Anticancer agent

Patent metadata

Field	Value
Publication number	US-10005752-B2
Application number	US-201515317471-A
Country	US
Kind code	B2
Filing date	Jun 9, 2015
Priority date	Jun 9, 2014
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

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 compound represented by the formula (IA):

wherein
R 1 in the number of n are each independently

hydrogen,
halogen,
C 1-6 alkoxy, 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 one or two substituent(s) selected from substituent group α,
C 2-6 alkynyl optionally substituted by one or two substituent(s) selected from optionally substituted amino and optionally substituted monocyclic heterocyclyl group,
C 3-7 cycloalkyl,
phenyl,
phenyl C 1-6 alkyl, or
monocyclic heterocyclyl group,
R 3 is hydrogen,
n is an integer of 1-4 when R 1 is hydrogen,
n is 1 or 2 when R 1 is not hydrogen, and
the substituent group α consists of

hydroxy,
optionally substituted amino,
carboxy,
C 1-6 alkoxycarbonyl,
sulfo group,
di C 1-6 alkyl phosphoric acid group,
optionally substituted C 1-6 alkyl,
C 3-7 cycloalkyl,
C 3-7 cycloalkyl C 1-6 alkyl,
optionally substituted C 1-6 alkoxy,
optionally substituted phenyl,
optionally substituted phenyloxy,
phenyl C 1-6 alkoxy,
optionally substituted monocyclic heterocyclyl group,
optionally substituted C 1-6 alkylcarbonyl,
monocyclic heterocyclylcarbonyl,
optionally substituted C 1-6 alkylcarbonyloxy,
optionally substituted C 3-7 cycloalkylcarbonyloxy,
phenylcarbonyloxy,
monocyclic heterocyclylcarbonyloxy,
optionally substituted C 1-6 alkoxycarbonyloxy,
optionally substituted monocyclic heterocyclyl C 1-6 alkoxycarbonyloxy,
C 3-7 cycloalkyloxycarbonyloxy,
monocyclic heterocyclyloxycarbonyloxy,
optionally substituted monocyclic heterocyclyloxy,
tri C 1-6 alkylammonio,
optionally substituted C 1-6 alkylsulfonyl and
C 1-6 alkylsulfamoylcarbonyl,

or a pharmaceutically acceptable salt thereof.

2. A compound represented by the formula (I):

wherein
R 1 is hydrogen or halogen,
R 2 is

C 1-12 alkyl optionally substituted by one or two substituent(s) selected from substituent group α,
C 2-6 alkynyl optionally substituted by one or two substituent(s) selected from optionally substituted amino and optionally substituted monocyclic heterocyclyl group,
C 3-7 cycloalkyl,
phenyl
phenyl C 1-6 alkyl, or
monocyclic heterocyclyl group,
n is an integer of 1-4 when R 1 is hydrogen,
n is 1 or 2 when R 1 is not hydrogen, and
the substituent group α consists of

hydroxy,
optionally substituted amino,
carboxy,
C 1-6 alkoxycarbonyl,
sulfo group,
di C 1-6 alkyl phosphoric acid group,
optionally substituted C 1-6 alkyl,
C 3-7 cycloalkyl,
C 3-7 cycloalkyl C 1-6 alkyl,
optionally substituted C 1-6 alkoxy,
optionally substituted phenyl,
optionally substituted phenyloxy,
phenyl C 1-6 alkoxy,
optionally substituted monocyclic heterocyclyl group,
optionally substituted C 1-6 alkylcarbonyl,
monocyclic heterocyclylcarbonyl,
optionally substituted C 1-6 alkylcarbonyloxy,
optionally substituted C 3-7 cycloalkylcarbonyloxy,
phenylcarbonyloxy,
monocyclic heterocyclylcarbonyloxy,
optionally substituted C 1-6 alkoxycarbonyloxy,
optionally substituted monocyclic heterocyclyl C 1-6 alkoxycarbonyloxy,
C 3-7 cycloalkyloxycarbonyloxy,
monocyclic heterocyclyloxycarbonyloxy,
optionally substituted monocyclic heterocyclyloxy,
tri C 1-6 alkylammonio,
optionally substituted C 1-6 alkylsulfonyl and
C 1-6 alkylsulfamoylcarbonyl,

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 , wherein the substituent group α consists of
hydroxy,
optionally substituted amino,
carboxy,
C 1-6 alkoxycarbonyl,
sulfo group,
di C 1-6 alkyl phosphoric acid group,
C 1-6 alkyl,
C 3-7 cycloalkyl,
C 1-6 alkoxy,
optionally substituted phenyl,
optionally substituted phenyloxy,
phenyl C 1-6 alkoxy,
optionally substituted monocyclic heterocyclyl group,
optionally substituted C 1-6 alkylcarbonyl,
monocyclic heterocyclylcarbonyl,
optionally substituted C 1-6 alkylcarbonyloxy,
optionally substituted C 3-7 cycloalkylcarbonyloxy,
monocyclic heterocyclylcarbonyloxy,
optionally substituted C 1-6 alkoxycarbonyloxy,
optionally substituted monocyclic heterocyclyl C 1-6 alkoxycarbonyloxy,
C 3-7 cycloalkyloxycarbonyloxy,
monocyclic heterocyclyloxycarbonyloxy,
optionally substituted monocyclic heterocyclyloxy and
tri C 1-6 alkylammonio,

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2 , wherein
R 2 is C 1-6 alkyl optionally substituted by one or two substituent(s) selected from substituent group α, C 3-7 cycloalkyl, phenyl, phenyl C 1-6 alkyl, or monocyclic heterocyclyl group, and
the substituent group α consists of hydroxy, optionally substituted amino, carboxy, sulfo group, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, phenyl and monocyclic heterocyclyl group,

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 2 , wherein
R 2 is
(1) C 1-6 alkyl optionally substituted by one or two substituent(s) selected from hydroxy, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkylcarbonyloxy and monocyclic heterocyclylcarbonyloxy; o

Assignees

• Kyoto Pharma Ind
• Sumitomo Dainippon Pharma Co Ltd

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D307/92 Primary

  Naphthofurans; Hydrogenated naphthofurans · CPC title

• C07F9/65517

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• C07D405/12

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

• C07D407/12

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