Benzothiophene compound, alternative autophagy-inducing agent and anticancer agent including the compound as active ingredient, and method for screening for compound having anticancer activity

Patent metadata

Field	Value
Publication number	US-10954222-B2
Application number	US-201314376671-A
Country	US
Kind code	B2
Filing date	Feb 7, 2013
Priority date	Feb 9, 2012
Publication date	Mar 23, 2021
Grant date	Mar 23, 2021

Abstract

It has been found that efficient screening for a compound having anticancer activity can be achieved by selecting a compound having activity to induce alternative autophagy using, as an index, formation of fluorescent bright spots due to aggregation of a lysosomal protein to which a fluorescent protein is attached in cells expressing the lysosomal protein. In addition, it has been found that a benzothiophene compound represented by the following general formula (1) has alternative autophagy-inducing activity and anticancer activity:

First claim

The invention claimed is:

1. A method for inducing alternative autophagy, comprising
introducing a benzothiophene compound represented by the following general formula (1) into any one of a cultured cell and an animal:

in the formula (1), R 1 is an optionally substituted 5- to 10-membered aromatic carbon ring, an optionally substituted 5- to 10-membered aromatic heterocycle, or a group represented by —R 6 —R 7 , R 2 is a halogen atom, a hydroxyl group, or a group represented by —O—R 6 —R 7 or —O—R 6 —R 8 , R 3 is a hydrogen atom or a group represented by —C(═O)R 9 , R 4 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and R 5 is an oxygen atom or an imino group, and also in the formula (1), R 6 s, which may be the same or different, each independently is a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms, R 7 s, which may be the same or different, each independently is an amino group optionally substituted by a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkenyl group having 2 to 6 carbon atoms, or a linear, branched, or cyclic hydroxyalkyl group having 1 to 6 carbon atoms, R 8 is an optionally substituted 5- to 10-membered aromatic carbon ring or an optionally substituted 5- to 10-membered aromatic heterocycle, and R 9 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, an optionally substituted 5- to 10-membered aromatic carbon ring, or an optionally substituted 5- to 10-membered aromatic heterocycle, and inducing alternative autophagy in any one of the cultured cell or the animal.

2. At least one benzothiophene compound selected from the group consisting of the following (a) and (b):
(a) a benzothiophene compound represented by the following general formula (1):

in the formula (1), R 1 is an optionally substituted 5- to 10-membered aromatic carbon ring or an optionally substituted 5- to 10-membered aromatic heterocycle, R 2 is a halogen atom, a hydroxyl group, or a group represented by —O—R 6 —R 7 or —O—R 6 —R 8 , R 3 is a hydrogen atom or a group represented by —C(═O)R 9 , R 4 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and R 5 is an oxygen atom or an imino group, and also in the formula (1), R 6 is a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms, R 7 is an amino group optionally substituted by a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkenyl group having 2 to 6 carbon atoms, or a linear, branched, or cyclic hydroxyalkyl group having 1 to 6 carbon atoms, R 8 is an optionally substituted 5- to 10-membered aromatic carbon ring or an optionally substituted 5- to 10-membered aromatic heterocycle, and R 9 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, an optionally substituted 5- to 10-membered aromatic carbon ring, or an optionally substituted 5- to 10-membered aromatic heterocycle; and
(b) a benzothiophene compound represented by the general formula (1):
in the formula (1), R 1 is a halogen atom, R 2 is a halogen atom or a group represented by —O—R 6 —R 7 , R 3 is a group represented by a hydrogen atom, R 4 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and R 5 is an oxygen atom or an imino group, and also in the formula (1), R 6 is a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms, and R 7 is an amino group optionally substituted by a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, a linear, branched, or cyclic alkenyl group having 2 to 6 carbon atoms, or a linear, branched, or cyclic hydroxyalkyl group having 1 to 6 carbon atoms,
and the benzothiophene compound having alternative autophagy-inducing activity.

3. An anticancer agent comprising the benzothiophene compound according to claim 2 as an active ingredient, and any one of pharmacologically acceptable carriers and media.

4. A method for treating cancer, comprising a step of administering the benzothiophene compound according to claim 2 to a patient.

5. A benzothiophene compound represented by the following general formula (1):

in the formula (1), R 1 is a group selected from the following groups

R 2 is a group represented by —O—C 2 H 4 —N(C 2 H 5 ) 2 , R 3 is a group represented by —C(═O) CH 3 , R 4 is a group represented by —C 2 H 5 , R 5 is an oxygen atom.

6. An anticancer agent comprising the benzothiophene compound according to claim 5 as an active ingredient and any one of pharmacologically acceptable carriers and media.

7. A method for inducing alternative autophagy, comprising
introducing the benzothiophene compound according to claim 2 into any one of a cultured cell and an animal, and
inducing alternative autophagy in any one of the cultured cell and the animal.

Assignees

• Univ Nat Corp Tokyo Medical & Dental

Inventors

• Shimizu Shigeomi
• Hosoya Takamitsu
• Murohashi Michiko
• Yoshida Suguru

Classifications

• A61K31/381

  having five-membered rings · CPC title

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title

• C07D333/68

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D409/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title