# US 12,600,701 B2 · N-acylhydrazonic compounds, use in the treatment of amyloid and non-amyloid degenerative aggregopathies, and pharmaceutical composition

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- Number: US 12,600,701 B2
- Document ID: US12600701B2
- Status: Granted
- Kind: B2
- Application number: 17/912,427
- Filed: 2021-03-15
- Published: 2023-05-04
- Granted: 2026-04-14
- Earliest claimed: 2020-03-18
- Assignees: Faculdades Catolicas
- Applicants: Faculdades CatóLicas
- Inventors: Nicolás Adrián Rey; Daphne Schneider Cukierman Rey
- Web page: https://patentgrep.com/patent/US12600701B2

## CPC

- A61P 25/16: Anti-Parkinson drugs
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 27/12: for cataracts
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## Abstract

The present invention relates to a family of N-acylhydrazonic compounds structurally derived from 1-methyl-1H-imidazole-2-carboxaldehyde, or pharmaceutically acceptable salts thereof, and the use of said compounds to prevent and/or treat amyloid (such as Alzheimer's, Parkinson's and type 2 diabetes) and non-amyloid (such as cataracts) degenerative aggregopathies These compounds act as attenuators of the metal-protein interaction, preventing and/or decreasing protein oligomerization through competition with the target peptide or protein for the binding of physiological metal ions and, possibly, by modulating the protein-protein interaction itself. The invention also details four compounds specifically described as examples of N-acylhydrazones derived from 1-methyl-1H-imidazole-2-carboxaldehyde, namely: 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone, 1-methyl-1H-imidazole-2-carboxaldehyde benzoyl hydrazone, 1-methyl-1H-imidazole-2-carboxaldehyde 2-furoyl hydrazone and 1-methyl-1H-imidazole-2-carboxaldehyde 2-thiophenyl hydrazone. The current application also comprises pharmaceutical compositions.

## Claims

### Claim 1

An N-acylhydrazonic compound, structurally derived from 1-methyl-1H-imidazole-2-carboxaldehyde, or a pharmaceutically acceptable salt thereof, having the following formula (I):
in which Ar is a 5- or 6-membered heteroaromatic ring.

### Claim 2 (depends on 1)

The N-acylhydrazonic compound according to claim 1, having the following formulae (II) or (III):
in which:
A represents CR4 or N;
D represents CR4 or N;
E represents CR4 or N;
X represents O, S or NH;
Z represents CR4 or N;
R1 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group;
R2 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group;
R3 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group; and
R4 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group,
or a pharmaceutically acceptable salt thereof,
with the proviso that at least one of A, D or E represents N.

### Claim 3 (depends on 2)

The N-acylhydrazonic compound according to claim 2, wherein A, D and E represent a number of nitrogen heteroatoms not more than two,
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

The N-acylhydrazonic compound according to claim 2, wherein A=D=CR4, E=N and R1=R2=R4=H, which structure is represented by the formula (IV):
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 2)

The N-acylhydrazonic compound according to claim 2, wherein X=O, Z=CR4 and R3=R4=H, which structure is represented by the formula (VI):
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 2)

The N-acylhydrazonic compound according to claim 2, wherein X=S, Z=CR4 and R3=R4=H, which structure is represented by the formula (VII):
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A method for treating amyloid or non-amyloid degenerative aggregopathy, comprising:
administering, to a subject in need thereof, the N-acylhydrazonic compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, as an active component.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the amyloid or non-amyloid degenerative aggregopathy is Alzheimer's, Parkinson's, type 2 diabetes, or cataracts.

### Claim 9 (depends on 7)

The method according to claim 7, wherein said N-acylhydrazonic compound is a compound represented by the following formulae (II) or (III):
in which:
A represents CR4 or N;
D represents CR4 or N;
E represents CR4 or N;
X represents O, S or NH;
Z represents CR4 or N;
R1 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group;
R2 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group;
R3 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group; and
R4 a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group,
or a pharmaceutically acceptable salt thereof,
with the proviso that at least one of A, D or E represents N.

### Claim 10 (depends on 9)

The method according to claim 9, wherein said compounds of formulas (II) or (III) are selected between those represented by the formulae (IV), (VI) or (VII):
or pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition, comprising:
a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically suitable excipient.

### Claim 12 (depends on 11)

The pharmaceutical composition according to claim 11, wherein the compound of formula (I) has the following formulae (II) or (III):
in which:
A represents CR4 or N;
D represents CR4 or N;
E represents CR4 or N;
X represents O, S or NH;
Z represents CR4 or N;
R1 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group;
R2 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group;
R3 represents a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group, a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group; and
R4 a hydrogen, a halogen, an alkyl group, an alkoxyl group, an ester group, an acyl group,
a phenoxyl group, a cyano group, a nitro group, a hydroxyl group, or a thioalkoxyl group,
or a pharmaceutically acceptable salt thereof,
with the proviso that at least one of A, D or E represents N.

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12, wherein the compounds of formulae (II) or (III) are one of the compounds of formulae (IV), (VI) or (VII):
or pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 2)

A method for treating amyloid or non-amyloid degenerative aggregopathy, comprising:
administering, to a subject in need thereof, the N-acylhydrazonic compound of claim 2, or a pharmaceutically acceptable salt thereof, as an active component.

### Claim 15 (depends on 3)

A method for treating amyloid or non-amyloid degenerative aggregopathy, comprising:
administering, to a subject in need thereof, the N-acylhydrazonic compound of claim 3, or a pharmaceutically acceptable salt thereof, as an active component.

### Claim 16 (depends on 4)

A method for treating amyloid or non-amyloid degenerative aggregopathy, comprising:
administering, to a subject in need thereof, the N-acylhydrazonic compound of claim 4, or a pharmaceutically acceptable salt thereof, as an active component.

### Claim 17 (depends on 5)

A method for treating amyloid or non-amyloid degenerative aggregopathy, comprising:
administering, to a subject in need thereof, the N-acylhydrazonic compound of claim 5, or a pharmaceutically acceptable salt thereof, as an active component.

### Claim 18 (depends on 6)

A method for treating amyloid or non-amyloid degenerative aggregopathy, comprising:
administering, to a subject in need thereof, the N-acylhydrazonic compound of claim 6, or a pharmaceutically acceptable salt thereof, as an active component.