U.S. patent application number 15/300917 was filed with the patent office on 2017-01-19 for new tricyclic quinone derivative.
This patent application is currently assigned to Boston Biomedical, Inc.. The applicant listed for this patent is Boston Biomedical, Inc. Invention is credited to Hitoshi BAN, Tomoyuki FURUTA, Seiji KAMIOKA, Hiroyuki KITANO, Chiang Jia Li, Shoukou RI.
Application Number | 20170015677 15/300917 |
Document ID | / |
Family ID | 54239835 |
Filed Date | 2017-01-19 |
United States Patent
Application |
20170015677 |
Kind Code |
A1 |
BAN; Hitoshi ; et
al. |
January 19, 2017 |
NEW TRICYCLIC QUINONE DERIVATIVE
Abstract
This invention provides a compound represented by formula (1) or
a pharmaceutically acceptable salt thereof. Specifically, the
present invention provides a compound represented by formula (1) or
a pharmaceutically acceptable salt thereof [Therein, A is O, S, or
N--R.sup.6; ring G is a 5-membered or 6-membered aromatic ring,
etc., including 1-3 heteroatoms selected from O, S and N as
constituent atoms; R.sup.1 and R.sup.2 are each independently a
hydrogen atom, a halogen atom, or an optionally-substituted
C.sub.1-6 alkyl carbonyl group, etc.; R.sup.3, R.sup.4 and R.sup.5
are each independently a hydrogen atom, a halogen atom, or an
optionally-substituted C.sub.1-6 alkyl carbonyl group, etc.; and
R.sup.6 is a hydrogen atom or an optionally-substituted C.sub.1-6
alkyl group, etc.]. ##STR00001##
Inventors: |
BAN; Hitoshi; (Osaka,
JP) ; KAMIOKA; Seiji; (Osaka, JP) ; RI;
Shoukou; (Osaka, JP) ; FURUTA; Tomoyuki;
(Osaka, JP) ; KITANO; Hiroyuki; (Osaka, JP)
; Li; Chiang Jia; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boston Biomedical, Inc |
Cambridge |
MA |
US |
|
|
Assignee: |
Boston Biomedical, Inc.
Cambridge
MA
|
Family ID: |
54239835 |
Appl. No.: |
15/300917 |
Filed: |
March 30, 2015 |
PCT Filed: |
March 30, 2015 |
PCT NO: |
PCT/JP2015/001814 |
371 Date: |
September 30, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 491/048 20130101; A61P 35/00 20180101; A61K 31/381 20130101;
A61P 35/02 20180101; A61K 31/4355 20130101; C07D 495/04 20130101;
A61K 31/5377 20130101; A61K 31/4365 20130101 |
International
Class: |
C07D 495/04 20060101
C07D495/04; C07D 491/048 20060101 C07D491/048 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2014 |
JP |
2014-072398 |
Claims
1. A compound represented by formula (1) or a pharmacologically
acceptable salt thereof: ##STR00165## wherein A is O, S, or
N--R.sup.6; the ring G is a 5- or 6-membered aromatic ring that
contains one to three heteroatoms consisting of O, S, and N as
constituent atoms; R.sup.1 is each independently a hydrogen atom, a
halogen atom, a cyano group, an optionally substituted 3- to
8-membered cyclic amino group, an optionally substituted C.sub.1-6
alkyl group, with the proviso that an unsubstituted methyl group
and a C.sub.1-6 alkyl group substituted with one dimethyl amino
group or one chlorine atom are excluded, an optionally substituted
C.sub.3-10 cycloalkyl group, an optionally substituted C.sub.1-6
alkenyl group, an optionally substituted C.sub.1-6 alkynyl group,
an optionally substituted C.sub.6-10 aryl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic heterocyclic
group, an optionally substituted C.sub.1-6 alkylcarbonyl group, an
optionally substituted C.sub.3-10 cycloalkylcarbonyl group, an
optionally substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, a carboxyl group, an optionally
substituted C.sub.3-10 cycloalkyloxycarbonyl group, an optionally
substituted C.sub.6-10 aryloxycarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group, an optionally substituted
aminocarbonyl group, an optionally substituted 3- to 8-membered
cyclic aminocarbonyl group, an optionally substituted C.sub.1-6
alkylthio group, an optionally substituted C.sub.3-10
cycloalkylthio group, an optionally substituted C.sub.6-10 arylthio
group, an optionally substituted 5- to 12-membered monocyclic or
polycyclic heterocyclylthio group, a sulfinate group, an optionally
substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted aminosulfinyl
group, an optionally substituted 3- to 8-membered cyclic
aminosulfinyl group, a sulfonate group, an optionally substituted
C.sub.1-6 alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, an optionally
substituted aminosulfonyl group, or an optionally substituted 3- to
8-membered cyclic aminosulfonyl group; R.sup.2 is each
independently a hydrogen atom, a halogen atom, a cyano group, a
substituted amino group, an optionally substituted 3- to 8-membered
cyclic amino group, an optionally substituted C.sub.1-6 alkyl group
with the proviso that an unsubstituted methyl group is excluded, an
optionally substituted C.sub.3-10 cycloalkyl group, an optionally
substituted C.sub.1-6 alkenyl group, an optionally substituted
C.sub.1-6 alkynyl group, an optionally substituted C.sub.6-10 aryl
group, an optionally substituted 5- to 12-membered monocyclic or
polycyclic heterocyclic group, an optionally substituted C.sub.1-6
alkylcarbonyl group, an optionally substituted C.sub.3-10
cycloalkylcarbonyl group, an optionally substituted C.sub.6-10
arylcarbonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylcarbonyl group, a carboxyl
group, an optionally substituted C.sub.1-6 alkoxycarbonyl group, an
optionally substituted C.sub.3-10 cycloalkyloxycarbonyl group, an
optionally substituted C.sub.6-10 aryloxycarbonyl group, an
optionally substituted 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group, an optionally substituted
aminocarbonyl group, an optionally substituted 3- to 8-membered
cyclic aminocarbonyl group, an optionally substituted C.sub.1-6
alkylthio group, an optionally substituted C.sub.3-10
cycloalkylthio group, an optionally substituted C.sub.6-10 arylthio
group, an optionally substituted 5- to 12-membered monocyclic or
polycyclic heterocyclylthio group, a sulfinate group, an optionally
substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted aminosulfinyl
group, an optionally substituted 3- to 8-membered cyclic
aminosulfinyl group, a sulfonate group, an optionally substituted
C.sub.1-6 alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, an optionally
substituted aminosulfonyl group, or an optionally substituted 3- to
8-membered cyclic aminosulfonyl group; R.sup.3, R.sup.4, or R.sup.5
is each independently a hydrogen atom, a halogen atom, a cyano
group, an hydroxyl group, an optionally substituted amino group, an
optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.3-10 cycloalkyl group, an optionally substituted
C.sub.1-6 alkenyl group, an optionally substituted C.sub.1-6
alkynyl group, an optionally substituted C.sub.1-6 alkoxy group, an
optionally substituted C.sub.6-10 aryl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic heterocyclic
group, an optionally substituted C.sub.1-6 alkylcarbonyl group, an
optionally substituted C.sub.3-10 cycloalkylcarbonyl group, an
optionally substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, a carboxyl group, an optionally
substituted C.sub.1-6 alkoxycarbonyl group, an optionally
substituted C.sub.3-10 cycloalkyloxycarbonyl group, an optionally
substituted C.sub.6-10 aryloxycarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group, an optionally substituted
aminocarbonyl group, an optionally substituted C.sub.1-6 alkylthio
group, an optionally substituted C.sub.3-10 cycloalkylthio group,
an optionally substituted C.sub.6-10 arylthio group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylthio group, a sulfinate group, an optionally
substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted aminosulfinyl
group, a sulfonate group, an optionally substituted C.sub.1-6
alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, or an
optionally substituted aminosulfonyl group, R.sup.6 is a hydrogen
atom, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted C.sub.3-10 cycloalkyl group, an optionally
substituted C.sub.6-10 aryl group, an optionally substituted 5- to
12-membered monocyclic or polycyclic heterocyclic group, an
optionally substituted C.sub.1-6 alkylcarbonyl group, an optionally
substituted C.sub.3-10 cycloalkylcarbonyl group, an optionally
substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, an optionally substituted C.sub.1-6
alkoxycarbonyl group, an optionally substituted C.sub.3-10
cycloalkyloxycarbonyl group, an optionally substituted C.sub.6-10
aryloxycarbonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclyloxycarbonyl group, an
optionally substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted C.sub.1-6
alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, or an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, with the
proviso that in the formula (1), a compound in which R.sup.1 and
R.sup.2 are both hydrogen atoms, a compound in which when A is O,
the ring G is a furan ring or an imidazole ring, a compound in
which when A is S, the ring G is a thiophene ring or an imidazole
ring, a compound in which when A is N--R.sup.6, the ring G is a
pyrrole ring, a pyrazole ring, or an imidazole ring, an
2-isopropylfuro[3,2-g]quinoline-4,9-dione compound, and an ethyl
4,8-dioxo-2,7-diphenyl-4,8-dihydrothieno[2,3-f]benzofuran-6-carboxylate
compound are excluded.
2. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein A is S.
3. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein A is O.
4. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein A is N--R.sup.6.
5. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein the ring G is chosen from the following formulas
(a) to (l): ##STR00166## ##STR00167##
6. The compound of claim 5 or a pharmacologically acceptable salt
thereof, wherein the ring G is chosen from the following formulas
(a) to (h): ##STR00168##
7. The compound of claim 6 or a pharmacologically acceptable salt
thereof, wherein the ring G is chosen from the following formulas
(a) to (f): ##STR00169##
8. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein R.sup.1 is chosen from: 1: a hydrogen atom; 2: a
cyano group; 3: a C.sub.1-6 alkyl group optionally substituted with
one to three groups chosen from a fluorine atom, an hydroxyl group,
a C.sub.1-6 alkoxy group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-10 aryl group, and a 3- to 8-membered cyclic amino group;
4: a C.sub.1-6 alkylcarbonyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group optionally substituted with one to three C.sub.1-6 alkyl
groups; 5: a C.sub.6-10 aryl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 6: a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 7: a carboxyl group; 8: an aminocarbonyl group, wherein the
amino group is optionally substituted with one or two groups chosen
from (a) a C.sub.1-6 alkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group, and a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three C.sub.1-6 alkyl groups, (b) a
C.sub.3-10 cycloalkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, (c) a
C.sub.6-10 aryl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; and 9: a 3- to 8-membered cyclic aminocarbonyl group,
wherein the cyclic amino group is optionally substituted with one
to three C.sub.1-6 alkyl groups.
9. The compound of claim 8 or a pharmacologically acceptable salt
thereof, wherein R.sup.1 is a hydrogen atom or a C.sub.1-6
alkylcarbonyl group, wherein the alkyl group is optionally
substituted with a 3- to 8-membered cyclic amino group.
10. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein R.sup.2 is chosen from 1: a hydrogen atom; 2: a
halogen atom; 3: a cyano group; 4: an amino group substituted with
one or two groups chosen from (a) a C.sub.1-6 alkyl group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group optionally substituted with one to
three C.sub.1-6 alkyl groups, (b) a C.sub.1-6 alkylcarbonyl group,
wherein the alkyl is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-4
alkoxy group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group optionally substituted
with one to three C.sub.1-6 alkyl groups, (c) a C.sub.3-10
cycloalkyl group optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group, (d) a C.sub.6-10 aryl group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group, and (e) a 5- to 12-membered monocyclic or
polycyclic heterocycle group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxy group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 5: a 3- to
8-membered cyclic amino group optionally substituted with one to
three C.sub.1-6 alkyl groups; 6: a C.sub.1-6 alkyl group optionally
substituted with one to three groups chosen from (a) a halogen
atom, (b) an hydroxyl group, (c) an amino group optionally
substituted with one or two groups chosen from (i) a C.sub.1-6
alkyl group optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group,
an aminocarbonyl group, wherein the amino group is optionally
substituted with one to three C.sub.1-6 alkyl groups, a C.sub.6-10
aryl group, and a 5- to 12-membered monocyclic or polycyclic
heterocycle group optionally substituted with one to three
C.sub.1-6 alkyl groups, (ii) a C.sub.3-8 cycloalkyl group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group, (iii) a C.sub.1-6 alkylcarbonyl group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxy group, a C.sub.1-4
alkoxy group, a C.sub.6-10 aryl group, or a 5- to 12-membered
monocyclic or polycyclic heterocycle group optionally substituted
with one to three C.sub.1-6 alkyl groups, (iv) a C.sub.1-6
alkoxycarbonyl group, wherein the alkyl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 12-membered monocyclic or polycyclic heterocycle group
optionally substituted with one to three C.sub.1-6 alkyl groups,
(v) a C.sub.1-6 alkylsulfinyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group optionally substituted with one to
three C.sub.1-6 alkyl groups, (vi) a C.sub.1-6 alkylsulfonyl group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-4
alkoxy group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group optionally substituted
with one to three C.sub.1-6 alkyl groups, (vii) an aminocarbonyl
group, wherein the amino group is optionally substituted with one
or two C.sub.1-6 alkyl groups optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group, and a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three C.sub.1-6 alkyl groups, (viii) a 3-
to 8-membered cyclic amino group optionally substituted with one to
three C.sub.1-6 alkyl groups, and (ix) a C.sub.3-10
cycloalkylcarbonyl group, (d) a 3- to 8-membered cyclic amino group
optionally substituted with one to three C.sub.1-6 alkylcarbonyl
group, (e) a C.sub.1-6 alkoxy group optionally substituted with one
to three C.sub.6-10 aryl groups, (f) a C.sub.3-10 cycloalkyl group,
(g) a C.sub.6-10 aryl group, and (h) a 5- to 12-membered monocyclic
or polycyclic heterocycle group; 7: a C.sub.3-10 cycloalkyl group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 8: a C.sub.1-6 alkenyl group optionally
substituted with one to three groups chosen from C.sub.1-6 alkyl
and C.sub.1-6 alkoxycarbonyl groups; 9: a C.sub.1-6 alkynyl group
optionally substituted with one to three groups chosen from
C.sub.1-6 alkyl and C.sub.1-6 alkoxycarbonyl groups; 10: a
C.sub.6-10 aryl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 11: a 5- to 12-membered
monocyclic or polycyclic heterocyclic group, wherein the
heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 12: a C.sub.3-10
cycloalkyloxy group, wherein the cycloalkyl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 13: a C.sub.6-10 aryloxy group, wherein the aryl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 14: a 5- to 12-membered monocyclic or
polycyclic heterocyclyloxy group, wherein the heterocycle group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 15: a carboxyl group; 16: a C.sub.1-6
alkylcarbonyl group, wherein the alkyl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, an amino group optionally substituted with one or
two C.sub.1-6 alkyl groups, a C.sub.1-6 alkoxy group, a C.sub.3-10
cycloalkyl group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group; 17: a C.sub.3-10
cycloalkylcarbonyl group, wherein the cycloalkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 18: a C.sub.6-10 arylcarbonyl group,
wherein the aryl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 19: a 5- to 12-membered
monocyclic or polycyclic heterocyclylcarbonyl group, wherein the
heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 20: a C.sub.3-10
cycloalkyloxycarbonyl group, wherein the cycloalkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 21: a C.sub.6-10 aryloxycarbonyl group,
wherein the aryl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 22: a 5- to 12-membered
monocyclic or polycyclic heterocyclyloxycarbonyl group, wherein the
heterocycle is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 23: an aminocarbonyl group,
wherein the amino group is optionally substituted with one or two
groups chosen from (a) a C.sub.1-6 alkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 12-membered monocyclic or polycyclic heterocycle group
optionally substituted with one to three C.sub.1-6 alkyl groups,
(b) a C.sub.3-10 cycloalkyl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group), (c) a
C.sub.6-10 aryl group, wherein the aryl is optionally substituted
with one to three groups chosen from a halogen atom, an hydroxyl
group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, and
(d) a 5- to 12-membered monocyclic or polycyclic heterocycle group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 24: a 3- to 8-membered cyclic aminocarbonyl
group, wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl groups; 25: a C.sub.1-6 alkylthio group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, an amino
group optionally substituted with one or two C.sub.1-6 alkyl
groups, a C.sub.1-6 alkoxy group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group; 26: a C.sub.3-10 cycloalkylthio
group, wherein the cycloalkyl group is optionally substituted with
one to three groups chosen from a halogen atom, an hydroxyl group,
a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 27: a
C.sub.6-10 arylthio group, wherein the aryl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 28: a 5- to 12-membered monocyclic or polycyclic
heterocyclylthio group, wherein the heterocycle group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 29: a sulfinate group; 30: a C.sub.1-6 alkylsulfinyl group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, an amino
group optionally substituted with one or two C.sub.1-6 alkyl
groups, a C.sub.1-6 alkoxy group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group; 31: a C.sub.3-10 cycloalkylsulfinyl
group, wherein the cycloalkyl group is optionally substituted with
one to three groups chosen from a halogen atom, an hydroxyl group,
a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 32: a
C.sub.6-10 arylsulfinyl group, wherein the aryl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 33: a 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, wherein the heterocycle group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 34: an aminosulfinyl group, wherein the
amino group is optionally substituted with one or two groups chosen
from (a) a C.sub.1-6 alkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group, and a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three C.sub.1-6 alkyl group, (b) a
C.sub.3-10 cycloalkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, (c) a
C.sub.6-10 aryl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle group wherein the
heterocycle is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 35: a 3- to 8-membered cyclic
aminosulfinyl group, wherein the cyclic amino group is optionally
substituted with one to three C.sub.1-6 alkyl groups; 36: a
sulfonate group; 37: a C.sub.1-6 alkylsulfonyl group, wherein the
alkyl is optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group; 38: a C.sub.3-10 cycloalkylsulfonyl group, wherein the
cycloalkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 39: a C.sub.6-10 arylsulfonyl
group, wherein the aryl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 40: a 5- to
12-membered monocyclic or polycyclic heterocyclylsulfonyl group,
wherein the heterocycle group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 41: an
aminosulfonyl group wherein the amino group is optionally
substituted with one or two groups chosen from (a) a C.sub.1-6
alkyl group optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group optionally substituted with one to
three C.sub.1-6 alkyl, (b) a C.sub.3-10 cycloalkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group, (c) a C.sub.6-10 aryl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5-
to 12-membered monocyclic or polycyclic heterocycle group, wherein
the heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; and 42: a 3- to
8-membered cyclic aminosulfinyl group, wherein the cyclic amino
group is optionally substituted with one to three C.sub.1-6 alkyl
groups.
11. The compound of claim 10 or a pharmacologically acceptable salt
thereof, wherein R.sup.2 is a group chosen from: 1: a hydrogen
atom; 2: a halogen atom; 3: a cyano group; 4: an amino group
optionally substituted with one to three C.sub.1-6 alkyl groups; 5:
a 3- to 8-membered cyclic amino group, wherein the cyclic amino
group is optionally substituted with one to three C.sub.1-6 alkyl
groups; 6: a C.sub.1-6 alkyl group optionally substituted with one
to three groups chosen from (a) a halogen atom, (b) an hydroxyl
group, (c) an amino group optionally substituted with one or two
groups chosen from (i) a C.sub.1-6 alkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, and a C.sub.1-4 alkoxy group, (ii) a C.sub.3-8
cycloalkyl group, (iii) a C.sub.1-6 alkylcarbonyl group, (iv) a
C.sub.1-6 alkoxycarbonyl group, and (v) a C.sub.1-6 alkylsulfonyl
group, (d) a 3- to 8-membered cyclic amino group, (e) a C.sub.1-6
alkoxy group, (f) a C.sub.3-10 cycloalkyl group, (g) a phenyl
group, and (h) a 5- to 6-membered monocyclic or polycyclic
heterocycle group; 7: a C.sub.1-6 alkenyl group optionally
substituted with one to three groups chosen from a C.sub.1-6 alkyl
and C.sub.1-6 alkoxycarbonyl groups; 8: a C.sub.1-6 alkynyl group
optionally substituted with one to three groups chosen from
C.sub.1-6 alkyl and C.sub.1-6 alkoxycarbonyl groups; 9: a 5- to
12-membered monocyclic or polycyclic heterocyclic group; 10: a
C.sub.1-6 alkylcarbonyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-4
alkoxy group, a C.sub.3-8 cycloalkyl group, a phenyl group, and a
5- to 6-membered monocyclic heterocycle group optionally
substituted with one to three C.sub.1-6 alkyl groups; 11: an
aminocarbonyl group, wherein the amino group is optionally
substituted with one to three groups chosen from (a) a C.sub.1-6
alkyl group optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group, a
phenyl group, and a 5- to 6-membered monocyclic heterocycle group
optionally substituted with one to three C.sub.1-4 alkyl groups,
(b) a C.sub.3-8 cycloalkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, (c) a phenyl
group, wherein the aryl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5-
to 6-membered monocyclic heterocycle group optionally substituted
with one to three groups chosen from a halogen atom, an hydroxyl
group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; and
12: a 3- to 8-membered cyclic aminocarbonyl group, wherein the
cyclic amino group is optionally substituted with one to three
C.sub.1-6 alkyl groups.
12. The compound of claim 11 or a pharmacologically acceptable salt
thereof, wherein R.sup.2 is a group chosen from: 1: a C.sub.1-6
alkyl group optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-4
alkoxy group, a C.sub.3-8 cycloalkyl group, a phenyl group, and a
5- to 6-membered monocyclic heterocycle group; 2: a C.sub.1-6
alkylcarbonyl group, wherein the alkyl is optionally substituted
with one to three groups chosen from a halogen atom, an hydroxyl
group, an amino group optionally substituted with one or two
C.sub.1-6 alkyl groups, a C.sub.1-4 alkoxy group, a C.sub.3-8
cycloalkyl group, a phenyl group, and a 5- to 6-membered monocyclic
heterocycle group optionally substituted with one to three
C.sub.1-6 alkyl group; 3: an aminocarbonyl group, wherein the amino
group is optionally substituted with one or two groups chosen from
(a) a C.sub.1-6 alkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-4 alkoxy group, a phenyl group, and a 5- to 6-membered
monocyclic heterocycle group optionally substituted with one to
three C.sub.1-4 alkyl group, (b) a C.sub.3-8 cycloalkyl group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group, (c) a phenyl group, wherein the aryl is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group, and (d) a 5- to 6-membered monocyclic
heterocycle group optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; and 4: a 3- to 8-membered
cyclic aminocarbonyl group, wherein the cyclic amino group is
optionally substituted with one to three C.sub.1-6 alkyl
groups.
13. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein R.sup.3, R.sup.4, or R.sup.5 is each independently
a group chosen from: 1: a hydrogen atom; 2: a halogen atom; 3: a
cyano group; 4: an hydroxyl group; 5: an amino group optionally
substituted with one or two groups chosen from (a) C.sub.1-6 alkyl
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group optionally substituted with one to
three C.sub.1-6 alkyl groups, (b) C.sub.1-6 alkylcarbonyl, wherein
the alkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy
group, a C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic
or polycyclic heterocycle group optionally substituted with one to
three C.sub.1-6 alkyl groups, (c) C.sub.3-10 cycloalkyl group,
wherein the cycloalkyl is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, (d) C.sub.6-10 aryl
group, wherein the aryl is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, and (e) a 5- to
12-membered monocyclic or polycyclic heterocycle group, wherein the
heterocycle is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 6: a 3- to 8-membered cyclic
amino group optionally substituted with one to three C.sub.1-6
alkyl group; 7: a C.sub.1-6 alkyl group optionally substituted with
one to three groups chosen from a halogen atom, an hydroxyl group,
an amino group optionally substituted with one or two C.sub.1-6
alkyl groups, a C.sub.1-6 alkoxy group, a C.sub.3-10 cycloalkyl
group, a C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic
or polycyclic heterocycle group; 8: a C.sub.3-10 cycloalkyl group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group); 9: a C.sub.6-10 aryl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 10: a 5- to 12-membered monocyclic or polycyclic
heterocyclic group, wherein the heterocycle is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 11: a C.sub.1-6 alkoxy group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic
heterocycle; 12: a C.sub.3-10 cycloalkyloxy group, wherein the
cycloalkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 13: a C.sub.6-10 aryloxy
group, wherein the aryl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 14: a 5- to
12-membered monocyclic or polycyclic heterocyclyloxy group, wherein
the heterocycle is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 15: a carboxyl group; 16: a
C.sub.1-6 alkylcarbonyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group; 17: a C.sub.3-10 cycloalkylcarbonyl group, wherein the
cycloalkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 18: a C.sub.6-10 arylcarbonyl
group, wherein the aryl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 19: a 5- to
12-membered monocyclic or polycyclic heterocyclylcarbonyl group,
wherein the heterocycle group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 20: a
C.sub.1-6 alkoxycarbonyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group; a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group; 21: a C.sub.3-10 cycloalkyloxycarbonyl group, wherein the
cycloalkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 22: a C.sub.6-10
aryloxycarbonyl group, wherein the aryl is optionally substituted
with one to three groups chosen from a halogen atom, an hydroxyl
group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 23: a
5- to 12-membered monocyclic or polycyclic heterocyclyloxycarbonyl
group, wherein the heterocycle group is optionally substituted with
one to three groups chosen from a halogen atom, an hydroxyl group,
a C.sub.1-6 alkyl, and a C.sub.1-6 alkoxy; 24: an aminocarbonyl
group, wherein the amino group is optionally substituted with one
or two groups chosen from (a) a C.sub.1-6 alkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 12-membered monocyclic or polycyclic heterocycle group
optionally substituted with one to three C.sub.1-6 alkyl groups,
(b) a C.sub.3-10 cycloalkyl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, (c) a
C.sub.6-10 aryl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle, wherein the
heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 25: a 3- to 8-membered
cyclic aminocarbonyl group, wherein the cyclic amino group is
optionally substituted with one to three C.sub.1-6 alkyl groups;
26: a C.sub.1-6 alkylthio group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group; 27: a C.sub.3-10 cycloalkylthio group, wherein the
cycloalkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 28: a C.sub.6-10 arylthio
group, wherein the aryl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 29: a 5- to
12-membered monocyclic or polycyclic heterocyclylthio group,
wherein the heterocycle group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 30: a
sulfinate group; 31: a C.sub.1-6 alkylsulfinyl group, wherein the
alkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, an amino group
optionally substituted with one or two C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10
aryl group, and a 5- to 12-membered monocyclic or polycyclic
heterocycle group; 32: a C.sub.3-10 cycloalkylsulfinyl group,
wherein the cycloalkyl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 33: a
C.sub.6-10 arylsulfinyl group, wherein the aryl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 34: a 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, wherein the heterocycle group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 35: an aminosulfinyl group, wherein the
amino group is optionally substituted with one or two groups chosen
from (a) a C.sub.1-6 alkyl group optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group, and a 5- to
12-membered monocyclic or polycyclic heterocycle substituted with
one to three C.sub.1-6 alkyl groups, (b) a C.sub.3-10 cycloalkyl
group optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group, (c) a C.sub.6-10 aryl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group, and (d) a 5- to 12-membered monocyclic or polycyclic
heterocycle group, wherein the heterocycle group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 36: a 3- to 8-membered cyclic aminosulfinyl group, wherein
the cyclic amino group is optionally substituted with one to three
C.sub.1-6 alkyl groups; 37: a sulfonate group; 38: a C.sub.1-6
alkylsulfonyl group, wherein the alkyl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, an amino group optionally substituted with one or
two C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.3-10
cycloalkyl group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group; 39: a C.sub.3-10
cycloalkylsulfonyl group, wherein the cycloalkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 40: a C.sub.6-10 arylsulfonyl group,
wherein the aryl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 41: a 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, wherein the
heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 42: an aminosulfonyl
group, wherein the amino group is optionally substituted with one
or two groups chosen from (a) a C.sub.1-6 alkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 12-membered monocyclic or polycyclic heterocycle group
optionally substituted with one to three C.sub.1-6 alkyl groups,
(b) a C.sub.3-10 cycloalkyl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, (c) a
C.sub.6-10 aryl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; and 43: a 3- to 8-membered cyclic aminosulfonyl group,
wherein the cyclic amino group is optionally substituted with one
to three C.sub.1-6 alkyl groups.
14. The compound of claim 13 or a pharmacologically acceptable salt
thereof, wherein R.sup.3, R.sup.4, or R.sup.5 is each independently
a group chosen from: 1: a hydrogen atom; 2: a halogen atom; 3: a
cyano group; 4: an hydroxyl group; 5: an amino group optionally
substituted with one or two groups chosen from (a) a C.sub.1-6
alkyl optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-4 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group optionally substituted with one to
three C.sub.1-6 alkyl groups, (b) a C.sub.1-6 alkylcarbonyl group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-4
alkoxy group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group optionally substituted
with one to three C.sub.1-6 alkyl groups, (c) a C.sub.3-10
cycloalkyl group optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group, (d) a C.sub.6-10 aryl (wherein
the aryl is optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group,
and a C.sub.1-6 alkoxy group, and (e) a 5- to 12-membered
monocyclic or polycyclic heterocycle group, wherein the heterocycle
is optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 6: a 3- to 8-membered cyclic amino group
optionally substituted with one to three C.sub.1-6 alkyl groups; 7:
a C.sub.1-6 alkyl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, an amino
group optionally substituted with one or two C.sub.1-6 alkyl
groups, a C.sub.1-6 alkoxy group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-10 aryl group, and a 5- to 12-membered monocyclic or
polycyclic heterocycle group; 8: a C.sub.1-6 alkoxy group
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group; 9: a C.sub.1-6 alkylcarbonyl group, wherein the alkyl group
is optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-6
alkoxy group, a C.sub.3-10 cycloalkyl group, a C.sub.6-10 aryl
group, and a 5- to 12-membered monocyclic or polycyclic heterocycle
group; 10: an aminocarbonyl group, wherein the amino group is
optionally substituted with one or two groups chosen from (a) a
C.sub.1-6 alkyl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-4
alkoxy group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group optionally substituted
with one to three C.sub.1-6 alkyl groups, (b) a C.sub.3-10
cycloalkyl group optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group, (c) a C.sub.6-10 aryl group,
wherein the aryl is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group, and (d) a 5- to 12-membered
monocyclic or polycyclic heterocycle group, wherein the heterocycle
is optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 11: a 3- to 8-membered cyclic aminocarbonyl
group, wherein the cyclic amino group is optionally substituted
with one to three C.sub.1-6 alkyl groups; 12: a C.sub.1-6
alkylsulfonyl group, wherein the alkyl group is optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, an amino group optionally substituted with one or
two C.sub.1-6 alkyl groups, a C.sub.1-6 alkoxy group, a C.sub.3-10
cycloalkyl group, a C.sub.6-10 aryl group, and a 5- to 12-membered
monocyclic or polycyclic heterocycle group; 13: an aminosulfonyl
group, wherein the amino group is optionally substituted with one
or two groups chosen from (a) a C.sub.1-6 alkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 12-membered monocyclic or polycyclic heterocycle
optionally substituted with one to three C.sub.1-6 alkyl groups,
(b) a C.sub.3-10 cycloalkyl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group, (c) a
C.sub.6-10 aryl group optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group, and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle group, wherein the
heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; and 14: a 3- to
8-membered cyclic aminosulfonyl group, wherein the cyclic amino
group is optionally substituted with one to three C.sub.1-6 alkyl
groups.
15. The compound of claim 14 or a pharmacologically acceptable salt
thereof, wherein R.sup.3, R.sup.4, and/or R.sup.5 is a hydrogen
atoms.
16. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein R.sup.6 is a group chosen from: 1: a hydrogen
atom; 2: a C.sub.1-6 alkyl group optionally substituted with one to
three groups chosen from a halogen atom, C.sub.1-6 alkoxy group,
C.sub.6-10 aryl group, and a 5- to 6-membered monocyclic
heterocycle optionally substituted with one to three C.sub.1-4
alkyl groups; 3: a C.sub.3-10 cycloalkyl group optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy
group; 4: a C.sub.1-6 alkylcarbonyl group, wherein the alkyl group
is optionally substituted with one to three groups chosen from a
halogen atom, a C.sub.1-6 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 6-membered monocyclic heterocycle group optionally
substituted with one to three C.sub.1-4 alkyl groups; 5: a
C.sub.3-10 cycloalkylcarbonyl group; 6: a C.sub.6-10 arylcarbonyl
group; 7: a 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group; 8: a C.sub.1-6 alkoxycarbonyl group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, a C.sub.1-6 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 6-membered monocyclic
heterocycle group optionally substituted with one to three
C.sub.1-4 alkyl groups; 9: a C.sub.3-10 cycloalkyloxycarbonyl
group, wherein the cycloalkyl group is optionally substituted with
one to three groups chosen from a halogen atom, an hydroxyl group,
a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 10: a
C.sub.6-10 aryloxycarbonyl group, wherein the aryl group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 11: a 5- to 12-membered monocyclic or
polycyclic heterocyclyloxycarbonyl group, wherein the heterocycle
group is optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group,
and a C.sub.1-6 alkoxy group; 12: a C.sub.1-6 alkylsulfinyl group,
wherein the alkyl group is optionally substituted with one to three
groups chosen from a halogen atom, a C.sub.1-6 alkoxy group, a
C.sub.6-10 aryl group, and a 5- to 6-membered monocyclic
heterocycle optionally substituted with one to three C.sub.1-4
alkyl group; 13: a C.sub.3-10 cycloalkylsulfinyl group, wherein the
cycloalkyl group is optionally substituted with one to three groups
chosen from a halogen atom, an hydroxyl group, a C.sub.1-6 alkyl
group, and a C.sub.1-6 alkoxy group; 14: a C.sub.6-10 arylsulfinyl
group, wherein the aryl group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 15: a 5- to
12-membered monocyclic or polycyclic heterocyclylsulfinyl group,
wherein the heterocycle group is optionally substituted with one to
three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group; 16: a
C.sub.1-6 alkylsulfonyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, a C.sub.1-6 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 6-membered monocyclic heterocycle optionally
substituted with one to three C.sub.1-4 alkyl groups; 17: a
C.sub.3-10 cycloalkylsulfonyl group, wherein the cycloalkyl group
is optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; 18: a C.sub.6-10 arylsulfonyl group,
wherein the aryl group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 19: a 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, wherein the
heterocycle group is optionally substituted with one to three
groups chosen from a halogen atom, an hydroxyl group, a C.sub.1-6
alkyl group, and a C.sub.1-6 alkoxy group; 20: a C.sub.6-10 aryl
group optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group; and 21: a 5- to 12-membered monocyclic or
polycyclic heterocyclic group, wherein the heterocycle group is
optionally substituted with one to three groups chosen from a
halogen atom, an hydroxyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group.
17. The compound of claim 16 or a pharmacologically acceptable salt
thereof, wherein R.sup.6 is a group chosen from: 1: a hydrogen
atom; 2: a C.sub.1-6 alkyl group optionally substituted with one to
three groups chosen from a halogen atom, a C.sub.1-6 alkoxy group,
a C.sub.6-10 aryl group, and a 5- to 6-membered monocyclic
heterocyclic group optionally substituted with one to three
C.sub.1-4 alkyl groups; 3: a C.sub.1-6 alkylcarbonyl group, wherein
the alkyl group is optionally substituted with one to three groups
chosen from a halogen atom, a C.sub.1-6 alkoxy group, a C.sub.6-10
aryl group, and a 5- to 6-membered monocyclic heterocycle
optionally substituted with one to three C.sub.1-4 alkyl groups;
and 4: a C.sub.1-6 alkylsulfonyl group, wherein the alkyl group is
optionally substituted with one to three groups chosen from a
halogen atom, C.sub.1-6 alkoxy group, C.sub.6-10 aryl group, and a
5- to 6-membered monocyclic heterocycle optionally substituted with
one to three C.sub.1-4 alkyl groups.
18. The compound of claim 17 or a pharmacologically acceptable salt
thereof, wherein R.sup.6 is a hydrogen atom.
19. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein R.sup.2 is a group chosen from: 1: a C.sub.1-6
alkyl group optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-4
alkoxy group, a C.sub.3-8 cycloalkyl group, and a 5- to 6-membered
monocyclic heterocycle group; 2: a C.sub.1-6 alkylcarbonyl group;
3: an aminocarbonyl group, wherein the amino group is optionally
substituted with one to three C.sub.1-6 alkyl groups optionally
substituted with one to three halogen atoms; and 4: a 3- to
8-membered cyclic aminocarbonyl group, wherein the cyclic amino
group is optionally substituted with one to three C.sub.1-6 alkyl
groups.
20. The compound of claim 1 or a pharmacologically acceptable salt
thereof, wherein A is O or S; the ring G is either one chosen from
the following formula (b) or (e): ##STR00170## R.sup.1 is a
hydrogen atom; and R.sup.2 is a group chosen from: 1: a C.sub.1-6
alkyl group optionally substituted with one to three groups chosen
from a halogen atom, an hydroxyl group, an amino group optionally
substituted with one or two C.sub.1-6 alkyl groups, a C.sub.1-4
alkoxy, a C.sub.3-8 cycloalkyl, and a 5- to 6-membered monocyclic
heterocycle; 2: a C.sub.1-6 alkylcarbonyl group; 3: an
aminocarbonyl group, wherein the amino group is optionally
substituted with one to three C.sub.1-6 alkyl groups optionally
substituted with one to three halogen atoms; and 4: a 3- to
8-membered cyclic aminocarbonyl group, wherein the cyclic amino
group is optionally substituted with one to three C.sub.1-6 alkyl
group; and R.sup.3, R.sup.4, and R.sup.5 are hydrogen atoms.
21. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein the compound is chosen from the following
compounds: 2-acetylthieno[2,3-g]quinoline-4,9-dione;
2-acetylthieno[2,3-g]isoquinoline-4,9-dione;
2-(1-hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione;
2-(2-hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione;
2-[cyclopropyl(hydroxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione;
N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamid-
e; 2-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione;
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-ca-
rboxyamide;
2-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione-
;
2-{[(2,2-difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione;
2-[(4-acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-di
one; 4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile;
2-(1-fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione;
2-(3-ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione;
2-acetylthieno[3,2-g]isoquinoline-4,9-dione;
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carb-
oxamide; 2-(1-hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione;
2-acetylthieno[3,2-f][1]benzofuran-4,8-dione; and
2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-4,8-dione.
22. A pharmaceutical composition comprising a compound of claim 1
or a pharmacologically acceptable salt thereof.
23. An anticancer agent comprising a compound of claim 1 or a
pharmacologically acceptable salt thereof as an active
ingredient.
24. The anticancer agent according to claim 23, wherein the cancer
is at least one cancer chosen from acute leukemia, chronic
lymphocytic leukemia, chronic myelocytic leukemia, polycythemia
vera, malignant lymphoma, brain tumor, head and neck cancer,
esophageal cancer, thyroid cancer, small cell lung cancer,
non-small-cell lung cancer, breast cancer, gastric cancer,
gallbladder bile duct cancer, hepatoma, pancreatic cancer, colon
cancer, rectal cancer, chorioepithelioma, endometrial cancer,
cervical cancer, urothelial cancer, renal cell cancer, testicular
tumor, Wilms' tumor, skin cancer, malignant melanoma,
neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue
sarcoma.
25. A method of producing a compound represented by formula (1) or
a pharmacologically acceptable salt thereof: ##STR00171## wherein
A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are defined
according to claim 1, and wherein the method is characterized by
comprising a step of mixing a compound represented by formula (2)
or a salt thereof: ##STR00172## wherein A, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, and R.sup.5 are defined according to claim 1, or
R.sup.1 and R.sup.2 are optionally substituted alkoxycarbonyl
groups; and R.sup.7 and R.sup.8 are each C.sub.1-6 alkyl optionally
substituted with one to three groups chosen from a halogen atom, an
hydroxyl group, a C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group,
and a 5- to 12-membered monocyclic or polycyclic heterocycle group
optionally substituted with one to three C.sub.1-6 alkyl groups,
with an oxidant.
26. A compound represented by formula (2) or a salt thereof:
##STR00173## wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 are defined according to claim 1; and R.sup.7 and R.sup.8
are each an C.sub.1-6 alkyl group optionally substituted with one
to three groups chosen from a halogen atom, an hydroxyl group, a
C.sub.1-4 alkoxy group, a C.sub.6-10 aryl group, and a 5- to
12-membered monocyclic or polycyclic heterocycle group optionally
substituted with one to three C.sub.1-6 alkyl groups.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel tricyclic quinone
derivatives useful as medicament or a pharmacologically acceptable
salt thereof. More particularly, the invention relates to
pharmaceutical compositions comprising a novel tricyclic quinone
derivative or a pharmacologically acceptable salt thereof. The
invention relates to therapeutic agents comprising a novel
tricyclic quinone derivative comprising the compound, or a
pharmacologically acceptable salt thereof.
BACKGROUND ART
[0002] Cancer develops when abnormality in gene occurs by an action
of radiation, ultra violet rays, carcinogen, virus, or the like.
The number of deaths by cancer increases year by year, and cancer
is currently the top cause of death in Japan. As means for such
cancer therapy, antitumor agents, surgical operation, radiotherapy,
immunotherapy, and the like are performed. However, among these,
the therapeutic use of an antitumor agent is the most important as
an internally therapeutic means. Major antitumor agents act on any
of metabolism, DNA synthesis, RNA synthesis, or protein synthesis
of a nucleic acid precursor. However, such metabolic processes
occur in not only cancer cells, but also normal cells. Therefore,
many antitumor agents act on not only on cancer cells, but also on
normal cells, and consequently any types of side effects
develop.
[0003] In recent years, a new type of antitumor agent, called
molecular targeting agent, has been introduced. This molecular
targeting agent is a pharmaceutical agent designed to target a
molecule specifically expressed in each cancer. Therefore, it is
believed that a molecular targeting agent has higher specificity to
cancer cells than conventional antitumor agents, and has fewer side
effects. However, with regard to molecular targeting agents,
although previous side effects are reduced, there are problems that
new side effects are exhibited and alternatives of pharmaceutical
agents are limited. Although the aforementioned antitumor agents
were clinically used for the purpose of cancer therapy and
prolonging the life of a cancer patients, there are still a number
of unsolved problems including problems of side effects and the
like as described above. Accordingly, it is recognized that the
development of a novel antitumor agent is an important topic in the
future.
[0004] In recent studies, the existence of cancer stem cells (CSC)
having replication competence has been revealed, the CSC is closely
related to the malignant transformation of cancer. In nearly all of
major types of cancer in human, such as breast cancer, colon
cancer, lung cancer, hematological malignancy, and the like, CSCs
are identified. A CSC and a normal cancer cell differentiated from
the CSC are significantly different in biological characteristics.
A CSC is shown to be important in continuous proliferation of
malignant tumor, metastasis and recurrence of cancer, and its
resistance to an antitumor agent. Although Conventional therapy
that targets normal cancer cells accounting for most part of tumor
lumps can reduce the size of a tumor, as long as a CSC is also
targeted at the same time, a meaningful survival effect cannot be
expected. Therefore, targeting a CSC is very promising as a new
method to treat a cancer (Non Patent Literature 1). One of the
characteristics of CSCs is to have replication competence. Reliable
methods established as a method of measuring replication competence
of a cell include measurement of cancer cell sphere-forming ability
in non-adhesion state in the absence of serum (Non Patent
Literature 2). A compound that inhibits not only the proliferation
of a non-CSC cancer cell, but also cancer cell sphere-forming
ability is possibly very useful as a novel antitumor agent.
[0005] (1) Non Patent Literature 2 describes the following
compounds as quinone derivatives isolated from the extract of a
plant of the Tabebuia genus in the Bignoniaceae family.
##STR00002##
[wherein R.sup.1, R.sup.2, and R.sup.3 are hydrogen atoms; R.sup.1
and R.sup.3 are H, R.sup.2 is a hydroxyl group; R.sup.1 is a
hydroxyl group, R.sup.2 and R.sup.3 and hydrogen atoms; R.sup.1 and
R.sup.2 and hydrogen atoms, and R.sup.3 is COCH.sub.3; or R.sup.1
and R.sup.2 are hydrogen atoms, R.sup.3 is
COC(CF.sub.3)(OCH.sub.3)C.sub.6H.sub.5.] It also discloses that
these compounds have antitumor activity.
[0006] (2) Patent Literature 1 describes the following compound
having antitumor activity and cancer cell sphere-forming
ability.
##STR00003##
[wherein X is O or S, R.sup.1 is a hydrogen atom, a halogen atom, a
cyano group, a nitro group, a trifluoromethyl group, a
trifluoromethoxy group, an optionally substituted alkyl group, or
the like, R.sup.3 is a hydrogen atom, a cyano group, an optionally
substituted alkyl group, or the like, R.sup.7 is a hydrogen atom, a
halogen atom, a cyano group, a nitro group, an optionally
substituted alkyl group, or the like, n is 1 to 4, with the proviso
that when R.sup.3 is not an amino group, R.sup.7 is not a hydrogen
atom and at least one of R.sup.1 and R.sup.7 is a halogen atom, or
an optionally substituted aryl group.]
[0007] Patent Literature 2 describes the following compound having
antitumor activity.
##STR00004##
[wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are the
same as or different from one another, and are a hydrogen atom, an
alkyl group, an alkenyl group, an aryl group, or a substituent
having a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus
atom, or a halogen atom.]
[0008] Patent Literature 3 describes the following compound having
antifungal activity.
##STR00005##
[wherein R.sup.1 is a nitro group, an amino group, a cyano group,
an alkyl group, a halogen atom, or the like, R.sup.2 is a hydrogen
atom, a halogen atom, a short-chain alkyl group, a substituted aryl
group, a methacrylate group, or the like, and the ring A is
pyridine, isoxazole, or aryl.]
[0009] Non Patent Literature 3 describes the following compounds
having antitumor activity.
##STR00006##
[0010] However, None of Non Patent Literatures 5 and 6 and Patent
Literatures 1-3 describes any specific compound represented by
formula (1) of the present invention.
CITATION LIST
Patent Literature
[0011] [Patent Literature 1]: International Publication No.
2009/036059 pamphlet [0012] [Patent Literature 2]: Japanese
Laid-Open Publication No. 2002-284684 [0013] [Patent Literature 3]:
Chinese Patent Publication No. 103265559
Non Patent Literature
[0013] [0014] [Non Patent Literature 1]: Ponti et al. Cancer Res
65(13):5506-11. 2005 [0015] [Non Patent Literature 2]: Rao et al. J
Nat Prod 45(5):600-4. 1982 [0016] [Non Patent Literature 3]: Koyama
et al. Molecules 15(9):6559-69. 2010
SUMMARY OF INVENTION
Technical Problem
[0017] The problem of the present invention is to provide
significantly useful compound as a novel antitumor agent by
providing a compound that is targeted to CSC, which is important in
continuous proliferation of a malignant tumor, metastasis and
recurrence of cancer, and its resistance to an antitumor agent, and
the compound inhibits not only the proliferation of non-CSC cancer
cell but also cancer cell sphere-forming ability.
Solution to Problem
[0018] The present inventors focused on quinone derivatives, and
intensively studied with regard to their antitumor activities to
find that a compound represented by the following formula (1) or a
pharmacologically acceptable salt thereof (hereinafter also
referred to as "the present compound") has excellent effects on the
inhibition of the proliferation of a cancer cell and cancer cell
sphere-forming ability, and is significantly useful as a novel
antitumor agent. The present inventors finally reached the
completion of the present invention.
[0019] Specifically, the present invention is as described
below.
Item 1: A compound represented by formula (1) or a
pharmacologically acceptable salt thereof:
##STR00007##
wherein
A is O, S, or N--R.sup.6;
[0020] the ring G is a 5- or 6-membered aromatic ring that contains
one to three heteroatoms consisting of O, S, and N as constituent
atoms; R.sup.1 is each independently a hydrogen atom, a halogen
atom, a cyano group, an optionally substituted 3- to 8-membered
cyclic amino group, an optionally substituted C.sub.1-6 alkyl group
(with the proviso that an unsubstituted methyl group, and a
C.sub.1-6 alkyl group substituted with one dimethyl amino group or
one chlorine atom are excluded), an optionally substituted
C.sub.3-10 cycloalkyl group, an optionally substituted C.sub.1-6
alkenyl group, an optionally substituted C.sub.1-6 alkynyl group,
an optionally substituted C.sub.6-10 aryl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic heterocyclic
group, an optionally substituted C.sub.1-6 alkylcarbonyl group, an
optionally substituted C.sub.3-10 cycloalkylcarbonyl group, an
optionally substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, a carboxyl group, an optionally
substituted C.sub.3-10 cycloalkyloxycarbonyl group, an optionally
substituted C.sub.6-10 aryloxycarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group, an optionally substituted
aminocarbonyl group, an optionally substituted 3- to 8-membered
cyclic aminocarbonyl group, an optionally substituted C.sub.1-6
alkylthio group, an optionally substituted C.sub.3-10
cycloalkylthio group, an optionally substituted C.sub.6-10 arylthio
group, an optionally substituted 5- to 12-membered monocyclic or
polycyclic heterocyclylthio group, a sulfinate group, an optionally
substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted aminosulfinyl
group, an optionally substituted 3- to 8-membered cyclic
aminosulfinyl group, a sulfonate group, an optionally substituted
C.sub.1-6 alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, an optionally
substituted aminosulfonyl group, or an optionally substituted 3- to
8-membered cyclic aminosulfonyl group; R.sup.2 is each
independently a hydrogen atom, a halogen atom, a cyano group, a
substituted amino group, an optionally substituted 3- to 8-membered
cyclic amino group, an optionally substituted C.sub.1-6 alkyl group
(with the proviso that an unsubstituted methyl group is excluded),
an optionally substituted C.sub.3-10 cycloalkyl group, an
optionally substituted C.sub.1-6 alkenyl group, an optionally
substituted C.sub.1-6 alkynyl group, an optionally substituted
C.sub.6-10 aryl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclic group, an optionally
substituted C.sub.1-6 alkylcarbonyl group, an optionally
substituted C.sub.3-10 cycloalkylcarbonyl group, an optionally
substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, a carboxyl group, an optionally
substituted C.sub.3-10 cycloalkyloxycarbonyl group, an optionally
substituted C.sub.6-10 aryloxycarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group, an optionally substituted
aminocarbonyl group, an optionally substituted 3- to 8-membered
cyclic aminocarbonyl group, an optionally substituted C.sub.1-6
alkylthio group, an optionally substituted C.sub.3-10
cycloalkylthio group, an optionally substituted C.sub.6-10 arylthio
group, an optionally substituted 5- to 12-membered monocyclic or
polycyclic heterocyclylthio group, a sulfinate group, an optionally
substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted aminosulfinyl
group, an optionally substituted 3- to 8-membered cyclic
aminosulfinyl group, a sulfonate group, an optionally substituted
C.sub.1-6 alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, an optionally
substituted aminosulfonyl group, or an optionally substituted 3- to
8-membered cyclic aminosulfonyl group; R.sup.3, R.sup.4, or R.sup.5
is each independently a hydrogen atom, a halogen atom, a cyano
group, a hydroxyl group, an optionally substituted amino group, an
optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.3-10 cycloalkyl group, an optionally substituted
C.sub.1-6 alkenyl group, an optionally substituted C.sub.1-6
alkynyl group, an optionally substituted C.sub.1-6 alkoxy group, an
optionally substituted C.sub.6-10 aryl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic heterocyclic
group, an optionally substituted C.sub.1-6 alkylcarbonyl group, an
optionally substituted C.sub.3-10 cycloalkylcarbonyl group, an
optionally substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, a carboxyl group, an optionally
substituted C.sub.1-6 alkoxycarbonyl group, an optionally
substituted C.sub.3-10 cycloalkyloxycarbonyl group, an optionally
substituted C.sub.6-10 aryloxycarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group, an optionally substituted
aminocarbonyl group, an optionally substituted C.sub.1-6 alkylthio
group, an optionally substituted C.sub.3-10 cycloalkylthio group,
an optionally substituted C.sub.6-10 arylthio group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylthio group, a sulfinate group, an optionally
substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted aminosulfinyl
group, a sulfonate group, an optionally substituted C.sub.1-6
alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group, or an
optionally substituted aminosulfonyl group; R.sup.6 is a hydrogen
atom, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted C.sub.3-10 cycloalkyl group, an optionally
substituted C.sub.6-10 aryl group, an optionally substituted 5- to
12-membered monocyclic or polycyclic heterocyclic group, an
optionally substituted C.sub.1-6 alkylcarbonyl group, an optionally
substituted C.sub.3-10 cycloalkylcarbonyl group, an optionally
substituted C.sub.6-10 arylcarbonyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylcarbonyl group, an optionally substituted C.sub.1-6
alkoxycarbonyl group, an optionally substituted C.sub.3-10
cycloalkyloxycarbonyl group, an optionally substituted C.sub.6-10
aryloxycarbonyl group, an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclyloxycarbonyl group, an
optionally substituted C.sub.1-6 alkylsulfinyl group, an optionally
substituted C.sub.3-10 cycloalkylsulfinyl group, an optionally
substituted C.sub.6-10 arylsulfinyl group, an optionally
substituted 5- to 12-membered monocyclic or polycyclic
heterocyclylsulfinyl group, an optionally substituted C.sub.1-6
alkylsulfonyl group, an optionally substituted C.sub.3-10
cycloalkylsulfonyl group, an optionally substituted C.sub.6-10
arylsulfonyl group, or an optionally substituted 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group; with the
proviso that in the formula (1), a compound in which R.sup.1 and
R.sup.2 are both hydrogen atoms, a compound in which when A is O,
the ring G is a furan ring or an imidazole ring, a compound in
which when A is S, the ring G is a thiophene ring or an imidazole
ring, a compound in which when A is N--R.sup.6, the ring G is a
pyrrole ring, a pyrazole ring, or an imidazole ring,
2-isopropylfuro[3,2-g]quinoline-4,9-dione, and ethyl
4,8-dioxo-2,7-diphenyl-4,8-dihydrothieno[2,3-f]benzofuran-6-car-
boxylate are excluded. Item 2: The compound according to item 1 or
a pharmacologically acceptable salt thereof, wherein A is S. Item
3: The compound according to item 1 or a pharmacologically
acceptable salt thereof, wherein A is O. Item 4: The compound
according to item 1 or a pharmacologically acceptable salt thereof,
wherein A is N--R.sup.6. Item 5: The compound according to any one
of items 1-4 or a pharmacologically acceptable salt thereof,
wherein the ring G is of any formula selected from the group
consisting of the following formulas (a) to (l):
##STR00008## ##STR00009##
Item 6: The compound according to item 5 or a pharmacologically
acceptable salt thereof, wherein the ring G is of any formula
selected from the group consisting of the following formulas (a) to
(h):
##STR00010##
Item 7: The compound according to item 6 or a pharmacologically
acceptable salt thereof, wherein the ring G is of any formula
selected from the group consisting of the following formulas (a) to
(f):
##STR00011##
Item 8: The compound according to item 7 or a pharmacologically
acceptable salt thereof, wherein the ring G is of any formula
selected from the group consisting of the following formulas (b) or
(e):
##STR00012##
Item 9: The compound according to any one of items 1-8 or a
pharmacologically acceptable salt thereof, wherein R.sup.1 is a
group selected from the group consisting of: 1: a hydrogen atom; 2:
a cyano group; 3: a C.sub.1-6 alkyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a fluorine atom, hydroxy, C.sub.1-6 alkoxy,
C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and 3- to 8-membered cyclic
amino); 4: a C.sub.1-6 alkylcarbonyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, amino (which is
optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5-
to 12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)); 5: a
C.sub.6-10 aryl group (wherein the aryl is optionally substituted
one to three groups selected from a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 6: a 5- to 12-membered
monocyclic or polycyclic heterocyclic group (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 7: a carboxyl group; 8: an
aminocarbonyl group (wherein the amino is optionally substituted
with one or two groups selected from the group consisting of (a)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (b)
C.sub.3-10 cycloalkyl (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, or
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from a halogen atom,
hydroxy, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy)); and 9: a 3- to
8-membered cyclic aminocarbonyl group (wherein the cyclic amino is
optionally substituted with one to three C.sub.1-6 alkyl). Item 10:
The compound according to item 9 or a pharmacologically acceptable
salt thereof, wherein R.sup.1 is a hydrogen atom or a C.sub.1-6
alkylcarbonyl group (wherein the alkyl is optionally substituted
with 3- to 8-membered cyclic amino). Item 11: The compound
according to any one of items 1-10 or a pharmacologically
acceptable salt thereof, wherein R.sup.2 is a group selected from
the group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3:
a cyano group; 4: an amino group (wherein the amino is substituted
with one or two groups selected from the group consisting of (a)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (b)
C.sub.1-6 alkylcarbonyl (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10
aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle
(which is optionally substituted with one to three C.sub.1-6
alkyl)), (c) C.sub.3-10 cycloalkyl (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (d) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (e) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); 5: a 3- to 8-membered cyclic amino group
(wherein the cyclic amino is optionally substituted with one to
three C.sub.1-6 alkyl); 6: a C.sub.1-6 alkyl group (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of (a) a halogen atom, (b) hydroxy, (c)
amino (wherein the amino is optionally substituted with one or two
groups selected from the group consisting of (i) C.sub.1-6 alkyl
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-4 alkoxy, an aminocarbonyl group (wherein the
amino is optionally substituted with one to three C.sub.1-6 alkyl),
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl))), (ii) C.sub.3-8 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy), (iii) C.sub.1-6
alkylcarbonyl (wherein the alkyl is optionally substituted with one
to three groups selected from a halogen atom, hydroxy, C.sub.1-4
alkoxy, C.sub.6-10 aryl, or a 5- to 12-membered monocyclic or
polycyclic heterocycle (which is optionally substituted with one to
three C.sub.1-6 alkyl)), (iv) C.sub.1-6 alkoxycarbonyl (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-4
alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle (which is optionally substituted with one to
three C.sub.1-6 alkyl)), (v) C.sub.1-6 alkylsulfinyl (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-4
alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle (which is optionally substituted with one to
three C.sub.1-6 alkyl)), (vi) C.sub.1-6 alkylsulfonyl (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-4
alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle (which is optionally substituted with one to
three C.sub.1-6 alkyl)), (vii) aminocarbonyl (wherein the amino is
optionally substituted with one or two C.sub.1-6 alkyl (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-4
alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle (which is optionally substituted with one to
three C.sub.1-6 alkyl))), (viii) 3- to 8-membered cyclic amino
(wherein the cyclic amino is optionally substituted with one to
three C.sub.1-6 alkyl), and (ix) C.sub.3-10 cycloalkylcarbonyl, (d)
3- to 8-membered cyclic amino (wherein the cyclic amino is
optionally substituted with one to three C.sub.1-6 alkylcarbonyl),
(e) C.sub.1-6 alkoxy (wherein the alkoxy is optionally substituted
with one to three C.sub.6-10 aryl), (f) C.sub.3-10 cycloalkyl, (g)
C.sub.6-10 aryl, and (h) a 5- to 12-membered monocyclic or
polycyclic heterocycle); 7: a C.sub.3-10 cycloalkyl group (wherein
the cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 8: a C.sub.1-6 alkenyl
group (the alkenyl is optionally substituted with one to three
groups selected from C.sub.1-6 alkyl and C.sub.1-6 alkoxycarbonyl
groups); 9: a C.sub.1-6 alkynyl group (the alkynyl is optionally
substituted with one to three groups selected from C.sub.1-6 alkyl
and C.sub.1-6 alkoxycarbonyl groups); 10: a C.sub.6-10 aryl group
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 11: a 5- to
12-membered monocyclic or polycyclic heterocyclic group (wherein
the heterocycle is optionally substituted with one to three groups
selected from a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 12: a C.sub.3-10 cycloalkyloxy group (wherein
the cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 13: a C.sub.6-10 aryloxy
group (wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 14: a 5- to
12-membered monocyclic or polycyclic heterocyclyloxy group (wherein
the heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 15: a carboxyl group; 16: a
C.sub.1-6 alkylcarbonyl group (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, amino (which is optionally
substituted with one or two C.sub.1-6 alkyl groups), C.sub.1-6
alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle); 17: a C.sub.3-10
cycloalkylcarbonyl group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 18: a C.sub.6-10 arylcarbonyl group (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy); 19: a 5- to 12-membered monocyclic or
polycyclic heterocyclylcarbonyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 20: a C.sub.3-10 cycloalkyloxycarbonyl group
(wherein the cycloalkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 21: a C.sub.6-10
aryloxycarbonyl group (wherein the aryl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 22:
a 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 23: an aminocarbonyl group (wherein the amino is
optionally substituted with one or two groups selected from (a)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (b)
C.sub.3-10 cycloalkyl (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); 24: a 3- to 8-membered cyclic aminocarbonyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl); 25: a C.sub.1-6 alkylthio group (wherein
the alkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
amino (which is optionally substituted with one or two C.sub.1-6
alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10
aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle); 26: a C.sub.3-10 cycloalkylthio group (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 27: a C.sub.6-10 arylthio
group (wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 28: a 5- to
12-membered monocyclic or polycyclic heterocyclylthio group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 29: a sulfinate
group; 30: a C.sub.1-6 alkylsulfinyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, amino (which is
optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5-
to 12-membered monocyclic or polycyclic heterocycle); 31: a
C.sub.3-10 cycloalkylsulfinyl group (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 32: a C.sub.6-10 arylsulfinyl group (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy); 33: a 5- to 12-membered monocyclic or
polycyclic heterocyclylsulfinyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 34: an aminosulfinyl group (wherein the amino is
optionally substituted with one or two groups selected from the
group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C
.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); 35: a 3- to 8-membered cyclic aminosulfinyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl); 36: a sulfonate group; 37: a C.sub.1-6
alkylsulfonyl group (wherein the alkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, amino (which is optionally substituted with
one or two C.sub.1-6 alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 38: a C.sub.3-10 cycloalkylsulfonyl group
(wherein the cycloalkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 39: a C.sub.6-10
arylsulfonyl group (wherein the aryl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 40: a 5- to
12-membered monocyclic or polycyclic heterocyclylsulfonyl group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 41: an
aminosulfonyl group (wherein the amino is optionally substituted
with one or two groups selected from the group consisting of (a)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (b)
C.sub.3-10 cycloalkyl (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); and 42: a 3- to 8-membered cyclic aminosulfinyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl). Item 12: The compound according to any
one of items 1-11 or a pharmacologically acceptable salt thereof,
wherein R.sup.2 is a group selected from the group consisting of:
1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: an
amino group (wherein the amino is substituted with one or two
groups selected from the group consisting of (a) C.sub.1-6 alkyl
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered
monocyclic or polycyclic heterocycle (which is optionally
substituted with one to three C.sub.1-6 alkyl)), (b) C.sub.1-6
alkylcarbonyl (wherein the alkyl is optionally substituted with one
to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (c)
C.sub.3-10 cycloalkyl (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (d) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (e) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); 5: a 3- to 8-membered cyclic amino group
(wherein the cyclic amino is optionally substituted with one to
three C.sub.1-6 alkyl); 6: a C.sub.1-6 alkyl group (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of (a) a halogen atom, (b) hydroxy, (c)
amino (wherein the amino is optionally substituted with one or two
groups selected from the group consisting of (i) C.sub.1-6 alkyl
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered
monocyclic or polycyclic heterocycle (which is optionally
substituted with one to three C.sub.1-6 alkyl)), (ii) C.sub.3-8
cycloalkyl (wherein the cycloalkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy), (iii)
C.sub.1-6 alkylcarbonyl (wherein the alkyl is optionally
substituted with one to three groups selected from a halogen atom,
hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, or a 5- to 12-membered
monocyclic or polycyclic heterocycle (which is optionally
substituted with one to three C.sub.1-6 alkyl)), (iv) C.sub.1-6
alkoxycarbonyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (v)
C.sub.1-6 alkylsulfinyl (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10
aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle
(which is optionally substituted with one to three C.sub.1-6
alkyl)), (vi) C.sub.1-6 alkylsulfonyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (vii) aminocarbonyl (wherein the amino is
optionally substituted with one or two C.sub.1-6 alkyl (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-4
alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle (which is optionally substituted with one to
three C.sub.1-6 alkyl))), and (viii) 3- to 8-membered cyclic amino
(wherein the cyclic amino is optionally substituted with one to
three C.sub.1-6 alkyl)), (d) 3- to 8-membered cyclic amino, (e)
C.sub.1-6 alkoxy, (f) C.sub.3-10 cycloalkyl, (g) C.sub.6-10 aryl,
and (h) a 5- to 12-membered monocyclic or polycyclic heterocycle);
7: a C.sub.3-10 cycloalkyl group (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 8: a C.sub.6-10 aryl group (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 9: a 5- to 12-membered monocyclic or polycyclic
heterocyclic group (wherein the heterocycle is optionally
substituted with one to three groups selected from a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 10: a C.sub.3-10
cycloalkyloxy group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 11: a C.sub.6-10 aryloxy group (wherein the aryl
is optionally substituted with one to three groups selected from
the group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl,
and C.sub.1-6 alkoxy); 12: a 5- to 12-membered monocyclic or
polycyclic heterocyclyloxy group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 13: a carboxyl group; 14: a C.sub.1-6
alkylcarbonyl group (wherein the alkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, amino (which is optionally substituted with
one or two C.sub.1-6 alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 15: a C.sub.3-10 cycloalkylcarbonyl group
(wherein the cycloalkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 16: a C.sub.6-10
arylcarbonyl group (wherein the aryl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 17: a 5- to
12-membered monocyclic or polycyclic heterocyclylcarbonyl group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 18: a C.sub.3-10
cycloalkyloxycarbonyl group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 19: a C.sub.6-10 aryloxycarbonyl group (wherein
the aryl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 20: a 5- to 12-membered
monocyclic or polycyclic heterocyclyloxycarbonyl group (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 21: an aminocarbonyl group
(wherein the amino is optionally substituted with one or two groups
selected from (a) C.sub.1-6 alkyl (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10
aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle
(which is optionally substituted with one to three C.sub.1-6
alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); 22: a 3- to 8-membered cyclic aminocarbonyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl); 23: a C.sub.1-6 alkylthio group (wherein
the alkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
amino (which is optionally substituted with one or two C.sub.1-6
alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10
aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle); 24: a C.sub.3-10 cycloalkylthio group (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 25: a C.sub.6-10 arylthio
group (wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 26: a 5- to
12-membered monocyclic or polycyclic heterocyclylthio group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 27: a sulfinate
group; 28: a C.sub.1-6 alkylsulfinyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, amino (which is
optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5-
to 12-membered monocyclic or polycyclic heterocycle); 29: a
C.sub.3-10 cycloalkylsulfinyl group (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 30: a C.sub.6-10 arylsulfinyl group (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy); 31: a 5- to 12-membered monocyclic or
polycyclic heterocyclylsulfinyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 32: an aminosulfinyl group (wherein the amino is
optionally substituted with one or two groups selected from the
group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); 33: a 3- to 8-membered
cyclic aminosulfinyl group (wherein the cyclic amino is optionally
substituted with one to three C
.sub.1-6 alkyl); 34: a sulfonate group; 35: a C.sub.1-6
alkylsulfonyl group (wherein the alkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, amino (which is optionally substituted with
one or two C.sub.1-6 alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 36: a C.sub.3-10 cycloalkylsulfonyl group
(wherein the cycloalkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 37: a C.sub.6-10
arylsulfonyl group (wherein the aryl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 38: a 5- to
12-membered monocyclic or polycyclic heterocyclylsulfonyl group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 39: an
aminosulfonyl group (wherein the amino is optionally substituted
with one or two groups selected from the group consisting of (a)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (b)
C.sub.3-10 cycloalkyl (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); and 40: a 3- to 8-membered cyclic aminosulfinyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl). Item 13: The compound according to any
one of items 1-11 or a pharmacologically acceptable salt thereof,
wherein R.sup.2 is a group selected from the group consisting of:
1: a hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: an
amino group (wherein the amino is optionally substituted with one
to three C.sub.1-6 alkyl groups); 5: a 3- to 8-membered cyclic
amino group (wherein the cyclic amino is optionally substituted
with one to three C.sub.1-6 alkyl); 6: a C.sub.1-6 alkyl group
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of (a) a halogen atom,
(b) hydroxy, (c) amino (wherein the amino is optionally substituted
with one or two groups selected from the group consisting of (i)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, and C.sub.1-4 alkoxy), (ii) C.sub.3-8 cycloalkyl,
(iii) C.sub.1-6 alkylcarbonyl, (iv) C.sub.1-6 alkoxycarbonyl, and
(v) C.sub.1-6 alkylsulfonyl), (d) 3- to 8-membered cyclic amino,
(e) C.sub.1-6 alkoxy, (f) C.sub.3-10 cycloalkyl, (g) phenyl, and
(h) a 5- to 6-membered monocyclic or polycyclic heterocycle); 7: a
C.sub.1-6 alkenyl group (wherein the alkenyl is optionally
substituted with one to three groups selected from C.sub.1-6 alkyl
and C.sub.1-6 alkoxycarbonyl groups); 8: a C.sub.1-6 alkynyl group
(wherein the alkynyl is optionally substituted with one to three
groups selected from C.sub.1-6 alkyl and C.sub.1-6 alkoxycarbonyl
groups); 9: a 5- to 12-membered monocyclic or polycyclic
heterocyclic group; 10: a C.sub.1-6 alkylcarbonyl group (wherein
the alkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
amino (which is optionally substituted with one or two C.sub.1-6
alkyl groups), C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl, phenyl, and
a 5- to 6-membered monocyclic heterocycle (which is optionally
substituted with one to three C.sub.1-6 alkyl)); 11: an
aminocarbonyl group (wherein the amino is (a) C.sub.1-6 alkyl
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-4 alkoxy, phenyl, and a 5- to 6-membered
monocyclic heterocycle (which is optionally substituted with one to
three C.sub.1-4 alkyl)), (b) C.sub.3-8 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (c) phenyl (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy), and (d) a 5- to 6-membered monocyclic
heterocycle (wherein the heterocycle is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); and 12: a
3- to 8-membered cyclic aminocarbonyl group (wherein the cyclic
amino is optionally substituted with one to three C.sub.1-6 alkyl).
Item 14: The compound according to item 13 or a pharmacologically
acceptable salt thereof, wherein R.sup.2 is a group selected from
the group consisting of: 1: a C.sub.1-6 alkyl group (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, amino (which
is optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl, phenyl, and a 5- to
6-membered monocyclic heterocycle); 2: a C.sub.1-6 alkylcarbonyl
group (wherein the alkyl is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, amino (which is optionally substituted with one or two
C.sub.1-6 alkyl groups), C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl,
phenyl, and a 5- to 6-membered monocyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)); 3: an
aminocarbonyl group (wherein the amino is optionally substituted
with one or two groups selected from (a) C.sub.1-6 alkyl (wherein
the alkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-4 alkoxy, phenyl, and a 5- to 6-membered monocyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-4 alkyl)), (b) C.sub.3-8 cycloalkyl (wherein the cycloalkyl
is optionally substituted with one to three groups selected from
the group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl,
and C.sub.1-6 alkoxy), (c) phenyl (wherein the aryl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 6-membered monocyclic
heterocycle (wherein the heterocycle is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); and 4: a 3-
to 8-membered cyclic aminocarbonyl group (wherein the cyclic amino
is optionally substituted with one to three C.sub.1-6 alkyl). Item
15: The compound according to any one of items 1-14 or a
pharmacologically acceptable salt thereof, wherein R.sup.3,
R.sup.4, or R.sup.5 is each independently a group selected from the
group consisting of: 1: a hydrogen atom; 2: a halogen atom; 3: a
cyano group; 4: a hydroxyl group; 5: an amino group (wherein the
amino is optionally substituted with one or two groups selected
from the group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl
is optionally substituted with one to three groups selected from
the group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.1-6 alkylcarbonyl (wherein the alkyl
is optionally substituted with one to three groups selected from
the group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (c) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (d) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (e) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); 6: a 3- to 8-membered
cyclic amino group (wherein the cyclic amino is optionally
substituted with one to three C.sub.1-6 alkyl); 7: a C.sub.1-6
alkyl group (wherein the alkyl is optionally substituted with one
to three groups selected from a halogen atom, hydroxy, amino (which
is optionally substituted with one or two C.sub.1-6 alkyl),
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5-
to 12-membered monocyclic or polycyclic heterocycle); 8: a
C.sub.3-10 cycloalkyl group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 9: a C.sub.6-10 aryl group (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 10: a 5- to 12-membered monocyclic or polycyclic
heterocyclic group (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 11: a C.sub.1-6 alkoxy group (wherein the alkyl
is optionally substituted with one to three groups selected from
the group consisting of a halogen atom, hydroxy, amino (which is
optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5-
to 12-membered monocyclic or polycyclic heterocycle); 12: a
C.sub.3-10 cycloalkyloxy group (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 13: a C.sub.6-10 aryloxy group (wherein the aryl
is optionally substituted with one to three groups selected from
the group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl,
and C.sub.1-6 alkoxy); 14: a 5- to 12-membered monocyclic or
polycyclic heterocyclyloxy group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 15: a carboxyl group; 16: a C.sub.1-6
alkylcarbonyl group (wherein the alkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, amino (which is optionally substituted with
one or two C.sub.1-6 alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 17: a C.sub.3-10 cycloalkylcarbonyl group
(wherein the cycloalkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 18: a C.sub.6-10
arylcarbonyl group (wherein the aryl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 19: a 5- to
12-membered monocyclic or polycyclic heterocyclylcarbonyl group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 20: a C.sub.1-6
alkoxycarbonyl group (wherein the alkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, amino (which is optionally substituted with
one or two C.sub.1-6 alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 21: a C.sub.3-10 cycloalkyloxycarbonyl
group (wherein the cycloalkyl is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 22: a C.sub.6-10
aryloxycarbonyl group (wherein the aryl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 23:
a 5- to 12-membered monocyclic or polycyclic
heterocyclyloxycarbonyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 24: an aminocarbonyl group (wherein the amino is
optionally substituted with one or two groups selected from the
group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); 25: a 3- to 8-membered
cyclic aminocarbonyl group (wherein the cyclic amino is optionally
substituted with one to three C.sub.1-6 alkyl); 26: a C.sub.1-6
alkylthio group (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, amino (which is optionally substituted with one or
two C.sub.1-6 alkyl), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 27: a C.sub.3-10 cycloalkylthio group
(wherein the cycloalkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 28: a C.sub.6-10
arylthio group (wherein the aryl is optionally substituted with one
to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 29: a 5- to
12-membered monocyclic or polycyclic heterocyclylthio group
(wherein the heterocycle is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 30: a sulfinate
group; 31: a C.sub.1-6 alkylsulfinyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, amino (which is
optionally substituted with one or two C.sub.1-6 alkyl), C.sub.1-6
alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle); 32: a C.sub.3-10
cycloalkylsulfinyl group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 33: a C.sub.6-10 arylsulfinyl group (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy); 34: a 5- to 12-membered monocyclic or
polycyclic heterocyclylsulfinyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 35: an aminosulfinyl group (wherein the amino is
optionally substituted with one or two groups selected from the
group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); 36: a 3- to 8-membered
cyclic aminosulfinyl group (wherein the cyclic amino is optionally
substituted with one to three C.sub.1-6 alkyl); 37: a sulfonate
group; 38: a C.sub.1-6 alkylsulfonyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, amino (which is
optionally substituted with one or two C.sub.1-6 alkyl), C.sub.1-6
alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle); 39: a C.sub.3-10
cycloalkylsulfonyl group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 40: a C.sub.6-10 arylsulfonyl group (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy); 41: a 5- to 12-membered monocyclic or
polycyclic heterocyclylsulfonyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 42: an aminosulfonyl group (wherein the amino is
optionally substituted with one or two groups selected from the
group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); and 43: a 3- to 8-membered
cyclic aminosulfonyl group (wherein the cyclic amino is optionally
substituted with one to three C.sub.1-6 alkyl). Item 16: The
compound according to item 15 or a pharmacologically acceptable
salt thereof, wherein R.sup.3, R.sup.4, or R.sup.5 is each
independently a group selected from the group consisting of: 1: a
hydrogen atom; 2: a halogen atom; 3: a cyano group; 4: a hydroxyl
group; 5: an amino group (wherein the amino is optionally
substituted with one or two groups selected from the group
consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10
aryl, and a 5- to 12-membered monocyclic or polycyclic heterocycle
(which is optionally substituted with one to three C.sub.1-6
alkyl)), (b) C.sub.1-6 alkylcarbonyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (c) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (d) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (e) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); 6: a 3- to 8-membered
cyclic amino group (wherein the cyclic amino is optionally
substituted with one to three C.sub.1-6 alkyl); 7: a C.sub.1-6
alkyl group (wherein the alkyl is optionally substituted with one
to three groups selected from the group consisting of a halogen
atom, hydroxy, amino (which is optionally substituted with one or
two C.sub.1-6 alkyl groups), C.sub.1-6 alkoxy, C.sub.3-10
cycloalkyl, C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or
polycyclic heterocycle); 8: a C.sub.1-6 alkoxy group (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, amino (which
is optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5-
to 12-membered monocyclic or polycyclic heterocycle); 9: a
C.sub.1-6 alkylcarbonyl group (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, amino (which is optionally
substituted with one or two C.sub.1-6 alkyl groups), C.sub.1-6
alkoxy, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle); 10: an
aminocarbonyl group (wherein the amino is optionally substituted
with one or two groups selected from the group consisting of (a)
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), (b)
C.sub.3-10 cycloalkyl (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl (wherein the aryl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy), and (d) a 5- to 12-membered monocyclic or
polycyclic heterocycle (wherein the heterocycle is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy)); 11: a 3- to 8-membered cyclic aminocarbonyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl); 12: a C.sub.1-6 alkylsulfonyl group
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, amino (which is optionally substituted with one or two
C.sub.1-6 alkyl), C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle); 13: an aminosulfonyl group (wherein the amino is
optionally substituted with one or two groups selected from the
group consisting of (a) C.sub.1-6 alkyl (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-4 alkoxy,
C.sub.6-10 aryl, and a 5- to 12-membered monocyclic or polycyclic
heterocycle (which is optionally substituted with one to three
C.sub.1-6 alkyl)), (b) C.sub.3-10 cycloalkyl (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), (c) C.sub.6-10 aryl
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), and (d) a 5- to
12-membered monocyclic or polycyclic heterocycle (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy)); and 14: a 3- to 8-membered
cyclic aminosulfonyl group (wherein the cyclic amino is optionally
substituted with one to three C.sub.1-6 alkyl). Item 17: The
compound according to item 16 or a pharmacologically acceptable
salt thereof, wherein R.sup.3, R.sup.4, or R.sup.5 is all hydrogen
atoms. Item 18: The compound according to any one of item 1 or 4-17
or a pharmacologically acceptable salt thereof, wherein R.sup.6 is
a group selected from the group consisting of: 1: a hydrogen atom;
2: a C.sub.1-6 alkyl group (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, C.sub.1-6 alkoxy, C.sub.6-10 aryl,
and a 5- to 6-membered monocyclic heterocycle (which is optionally
substituted with one to three C.sub.1-4 alkyl)); 3: a C.sub.3-10
cycloalkyl group (wherein the cycloalkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 4: a
C.sub.1-6 alkylcarbonyl group (wherein the alkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, C.sub.1-6 alkoxy, C.sub.6-10 aryl,
and a 5- to 6-membered monocyclic heterocycle (which is optionally
substituted with one to three C.sub.1-4 alkyl)); 5: a C.sub.3-10
cycloalkylcarbonyl group; 6: a C.sub.6-10 arylcarbonyl group; 7: a
5- to 12-membered monocyclic or polycyclic heterocyclylcarbonyl
group; 8: a C.sub.1-6 alkoxycarbonyl group (wherein the alkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, C.sub.1-6 alkoxy, C.sub.6-10
aryl, and a 5- to 6-membered monocyclic heterocycle (which is
optionally substituted with one to three C.sub.1-4 alkyl)); 9: a
C.sub.3-10 cycloalkyloxycarbonyl group (wherein the cycloalkyl is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 10: a C.sub.6-10 aryloxycarbonyl group (wherein
the aryl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 11: a 5- to 12-membered
monocyclic or polycyclic heterocyclyloxycarbonyl group (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 12: a C.sub.1-6
alkylsulfinyl group (wherein the alkyl is optionally substituted
with one to three groups selected from the group consisting of a
halogen atom, C.sub.1-6 alkoxy, C.sub.6-10 aryl, and a 5- to
6-membered monocyclic heterocycle (which is optionally substituted
with one to three C.sub.1-4 alkyl)); 13: a C.sub.3-10
cycloalkylsulfinyl group (wherein the cycloalkyl is optionally
substituted with one to three groups selected from the group
consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 14: a C.sub.6-10 arylsulfinyl group (wherein the
aryl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, C.sub.1-6
alkyl, and C.sub.1-6 alkoxy); 15: a 5- to 12-membered monocyclic or
polycyclic heterocyclylsulfinyl group (wherein the heterocycle is
optionally substituted with one to three groups selected from the
group consisting of a halogen atom, hydroxy, C.sub.1-6 alkyl, and
C.sub.1-6 alkoxy); 16: a C.sub.1-6 alkylsulfonyl group (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, C.sub.1-6 alkoxy,
C.sub.6-10 aryl, and a 5- to 6-membered monocyclic heterocycle
(which is optionally substituted with one to three C.sub.1-4
alkyl)); 17: a C.sub.3-10 cycloalkylsulfonyl group (wherein the
cycloalkyl is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 18: a C.sub.6-10
arylsulfonyl group (wherein the aryl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C
.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 19: a 5- to 12-membered
monocyclic or polycyclic heterocyclylsulfonyl group (wherein the
heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); 20: a C.sub.6-10 aryl group
(wherein the aryl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy); and 21: a 5- to
12-membered monocyclic or polycyclic heterocyclic group (wherein
the heterocycle is optionally substituted with one to three groups
selected from the group consisting of a halogen atom, hydroxy,
C.sub.1-6 alkyl, and C.sub.1-6 alkoxy). Item 19: The compound
according to item 18 or a pharmacologically acceptable salt
thereof, wherein R.sup.6 is a group selected from the group
consisting of: 1: a hydrogen atom; 2: a C.sub.1-6 alkyl group
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
C.sub.1-6 alkoxy, C.sub.6-10 aryl, and a 5- to 6-membered
monocyclic heterocycle (which is optionally substituted with one to
three C.sub.1-4 alkyl)); 3: a C.sub.1-6 alkylcarbonyl group
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
C.sub.1-6 alkoxy, C.sub.6-10 aryl, and a 5- to 6-membered
monocyclic heterocycle (which is optionally substituted with one to
three C.sub.1-4 alkyl)); and 4: a C.sub.1-6 alkylsulfonyl group
(wherein the alkyl is optionally substituted with one to three
groups selected from the group consisting of a halogen atom,
C.sub.1-6 alkoxy, C.sub.6-10 aryl, and a 5- to 6-membered
monocyclic heterocycle (which is optionally substituted with one to
three C.sub.1-4 alkyl)). Item 20: The compound according to item 19
or a pharmacologically acceptable salt thereof, wherein R.sup.6 is
a hydrogen atom. Item 21: The compound according to items 1-20 or a
pharmacologically acceptable salt thereof, wherein R.sup.2 is a
group selected from the group consisting of: 1: a C.sub.1-6 alkyl
group (wherein the alkyl is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, amino (which is optionally substituted with one or two
C.sub.1-6 alkyl groups), C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl,
and a 5- to 6-membered monocyclic heterocycle); 2: a C.sub.1-6
alkylcarbonyl group; 3: an aminocarbonyl group (wherein the amino
is optionally substituted with one to three C.sub.1-6 alkyl groups
(wherein the alkyl is optionally substituted with one to three
halogen atoms)); and 4: a 3- to 8-membered cyclic aminocarbonyl
group (wherein the cyclic amino is optionally substituted with one
to three C.sub.1-6 alkyl). Item 22: The compound according to item
1 or a pharmacologically acceptable salt thereof, wherein
A is O or S;
[0021] the ring G is either one selected from the group consisting
of the following formula (b) or (e):
##STR00013##
R.sup.1 is a hydrogen atom; and R.sup.2 is a group selected from
the group consisting of: 1: a C.sub.1-6 alkyl group (wherein the
alkyl is optionally substituted with one to three groups selected
from the group consisting of a halogen atom, hydroxy, amino (which
is optionally substituted with one or two C.sub.1-6 alkyl groups),
C.sub.1-4 alkoxy, C.sub.3-8 cycloalkyl, and a 5- to 6-membered
monocyclic heterocycle); 2: a C.sub.1-6 alkylcarbonyl group; 3: an
aminocarbonyl group (wherein the amino is optionally substituted
with one to three C.sub.1-6 alkyl groups (wherein the alkyl is
optionally substituted with one to three halogen atoms)); and 4: a
3- to 8-membered cyclic aminocarbonyl group (wherein the cyclic
amino is optionally substituted with one to three C.sub.1-6 alkyl).
R.sup.3, R.sup.4, and R.sup.5 are hydrogen atoms. Item 23: The
compound according to item 1 or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from the following
compounds: [0022] 2-acetylthieno[2,3-g]quinoline-4,9-dione; [0023]
2-acetylthieno[2,3-g]isoquinoline-4,9-dione; [0024]
2-(1-hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione; [0025]
2-(2-hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione; [0026]
2-[cyclopropyl(hydroxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione;
[0027]
N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamid-
e; [0028]
2-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione;
[0029]
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoli-
ne-2-carboxyamide; [0030]
2-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione-
; [0031]
2-{[(2,2-difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-
-dione; [0032]
2-[(4-acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-dione;
[0033]
4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile;
[0034] 2-(1-fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione; [0035]
2-(3-ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione;
[0036] 2-acetylthieno[3,2-g]isoquinoline-4,9-dione; [0037]
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carb-
oxamide; [0038]
2-(1-hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione; [0039]
2-acetylthieno[3,2-f][1]benzofuran-4,8-dione; and [0040]
2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-4,8-dione.
Item 24: A pharmaceutical composition comprising a compound
according to any one of items 1-23 or a pharmacologically
acceptable salt thereof. Item 25: An anticancer agent comprising a
compound according to any one of items 1-23 or a pharmacologically
acceptable salt thereof as an active ingredient. Item 26: The
anticancer agent according to item 25, wherein the cancer is at
least one cancer selected from the group consisting of acute
leukemia, chronic lymphocytic leukemia, chronic myelocytic
leukemia, polycythemia vera, malignant lymphoma, brain tumor, head
and neck cancer, esophageal cancer, thyroid cancer, small cell lung
cancer, non-small-cell lung cancer, breast cancer, gastric cancer,
gallbladder.cndot.bile duct cancer, hepatoma, pancreatic cancer,
colon cancer, rectal cancer, chorioepithelioma, endometrial cancer,
cervical cancer, urothelial cancer, renal cell cancer, testicular
tumor, Wilms' tumor, skin cancer, malignant melanoma,
neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue
sarcoma. Item 27: A method for treating a cancer, characterized by
administering a therapeutically effective amount of a compound
according to any one of items 1-23 or a pharmacologically
acceptable salt thereof to a patient in need of the treatment. Item
28: The method for treating according to item 27, wherein the
cancer is at least one cancer selected from the group consisting of
acute leukemia, chronic lymphocytic leukemia, chronic myelocytic
leukemia, polycythemia vera, malignant lymphoma, brain tumor, head
and neck cancer, esophageal cancer, thyroid cancer, small cell lung
cancer, non-small-cell lung cancer, breast cancer, gastric cancer,
gallbladder.cndot.bile duct cancer, hepatoma, pancreatic cancer,
colon cancer, rectal cancer, chorioepithelioma, endometrial cancer,
cervical cancer, urothelial cancer, renal cell cancer, testicular
tumor, Wilms' tumor, skin cancer, malignant melanoma,
neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue
sarcoma. Item 29: The use of a compound according to any one of
items 1-23 or a pharmacologically acceptable salt thereof for the
manufacture of a therapeutic agent for cancer. Item 30: The use of
a compound according to item 29 or a pharmacologically acceptable
salt thereof, wherein the cancer is at least one cancer selected
from the group consisting of acute leukemia, chronic lymphocytic
leukemia, chronic myelocytic leukemia, polycythemia vera, malignant
lymphoma, brain tumor, head and neck cancer, esophageal cancer,
thyroid cancer, small cell lung cancer, non-small-cell lung cancer,
breast cancer, gastric cancer, gallbladder.cndot.bile duct cancer,
hepatoma, pancreatic cancer, colon cancer, rectal cancer,
chorioepithelioma, endometrial cancer, cervical cancer, urothelial
cancer, renal cell cancer, testicular tumor, Wilms' tumor, skin
cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's
sarcoma, and soft tissue sarcoma. Item 31: A compound according to
any one of items 1-23 or a pharmacologically acceptable salt
thereof for use in treating cancer. Item 32: The compound according
to item 31 or a pharmacologically acceptable salt thereof, wherein
the cancer is at least one cancer selected from the group
consisting of acute leukemia, chronic lymphocytic leukemia, chronic
myelocytic leukemia, polycythemia vera, malignant lymphoma, brain
tumor, head and neck cancer, esophageal cancer, thyroid cancer,
small cell lung cancer, non-small-cell lung cancer, breast cancer,
gastric cancer, gallbladder.cndot.bile duct cancer, hepatoma,
pancreatic cancer, colon cancer, rectal cancer, chorioepithelioma,
endometrial cancer, cervical cancer, urothelial cancer, renal cell
cancer, testicular tumor, Wilms' tumor, skin cancer, malignant
melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft
tissue sarcoma. Item 33: A method of producing a compound
represented by formula (1) or a pharmacologically acceptable salt
thereof:
##STR00014##
[0040] wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5
are defined as in above item 1, wherein the method is characterized
by comprising a step of mixing a compound represented by formula
(2) or a salt thereof:
##STR00015##
wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in above item 1; R.sup.7 and R.sup.8 are each C.sub.1-6
alkyl (wherein the alkyl is optionally substituted with one to
three groups selected from the group consisting of a halogen atom,
hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to 12-membered
monocyclic or polycyclic heterocycle (which is optionally
substituted with one to three C.sub.1-6 alkyl)), with an oxidant.
Item 34: A method of producing a compound represented by formula
(1) or a pharmacologically acceptable salt thereof:
##STR00016##
wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in above item 1, and wherein the method is characterized
by comprising a step of mixing a compound represented by formula
(2) or a salt thereof:
##STR00017##
wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in above item 1, or R.sup.1 and R.sup.2 are optionally
substituted alkoxycarbonyl groups, and R.sup.7 and R.sup.8 are each
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)), with an
oxidant. Item 35: A compound represented by the following formula
(2) or a salt thereof:
##STR00018##
wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
defined as in above item 1, and R.sup.7 and R.sup.8 are each
C.sub.1-6 alkyl (wherein the alkyl is optionally substituted with
one to three groups selected from the group consisting of a halogen
atom, hydroxy, C.sub.1-4 alkoxy, C.sub.6-10 aryl, and a 5- to
12-membered monocyclic or polycyclic heterocycle (which is
optionally substituted with one to three C.sub.1-6 alkyl)).
[0041] Moreover, it will be understood that the characteristics of
the above-described embodiments of the present invention can be
used alone or in combination. Accordingly, in the present
invention, it is intended that in addition to the clarified
combinations, the above-mentioned one or more characteristics can
be further combined and provided.
Advantageous Effects of Invention
[0042] The compounds represented by the formula (1) or the
pharmacologically acceptable salts thereof (also referred to as the
present compound(s)) exhibit strong inhibitory effects on
proliferation of a cancer cell and cancer cell sphere-forming
ability, and these compounds are useful, for example, as medicament
to be effective in prevention and/or treatment of cancer.
DESCRIPTION OF EMBODIMENTS
[0043] The present invention is described below in more detail.
[0044] In the present specification, the number of substituents of
a group defined by "an optionally substituted" or "substituted" is
not particularly limited if it is substitutable, and is one or
plural. In addition, unless otherwise indicated, the description
for each group is also applied when the group is one part of or a
substituent on other groups.
[0045] In the present specification, examples of "halogen atom"
include a fluorine atom, a chlorine atom, a bromine atom, and an
iodine atom. Preferably, it is a fluorine atom or a chlorine
atom.
[0046] A "C.sub.1-6 alkyl group" means a linear or branched,
saturated hydrocarbon group of which the carbon number is one to
six. Preferably, it includes a "C.sub.1-4 alkyl group" and the
like. Specific examples of the "C.sub.1-6 alkyl group" include, for
example, methyl, ethyl, propyl, 1-methylethyl, butyl,
2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl,
3-methylbutyl, 2-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,
1,1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 1-methylpentyl, and the like. Specific examples of
the "C.sub.1-4 alkyl group" include those having a carbon number
from 1 to 4 that are exemplified in the specific examples of
"C.sub.1-10 alkyl group". In the specification, for example,
C.sub.1-6 represents that the carbon number is one to six,
C.sub.1-4 represents that the carbon number is one to four, or
C.sub.6 represents that the carbon number is six. The same applies
to cases of other numbers.
[0047] A "C.sub.2-6 alkenyl group" means a linear or branched,
unsaturated hydrocarbon group that has two to six carbons and
contains one to three double bonds. Specific examples of "C.sub.2-6
alkenyl group" include, for example, vinyl, propenyl,
methylpropenyl, butenyl, methylbutenyl, pentenyl, hexenyl, and the
like.
[0048] A "C.sub.2-6 alkynyl group" means a linear or branched,
unsaturated hydrocarbon group that has two to six carbons and
contains one triple bond. Specific examples of "C.sub.2-6 alkynyl
group" include, for example, propynyl, methylpropynyl, butynyl,
methylbutynyl, pentynyl, hexynyl, and the like.
[0049] A "C.sub.3-10 cycloalkyl group" means a cyclic saturated
hydrocarbon group of which the carbon number is three to ten, and
also includes those having a partially crosslinked structure.
Preferably, it includes a "C.sub.3-7 cycloalkyl group" and the
like. Specific examples of "C.sub.3-10 cycloalkyl group" include,
for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and the
like. Specific examples of "C.sub.3-7 cycloalkyl group" include,
for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like. The "C.sub.3-10 cycloalkyl group" also
encompasses a compound fused to an aromatic ring. Specific examples
thereof include, for example, groups represented by the
following:
##STR00019##
and the like.
[0050] A "C.sub.1-6 alkoxy group" refers to a "C.sub.1-6 alkyloxy
group" and the "C.sub.1-6 alkyl" moiety in a "C.sub.1-6 alkoxy
group" is defined the same as the above-described "C.sub.1-6
alkyl". The "C.sub.1-6 alkoxy group" includes, preferably, a
"C.sub.1-4 alkoxy group" and the like. Examples of "C.sub.1-6
alkoxy group" include, for example, methoxy, ethoxy, propoxy,
1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy,
1,1-dimethylethoxy, pentyloxy, 3-methylbutoxy, 2-methylbutoxy,
2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, hexyloxy,
4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,
1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,
1,1-dimethylbutoxy, 1,2-dimethylbutoxy, and the like.
[0051] The "C.sub.3-10 cycloalkyl" moiety in a "C.sub.3-10
cycloalkyloxy group" is defined the same as the above described
"C.sub.3-10 cycloalkyl group". Preferably, it is a "C.sub.3-7
cycloalkyloxy group" and the like. Examples of "C.sub.3-10
cycloalkyloxy group" include, for example, cyclopropoxy,
cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the
like.
[0052] The "C.sub.1-6 alkyl" moiety in a "C.sub.1-6 alkylcarbonyl
group" is defined the same as the above-described "C.sub.1-6 alkyl
group". The "C.sub.1-6 alkylcarbonyl group" includes, preferably, a
"C.sub.1-4 alkylcarbonyl group" and the like. Specific examples of
"C.sub.1-6 alkylcarbonyl group" include, for example,
methylcarbonyl, ethylcarbonyl, propylcarbonyl,
1-methylethylcarbonyl, butylcarbonyl, 2-methylpropylcarbonyl,
1-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl, and the
like.
[0053] The "C.sub.3-10 cycloalkyl" moiety in a "C.sub.3-10
cycloalkylcarbonyl group" is defined the same as the above
described "C.sub.3-10 cycloalkyl group". Preferably, it is a
"C.sub.3-7 cycloalkylcarbonyl group" and the like. Specific
examples of "C.sub.3-10 cycloalkylcarbonyl group" include, for
example, cyclopropylcarbonyl, cyclobutylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, and
the like.
[0054] The "C.sub.1-6 alkylcarbonyl" moiety in a "C.sub.1-6
alkylcarbonyloxy group" is defined the same as the above-described
"C.sub.1-6 alkylcarbonyl group". The "C.sub.1-6 alkylcarbonyloxy
group" includes, preferably, a "C.sub.1-4 alkylcarbonyloxy group"
and the like. Specific examples of "C.sub.1-6 alkylcarbonyloxy
group" include methylcarbonyloxy, ethylcarbonyloxy,
propylcarbonyloxy, 1-methylethylcarbonyloxy, butylcarbonyloxy,
2-methylpropylcarbonyloxy, 1-methylpropylcarbonyloxy,
1,1-dimethylethylcarbonyloxy, and the like.
[0055] The "C.sub.1-6 alkylcarbonyl" moiety in a "C.sub.1-6
alkylcarbonylamino group" is defined the same as the
above-described "C.sub.1-6 alkylcarbonyl group". Specific examples
of "C.sub.1-6 alkylcarbonylamino group" include, for example,
methylcarbonylamino, ethylcarbonylamino, and the like.
[0056] The "C.sub.1-6 alkyl" moiety in a "C.sub.1-6 alkylthio
group" is defined the same as the above-described "C.sub.1-6 alkyl
group". The "C.sub.1-6 alkylthio group" includes, preferably,
"C.sub.1-4 alkylthio group" and the like. Specific examples of
"C.sub.1-6 alkylthio group" include, for example, methylthio,
ethylthio, propylthio, 1-methylethylthio, butylthio,
2-methylpropylthio, 1-methylpropylthio, 1,1-dimethylethylthio, and
the like.
[0057] The "C.sub.3-10 cycloalkyl" moiety in a "C.sub.3-10
cycloalkylthio group" is defined the same as the above-described
"C.sub.3-10 cycloalkyl group". Preferably, it is a "C.sub.3-7
cycloalkylthio group" and the like. Specific examples of
"C.sub.3-10 cycloalkylthio group" include, for example,
cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio,
cycloheptylthio, and the like.
[0058] The "C.sub.1-6 alkyl" moiety in a "C.sub.1-6 alkylsulfinyl
group" is defined the same as the above-described "C.sub.1-6 alkyl
group". The "C.sub.1-6 alkylsulfinyl group" includes, preferably,
"C.sub.1-4 alkylsulfinyl group" and the like. Specific examples of
"C.sub.1-6 alkylsulfinyl group" include, for example,
methylsulfinyl, ethylsulfinyl, propylsulfinyl,
1-methylethylsulfinyl, butylsulfinyl, 2-methylpropylsulfinyl,
1-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, and the
like.
[0059] The "C.sub.3-10 cycloalkyl" moiety in a "C.sub.3-10
cycloalkylsulfinyl group" is defined the same as the
above-described "C.sub.3-10 cycloalkyl group". Preferably, it is a
"C.sub.3-7 cycloalkylsulfinyl group" and the like. Specific
examples of "C.sub.3-10 cycloalkylsulfinyl group" include, for
example, cyclopropylsulfinyl, cyclobutylsulfinyl,
cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, and
the like.
[0060] The "C.sub.1-6 alkyl" moiety in a "C.sub.1-6 alkylsulfonyl
group" is defined the same as the above-described "C.sub.1-6 alkyl
group". Preferably, it includes a "C.sub.1-4 alkylsulfonyl group"
and the like. Specific examples of "C.sub.1-6 alkylsulfonyl group"
include, for example, methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl,
hexylsulfonyl, and the like.
[0061] The "C.sub.3-10 cycloalkyl" moiety in a "C.sub.3-10
cycloalkylsulfonyl group" is defined the same as the
above-described "C.sub.3-10 cycloalkyl group". Preferably, it is a
"C.sub.3-7 cycloalkylsulfonyl group" and the like. Specific
examples of "C.sub.3-10 cycloalkylsulfonyl group" include, for
example, cyclopropylsulfonyl, cyclobutylsulfonyl,
cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and
the like.
[0062] The "C.sub.1-6 alkoxy" moiety in a "C.sub.1-6 alkoxycarbonyl
group" is defined the same as the above-described "C.sub.1-6 alkoxy
group". Specific examples of "C.sub.1-6 alkoxycarbonyl group"
include, for example, methoxycarbonyl, ethoxycarbonyl, and the
like. In the relevant field, although an "alkoxycarbonyl group" may
be referred to as an "alkyloxycarbonyl group", the two are
synonymous.
[0063] The "C.sub.3-10 cycloalkyl" moiety in a "C.sub.3-10
cycloalkyloxycarbonyl group" is defined the same as the
above-described "C.sub.3-10 cycloalkyl group". Preferably, it is a
"C.sub.3-7 cycloalkyloxycarbonyl group" and the like. Specific
examples of "C.sub.3-10 cycloalkyloxycarbonyl group" include, for
example, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl,
cyclopentyloxycarbonyl, cyclohexyloxycarbonyl,
cycloheptyloxycarbonyl, and the like.
[0064] A "C.sub.6-10 aryl group" means an aromatic hydrocarbon of
which the carbon number is six to ten. Specific examples of
"C.sub.6-10 aryl group" include, for example, phenyl, 1-naphthyl,
2-naphthyl, and the like. Particularly preferably, it includes a
phenyl group. The "C.sub.6-10 aryl group" also encompasses a 8- to
14-membered polycyclic group in which an aromatic ring and a
C.sub.4-6 cycloalkyl are ring-fused, or 9- to 14-membered
polycyclic group in which an aromatic ring is fused to, for
example, 5- to 6-membered heterocyclic group having one to three
atoms that are identical or different and are selected from a
nitrogen atom, an oxygen atom, or a sulfur atom. Specific examples
thereof include, for example, groups represented by the
following:
##STR00020##
and the like.
[0065] Examples of "heterocyclic group" include 3- to 10-membered
heterocyclic group having one to three atoms that are identical or
different and are selected from a nitrogen atom, an oxygen atom, or
a sulfur atom, and the like. Preferably, it is a 4- to 7-membered
group, more preferably, a 5- or 6-membered group. All the
aforementioned nitrogen atom, oxygen atom, and sulfur atom are
atoms constituting a ring. The heterocyclic group may be any of
saturated, partially unsaturated, or unsaturated heterocyclic
groups, and a saturated heterocyclic group is more preferred.
Specific examples of "heterocyclic group" include epoxy, aziridine,
azetidine, pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl,
hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl,
oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl,
dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl,
tetrahydropyridinyl, oxetanyl, tetrahydropyranyl, and the like. It
is noted that the group encompasses heterocyclic groups having a
bridge structure. In the group, a bond on the "group" cannot be
from a nitrogen atom constituting a ring. That is, the group does
not encompass the concept of, for example, a 1-pyrrolidino group
and the like.
[0066] The aforementioned "heterocyclic group" may form a fused
ring with a 6-membered aromatic hydrocarbon or a 6-membered
heteroaryl. Examples thereof include a bicyclic "heterocycle"
having eleven or twelve ring-constituting atoms, wherein the
foregoing 5- or 6-membered "heterocyclic ring" is fused to a
6-membered aromatic hydrocarbon or a 6-membered heteroaryl.
Examples of the 6-membered aromatic hydrocarbon include benzene and
the like. Examples of a 6-membered unsaturated heterocyclic group
include pyridine, pyrimidine, pyridazine, and the like. Specific
examples of the fused ring include dihydroindolyl,
dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl,
dihydrobenzodioxanyl, isoindolyl, indazolyl, pyrrolidinyl,
tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroisoquinolinyl, tetrahydronaphthyridinyl,
tetrahydropyridoazepinyl, and the like.
[0067] Examples of a "saturated heterocyclic group" include a 5- to
10-membered monocyclic or polycyclic group and the like. The group
contains one or more (e.g., one to four) heteroatoms that are
identical or different and are selected from a nitrogen atom, a
sulfur atom, or an oxygen atom. Preferably, examples thereof
include a 5- or 6-membered monocyclic heteroaryl group, and the
like. Specific examples of a "heteroaryl group" include, for
example, pyrrolyl, thienyl, benzothienyl, benzofuranyl,
benzoxazolyl, benzothiazolyl, furyl, oxazolyl, triazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, benzisoxazolyl,
benzisothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl,
pyrimidyl, pyridazyl, quinolyl, isoquinolyl, triazolyl, triazinyl,
tetrazolyl, indolyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl,
[1,2,4]triazolo[1,5-a]pyridyl, benzimidazolyl, quinoxalyl,
cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl,
isoquinolinolyl, and the like.
[0068] The "heterocycle" moiety in a "heterocyclyloxy group" is
defined the same as the above-described "heterocyclic group". It is
preferably 4- to 7-membered, and more preferably 5- or 6-membered.
Specific examples thereof include a 4-pyranyloxy group and the
like.
[0069] The "heterocycle" moiety in a "heterocyclylthio group" is
defined the same as the above-described "heterocyclic group". It is
preferably 4- to 7-membered, and more preferably 5- or 6-membered.
Specific examples thereof include a 4-pyranylthio group and the
like.
[0070] The "heterocycle" moiety in a "heterocyclyloxycarbonyl
group" is defined the same as the above-described "heterocyclic
group". It is preferably 4- to 7-membered, and more preferably 5-
or 6-membered. Specific examples thereof include a
pyranyloxycarbonyl group and the like.
[0071] The "heterocycle" moiety in a "heterocyclylsulfinyl group"
is defined the same as the above-described "heterocyclic
group".
[0072] It is preferably 4- to 7-membered, and more preferably 5- or
6-membered. Specific examples thereof include a pyranylsulfinyl
group and the like.
[0073] The "heterocycle" moiety in a "heterocyclylsulfonyl group"
is defined the same as the above-described "heterocyclic group". It
is preferably 4- to 7-membered, and more preferably 5- or
6-membered. Specific examples thereof include a pyranylsulfonyl
group and the like.
[0074] The "C.sub.6-10 aryl" moiety in a "C.sub.6-10 aryloxy group"
is defined the same as the above-described "C.sub.6-10 aryl group".
It preferably includes a "C.sub.6 aryloxy group" (phenoxy group).
Specific groups thereof include, for example, phenoxy, 1-naphthoxy,
2-naphthoxy, and the like.
[0075] The "C.sub.6-10 aryl" moiety in a "C.sub.6-10 arylthio
group" is defined the same as the above-described "C.sub.6-10 aryl
group". It includes preferably a "C.sub.6 arylthio group". Specific
examples thereof include, for example, phenylthio, 1-naphthylthio,
2-naphthylthio, and the like.
[0076] A "C.sub.6-10 arylcarbonyl group" means a group having the
above-described "C.sub.6-10 aryl group" bound with a carbonyl
group. The "C.sub.6-10 aryl" moiety is defined the same as the
above-described "C.sub.6-10 aryl group". It preferably includes a
"C.sub.6 arylcarbonyl group" (a phenylcarbonyl group). Specific
examples of the "C.sub.6-10 arylcarbonyl group" include, for
example, benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.
[0077] The "C.sub.6-10 aryl" moiety in a "C.sub.6-10 arylsulfinyl
group" is defined the same as the above-described "C.sub.6-10 aryl
group". It preferably includes a "C.sub.6 arylsulfinyl group".
Specific examples thereof include, for example, phenylsulfinyl,
1-naphthylsulfinyl, 2-naphthylsulfinyl, and the like.
[0078] The "C.sub.6-10 aryl" moiety in a "C.sub.6-10 arylsulfonyl
group" is defined the same as the above-described "C.sub.6-10 aryl
group". It preferably includes a "C.sub.6 arylsulfonyl group".
Specific examples thereof include, for example, phenylsulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.
[0079] A "C.sub.6-10 aryloxycarbonyl group" means a group having
the above-described "C.sub.6-10 aryloxy group" bound to a carbonyl
group. It preferably includes a "C.sub.6 aryloxycarbonyl group" (a
phenyloxycarbonyl group). Specific examples of the "C.sub.6-10
aryloxycarbonyl group" include, for example, phenoxycarbonyl,
1-naphthoxycarbonyl, 2-naphthoxycarbonyl, and the like.
[0080] Examples of "an optionally substituted amino group" include
amino, mono- or di-substituted amino.
[0081] Examples of the "mono- or di-substituted amino" include
"C.sub.1-6 alkyl", "C.sub.3-10 cycloalkyl", "C.sub.3-10 cycloalkyl
C.sub.1-4 alkyl", "C.sub.3-7 cycloalkyl C.sub.1-4 alkoxycarbonyl",
"C.sub.1-4 alkylcarbonyl", "C.sub.1-4 alkoxycarbonyl", "a 4- to
7-membered saturated heterocycle", "4- to 7-membered saturated
heterocyclyl C.sub.1-4 alkyl", "4- to 7-membered saturated
heterocyclyl carbonyl", "4- to 7-membered saturated
heterocyclyloxycarbonyl", "4- to 7-membered saturated heterocyclyl
C.sub.1-4 alkylcarbonyl", "C.sub.6-10 aryl", "C.sub.7-14 aralkyl",
"C.sub.6-10 arylcarbonyl", "C.sub.6-10 aryloxycarbonyl", "5- or
6-membered monocyclic heteroaryl", "5- or 6-membered monocyclic
heteroaryl C.sub.1-4 alkyl", and the like.
[0082] Specific examples of the "mono-substituted amino" include,
for example, "mono-C.sub.1-6 alkylamino" (e.g., methylamino,
ethylamino, propylamino, 1-methylethylamino, butylamino,
2-methylpropylamino, 1-methylpropylamino, 1,1-dimethylethylamino,
and the like);
"C.sub.3-8 cycloalkylamino" (e.g., cyclopropylamino,
cyclobutylamino, cyclopentylamino, cyclohexylamino,
cycloheptylamino, and the like); "(C.sub.3-8 cycloalkylC.sub.1-4
alkyl)amino" (e.g., cyclopropylmethylamino, cyclobutylmethylamino,
cyclopentylmethylamino, cyclohexylmethylamino,
cycloheptylmethylamino, and the like); "(C.sub.3-8
cycloalkylC.sub.1-4 alkoxycarbonyl)amino" (e.g.,
cyclopropoxycarbonylamino, cyclobutoxycarbonylamino,
cyclopentoxycarbonylamino, cyclohexyloxycarbonylamino,
cycloheptyloxycarbonylamino, and the like); "(C.sub.1-4
alkylcarbonyl)amino" (e.g., methylcarbonylamino,
ethylcarbonylamino, propylcarbonylamino,
1-methylpropylcarbonylamino, 2-methylpropylcarbonylamino,
butylcarbonylamino, 2,2-dimethylethylcarbonylamino, and the like);
"(C.sub.1-4 alkoxycarbonyl)amino" (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino,
1-methylpropoxycarbonylamino, 2-methylpropoxycarbonylamino,
butoxycarbonylamino, 2,2-dimethylethoxycarbonylamino, and the
like); "C.sub.5-10 arylamino" (e.g., phenylamino, 1-naphthylamino,
2-naphthylamino, and the like); "C.sub.7-14 aralkylamino" (e.g.,
benzylamino, 1-naphthylmethylamino, 2-naphthylmethylamino, and the
like); "C.sub.6-10 arylcarbonylamino" (e.g., phenylcarbonylamino,
1-naphthylcarbonylamino, 2-naphthylcarbonylamino, and the like);
"C.sub.6-10 aryloxycarbonylamino" (e.g., phenoxycarbonylamino,
1-naphthoxycarbonylamino, 2-naphthoxycarbonylamino, and the like);
"3- to 8-membered saturated heterocyclyl-amino" (e.g.,
tetrahydropyranylamino, tetrahydropyridinylamino,
pyrrolidinylamino, oxopyrrolidinylamino, tetrahydrofuranylamino,
piperidinylamino, and the like); "(3- to 8-membered saturated
heterocyclyl C.sub.1-4 alkyl)amino" (e.g.,
tetrahydropyranylmethylamino, tetrahydropyridinylmethylamino,
pyrrolidinylmethylamino, oxopyrrolidinylmethylamino,
tetrahydrofuranylmethylamino, piperidinylmethylamino,
piperazinylmethylamino, morpholinylmethylamino, and the like); "3-
to 8-membered saturated heterocyclyl carbonylamino" (e.g.,
tetrahydropyranylcarbonylamino, tetrahydropyridinylcarbonylamino,
pyrrolidinylcarbonylamino, oxopyrrolidinylcarbonylamino,
tetrahydrofuranylcarbonylamino, piperidinylcarbonylamino, and the
like); "3- to 8-membered saturated heterocyclyloxycarbonylamino"
(e.g., tetrahydropyranyloxycarbonylamino,
tetrahydropyridinyloxycarbonylamino, pyrrolidinyloxycarbonylamino,
oxopyrrolidinyloxycarbonylamino, tetrahydrofuranyloxycarbonylamino,
piperidinyloxycarbonylamino, and the like); "(5- or 6-membered
monocyclic heteroaryl)amino" (e.g., pyrrolylamino, thienylamino,
furylamino, oxazolylamino, triazolylamino, isoxazolylamino,
isothiazolylamino, imidazolylamino, pyrazolylamino, triazolylamino,
oxadiazolylamino, thiadiazolylamino, tetrazolylamino, pyridylamino,
pyrazylamino, pyrimidylamino, pyridazylamino, triazinylamino, and
the like); "(5- or 6-membered monocyclic heteroaryl C.sub.1-4
alkyl)amino" (e.g., pyrrolylmethylamino, thienylmethylamino,
furylmethylamino, oxazolylmethylamino, thiazolylmethylamino,
isoxazolylmethylamino, isothiazolylmethylamino,
imidazolylmethylamino, pyrazolylmethylamino, triazolylmethylamino,
oxadiazolylmethylamino, thiadiazolylmethylamino,
tetrazolylmethylamino, pyridylmethylamino, pyrazylmethylamino,
pyrimidylmethylamino, pyridazylmethylamino, triazinylmethylamino,
and the like); and the like.
[0083] Specific examples of the "di-substituted amino" include, for
example,
"di-C.sub.1-6 alkylamino" (e.g., dimethylamino, diethylamino,
dipropylamino, di-1-methylethylamino, dibutylamino,
di-2-methylpropylamino, di-1-methylpropylamino,
di-1,1-dimethylethylamino, and the like); "N--(C.sub.1-6
alkyl)-N--(C.sub.3-10 cycloalkyl)amino" (e.g.,
methylcyclopropylamino, methylcyclobutylamino,
methylcyclopentylamino, methylcyclohexylamino,
methylcycloheptylamino, and the like); "N--(C.sub.1-6 alkyl)-N-(4-
to 7-membered saturated heterocyclyl)amino" (e.g.,
methyltetrahydropyranylamino, methyltetrahydropyridinylamino,
methylpyrrolidinylamino, methyloxopyrrolidinylamino,
methyltetrahydrofuranylamino, methylpiperidinylamino, and the
like); and the like.
[0084] Examples of the "3- to 8-membered cyclic amino" include 3-
to 8-membered monocyclic cyclic amino having one to three
heteroatoms that are identical or different and are selected from a
nitrogen atom, an oxygen atom, or a sulfur atom. It is preferably a
5- to 6-membered monocyclic cyclic amino group. In the "3- to
8-membered cyclic amino", a bond on the "group" will be from a
nitrogen atom constituting a ring. Specific examples of the "3- to
8-membered cyclic amino" include, for example, azetidino,
pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperazino,
piperidino, morpholino, thiomorpholino, azepano, oxoazepano, and
the like. It is noted that the group encompasses cyclic amino of
which the ring contains a partially unsaturated bond.
[0085] The "3- to 8-membered cyclic amino" or "5- or 6-membered
cyclic amino" may form a fused ring with C.sub.3-6 cycloalkyl,
6-membered aromatic hydrocarbon, or a 5- or 6-membered heterocycle.
Specific examples of cyclic amino forming such a fused ring include
"groups" represented by the following:
##STR00021## ##STR00022##
and the like.
[0086] An "aminocarbonyl group" means a group having the
above-described "amino group" bound to a carbonyl group. In this
regard, the "amino" means an unsubstituted amino group, a
mono-substituted amino group, a di-substituted amino group, or 3-
to 8-membered cyclic amino.
[0087] An "aminosulfinyl group" means a group having the
above-described "amino group" bound to a sulfinyl group. In this
regard, the "amino" means an unsubstituted amino group, a
mono-substituted amino group, a di-substituted amino group, or 3-
to 8-membered cyclic amino.
[0088] An "aminosulfonyl group" means a group having the
above-described "amino group" bound to a carbonyl group. In this
regard, the "amino" is an unsubstituted amino group, a
mono-substituted amino group, a di-substituted amino group, or 3-
to 8-membered cyclic amino.
[0089] The "aminocarbonyl" moiety in an "aminocarbonyloxy group" is
defined the same as the above-described "aminocarbonyl group".
[0090] A "C.sub.1-6 alkylaminocarbonyl group" means a group that is
the above-described "mono- or di-substituted amino" in which the
amino group substituted with one or two C.sub.1-6 alkyl is bound to
a carbonyl group.
[0091] The "C.sub.1-6 alkylaminocarbonyl" moiety of a "C.sub.1-6
alkylaminocarbonylamino group" is defined the same as the
above-described "C.sub.1-6 alkylaminocarbonyl group".
[0092] Examples of a substituent of "an optionally substituted
C.sub.1-6 alkyl group" include:
(a) a halogen atom; (b) a cyano group; (c) a hydroxy group; (d) a
formyl group; (e) a C.sub.1-6 alkylcarbonyl group; (f) a C.sub.1-6
alkylcarbonyloxy group; (g) a carboxy group; (h) amino (wherein the
amino is optionally substituted with one or two groups that are
identical or different and are selected from the group consisting
of (h1) C.sub.1-6 alkyl (wherein the alkyl is optionally
substituted with (h11) hydroxy, (h12) cyano, (h13) a halogen atom,
(h14) amino (wherein the amino is optionally substituted with one
or two C.sub.1-6 alkyl groups or C.sub.1-6 alkylcarbonyl groups
that are identical or different), (h15) C.sub.1-6 alkoxy, (h16) 5-
or 6-membered monocyclic heteroaryl, (h17) a 4- to 7-membered
saturated heterocycle, or (h18) a C.sub.3-10 cycloalkylcarbonyl)
(h2) C.sub.3-10 cycloalkyl (wherein the ring is optionally
substituted with C.sub.1-6 alkyl), (h3) C.sub.3-10 cycloalkyl
C.sub.1-4 alkyl, (h4) a 4- to 7-membered saturated heterocycle
(wherein the ring is optionally substituted with a halogen atom or
C.sub.1-6 alkyl), (h5) a 4- to 7-membered saturated
heterocyclyl-C.sub.1-4 alkyl, (h6) C.sub.6-10 aryl (wherein the
ring is optionally substituted with a halogen atom or C.sub.1-6
alkyl), (h7) C.sub.7-14 aralkyl (wherein the ring is optionally
substituted with a halogen atom, C.sub.1-6 alkyl, or C.sub.1-6
alkoxy), (h8) a 5- or 6-membered monocyclic heteroaryl (wherein the
ring is optionally substituted with a halogen atom or C.sub.1-6
alkyl), and (h9) 5- or 6-membered monocyclic heteroaryl C.sub.1-4
alkyl); (i) C.sub.1-6 alkoxy (wherein the group is optionally
substituted with (i1) hydroxy, (i2) C.sub.1-6 alkoxy (wherein the
group is optionally substituted with one to three fluorine atoms),
(i3) C.sub.3-10 cycloalkyl, (i4) 4- to 7-membered cyclic amino
(wherein the group is optionally substituted with (i41) hydroxy,
(i42) cyano, (i43) one to four fluorine atoms, (i44) C.sub.1-6
alkyl (wherein the alkyl is optionally substituted with one to
three fluorine atoms or C.sub.1-6 alkoxy) (i45) C.sub.1-6 alkoxy
(wherein the alkoxy is optionally substituted with one to three
C.sub.6-10 aryl), (i46) formyl, (i47) C.sub.1-6 alkylcarbonyl,
(i48) C.sub.1-6 alkylsulfonyl, or (i49) oxo), (i5) a 4- to
7-membered saturated heterocycle (wherein the heterocycle is
optionally substituted with a group selected from the
above-described (i41)-(i49)), (i6) 5- or 6-membered monocyclic
heteroaryl (wherein the ring is optionally substituted with a
halogen atom or C.sub.1-6 alkyl), (i7) C.sub.6-10 aryl (wherein the
group is optionally substituted with a halogen atom, C.sub.1-4
alkyl, or C.sub.1-4 alkoxy), (i8) C.sub.1-6 alkylcarbonylamino,
(i9) amino (wherein the amino is optionally substituted with one or
two groups that are identical or different and are selected from
the group consisting of C.sub.1-6 alkyl (wherein the group is
optionally substituted with hydroxy), C.sub.3-10 cycloalkyl, and
C.sub.3-10 cycloalkyl C.sub.1-4 alkyl), (i10) mono- or di-C.sub.1-6
alkylaminocarbonyl, (i11) a halogen atom, or (i12) C.sub.7-14
aralkyloxy); (j) a C.sub.3-10 cycloalkyloxy group (wherein the ring
is optionally substituted with C.sub.1-6 alkyl); (k) an oxo group;
(l) 5- or 6-membered monocyclic heteroaryl group (wherein the group
is optionally substituted with a halogen atom or C.sub.1-6 alkyl);
(m) a 4- to 7-membered saturated heterocycle (wherein the
heterocycle is optionally substituted with a group selected from
the above-described (i41)-(i49)); (n) an optionally substituted
aminocarbonyl group; (o) an optionally substituted aminosulfonyl
group; (p) an optionally substituted aminocarbonyloxy group; (q) a
C.sub.7-14 aralkyloxy group; (r) a 5- or 6-membered monocyclic
heteroaryloxy group (wherein the ring is optionally substituted
with a halogen atom or C.sub.1-6 alkyl); (s) a 4- to 7-membered
saturated heterocyclyloxy group (wherein the ring is optionally
substituted with C.sub.1-6 alkyl optionally substituted with one to
three halogen atoms); (t) a C.sub.1-6 alkylsulfonyl group; (u) a
C.sub.1-6 alkoxycarbonyl group; (v) a C.sub.1-6 alkylsulfonyloxy
group; (w) a C.sub.1-6 alkoxycarbonylamino group; (x) a C.sub.1-6
alkylcarbonylamino group (wherein the group is optionally
substituted with (x1) hydroxy, (x2) a halogen atom, (x3) C.sub.1-6
alkoxy, or (x4) C.sub.1-6 alkylcarbonyloxy); (y) a 5- or 6-membered
monocyclic heteroarylcarbonylamino group (wherein the group is
optionally substituted with C.sub.1-6 alkyl); (z) a 4- to
7-membered saturated heterocyclylcarbonylamino group (wherein the
group is optionally substituted with C.sub.1-6 alkyl optionally
substituted with one to three fluorine atoms); (aa) a mono- or
di-C.sub.1-6 alkylaminocarbonylamino group; (ab) a 4- to 7-membered
cyclic amino group (wherein the ring is optionally substituted with
a group selected from the above-described (i41)-(i49)); and the
like.
[0093] Examples of a substituent of "an optionally substituted
C.sub.1-6 alkenyl group", "an optionally substituted C.sub.1-6
alkynyl group", "an optionally substituted C.sub.1-6 alkoxy group",
"an optionally substituted C.sub.1-6 alkylcarbonyl group", "an
optionally substituted C.sub.1-6 alkylcarbonyloxy group", "an
optionally substituted C.sub.1-6 alkylcarbonylamino group", "an
optionally substituted C.sub.1-6 alkylthio group", "an optionally
substituted C.sub.1-6 alkylsulfinyl group", "an optionally
substituted C.sub.1-6 alkylsulfonyl group", "an optionally
substituted C.sub.1-6 alkoxycarbonyl group", "an optionally
substituted C.sub.1-6 alkylamino group", "an optionally substituted
C.sub.1-6 alkylaminocarbonyl group", "an optionally substituted
C.sub.1-6 alkylaminocarbonylamino group", and "an optionally
substituted C.sub.1-6 alkylaminocarbonylamino group" include: one
group selected from the group consisting of the above-described (a)
to (ab), which are examples of a substituent of the "optionally
substituted C.sub.1-6 alkyl group"; and the like.
[0094] Examples of a substituent of "an optionally substituted
C.sub.3-10 cycloalkyl group", "an optionally substituted C.sub.3-10
cycloalkyloxy group", "an optionally substituted C.sub.3-10
cycloalkylthio group", "an optionally substituted C.sub.3-10
cycloalkylsulfinyl group", "an optionally substituted C.sub.3-10
cycloalkylsulfonyl group", "an optionally substituted C.sub.3-10
cycloalkyloxycarbonyl group", "an optionally substituted 3- to
8-membered heterocyclic group", "an optionally substituted 3- to
8-membered heterocyclyloxy group", "an optionally substituted 3- to
8-membered heterocyclyloxycarbonyl group", "an optionally
substituted 3- to 8-membered heterocyclylsulfinyl group", "an
optionally substituted 3- to 8-membered heterocyclylsulfonyl
group", "3- to 8-membered cyclic amino group", "3- to 8-membered
cyclic aminocarbonyl group", "3- to 8-membered cyclic aminosulfinyl
group", and "3- to 8-membered cyclic aminosulfonyl group" include:
one group selected from the group consisting of the above-described
(a) to (ab), which are examples of a substituent of the "optionally
substituted C.sub.1-6 alkyl group", and C.sub.1-4 alkyl; and the
like. It is noted that a ring of the substituent (e.g., cycloalkyl,
cyclic amino, and the like) is optionally substituted with oxo or
thioxo.
[0095] Examples of a substituent of "an optionally substituted
C.sub.6-10 aryl group", "an optionally substituted C.sub.6-10
aryloxy group", "an optionally substituted C.sub.6-10 arylcarbonyl
group", "an optionally substituted C.sub.6-10 aryloxycarbonyl
group", "an optionally substituted C.sub.6-10 arylthio group", "an
optionally substituted C.sub.6-10 arylsulfinyl group", "an
optionally substituted C.sub.6-10 arylsulfonyl group", "an
optionally substituted 5- or 6-membered monocyclic heteroaryl
group", "an optionally substituted 5- or 6-membered monocyclic
heteroaryloxy group", "an optionally substituted 5- or 6-membered
monocyclic heteroarylcarbonyl group", "an optionally substituted 5-
or 6-membered monocyclic heteroaryloxycarbonyl group", "an
optionally substituted 5- or 6-membered monocyclic heteroarylthio
group", "an optionally substituted 5- or 6-membered monocyclic
heteroarylsulfinyl group", and "an optionally substituted 5- or
6-membered monocyclic heteroarylsulfonyl group" include:
(a2) a halogen atom; (b2) a cyano group; (c2) an optionally
substituted C.sub.1-6 alkyl group; (d2) C.sub.1-6 alkylsulfonyl
group (wherein the group is optionally substituted with (d21) a
halogen atom, (d22) hydroxy, (d23) C.sub.1-6 alkoxy, (d24)
C.sub.3-10 cycloalkyl, (d25) C.sub.3-10 cycloalkyloxy, (d26)
di-C.sub.1-6 alkylamino, (d27) 4- to 7-membered cyclic amino, or
(d28) 4- to 7-membered saturated heterocycle); (e2) an amino group
(wherein the amino is optionally substituted with one or two groups
that are identical or different and are selected from the group
consisting of the above-described (h1) to (h9)); (f2) an
aminosulfonyl group (wherein the amino is optionally substituted
with one or two C.sub.1-6 alkyl groups that are identical or
different (wherein the alkyl is optionally substituted with a
halogen atom, hydroxy, C.sub.1-4 alkoxy, or di-C.sub.1-6
alkylamino)); (g2) a 4- to 7-membered cyclic amino group (wherein
the ring is optionally substituted with the above-described (i1) to
(i12)); (h2) an aminocarbonyl group (wherein the amino group is
optionally substituted with one or two groups that are identical or
different and are selected from the group consisting of the (h1) to
(h9)); (i2) a 4- to 7-membered saturated heterocycle (wherein the
ring is optionally substituted with a group selected from the group
consisting of the above-described (i1) to (i12)); (j2) a carboxy
group; (k2) a C.sub.1-6 alkoxy group (wherein the group is
optionally substituted with a group selected from the group
consisting of the above-described (i1) to (i12)); (l2) C.sub.3-10
cycloalkyloxy group; (m2) a 4- to 7-membered saturated
heterocyclyloxy group (wherein the ring is optionally substituted
with a group selected from the group consisting of the
above-described (i1) to (i12)); (n2) a C.sub.7-14 aralkyloxy group;
(o2) a C.sub.1-6 alkoxycarbonyl group (wherein the group is
optionally substituted with a group selected from the group
consisting of the above-described (i1) to (i12)); (p2) a C.sub.1-6
alkylcarbonylamino group (wherein the amino is optionally
substituted with C.sub.1-6 alkyl, and the alkyl is optionally
substituted with a group selected from the group consisting of the
above-described (d21) to (d28); (q2) a C.sub.3-10
cycloalkylcarbonylamino group (wherein the amino is optionally
substituted with C.sub.1-6 alkyl); (r2) a 5- or 6-membered
monocyclic heteroarylcarbonylamino group (wherein the amino is
optionally substituted with C.sub.1-6 alkyl); (s2) a 4- to
7-membered saturated heterocyclylcarbonylamino group (wherein the
amino is optionally substituted with C.sub.1-6 alkyl, and the ring
is optionally substituted with a group selected from the group
consisting of the above-described (i1) to (i12)); (t2) a mono- or
di-C.sub.1-6 alkylaminocarbonylamino group (wherein the amino is
optionally substituted with C.sub.1-6 alkyl); (u2) C.sub.1-6
alkoxycarbonylamino group (wherein the amino is optionally
substituted with C.sub.1-6 alkyl, and the alkoxy is optionally
substituted with a group selected from the group consisting of the
above-described (i1) to (i12)); (v2) a C.sub.6-10 aryl group; (w2)
a 5- or 6-membered monocyclic heteroaryl group; and the like.
[0096] Preferred embodiments of the present invention are further
described.
[0097] In the present specification, formula (1) is an isomer
having a relationship with the following formula (1') between an
oxidant and a reductant that can attain equilibrium. They can be
considered as being synonymous.
##STR00023##
[0098] It is preferable that "A" is an oxygen atom or a sulfur
atom.
[0099] It is preferable that "ring G" is the following formulas (a)
to (h):
##STR00024##
[0100] It is more preferable that "ring G" is the following
formulas (a) to (f):
##STR00025##
[0101] It is further preferable that "ring G" is the following
formulas (a) to (d):
##STR00026##
[0102] It is further preferable that "ring G" is the following
formula (e) or (f):
##STR00027##
[0103] It is preferable that "R.sup.1" is a hydrogen atom or a
C.sub.1-6 alkylcarbonyl group (wherein the alkyl is optionally
substituted with 3- to 8-membered cyclic amino).
[0104] It is preferable that "R.sup.2" is a hydrogen atom.
[0105] It is preferable that all of "R.sup.3", "R.sup.4", and
"R.sup.5" are hydrogen atoms.
[0106] It is preferable that "R.sup.6" is a hydrogen atom.
[0107] Preferred embodiments of the present invention encompass
compounds represented by the following formulas (1a) to (1p).
[0108] (1) A compound represented by the following formula (1a) or
a pharmacologically acceptable salt thereof:
##STR00028##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1a) are the same as the preferred
embodiments in the compound represented by formula (1).
[0109] (2) A compound represented by the following formula (1b) or
a pharmacologically acceptable salt thereof:
##STR00029##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1b) are the same as the preferred
embodiments in the compound represented by formula (1).
[0110] (3) A compound represented by the following formula (1c) or
a pharmacologically acceptable salt thereof:
##STR00030##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1c) are the same as the preferred
embodiments in the compound represented by formula (1).
[0111] (4) A compound represented by the following formula (1d) or
a pharmacologically acceptable salt thereof:
##STR00031##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1d) are the same as the preferred
embodiments in the compound represented by formula (1).
[0112] (5) A compound represented by the following formula (1e) or
a pharmacologically acceptable salt thereof:
##STR00032##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1e) are the same as the preferred
embodiments in the compound represented by formula (1)
[0113] (6) A compound represented by the following formula (1f) or
a pharmacologically acceptable salt thereof:
##STR00033##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1f) are the same as the preferred
embodiments in the compound represented by formula (1)
[0114] (7) A compound represented by the following formula (1 g) or
a pharmacologically acceptable salt thereof:
##STR00034##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1 g) are the same as the
preferred embodiments in the compound represented by formula
(1).
[0115] (8) A compound represented by the following formula (1h) or
a pharmacologically acceptable salt thereof:
##STR00035##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1h) are the same as the preferred
embodiments in the compound represented by formula (1).
[0116] (9) A compound represented by the following formula (1i) or
a pharmacologically acceptable salt thereof:
##STR00036##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1i) are the same as the preferred
embodiments in the compound represented by formula (1).
[0117] (10) A compound represented by the following formula (1j) or
a pharmacologically acceptable salt thereof:
##STR00037##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1j) are the same as the preferred
embodiments in the compound represented by formula (1)
[0118] (11) A compound represented by the following formula (1k) or
a pharmacologically acceptable salt thereof:
##STR00038##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1k) are the same as the preferred
embodiments in the compound represented by formula (1).
[0119] (12) A compound represented by the following formula (1l) or
a pharmacologically acceptable salt thereof:
##STR00039##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1l) are the same as the preferred
embodiments in the compound represented by formula (1)
[0120] (13) A compound represented by the following formula (1m) or
a pharmacologically acceptable salt thereof:
##STR00040##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1m) are the same as the preferred
embodiments in the compound represented by formula (1).
[0121] (14) A compound represented by the following formula (1n) or
a pharmacologically acceptable salt thereof:
##STR00041##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1n) are the same as the preferred
embodiments in the compound represented by formula (1)
[0122] (15) A compound represented by the following formula (1o) or
a pharmacologically acceptable salt thereof:
##STR00042##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1o) are the same as the preferred
embodiments in the compound represented by formula (1).
[0123] (16) A compound represented by the following formula (1p) or
a pharmacologically acceptable salt thereof:
##STR00043##
[each symbol in the formula is defined the same as item 1].
Preferred embodiments of respective symbols in the compound
represented by the above formula (1p) are the same as the preferred
embodiments in the compound represented by formula (1).
[0124] A "pharmacologically acceptable salt" includes acid addition
salts and base addition salts. Examples of acid addition salts
include: inorganic acid salts such as hydrochlorides,
hydrobromides, sulfates, hydroiodides, nitrates, phosphates, and
the like; and organic acid salts such as citrate, oxalate,
phthalate, fumarate, maleate, succinate, malate, acetate, formate,
propionate, benzoate, trifluoroacetate, methanesulfonate,
benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the
like; and examples of base addition salts include inorganic base
salts such as sodium, potassium, calcium, magnesium, barium, and
aluminum salts, and the like, organic base salts such as
trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,
ethanolamine, diethanolamine, triethanolamine, tromethamine
[tris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine,
dicyclohexylamine, and N,N-dibenzylethylamine, and the like, and
further salts of an amino acid such as basic and acidic amino acids
including arginine, lysine, ornithine, aspartic acid, glutamic
acid, and the like.
[0125] Suitable salts and pharmaceutically acceptable salts of
starting compounds and target compounds are conventional nontoxic
salts. They include acid addition salts such as organic acid salts
(e.g., acetate, trifluoroacetate, maleate, fumarate, citrate,
tartrate, methanesulfonate, benzenesulfonate, formate,
p-toluenesulfonate, or the like) and inorganic acid salts (e.g.,
hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,
phosphate, or the like), salts with an amino acid (e.g., arginine,
aspartic acid, glutamic acid, or the like), metal salts such as
alkali metal salts (e.g., sodium salt, potassium salt, or the
like), alkali earth metal salts (e.g., calcium salt, magnesium
salt, or the like), and the like, ammonium salts, organic base
salts (e.g., trimethylamine salts, triethylamine salts, pyridine
salts, picoline salts, dicyclohexylamine salts,
N,N'-dibenzylethylene diamine salts, or the like), or the like, and
additionally those skilled in the art can appropriately select
them.
[0126] When it is desired to obtain a salt of the present compound,
if the present compound is obtained in a salt form, it may be
purified as it is, or if it is obtained in free form, it may be
dissolved or suspended in a suitable organic solvent, and an acid
or a base is added thereto to form a salt in accordance with a
general method.
[0127] In addition, although the present compounds and
pharmacologically acceptable salts thereof may exist in an adduct
form with water or any kind of solvent, these adducts are also
encompassed by the present invention.
[0128] In addition, the present invention encompasses compounds
represented by formula (1) or prodrugs thereof, or
pharmacologically acceptable salts thereof. It also encompasses
hydrates or solvates (such as ethanol solvates and the like)
thereof. Further, the present invention encompasses all tautomers
and all present stereoisomers of the present compound (1) as well
as those in all modes of crystal forms.
[0129] The term "a prodrug of a compound of formula (1)" in the
present specification means a compound that is converted to a
compound of formula (1) by reaction with an enzyme, gastric acid,
or the like under physiological condition in vivo, for example, a
compound that is converted to a compound of formula (1) by
enzymatic oxidation, reduction, hydrolysis, or the like.
[0130] Among the present compounds (1), there are compounds that
may exist as enantiomers based on an optically-active center,
atropisomers based on axial or planar chirality caused by
restriction of intramolecular rotation, other stereoisomers,
tautomers, geometric isomer, and the like. However, all possible
isomers and mixtures thereof, including these, are encompassed
within the scope of the present invention.
[0131] In particular, an enantiomer and an atropisomer can be
obtained as a racemic body, or an optically-active substance when
an optically-active starting material or intermediate is used,
respectively. If necessary, in an appropriate step of the
above-described production method, a corresponding starting
material, intermediate, or racemic body as a final product can be
physically or chemically resolved into their optical enantiomers by
a known separation method, such as a method using an optically
active column, a fractional crystallization method, or the like.
Specifically, for example, in a diastereomer method, two types of
diastereomers are formed from a racemic body by reaction using an
optical active resolving agent. Since these different diastereomers
generally have different physical properties, they can be separated
by a known method such as fractional crystallization and the
like.
[0132] Hereinafter, production methods of compounds represented by
formula (1) in the present invention are described. Compounds
represented by formula (1) or pharmacologically acceptable salts
thereof (hereinafter sometimes referred to as "the present
compound(s)") are described with examples. However, the scope of
present invention is certainly not limited to these examples.
[0133] A compound of the present invention represented by formula
(1) or a salt thereof can be produced from a known compound, for
example, the following production methods: Methods 1 to 14, and
methods in accordance therewith, or by appropriately combining
synthesis methods well-known to those skilled in the art.
[0134] It is noted that a compound in a reaction includes the case
where it forms a salt, for example, salts similar to salts in
compound (1) and the like are used as such a salt.
[0135] In addition, a compound obtained in each step can be used in
a next reaction as a reaction solution or as a composition.
However, it can be isolated from a reaction mixture in accordance
with a routine method, and readily purified by a separation means
such as recrystallization, distillation, chromatography, and the
like.
[0136] Each symbol of compounds in the following reactions is
defined the same as above, unless specifically indicated.
[0137] Production Method 1:
##STR00044##
(In the formulas, A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7, R.sup.8, and G are defined the same as the above-described
item 21.)
[0138] To this step 1, a method described in literature [for
example, European Journal of Organic Chemistry, 3876, vol. 20,
(2010), Tetrahedron, 4213, vol. 57, (2001), Journal of Medicinal
Chemistry, 7273, vol. 55, (2012, ACS Applied Materials &
Interfaces, 3994, vol. 4, (2012), and the like] is applied, and
Compound (1-2) can be produced from Compound (1-1).
[0139] It is noted that in the present invention, this method is
applied to compound (1-1) where ring G is a saturated heterocycle,
and however, until now, there has been no report that this method
has been applied to the production of the heterocyclic compound
(1-2).
[0140] Compound (1-2) can be produced by reacting it, in solvent in
the presence of an oxidant, with (1-1) obtained by a known
synthesis method or the following production method. Organic
solvent includes aprotic solvent (N,N-dimethylformamide,
N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile,
propionitrile, and the like), ether type solvent (tetrahydrofuran,
1,4-dioxane, and the like), halogenated hydrocarbons
(dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene,
and the like), hydrocarbons (toluene, benzene, and the like),
water, mixed solvents thereof, and the like, and suitably a mixed
solvent of acetonitrile and water. The following can be used as
oxidants: metal type oxidants [osmium tetraoxide, potassium
permanganate, silver(II) picolinate, ammonium
hexanitratocerate(IV), benzeneseleninic acid, bis(4-methoxyphenyl)
selenoxide, bis(tetrabutylammonium) dichromate, lead tetraacetate,
phosphomolybdic acid hydrate, pyridinium chlorochromate, pyridinium
dichromate, pyridinium fluorochromate, quinolinium dichromate,
silver(II) pyridine-2-carboxylate, tetrapropylammonium
perruthenate, and the like], hypervalent iodine oxidants
[(2-iodoxybenzoic acid, Dess-Martin periodinane,
1-(tert-butylperoxy)-1,2-benziodoxol-3-(1H)-one,
bis(pyridine)iodonium tetrafluoroborate, iodosobenzene,
iodomesitylene diacetate, {hydroxy(tosyloxy)iodo}benzene,
poly{4-(diacetoxyiodo)styrene}, (diacetoxyiodo)benzene,
bis(trifluoroacetoxy)iodobenzene,
{bis(trifluoroacetoxy)iodo}pentafluorobenzene, and the like],
N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and the
like, and suitably, ammonium hexanitratocerate(IV),
(diacetoxyiodo)benzene, N-bromosuccinimide, and the like. The
amount of an oxidant used is, generally, 2 to 10 mol, preferably,
to 3 mol per mol of compound (1-1). A reaction time is, generally,
about 0.5 to about 48 hours, preferably, about 0.5 to about 12
hours. A reaction temperature is, generally, about -20 to about
180.degree. C., preferably, about 0 to about 100.degree. C.
[0141] Production Method 2:
##STR00045##
(In the formulas, A, R.sup.7, and R.sup.8 are defined the same as
above. R.sup.9 is C.sub.1-6 alkyl.)
[0142] This step 1 can produce compound (2-3) from compound (2-1)
in accordance with a similar method to methods and the like
described in literature [for example, Heterocycles, 1913, vol. 75,
(2008), Journal of Medicinal Chemistry, 1819, vol. 53, (2010),
Journal of the Chilean Chemical Society, 14, vol. 54, (2009),
Molecules, 1388, vol. 17, (2012), Bioorganic & Medicinal
Chemistry Letters, 4961, vol. 15, (2005), Synlett, 670, vol. 5,
(2001), and the like].
[0143] A solvent used in this step 1 may be any solvent as long as
it is inactive in the reaction, and although it is not particularly
limited, for example, THF, 1,4-dioxane, DME, benzene, toluene,
xylene, DMF, DMA, NMP, and the like can be used alone or after
mixing them. Among others, THF or DMF is preferred.
[0144] As a base, for example, basic salts such as sodium
carbonate, potassium carbonate, cesium carbonate, sodium acetate,
sodium hydride, calcium hydride, and the like, aromatic amines such
as pyridine, lutidine, and the like, tertiary amines such as
triethylamine, tripropylamine, tributylamine,
cyclohexyldimethylamine, 4-dimethylaminopyridine,
N,N-diisopropylethylamine, N,N-dimethylaniline, N-methylpiperidine,
N-methylpyrrolidine, N-methylmorpholine, and the like can be used.
Among others, potassium carbonate or sodium hydride is
preferred.
[0145] A reaction is performed from at a temperature between room
temperature and the boiling point of a solvent used, preferably, 0
to 80.degree. C., generally, for 0.5 to 24 hours.
[0146] Production Method 3
##STR00046##
(In the formulas, A, R.sup.7, R.sup.8, and R.sup.9 are defined the
same as above.)
[0147] This step 1 can produce compound (3-3) from compound (3-1)
in accordance with a similar method to methods and the like
described in literature [for example, Tetrahedron, 12227, vol. 55,
(1999), Journal of Organic Chemistry, 4692, vol. 76, (2011),
Journal of Heterocyclic Chemistry, 683, vol. 49, (2012), and the
like].
[0148] Production Method 4:
##STR00047##
(In the formulas, R.sup.1, R.sup.2, R.sup.7, R.sup.8, and A are
defined the same as above.)
[0149] This step 1 can produce compound (4-2) and compound (4-3)
from compound (4-1) in accordance with a similar method to methods
and the like described in literature [for example, Organic Letters,
2157, vol. 7, (2005), Journal of Medicinal Chemistry, 7574, vol.
56, (2013), Bioorganic & Medicinal Chemistry Letters, 138, vol.
22, (2012), Khimiya Geterotsiklicheskikh Soedinenii, 27, vol. 1,
(1980), and the like].
[0150] Production Method 5:
##STR00048##
(In the formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, and A are defined the same as above.)
[0151] These steps (1 to 3) can produce compound (5-4) from
compound (4-2) in accordance with similar methods to methods and
the like described in literature [for example, Bioorganic &
Medicinal Chemistry Letters, 806, vol. 22, 2012 Journal of
Medicinal Chemistry, 7574, vol. 56, (2013), Khimiya
Geterotsiklicheskikh Soedinenii, 27, vol. 1, (1980), Synlett, 1781,
vol. 11, (2009), Tetrahedron Letters, 5452, vol. 52, (2011),
Bulletin of the Chemical Society of Japan, 891, vol. 70, (1997),
Synlett, 116, vol. 1, (2011), Tetrahedron, 4612, vol. 69, (2013),
Tetrahedron Letters, 5145, vol. 52, (2011), Chemistry Letters,
1422, vol. 36, (2007), European Journal of Organic Chemistry, 4039,
vol. 19, (2004), Tetrahedron, 2755, vol. 64, (2008), and the
like].
[0152] Production Method 6:
##STR00049##
(In the formulas, R.sup.1, R.sup.2, R.sup.7, R.sup.8, and A are
defined the same as above.)
[0153] This step can produce compound (6-1) and compound (6-2) from
compound (4-1) in accordance with a similar method to methods and
the like described in literature [for example, Physiological
Zoology, 312, vol. 36, (1963), European Journal of Medicinal
Chemistry, 4827, vol. 46, (2011), Synthetic Metals, 2491, vol. 159,
(2009), Journal of the American Chemical Society, 4466, vol. 132,
(2010), Bulletin of the Chemical Society of Japan, 4464, vol. 61,
(1988), and the like].
[0154] Production Method 7:
##STR00050##
(In the formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, R.sup.9, and A are defined the same as above. R.sup.10 is
C.sub.1-6 alkyl.)
[0155] These steps (1 to 3) can produce compound (7-4) from
compound (6-1) in accordance with similar methods to methods and
the like described in literature [for example, Journal of Organic
Chemistry, 5026, vol. 78, (2013), Tetrahedron, 5787, vol. 62,
(2006), Tetrahedron Letters, 8527, vol. 38, (1997), Indian Journal
of Chemistry, Section B: Organic Chemistry Including Medicinal
Chemistry, 72, vol. 25B, (1986), and the like].
[0156] Production Method 8
##STR00051##
[In the formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, and A are defined the same as above. X represents a
leaving group (e.g., a chlorine atom, a bromine atom, an iodine
atom, methoxy, ethoxy, propoxy, butoxy, imidazole, pyrrole,
optionally substituted phenoxy, and the like).]
[0157] These steps (1 to 4) can produce compound (8-6) from
compound (6-1) in accordance with similar methods to methods and
the like described in literature [for example, Compt. Rend., 1265,
vol. 120, (1895), Journal of Organic Chemistry, 1418, vol. 68,
(2003), Journal of the American Chemical Society, 3554, vol. 77,
(1955), Journal of Organic Chemistry, 2353, vol. 60, (1995),
Journal of Organic Chemistry, 3742, vol. 46, (1981), Tetrahedron:
Asymmetry, 1395, vol. 22, (2011), Journal of Medicinal Chemistry,
8287, vol. 53, (2010), Tetrahedron, 11020, vol. 64, (2008),
Tetrahedron: Asymmetry, 2281, vol. 6, (1995), Journal of Organic
Chemistry, 650, vol. 14, (1949), Polish Journal of Chemistry, 1317,
vol. 75, (2001), and the like].
[0158] Production Method 9:
##STR00052##
(In the formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7, R.sup.8, and A are defined the same as above.)
[0159] These steps (1 to 2) can produce compound (9-3) from
compound (4-3) in accordance with similar methods to methods and
the like described in literature [for example, Bulletin of the
Chemical Society of Japan, 891, vol. 70, (1997), Tetrahedron
Letters, 1783, vol. 47, (2006), Tetrahedron, 1763, vol. 67, (2011),
Tetrahedron Letters, 6869, vol. 50, (2009), Synlett, 449, vol. 3,
(2004), Heterocycles, 2631, vol. 60, (2003), Tetrahedron, 3259,
vol. 42, (1986), Journal of Medicinal Chemistry, 1832, vol. 28,
(1985), and the like].
[0160] Production Method 10:
##STR00053##
(In the formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, and A are defined the same as above.)
[0161] These steps (1 to 3) can produce compound (10-4) from
compound (4-1) in accordance with similar methods to methods and
the like described in literature [for example, European Journal of
Medicinal Chemistry, 611, vol. 24, (1989), Heterocycles, 1623, vol.
34, (1992), European Journal of Medicinal Chemistry, 611, vol. 24,
(1989), Journal of Medicinal Chemistry, 614, vol. 33, (1990), Asian
Journal of Chemistry, 5575, vol. 22, (2010), Journal of the
American Chemical Society, 8227, vol. 135, (2013), Journal of
Organic Chemistry, 2548, vol. 73, (2008), Journal of Organic
Chemistry, 6599, vol. 72, (2007), Bioorganic & Medicinal
Chemistry Letters, 3771, vol. 14, (2004), Russian Chemical
Bulletin, 414, vol. 58, (2010), Collection of Czechoslovak Chemical
Communications, 285, vol. 49, (1984), and the like].
[0162] Production Method 11:
##STR00054##
(In the formulas, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, A,
and G are defined the same as above.)
[0163] This step can produce compounds (11-2) and (11-3) from
compound (11-1) in accordance with a similar method to methods and
the like described in literature [for example, Physiological
Zoology, 312, vol. 36, (1963), European Journal of Medicinal
Chemistry, 4827, vol. 46, (2011), Synthetic Metals, 2491, vol. 159,
(2009), Journal of the American Chemical Society, 4466, vol. 132,
(2010), Bulletin of the Chemical Society of Japan, 4464, vol. 61,
(1988), and the like].
[0164] Production Method 12:
##STR00055##
(In the formula, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9, A, and G are defined the same as above.)
[0165] These steps (1 to 2) can produce compound (12-3) from
compound (11-2) in accordance with similar methods to methods and
the like described in literature [for example, Organic Letters,
2157, vol. 7, (2005), Journal of Medicinal Chemistry, 7574, vol.
56, (2013), Bioorganic & Medicinal Chemistry Letters, 138, vol.
22, (2012), Khimiya Geterotsiklicheskikh Soedinenii, 27, vol. 1,
(1980), Heterocycles, 1913, vol. 75, (2008), Journal of Medicinal
Chemistry, 1819, vol. 53, (2010), Journal of the Chilean Chemical
Society, 14, vol. 54, (2009), Molecules, 1388, vol. 17, (2012),
Bioorganic & Medicinal Chemistry Letters, 4961, vol. 15,
(2005), Synlett, 670, vol. 5, (2001), and the like].
[0166] Production Method 13:
##STR00056##
[In the formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, A,
and G are defined the same as above. L.sup.1 and L.sup.2 represent
hydrogen, a hydroxyl group, or a leaving group (e.g., a chlorine
atom, a bromine atom, an iodine atom, methanesulfonyloxy, tri
fluoromethanesulfonyloxy, p-toluenesulfonyloxy, or the like).]
[0167] Step 1
[0168] In this step 1, compound (10-3) can be produced by reacting,
in an organic solvent in the presence of a base, (13-1) obtained as
a commercially available product or in accordance with a known
method [for example, Journal of Medicinal Chemistry, 1329, vol. 29,
(1986), European Journal of Medicinal Chemistry, 3938, vol. 45,
(2010), Bioorganic & Medicinal Chemistry Letters, 952, vol. 21,
(2011), European Journal of Organic Chemistry, 4201, vol. 18,
(2006), Journal of Organic Chemistry, 5026, vol. 78, (2013), and
the like], with (13-2) obtained as a commercially available product
or in accordance with a known synthesis method [for example,
Bioorganic & Medicinal Chemistry, 5705, vol. 20, (2012),
Journal of American Chemical Society, 3460, vol. 103, (1981),
Journal of Medicinal Chemistry, 1347, vol. 40, (1997), Journal of
Medicinal Chemistry, 5233, vol. 45, (2002), Organic Letters, 2856,
vol. 11, (2009), and the like]. Organic solvent includes aprotic
solvent such as N,N-dimethylformamide, N-methyl-2-pyrrolidone,
dimethyl sulfoxide, and the like, ether type solvent such as
tetrahydrofuran, 1,4-dioxane, and the like, halogenated
hydrocarbons such as dichloromethane, chloroform,
1,2-dichloroethane, chlorobenzene, and the like, hydrocarbons such
as toluene, benzene, and the like, mixed solvents thereof, and the
like, and suitably N,N-dimethylformamide, N-methyl-2-pyrrolidone,
dimethyl sulfoxide, acetonitrile, and tetrahydrofuran. In addition,
it can be produced in a two-layer system of organic solvent--water.
Both of organic bases and inorganic bases can be used as a base.
Organic bases include 1-hydroxybenzotriazole, N-methylmorpholine,
triethylamine, diisopropylethylamine, tributylamine,
1,8-diazabicyclo[5.4.0]undec-7-ene,
1,5-diazabicyclo[4.3.0]non-5-ene,
1,4-diazabicyclo[5.4.0]undec-7-ene, pyridine,
dimethylaminopyridine, picoline, and the like. Inorganic bases
include alkali halides such as potassium fluoride and the like,
alkali hydroxide such as sodium hydroxide, potassium hydroxide, and
the like, alkali carbonate such as sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydrogen carbonate, and the
like, alkali alkoxide such as sodium ethoxide, sodium
tert-butoxide, potassium tert-butoxide, and the like, alkali metal
such as n-butyl lithium, methyl lithium, isopropylmagnesium
bromide, and the like. The amount of compound (9-2) used is
generally 1 to 5 mol, preferably, 1.2 to 3 mol per mol of compound
(9-1). The amount of a base used is generally 2 to 10 mol,
preferably, 2 to 3 mol per mol of compound (1-1). A reaction time
is generally about 0.5 to about 48 hours, preferably, about 0.5 to
about 12 hours. A reaction temperature is generally about -20 to
about 180.degree. C., preferably, about 0 to about 150.degree.
C.
[0169] Production Method 14:
##STR00057##
[In the formulas, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7,
R.sup.8, L.sup.1, L.sup.2, A, and G are defined the same as
above.]
[0170] These steps (1 to 3) can produce compound (14-6) from
compound (13-1) in accordance with similar methods to methods and
the like described in literature [for example, US2012/0077986A1 and
the like].
[0171] In each reaction of the production methods described above,
in a case other than the case where the use of a protecting group
is specifically and explicitly indicated, if any functional group
other than a reaction point is modified under a described reaction
condition or is unsuitable for performing the described method, a
target compound can be obtained by protecting any point other than
the reaction point as necessary, and unprotecting after the
reaction is finished or a series of reactions are performed.
[0172] As a protecting group, a common protecting group such as
those described in literature (e.g., Protective Groups in Organic
Synthesis, 3.sup.rd ed., T. W. Greene, John Wiley & Sons Inc.
(1999), and the like) can be used. Further specifically, examples
of a protecting group for an amino group can include
benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the
like, and examples of a protecting group for a hydroxyl group
include trialkylsilyl groups such as trimethylsilyl,
tert-butyldimethylsilyl, and the like, acetyl, benzyl, and the
like, respectively.
[0173] Introduction and removal of a protecting group can be
performed by routine methods in synthetic organic chemistry (e.g.,
refer to Protective Groups in Organic Synthesis, described above)
or methods in accordance therewith.
[0174] In addition, intermediates or final products in the
above-described production methods can be derived to other
compounds encompassed by the present invention by appropriately
converting a functional group thereof, and in particular, extend
any kind of side chain using an amino group, a hydroxyl group, a
carbonyl group, a halogen group, or the like as an aid, and at this
time, as necessary, performing the above-described protection and
deprotection. Conversion of a functional group and extension of a
side chain can be performed by a routine, general method (refer to,
e.g., Comprehensive Organic Transformations, R. C. Larock, John
Wiley & Sons Inc. (1999), and the like).
[0175] Intermediates and target compounds in the above-described
respective production methods can be subjected to a routine
purification method in synthetic organic chemistry, for example,
neutralization, filtration, extraction, washing, drying,
concentration, recrystallization, any kind of chromatography, and
the like to isolate and purify it. In addition, the intermediates
can be subjected to a next reaction without particular
purification.
[0176] Among starting materials and intermediates in respective
production methods described above, those of which production
methods are not particularly and repeatedly described are
commercially available compounds or can be synthesized from a
commercially available compound by a known method to those skilled
in the art or a method in accordance therewith.
[0177] The present compound is provided, for example, as an
anticancer agent. Although the type of cancer to which it is
applied is not limited, specific examples thereof include acute
leukemia, chronic lymphocytic leukemia, chronic myelocytic
leukemia, polycythemia vera, malignant lymphoma, brain tumor, head
and neck cancer, esophageal cancer, thyroid cancer, small cell lung
cancer, non-small-cell lung cancer, breast cancer, gastric cancer,
gallbladder.cndot.bile duct cancer, hepatoma, pancreatic cancer,
colon cancer, rectal cancer, chorioepithelioma, endometrial cancer,
cervical cancer, urothelial cancer, renal cell cancer, testicular
tumor, Wilms' tumor, skin cancer, malignant melanoma,
neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue
sarcoma. Hematological cancer in the present invention is a concept
encompassing lymphoma and leukemia, and has an effect to reduce or
annihilate carcinoma or to inhibit the growth of carcinoma for the
purposes of preventing/or treating cancer. It is noted that in the
present invention, "prevention (preventing)" is an action to
administer an active ingredient of the present invention to a
healthy human that does not develop a disease, and a purpose
thereof is, for example, to prevent the onset of a disease.
"Treatment (treating)" is an action to administer an active
ingredient of the present invention to a person (patient) diagnosed
as developing a disease by a medical doctor, and a purpose thereof
is, for example, to alleviate the disease and symptoms, to inhibit
the growth of carcinoma, or to return it to a state prior to the
onset of the disease. In addition, even when the purpose of
administration is to prevent a disease or symptoms from
deteriorating or carcinoma from growing, if it is administered to a
patient, it is an action for therapy.
[0178] When the present compound is administered, the amount of the
compound used varies depending on symptoms, age, administration
method, and the like. For example, in the case of oral
administration, it is desirable to administer to an adult 0.01 mg
as the lower limit (preferably 1 mg) and 5000 mg as the upper limit
(preferably 500 mg) once or in several batches daily depending on
the symptoms. In the case of intravenous injection, an effect is
expected by administering to an adult 0.01 mg as the lower limit
(preferably 0.1 mg) and 1000 mg as the upper limit (preferably 30
mg) once or in several batches daily depending on the symptoms.
Examples of its administration schedule include single-dose
administration, once a day administration for three days in a row,
and the like. Further, each administration described above can be
repeated at intervals of about 7 days to about 60 days.
[0179] The present compound can be administered orally or
parenterally (e.g., intravenous, subdermal, or intramuscular
injection, ocular administration, transrectally, percutaneously,
transnasally, or the like). For oral administration, for example,
tablets, capsules, pills, granules, powders, solutions,
suspensions, and the like can be used. In addition, for parenteral
administration, injections, eye drops, suppositories, patches,
poultices, lotions, creams, and the like can be used. These
preparations comprise the present compound and pharmacologically
acceptable additives, and produced using conventional known
techniques.
[0180] More specifically, depending on parenteral or oral
administration, the present compound can be formed into a
preparation using a suitable dosage form, and administrated.
Examples of the dosage form include, but are not limited to,
tablets, capsules, powders, granules, solutions, suspensions,
injections, patches, poultices, and the like. The preparation is
produced by a known method using a pharmaceutically acceptable
additive.
[0181] As additives, excipients, disintegrants, binders,
fluidizers, lubricants, coating agents, solvents, solubilizing
agents, thickeners, dispersants, stabilizers, sweeteners, flavors,
and the like can be used in accordance with a purpose. Specific
examples thereof include lactose, mannitol, crystalline cellulose,
low-substituted hydroxypropylcellulose, corn starch, partly
pregelatinized starch, carmellose calcium, croscarmellose sodium,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl
alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene
glycol, propylene glycol, titanium oxide, talc, and the like.
[0182] It is possible to more effectively perform preventive
treatment of cancer by combining one to three types selected from
the group consisting of: (1) administering an effective amount of
the present compound; and (2) (i) administering an effective amount
of another anticancer agent, (ii) administering an effective amount
of a hormonal therapeutic agent; and (iii) non-pharmacological
therapy. Examples of non-pharmacological therapy include surgery,
radiotherapy, gene therapy, thermotherapy, cryotherapy, laser
cauterization therapy, and the like. Two or more types of these
also can be combined.
[0183] The present compound can be used in combination with another
drug for purpose of enhancing its effect. Specifically, the present
compound can be used in combination with a drug such as a hormonal
therapeutic agent, a chemotherapeutic agent, an immunotherapeutic
agent, or a cell growth factor, a pharmaceutical agent to inhibit
its receptor activity, and the like. Hereinafter, a drug that may
be used in combination with the present compound is abbreviated to
a combination drug.
[0184] The present compound, even when used as a single agent,
exhibits excellent anticancer effect, and further the combination
use with one or several of the above-described combination drugs
(polypharmacy) can further enhance its effect or improve the QOL of
a patient.
[0185] Examples of "hormonal therapeutic agents" include
Fosfestrol, Diethylstilbestrol, Chlorotrianisene,
Medroxyprogesterone acetate, Megestrol acetate, Chlormadinone
acetate, Cyproterone acetate, Danazol, Dienogest, Asoprisnil,
Allylestrenol, Gestrinone, Nomegestrol, Tadenan, Mepartricin,
Raloxifene, Ormeloxifene, Levormeloxifene, antiestrogen (e.g.,
Tamoxifen citrate, Toremifene citrate, and the like), pill
preparation, Mepitiostane, Testololactone, aminoglutethimide, LH-RH
derivatives (LH-RH agonist (e.g., Goserelin acetate, Buserelin,
Leuprorelin, and the like), LH-RH antagonist), Droloxifene,
Epitiostanol, ethynyl estradiol sulfonate, aromatase inhibitor
(e.g., Fadrozole hydrochloride, Anastrozole, Letrozole, exemestane,
vorozole, formestane, and the like), anti-androgen (e.g.,
Flutamide, Bicalutamide, Nilutamide, and the like), adrenocortical
hormone type pharmaceutical agent (e.g., Dexamethasone,
Prednisolone, Betamethasone, Triamcinolone, and the like), androgen
synthesis inhibitor (e.g., Abiraterone and the like), retinoid and
a pharmaceutical agent to delay the metabolism of retinoid (e.g.,
Liarozole and the like), and the like.
[0186] As "chemotherapeutic agents", for example, alkylating
agents, antimetabolites, anticancer antibiotics, plant-derived
anticancer agents, other chemotherapeutic agents, and the like are
used. Representative examples are described below.
[0187] Examples of "alkylating agents" include Nitrogen mustard,
Nitrogen mustard N-oxide hydrochloride, Chlorambucil,
Cyclophosphamide, Ifosfamide, Thiotepa, Carboquone, Improsulfan
tosylate, Busulfan, Nimustine hydrochloride, Mitobronitol,
Melphalan, Dacarbazine, Ranimustine, Estramustine phosphate sodium,
Triethylenemelamine, Carmustine, Lomustine, Streptozocin,
Pipobroman, Etoglucide, Carboplatin, Cisplatin, miriplatin,
Nedaplatin, Oxaliplatin, Altretamine, Ambamustine, Dibrospidium
chloride, Fotemustine, Prednimustine, Pumitepa, Ribomustin,
Temozolomide, Treosulfan, Trofosfamide, Zinostatin stimalamer,
Adozelesin, Cystemustine, Bizelesin, and DDS preparations thereof,
and the like.
[0188] Examples of "antimetabolites" include Mercaptopurine,
6-Mercaptopurine riboside, Thioinosine, Methotrexate, Pemetrexed,
Enocitabine, Cytarabine, Cytarabin ocfosfate, Ancitabine
hydrochloride, 5-FU type pharmaceutical agent (e.g., Fluorouracil,
Tegafur, UFT, Doxifluridine, Carmofur, Galocitabine, Emitefur,
Capecitabine, and the like), Aminopterin, Nelarabine, Leucovorin
calcium, tabloid, Butocin, calcium folinate, calcium levofolinate,
Cladribine, Emitefur, Fludarabine, Gemcitabine, hydroxycarbamide,
Pentostatin, Piritrexim, Idoxuridine, Mitoguazone, Tiazofurin,
Ambamustine, Bendamustine, and DDS preparations thereof, and the
like.
[0189] Examples of "anticancer antibiotics" include Actinomycin D,
Actinomycin C, Mitomycin C, Chromomycin A3, Bleomycin
hydrochloride, Bleomycin sulfate, Peplomycin sulfate, Daunorubicin
hydrochloride, Doxorubicin hydrochloride, Aclarubicin
hydrochloride, Pirarubicin hydrochloride, Epirubicin hydrochloride,
Neocarzinostatin, Mithramycin, Sarkomycin, Carzinophilin, Mitotane,
Zorubicin hydrochloride, Mitoxantrone hydrochloride, Idarubicin
hydrochloride, and DDS preparations thereof, and the like.
[0190] Examples of "plant-derived anticancer agents" include
Etoposide, Etoposide phosphate, Vinblastine sulfate, Vincristine
sulfate, Vindesine sulfate, Teniposide, Paclitaxel, Docetaxel,
DJ-927, Vinorelbine, Irinotecan, Topotecan, and DDS preparations
thereof, and the like.
[0191] Examples of "other chemotherapeutic agents" include
Sobuzoxane and the like.
[0192] Examples of "immunotherapeutic agents (BRM)" include
Picibanil, Krestin, Sizofiran, Lentinan, Ubenimex, interferon,
interleukin, macrophage colony stimulating factor,
granulocyte-colony stimulating factor, Erythropoietin, Lymphotoxin,
BCG vaccine, Corynebacterium parvum, Levamisole, polysaccharide K,
Procodazole, anti-CTLA4 antibody, PD-1 antibody, Toll-like
Receptors agonist (e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist,
and the like).
[0193] A cell growth factor and a cell growth factor in a
pharmaceutical agent to inhibit the activity of its receptor may be
any substance as long as it promotes cell growth. Generally, they
include a factor that is a peptide having a molecular weight of
20,000 or less and exhibits an effect at a low concentration by
binding with a receptor. Specifically, they include EGF (epidermal
growth factor) or substances having substantially the same activity
as it (e.g., TGFalpha and the like), insulin or substances having
substantially the same activity as it (e.g., insulin, IGF
(insulin-like growth factor)-1, IGF-2, and the like), FGF
(fibroblast growth factor) or substances having substantially the
same activity as it (e.g., acidic FGF, basic FGF, KGK (keratinocyte
growth factor), FGF-10, and the like), and other cell growth
factors (e.g., CSF (colony stimulating factor), EPO
(erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor),
PDGF (platelet-derived growth factor), TGF-beta (transforming
growth factor beta), HGF (hepatocyte growth factor), VEGF (vascular
endothelial growth factor), heregulin, angiopoietin, and the
like).
[0194] The period of administration of the present compound and a
combination pharmaceutical agent is not limited, and these may be
administered concurrently or at intervals to a subject to be
administered. In addition, a mixture of the present compound and a
combination pharmaceutical agent may be made. The dosage of a
combination pharmaceutical agent can be appropriately selected
using clinically used dose as criteria. In addition, the mixing
ratio of the present compound and a combination pharmaceutical
agent can be appropriately selected depending on a subject to be
administered, an administration route, target disease, symptoms,
combinations, and the like. For example, when a subject to be
administered is a human, 0.01 to 100 parts by weight of a
combination pharmaceutical agent may be used relative to one part
by weight of the present compound. In addition, for purpose of
inhibiting its side effect, they can be used in combination with a
pharmaceutical agent (a combination pharmaceutical agent) such as
an antiemetic agent, a sleep-inducing agent, an anticonvulsant, and
the like.
EXAMPLES
[0195] Hereinafter, the present invention is more specifically
described with reference examples, examples, and test examples.
However, the scope of the present invention is certainly not
limited to these examples. It is noted that compound names shown in
the following reference examples and examples do not always follow
the IUPAC nomenclature. It is noted that although abbreviations are
sometimes used to simplify a description, these abbreviations are
defined the same as the above descriptions.
[0196] In the present specification, the following abbreviations
are sometimes used.
[0197] In NMR and MS data of reference examples and examples, the
following abbreviations are used.
Me: a methyl group Et: an ethyl group Ns: a 2-nitrobenzenesulfonyl
group Ts: a p-toluenesulfonyl group tert: tertiary Boc: a
tert-butoxycarbonyl group
DMF: N,N-dimethylformamide
[0198] DMSO: dimethyl sulfoxide HATU:
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HOBt: 1-hydroxybenzotriazole
NMP: N-methylpyrrolidone
[0199] THF: tetrahydrofuran WSC.HCl:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride s:
singlet brs: broad singlet d: doublet dd: double doublet t: triplet
q: quartet m: multiplet br: broad J: coupling constant
Hz: Hertz
[0200] CDCl.sub.3: deuterated chloroform DMSO-d.sub.6: deuterated
dimethyl sulfoxide
[0201] Analysis conditions for identification of a compound are as
follow.
[0202] NMR: 400 MHz
[0203] MS: Kinetex, C18, 0.05% trifluoroacetic acid in water/0.05%
trifluoroacetic acid in acetonitrile, acetonitrile 10-99% 3.0 min,
0.5 mL/min, or BEH, C18, 0.05% formic acid in water/acetonitrile,
acetonitrile 2-96% 2.2 min, 0.8 mL/min.
Reference Example 1
methyl 4,7-dimethoxy-1-benzothiophene-2-carboxylate
##STR00058##
[0205] To a solution of 3,6-dimethoxy-2-nitrobenzaldehyde (70.0 g)
in DMF (420 mL) was added dropwise methyl mercaptoacetate (33.4 mL)
at room temperature. Subsequently, potassium carbonate (137 g) was
added thereto in 10 parts, and then at unchanged constant
temperature the reaction mixture was stirred for 1 hour. Methyl
iodide (41.3 mL) was added dropwise thereto, followed by stirring
for another 1 hour. The insoluble substance was removed through
Celite, and then solvent was evaporated off. The resulting residue
was dissolved in ethyl acetate (700 mL), washed with water
(2.times.700 mL) and saturated brine (700 mL), and then dried over
sodium sulfate. The solvent was then evaporated off to yield a
standard compound as a flesh-colored powder (81.1 g).
[0206] .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.04 (1H, s), 7.04
(1H, d, J=8.4 Hz), 6.90 (1H, d, J=8.4 Hz), 3.92 (3H, s), 3.89 (3H,
s), 3.88 (3H, s) MS (ESI+) 253 (M.sup.++1).
Reference Example 2
methyl 5-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate
(2A)
Reference Example 3
methyl 6-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate
(2B)
##STR00059##
[0208] To a solution of methyl
4,7-dimethoxy-1-benzothiophene-2-carboxylate (2.04 g) (which was
obtained in Reference example 1) in acetic acid (102 mL) was added
dropwise 70% aqueous nitric acid solution (512 .mu.L), and then the
reaction mixture was stirred at 70.degree. C. for 1 hour. After it
was returned to room temperature, the reaction solution was poured
into iced water, and then extracted with chloroform two times. The
resulting organic layer was washed with saturated brine, and then
dried over sodium sulfate. The solvent was then evaporated off to
yield a mixture of 1A and 1B (2.57 g). This was used in the next
reaction without further purification.
[0209] To a suspension of 90% reduced iron (2.68 g) and ammonium
chloride (555 mg) in methanol/water (57.6 mL/28.8 mL), which had
been heated and stirred at 75.degree. C., was added dropwise a
suspension of the obtained mixture of 1A and 1B (2.57 g) in
methanol (8.65 mL), and then the reaction mixture was stirred at
75.degree. C. for 2 hours. After the reaction solution was cooled
to room temperature, it was filtered through Celite, and then the
solvent of the resulting filtrate was evaporated off. The resulting
residue was dissolved in ethyl acetate, washed with aqueous
saturated sodium bicarbonate and saturated brine, and then dried
over sodium sulfate. The solvent was evaporated off, and then the
resulting residue was purified by silica gel column chromatography
(ethyl acetate/hexane) to yield Compound 2A as a brown solid (1.74
g), and Compound 2B as a flesh-colored solid (474 mg).
[0210] (2A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 7.94 (1H, s),
6.69 (1H, s), 5.15 (2H, s), 3.92 (3H, s), 3.91 (3H, s), 3.79 (3H,
s).
[0211] MS (ESI+) 268 (M.sup.++1).
[0212] (2B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 7.90 (1H, s),
6.46 (1H, s), 5.71 (2H, s), 3.88 (3H, s), 3.87 (3H, s), 3.77 (3H,
s).
[0213] MS (ESI+) 268 (M.sup.++1).
Reference Example 4
methyl 4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (3B)
##STR00060##
[0214] (a)
4,7-Dimethoxy-5-(prop-2-yn-1-ylamino)-1-benzothiophene-2-carbox-
ylate (3A)
[0215] To a solution of methyl
5-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate (274 mg)
(which was obtained in Reference example 2) in acetonitrile (3.1
mL) were added potassium carbonate (213 mg) and 3-bromopropyne (117
.mu.L), and then the reaction mixture was heated and stirred at
70.degree. C. for 6 hours. The reaction solution was returned to
room temperature, and then the solvent was evaporated off. The
resulting residue was dissolved in ethyl acetate, washed with water
and saturated brine, and then dried over sodium sulfate. The
solvent was evaporated off, and then the resulting residue was
purified by silica gel column chromatography (ethyl acetate/hexane)
to yield Compound 3A as a yellow solid (142 mg).
(b) Methyl 4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate
(3B)
[0216] To a solution of Compound 3A (90.2 mg) (which was obtained
above) in DMSO (6 mL) was added silver hexafluoroantimonate (10.2
mg), and then the reaction mixture was heated and stirred at
110.degree. C. for 3 hours. The reaction solution was returned to
room temperature, ethyl acetate and water were added thereto,
followed by stirring for 5 minutes. The resulting organic layer was
washed with aqueous saturated sodium bicarbonate and saturated
brine, and then dried over sodium sulfate. The solvent was
evaporated off, and then the resulting residue was purified by
silica gel column chromatography (ethyl acetate/hexane) to yield
Compound 3B as a yellow solid (20.4 mg).
[0217] (3A) .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.04 (1H, s),
7.26 (1H, s), 6.54 (2H, s), 4.49 (1H, brs), 4.05 (2H, s), 3.98 (3H,
s), 3.94 (3H, s), 3.87 (3H, s), 2.23 (1H, s).
[0218] MS (ESI+) 306 (M.sup.++1).
[0219] (3B) .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.97 (1H, dd,
J=1.6, 4.0 Hz), 8.55 (1H, dd, J=1.6, 8.8 Hz), 8.42 (1H, s), 7.46
(1H, dd, J=4.0, 8.8 Hz), 4.34 (3H, s), 4.16 (3H, s), 3.99 (3H,
s).
[0220] MS (ESI+) 304 (M.sup.++1).
Reference Example 5
4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylic acid
##STR00061##
[0222] To a solution of methyl
4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (70.0 mg) (which
was obtained in Reference example 4) in THF/ethanol (346 .mu.L/346
.mu.L) was added 1 N aqueous sodium hydroxide solution (692 .mu.L),
and then the reaction mixture was stirred at room temperature for 2
hours. After the solvent was evaporated off, water was added
thereto, and then the liquid property was made acidic (pH=2 to 3)
with 2 N aqueous hydrochloric acid solution. The reaction mixture
was extracted with Ethyl acetate three times, and then the
resulting organic layer was washed with saturated brine. The
organic layer was dried over sodium sulfate, and then the solvent
was evaporated off to yield the title compound as a brown solid
(65.2 mg).
[0223] .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.99 (1H, dd,
J=1.2, 4.4 Hz), 8.59 (1H, dd, J=1.2, 8.4 Hz), 8.20 (1H, s), 7.63
(1H, dd, J=4.4, 8.4 Hz), 4.27 (3H, s), 4.10 (3H, s).
[0224] MS (ESI+) 290 (M.sup.++1).
Reference Example 6
1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanone (4B)
##STR00062##
[0225] (a) (4,9-Dimethoxythieno[2,3-g]quinolin-2-yl)
(morpholin-4-yl)methanone (4A)
[0226] To a solution of
4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylic acid (35.2 mg)
(which was obtained in Reference example 5) in DMF (1.2 mL) were
added morpholine (21.2 .mu.L), HATU (92.6 mg), and Hunig's base
(128 .mu.L), and then the reaction mixture was stirred at room
temperature for 1.5 hours. The reaction solution was poured into
water, and then extracted with ethyl acetate three times. The
resulting organic layer was washed with saturated brine, and then
dried over sodium sulfate. The solvent was then evaporated off to
yield Compound 4A as a yellow solid (41.0 mg).
(b) 1-(4,9-Dimethoxythieno[2,3-g]quinolin-2-yl)ethanone (4B)
[0227] To a solution of Compound 4A (which was obtained above) in
THF (1.14 mL), under ice-cooling, was added dropwise
methylmagnesium bromide (114 .mu.L), and then the reaction mixture
was stirred at room temperature for 3.5 hours. The reaction
solution was poured into water, and then extracted with ethyl
acetate two times. The resulting organic layer was washed with
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off to yield Compound 4B as a brown solid (36.0
mg).
[0228] (4A) MS (ESI+) 359 (M.sup.++1).
[0229] (4B) .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.97 (1H, dd,
J=1.6, 4.0 Hz), 8.56 (1H, dd, J=1.6, 8.8 Hz), 8.30 (1H, s), 7.47
(1H, dd, J=4.0, 8.8 Hz), 4.39 (3H, s), 4.16 (3H, s), 2.74 (3H,
s).
[0230] MS (ESI+) 288 (M.sup.++1).
Example 1
2-acetylthieno[2,3-g]quinoline-4,9-dione
##STR00063##
[0232] To a mixture solution of
1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanone (4.0 mg) (which
was obtained in Reference example 6) in acetonitrile (1 mL) and
water (1 mL) was added Ammonium Cerium Nitrate (16 mg) at 0.degree.
C., and then the reaction mixture was stirred for 1 hour. Aqueous
saturated sodium hydrogen carbonate solution was added to the
reaction solution, which was then extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate)
to yield the title compound as a yellow solid (1.8 mg).
[0233] MS (ESI+) 258 (M.sup.++1).
Example 2
2-(1-hydroxyethyl)thieno[2,3-g]quinoline-4,9-dione (5B)
##STR00064##
[0234] (a) 1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanol
(5A)
[0235] To a solution of
1-(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)ethanone (34.9 mg)
(which was obtained in Reference example 6) in THF (1.2 mL), under
ice-cooling, was added sodium borohydride (10.0 mg), and then the
reaction mixture was stirred at room temperature for 2 hours.
Aqueous saturated ammonium chloride solution was added thereto, and
then extraction with ethyl acetate was performed two times. The
resulting organic layer was washed with saturated brine, and then
dried over sodium sulfate. The solvent was then evaporated off to
yield Compound 5A as a brown solid (33.3 mg).
(b) 2-(1-Hydroxyethyl)thieno[2,3-g]quinoline-4,9-dione (5B)
[0236] Using Compound 5A (32.1 mg) obtained above and according to
the same method as Example 1, Compound 5B was obtained as a yellow
solid (10.4 mg).
[0237] (5A) .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.95 (1H, dd,
J=2.0, 3.6 Hz), 8.53 (1H, dd, J=2.0, 8.8 Hz), 7.53 (1H, s), 7.41
(1H, dd, J=3.6, 8.8 Hz), 5.29-5.21 (1H, m), 4.26 (3H, s), 4.14 (3H,
s), 1.72 (3H, d, J=6.0 Hz).
[0238] MS (ESI+) 290 (M.sup.++1).
[0239] (5B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.02 (1H, dd,
J=2.0, 4.4 Hz), 8.47 (1H, dd, J=2.0, 8.0 Hz), 7.85 (1H, dd, J=4.4,
8.0 Hz), 7.57 (1H, s), 6.14 (1H, d, J=5.2 Hz), 5.18-4.98 (1H, m),
1.50 (3H, d, J=6.0 Hz).
[0240] MS (ESI+) 260 (M.sup.++1).
Example 3
N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]quinoline-2-carboxamide
(6B)
##STR00065##
[0241] (a)
4,9-Dimethoxy-N,N-dimethylthieno[2,3-g]quinoline-2-carboxamide
(6A)
[0242] To a solution of
4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylic acid (25.9 mg)
(which was obtained in Reference example 5) in DMF (1.0 mL) were
added dimethylamine hydrochloride (8.8 mg), WSC.HCl (25.8 mg), HOBt
(18.2 mg), and Hunig's base (57.9 .mu.L), and then the reaction
mixture was stirred at room temperature for 1.5 hours. The reaction
solution was poured into water, and then extracted with ethyl
acetate two times. The resulting organic layer was washed with
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off to yield Compound 6A as a yellow solid
(17.3 mg).
(b)
N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]quinoline-2-carboxamide
(6B)
[0243] Using Compound 6A (17.3 mg) obtained above and according to
the same method as Example 1, the title compound 6B was obtained as
a pale green solid (5.5 mg).
[0244] (6A) MS (ESI+) 317 (M.sup.++1).
[0245] (6B) MS (ESI+) 287 (M.sup.++1).
Reference Example 7
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]quinoline (7A)
##STR00066##
[0246] (a) (4,9-Dimethoxythieno[2,3-g]quinolin-2-yl)methanol
(7A)
[0247] To a solution of methyl
4,9-dimethoxythieno[2,3-g]quinoline-2-carboxylate (27.8 mg) (which
was obtained in Reference example 4) in dichloromethane (1.0 mL),
under ice-cooling, was added lithium aluminum hydride (73.6 mg),
and then the reaction mixture was stirred at room temperature
overnight. Under ice-cooling, aqueous saturated Rochelle salt
solution was added thereto, and then extraction with ethyl acetate
was performed two times. The resulting organic layer was washed
with saturated brine, and then dried over sodium sulfate. The
solvent was then evaporated off to yield Compound 7A as a yellow
oil (22.7 mg).
(b) 2-(Chloromethyl)-4,9-dimethoxythieno[2,3-g]quinoline (7B)
[0248] To a solution of Compound 7A (22.7 mg) (which was obtained
above) in dichloromethane (1.0 mL), under ice-cooling, was added
thionyl chloride (7.6 .mu.L), and then the reaction mixture was
stirred at room temperature for 2 hours. The solvent was evaporated
off, and then azeotropy of the resulting residue with toluene
yields Compound 7B as a brown oil (23.7 mg).
[0249] (7A) MS (ESI+) 276 (M.sup.++1).
[0250] (7B) MS (ESI+) 294 (M.sup.++1).
Reference Example 8
4,9-dimethoxy-2-(morpholin-4-ylmethyl)thieno[2,3-g]quinoline
##STR00067##
[0252] To a solution of
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]quinoline (which was
obtained in Reference example 7) in acetonitrile (1.0 mL) were
added Hunig's base (28.8 .mu.L), morpholine (7.9 .mu.L), and sodium
iodide (a catalytic amount), and then the reaction mixture was
stirred at room temperature overnight. The solvent was evaporated
off, and then the resulting residue was purified by silica gel
column chromatography (ethyl
acetate/hexane.fwdarw.chloroform/methanol) to yield the title
compound as a yellow solid (19.1 mg).
[0253] MS (ESI+) 345 (M.sup.++1).
Example 4
2-(morpholin-4-ylmethyl)thieno[2,3-g]quinoline-4,9-dione
##STR00068##
[0255] Using
4,9-dimethoxy-2-(morpholin-4-ylmethyl)thieno[2,3-g]quinoline (19.1
mg) obtained in Reference example 8 and according to the same
method as Example 1, the title compound was obtained as a pale
green solid (13.3 mg).
[0256] MS (ESI+) 315 (M.sup.++1).
Example 5
2-{[cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione
(8B)
##STR00069##
[0257] (a)
N-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N-ethylcycl-
ohexaneamine (8A)
[0258] Using cyclohexylethylamine (16.8 .mu.L) and according to the
same method as Reference example 8, Compound 8A was obtained as a
yellow oil (13.5 mg).
(b)
2-{[Cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione
(8B)
[0259] Using Compound 8A (13.5 mg) obtained above and according to
the same method as Example 1, the title compound 8B was obtained as
a brown solid (7.9 mg).
[0260] (8A) MS (ESI+) 385 (M.sup.++1).
[0261] (8B) MS (ESI+) 355 (M.sup.++1).
Example 6
2-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione
(9B)
##STR00070##
[0262] (a)
N-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-m-
ethoxyethaneamine (9A)
[0263] Using 2-methoxyethylethylamine (14.9 .mu.L) and according to
the same method as Reference example 8, Compound 9A was obtained as
a yellow oil (13.3 mg).
(b)
2-{[Ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione
(9B)
[0264] Using Compound 9A (13.3 mg) obtained above and according to
the same method as Example 1, the title compound 9B was obtained as
a brown solid (11.5 mg).
[0265] (9A) MS (ESI+) 361 (M.sup.++1).
[0266] (9B) MS (ESI+) 331 (M.sup.++1).
Example 7
2-{[ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione
(10B)
##STR00071##
[0267] (a)
N-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N-(pyridin--
4-ylmethyl)ethanamine (10A)
[0268] Using N-ethyl-4-picolylamine (26.4 mg) and according to the
same method as Reference example 8, Compound 10A was obtained as a
brown solid (18.0 mg).
(b)
2-{[Ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-d-
ione (10B)
[0269] Using Compound 10A (18.0 mg) obtained above and according to
the same method as Example 1, the title compound 10B was obtained
as a brown solid (10.3 mg).
[0270] (10A) MS (ESI+) 394 (M.sup.++1).
[0271] (10B) MS (ESI+) 364 (M.sup.++1).
Example 8
2-{[ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-dione
(11B)
##STR00072##
[0272] (a)
N'2'-[(4,9-dimethoxythieno[2,3-g]quinolin-2-yl)methyl]-N'2'-eth-
yl-N,N-dimethylglycinamide (11A)
[0273] Using 2-ethylamino-N,N-dimethylacetamide (25.2 mg) and
according to the same method as Reference example 8, Compound 11A
was obtained as a brown solid (28.0 mg).
(b)
2-{[Ethyl(pyridin-4-ylmethyl)amino]methyl}thieno[2,3-g]quinoline-4,9-d-
ione (11B)
[0274] Using Compound 11A (28.0 mg) obtained above and according to
the same method as Example 1, the title compound 11B was obtained
as a brown oil (16.0 mg).
[0275] (11A) MS (ESI+) 388 (M.sup.++1).
[0276] (11B) MS (ESI+) 358 (M.sup.++1).
Reference Example 9
N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethanamine
##STR00073##
[0278] Using ethylamine and according to the same method as
[0279] Reference example 8, the title compound was obtained as a
brown oil (127 mg).
[0280] MS (ESI+) 303 (M.sup.++1).
Example 9
N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-3-methyl-
butanamide (12B)
##STR00074##
[0281] (a)
N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-3-met-
hylbutanamide (12A)
[0282] To a solution of
N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethaneamine (40.0
mg) (which was obtained in Reference example 9) in THF (1 mL),
under ice-cooling, were added dropwise isovaleyl chloride (19.4
.mu.L) and triethylamine (27.7 .mu.L), and then the reaction
mixture was stirred at room temperature for 1 hour. Aqueous
saturated sodium bicarbonate was added thereto, and then extraction
with ethyl acetate was performed. The resulting organic layer was
washed with saturated brine, and then dried over sodium sulfate.
The solvent was then evaporated off. The resulting residue was
purified by silica gel column chromatography (ethyl acetate/hexane)
to yield Compound 12A as a yellow solid (26.1 mg).
(b)
N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-3-me-
thylbutanamide (12B)
[0283] Using Compound 12A (28.0 mg) obtained above and according to
the same method as Example 1, the title compound 12B was obtained
as a yellow powder (17.7 mg).
[0284] (12A) MS (ESI+) 387 (M.sup.++1).
[0285] (12B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.02 (1H, d,
J=2.8 Hz), 8.46 (1H, dd, J=1.6, 8.0 Hz), 7.84 (1H, dd, J=4.4, 8.0
Hz), 7.70-7.64 (1H, m), 4.92-4.75 (2H, m), 3.48-3.36 (2H, m), 2.26
(2H, d, J=6.8 Hz), 2.15-2.02 (1H, m), 1.17-1.01 (3H, m), 0.96-0.84
(6H, m).
[0286] MS (ESI+) 357 (M.sup.++1).
Example 10
N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-methyl-
propane-1-sulfonamide (13B)
##STR00075##
[0287] (a)
N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-met-
hylpropane-1-sulfonamide (13A)
[0288] Using
N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethaneamine (40.0
mg) (which was obtained in Reference example 9) and
isobutanesulfonyl chloride (20.7 .mu.L) and according to the same
method as Example 9a, Compound 13A was obtained as a yellow solid
(21.2 mg).
(b)
N-[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]-N-ethyl-2-me-
thylpropane-1-sulfonamide (13B)
[0289] Using Compound 13A (20.5 mg) obtained above and according to
the same method as Example 1, the title compound 13B was obtained
as a yellow powder (16.8 mg).
[0290] (13A) MS (ESI+) 423 (M.sup.++1).
[0291] (13B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.03 (1H, dd,
J=2.0, 4.4 Hz), 8.48 (1H, dd, J=2.0, 8.0 Hz), 7.86 (1H, dd, J=4.8,
8.0 Hz), 7.70-7.64 (1H, m), 4.72-4.65 (2H, m), 3.36-3.22 (2H, m),
3.08 (2H, d, J=6.4 Hz), 2.19-2.08 (1H, m), 1.15-1.08 (3H, m),
1.08-1.02 (6H, m).
[0292] MS (ESI+) 393 (M.sup.++1).
Example 11
ethyl
[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]ethylcarbamat-
e (14B)
##STR00076##
[0293] (a) Ethyl
[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethylcarbamate
(14A)
[0294] Using
N-[(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)methyl]ethaneamine (40.0
mg) (which was obtained in Reference example 9) and ethyl
chloroformate (15.1 .mu.L) and according to the same method as
Example 9a, Compound 14A was obtained as a yellow solid (21.9
mg).
(b) Ethyl
[(4,9-dioxo-4,9-dihydrofuro[2,3-g]quinolin-2-yl)methyl]ethylcarb-
amate (14B)
[0295] Using Compound 14A (21.5 mg) obtained above and according to
the same method as Example 1, the title compound 14B was obtained
as a yellow powder (16.2 mg).
[0296] (14A) MS (ESI+) 375 (M.sup.++1).
[0297] (14B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.03 (1H, d,
J=4.8 Hz), 8.47 (1H, d, J=7.2 Hz), 7.89-7.82 (1H, m), 7.69 (1H, s),
4.72 (2H, s), 4.13 (2H, q, J=6.8), 3.32 (2H, q, J=6.8 Hz), 1.22
(3H, t, J=6.8 Hz), 1.08 (3H, t, J=6.8 Hz).
[0298] MS (ESI+) 345 (M.sup.++1).
Reference Example 10
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (15D)
##STR00077##
[0299] (a) Methyl
5-formyl-4,7-dimethoxy-1-benzothiophene-2-carboxylate (15A)
[0300] Under nitrogen atmosphere, to a solution of methyl
4,7-dimethoxy-1-benzothiophene-2-carboxylate (10 g) (which was
obtained in Reference example 1) in dichloromethane (250 mL) was
added dropwise titanium tetrachloride (9.9 mL) at 0.degree. C., and
then the reaction mixture was stirred for 30 minutes.
1,1-Dichloromethyl methyl ether (4.6 mL) was added dropwise
thereto, and then the reaction mixture was stirred at 0.degree. C.
for 2 hours followed by at room temperature for 1 hour. The
reaction solution was poured into iced water, and then extracted
with chloroform. The organic layer was dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure.
The resulting residue was recrystallized from ethyl acetate to
yield Compound 15A (10.2 g).
(b) Methyl
5-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzothio-
phene-2-carboxylate (15B)
[0301] A solution of Compound 15A (31.8 g) (which was obtained
above), aminoacetaldehyde dimethyl acetal (25 mL), and trimethyl
orthoformate (5 mL) in toluene (500 mL) was heated at reflux for 2
hours using Dean-Stark apparatus. The residue resulting from the
concentration of the reaction solution under reduced pressure was
dissolved in methanol (300 mL), and then sodium borohydride (4.3 g)
was added at 0.degree. C. thereto, followed by stirring for 30
minutes. Water (300 mL) was added to the residue resulting from the
concentration of the reaction solution under reduced pressure, and
then extraction with ethyl acetate was performed. The organic layer
was dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The resulting residue was
recrystallized at -78.degree. C. using a mixed solvent of diethyl
ether and hexane to yield Compound 15B (32.6 g).
(c) Methyl
5-({(2,2-dimethoxyethyl)[(2-nitrophenyl)sulfonyl]amino}methyl)--
4,7-dimethoxy-1-benzothiophene-2-carboxylate (15C)
[0302] To a solution of Compound 15B (25 g) (which was obtained
above) in chloroform (300 mL) was added aqueous saturated sodium
hydrogen carbonate solution (200 mL) and 2-nitrobenzenesulfonyl
chloride (15 g), and then the reaction mixture was stirred at room
temperature for 4 hours. The reaction solution was extracted with
chloroform. The organic layer was dried over anhydrous sodium
sulfate, filtered, and then concentrated under reduced pressure.
The resulting residue was recrystallized from diethyl ether to
yield Compound 15C (35.6 g).
(d) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid
(15D)
[0303] To a solution of Compound 15C (1 g) (which was obtained
above) in 1,4-dioxane (10 mL) was added 35% hydrochloric acid (10
mL), and then the reaction mixture was heated at reflux for 5
hours. The reaction solution was poured into iced water, and then
the precipitated solid was collected by filtration and dried. The
resulting residue was dissolved in methanol (10 mL), and then
activated carbon (200 mg) was added thereto. After stirring for 30
minutes, it was filtered, and then concentrated under reduced
pressure. The resulting residue was washed with ethyl acetate, and
then collected by filtration to yield Compound 15D (330 mg).
[0304] (15A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 10.36 (1H,
s), 8.27 (1H, s), 7.22 (1H, s), 4.09 (3H, s), 3.99 (3H, s), 3.91
(3H, s).
[0305] MS (ESI+) 281 (M.sup.++1).
[0306] (15B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.06 (1H, s),
7.17 (1H, s), 4.41 (1H, t, J=5.2 Hz), 3.93 (3H, s), 3.88 (3H, s),
3.85 (3H, s), 3.81 (2H, s), 2.59 (2H, d, J=5.5 Hz).
[0307] MS (ESI+) 370 (M.sup.++1).
[0308] (15C) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.10 (1H, s),
8.05 (1H, d, J=7.3 Hz), 7.99 (1H, d, J=7.3 Hz), 7.85 (1H, t, J=7.6
Hz), 7.75 (1H, t, J=7.6 Hz), 6.75 (1H, s), 4.73 (2H, s), 4.38 (1H,
t, J=5.2 Hz), 3.89 (3H, s), 3.87 (3H, s), 3.75 (3H, s), 3.39-3.34
(2H, m), 3.16 (6H, s).
[0309] MS (ESI+) 555 (M.sup.++1).
[0310] (15D) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.85 (1H, s),
8.57 (1H, d, J=6.7 Hz), 8.45 (1H, s), 8.27 (1H, d, J=6.7 Hz), 4.35
(3H, s), 4.11 (3H, s).
[0311] MS (ESI+) 290 (M.sup.++1).
Reference Example 11
1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone (16B)
##STR00078##
[0312] (a) (4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)
(morpholin-4-yl)methanone (16A)
[0313] Using 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic
acid (286.0 mg) obtained in Reference example 10 and according to
the same method as Reference example 6a, the title compound 16A was
obtained as a yellow powder (132 mg).
(b) 1-(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone
(16B)
[0314] Using Compound 16A (132.0 mg) obtained above and according
to the same method as Reference example 6b, the title compound 16B
was obtained as a yellow powder (46 mg).
[0315] (16A) MS (ESI+) 359 (M.sup.++1).
[0316] (16B) MS (ESI+) 288 (M.sup.++1).
Example 12
2-acetylthieno[2,3-g]isoquinoline-4,9-dione
##STR00079##
[0318] Using 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone
(46.0 mg) obtained in Reference example 11 and according to the
same method as Example 1, the title compound was obtained as a
yellow powder (19 mg).
[0319] MS (ESI+) 258 (M.sup.++1).
Example 13
2-(1-hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione (17B)
##STR00080##
[0320] (a) 1-(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanol
(17A)
[0321] Using 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone
(52.0 mg) obtained in Reference example 11 and according to the
same method as Example 2a, Compound 17A was obtained as a yellow
powder (44.0 mg).
(b) 2-(1-Hydroxyethyl)thieno[2,3-g]isoquinoline-4,9-dione (17B)
[0322] Using Compound 17A (44.0 mg) obtained above and according to
the same method as Example 1, the title compound 17B was obtained
as a yellow powder (29.0 mg).
[0323] (17A) MS (ESI+) 290 (M.sup.++1).
[0324] (17B) MS (ESI+) 260 (M.sup.++1).
Reference Example 12
(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol
##STR00081##
[0326] To a solution of
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (100 mg)
(which was obtained in Reference example 10) and N-methylmorpholine
(411 .mu.L) in dimethoxyethane (5.0 mL), under ice-cooling, was
added isobutyl chloroformate (270 .mu.L), and then the reaction
mixture was stirred for 20 minutes. After Celite filtration, under
ice-cooling, an aqueous solution of sodium borohydride (257 mg) was
added to the filtrate. After stirring for 2 hours, 2.0 mol/L
aqueous sodium hydroxide solution was added thereto, and then the
mixture was stirred for 24 hours. After the reaction solution was
extracted with ethyl acetate, the resulting organic layer was
washed with water and saturated brine, and then dried over sodium
sulfate. The solvent was then evaporated off. The resulting residue
was purified by silica gel column chromatography
(chloroform/methanol) to yield the title compound (41 mg).
[0327] MS (ESI+) 276 (M.sup.++1).
Example 14
2-(1-hydroxymethyl)thieno[2,3-g]isoquinoline-4,9-dione
##STR00082##
[0329] Using (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol
(20 mg) obtained in Reference example 12 and according to the same
method as Example 1, the title compound was obtained as a yellow
powder (9.0 mg).
[0330] MS (ESI+) 246 (M.sup.++1).
Example 15
2-(2-hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione
(18B)
##STR00083##
[0331] (a)
2-(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)propan-2-ol (18A)
[0332] To a solution of
1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanone (33 mg)
(which was obtained in Reference example 11) in THF (1.0 mL), under
ice-cooling, was added dropwise 3 N methylmagnesium bromide (1.0
mL), and then the reaction mixture was stirred for 1 hour. Methanol
was added to the reaction solution, and then aqueous saturated
ammonium chloride solution was added. After extraction with ethyl
acetate two times, the resulting organic layer was washed with
water and saturated brine, and then dried over sodium sulfate. The
solvent was then evaporated off. The resulting residue was purified
by silica gel column chromatography (chloroform/methanol) to yield
Compound 18A (23 mg).
(b) 2-(2-Hydroxypropan-2-yl)thieno[2,3-g]isoquinoline-4,9-dione
(18B)
[0333] Using Compound 18A (23 mg) obtained above and according to
the same method as Example 1, the title compound 18B was obtained
as a yellow powder (9.0 mg).
[0334] (18A) MS (ESI+) 304 (M.sup.++1).
[0335] (18B) MS (ESI+) 274 (M.sup.++1).
Reference Example 13
2-[cyclopropyl(ethoxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline
(19C)
##STR00084##
[0336] (a)
Cyclopropyl(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanon- e
(19A)
[0337] Using (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)
(morpholin-4-yl)methanone (100 mg) (which was obtained in Reference
example 11a) and cyclopropylmagnesium bromide (1.95 mL) and
according to the same method as Reference example 6b, Compound 19A
was obtained (23 mg).
(b) Cyclopropyl(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol
(19B)
[0338] Using Compound 19A (52 mg) obtained above and according to
the same method as Example 2a, Compound 19B was obtained (17
mg).
(c)
2-[Cyclopropyl(ethoxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline
(19C)
[0339] To a solution of Compound 19B (28 mg) (which was obtained
above) in THF (1.0 mL), under ice-cooling, was added sodium hydride
(6.0 mg), and then the reaction mixture was stirred for minutes.
Subsequently, ethyl iodide (28 .mu.L) was added dropwise. After
that, dimethylformamide (1.0 mL) was added, and then the reaction
mixture was stirred at room temperature for 1 hour. Water was
added, and then extracted with ethyl acetate. The resulting organic
layer was washed with saturated brine, and then dried over sodium
sulfate. The solvent was then evaporated off. The resulting residue
was purified by silica gel column chromatography (hexane/ethyl
acetate) to yield the title compound 19C (8.0 mg).
[0340] (19A) MS (ESI+) 314 (M.sup.++1).
[0341] (19B) MS (ESI+) 316 (M.sup.++1).
[0342] (19C) MS (ESI+) 344 (M.sup.++1).
Example 16
2-[cyclopropyl(hydroxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione
##STR00085##
[0344] Using
cyclopropyl(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol (17
mg) obtained in Reference example 13b and according to the same
method as Example 1, the title compound was obtained as a yellow
powder (9.0 mg).
[0345] MS (ESI+) 286 (M.sup.++1).
Example 17
2-[cyclopropyl(ethoxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione
##STR00086##
[0347] Using
2-[cyclopropyl(ethoxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline
(8.0 mg) obtained in Reference example 13c and according to the
same method as Example 1, the title compound was obtained as a
yellow powder (9.0 mg).
[0348] MS (ESI+) 314 (M.sup.++1).
Example 18
2-[(benzyloxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione (20B)
##STR00087##
[0349] (a)
2-[(Benzyloxy)methyl]-4,9-dimethoxythieno[2,3-g]isoquinoline
(20A)
[0350] To a solution of
(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol (20 mg) (which
was obtained in Reference example 12), phenol (10 mg), and
triphenylphosphine (29 mg) in toluene (2 mL) was added dropwise
diisopropyl azodicarboxylate (22 .mu.L), and then the reaction
mixture was stirred at room temperature for 2 hours. The reaction
solution was purified by silica gel column chromatography
(hexane:ethyl acetate=100:0 to 0:100) to yield a mixture comprising
Compound 20A.
(b) 2-[(Benzyloxy)methyl]thieno[2,3-g]isoquinoline-4,9-dione
(20B)
[0351] Using a mixture comprising 20A obtained above and according
to the same method as Example 1, the title compound 20B (1.8 mg)
was obtained.
[0352] (20A) MS (ESI+) 352 (M.sup.++1).
[0353] (20B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.36 (1H, br
s), 9.20 (1H, br s), 8.03 (1H, br s), 7.88 (1H, s), 7.40 (2H, t,
J=7.9 Hz), 7.15 (2H, d, J=7.9 Hz), 7.06 (1H, t, J=7.3 Hz), 5.59
(2H, br s).
[0354] MS (ESI+) 323 (M.sup.++1).
Reference Example 14
methyl 4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxylate
(21B)
##STR00088##
[0355] (a) Methyl
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylate (21A)
[0356] To a solution of
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (55.0 mg)
(which was obtained in Reference example 10) in DMF (10 mL) were
added potassium carbonate (50 g) and methyl iodide (10 .mu.L) at
room temperature, and then the reaction mixture was stirred for 1
hour. The insoluble was removed by Celite, and then the solvent was
evaporated off. The resulting residue was purified by silica gel
column chromatography (chloroform/ethyl acetate) to yield Compound
21A (52 mg).
(b) Methyl
4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxylate
(21B)
[0357] Using Compound 21A (52 mg) obtained above and according to
the same method as Example 1, the title compound 21B was obtained
as a yellow powder (29 mg).
[0358] (21A) MS (ESI+) 304 (M.sup.++1).
[0359] (21B) MS (ESI+) 274 (M.sup.++1).
Example 19
N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxyamide
(22B)
##STR00089##
[0360] (a)
4,9-Dimethoxy-N,N-dimethylthieno[2,3-g]isoquinoline-2-carboxyam-
ide (22A)
[0361] Using 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic
acid (99.0 mg) (which was obtained in Reference example 10) and
dimethylamine hydrochloride and according to the same method as
Reference example 6a, Compound 22A was obtained as a yellow solid
(46 mg).
(b)
N,N-dimethyl-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carboxam-
ide (22B)
[0362] Using Compound 22A (46.0 mg) obtained above and according to
the same method as Example 1, the title compound 22B was obtained
as a pale yellow solid (18.0 mg).
[0363] (22A) MS (ESI+) 317 (M.sup.++1).
[0364] (22B) MS (ESI+) 287 (M.sup.++1).
Example 20
2-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione
##STR00090##
[0366] Using Compound 16A (50 mg) obtained in Reference example 11a
and according to the same method as Example 1, the title compound
was obtained as a pale yellow solid (18.0 mg).
[0367] MS (ESI+) 329 (M.sup.++1).
Example 21
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-car-
boxyamide (23B)
##STR00091##
[0368] (a)
N-(2,2-difluoroethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline-2--
carboxyamide (23A)
[0369] Using 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic
acid (30 mg) (which was obtained in Reference example 10) and
2,2-difluoroethylamine (20 .mu.L) and according to the same method
as Reference example 6a, Compound 23A was obtained.
(b)
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-
-carboxyamide (23B)
[0370] Using Compound 23A obtained above and according to the same
method as Example 1, the title compound 23B was obtained as a pale
yellow solid (6.1 mg).
[0371] (23A) MS (ESI+) 353 (M.sup.++1).
[0372] (23B) MS (ESI+) 323 (M.sup.++1).
Example 22
3-(morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione
(24G)
##STR00092## ##STR00093##
[0373] (a) Methyl 4,7-dimethoxy-1-benzothiophene-3-carboxylate
(24A)
[0374] A solution of 2,5-dimethoxythiophenol (1 g),
azobisisobutyronitrile (19 mg), and methyl propiolate (0.53 mL) in
trifluorotoluene (5 mL) was stirred at 90.degree. C. for 2 hours.
The residue resulting from the concentration of the reaction
solution under reduced pressure was purified by silica gel column
chromatography (hexane:ethyl acetate=100:0 to 70:30) to yield
Compound 24A (130 mg).
(b) Methyl 5-formyl-4,7-dimethoxy-1-benzothiophene-3-carboxylate
(24B)
[0375] Using Compound 24A (130 mg) obtained above and according to
the same procedure as Reference example 10a, Compound 24B (96 mg)
was obtained.
(c) Methyl
5-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzothio-
phene-3-carboxylate (24C)
[0376] Using Compound 24B (96 mg) obtained above and according to
the same method as Reference example 10b, Compound 24C was obtained
as a crude product. The whole amount thereof was used in the next
reaction without further purification.
(d) Methyl
5-({(2,2-dimethoxyethyl)[(2-nitrophenyl)sulfonyl]amino}methyl)--
4,7-dimethoxy-1-benzothiophene-3-carboxylate (24D)
[0377] Using the crude product of Compound 24C obtained above and
according to the same procedure as Reference example 10c, Compound
24D (174 mg) was obtained.
(e) 4,9-Dimethoxythieno[2,3-g]isoquinoline-3-carboxylic acid
(24E)
[0378] To a solution of Compound 24D (174 mg) (which was obtained
above) in 1,4-dioxane (1 mL) was added 35% hydrochloric acid (1
mL), and then the reaction mixture was heated at reflux for 5
hours. The reaction solution was poured into iced water, and then
the precipitated solid was removed by Celite filtration. The
filtrate was neutralized with 28% ammonia water, and then extracted
with ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate, filtered, and then concentrated under reduced
pressure. The resulting residue was recrystallized from a mixed
solution of ethyl acetate and hexane to yield Compound 24E (7
mg).
(f) (4,9-Dimethoxythieno[2,3-g]isoquinolin-3-yl)
(morpholin-4-yl)methanone (24F)
[0379] Using the above-described Compound 24E (7 mg) and according
to the same procedure as Reference example 6a, Compound 24F (8 mg)
was obtained.
(g) 3-(Morpholin-4-ylcarbonyl)thieno[2,3-g]isoquinoline-4,9-dione
(24G)
[0380] Using the above-described Compound 24F (8 mg) and according
to the same method as Example 1, the title compound 24G (2.8 mg)
was obtained.
[0381] (24A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.04 (1H, s),
6.93 (2H, d, J=8.5 Hz), 6.89 (2H, d, J=8.5 Hz), 3.90 (3H, s), 3.82
(3H, s), 3.80 (3H, s).
[0382] MS (ESI+) 253 (M.sup.++1).
[0383] (24B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 10.36 (1H,
s), 8.38 (1H, s), 7.14 (1H, s), 4.08 (3H, s), 3.89 (3H, s), 3.84
(3H, s).
[0384] MS (ESI+) 281 (M.sup.++1).
[0385] (24C) MS (ESI+) 370 (M.sup.++1).
[0386] (24D) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.10-8.07
(2H, m), 8.00 (1H, d, J=7.3 Hz), 7.87 (1H, td, J=7.9, 1.2 Hz), 7.78
(1H, td, J=7.6, 1.2 Hz), 6.63 (1H, s), 4.75 (2H, s), 4.37 (1H, t,
J=5.2 Hz), 3.85 (3H, s), 3.81 (3H, s), 3.63 (3H, s), 3.34 (2H, d,
J=4.9 Hz).
[0387] MS (ESI+) 555 (M.sup.++1).
[0388] (24E) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 13.40 (1H, br
s), 9.58 (1H, s), 8.53 (1H, d, J=6.1 Hz), 8.26 (1H, s), 8.01 (1H,
d, J=6.1 Hz), 4.16 (3H, s), 3.94 (3H, s).
[0389] MS (ESI+) 290 (M.sup.++1).
[0390] (24F) MS (ESI+) 359 (M.sup.++1).
[0391] (24G) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.29 (1H, s),
9.13 (1H, br s), 8.26 (1H, br s), 7.98 (1H, br s), 3.80-3.56 (4H,
m), 3.49-3.40 (2H, m), 3.22-3.04 (2H, m).
[0392] MS (ESI+) 329 (M.sup.++1).
Example 23
2-[1-(morpholin-4-yl)ethyl]thieno[2,3-g]isoquinoline-4,9-dione
(25C)
##STR00094##
[0393] (a) 2-(1-Chloroethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline
(25A)
[0394] Using 1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanol
(36.5 mg) obtained in Example 13a and according to the same method
as Reference example 7b, Compound 25A was obtained as a yellow
solid.
(b)
4,9-Dimethoxy-2-[1-(morpholin-4-yl)ethyl]thieno[2,3-g]isoquinoline
(25B)
[0395] Using Compound 25A (which was obtained above) and morpholine
and according to the same method as Reference example 8, Compound
25B was obtained (5.9 mg).
(c) 2-[1-(Morpholin-4-yl)ethyl]thieno[2,3-g]isoquinoline-4,9-dione
(25C)
[0396] Using Compound 25B (5.7 mg) obtained above and according to
the same method as Example 1, the title compound 25C was obtained
as a yellow solid (5.0 mg).
[0397] (25A) MS (ESI+) 308 (M.sup.++1).
[0398] (25B) MS (ESI+) 359 (M.sup.++1).
[0399] (25C) MS (ESI+) 329 (M.sup.++1).
Reference Example 15
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline
##STR00095##
[0401] Using (4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol
(190 mg) obtained in Reference example 12 and according to the same
method as Reference example 7b, the title compound was obtained as
a crude product (265 mg). This was used in the next reaction
without further purification.
[0402] MS (ESI+) 294 (M.sup.++1).
Example 24
2-{[ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione
(26A)
##STR00096##
[0403] (a)
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethyl--
2-methoxyethaneamine (26A)
[0404] Using
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (which was
obtained in Reference example 15) in acetonitrile (1.0 mL) and
N-ethyl-2-methoxyethaneamine (14 .mu.L) and according to the same
method as Reference example 8, Compound 26A was obtained (20
mg).
(b)
2-{[Ethyl(2-methoxyethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-di-
one (26B)
[0405] Using
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethyl-2-methoxye-
thaneamine (20 mg) obtained above and according to the same method
as Example 1, the title compound 26B was obtained as a yellow solid
(13.2 mg).
[0406] (26A) MS (ESI+) 361 (M.sup.++1).
[0407] (26B) MS (ESI+) 331 (M.sup.++1).
Example 25
cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione
(27B)
##STR00097##
[0408] (a)
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethylc-
yclohexylamine (27A)
[0409] Using
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (30 mg)
(which was obtained in Reference example 15) and
N-ethylcyclohexylamine (17 .mu.L) and according to the same method
as Reference example 8, Compound 27A was obtained (16 mg).
(b)
2-{[Cyclohexyl(ethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione
(27B)
[0410] Using
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-N-ethylcyclohexyla-
mine (16.0 mg) obtained above and according to the same method as
Example 1, the title compound 27B was obtained as a yellow solid
(13.2 mg).
[0411] (27A) MS (ESI+) 385 (M.sup.++1).
[0412] (27B) MS (ESI+) 355 (M.sup.++1).
Example 26
2-{[(2,2-difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dione
(28B)
##STR00098##
[0413] (a)
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-2,2-difl-
uoroethaneamine (28A)
[0414] Using
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (30 mg)
(which was obtained in Reference example 15) and
2,2-difluoroethylamine (70 .mu.L) and according to the same method
as Reference example 8, Compound 28A was obtained (21 mg).
(b)
2-{[(2,2-Difluoroethyl)amino]methyl}thieno[2,3-g]isoquinoline-4,9-dion-
e (28B)
[0415] Using
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-2,2-difluoroethane-
amine (21 mg) obtained above and according to the same method as
Example 1, the title compound 28B was obtained as a yellow solid
(13.2 mg).
[0416] (28A) MS (ESI+) 385 (M.sup.++1).
[0417] (28B) MS (ESI+) 309 (M.sup.++1).
Example 27
2-[(4-acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-dione
(29B)
##STR00099##
[0418] (a)
1-{4-[(4,9-Dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]pipera-
zin-1-yl}ethanone (29A)
[0419] Using
2-(chloromethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline (30 mg)
(which was obtained in Reference example 15) and 1-acetylpiperazine
(14 mg) and according to the same method as Reference example 8,
Compound 29A was obtained (21 mg).
(b)
2-[(4-Acetylpiperazin-1-yl)methyl]thieno[2,3-g]isoquinoline-4,9-dione
(29B)
[0420] Using
1-{4-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]piperazin-1-yl}e-
thanone (9.7 mg) obtained above and according to the same method as
Example 1, the title compound 29B was obtained as a yellow solid
(2.6 mg).
[0421] (29A) MS (ESI+) 386 (M.sup.++1).
[0422] (29B) MS (ESI+) 356 (M.sup.++1).
Example 28
N-(2,2-difluoroethyl)-N-[(4,9-dihydrothieno[2,3-g]isoquinolin-2-yl)methyl]-
cyclohexanecarboxyamide (30B)
##STR00100##
[0423] (a)
N-(2,2-difluoroethyl)-N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-
-2-yl)methyl]cyclohexanecarboxyamide (30A)
[0424] Using
N-[(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methyl]-2,2-difluoroethane-
amine (36 mg) (which was obtained in Example 26a) and
cyclohexanecarbonyl chloride (16 .mu.L) and according to the same
method as Example 9a, Compound 30A was obtained (48 mg).
(b)
N-(2,2-Difluoroethyl)-N-[(4,9-dihydrothieno[2,3-g]isoquinolin-2-yl)met-
hyl]cyclohexanecarboxyamide (30B)
[0425] Using Compound 30A (48 mg) obtained above and according to
the same method as Example 1, the title compound 30B was obtained
as a yellow solid (1.2 mg).
[0426] (30A) MS (ESI+) 449 (M.sup.++1).
[0427] (30B) MS (ESI+) 419 (M.sup.++1).
Example 29
4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile
(31D)
##STR00101##
[0428] (a) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carbonyl
chloride (31A)
[0429] To 4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid
(50 mg) (which was obtained in Reference example 10) was added
thionyl chloride (2.0 mL), and the reaction mixture was heated at
reflux for 1 hour. After the solvent was evaporated off, the
resulting residue was suspended in diethyl ether, and then
collected by filtration to yield Compound 31A (37 mg).
(b) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carboxyamide (31B)
[0430] To Compound 31A (33 mg) (which was obtained above) was added
28% aqueous ammonia solution (2.0 mL), and then the reaction
mixture was stirred for 1 hour. From the reaction solution, the
solid was collected by filtration to yield Compound 31B (20.0
mg).
(c) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-carbonitrile (31C)
[0431] To Compound 31B (20.0 mg) (which was obtained above) was
added phosphoryl chloride (1.0 mL), and then the reaction mixture
was heated at reflux for 1 hour. After the solvent was evaporated
off, chloroform followed by aqueous saturated sodium hydrogen
carbonate solution were added. After extraction with ethyl acetate
two times, the resulting organic layer was washed with water and
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off. The resulting residue was purified by
silica gel column chromatography (chloroform/methanol) to yield
Compound 31C (24 mg).
(d) 4,9-Dioxo-4,9-dihydrothieno[2,3-g]isoquinoline-2-carbonitrile
(31D)
[0432] Using Compound 31C (24 mg) obtained above and according to
the same method as Example 1, the title compound 31D was obtained
as a yellow solid (1.2 mg).
[0433] (31B) MS (ESI+) 289 (M.sup.++1).
[0434] (31C) MS (ESI+) 304 (M.sup.++1).
[0435] (31D) MS (ESI+) 241 (M.sup.++1).
Example 30
2-(1-fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione (32B)
##STR00102##
[0436] (a) 2-(1-Fluoroethyl)-4,9-dimethoxythieno[2,3-g]isoquinoline
(32A)
[0437] To a solution of
1-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)ethanol (46 mg)
(which was obtained in Example 13a) in dichloromethane (1.0 mL),
under ice-cooling, was added FLUOLEAD.TM. (66 mg), and then the
reaction mixture was stirred for 1 hour. Aqueous sodium hydroxide
solution (2 N) was added thereto. After extraction with ethyl
acetate, the resulting organic layer was washed with water and
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off. The resulting residue was purified by
silica gel column chromatography (chloroform/methanol) to yield
Compound 32A (24 mg).
(b) 2-(1-Fluoroethyl)thieno[2,3-g]isoquinoline-4,9-dione (32B)
[0438] Using Compound 32A (24 mg) obtained above and according to
the same method as Example 1, the title compound 32B was obtained
as a yellow solid (1.2 mg).
[0439] (32A) MS (ESI+) 292 (M.sup.++1).
[0440] (32B) MS (ESI+) 262 (M.sup.++1).
Example 31
2-(3-ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione
(33B)
##STR00103##
[0441] (a)
2-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4,9-dimethoxythieno[2,3-g]isoq-
uinoline (33A)
[0442] To a solution of
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbonyl chloride (960 mg)
(which was obtained in Example 29a) in chloroform (40 mL) were
added N-hydroxypropionamidine (288 mg) and Hunig's base (1.6 mL),
and then the reaction mixture was stirred at room temperature for 1
hour. Aqueous saturated sodium hydrogen carbonate solution was
added to the reaction solution, and then extraction with ethyl
acetate was performed. The resulting organic layer was washed with
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off. To the solution of the resulting residue
in THF (20 mL), tetra-N-butylammonium fluoride (2.5 mL) was added,
followed by heating at reflux for 1 hour. The reaction solution was
returned to room temperature, aqueous saturated sodium hydrogen
carbonate solution was added thereto, and then extraction with
ethyl acetate was performed. The resulting organic layer was washed
with saturated brine, and then dried over sodium sulfate. The
solvent was then evaporated off. The resulting residue was
suspended in methanol and collected by filtration to yield Compound
33A (285 mg).
(b)
2-(3-Ethyl-1,2,4-oxadiazol-5-yl)thieno[2,3-g]isoquinoline-4,9-dione
(33B)
[0443] Using Compound 33A (50 mg) obtained above and according to
the same method as Example 1, the title compound 33B was obtained
as a yellow solid (32 mg).
[0444] (33A) MS (ESI+) 342 (M.sup.++1).
[0445] (33B) MS (ESI+) 312 (M.sup.++1).
Example 32
2-(morpholin-4-yl)thieno[2,3-g]isoquinoline-4,9-dione (34D)
##STR00104##
[0446] (a) Tert-butyl
(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)carbamate (34A)
[0447] A solution of
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carboxylic acid (200 mg)
(which was obtained in Reference example 10), diisopropylethylamine
(120 .mu.L), diphenylphosphoryl azide (310 .mu.L), and tert-butyl
alcohol (1 mL) in NMP (1 mL) was stirred at room temperature for 30
minutes, and then heated at reflux for 2 hours. The reaction
solution was purified by silica gel column chromatography
(hexane:ethyl acetate=50:50 to 0:100) to yield Compound 34A (140
mg).
(b) 4,9-Dimethoxythieno[2,3-g]isoquinoline-2-amine.dihydrochloride
(34B)
[0448] To Compound 34A (140 mg) obtained above was added 4 mol/L
solution (3 mL) of hydrogen chloride in 1,4-dioxane, and then the
reaction mixture was stirred at room temperature for 1 hour. The
reaction solution was concentrated under reduced pressure to yield
Compound 34B (110 mg).
(c) 4,9-Dimethoxy-2-(morpholin-4-yl)thieno[2,3-g]isoquinoline
(34C)
[0449] A solution of Compound 34B (50 mg) (which was obtained
above), diisopropylethylamine (260 .mu.L), and bisbromoethyl ether
(94 .mu.L) in DMF (1.5 mL) was stirred at 90.degree. C. for 2
hours. Cesium carbonate (100 mg) was added to the reaction
solution, which was then stirred at 120.degree. C. for another 3
hours. Water (5 mL) was added to the reaction solution, which was
then extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=100:0 to 0:100) to
yield a mixture comprising Compound 34C.
(d) 2-(Morpholin-4-yl)thieno[2,3-g]isoquinoline-4,9-dione (34D)
[0450] Using a mixture comprising Compound 34C obtained above and
according to the same method as Example 1, the title compound 34D
was obtained (1.3 mg).
[0451] (34A) MS (ESI+) 361 (M.sup.++1).
[0452] (34B) MS (ESI+) 261 (M.sup.++1).
[0453] (34C) MS (ESI+) 331 (M.sup.++1).
[0454] (34D) MS (ESI+) 301 (M.sup.++1).
Reference Example 16
4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylic acid (35E)
##STR00105##
[0455] (a) Methyl
5-(1-hydroxy-2-nitroethyl)-4,7-dimethoxy-1-benzothiophene-2-carboxylate
(35A)
[0456] A solution of methyl
5-formyl-4,7-dimethoxy-1-benzothiophene-2-carboxylate (10 g) (which
was obtained in Reference example 10a) and diisopropylethylamine
(40 mL) in nitromethane (200 mL) was stirred at room temperature
for 4 hours. Thirty percent aqueous sodium hydrogen sulfite
solution (200 mL) was added to the reaction solution, it was
stirred for 30 minutes, and then extraction with ethyl acetate was
performed. The organic layer was washed with saturated sodium
hydrogen carbonate, dried over anhydrous sodium sulfate, filtered,
and then concentrated under reduced pressure to yield Compound 35A.
This product was used in the next reaction without further
purification.
(b) Methyl
5-(2-amino-1-hydroxyethyl)-4,7-dimethoxy-1-benzothiophene-2-car-
boxylate (35B)
[0457] To a solution of Compound 35A (which was obtained above) and
nickel chloride hexahydrate (33.9 g) in methanol (300 mL), under
ice-cooling, was added portionwise sodium borohydride (5.4 g) over
a period of 30 or more minutes, and then the reaction mixture was
stirred for another hour. Water (200 mL) was added to the reaction
solution, and then the precipitated solid was removed through
Celite filtration. After methanol was evaporated off under reduced
pressure, the aqueous layer was extracted with ethyl acetate, and
then the organic layer was washed with 28% ammonium water. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and then concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=20:80 to 0:100, then chloroform:methanol=100:0 to 90:10) to
yield Compound 35B (9 g).
(c) Methyl
5-[2-(formylamino)-1-hydroxyethyl]-4,7-dimethoxy-1-benzothiophe-
ne-2-carboxylate (35C)
[0458] A solution of Compound 35B (9 g) (which was obtained above)
and acetic anhydride (450 .mu.L) in formic acid (100 mL) was heated
at reflux for 3 hours. To the residue resulting from the
concentration of the reaction solution under reduced pressure,
saturated potassium carbonate/methanol solution (100 mL) was added,
and then the reaction mixture was stirred at room temperature for 2
hours. The reaction solution was filtered through Celite, and then
the filtrate was concentrated under reduced pressure. Water (100
mL) was added to the resulting residue, and then it was extracted
with ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate, filtered, and then concentrated under reduced
pressure. The resulting residue recrystallized from mixed solution
of ethyl acetate and hexane to yield Compound 35C (8 g).
(d) Methyl 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylate
(35D)
[0459] A solution of Compound 35C (1.7 g) (which was obtained
above) and phosphorus oxychloride (1.4 mL) in acetonitrile (5 mL)
was heated at reflux for 3 hours. The residue resulting from the
concentration of the reaction solution under reduced pressure was
neutralized with aqueous saturated sodium hydrogen carbonate
solution. The aqueous layer was extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and then concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=100:0 to 50:50) to Compound 35D to yield (320 mg).
(e) 4,9-Dimethoxythieno[3,2-g]isoquinoline-2-carboxylic acid
(35E)
[0460] Using Compound 35D (320 mg) obtained above and according to
the same method as Reference example 5, the title compound 35E was
obtained (297 mg).
[0461] (35A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.13 (1H, s),
7.20 (1H, s), 6.19 (1H, d, J=5.5 Hz), 5.71-5.65 (1H, m), 4.81-4.6
(2H, m), 3.97 (3H, s), 3.94 (3H, s), 3.89 (3H, s).
[0462] MS (ESI+) 342 (M.sup.++1).
[0463] (35B) MS (ESI+) 312 (M.sup.++1).
[0464] (35C) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.21 (1H, s),
8.09 (1H, s), 6.97 (1H, s), 6.05-5.94 (1H, m), 5.27-5.19 (1H, m),
3.97 (3H, s), 3.95 (3H, s), 3.93 (3H, s), 3.80-3.72 (1H, m),
3.58-3.49 (1H, m).
[0465] MS (ESI+) 340 (M.sup.++1).
[0466] (35D) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.61 (1H, s),
8.55 (1H, d, J=6.1 Hz), 8.36 (1H, s), 8.04 (1H, d, J=6.1 Hz), 4.19
(3H, s), 4.14 (3H, s), 3.94 (3H, s).
[0467] MS (ESI+) 304 (M.sup.++1).
[0468] (35E) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 14.03 (1H, br
s), 9.58 (1H, s), 8.53 (1H, s), 8.17 (1H, s), 8.02 (1H, s), 4.18
(3H, s), 4.12 (3H, s).
[0469] MS (ESI+) 290 (M.sup.++1).
Reference Example 17
1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanone (36B)
##STR00106##
[0471] Using 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylic
acid (29 mg) obtained in Reference example 16 and according to the
same method as Reference example 6, the title compound 36B was
obtained.
[0472] (36A) MS (ESI+) 359 (M.sup.++1).
[0473] (36B) MS (ESI+) 288 (M.sup.++1).
Example 33
2-acetylthieno[3,2-g]isoquinoline-4,9-dione
##STR00107##
[0475] Using 1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanone
obtained in Reference example 17 and according to the same method
as Example 1, synthesis was carried out to yield the title compound
(5.5 mg).
[0476] .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.26 (1H, s), 9.10
(1H, br s), 7.96 (1H, br s), 7.55 (1H, s), 6.15 (1H, d, J=4.9 Hz),
5.09 (1H, br s), 1.48 (3H, d, J=6.1 Hz).
[0477] MS (ESI+) 258 (M.sup.++1).
Example 34
1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanol (37B)
##STR00108##
[0479] Using 1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)ethanone
(40 mg) obtained in Reference example 17 and according to the same
method as Example 2, synthesis was carried out to yield the title
compound 37B (12 mg).
[0480] (37A) MS (ESI+) 290 (M.sup.++1).
[0481] (37B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.26 (1H, s),
9.10 (1H, br s), 7.96 (1H, br s), 7.55 (1H, s), 6.15 (1H, d, J=4.9
Hz), 5.09 (1H, br s), 1.48 (3H, d, J=6.1 Hz).
[0482] MS (ESI+) 260 (M.sup.++1).
Example 35
N-[(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)methyl]-2,2-difluoroethanea-
mine (38E)
##STR00109##
[0483] (a) (4,9-Dimethoxythieno[3,2-g]isoquinolin-2-yl)methanol
(38A)
[0484] Using 4,9-dimethoxythieno[3,2-g]isoquinoline-2-carboxylic
acid (60 mg) obtained in Reference example 16 and according to the
same method as Reference example 12, synthesis was carried out to
yield Compound 38A (37 mg).
(b) 4,9-Dimethoxythieno[3,2-g]isoquinoline-2-carbaldehyde (38B)
[0485] A suspension of Compound 38A (37 mg) (which was obtained
above) and manganese dioxide (240 mg) in chloroform (2 mL) was
stirred at room temperature for 3 hours. The reaction solution was
filtered through Celite, and then the filtrate was concentrated
under reduced pressure to yield a crude product of Compound 38B (36
mg). The whole amount of this product was used in the next reaction
without further purification.
(c)
(E)-N-(2,2-difluoroethyl)-1-(4,9-dimethoxythieno[3,2-g]isoquinolin-2-y-
l)methanimine (38C)
[0486] To a solution of the crude product 38B (36 mg) (which was
obtained above), difluoroethylamine (19 .mu.L), and acetic acid (23
.mu.L) in THF (2 mL) was added sodium triacetoxyborohydride (57
mg), and then the reaction mixture was stirred at room temperature
for 1 hour. Aqueous saturated sodium hydrogen carbonate solution (2
mL) was added to the reaction solution, which was then extracted
with ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate, filtered, and then concentrated under reduced
pressure to yield Compound 38C as a crude product. The whole amount
of this product was used in the next reaction without further
purification.
(d)
N-[(4,9-dimethoxythieno[3,2-g]isoquinolin-2-yl)methyl]-2,2-difluoroeth-
aneamine (38D)
[0487] To a solution of the crude product 38C in THF (2 mL) was
added sodium borohydride (15 mg), and then the reaction mixture was
stirred at room temperature for 2 hours. After that, methanol (0.2
mL) was added to the reaction solution, and then stirred for
another 10 minutes.
[0488] Water was added to the reaction solution. After extraction
with ethyl acetate, the organic layer was dried over anhydrous
sodium sulfate, filtered, and then concentrated under reduced
pressure to yield Compound 38D as a crude product. The whole amount
of this product was used in the next reaction without further
purification.
(e)
2-{[(2,2-Difluoroethyl)amino]methyl}thieno[3,2-g]isoquinoline-4,9-dion-
e (38E)
[0489] Using the crude product 38D obtained above and according to
the same method as Example 1, the title compound 38E was obtained
(2.3 mg).
[0490] (38A) MS (ESI+) 276 (M.sup.++1).
[0491] (38B) MS (ESI+) 274 (M.sup.++1).
[0492] (38C) MS (ESI+) 337 (M.sup.++1).
[0493] (38D) MS (ESI+) 339 (M.sup.++1).
[0494] (38E) MS (ESI+) 309 (M.sup.++1).
Reference Example 18
1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanol (39E)
##STR00110##
[0495] (a) Methyl 4,9-dimethoxy-[3,2-g]quinoline-2-carboxylate
(39A)
[0496] To a solution of methyl
6-amino-4,7-dimethoxy-1-benzothiophene-2-carboxylate (1.2 g) (which
was obtained in Reference example 3) in acetic acid (4.0 mL) were
added aqueous hydrogen bromide solution (4.0 mL) and 2-propenal
(670 .mu.L), and then the reaction mixture was stirred at
70.degree. C. for 3 hours. After it was returned to room
temperature, the solvent was evaporated off to yield Compound 39A
as a crude product. This was used in the next reaction without
further purification.
(b) 4,9-Dimethoxythieno[3,2-g]quinoline-2-carboxylic acid (39B)
[0497] Using Compound 39A obtained above and according to the same
method as Reference example 5, Compound 39B was obtained as a crude
product. This was used in the next reaction without further
purification.
(c) (4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)
(morpholin-4-yl)methanone (39C)
[0498] Using Compound 39B obtained above and according to the same
method as Reference example 6a, Compound 39C was obtained (110
mg).
(d) 1-(4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)ethanone (39D)
[0499] Using Compound 39C (110 mg) obtained above and according to
the same method as Reference example 6b, Compound 39D was obtained
as a crude product. This was used in the next reaction without
further purification.
(e) 1-(4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)ethanol (39E)
[0500] Using Compound 39D obtained above and according to the same
method as Example 2a, the title compound 39E was obtained as a
crude product (90 mg). This was used in the next reaction without
further purification.
[0501] (39A) MS (ESI+) 304 (M.sup.++1).
[0502] (39B) MS (ESI+) 290 (M.sup.++1).
[0503] (39C) MS (ESI+) 359 (M.sup.++1).
[0504] (39D) MS (ESI+) 288 (M.sup.++1).
[0505] (39E) MS (ESI+) 290 (M.sup.++1).
Example 36
2-acetylthieno[3,2-g]quinoline-4,9-dione
##STR00111##
[0507] Using 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanone
(17 mg) obtained in Reference example 18d and according to the same
method as Example 1, the title compound was obtained (9.3 mg).
[0508] MS (ESI+) 258 (M.sup.++1).
Example 37
2-(1-hydroxyethyl)thieno[3,2-g]quinoline-4,9-dione
##STR00112##
[0510] Using 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanol
obtained in Reference example 18 and according to the same method
as Example 1, the title compound was obtained (1.9 mg).
[0511] .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.01 (1H, d, J=3.1
Hz), 8.46 (1H, dd, J=7.9, 1.8 Hz), 7.85 (1H, dd, J=7.9, 4.9 Hz),
7.53 (1H, s), 6.13 (1H, s), 5.07 (1H, d, J=6.1 Hz), 1.48 (3H, d,
J=7.3 Hz).
[0512] MS (ESI+) 260 (M.sup.++1).
Example 38
2-(1-methoxyethyl)thieno[3,2-g]quinoline-4,9-dione (40B)
##STR00113##
[0513] (a)
(4,9-Dimethoxythieno-2-(1-methoxyethyl)thieno[3,2-g]quinoline
(40A)
[0514] Using 1-(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)ethanol (90
mg) (which was obtained in Reference example 18e) and methyl iodide
(80 .mu.L) and according to the same method as Reference example
13c, Compound 40A was obtained (95 mg).
(b) 2-(1-Methoxyethyl)thieno[3,2-g]quinoline-4,9-dione (40B)
[0515] Using Compound 40A (95 mg) obtained above and according to
the same method as Example 1, the title compound 40B was obtained
(24.8 mg).
[0516] (40A) MS (ESI+) 304 (M.sup.++1).
[0517] (40B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.02 (1H, dd,
J=4.6, 1.5 Hz), 8.47 (1H, dd, J=7.9, 1.2 Hz), 7.86 (1H, dd, J=7.9,
4.3 Hz), 7.65 (1H, s), 4.80 (1H, q, J=6.3 Hz), 3.31 (3H, s), 1.50
(3H, d, J=6.1 Hz).
[0518] MS (ESI+) 274 (M.sup.++1).
Example 39
2-[(3,5-dimethylpiperidin-5-yl)carbonyl]thieno[3,2-g]quinoline-4,9-dione
(41B)
##STR00114##
[0519] (a) (4,9-Dimethoxythieno[3,2-g]quinolin-2-yl)
(3,5-dimethylpiperidin-5-yl)methanone (41A)
[0520] Using 4,9-dimethoxythieno[3,2-g]quinoline-2-carboxylic acid
(89 mg) (which was obtained in Reference example 18b) and
3,5-dimethylpiperidine (83 .mu.L) and according to the same method
as Reference example 6a, Compound 41A was obtained (18 mg).
(b)
2-[(3,5-Dimethylpiperidin-5-yl)carbonyl]thieno[3,2-g]quinoline-4,9-dio-
ne (41B)
[0521] Using Compound 41A (18 mg) obtained above and according to
the same method as Example 1, the title compound 41B was obtained
(10.5 mg).
[0522] (41A) MS (ESI+) 385 (M.sup.++1).
[0523] (41B) MS (ESI+) 355 (M.sup.++1).
Example 40
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydroxythieno[3,2-g]quinoline-2-carb-
oxyamide (42B)
##STR00115##
[0524] (a)
N-(2,2-Difluoroethyl)-4,9-dimethoxythieno[3,2-g]quinoline-2-car-
boxyamide (42A)
[0525] Using 4,9-dimethoxythieno[3,2-g]quinoline-2-carboxylic acid
(73 mg) obtained in Reference example 18b and according to the same
method as Example 21a, Compound 42A was obtained (30 mg).
(b)
N-(2,2-Difluoroethyl)-4,9-dioxo-4,9-dihydroxythieno[3,2-g]quinoline-2--
carboxyamide (42B)
[0526] Using Compound 42A (30 mg) obtained above and according to
the same method as Example 1, the title compound 42B was obtained
(21.9 mg).
[0527] (42A) MS (ESI+) 353 (M.sup.++1).
[0528] (42B) MS (ESI+) 323 (M.sup.++1).
Example 41
tert-butyl
(4,9-dioxo-4,9-dihydrothieno[3,2-g]quinolin-2-yl)methylcarbamat- e
(43C)
##STR00116##
[0529] (a) Tert-butyl (4,9-dimethoxythieno[3,2-g]quinolin-2-yl)
carbamate (43A)
[0530] To a solution of
4,9-dimethoxythieno[3,2-g]quinoline-2-carboxylic acid (22 mg)
(which was obtained in Reference example 18b) in tert-butanol (1.0
mL) were added triethylamine (42 .mu.L) and diphenylphosphoryl
azide (24 .mu.L), and then the reaction mixture was stirred for 12
hours. Water was added thereto, and then extracted with ethyl
acetate. The resulting organic layer was washed with saturated
brine, and then dried over sodium sulfate. The solvent was then
evaporated off. The resulting residue was purified by silica gel
column chromatography (hexane/ethyl acetate) to yield Compound 43A
(7.0 mg).
(b) Tert-butyl
(4,9-dimethoxythieno[3,2-g]quinolin-2-yl)methylcarbamate (43B)
[0531] To a solution of Compound 43A (7.0 mg) (which was obtained
above) in dimethylformamide (500 .mu.L), under ice-cooling, was
added sodium hydride (1.0 mg), and then the reaction mixture was
stirred at room temperature for 20 minutes. Subsequently, methyl
iodide (3.0 .mu.L) was added thereto, and then the reaction mixture
was stirred for 1 hour. After that, aqueous saturated ammonium
chloride solution was added thereto, and then extraction with ethyl
acetate was performed. The resulting organic layer was washed with
water and saturated brine, and then dried over sodium sulfate. The
solvent was then evaporated off. The resulting residue was purified
by silica gel column chromatography (hexane/ethyl acetate) to yield
Compound 43B (3.7 mg).
(c) Tert-butyl
(4,9-dioxo-4,9-dihydrothieno[3,2-g]quinolin-2-yl)methylcarbamate
(43C)
[0532] Using Compound 43B (3.7 mg) obtained above and according to
the same method as Example 1, the title compound 43C was obtained
(3.8 mg).
[0533] (43A) MS (ESI+) 361 (M.sup.++1).
[0534] (43B) MS (ESI+) 375 (M.sup.++1).
[0535] (43C) MS (ESI+) 345 (M.sup.++1).
Reference Example 19
methyl 4,7-dimethoxy-1-benzofuran-2-carboxylate
##STR00117##
[0537] To a solution of methyl glycolate (25.0 g) in THF (400 mL),
under ice-cooling, sodium hydride (13.1 g) was added in 10 parts,
and the reaction mixture was stirred at room temperature for 1
hour. To the reaction solution ice-cooled again,
3,6-dimethoxy-2-nitrobenzaldehyde (48.8 g) was added in 10 parts,
and the reaction mixture was heated and stirred at 60.degree. C.
for 6 hours. The reaction solution was cooled to room temperature,
aqueous saturated sodium bicarbonate (500 mL) was added thereto,
and then extraction with chloroform (2.times.500 mL) was performed.
The resulting organic layer was washed with saturated brine, dried
over sodium sulfate, and then purified by amino-silica gel
chromatography (chloroform). The resulting crude product was
suspended in methanol, stirred at room temperature for 1 hour,
filtered, and then dried to yield the title compound as an opaque
white solid (7.7 g).
[0538] .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 7.63 (1H, s), 7.03
(1H, d, J=8.4 Hz), 6.74 (1H, d, J=8.4 Hz), 3.90 (3H, s), 3.88 (3H,
s), 3.87 (3H, s).
Reference Example 20
methyl 5-amino-4,7-dimethoxy-1-benzofuran-2-carboxylate (45A)
Reference Example 21
methyl 6-amino-4,7-dimethoxy-1-benzofuran-2-carboxylate (45B)
##STR00118##
[0540] Using methyl 4,7-dimethoxy-1-benzofuran-2-carboxylate (5.00
g) obtained in Reference example 19 and according to the same
methods as Reference examples 2 and 3, Compound 45A was obtained as
a brown powder (1.38 g) and Compound 45B was obtained as an opaque
white solid (707 mg).
[0541] (45A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 7.63 (1H, s),
6.60 (1H, s), 4.76 (2H, s), 3.87 (3H, s), 3.84 (3H, s), 3.79 (3H,
s).
[0542] (45B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 7.46 (1H, s),
6.28 (1H, s), 5.48 (2H, s), 3.83 (3H, s), 3.79 (3H, s), 3.79 (3H,
s).
Reference Example 22
methyl 4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylate (46B)
##STR00119##
[0543] (a) Methyl
4,7-dimethoxy-5-(prop-2-yn-1-ylamino)-1-benzofuran-2-carboxylate
(46A)
[0544] Using Compound 45A (920 mg) obtained in Reference example 20
and according to the same method as Reference example 4a, Compound
46A was obtained as a yellow powder (477 mg).
(b) Methyl 4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylate
(46B)
[0545] Using Compound 46A (440 mg) and according to the same method
as Reference example 4b, Compound 46B was obtained as a yellow
solid (112 mg).
[0546] (46A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 7.70 (1H, s),
6.70 (1H, s), 5.31 (1H, s), 4.00 (2H, brs), 3.91 (3H, s), 3.88 (3H,
s), 3.82 (3H, s), 3.03 (1H, s).
[0547] MS (ESI+) 290 (M.sup.++1).
[0548] (46B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.90 (1H, d,
J=4.0 Hz), 8.61 (1H, d, J=8.4 Hz), 7.94 (1H, s), 7.53 (1H, dd,
J=4.0, 8.4 Hz), 4.31 (3H, s), 4.27 (3H, s), 3.97 (3H, s).
[0549] MS (ESI+) 288 (M.sup.++1).
Reference Example 23
4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylic acid
##STR00120##
[0551] Using Compound 46B (110 mg) obtained in Reference example 22
and according to the same method as Reference example 5, the title
compound was obtained as a brown solid (100 mg).
[0552] MS (ESI+) 274 (M.sup.++1).
Reference Example 24
1-(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone (47B)
##STR00121##
[0553] (a) (4,9-Dimethoxyfuro[2,3-g]quinolin-2-yl)
(morpholin-4-yl)methanone (47A)
[0554] Using 4,9-dimethoxyfuro[2,3-g]quinoline-2-carboxylic acid
(100 mg) obtained in Reference example 23 and according to the same
method as Reference example 6a, Compound 47A was obtained as a
brown solid (90.1 mg).
(b) 1-(4,9-Dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone (47B)
[0555] Using Compound 47A (89.0 mg) obtained above and according to
the same method as Reference example 6b, Compound 47B was obtained
as a yellow solid (67.0 mg).
[0556] (47A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.89 (1H, dd,
J=1.6, 4.0 Hz), 8.61 (1H, dd, J=1.6, 8.4 Hz), 7.70 (1H, s), 7.54
(1H, dd, J=4.0, 8.4 Hz), 4.25 (3H, s), 4.23 (3H, s), 3.98-3.90 (8H,
m).
[0557] MS (ESI+) 343 (M.sup.++1).
[0558] (47B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.90 (1H, d,
J=4.0 Hz), 8.61 (1H, d, J=8.4 Hz), 8.29 (1H, s), 7.57 (1H, dd,
J=4.0, 8.4 Hz), 4.31 (3H, s), 4.24 (3H, s), 2.65 (3H, s).
[0559] MS (ESI+) 272 (M.sup.++1).
Example 42
2-acetylfuro[2,3-g]quinoline-4,9-dione
##STR00122##
[0561] Using 1-(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone
(24.0 mg) obtained in Reference example 24 and according to the
same method as Example 1, the title compound was obtained as a
yellow powder (15.7 mg).
[0562] MS (ESI+) 242 (M.sup.++1).
Example 43
2-(1-hydroxyethyl)furo[2,3-g]quinoline-4,9-dione (48B)
##STR00123##
[0563] (a) 1-(4,9-Dimethoxyfuro[2,3-g]quinolin-2-yl)ethanol
(48A)
[0564] Using 1-(4,9-dimethoxyfuro[2,3-g]quinolin-2-yl)ethanone
(42.2 mg) obtained in Reference example 24 and according to the
same method as Example 2a, Compound 48A was obtained as a yellow
solid (38.3 mg).
(b) 2-(1-Hydroxyethyl)furo[2,3-g]quinoline-4,9-dione (48B)
[0565] Using Compound 48A and according to the same method as
Example 1, the title compound 48B was obtained as a yellow powder
(29.2 mg).
[0566] (48A) MS (ESI+) 274 (M.sup.++1).
[0567] (48B) MS (ESI+) 244 (M.sup.++1).
Reference Example 25
methyl 5-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (49A)
Reference Example 26
methyl 6-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (49B)
##STR00124##
[0569] Under nitrogen atmosphere, to a solution of methyl
4,7-dimethoxy-1-benzofuran-2-carboxylate (9.00 mg) (which was
obtained in Reference example 19) in dichloromethane (200 mL) was
added dropwise titanium tetrachloride (12.3 mL) at 0.degree. C.,
and then the reaction mixture was stirred for 30 minutes.
1,1-Dichloromethylmethyl ether (4.50 mL) was added dropwise,
stirred at 0.degree. C. for 1 hour, and then stirred at room
temperature for 3 hours. The reaction solution was poured into iced
water, and then extracted with chloroform. The organic layer was
dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (ethyl acetate/chloroform) to
yield Compound 49A (6.20 g) and Compound 49B (0.68 g) as a yellow
solid, respectively.
[0570] (49A) MS (ESI+) 265 (M.sup.++1).
[0571] (49B) MS (ESI+) 265 (M.sup.++1).
Reference Example 27
4, 9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid (50D)
##STR00125##
[0572] (a) Methyl
5-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzofuran-2-carbox-
ylate (50A)
[0573] Using methyl
5-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (1.30 g) obtained
in Reference example 25 and according to the same method as
Reference example 10b, Compound 50A (1.50 g) was obtained.
(b) Methyl
5-({(2,2-dimethoxyethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-
-4,7-dimethoxy-1-benzofuran-2-carboxylate (50B)
[0574] To a solution of Compound 50A (1.50 g) (which was obtained
above) in chloroform (50 mL) were added aqueous saturated sodium
hydrogen carbonate solution (200 mL) and p-toluenesulfonyl chloride
(1.88 g), and then the reaction mixture was stirred at room
temperature for 2 hours. Aqueous saturated sodium hydrogen
carbonate solution (50 mL) was added to the reaction solution,
which was then extracted with chloroform. The organic layer was
dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (methanol/chloroform) to
yield Compound 50B (1.67 g).
(c) Methyl 4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylate
(50C)
[0575] Under nitrogen atmosphere, to a solution of Compound 50B
(1.67 g) (which was obtained above) in methylene chloride (50 mL)
was added titanium tetrachloride (1.62 mL) at 0.degree. C., and
then the reaction mixture was stirred at room temperature for 6
hours. The reaction solution was poured into iced water,
neutralized with sodium hydrogen carbonate (pH=7-8), and then
extracted with chloroform. The organic layer was dried over
anhydrous sodium sulfate, filtered, and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (ethyl acetate/chloroform) to yield Compound 50C
(0.28 g).
(d) 4,9-Dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid
(50D)
[0576] Using Compound 50C (0.28 g) obtained above and according to
the same method as Reference example 5, Compound 50D (0.23 g) was
obtained.
[0577] (50A) MS (ESI+) 354 (M.sup.++1).
[0578] (50B) MS (ESI+) 508 (M.sup.++1).
[0579] (50C) MS (ESI+) 288 (M.sup.++1).
[0580] (50D) MS (ESI+) 273 (M.sup.++1).
Reference Example 28
1-(4,9-dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone (51B)
##STR00126##
[0581] (a) (4,9-Dimethoxyfuro[2,3-g]isoquinolin-2-yl)
(morpholin-4-yl)methanone (51A)
[0582] Using 4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid
(0.23 g) obtained in Reference example 27 and according to the same
method as Reference example 6a, Compound 51A was obtained as a
yellow powder (0.24 g).
(b) 1-(4,9-Dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone (51B)
[0583] Using Compound 51A (0.24 g) obtained above and according to
the same method as Reference example 6b, Compound 51B was obtained
as a yellow powder (0.18 g).
[0584] (51A) MS (ESI+) 343 (M.sup.++1).
[0585] (51B) MS (ESI+) 272 (M.sup.++1).
Example 44
2-acetylfuro[2,3-g]isoquinoline-4,9-dione
##STR00127##
[0587] Using 1-(4,9-dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone
(70 mg) obtained in Reference example 28 and according to the same
method as Example 1, the title compound was obtained as a yellow
powder (38 mg).
[0588] MS (ESI+) 242 (M.sup.++1).
Example 45
2-(1-hydroxyethyl)furo[2,3-g]isoquinoline-4,9-dione (52B)
##STR00128##
[0589] (a) 1-(4,9-Dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanol
(52A)
[0590] Using 1-(4,9-dimethoxyfuro[2,3-g]isoquinolin-2-yl)ethanone
(52.0 mg) obtained in Reference example 28 and according to the
same method as Example 2a, Compound 52A was obtained as a yellow
powder (44.0 mg).
(b) 2-(1-Hydroxyethyl)furo[2,3-g]isoquinoline-4,9-dione (52B)
[0591] Using Compound 52A (44.0 mg) obtained above and according to
the same method as Example 1, Compound 52B was obtained as a yellow
powder (29.0 mg).
[0592] (52A) MS (ESI+) 274 (M.sup.++1).
[0593] (52B) MS (ESI+) 244 (M.sup.++1).
Example 46
N-(2,2-difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-carbo-
xamide (53B)
##STR00129##
[0594] (a)
N-(2,2-Difluoroethyl)-4,9-dimethoxyfuro[2,3-g]isoquinoline-2-ca-
rboxamide (53A)
[0595] Using 4,9-dimethoxyfuro[2,3-g]isoquinoline-2-carboxylic acid
(7.9 mg) obtained in Reference example 27 and according to the same
method as Example 21a, Compound 53A (3.9 mg) was obtained.
(b)
N-(2,2-Difluoroethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-2-c-
arboxamide (53B)
[0596] Using Compound 53A (3.9 mg) obtained above and according to
the same method as Example 1, the title compound 53B was obtained
(2.4 mg).
[0597] (53A) MS (ESI+) 337 (M.sup.++1).
[0598] (53B) MS (ESI+) 307 (M.sup.++1).
Reference Example 29
methyl
2-(1,1-dimethoxyethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-
-3-carboxylate
##STR00130##
[0600] A solution of 6,7-dichloroisoquinoline-5,8-dione (1.14 g),
methyl 4,4-dimethoxy-3-oxovalerate (1.05 g), and potassium
carbonate (1.73 g) in acetonitrile (50 mL) was heated and stirred
at 90.degree. C. for 5 hours. After the heating was finished, the
precipitated solid was filtered through Celite with ethyl acetate.
After the filtrate was concentrated under reduced pressure, the
resulting residue was purified by silica gel column chromatography
(chloroform) to yield the title compound as a yellow solid (1.15
g).
[0601] MS (ESI+) 346 (M.sup.++1).
Reference Example 30
methyl
2-acetyl-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxylate
##STR00131##
[0603] A solution of Compound (1.15 g) (which was obtained in
Reference example 29) in formic acid (10 mL) was stirred at
25.degree. C. for 4 hours. After the reaction solution was
concentrated under reduced pressure, the resulting residue was
purified by silica gel column chromatography (chloroform) to yield
the title compound as a yellow solid (0.87 g).
[0604] MS (ESI+) 300 (M.sup.++1).
Example 47
2-acetyl-3-(morpholin-4-carbonyl)furo[2,3-g]isoquinoline-4,9-dione
##STR00132##
[0606] A solution of the compound (0.5 g) (which was obtained in
Reference example 29) in a mixture of 4 N hydrochloric acid in
1,4-dioxane (10 mL) and concentrated hydrochloric acid (4 mL) was
stirred at 120.degree. C. for 9 hours. The reaction solution was
concentrated under reduced pressure, and then a solution of DMF (10
mg) in toluene (5 mL) was added thereto. Subsequently, thionyl
chloride (143 mg) was added dropwise, and then heated and stirred
at 90.degree. C. for 4 hours. After the heating was finished,
concentration under reduced pressure was performed. To the residue,
THF (5 mL) was added, and then morpholine (0.5 mL) was added
dropwise at 0.degree. C. After stirring at 25.degree. C. for 1
hour, concentration under reduced pressure was performed. The
resulting residue was purified by silica gel column chromatography
(chloroform) to yield the title compound as a yellow solid (70
mg).
[0607] MS (ESI+) 355 (M.sup.++1).
Reference Example 31
4, 9-dimethoxyfuro[2,3-g]isoquinoline-3-carboxylic acid (54C)
##STR00133##
[0608] (a) Methyl
6-{[(2,2-dimethoxyethyl)amino]methyl}-4,7-dimethoxy-1-benzofuran-2-carbox-
ylate (54A)
[0609] Using Compound 49B (605 mg) obtained in Reference example 26
and according to the same method as Reference example 10b, Compound
54A was obtained as a crude product. The whole amount of this
product was used in the next reaction.
(b) Methyl
6-({(2,2-dimethoxyethyl)[(2-nitrophenyl)sulfonyl]amino}methyl)--
4,7-dimethoxy-1-benzofuran-2-carboxylate (54B)
[0610] Using the above-described crude product 54A and according to
the same method as Reference example 10c, Compound 54B (1.10 g) was
obtained.
(c) 4,9-Dimethoxyfuro[2,3-g]isoquinoline-3-carboxylic acid
(54C)
[0611] Using Compound 54B (500 mg) obtained above and according to
the same method as Reference example 10d, the title compound 54C
was obtained (126 mg).
[0612] (54A) MS (ESI+) 354 (M.sup.++1).
[0613] (54B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.02 (2H, d,
J=7.9 Hz), 7.98 (2H, d, J=7.9 Hz), 7.85 (1H, t, J=7.6 Hz), 7.76
(1H, t, J=7.6 Hz), 7.62 (1H, s), 6.52 (1H, s), 4.71 (2H, s), 4.38
(1H, t, J=4.9 Hz), 3.96 (3H, s), 3.88 (3H, s), 3.70 (3H, s), 3.35
(2H, d, J=5.5 Hz), 3.17 (6H, s).
[0614] MS (ESI+) 539 (M.sup.++1).
[0615] (54C) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 14.05 (1H, br
s), 9.57 (1H, s), 8.44 (1H, d, J=6.1 Hz), 8.08 (1H, s), 7.97 (1H,
d, J=6.1 Hz), 4.27 (6H, s).
[0616] MS (ESI+) 274 (M.sup.++1).
Reference Example 32
1-(4,9-dimethoxyfuro[3,2-g]isoquinolin-2-yl)ethanone (55B)
##STR00134##
[0617] (a) (4,9-Dimethoxyfuro[3,2-g]isoquinolin-2-yl)
(morpholin-4-yl)methanone (55A)
[0618] Using 4,9-dimethoxyfuro[2,3-g]isoquinoline-3-carboxylic acid
obtained in Reference example 31 and according to the same method
as Reference example 6a, Compound 55A was obtained (80.0 mg).
(b) 1-(4,9-Dimethoxyfuro[3,2-g]isoquinolin-2-yl)ethanone (55B)
[0619] Using Compound 55A (80.0 mg) obtained above and according to
the same method as Reference example 6b, the title compound 55B was
obtained (27.0 mg).
[0620] (55A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.56 (1H, s),
8.44 (1H, d, J=6.1 Hz), 7.95 (1H, d, J=6.1 Hz), 7.84 (1H, s), 4.29
(3H, s), 4.22 (3H, s), 3.87-3.57 (8H, m).
[0621] MS (ESI+) 343 (M.sup.++1).
[0622] (55B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.61 (1H, s),
8.55 (1H, d, J=6.1 Hz), 8.36 (1H, s), 8.04 (1H, d, J=6.1 Hz), 4.19
(3H, s), 4.14 (3H, s), 3.94 (3H, s).
[0623] MS (ESI+) 272 (M.sup.++1).
Example 48
2-acetylfuro[3,2-g]isoquinoline-4,9-dione
##STR00135##
[0625] Using Compound 55B (27.0 mg) of Reference example 32 and
according to the same method as Example 1, the title compound was
obtained (15.0 mg).
[0626] MS (ESI+) 242 (M.sup.++1).
Example 49
2-(1-hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione (56B)
##STR00136##
[0627] (a) 1-(4,9-Dimethoxyfuro[3,2-g]isoquinolin-2-yl)ethanol
(56A)
[0628] Using Compound 55B (60.0 mg) of Reference example 32 and
according to the same method as Reference example 2a, Compound 56A
was obtained (24.0 mg).
(b) 2-(1-Hydroxyethyl)furo[3,2-g]isoquinoline-4,9-dione (56B)
[0629] Using Compound 56A (24.0 mg) obtained above and according to
the same method as Example 2b, the title compound 56B was obtained
(15.0 mg).
[0630] (56A) MS (ESI+) 242 (M.sup.++1).
[0631] (56B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.24 (1H, s),
9.10 (1H, br s), 7.92 (1H, br s), 6.95 (1H, br s), 5.83 (1H, d,
J=5.5 Hz), 4.92-4.85 (1H, m), 1.46 (3H, d, J=6.7 Hz).
[0632] MS (ESI+) 244 (M.sup.++1).
Reference Example 33
1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanol (57E)
##STR00137##
[0633] (a) Methyl 4,9-dimethoxyfuro[3,2-g]quinoline-2-carboxylate
(57A)
[0634] To a solution of methyl
6-amino-4,7-dimethoxybenzofuran-2-carboxylate (100 mg) (which was
obtained in Reference example 21) in methanol (0.9 mL) were added
in concentrated hydrochloric acid (0.4 mL), and 2-propenal (60
.mu.L), and then the reaction mixture was stirred at 70.degree. C.
for 2 hours. After it was returned to room temperature, the solvent
was evaporated off to yield Compound 57A. The obtained compound was
used in the next reaction without purification.
(b) 4,9-Dimethoxyfuro[3,2-g]quinoline-2-carboxylic acid (57B)
[0635] Methyl 4,9-dimethoxyfuro[3,2-g]quinoline-2-carboxylate
(which was obtained above) was added to concentrated hydrochloric
acid (1.0 mL), and then the reaction mixture was heated at reflux
for 1 hour. After it was returned to room temperature, the solvent
was evaporated off to yield Compound 57B. The obtained compound was
used in the next reaction without purification.
(c) (4,9-Dimethoxyfuro[3,2-g]quinolin-2-yl)
(morpholin-4-yl)methanone (57C)
[0636] Using 4,9-dimethoxyfuro[3,2-g]quinoline-2-carboxylic acid
obtained above and according to the same method as Reference
example 6a, Compound 57C was obtained (53.0 mg).
(d) 1-(4,9-Dimethoxyfuro[3,2-g]quinolin-2-yl)ethanone (57D)
[0637] Using (4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)
(morpholin-4-yl)methanone (53 mg) obtained above and according to
the same method as Reference example 6b, Compound 57D was
obtained.
(e) 1-(4,9-Dimethoxyfuro[3,2-g]quinolin-2-yl)ethanol (57E)
[0638] Using 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanone (10
mg) obtained above and according to the same method as Example 2a,
the title compound 57E was obtained.
[0639] (57A) MS (ESI+) 288 (M.sup.++1).
[0640] (57B) MS (ESI+) 274 (M.sup.++1).
[0641] (57C) MS (ESI+) 343 (M.sup.++1).
[0642] (57D) MS (ESI+) 272 (M.sup.++1).
[0643] (57E) MS (ESI+) 274 (M.sup.++1).
Example 50
2-acetylfuro[3,2-g]quinoline-4,9-dione
##STR00138##
[0645] Using 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanone (35
mg) obtained in Reference example 33 and according to the same
method as Example 1, the title compound was obtained (7.1 mg).
[0646] MS (ESI+) 242 (M.sup.++1).
Example 51
2-(1-hydroxyethyl)furo[3,2-g]quinoline-4,9-dione
##STR00139##
[0648] Using 1-(4,9-dimethoxyfuro[3,2-g]quinolin-2-yl)ethanol
obtained in Reference example 33 and according to the same method
as Example 1, the title compound was obtained (3.7 mg).
[0649] MS (ESI+) 244 (M.sup.++1).
Reference Example 34
(4,7-dimethoxy-1-benzofuran-2-yl) (morpholin-4-yl)methanone
(58B)
##STR00140##
[0650] (a) 4,7-Dimethoxy-1-benzofuran-2-carboxylic acid (58A)
[0651] Using methyl 4,7-dimethoxy-1-benzofuran-2-carboxylate (16.0
g) obtained in Reference example 19 and according to the same
method as Reference example 5, Compound 58A (7.2 g) was
obtained.
(b) (4,7-Dimethoxy-1-benzofuran-2-yl) (morpholin-4-yl)methanone
(58B)
[0652] Using Compound 58A (7.2 g) obtained above and according to
the same method as Reference example 6a, the title compound 58B was
obtained as a yellow powder (9.8 g).
[0653] (58A) MS (ESI+) 223 (M.sup.++1).
[0654] (58B) MS (ESI+) 292 (M.sup.++1).
Reference Example 35
4,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-5-carbaldehyde
(59A)
Reference Example 36
4,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-6-carbaldehyde
(59B)
##STR00141##
[0656] Using (4,7-dimethoxy-1-benzofuran-2-yl)
(morpholin-4-yl)methanone (9.8 g) under nitrogen atmosphere and
according to the same methods as Reference examples 25 and 26,
Compound 59A (8.8 g) and Compound 59B (0.88 g) were obtained as
yellow solids, respectively.
[0657] (59A) MS (ESI+) 320 (M.sup.++1).
[0658] (59B) MS (ESI+) 320 (M.sup.++1).
Reference Example 37
1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (60E)
##STR00142##
[0659] (a)
4,7-Dimethoxy-2-(morpholin-4-ylcarbonyl)-6-nitro-1-benzofuran-5-
-carbaldehyde (60A)
[0660] To a solution of
4,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-5-carbaldehyde
(8.8 g) (which was obtained in Reference example 35) in acetic acid
(50 mL) was added dropwise 70% aqueous nitric acid solution (12.3
mL), and then the reaction mixture was heated and stirred at
70.degree. C. for 1.5 hours. After the reaction solution was cooled
to room temperature, it was poured into iced water, and then
extracted with ethyl acetate two times. The resulting organic layer
was washed with water and saturated brine, and then dried over
sodium sulfate. The solvent was then evaporated off. The resulting
residue was purified by silica gel chromatography (ethyl
acetate/chloroform) to yield Compound 60A (7.09 g) as a yellow
solid.
(b) Methyl
4,8-dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofu-
ran-6-carboxylate (60B)
[0661] Using Compound 60A (7.09 g) obtained above and according to
the same method as Reference example 1, Compound 60B (4.06 g) was
obtained as a yellow solid.
(c)
4,8-Dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-6-c-
arboxylic acid (60C)
[0662] Using Compound 60B (4.06 g) obtained above and according to
the same method as Reference example 5, Compound 60C (3.5 g) was
obtained.
(d) (4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)
(morpholin-4-yl)methanone (60D)
[0663] To a solution of Compound 60C (3.50 g) (which was obtained
above) in quinoline (10 mL) was added copper (3.40 g), and then the
reaction mixture was stirred at 190.degree. C. for 5 hours. After
the reaction solution was cooled to room temperature, it was poured
into iced water, neutralized to pH=3-5 with 1 N aqueous
hydrochloric acid solution, and then extracted with ethyl acetate.
The resulting organic layer was washed with water and saturated
brine, and then dried over sodium sulfate. The solvent was then
evaporated off. The resulting residue was purified by silica gel
chromatography (ethyl acetate/chloroform) to yield Compound 60D
(670 mg) as a yellow solid.
(e) 1-(4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone
(60E)
[0664] Using Compound 60D (580 mg) obtained above and according to
the same method as Reference example 6b, the title compound 60E was
obtained as a yellow powder (350 mg).
[0665] (60A) MS (ESI+) 365 (M.sup.++1).
[0666] (60B) MS (ESI+) 406 (M.sup.++1).
[0667] (60C) MS (ESI+) 392 (M.sup.++1).
[0668] (60D) MS (ESI+) 348 (M.sup.++1).
[0669] (60E) MS (ESI+) 277 (M.sup.++1).
Example 52
2-acetylthieno[3,2-f][1]benzofuran-4,8-dione
##STR00143##
[0671] Using
1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (300 mg)
obtained in Reference example 37 and according to the same method
as Example 1, the title compound was obtained as a yellow powder
(260 mg).
[0672] MS (ESI+) 247 (M.sup.++1).
Example 53
2-(1-hydroxyethyl)thieno[3,2-f][1]benzofuran-4,8-dione (61B)
##STR00144##
[0673] (a) 1-(4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanol
(61A)
[0674] Using
1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (50 mg)
obtained in Reference example 37 and according to the same method
as Example 2a, Compound 61A was obtained as a yellow solid (50
mg).
(b) 2-(1-Hydroxyethyl)thieno[3,2-f][1]benzofuran-4,8-dione
(61B)
[0675] Using Compound 61A (50 mg) obtained above and according to
the same method as Example 1, the title compound 61B was obtained
as a yellow powder (33 mg).
[0676] (61A) MS (ESI+) 279 (M.sup.++1).
[0677] (61B) MS (ESI+) 249 (M.sup.++1).
Example 54
2-(2-hydroxypropan-2-yl)thieno[3,2-f][1]benzofuran-4,8-dione
(62B)
##STR00145##
[0678] (a)
2-(4,8-Dimethoxythieno[3,2-f][1]benzofuran-2-yl)propan-2-ol
(62A)
[0679] Using
1-(4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)ethanone (50 mg)
obtained in Reference example 37 and according to the same method
as Example 15a, Compound 62A was obtained as a yellow solid (49
mg).
(b) 2-(2-Hydroxypropan-2-yl)thieno[3,2-f][1]benzofuran-4,8-dione
(62B)
[0680] Using Compound 62A (50 mg) obtained above and according to
the same method as Example 1, the title compound 62B was obtained
as a yellow powder (33 mg).
[0681] (62A) MS (ESI+) 293 (M.sup.++1).
[0682] (62B) MS (ESI+) 263 (M.sup.++1).
Example 55
2-(morpholin-4-ylcarbonyl)thieno[3,2-f][1]benzofuran-4,8-dione
##STR00146##
[0684] Using (4,8-dimethoxythieno[3,2-f][1]benzofuran-2-yl)
(morpholin-4-yl)methanone (84 mg) obtained in Reference example 37d
and according to the same method as Example 1, the title compound
was obtained as a yellow powder (66 mg).
[0685] MS (ESI+) 318 (M.sup.++1).
Example 56
2-acetylthieno[2,3-f][1]benzofuran-4,8-dione (63F)
##STR00147##
[0686] (a)
4,7-Dimethoxy-2-(morpholin-4-ylcarbonyl)-5-nitro-1-benzofuran-6-
-carbaldehyde (63A)
[0687] Using
4,7-dimethoxy-2-(morpholin-4-ylcarbonyl)-1-benzofuran-6-carbaldehyde
(880 mg) obtained in Reference example 36 and according to the same
method as Reference example 37a, Compound 63A was obtained as a
yellow powder (840 mg).
(b) Methyl
4,8-dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[2,3-f][1]benzofu-
ran-6-carboxylate (63B)
[0688] Using Compound 63A (840 mg) obtained above and according to
the same method as Reference example 37b, Compound 63B was obtained
as a yellow powder (460 mg).
(c)
4,8-Dimethoxy-2-(morpholin-4-ylcarbonyl)thieno[2,3-f][1]benzofuran-6-c-
arboxylic acid (63C)
[0689] Using Compound 63B (460 mg) obtained above and according to
the same method as Reference example 37c, Compound 63C was obtained
as a yellow powder (190 mg).
(d) (4,8-Dimethoxythieno[2,3-f][1]benzofuran-2-yl)
(morpholin-4-yl)methanone (63D)
[0690] Using Compound 63C (190 mg) obtained above and according to
the same method as Reference example 37d, Compound 63D was obtained
as a yellow powder (80 mg).
(e) 1-(4,8-Dimethoxythieno[2,3-f][1]benzofuran-2-yl)ethanone
(63E)
[0691] Using Compound 63D (80 mg) obtained above and according to
the same method as Reference example 37e, Compound 63E was obtained
as a yellow powder (47 mg).
(f) 2-Acetylthieno[2,3-f][1]benzofuran-4,8-dione (63F)
[0692] Using Compound 63E (47 mg) obtained above and according to
the same method as Example 1, the title compound 63F was obtained
as a yellow powder (19 mg).
[0693] (63A) MS (ESI+) 365 (M.sup.++1).
[0694] (63B) MS (ESI+) 406 (M.sup.++1).
[0695] (63C) MS (ESI+) 392 (M.sup.++1).
[0696] (63D) MS (ESI+) 348 (M.sup.++1).
[0697] (63E) MS (ESI+) 277 (M.sup.++1).
[0698] (63F) MS (ESI+) 247 (M.sup.++1).
Reference Example 38
dimethyl
4,8-dioxo-4,8-dihydrothieno[3,2-f][1]benzofuran-2,6-dicarboxylate
(64C)
##STR00148##
[0699] (a) Methyl
5-formyl-4,7-dimethoxy-6-nitro-1-benzofuran-2-carboxylate (64A)
[0700] Using methyl
5-formyl-4,7-dimethoxy-1-benzofuran-2-carboxylate (33 mg) obtained
in Reference example 25 and according to the same method as
Reference example 37a, Compound 64A was obtained as a yellow powder
(21 mg).
(b) Dimethyl
4,8-dimethoxythieno[3,2-f][1]benzofuran-2,6-dicarboxylate (64B)
[0701] Using Compound 64A (21 mg) obtained above and according to
the same method as Reference example 37b, Compound 64B was obtained
as a yellow powder (11 mg).
(c) Dimethyl
4,8-dioxo-4,8-dihydrothieno[3,2-f][1]benzofuran-2,6-dicarboxylate
(64C)
[0702] Using Compound 64B (11 mg) obtained above and according to
the same method as Example 1, the title compound 64C was obtained
as a yellow powder (4 mg).
[0703] (64A) MS (ESI+) 310 (M.sup.++1).
[0704] (64B) MS (ESI+) 351 (M.sup.++1).
[0705] (64C) MS (ESI+) 321 (M.sup.++1).
Reference Example 39
5, 9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic acid (65D)
##STR00149##
[0706] (a) Methyl
4,7-dimethoxy-5,6-dinitro-1-benzothiophene-2-carboxylate (65A)
[0707] A solution of methyl
4,7-dimethoxy-1-benzothiophene-2-carboxylate (3.70 g) (which was
obtained in Reference example 1) in aqueous nitric acid solution
(37 mL) was stirred for 1.5 hours under heating at reflux. After it
was returned to room temperature, the reaction solution was poured
into iced water, and then extracted with ethyl acetate two times.
The resulting organic layer was washed with aqueous saturated
sodium bicarbonate and saturated brine, and then dried over sodium
sulfate. The solvent was then evaporated off to yield Compound 65A
as a yellow powder (5.05 g).
(b) Methyl 5,6-diamino-4,7-dimethoxy-1-benzothiophene-2-carboxylate
(65B)
[0708] To a solution of Compound 65A (5.05 g) (which was obtained
above) in methanol (50 mL), under ice-cooling, were slowly added
nickel chloride (1.90 g), sodium borohydride (2.77 g), and then the
reaction mixture was stirred at 0.degree. C. for 1.5 hours. The
reaction solution was returned to room temperature, and then
filtered through Celite. The solvent of the filtrate was then
evaporated off. The resulting residue was dissolved in ethyl
acetate, washed with aqueous saturated sodium bicarbonate and
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off to yield Compound 65B as a brown solid
(0.64 g).
(c) Methyl 5, 9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylate
(65C)
[0709] To a solution of Compound 65B (640 mg) (which was obtained
above) in THF (68.0 mL) was added 40% aqueous glyoxal solution
(2.27 mL), and then the reaction mixture was stirred for 1 hour
under heating at reflux. The reaction solution was returned to room
temperature, and then the solvent was evaporated off. The resulting
residue was dissolved in chloroform, washed with water and
saturated brine, and then dried over sodium sulfate. The solvent
was then evaporated off to yield Compound 65C as a yellow powder
(679 mg).
(d) 5,9-Dimethoxythieno[2,3-g]quinoxaline-7-carboxylic acid
(65D)
[0710] Using Compound 65C (679 mg) obtained above and according to
the same method as Reference example 5, the title compound 65D was
obtained as a yellow solid.
[0711] (65A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.51 (1H, s),
4.16 (3H, s), 4.15 (3H, s), 3.97 (3H, s).
[0712] (65B) .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.04 (1H, s),
3.94 (3H, s), 3.93 (3H, s), 3.92 (3H, s).
[0713] MS (ESI+) 283 (M.sup.++1).
[0714] (65C) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.01-8.99
(2H, m), 8.33 (1H, s), 4.30 (3H, s), 4.27 (3H, s), 3.94 (3H,
s).
[0715] MS (ESI+) 305 (M.sup.++1).
[0716] (65D) MS (ESI+) 291 (M.sup.++1).
Example 57
7-(morpholin-4-ylcarbonyl)thieno[2,3-g]quinoxaline-5,9-dione
(66B)
##STR00150##
[0717] (a)
5,9-Dimethoxythieno[2,3-g]quinoxalin-7-yl(morpholin-4-yl)methan-
one (66A)
[0718] Using 5,9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic
acid (64.7 mg) obtained in Reference example 39 and according to
the same method as Reference example 6a, Compound 66A was obtained
as a brown solid (98.7 mg).
(b) 7-(Morpholin-4-ylcarbonyl)thieno[2,3-g]quinoxaline-5,9-dione
(66B)
[0719] Using Compound 66A (15.0 mg) obtained above and according to
the same method as Example 1, the title compound 66B was obtained
as a yellow solid (2.5 mg).
[0720] (66A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.98 (2H, s),
7.92 (1H, s), 4.26 (3H, s), 4.25 (3H, s), 3.80-3.63 (8H, m).
[0721] MS (ESI+) 360 (M.sup.++1).
[0722] (66B) MS (ESI+) 330 (M.sup.++1).
Example 58
7-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}thieno[2,3-g]quinoxaline-5-
,9-dione (67B)
##STR00151##
[0723] (a)
5,9-Dimethoxythieno[2,3-g]quinoxalin-7-yl)[(2R,6S)-2,6-dimethyl-
morpholin-4-yl]methanone (67A)
[0724] Using 5,9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic
acid (which was obtained in Reference example 39) and
(2S,6R)-2,6-dimethylmorpholine (51.4 mg) and according to the same
method as Reference example 6a, Compound 67A was obtained as a
brown solid (82.4 mg).
(b)
7-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}thieno[2,3-g]quinoxali-
ne-5,9-dione (67B)
[0725] Using Compound 67A (16.5 mg) obtained above and according to
the same method as Example 1, the title compound 67B was obtained
as a yellow solid (9.7 mg).
[0726] (67A) MS (ESI+) 388 (M.sup.++1).
[0727] (67B) MS (ESI+) 358 (M.sup.++1).
Reference Example 40
5, 9-dimethoxy-7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline
(68C)
##STR00152##
[0728] (a) (5,9-Dimethoxythieno[2,3-g]quinoxalin-7-yl)methanol
(68A)
[0729] Using 5,9-dimethoxythieno[2,3-g]quinoxaline-7-carboxylic
acid (31.4 mg) obtained in Reference example 39 and according to
the same method as Reference example 12, Compound 68A was obtained
as a yellow powder (9.0 mg).
(b) 7-(Chloromethyl)-5,9-dimethoxythieno[2,3-g]quinoxaline
(68B)
[0730] Using Compound 68A (7.0 mg) obtained above and according to
the same method as Reference example 7b, Compound 68B was obtained
as a yellow solid.
(c) 5,9-Dimethoxy-7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline
(68C)
[0731] Using Compound 68B obtained above and according to the same
method as Reference example 8, the title compound 68C was obtained
as a yellow powder (4.4 mg).
[0732] (68A) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 8.95-8.92
(2H, m), 7.54 (1H, s), 5.84 (1H, t, J=6.0 Hz), 4.81 (2H, d, J=6.0
Hz), 4.23 (3H, s), 4.18 (3H, s).
[0733] MS (ESI+) 277 (M.sup.++1).
[0734] (68B) .sup.1H-NMR (DMSO-d.sub.6, .delta. ppm): 9.00-8.91
(2H, m), 7.82 (1H, s), 5.21 (2H, s), 4.22 (3H, s), 4.18 (3H,
s).
[0735] MS (ESI+) 295 (M.sup.++1).
[0736] (68C) MS (ESI+) 346 (M.sup.++1).
Example 59
7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline-5,9-dione
##STR00153##
[0738] Using 5,
9-dimethoxy-7-(morpholin-4-ylmethyl)thieno[2,3-g]quinoxaline (4.0
mg) obtained in Reference example 40 and according to the same
method as Example 1, the title compound was obtained as a yellow
solid (0.6 mg).
[0739] .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 8.98-8.96 (2H, m),
7.59 (1H, s), 3.90-3.50 (6H, m), 2.70-2.40 (4H, m).
[0740] MS (ESI+) 316 (M.sup.++1).
Reference Example 41
methyl
2-(1,1-dimethoxyethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]phthalazine--
3-carboxylate
##STR00154##
[0742] Using 6,7-dichlorophthalazine-5,8-dione (1.14 g) and
according to the same method as Reference example 29, the title
compound was obtained as a yellow solid (0.1 g).
[0743] MS (ESI+) 341 (M.sup.++1).
Reference Example 42
methyl
2-acetyl-4,9-dioxo-4,9-dihydrofuro[2,3-g]phthalazine-3-carboxylate
##STR00155##
[0745] Using the compound (0.1 g) obtained in Reference example 41
and according to the same method as Reference example 30, the title
compound was obtained as a yellow solid (0.03 g).
[0746] MS (ESI+) 301 (M.sup.++1).
Reference Example 43
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbaldehyde
##STR00156##
[0748] To a solution of
(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)methanol (315 mg)
(which was obtained in Reference example 12) in dichloromethane (30
mL) was added manganese dioxide (1.6 g) under room temperature, and
then the reaction mixture was stirred for 12 hours. The reaction
solution was filtered through Celite, and then the solvent of the
filtrate was evaporated off. The resulting residue was purified by
silica gel column chromatography (chloroform/methanol) to yield the
title compound (169 mg).
[0749] LC-MS: [M+H].sup.+/Rt(min)=274/0.39.
Reference Example 44
ethyl
(E)-3-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)acrylate
##STR00157##
[0751] To a solution of
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbaldehyde (86 mg)
(which was obtained in Reference example 43) in toluene (30 mL) was
added (carbethoxymethylene)triphenylphosphorane (164 mg) under room
temperature, and then the reaction mixture was stirred at
80.degree. C. for 2 hours. The reaction solution was cooled to room
temperature, and then the solvent of the filtrate was evaporated
off. The resulting residue was purified by silica gel column
chromatography (chloroform/ethyl acetate) to yield the title
compound (68 mg).
[0752] LC-MS: [M+H].sup.+/Rt(min)=344/0.87.
Example 60
ethyl
(E)-3-(4,9-dioxo-4,9-dihydrothieno[2,3-g]isoquinolin-2-yl)acrylate
##STR00158##
[0754] Using ethyl
(E)-3-(4,9-dimethoxythieno[2,3-g]isoquinolin-2-yl)acrylate (68 mg)
obtained in Reference example 44 and according to the same method
as Example 1, the title compound was obtained as a yellow powder
(24 mg).
[0755] LC-MS: [M+H].sup.+/Rt(min)=314/0.97.
Reference Example 45
2-ethynyl-4,9-dimethoxythieno[2,3-g]isoquinoline
##STR00159##
[0757] To a solution of
4,9-dimethoxythieno[2,3-g]isoquinoline-2-carbaldehyde (83 mg)
(which was obtained in Reference example 43) in methanol (30 mL)
was added potassium carbonate (126 mg) and
dimethyl(1-diazo-2-oxopropyl)phosphonate (88 mg) under room
temperature, and then the reaction mixture was stirred at 0.degree.
C. for 5 hours. The reaction solution was returned to room
temperature, and then filtrated through Celite. The solvent of the
filtrate was then evaporated off. The resulting residue was
purified by silica gel column chromatography (chloroform/ethyl
acetate) to yield the title compound (32 mg).
[0758] LC-MS: [M+H].sup.+/Rt(min)=270/0.76.
Example 61
2-ethynylthieno[2,3-g]isoquinoline-4,9-dione
##STR00160##
[0760] Using 2-ethynyl-4,9-dimethoxythieno[2,3-g]isoquinoline (32
mg) obtained in Reference example 45 and according to the same
method as Example 1, the title compound was obtained as a yellow
powder (9 mg).
[0761] LC-MS: [M+H].sup.+/Rt(min)=240/0.87.
Reference Example 46
ethyl
2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-ca-
rboxylate
##STR00161##
[0763] A solution of 6,7-dichloroisoquinoline-5,8-dione (355 mg),
ethyl 4,4-difluoroacetoacetate (288 .mu.L), potassium carbonate
(507 mg) in acetonitrile (15 mL) was stirred for 5 hours under
heating at reflux. The reaction solution was cooled to room
temperature. The insoluble substance was filtered and then the
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography
(hexane/ethyl acetate) to yield the title compound as a yellow
solid (225 mg).
[0764] MS (ESI+) 322 (M.sup.++1).
Reference Example 47
2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxyl-
ic acid
##STR00162##
[0766] A solution of ethyl
2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxy-
late (190 mg) (which was obtained in Reference example 46) in
concentrated hydrochloric acid (20 mL) was stirred for 2 hours
under heating at reflux. The reaction solution was cooled to room
temperature and then concentrated under reduced pressure to yield a
crude product of the title compound (176 mg).
[0767] MS (ESI+) 294 (M.sup.++1).
Example 62
2-(difluoromethyl)-3-(morpholine-4-carbonyl)furo[2,3-g]isoquinoline-4,9-di-
one
##STR00163##
[0769] DMF (10 .mu.L) was added to a solution of
2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxy-
lic acid (158 mg) (which was obtained in Reference example 47) in
thionyl chloride (5 mL), and then the reaction mixture was stirred
at 100.degree. C. for 5 hours. The reaction solution was cooled to
room temperature and then concentrated under reduced pressure. The
resulting residue was then dissolved in THF (5 mL) and cooled to
0.degree. C. Subsequently, morpholine (94 .mu.L) was added
dropwise, and then the reaction solution was stirred at room
temperature for 15 minutes. The reaction solution was concentrated
under reduced pressure, and then water and chloroform were added to
the residue, followed by extraction with chloroform. The organic
layer was dried over anhydrous sodium sulfate and then filtered.
The filtrate was concentrated under reduced pressure, and then the
resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate) to yield the title compound as a yellow
solid (41 mg).
[0770] MS (ESI+) 363 (M.sup.++1).
Example 63
2-(difluoromethyl)furo[2,3-g]isoquinoline-4,9-dione
##STR00164##
[0772] To a solution of
2-(difluoromethyl)-4,9-dioxo-4,9-dihydrofuro[2,3-g]isoquinoline-3-carboxy-
lic acid (211 mg) (which was obtained in Reference example 47) in
quinoline (3 mL) was added cupper powder (133 mg), and then the
reaction mixture was stirred at 150.degree. C. for 1 hour. The
reaction solution was cooled to room temperature, poured into iced
water, and then extracted with chloroform. The organic layer was
dried over anhydrous sodium sulfate, filtered, and then
concentrated under reduced pressure. The organic layer was dried
over anhydrous sodium sulfate, and then filtered. The filtrate was
concentrated under reduced pressure, and then the resulting residue
was purified by silica gel column chromatography (hexane/ethyl
acetate) to yield the title compound as a yellow solid (72 mg).
[0773] LC-MS: [M+H].sup.+/Rt(min)=250/0.75.
Test Example 1
Proliferation Inhibition Assay of Cancer Cells
[0774] HCT-116 cells (derived from human colon adenocarcinoma),
HT-29 cells (derived from human colon cancer), and FaDu cells
(derived from human hypopharynx cancer) were obtained from American
Type Culture Collection (ATCC). HCT-116 cells and HT-29 cells were
cultured using McCoy's 5a medium containing 10% fetal bovine serum
(FBS) and 1% penicillin/streptomycin, and FaDu cells were cultured
using MEM medium containing 10% FBS, 1% non-essential amino acid,
1% sodium pyruvate, and 1% penicillin/streptomycin, respectively,
at 37.degree. C. in the presence of 5% CO.sub.2. After cells were
seeded at 300-600 cells/well onto black .mu.Clear-plate 384 well
(Greiner bio-one Cat. No. 781091), a test substance was added such
that the final concentration of DMSO is 0.1%, and cultured for 4
days. The number of living cells was then counted using Cell
Titer-Glo (Registered trademark) Luminescent Cell Viability Assay
(Promega) to calculate a concentration for 50% inhibition of cell
proliferation of respective test substances (Bulk 1050 value;
.mu.M).
[0775] A test shown in Test example 1 was carried out for compounds
obtained in the Examples.
[0776] The concentrations for 50% inhibition of cell proliferation
of respective test substances (Bulk 1050 value; .mu.M) are shown in
Table 1.
TABLE-US-00001 TABLE 1 IC.sub.50 (.mu.M) Example HCT FaDu HT 1 0.01
0.01 0.57 2 0.08 0.10 0.86 3 0.06 0.07 0.56 4 0.57 0.46 0.68 5 0.45
0.54 0.92 6 0.39 0.41 0.93 7 0.40 0.40 2.64 8 0.38 0.37 0.83 9 0.53
0.60 >10 10 0.50 0.50 6.14 11 0.49 0.45 3.85 12 0.05 <0.01
0.18 13 0.06 0.02 0.37 14 0.06 0.03 0.48 15 0.34 0.04 0.61 16 0.06
<0.01 0.58 17 0.41 0.84 0.87 18 1.00 0.57 >10 19 0.07
<0.01 0.10 20 0.05 <0.01 0.09 21 0.06 <0.01 0.07 22 0.48
0.44 0.81 23 0.10 0.03 0.58 24 0.34 0.03 0.65 25 0.69 0.46 0.96 26
0.09 0.02 0.45 27 0.50 0.03 0.40 28 0.47 0.08 0.63 29 0.04 <0.01
0.32 30 <0.01 <0.01 0.05 31 0.04 <0.01 0.31 32 6.56 2.15
>10 33 <0.01 <0.01 0.09 34 0.07 0.04 0.64 35 0.08 0.05
0.60 36 0.10 0.09 0.73 37 0.06 0.08 0.62 38 0.55 0.44 0.66 39 0.38
0.09 3.71 40 0.07 0.05 0.55 41 0.70 0.78 4.52 42 0.54 0.47 0.72 43
0.62 0.66 5.62 44 0.06 0.03 0.51 45 0.06 0.03 0.52 46 <0.01
<0.01 0.05 47 0.36 0.05 0.41 48 0.07 0.06 0.62 49 0.04 <0.01
0.08 50 0.47 0.47 0.59 51 0.39 0.49 0.84 52 0.07 0.43 0.64 53 0.55
0.64 0.68 54 0.61 0.67 2.47 55 0.05 0.06 0.58 56 0.09 0.56 0.62 57
5.71 8.21 >10 58 0.64 3.71 7.06 59 0.28 0.36 0.84 60 2.71 0.75
>10 61 0.19 0.05 0.54 62 0.06 0.04 0.57 63 0.05 0.05 0.54
[0777] As shown in Table 1, the compounds of the present invention
exhibited strong inhibitory effects on the proliferation of cancer
cells in the proliferation inhibition test of cancer cells. The
compounds of Examples 1, 12, 16, 19, 20, 21, 29, 30, 31, 33, 46,
49, 62, and 63 exhibited a particularly strong effect on the
inhibition of the proliferation of cancer cells.
Test Example 2
Inhibition Assay of Cancer Cell Sphere-Forming Ability
[0778] HCT-116 cells (derived from human colon adenocarcinoma),
HT-29 cells (derived from human colon cancer), FaDu cells (derived
from human hypopharynx cancer) were obtained from American Type
Culture Collection (ATCC). HCT-116 cells and HT-29 cells were
cultured using McCoy's 5a medium containing 10% fetal bovine serum
(FBS) and 1% penicillin/streptomycin, and FaDu cells were cultured
using MEM medium containing 10% FBS, 1% non-essential amino acid,
1% sodium pyruvate, and 1% penicillin/streptomycin, respectively,
at 37.degree. C. in the presence of 5% CO.sub.2. HCT-116 cells,
HT-29 cells, and FaDu cells were seeded onto 384 Well Black Clear
Bottom Ultra-Low Attachment Microplate (Corning Cat. No. 3827)
using DMEM/F12 medium containing 2% B27 supplement (GIBCO), 20
ng/mL epidermal growth factor (EGF) (peprotech), 10 ng/mL basic
fibroblast growth factor (bFGF) (peprotech), 5 .mu.g/mL insulin
(Sigma), and 1% penicillin/streptomycin to be 350-800 cells/well. A
test substance was added so that the final concentration of DMSO is
0.1%, and then cultured for 4 days. The number of living cells was
then counted using Cell Titer-Glo (registered trademark)
Luminescent Cell Viability Assay (Promega) to calculate the
concentration for 50% inhibition of cell proliferation of
respective test substances (Sphere IC50 value; .mu.M).
[0779] A test shown in Test example 2 was carried out for compounds
obtained in the Examples.
[0780] The concentrations for 50% inhibition of cell proliferation
of respective test substances (Sphere IC50 value; .mu.M) are shown
in Table 2.
TABLE-US-00002 TABLE 2 IC.sub.50 (.mu.M) Example HCT FaDu HT 1 0.02
0.02 0.07 2 0.23 0.12 0.55 3 0.05 0.05 0.43 4 0.55 0.34 0.63 5 0.39
0.50 0.57 6 0.20 0.33 0.63 7 0.51 0.36 3.04 8 0.41 0.32 0.60 9 0.28
0.10 0.61 10 0.38 0.09 0.53 11 0.46 0.28 0.71 12 0.04 <0.01 0.03
13 0.05 <0.01 0.06 14 0.09 0.02 0.09 15 0.40 <0.01 0.46 16
0.22 <0.01 0.15 17 0.55 0.05 0.54 18 5.71 0.63 >10 19 0.05
<0.01 0.04 20 0.06 <0.01 0.06 21 0.05 <0.01 0.06 22 0.50
0.31 0.16 23 0.31 0.04 0.48 24 0.43 <0.01 0.18 25 0.80 0.06
<0.01 26 0.17 <0.01 0.07 27 0.47 <0.01 0.06 28 0.57 0.09
0.59 29 0.05 <0.01 0.05 30 <0.01 <0.01 <0.01 31 0.03
<0.01 <0.01 32 7.70 1.25 >10 33 0.02 <0.01 0.07 34 0.24
0.04 0.50 35 0.27 0.04 0.39 36 0.07 0.05 0.25 37 0.06 0.06 0.49 38
0.55 0.28 0.59 39 0.35 0.45 0.55 40 0.08 0.05 0.51 41 0.83 0.46
3.82 42 0.31 0.08 0.59 43 0.51 0.33 0.60 44 0.06 0.04 0.08 45 0.06
0.03 0.08 46 0.04 <0.01 0.05 47 0.26 0.05 0.17 48 0.07 0.05 0.55
49 0.04 <0.01 0.06 50 0.26 0.17 0.58 51 0.09 0.08 0.43 52 0.05
0.06 0.08 53 0.56 0.45 0.59 54 0.60 0.59 0.77 55 0.04 0.01 0.04 56
0.06 0.08 0.58 57 4.97 5.65 >10 58 0.56 0.76 5.97 59 0.05 0.06
0.63 60 7.41 0.83 8.98 61 0.28 0.05 0.24 62 0.05 <0.01 0.04 63
0.06 0.04 0.24
[0781] As shown in Table 2, the compounds of the present invention
exhibited strong effect to inhibit cancer cell sphere-forming
ability in the inhibition test of cancer cell sphere-forming
ability. The compounds of Examples 12, 13, 15, 16, 19, 20, 21, 24,
26, 27, 29, 30, 31, 33, 46, 49, 55, 62, and 63 exhibited a
particularly strong effect to inhibit cancer cell sphere-forming
ability.
[0782] As described above, the present invention is illustrated by
preferable embodiments of the present invention. However, it will
be understood that the scope of the present invention should be
interpreted only by the claims. It will be understood that the
contents of patents, patent applications, and literatures cited in
the present specification should be incorporated by reference to
the present specification as if their contents per se are
specifically described in the present specification. The present
application claims priority to Japanese Patent Application No.
2014-72398 (filed on Mar. 31, 2014) and its contents are
incorporated in the present application by reference in its
entirety.
INDUSTRIAL APPLICABILITY
[0783] The present invention provides novel tricyclic quinone
derivatives, or pharmacologically acceptable salts thereof,
production methods and uses thereof. The tricyclic quinone
derivatives of the present invention have strong inhibitory effect
on the proliferation of cancer cells and cancer cell sphere-forming
ability, and are useful in the prevention, treatment, and/or the
like of a disease such as cancer and the like.
* * * * *