Anticancer agent

Patent metadata

Field	Value
Publication number	US-11267797-B2
Application number	US-202016907463-A
Country	US
Kind code	B2
Filing date	Jun 22, 2020
Priority date	Jun 9, 2014
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

The problem of the present invention is to provide a useful prodrug compound of a naphthofuran compound. The present invention relates to a compound represented by the formula (IA):[wherein each symbol is as described in the DESCRIPTION] or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A production method of a compound represented by the formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein
each R 1 is independently
hydrogen
halogen
hydroxy,
amino,
cyano,
nitro,
C 1-12 alkyl,
C 2-6 alkenyl,
C 2-6 alkynyl,
C 3-7 cycloalkyl,
C 3-7 cycloalkenyl,
aryl,
heterocyclyl group,
C 1-6 alkoxy,
aryloxy,
C 1-6 alkylthio, or
arylthio, or
two R 1 bonded to the adjacent carbon atoms on a benzene ring are optionally joined to form C 1-4 alkylenedioxy,

R 2 is
C 1-12 alkyl optionally substituted by substituent(s) selected from substituent group α,
C 2-6 alkenyl optionally substituted by substituent(s) selected from substituent group α,
C 2-6 alkynyl optionally substituted by substituent(s) selected from substituent group α,
C 3-7 cycloalkyl optionally substituted by substituent(s) selected from substituent group α,
aryl optionally substituted by substituent(s) selected from substituent group α,
aryl C 1-6 alkyl optionally substituted by substituent(s) selected from substituent group α, or
heterocyclyl optionally substituted by substituent(s) selected from substituent group α,

n is an integer of 1-4 when R 1 is hydrogen,
n is an integer of 1 or 2 when R 1 is not hydrogen, and
the substituent group a consists of
halogen,
hydroxy,
optionally substituted amino,
carboxy,
C 1-6 alkoxycarbonyl,
sulfo group,
phosphoric acid group,
di C 1-6 alkyl phosphoric acid group,
cyano,
optionally substituted C 1-6 alkyl,
C 3-7 cycloalkyl,
C 3-7 cycloalkyl C 1-6 alkyl,
optionally substituted C 1-6 alkoxy,
C 1-6 alkylthio,
optionally substituted aryl,
optionally substituted aryloxy,
aryl C 1-6 alkoxy,
optionally substituted heterocyclyl,
optionally substituted C 1-6 alkylcarbonyl,
heterocyclylcarbonyl,
optionally substituted C 1-6 alkylcarbonyloxy,
optionally substituted C 3-7 cycloalkylcarbonyloxy,
arylcarbonyloxy,
monocyclic heterocyclylcarbonyloxy,
optionally substituted C 1-6 alkoxycarbonyloxy,
optionally substituted heterocyclyl C 1-6 alkoxycarbonyloxy,
C 3-7 cycloalkyloxycarbonyloxy,
heterocyclyloxycarbonyloxy,
optionally substituted heterocyclyloxy,
tri C 1-6 alkylammonio,
optionally substituted C 1-6 alkylsulfonyl, and
C 1-6 alkylsulfamoylcarbonyl, comprising

a step of reacting a compound represented by the formula (10):

or a salt thereof, wherein R 1 and n are as defined for R 1 and n in said formula (Ia), in inert solvent, and a compound represented by the formula (11):
R 2 —OH   (11)

or a salt thereof, wherein R 2 is as defined for R 2 in said formula (Ia).

2. The production method according to claim 1 , further comprising a step of producing a compound represented by the formula (10):

or a salt thereof, wherein R 1 and n are as defined above, by reacting a compound represented by the formula (2):

or a salt thereof, wherein R′, X, and n are as defined above,
in inert solvent in the presence of a base and a compound represented by the formula (9):

before the step of reacting a compound represented by the formula (10) or a salt thereof.

3. The production method according to claim 2 , wherein the base comprises N,N-dimethylaminopyridine.

4. The production method according to claim 2 , further comprising a step of producing a compound represented by the formula (2):

or a salt thereof, wherein R 1 , X, and n are as defined above, from a compound represented by the formula (1):

or a salt thereof, wherein R 1 and n are as defined above, before the step of reacting a compound represented by the formula (2) or a salt thereof.

5. The production method according to claim 1 , wherein R 1 is hydrogen or halogen.

6. The production method according to claim 1 , wherein the substituent group α consists of
halogen,
hydroxy,
optionally substituted amino,
carboxy,
C 1-6 alkoxycarbonyl,
sulfo group,
phosphoric acid group,
di C 1-6 alkyl phosphoric acid group,
cyano,
C 1-6 alkyl,
C 3-7 cycloalkyl,
C 1-6 alkoxy,
optionally substituted aryl,
optionally substituted aryloxy,
aryl C 1-6 alkoxy,
optionally substituted heterocyclyl group,
optionally substituted C 1-6 alkylcarbonyl,
heterocyclylcarbonyl,
optionally substituted C 1-6 alkylcarbonyloxy,
optionally substituted C 3-7 cycloalkylcarbonyloxy,
monocyclic heterocyclylcarbonyloxy,
optionally substituted C 1-6 alkoxycarbonyloxy,
optionally substituted heterocyclyl C 1-6 alkoxycarbonyloxy,
C 3-7 cycloalkyloxycarbonyloxy,
heterocyclyloxycarbonyloxy,
optionally substituted heterocyclyloxy, and
tri C 1-6 alkylammonio.

7. The production method according to claim 1 , wherein
R 2 is C 1-6 alkyl optionally substituted by substituent(s) selected from substituent group α, C 2-6 alkenyl optionally substituted by substituent(s) selected from substituent group α, C 3-7 cycloalkyl optionally substituted by substituent(s) selected from substituent group α, aryl optionally substituted by substituent(s) selected from substituent group α, aryl C 1-6 alkyl optionally substituted by substituent(s) selected from substituent group α, or heterocyclyl optionally substituted by substituent(s) selected from substituent group α, and
the substituent group a consists of halogen, hydroxy, optionally substituted amino, carboxy, sulfo group, phosphoric acid group, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, aryl, and heterocyclyl group.

8. The production method according to claim 1 , wherein R 2 is
(1) C 1-6 alkyl optionally substituted by substituent(s) selected from hydroxy, optionally substituted amino, carboxy, sulfo group, phosphoric acid group, di C 1-6 alkyl phosphoric acid group, heterocyclyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkylcarbonyloxy, monocyclic heterocyclylcarbonyloxy, C 3-7 cycloalkyloxycarbonyloxy, and heterocyclyloxycarbonyloxy,
(2) C 2-6 alkynyl optionally substituted by substituent(s) selected from hydroxy, optionally substituted amino, carboxy, sulfo group, phosphoric acid group, and heterocyclyl,
(3) heterocyclyl group optionally substituted by substituent(s) selected from hydroxy and optionally substituted C 1-6 alkyl, or
(4) aryl C 1-6 alkyl substituted by substituent(s) selected from hydroxy, optionally substituted amino, carboxy, sulfo group, phosphoric acid group, and heterocyclyl.

9. The production method according to claim 1 , wherein R 2 is
(1) C 1-6 alkyl optionally substituted by substituent(s) selected from hydroxy, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkylcarbonyloxy, and monocyclic heterocyclylcarbonyloxy, or
(2) C 2-6 alkynyl optionally substituted by substituent(s) selected from optionally substituted amino and heterocyclyl, or
(3) heterocyclyl optionally substituted by optionally substituted C 1-6 alkyl.

10. The production method accor

Assignees

• Kyoto Pharma Ind
• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Yoshimura Yoshinobu
• Kasai Masayasu
• Shoji Yoshimichi
• Takeda Shigemitsu

Classifications

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D307/92 Primary

  Naphthofurans; Hydrogenated naphthofurans · CPC title

• C07H15/26

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H7/06

  Heterocyclic radicals · CPC title