# US 11,077,097 B2 · Use of aromatic ring drug in inhibiting key transcription factor of malignant melanoma

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- Number: US 11,077,097 B2
- Document ID: US11077097B2
- Status: Granted
- Kind: B2
- Application number: 16/627,144
- Filed: 2018-06-04
- Published: 2020-04-30
- Granted: 2021-08-03
- Earliest claimed: 2017-06-27
- Assignees: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Applicants: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Inventors: Jing Wang; Min Guo; Pengfei Fang; Biao Yu
- Web page: https://patentgrep.com/patent/US11077097B2

## CPC

- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61P 35/00: Antineoplastic agents
- 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

## Abstract

Provided is the use of an aromatic ring drug in inhibiting a key transcription factor of malignant melanoma. In particular, provided is the use of a compound as represented by formula A, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition or preparation. The pharmaceutical composition or preparation is used for: (a) inhibiting a key transcriptional regulatory factor of malignant melanoma, namely MITF (Microphthalmia-associated Transcription Factor); (b) treating MITF-related diseases such as melanoma, pancreatic cancer, skin hypersensitivity and asthma; and (c) regulating physiological activities in which MITF is involved, such as skin whitening. In the formula, each group is as defined in the description.

## Claims

### Claim 1

A method for treating a MITF-related disease, which comprises a step of:
administering a compound of formula A, or an optical isomer, or a racemate, or a solvate or a pharmaceutically acceptable salt thereof to a subject in need thereof,
wherein,
Ar is phenyl, pyridyl, pyrimidinyl, or aromatic ring without or containing nitrogen, sulfur, oxygen heteroatom;
X1 and X2 are each independently selected from the group consisting of O atom, S atom, substituted or unsubstituted N atom, and C atom; wherein the term “substituted” refers to having one or more substituents selected from the group consisting of halogen, —OH, —NH2, —CN, —NH (C1-C3 alkyl), —N (C1-C3 alkyl)2, furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom; wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of substituted or unsubstituted phenyl, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NH2, —CN, —NH (C1-C3 alkyl), —N (C1-C3 alkyl)2, halogen, and benzyl;
R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, and substituted or unsubstituted C3-C8 cycloalkyl; wherein the “substituted” refers to having one or more substituents selected from the group consisting of halogen, —OH, —NH2, —CN, —NH (C1-C3 alkyl), —N (C1-C3 alkyl)2, furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom;
wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of substituted or unsubstituted phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 and R2 are each independently selected from the group consisting of substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, and substituted C3-C8 cycloalkyl; wherein the “substituted” refers to having one or more substituents selected from the group consisting of furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom, wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1- C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound of formula A has the following structure:
wherein,
Ar is pyridyl or benzene ring;
X1 and X2 are each independently selected from the group consisting of N atom, O atom, and S atom;
R1 and R2 are each independently selected from the group consisting of

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of formula A has the following structure:

### Claim 5 (depends on 1)

The method of claim 1, wherein the MITF-related disease is selected from the group consisting of malignant melanoma, pancreatic cancer, skin hypersensitivity, and asthma.

### Claim 6

A method for non-therapeutically inhibiting a key transcriptional regulatory factor of malignant melanoma MITF in vitro, which comprises a step of: contacting MITF with a compound of formula A, or an optical isomer, or a racemate, or a solvate or a pharmaceutically acceptable salt thereof, thereby inhibiting activity of MITF,
wherein,
Ar is phenyl, pyridyl, pyrimidinyl, or aromatic ring without or containing nitrogen, sulfur, oxygen heteroatom;
X1 and X2 are each independently selected from the group consisting of 0 atom, S atom, substituted or unsubstituted N atom, and C atom; wherein the term “substituted” refers to having one or more substituents selected from the group consisting of halogen, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom; wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of substituted or unsubstituted phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl;
R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, and substituted or unsubstituted C3-C8 cycloalkyl; wherein the “substituted” refers to having one or more substituents selected from the group consisting of halogen, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom;
wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of substituted or unsubstituted phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl.

### Claim 7 (depends on 6)

The method of claim 6, wherein R1 and R2 are each independently selected from the group consisting of substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, and substituted C3-C8 cycloalkyl; wherein the “substituted” refers to having one or more substituents selected from the group consisting of furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom, wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1- C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl.

### Claim 8 (depends on 6)

The method of claim 6, wherein the compound of formula A has the following structure:
wherein,
Ar is pyridyl or benzene ring;
X1 and X2 are each independently selected from the group consisting of N atom, O atom, and S atom;
R1 and R2 are each independently selected from the group consisting of

### Claim 9 (depends on 6)

The method of claim 6, wherein the compound of formula A has the following structure:

### Claim 10

A method for inhibiting melanin formation or for whitening skin, which comprises a step of: administering a compound of formula A, or an optical isomer, or a racemate, or a solvate or a pharmaceutically acceptable salt thereof to a subject in need thereof,
wherein,
Ar is phenyl, pyridyl, pyrimidinyl, or aromatic ring without or containing nitrogen, sulfur, oxygen heteroatom;
X1 and X2 are each independently selected from the group consisting of O atom, S atom, substituted or unsubstituted N atom, and C atom; wherein the term “substituted” refers to having one or more substituents selected from the group consisting of halogen, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom; wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of substituted or unsubstituted phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl;
R1 and R2 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, and substituted or unsubstituted C3-C8 cycloalkyl; wherein the “substituted” refers to having one or more substituents selected from the group consisting of halogen, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom;
wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of substituted or unsubstituted phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1-C3 alkyl)2, halogen, and benzyl.

### Claim 11 (depends on 10)

The method of claim 10, wherein R1 and R2 are each independently selected from the group consisting of substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C2-C8 alkenyl, substituted C2-C8 alkynyl, and substituted C3-C8 cycloalkyl; wherein the “substituted” refers to having one or more substituents selected from the group consisting of furan, and substituted or unsubstituted 5-7 membered heterocyclic ring containing O or S heteroatom, wherein the substituted heterocyclic ring contains 1-3 substituents selected from the group consisting of phenyl, C1-C3 alkyl, C1-C3 haloalkyl, −OH, −NH2, −CN, −NH (C1-C3 alkyl), −N (C1- C3 alkyl)2, halogen, and benzyl.

### Claim 12 (depends on 10)

The method of claim 10, wherein the compound of formula A has the following structure:
wherein,
Ar is pyridyl or benzene ring;
X1 and X2 are each independently selected from the group consisting of N atom, O atom, and S atom;
R1 and R2 are each independently selected from the group consisting of

### Claim 13 (depends on 10)

The method of claim 10, wherein the compound of formula A has the following structure: