# US 10,500,207 B2 · Compounds for the treatment of diseases associated with amyloid or amyloid-like proteins

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- Number: US 10,500,207 B2
- Document ID: US10500207B2
- Status: Granted
- Kind: B2
- Application number: 14/930,442
- Filed: 2015-11-02
- Published: 2016-06-09
- Granted: 2019-12-10
- Earliest claimed: 2010-04-16
- Assignees: AC Immune SA
- Applicants: AC Immune SA
- Inventors: Heiko Kroth; Cotinica Hamel; Pascal Benderitter; Wolfgang Froestl; Nampally Sreenivasachary; Andreas Muhs
- Web page: https://patentgrep.com/patent/US10500207B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61K 31/404: Indoles, e.g. pindolol
- 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 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/12: for cataracts
- A61P 35/00: Antineoplastic agents
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 401/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 2333/4709: Amyloid plaque core protein
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- 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)

## Abstract

The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.

## Claims

### Claim 1

A method of inhibiting Aß1-42 aggregation, Tau aggregation and/or alpha-synuclein aggregation comprising:
administering to a subject an effective amount of a compound having the formula (I):
A-L1-B (I)
or a stereoisomer, racemic mixture, or pharmaceutically acceptable salts thereof;
wherein A is:
L1 is:
B is:
wherein
R2 and R3 are each independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —CONR30R31, —N(R30)—C(O)—R31, a —O—C1-C6 alkyl, and C5-C10 heterocycloalkyl, or wherein R2 and R3 taken together form a 5- or 6-membered ring containing carbon atoms and optionally one or two heteroatoms selected from O, S, or N;
R1 is hydrogen or halogen;
Ra is hydrogen or C1-C6 alkyl;
for each occurrence, Rb is independently selected from the group consisting of: hydrogen, halogen, CN, CONR30R31, or C1-C6 alkyl;
for each occurrence, R30, R31, and R20 are each independently selected from the group consisting of hydrogen, or C1-C6 alkyl;
Y is CH or N; and
z is 1 or 2, thereby inhibiting Aß1-42 aggregation, Tau aggregation and/or alpha-synuclein aggregation.

### Claim 2 (depends on 1)

The method of claim 1, wherein Y is N.

### Claim 3 (depends on 1)

The method of claim 1, wherein Y is CH.

### Claim 4 (depends on 1)

The method of claim 1, wherein z is 1.

### Claim 5 (depends on 1)

The method of claim 1, wherein z is 2.

### Claim 6 (depends on 1)

The method of claim 1, wherein Y is N and z is 2.

### Claim 7 (depends on 1)

The method of claim 1,
wherein
B is:

### Claim 8 (depends on 7)

The method of claim 7,
wherein
B is:

### Claim 9 (depends on 8)

The method of claim 8,
wherein A is:
and
B is:

### Claim 10 (depends on 9)

The method of claim 9, wherein the compound is:

### Claim 11 (depends on 9)

The method of claim 9, wherein the compound is:

### Claim 12 (depends on 1)

The method of claim 1,
wherein
B is:

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is selected from:

### Claim 14 (depends on 1)

The method of claim 1, further comprising administering a cholinesterase inhibitor (ChEI).

### Claim 15 (depends on 1)

The method of claim 1, further comprising administering pirenzepin, 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), α-secretase activator, β-secretase inhibitor, γ-secretase inhibitor, tau protein, pyroglutamated amyloid beta 3-42, M1 agonists, neurotransmitters, β-sheet breakers, tacrine, rivastigmine, donepezil, galantamine, niacin and/or memantine.

### Claim 16 (depends on 1)

The method of claim 1, wherein the subject suffers from Alzheimer's disease (AD), Lewy body dementia (LBD), Down's syndrome, mild cognitive impairment (MCI), Parkinson's disease, glaucoma, or macular degeneration.

### Claim 17 (depends on 16)

The method of claim 16, wherein the macular degeneration is s age-related macular degeneration (AMD).

### Claim 18

A method of retaining or increasing cognitive memory capacity in a subject suffering from memory impairment comprising administering to a subject in need of such treatment an effective amount of a compound having the formula (I):
A-L1-B (I)
or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof;
wherein A is:
L1 is:
B is:
wherein
R2 and R3 are each independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —CONR30R31, —N(R30)—C(O)—R31, a —O—C1-C6 alkyl, and C5-C10 heterocycloalkyl, or wherein R2 and R3 taken together form a 5- or 6-membered ring containing carbon atoms and optionally one or two heteroatoms selected from O, S, or N;
R1 is hydrogen or halogen;
Ra is hydrogen or C1-C6 alkyl;
for each occurrence, Rb is independently selected from the group consisting of: hydrogen, halogen, CN, CONR30R31, or C1-C6 alkyl;
for each occurrence, R30, R31, and R20 are each independently selected from the group consisting of hydrogen, or C1-C6 alkyl;
Y is CH or N; and
z is 1 or 2.