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester,
2-{[1-(2-Hydroxynaphthalen-1-yl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester,
2-{[1-(2-Hydroxyphenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester,
2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide,
(E)-2-hydroxy-N′-((1-hydroxynaphthalen-2-yl)methylene)benzohydrazide,
or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is N-(2-Methoxy-phenyl)-2-oxo-2-{N′-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-prop-(Z)-ylidene]-hydrazino}-acetamide, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound is 2-{[1-(2-Hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is N-(2-Methoxy-phenyl)-2-{[1-(2-Hydroxynaphthalen-1-yl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is N-(2-Methoxy-phenyl)-2-{[1-(2-Hydroxyphenyl)-meth-(E)-ylidene-hydrazinooxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is N-(2-Methoxy-phenyl)-2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide, or a stcreoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is N-(2-Methoxy-phenyl)-(E)-2-hydroxy-N-((1-hydroxynaphthalen-2-yl)methylene)benzohydrazide, or a stereoisomer thereof or a mixture of the stereoisomers, or a pharmaceutical salt of the compound, stereoisomer or mixture.