Anticancer agent
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.
1. A production method of a compound represented by 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 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,
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 (2):
or a salt thereof, wherein X is halogen, and R 1 is as defined for R 2 in said formula (Ia), in inert solvent in the presence of a base and a compound represented by the formula (3):
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 , wherein the base comprises magnesium chloride or trimethylamine.
3. The production method according to claim 1 , further comprising
a step of producing a compound represented by the formula (2):
or a salt thereof, wherein 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.
4. The production method according to claim 1 , wherein R 1 is hydrogen or halogen.
5. 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.
6. 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 α 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.
7. 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, or a pharmaceutically acceptable salt thereof.
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 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, or a pharmaceutically acceptable salt thereof.
9. The production method according to claim 1 , wherein R 1 is hydrogen, or a pharmaceutically acceptable salt thereof.