# US 9,433,607 B2 · Composition for prevention or treatment of cancer comprising N-methylenenaphtho[2,1-b]furan-2-carbohydrazide derivatives as an active ingredient

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- Number: US 9,433,607 B2
- Document ID: US9433607B2
- Status: Granted
- Kind: B2
- Application number: 14/641,065
- Filed: 2015-03-06
- Published: 2015-07-02
- Granted: 2016-09-06
- Earliest claimed: 2012-09-07
- Assignees: Korea Research Institute of Bioscience and Biotechnology
- Applicants: Korea Research Institute of Bioscience and Biotechnology
- Inventors: Bo Yeon Kim; Krisada Sakchaisri; Sun Ok Kim; Ramegowda Thimmegowda Naraganahalli; Nak Kyun Soung; Jong Seog Ahn; Joonsung Hwang; In Ja Ryoo; Jae-Hyuk Jang
- Web page: https://patentgrep.com/patent/US9433607B2

## CPC

- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- 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

The present invention relates to ethyl(2-methyl-3{(E)-[(naphtho[2,1-b]furan-2-ylcarbonyl)hydrazono]methyl}-1H-indole-1-yl)acetate, the novel mitosis inhibitor. The said ethyl(2-methyl-3{(E)-[(naphtho[2,1-b]furan-2-ylcarbonyl)hydrazono]methyl}-1H-indole-1-yl)acetate not only induces apoptosis by inhibiting tubulin polymerization in the course of mitosis but also displays an excellent anticancer effect in the multi-drug resistant cancer cells, so that it can be effectively used for the treatment of cell proliferative disease including various cancers.

## Claims

### Claim 1

A method of treating cancer, comprising administering a pharmaceutically effective dose of a compound represented by the below formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject having cancer:
wherein
R1 is
wherein R2 is methyl, R3 is methyl, allyl, cyanomethyl or —CH2(C═O)OCH2CH3, and R4 is nitro, 4-bromophenyl, 2,3-dichlorophenyl, 4-nitrophenyl or 4-methyl-3-nitrophenyl.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound represented by formula 1 is selected from the group consisting of the following compounds:
(1) ethyl(2-methyl-3{(E)-[(naphtho[2,1-b]furan-2-ylcarbonyl)hydrazono]methyl}-1H-indole-1-yl)acetate;
(2) (E)-N′-(1,2-dimethyl-1H-indol-3-yl)methylene) naphtho[2,1-b]furan-2-carbohydrazide;
(3) (E)-N′-((1-allyl-2-methyl-1H-indol-3-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide;
(4) (E)-N″-((1-(cyanomethyl)-2-methyl-1H-indol-3-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide;
(5) (E)-N′-((5-(2,3-bromophenyl)furan-2-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide;
(6) (E)-N′-((5-2,3-dichlorophenyl)furan-2-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide
(7) (E)-N′-((5-(4-nitrophenyl)furan-2-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide;
(8) (E)-N′-((5-(4-methyl-3-nitrophenyl)furan-2-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide; and
(9) (E)-N′-((5-nitrofuran-2-yl)methylene)naphtho[2,1-b]furan-2-carbohydrazide.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the cancer is selected from the group consisting of rectal cancer, breast cancer, lung cancer, stomach cancer, liver cancer, leukemia, glioma, and uterine cervical cancer.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound represented by formula 1 induces microtubule depolymerization.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound represented by formula 1 characteristically binds to the cholchicine binding site of tubulin.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound represented by formula 1 induces apoptosis by arresting cell cycle in G2 or M phase.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound represented by formula 1 is effective against multidrug-resistant cancer cells.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the cancer is selected from the group consisting of rectal cancer, lung cancer, stomach cancer, liver cancer, leukemia, and glioma.