# US 12,110,281 B2 · Catechol derivatives or salt thereof, processes for preparing the same, and pharmaceutical compositions comprising the same

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- Number: US 12,110,281 B2
- Document ID: US12110281B2
- Status: Granted
- Kind: B2
- Application number: 17/261,561
- Filed: 2019-07-17
- Published: 2021-11-04
- Granted: 2024-10-08
- Earliest claimed: 2018-07-20
- Assignees: Hexapharmatec Co., Ltd.
- Applicants: Hexapharmatec Co., Ltd.
- Inventors: Shin Han; Jae-Hyoung Lee
- Web page: https://patentgrep.com/patent/US12110281B2

## CPC

- A61P 25/00: Drugs for disorders of the nervous system
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- 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
- 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)

## Abstract

Provided is a novel catechol derivative or pharmaceutically acceptable salt thereof having an alkyl moiety substituted with alkylamino and/or a N-alkyl-substituted thiophene-(thio)carboxamide moiety, a process for the preparation thereof, and a pharmaceutical composition including the same.

## Claims

### Claim 1

A compound of Formula 1 or pharmaceutically acceptable salt thereof:
wherein,
Y is O or S,
(1) when Y is O,
R1 is hydrogen; or a C1˜C4 alkyl group substituted with a mono- or di-C1˜C5 alkylamino,
R2 is a C1˜C6 alkyl group,
R3 is hydrogen, and
R4 is a (4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl group; a C1˜C4 alkyl group substituted with a mono- or di-C1˜C5 alkylamino; a C1˜C4 alkyl group substituted with a nitrogen-containing cyclic ring (wherein the nitrogen-containing cyclic ring is morpholine, piperidine, or pyrrolidine which is optionally substituted with C1˜C4 alkyl); or a piperidinyl group optionally substituted with C1˜C4 alkyl,
(2) when Y is S,
R1 and R2 are, independently of each other, hydrogen; a C1˜C6 alkyl group; or a C1˜C4 alkyl group substituted with a mono- or di-C1˜C5 alkylamino,
R3 is hydrogen, and
R4 is a C1˜C4 alkyl group substituted with a mono- or di-C1˜C5 alkylamino.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptable salt thereof of claim 1, wherein
Y is O,
R1 is hydrogen; or a diethylaminoethyl group, and
R2 is a methyl group.

### Claim 3 (depends on 1)

The compound or pharmaceutically acceptable salt thereof of claim 1, wherein
Y is O,
R1 is hydrogen; or a diethylaminoethyl group,
R2 is a methyl group,
R3 is hydrogen, and
R4 is a (4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl group; a dimethylaminoethyl group; a diethylaminoethyl group; a diisopropylaminoethyl group; a morpholinoethyl group optionally substituted with C1˜C4 alkyl; a piperidinoethyl group optionally substituted with C1˜C4 alkyl; a pyrrolidinoethyl group optionally substituted with C1˜C4 alkyl; or a piperidinyl group optionally substituted with C1˜C4 alkyl.

### Claim 4 (depends on 1)

The compound or pharmaceutically acceptable salt thereof of claim 1, wherein
Y is O,
R1 is hydrogen; or a diethylaminoethyl group,
R2 is a methyl group,
R3 is hydrogen, and
R4 is a (4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl group.

### Claim 5 (depends on 1)

The compound or pharmaceutically acceptable salt thereof of claim 1, wherein
Y is S,
R1 is hydrogen; or a diethylaminoethyl group, and
R2 is a methyl group.

### Claim 6 (depends on 1)

The compound or pharmaceutically acceptable salt thereof of claim 1, wherein
Y is S,
R1 is hydrogen; or a diethylaminoethyl group,
R2 is a methyl group,
R3 is hydrogen, and
R4 is a diisopropylaminoethyl group.

### Claim 7

A The compound or pharmaceutically acceptable salt thereof, which is one or more selected from the group consisting of:
N-(2-(diisopropylamino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(diisopropylamino)ethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(diisopropylamino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-thiocarboxamide hydrochloride;
N-(2-(diisopropylamino)ethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-thiocarboxamide hydrochloride;
N-isopropyl-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-isopropyl-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-thiocarboxamide hydrochloride;
N-(2-(diethylamino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(diethylamino)ethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(dimethylamino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(dimethylamino)ethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(4-morpholino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(1-piperidino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(1-piperidino)ethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(1-pyrrolidino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(4-(1-methyl)piperidinyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(2-(1-methyl)pyrrolidino)ethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N-(2-(2-(1-methyl)pyrrolidino)ethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride;
N—((S)-2-(1-ethyl)pyrrolidinomethyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride; and
N—((S)-2-(1-ethyl)pyrrolidinomethyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide hydrochloride.

### Claim 8

N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-5-(4-hydroxy-3-methoxyphenyl)thiophene-2-carboxamide or pharmaceutically acceptable salt thereof.

### Claim 9

N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-5-(4-(2-diethylamino)ethoxy-3-methoxyphenyl)thiophene-2-carboxamide or pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition for inducing autophagy, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10 for preventing, ameliorating or treating neurodegenerative diseases selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, prion disease, multiple sclerosis, and Lou Gehrig's disease; hepatic diseases selected from the group consisting of liver fibrosis, liver cirrhosis, hepatitis, and fatty liver disease; metabolic diseases selected from the group consisting of diabetes, hyperlipidemia, obesity, and inflammation; or sepsis.