# US 11,304,930 B2 · Ammonium salts of 3-(3,5-dibromo-4-hydroxybenzyliden)-5-indo-1,3-dihydroindol-2-one and uses thereof

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- Number: US 11,304,930 B2
- Document ID: US11304930B2
- Status: Granted
- Kind: B2
- Application number: 17/258,688
- Filed: 2019-07-24
- Published: 2021-09-16
- Granted: 2022-04-19
- Earliest claimed: 2018-08-07
- Assignees: Metagone Biotech Inc.
- Applicants: Metagone Biotech Inc.
- Inventors: Tai-Lung Cha; Tai-Wei Ly; Yi-Ta Tsai; Sheng-Chieh Lin; Yun Yu
- Web page: https://patentgrep.com/patent/US11304930B2

## CPC

- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61P 35/00: Antineoplastic agents
- C07D 209/34: in position 2
- 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)

## Abstract

Disclosed herein is a compound of formula (I), which is ammonium salt of GW5074, wherein R1, R2, and R3 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; or R1, R2, R3 and the nitrogen are taken together to form a 6-membered heterocyclyl; and the alkyl, the alkenyl, the alkynyl, the aryl, the heteroaryl, or the 6-membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of, —OH, —NH2, and —NRaRb, in which Ra and Rb are independently alkyl, aryl, or heteroaryl. Also disclosed herein is a pharmaceutical kit for the treatment of cancers. The pharmaceutical kit includes, a first formulation comprising a c-Raf inhibitor and a pharmaceutically acceptable carrier; and a second formulation comprising the compound of formula (I) and a pharmaceutically acceptable carrier. Also encompasses herein is a method of treating a subject having a cancer. The method comprises: (a) detecting whether the cancer cells of the subject has phosphorylation on serine 308 of death-associated protein kinase (DAPK); and (b) treating the subject based on the detection of the step (a) by, administering to the subject (i) an effective amount of a c-Raf inhibitor, and (ii) an effective amount of the compound of formula (I), when the phosphorylation on serine 308 of DAPK in the cancer cells is detected.

## Claims

### Claim 1

A compound of formula (I),
wherein,
R1, R2, and R3 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; or
R1, R2, R3 and the nitrogen are taken together to form a 6-membered heterocyclyl; and
the alkyl, the alkenyl, the alkynyl, the aryl, the heteroaryl, or the 6-membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of, —OH, —NaRb and a combination thereof, in which Ra and Rb are independently hydrogen, alkyl, aryl, or heteroaryl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein in the formula (I), R1 and R2 are independently hydrogen, and R3 is tertiary-butyl substituted with at least one hydroxyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein in the formula (I), R1 and R2 are independently hydrogen, and R3 is ethyl optionally substituted with at least one amino or hydroxy.

### Claim 4 (depends on 1)

The compound of claim 1, wherein in the formula (I), R1, R2, and R3 are independently ethyl substituted with hydroxyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein in the formula (I), R1 is hydrogen, and R2 is methyl, and R3 is hexyl substituted with 6 hydroxy groups.

### Claim 6 (depends on 1)

The compound of claim 1, wherein in the formula (I), R1 is hydrogen, and R2 is benzyl, and R3 is ethyl substituted with NH-benzyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein in the formula (I), R1, R2, R3 and the nitrogen are taken together to form piperazine, morpholine, or 4-(dimethylamino)pyridine.

### Claim 8 (depends on 1)

A pharmaceutical kit comprising:
a first formulation comprising sorafenib and a pharmaceutically acceptable carrier; and
a second formulation comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 8)

The pharmaceutical kit of claim 8, wherein in the compound of formula (I) of the second formulation, R1 and R2 are independently hydrogen, and R3 is tertiary-butyl substituted with at least one hydroxyl.

### Claim 10 (depends on 8)

The pharmaceutical kit of claim 8, wherein in the compound of formula (I) of the second formulation, R1 and R2 are independently hydrogen, and R3 is ethyl optionally substituted with at least one amino or hydroxy.

### Claim 11 (depends on 8)

The pharmaceutical kit of claim 8, wherein in the compound of formula (I) of the second formulation, R1, R2, and R3 are independently ethyl substituted with hydroxyl.

### Claim 12 (depends on 8)

The pharmaceutical kit of claim 8, wherein in the compound of formula (I) of the second formulation, R1 is hydrogen, and R2 is methyl, and R3 is R3 is hexyl substituted with 6 hydroxy groups.

### Claim 13 (depends on 8)

The pharmaceutical kit of claim 8, wherein in the compound of formula (I) of the second formulation, R1 is hydrogen, and R2 is benzyl, and R3 is ethyl substituted with NH-benzyl.

### Claim 14 (depends on 8)

The pharmaceutical kit of claim 8, wherein in the compound of formula (I) of the second formulation, R1, R2, R3 and the nitrogen are taken together to form piperazine, morpholine, or 4-(dimethylamino)pyridine.

### Claim 15 (depends on 1)

A method for treating a subject having a gastric cancer comprising:
(a) detecting whether the gastric cancer cells of the subject has phosphorylation on serine 308 of death-associated protein kinase (DAPK); and
(b) treating the subject based on the detection of the step (a) by,
administering to the subject (i) an effective amount of sorafenib, and (ii) an effective amount of the compound of claim 1, when the phosphorylation on serine 308 of DAPK in the gastric cancer cells is detected.

### Claim 16 (depends on 15)

The method of claim 15, wherein in the compound of formula (I), R1 and R2 are independently hydrogen, and R3 is tertiary-butyl substituted with at least one hydroxyl.

### Claim 17 (depends on 15)

The method of claim 15, wherein in the compound of formula (I) of the second formulation, R1 and R2 are independently hydrogen, and R3 is ethyl optionally substituted with at least one amino or hydroxy.

### Claim 18 (depends on 15)

The method of claim 15, wherein in the compound of formula (I) of the second formulation, R1, R2, and R3 are independently ethyl substituted with hydroxyl.

### Claim 19 (depends on 15)

The method of claim 15, wherein in the compound of formula (I) of the second formulation, R1 is hydrogen, and R2 is methyl, and R3 is R3 is hexyl substituted with 6 hydroxy groups.

### Claim 20 (depends on 15)

The method of claim 15, wherein in the compound of formula (I) of the second formulation, R1 is hydrogen, and R2 is benzyl, and R3 is ethyl substituted with —NH-benzyl.

### Claim 21 (depends on 15)

The method of claim 15, wherein in the compound of formula (I) of the second formulation, R1, R2, R3 and the nitrogen are taken together to form piperazine, morpholine, or 4-(dimethylamino)pyridine.